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WO2019037678A1 - Dérivé de pyrazolo[3,4-d]pyrimidin-3-one, composition pharmaceutique et utilisation associée - Google Patents

Dérivé de pyrazolo[3,4-d]pyrimidin-3-one, composition pharmaceutique et utilisation associée Download PDF

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Publication number
WO2019037678A1
WO2019037678A1 PCT/CN2018/101290 CN2018101290W WO2019037678A1 WO 2019037678 A1 WO2019037678 A1 WO 2019037678A1 CN 2018101290 W CN2018101290 W CN 2018101290W WO 2019037678 A1 WO2019037678 A1 WO 2019037678A1
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alkyl
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高大新
赵志明
陈寿军
武志恒
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Shanghai de Novo Pharmatech Co Ltd
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Shanghai de Novo Pharmatech Co Ltd
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    • 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
    • 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
    • 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
    • A61K31/535—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
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • 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
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a pyrazolo[3,4-d]pyrimidin-3-one derivative capable of inhibiting Wee1 and its signaling pathway, and a pharmaceutically acceptable salt thereof, comprising the derivative and pharmaceutically acceptable thereof A pharmaceutical composition of a salt, and the use of the derivative and pharmaceutically acceptable salt thereof for the treatment of a disease mediated by Wee1 and for the preparation of a medicament for treating Wee1-mediated diseases.
  • Wee1 (Wee1G2 checkpoint kinase; gene number: 7465) is a member of the serine/threonine protein kinase family, which directly phosphorylates cyclin-dependent kinase 1 (CDK1) and phosphorylates the tyrosine of CDK1
  • CDK1 cyclin-dependent kinase 1
  • the acid 15 residue which is an inhibitory phosphorylation site, negatively regulates CDK1 activity.
  • Activation of the G2 checkpoint is primarily through the inhibition of mitosis, promoting the cyclin B-CDK1 complex. Normal cells repair damaged DNA during the G1 arrest period. However, cancer cell G1-S detection sites are often deleted, and it is necessary to rely on the function of G2-M detection sites for DNA repair.
  • P53-deficient tumor cells lack the function of the G1 checkpoint and thus rely on the G2 checkpoint as a response to DNA damage in cell cycle arrest. After DNA damage, the G2 checkpoint prevents damaged cells from entering mitosis, thereby protecting them from mitotic catastrophe and apoptosis.
  • Wee1 is an indispensable factor in the function of the G2 checkpoint. Abolishing the G2 detection site by Wee1 inhibitor may selectively sensitize P53-deficient cancer cells to DNA damage and avoid affecting surrounding normal tissues. Wee1 also regulates S-phase CDK activity, preventing the induction of DNA damage during normal S-phase progression. In addition, Wee1 plays an active mediating role in homologous recombination (HR) repair, and homologous recombination repair is an important pathway for DNA double-strand break repair.
  • HR homologous recombination
  • Upregulation of Wee1 can be seen in many different types of cancer, including hepatocellular carcinoma (Masaki, et al, 2003), breast cancer, cervical cancer, lung cancer (Iom, et al, 2009), squamous cell carcinoma (Magnussen, et Al, 2013), glioma DIPG (Mueller, et al, 2014), malignant glioma (Mir, et al, 2010; Music, et al, 2016), medulloblastoma (Harris, et al, 2014), leukemia (Tibas, et al, 2012; Porter, et al, 2012), melanoma (Magnussen, et al, 2012), and ovarian cancer (Slipicevic, et al, 2014).
  • Wee1 is associated with poor prognosis of many types of cancer. Inhibition of Wee1 caused apoptosis in some P53 inactivated tumor cells. Inhibition of Wee1 can be sensitive to cancer cells that are resistant to chemotherapy and radiation therapy.
  • the latest study (Pfister, et al, 2015) demonstrates the interaction between synthetic lethality and H3K36me3 deletion, epigenetic changes in some cancer cells, and Wee1 inhibition, thereby clearly defining Wee1 inhibition and more precise targeted gene changes. The relationship between cancer patients provides strong evidence.
  • Wee1 is currently a highly attractive therapeutic target in the field of cancer therapy.
  • Wee1 there are still many opportunities to expand and benefit from its application.
  • the compounds described herein, compositions and methods of use thereof will contribute to the development of Wee1 inhibitors to meet clinically unmet drug needs.
  • the technical problem to be solved by the present invention is to provide a novel pyrazolo[3,4-d]pyrimidin-3-one derivative, a preparation method thereof, a pharmaceutical composition and use thereof.
  • the pyrazolo[3,4-d]pyrimidin-3-one derivatives of the present invention have a good inhibitory effect on Wee1 and related signaling pathways, and can effectively treat and/or alleviate cancer.
  • the present invention provides a compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt;
  • W is N or CR 7 ;
  • X is CR 8 or N;
  • U and V are respectively selected from N or CH, and U and V are not N at the same time; or, U and V are respectively selected from N or CR 8 , and U and V are not N at the same time;
  • R 1 is hydrogen, halogen, C 2-6 alkynyl, C 2-6 alkenyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl or substituted alkyl; when the alkyl group is substituted, Optionally substituted at one or more of the following positions: halogen, haloalkoxy, aminocycloalkyl, -SR a , -OR a , -OC(O)R a , -OC(O)NR a R b , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a R b , -NR a C(O)R b , -NR a S (O) 2 R b , -S(O) 1-2 R b , -S(O) 2 NR a R b and -NR a S(O) 2 NR a R b
  • R 2 is alkyl, haloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, alkenyl or alkynyl;
  • R 4 , R 5 , R 6 and R 7 are each independently hydrogen, halogen, hydroxy, cyano, nitro, decyl, amino, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, C 2-6 alkynyl, C 2-6 alkenyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -OC(O)R c , -OC(O)OR c , -OC(O) N(R c ) 2 , -C(O)OR c , -C(O)R c , -C(O)N(R c ) 2 , -N(R c ) 2 , -NHC(O)R c , -NHC(O)OR c , -NHC(O)N(R c ) 2 , -NHS(O) 2 R c , -S(O)
  • R 3 and R 4 are independent substituents, or R 3 and R 4 together with the ring atom to which they are attached form an A ring which is a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkane.
  • R 8 , R 9 or R 11 are each independently hydrogen, -C(O)OR c , -C(O)R c , -C(O)NR c R d , -S(O) 1-2 R c , -S(O) 2 NR c R d , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or not Substituted heteroaryl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group
  • R 1 and R 9 are each independently substituted, or R 1 and R 9 are bonded to each other to form a 4-8 membered heterocycloalkyl group, which may further be 1 to 3 C 1-6 alkyl groups or C 3-6 cycloalkyl optionally substituted;
  • Each R a and each R b are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 ring Alkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkyl C a 1-6 alkyl group, a phenyl C 1-6 alkyl group, or a 5-6 membered heteroaryl C 1-6 alkyl group; the C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2 ⁇ 6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, or 5-6 membered heteroaryl is unsubstituted or optionally 1 to 3 are selected from the group consist
  • R a and R b are independently substituted, or the R a and R b together with the N atom to which they are attached form a 3-12 membered heterocycloalkyl group, and the heterocycloalkyl group may further contain 1 to 3 selected a hetero atom or a group derived from N, O, S(O) 0-2 or C(O); the heterocycloalkyl group being unsubstituted or optionally 1 to 3 selected from the group consisting of halogen, hydroxy, amino, carboxy One or more substituents of a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylamino group, and a halogenated C 1-6 alkoxy group Replace at any position;
  • Each R c and each R d are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 ring Alkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkyl C a 1-6 alkyl group, a phenyl C 1-6 alkyl group, or a 5-6 membered heteroaryl C 1-6 alkyl group; the C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2 ⁇ 6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, or 5-6 membered heteroaryl is unsubstituted or optionally 1 to 3 are selected from the group consist
  • the present invention provides a compound of the formula (I'), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt;
  • W is N or CR 7 ;
  • X is CR 8 or N;
  • U and V are respectively selected from N or CR 8 , and U and V are not N at the same time;
  • R 2 is alkyl, haloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, alkenyl or alkynyl;
  • R 4 , R 5 , R 6 and R 7 are each independently hydrogen, halogen, hydroxy, cyano, nitro, decyl, amino, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, C 2-6 alkynyl, C 2-6 alkenyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -OC(O)R c , -OC(O)OR c , -OC(O) N(R c ) 2 , -C(O)OR c , -C(O)R c , -C(O)N(R c ) 2 , -N(R c ) 2 , -NHC(O)R c , -NHC(O)OR c , -NHC(O)N(R c ) 2 , -NHS(O) 2 R c , -S(O)
  • R 3 and R 4 are independent substituents, or R 3 and R 4 together with the ring atom to which they are attached form an A ring which is a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkane.
  • R 8 , R 9 or R 11 are each independently hydrogen, -C(O)OR c , -C(O)R c , -C(O)NR c R d , -S(O) 1-2 R c , -S(O) 2 NR c R d , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or not Substituted heteroaryl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group
  • Each R a and each R b are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 ring Alkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkyl C a 1-6 alkyl group, a phenyl C 1-6 alkyl group, or a 5-6 membered heteroaryl C 1-6 alkyl group; the C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2 ⁇ 6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, or 5-6 membered heteroaryl is unsubstituted or optionally 1 to 3 are selected from the group consist
  • R a and R b are independently substituted, or the R a and R b together with the N atom to which they are attached form a 3-12 membered heterocycloalkyl group, and the heterocycloalkyl group may further contain 1 to 3 selected a hetero atom or a group derived from N, O, S(O) 0-2 or C(O); the heterocycloalkyl group being unsubstituted or optionally 1 to 3 selected from the group consisting of halogen, hydroxy, amino, carboxy One or more substituents of a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylamino group, and a halogenated C 1-6 alkoxy group Replace at any position;
  • Each R c and each R d are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 ring Alkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkyl C a 1-6 alkyl group, a phenyl C 1-6 alkyl group, or a 5-6 membered heteroaryl C 1-6 alkyl group; the C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2 ⁇ 6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, or 5-6 membered heteroaryl is unsubstituted or optionally 1 to 3 are selected from the group consist
  • the W is preferably N.
  • the U is preferably CH.
  • the V is preferably CR 8 ; wherein R 8 is as defined above.
  • the X and Y are preferably any combination of the following:
  • X is N and Y is NR 9 ; wherein R 9 is as defined above.
  • X is CH and Y is NR 9 ; wherein R 9 is as defined above.
  • X is CR 8 and Y is O; wherein R 8 is as defined above.
  • X is CR 8 and Y is O; wherein R 8 is as defined above.
  • R 8 and R 11 are as defined above.
  • X and Y are X to be CH and Y to be NR 9 ; wherein R 9 is as defined above.
  • the (1) position is connected to the mother core
  • a group Preferably, the (2) position is linked to the parent core.
  • the (1) position is connected to the mother core
  • a group Preferably, the (2) position is linked to the parent core.
  • R 1 is preferably H or a substituted C 1-6 alkyl group; and R 1 is more preferably H.
  • the R 2 is preferably:
  • the R 2 is more preferably:
  • R 3 when the alkyl group, cycloalkyl group, heterocycloalkyl group, cycloalkylalkyl group or heterocycloalkyl group is substituted, it is preferably substituted by 1 to 3 substituents at any position. .
  • the substituents are as defined above.
  • the R 3 is preferably a substituted or unsubstituted C 1-6 alkyl group, and when the alkyl group is substituted, it is preferably substituted with one hydroxy group at an arbitrary position.
  • the R 4 is preferably H.
  • R 3 and R 4 together with the ring atom to which they are attached form an A ring, which is preferably a substituted or unsubstituted monocyclic cycloalkyl group, a substituted or unsubstituted monocyclic heterocycloalkyl group. a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group;
  • the A ring is preferably unsubstituted.
  • the A ring when substituted, it is preferably substituted at any position by 1 to 3 substituents.
  • the substituents are as defined above.
  • the R 5 is preferably H.
  • the R 6 is preferably H.
  • the R 8 is preferably H
  • the R 8 is preferably -NR c R d , -NR c S(O) 1-2 R d , -NR c C(O)R d , -NR c S(O) 2 NR c R d , -C(O)OR c , -C(O)R c , -C(O)NR c R d , -S(O) 1-2 R c , -S(O) 2 NR c R d , Substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted ring Alkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted ring Alky
  • the substituted or unsubstituted alkyl group is preferably a substituted or unsubstituted C 1-6 alkyl group; more preferably a substituted or unsubstituted C 1-4 alkyl group;
  • the substituted or unsubstituted cycloalkyl group is preferably a substituted or unsubstituted C 3-8 cycloalkyl group
  • the substituted or unsubstituted heterocycloalkyl group is preferably a substituted or unsubstituted 3-8 membered heterocycloalkyl group
  • the substituted or unsubstituted heterocycloalkyl group is preferably a substituted or unsubstituted one of the following groups: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, high piperazine Azinyl, morpholinyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, (1R,4R)-2,5-diazabicyclo[2.2.1]heptyl (1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptyl, (1S,4S)-2-oxo-5-azabicyclo[2.2.1]heptyl, or 4, 7-diazaspiro[2.5]octyl;
  • the substituted or unsubstituted cycloalkylalkyl group is preferably a substituted or unsubstituted C 3-8 cycloalkyl C 1-3 alkyl group;
  • the substituted or unsubstituted heterocycloalkylalkyl group is preferably a substituted or unsubstituted 3-8 membered heterocycloalkyl C 1-3 alkyl group;
  • the substituted or unsubstituted aryl group is preferably a substituted or unsubstituted phenyl group.
  • the substituted or unsubstituted heteroaryl group is preferably a substituted or unsubstituted 5-6 membered heteroaryl group.
  • the substituted or unsubstituted alkyl group is preferably a substituted or unsubstituted C 1-6 alkyl group; more preferably a substituted or unsubstituted C 1-4 alkyl group;
  • the substituted or unsubstituted cycloalkyl group is preferably a substituted or unsubstituted C 3-8 cycloalkyl group
  • the substituted or unsubstituted heterocycloalkyl group is preferably a substituted or unsubstituted 3-8 membered heterocycloalkyl group
  • the substituted or unsubstituted heterocycloalkyl group is preferably a substituted or unsubstituted group such as pyrrolidinyl, piperidinyl, azepanyl, azetidinyl, Oxetanyl, 4-azaspiro[2.5]octyl, or 5-azaspiro[2.5]octyl;
  • the substituted or unsubstituted cycloalkylalkyl group is preferably a substituted or unsubstituted C 3-8 cycloalkyl C 1-3 alkyl group;
  • the substituted or unsubstituted heterocycloalkylalkyl group is preferably a substituted or unsubstituted 3-8 membered heterocycloalkyl C 1-3 alkyl group;
  • the substituted or unsubstituted aryl group is preferably a substituted or unsubstituted phenyl group.
  • the substituted or unsubstituted heteroaryl group is preferably a substituted or unsubstituted 5-6 membered heteroaryl group.
  • each R 10 is independently preferably H, F, Cl, C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkane Base, amino C 1-6 alkyl, amino C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -CN, -NO 2 , -SR a , -OR a , -OC (O)R a , -OC(O)OR a , -OC(O)NR a R b , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a R b , -NR a C(O)R b , -N(R a )C(O)OR b , -N(R a )C(O)NR a R b , -NR
  • R a and R b are independently substituted, or the R a and R b together with the N atom to which they are attached form a 3-8 membered heterocycloalkyl group, and the heterocycloalkyl group may further contain 1 to 3 selected a hetero atom or a group derived from N, O, S(O) 0-2 or C(O); said heterocycloalkyl group being unsubstituted or optionally substituted by a substituent selected from a C 1-6 alkyl group Replace at any position;
  • each R 10 is independently more preferably H, D, F, Cl, amino, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, t-butyl, or ring.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (II) and/or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , V, X and W are as defined above.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (III) and/or a pharmaceutically acceptable salt thereof:
  • n 0, 1, 2, or 3;
  • R 1 , R 3 , R 4 , R 5 , X, R a , R b and W are as defined above.
  • n is one.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (IV) and/or a pharmaceutically acceptable salt thereof:
  • Z is N or CH;
  • L is CH 2 , CH(CH 3 ), C(CH 3 ) 2 , or u is 0, 1, or 2;
  • v is 0, 1, or 2;
  • R 1 , R 3 , R 4 , R 5 , R 10 , X and W are as described above.
  • L is N
  • u is 1, and v is 1;
  • u is 1, and v is 2;
  • u is 0 and v is 1;
  • u is 0 and v is 2;
  • u is 1, and v is 0;
  • u is 2 and v is 0;
  • Z is N; and R 10 is hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -S(O) 1- 2 R b , or -S(O) 2 NR a R b ; R a and R b are each independently hydrogen or a C 1-6 alkyl group.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (V) and/or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , U and W are as defined above.
  • U is CH
  • R 1 is H or methyl
  • R 8 is -NR c R d ;
  • R 8 is a substituted or unsubstituted 3-8 membered heterocycloalkyl; when the 3-8 membered heterocycloalkyl is substituted, the selectivity is 1 to 3 C 1-4 Alkylation, or C 3-6 cycloalkyl substitution at any position;
  • R 9 is C 1-4 alkyl, hydroxy C 1-4 alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;
  • R 2 is
  • the compound of formula (I') and/or a pharmaceutically acceptable salt is a compound of formula (VI) and/or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , U and W are as defined above.
  • U is CH
  • R 8 is -NR c R d ;
  • R 8 is a substituted or unsubstituted 3-8 membered heterocycloalkyl; when the 3-8 membered heterocycloalkyl is substituted, the selectivity is 1 to 3 C 1-4 Alkylation, or C 3-6 cycloalkyl substitution at any position;
  • R 9 is C 1-4 alkyl, hydroxy C 1-4 alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt are optionally the following compounds:
  • the compound of formula (I) and/or a pharmaceutically acceptable salt are optionally the following compounds:
  • the compound of formula (I) and/or a pharmaceutically acceptable salt are optionally the following compounds:
  • the present invention also provides a method for producing the compound represented by the formula (I) or (I'), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, which is any of the following method:
  • step 1) 1a Compound 1c is obtained by buchwald coupling reaction with 1b; step 2) oxidation of the methylthio group in compound 1c with m-chloroperoxybenzoic acid (m-CPBA) to sulfoxide to obtain compound 1d; step 3) compound 1d and 1e Or 1e' is reacted under basic conditions to give a compound of formula I or I'.
  • step 1) Compound 1c is obtained by buchwald coupling reaction with 1b
  • step 2) oxidation of the methylthio group in compound 1c with m-chloroperoxybenzoic acid (m-CPBA) to sulfoxide to obtain compound 1d; step 3) compound 1d and 1e Or 1e' is reacted under basic conditions to give a compound of formula I or I'.
  • m-CPBA m-chloroperoxybenzoic acid
  • the conditions and steps may be the conditions and steps of the conventional reaction in the art, and the present invention particularly preferably the following reaction conditions: step 1) under nitrogen protection, in the 1,4-dioxane solvent,
  • step 1) under nitrogen protection, in the 1,4-dioxane solvent
  • the reaction is carried out by the action of a base (1,2-N,N-dimethylethylenediamine, potassium carbonate) and cuprous chloride, and the amount of the agent is preferably 1 to 50 mL/mmol of the compound 1a, and the reaction time is preferably 0-24 hours, the temperature is preferably room temperature to reflux of the solvent, more preferably 80 to 100 ° C, and the molar ratio of the compound 1a and 1b is preferably 1:0.9 to 1:1.5.
  • Step 2 The compound 1d is obtained by oxidizing the compound 1c with m-chloroperoxybenzoic acid in a dichloromethane solvent; the amount of the agent is preferably 1 to 50 mL/mmol of the compound 1c, and the reaction time is preferably 0-24 hours, and the temperature is preferably 0.
  • the molar ratio of compound 1c to m-CPBA is preferably 1:1 to 1:3; in step 3) in toluene, under basic conditions (N,N-diisopropylethylamine or triethylamine), 1d And 1e or Ie' react to obtain a compound of the formula I or I', the amount of the agent is preferably 1 to 50 mL / mmol of the compound 1d, the reaction time is preferably 0-24 hours, the temperature is preferably room temperature to reflux of the solvent, the compound 1d
  • the molar ratio of 1e to base is preferably 1:0.9:1 to 1:2.5:2.5; the molar ratio of compound 1d, 1e' and base is preferably 1:0.9:1 to 1:2.5:2.5.
  • an acidic system such as p-toluenesulfonic acid, hydrochloric acid, hydrogen chloride or trifluoroacetic acid is used, or in the purification process, for example, in the mobile phase of prep-HPLC, the above acidic system is present.
  • the compound of formula I or I' will be the corresponding p-toluenesulfonate, hydrochloride or trifluoroacetate salt and the like.
  • the amino group, the hydroxyl group or the carboxyl group is preferably protected by a protecting group.
  • a protecting group to avoid any side reactions. If the above amino protecting group or hydroxy protecting group is present, it is necessary to undergo a subsequent deprotection step to give a compound of formula I and I'.
  • Any suitable amino protecting group for example, a tert-butoxycarbonyl (Boc) group, can be used to protect the amino group.
  • Boc is used as a protecting group
  • subsequent deprotection reactions can be carried out under standard conditions, for example, p-toluenesulfonic acid/methanol system, dichloromethane/trifluoroacetic acid system, saturated hydrogen chloride ether solution, or trifluoromethanesulfonate
  • the deprotection reaction can be deprotected under standard conditions, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide in tetrahydrofuran, water, and/or
  • the compound of the formula (I) or (I'), a pharmaceutically acceptable salt thereof, can be synthesized by a general chemical method.
  • the preparation of the salt can be carried out by reacting the free base or acid with an equivalent chemical equivalent or an excess of an acid (inorganic or organic acid) or a base (inorganic or organic base) in a suitable solvent or solvent composition.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable excipient; the active ingredient comprising a compound of formula (I) or (I'), One or more of a conformation, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt.
  • the active ingredient may also include other therapeutic agents for cancer, viral infection or autoimmune diseases.
  • the pharmaceutically acceptable excipient may include a pharmaceutically acceptable carrier, diluent, and/or excipient.
  • the pharmaceutical composition can be formulated into various types of dosage unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), etc., depending on the purpose of the treatment.
  • dosage unit dosage forms such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), etc.
  • any excipient known and widely used in the art can be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, dextrose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrating agents such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid esters of calcium, polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch and lactose; disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenation Oil; adsorption promoters such as quatern
  • any excipient known and widely used in the art may be used, for example, a carrier such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol, etc.; disintegrating agents such as agar and kelp powder.
  • a carrier such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.
  • disintegrating agents such as agar and kelp powder.
  • any excipient known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides, etc. .
  • the solution or suspension may be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin, etc.) to prepare an isotonic injection with blood.
  • Any of the commonly used carriers in the art can also be used in the preparation of the injection.
  • water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan can be added.
  • the content of the composition in the pharmaceutical composition is not particularly limited and can be selected within a wide range, and is usually from 5 to 95% by mass, preferably from 30 to 80% by mass. %.
  • the administration method of the pharmaceutical composition is not particularly limited.
  • Formulations of various dosage forms can be selected depending on the age, sex and other conditions and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; injections can be administered alone or in combination with injectable solutions (eg, glucose solutions and amino acid solutions); suppositories are given Drug to the rectum.
  • injectable solutions eg, glucose solutions and amino acid solutions
  • suppositories are given Drug to the rectum.
  • the present invention also provides a compound represented by the formula (I) or (I'), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition is prepared for Vee1 inhibition Application in the agent.
  • the present invention also provides a compound represented by the formula (I) or (I'), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition for preparing a cancer Use in sensitizers for chemotherapy or radiotherapy.
  • the sensitizer of chemotherapeutic or radiotherapy refers to the combination of radiation therapy and/or chemotherapy using an anticancer agent, in the field of cancer therapy, additive or synergistically improving these radiotherapy and / or the therapeutic effects of chemotherapy.
  • the present invention also provides a compound represented by the formula (I) or (I'), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition is prepared for treatment and / or use in a medicament for alleviating a disease associated with Wee1;
  • the invention preferably provides a compound of formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt
  • the use of the pharmaceutical composition for the preparation of a medicament for treating and/or preventing a disease associated with Wee1; the disease comprising a tumor and a non-neoplastic disease.
  • the disease is preferably cancer.
  • the present invention preferably uses the compound of the formula (I) or (I'), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition for the preparation of a treatment And/or ease the application of cancer drugs.
  • the present invention still further provides a compound represented by the formula (I) or (I'), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition
  • a method of treating cancer comprising: administering a compound of the formula (I) or (I'), an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, in a dose required for treatment in a mammal, Or a pharmaceutical composition.
  • Said mammal preferably a human.
  • the present invention still further provides the compound represented by the formula (I) or (I'), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition It may be used in combination with one or more other classes of therapeutic agents and/or methods of treatment for the treatment and/or alleviation of a related disease mediated by Wee1, preferably a cancer.
  • the present invention still further provides a combined preparation comprising a compound represented by the formula (I) or (I'), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the drug
  • a combined preparation comprising a compound represented by the formula (I) or (I'), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the drug
  • the compositions are combined with other types of therapeutic agents and/or therapeutic methods for treating cancer.
  • the other kind of therapeutic agent for example, other kinds of therapeutic agents for treating cancer
  • the other kinds of therapeutic agents and/or treatment methods for treating cancer may include, but are not limited to, for cancer treatment: tubulin inhibitors, alkylating agents, topoisomerase I/II inhibitors, Platinum compounds, antibiotics, antimetabolites, hormones and hormone analogues, targeted therapies (eg special kinase inhibitors), immunotherapeutics, interferons, other anticancer agents for cancer therapy and radiotherapy One or more.
  • the tubulin inhibitor may be selected from, but not limited to, a vinblastine series (eg, vinblastine, vincristine, vinorelbine, vindesine), a taxane (docetaxel, One or more of paclitaxel) and eribulin mesylate.
  • a vinblastine series eg, vinblastine, vincristine, vinorelbine, vindesine
  • a taxane docetaxel, One or more of paclitaxel
  • eribulin mesylate eribulin mesylate.
  • the alkylating agent may be selected from one or more of nitrogen mustard, ethyleneimine derivative, methanesulfonate, nitrosourea, and triazene.
  • the topoisomerase I/II inhibitor may be selected from, but not limited to, camptothecin, 10-hydroxycamptothecin, irinotecan, irinotecan metabolite SN-38, topotecan, Sinon One or more of temcon, Exactecan, Karenitecin, 9-nitrocamptothecin, doxorubicin, and dexrazoxane.
  • the platinum compound may be selected from, but not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin, omalimin, tetraplatinum, isopropylplatinum, spiroplatinum, cis-diamine dihydrate.
  • the antimetabolite may be selected from, but not limited to, a folic acid antagonist, a pyrimidine analog, a purine analog, an adenosine deaminase inhibitor, for example, methotrexate, 5-fluorouracil, fluorourea One or more of glycosides, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentastatin and gemcitabine.
  • a folic acid antagonist a pyrimidine analog
  • a purine analog for example, methotrexate, 5-fluorouracil, fluorourea One or more of glycosides, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentastatin and gemcitabine.
  • the immunotherapeutic agent may be selected from, but not limited to, an anti-tumor vaccine (for example, a synthetic peptide, a DNA vaccine, and a recombinant virus), an oncolytic virus, a monoclonal antibody (for example, PD-1 monoclonal antibody, PD- L1 monoclonal antibody, CTLA-4 monoclonal antibody, etc.), novel adjuvants, cytokine therapy (eg, IL2 and GM-CSF), chimeric antigen receptor T cell therapy (CAR-T), small molecule immunomodulator, One or more of a tumor microenvironmental modulator and an anti-angiogenic factor.
  • an anti-tumor vaccine for example, a synthetic peptide, a DNA vaccine, and a recombinant virus
  • an oncolytic virus for example, a monoclonal antibody (for example, PD-1 monoclonal antibody, PD- L1 monoclonal antibody, CTLA-4 monoclonal antibody, etc.), novel adju
  • the antibiotic for cancer treatment may be selected from, but not limited to, actinomycin D, doxorubicin, daunorubicin, bleomycin, pilomycin, mitomycin C.
  • actinomycin D actinomycin D
  • doxorubicin daunorubicin
  • bleomycin bleomycin
  • pilomycin pilomycin
  • mitomycin C mitomycin C.
  • arubicin pirarubicin
  • epirubicin epirubicin
  • net statin idarubicin
  • sirolimus sirolimus
  • valrubicin valrubicin
  • the interferon for cancer treatment may be selected from, but not limited to, interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a or interferon gamma- N1 and so on.
  • the cancer includes both metastatic and non-metastatic cancers, as well as family hereditary and sporadic cancers, and may also include solid tumors and non-solid tumors.
  • specific examples of the solid tumor may include, but are not limited to, eyes, bone, lung, stomach, pancreas, breast, prostate, brain (including glioblastoma and medulloblastoma), ovaries (including those Stromal cells, germ cells and mesenchymal cells produced from epithelial cells, bladder, testis, spinal cord, kidney (including adenocarcinoma, nephroblastoma), mouth, lips, throat, oral cavity (including squamous cell carcinoma), nasal cavity , small intestine, colon, rectum, parathyroid gland, gallbladder, bile duct, cervix, heart, inferior gland, bronchus, liver, ureter, vagina, anus, larynx, thyroid (including thyroid cancer and medullary carcinoma), esophagus, nose Pituitary gland, salivary gland, adrenal gland, head and neck intraepithelial neoplasia (including Bowen's disease and Paget's disease
  • the solid tumor is preferably human eye cancer, bone cancer, lung cancer, stomach cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer (including but not limited to malignant glioma, medulloblastoma), Ovarian cancer, bladder cancer, cervical cancer, testicular cancer, kidney cancer (including but not limited to adenocarcinoma, nephroblastoma), oral cancer (including squamous cell carcinoma), tongue cancer, laryngeal cancer, nasopharyngeal carcinoma, head and neck Cancer, colon cancer, small bowel cancer, rectal cancer, parathyroid cancer, thyroid cancer, esophageal cancer, gallbladder cancer, cholangiocarcinoma, cervical cancer, liver cancer, lung cancer (including but not limited to small cell lung cancer, non-small cell lung cancer), fluff One or more of epithelial cancer, osteosarcoma, Ewing's tumor, soft tissue sarcoma, and skin cancer.
  • brain cancer including but not limited to malignant gli
  • non-solid tumor may include, but are not limited to, lymphocytic leukemia (including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, Hodgkin's lymphoma). , non-Hodgkin's lymphoma, T-cell chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia), one of myeloid-associated leukemia (including acute myelogenous leukemia, chronic myelogenous leukemia) and AIDs-associated leukemia or A variety.
  • lymphocytic leukemia including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, Hodgkin's lymphoma
  • non-Hodgkin's lymphoma T-cell chronic lymphocytic leukemia
  • B-cell chronic lymphocytic leukemia B-cell chronic lymphocytic
  • the term "optionally substituted by one or more groups at any position" means that any one or more of the hydrogen atoms of the one or more atoms specified on the group are designated by The group is substituted, provided that it does not exceed the normal valence of the specified atom, which is a reasonable substitution that is common in the art at any position.
  • alkyl refers to a saturated straight or branched hydrocarbon group containing from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 8, from 1 to 4, or from 1 to 3
  • Representative examples of carbon atoms, alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, hexyl, g. Base, octyl, decyl, decyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and various isomers thereof Body and so on.
  • cycloalkyl refers to a monocyclic or polycyclic group containing from 3 to 20 carbon atoms which is saturated or partially unsaturated (comprising 1 or 2 double bonds).
  • “monocyclic cycloalkyl” is preferably a 3-10 membered monocycloalkyl group, more preferably a 3-8 membered monocycloalkyl group, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, ring Octyl, cyclodecyl, cyclododecyl, cyclohexenyl.
  • Polycyclic cycloalkyl includes “bridged ring”, “fused cycloalkyl” and “spirocycloalkyl”, and representative examples of “bridged ring” include, but are not limited to, borneol, bicyclo [2.2. 1] heptenyl, bicyclo [3.1.1] heptyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3. 1] nonylalkyl, bicyclo[4.2.1]nonanyl and adamantyl, and the like.
  • Fused cycloalkyl embraces a cycloalkyl ring fused to a phenyl, cycloalkyl, or heteroaryl group, including but not limited to: benzocyclobutene, 2,3-di Hydrogen-1-H-indole, 2,3-cyclopentenopyridine, 5,6-dihydro-4H-cyclopentyl[B]thiophene, decalin and the like.
  • “Spirocycloalkyl” refers to a bicyclic group formed by the sharing of one carbon atom by two monocyclic cycloalkyl groups, including but not limited to: spiro[2,5]octyl, spiro[2,4]g Base, snail [4,5] thiol and the like.
  • the polycyclic cycloalkyl group preferably contains from 7 to 12 carbon atoms.
  • a monocyclic cycloalkyl or polycyclic cycloalkyl group can be attached to the parent molecule through any one or two carbon atoms of the ring.
  • heterocycloalkyl refers to a non-aromatic cyclic group consisting of a carbon atom and a heteroatom consisting of a hetero atom selected from nitrogen, oxygen or sulfur, including one or two double bonds, which is a cyclic group.
  • the group may be a monocyclic or polycyclic group, and in the present invention, the number of hetero atoms in the heterocycloalkyl group is preferably 1, 2, 3 or 4, and the nitrogen, carbon or sulfur atom in the heterocycloalkyl group may optionally be Oxidized.
  • the nitrogen atom can optionally be further substituted with other groups to form a tertiary or quaternary ammonium salt.
  • the "monocyclic heterocycloalkyl group” is preferably a 3-10 membered monocyclic heterocycloalkyl group, more preferably a 3-8 membered monocyclic heterocycloalkyl group.
  • aziridine Azacyclobutyl Azacycloheptyl Oxahydrobutyl Pyrrolidinyl Tetrahydrofuranyl Morpholinyl Thiomorpholyl Thiomorpholyl-S-oxide Piperidinyl Piperazinyl High piperazinyl Wait.
  • Polycycloheterocycloalkyl includes "fused heterocycloalkyl", "spiroheterocyclyl” and "bridge heterocycloalkyl”.
  • “Fused heterocycloalkyl” includes a monocyclic heterocycloalkyl ring fused to a phenyl, cycloalkyl, heterocycloalkyl or heteroaryl group, including but not limited to: 2,3 - dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, indanyl, 2,3-dihydrobenzo[b]thienyl, dihydrobenzopyranyl, 1, 2,3,4-tetrahydroquinolyl and the like.
  • Spiroheterocyclyl means a bicyclic group formed by two heterocycloalkyl groups or a cycloalkyl group and a heterocycloalkyl group sharing one carbon atom, and spiroheterocyclyl groups include, but are not limited to, 5-aza [2.5 Xinji 4-aza[2.5]octyl 4-aza[2.4]heptyl 4,7-diazaspiro[2.5]octyl Wait.
  • Bridge heterocycloalkyl means a straight-chain group bridged by one or three additional carbon atoms or heteroatoms of any two unlinked ring atoms of a monocyclic heterocycloalkyl group (the linear chain) The group is selected from, but not limited to: -CH 2 -, -CH 2 CH 2 -, -CH 2 O-, -CH 2 NH-, -CH 2 CH 2 CH 2 -), bridged heterocycloalkyl including but not Limited to: (1R, 4R)-2,5-diazabicyclo[2.2.1]heptyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl (1S,4S)-2-oxo-5-azabicyclo[2.2.1]heptyl (1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptyl (1S,4R)-2-oxo-5-azabicyclo[2.2.1]heptyl (1S,4R)-2
  • Monocyclic heterocycloalkyl and polycyclic heterocycloalkyl groups can be attached to the parent molecule through any one or two ring atoms on the ring.
  • the above ring atoms specifically refer to carbon atoms and/or nitrogen atoms constituting the ring skeleton.
  • cycloalkylalkyl refers to a linkage between a cycloalkyl group and a parent core structure through an alkyl group.
  • cycloalkylalkyl embraces the definitions of alkyl and cycloalkyl as described above.
  • heterocycloalkylalkyl refers to an alkyl linkage between a heterocycloalkyl group and a parent core structure.
  • heterocycloalkylalkyl embraces the definitions of alkyl and heterocycloalkyl as described above.
  • alkoxy refers to a cyclic or acyclic alkyl group having the number of carbon atoms attached through an oxygen bridge, and includes an alkyloxy group, a cycloalkyloxy group, and a heterocycloalkyloxy group.
  • alkoxy includes the definitions of alkyl, heterocycloalkyl and cycloalkyl as described above.
  • hydroxyalkyl means that any one or more hydrogen atoms on the alkyl group are replaced by a hydroxy group, including but not limited to: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 C(CH 3 ) 2 OH, -CH(CH 3 ) 2 OH.
  • alkylthio refers to a cyclic or acyclic alkyl group having the number of carbon atoms attached through a sulfur bridge, the alkylthio group comprising an alkylthio group, a cycloalkylthio group, and a heterocycloalkylsulfide group. base.
  • alkylthio embraces the definitions of alkyl, heterocycloalkyl and cycloalkyl as described above.
  • alkenyl refers to a straight, branched or cyclic non-aromatic hydrocarbon radical containing at least one carbon to carbon double bond. There may be from 1 to 3 carbon-carbon double bonds, preferably one carbon-carbon double bond.
  • C2-4 alkenyl refers to an alkenyl group having 2 to 4 carbon atoms
  • C2-6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms, including vinyl and propenyl. , butenyl, 2-methylbutenyl and cyclohexenyl.
  • the alkenyl group may be substituted.
  • alkynyl refers to a straight, branched or cyclic hydrocarbon radical containing at least one carbon to carbon triple bond. There may be 1-3 carbon-carbon triple bonds, preferably one carbon-carbon triple bond.
  • C 2-6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms, and includes ethynyl, propynyl, butynyl and 3-methylbutynyl.
  • aryl refers to any stable 6-20 membered monocyclic or polycyclic aromatic group such as phenyl, naphthyl, tetrahydronaphthyl, indanyl or biphenyl. Wait.
  • heteroaryl refers to an aromatic ring radical formed by the replacement of a carbon atom on at least one ring with a heteroatom selected from nitrogen, oxygen or sulfur, which may be a 5-7 membered monocyclic structure or 7-20.
  • a fused ring structure preferably a 5-6 membered heteroaryl group.
  • the number of heteroatoms is preferably 1, 2 or 3, including but not limited to: pyridyl, pyrimidinyl, piperazinyl, pyridazine-3(2H)-one, furyl, thienyl, thiazolyl , pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadi Azyl, 1,3,4-thiadiazole, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, anthracene Sulfhydryl, isodecyl, benzofuranyl, benzothienyl, benzo[d][1,3]dioxolanyl, benzothiazolyl, benzoxazolyl,
  • arylalkyl refers to an alkyl linkage between the aryl group and the parent core structure.
  • arylalkyl embraces the definition of alkyl and aryl as defined above.
  • heteroarylalkyl refers to an alkyl linkage between a heterocycloalkyl group and a parent core structure.
  • heteroarylalkyl embraces the definitions of alkyl and heteroaryl as defined above.
  • halogen means fluoro, chloro, bromo or iodo.
  • haloalkyl refers to an alkyl group optionally substituted by halogen.
  • haloalkyl embraces the definitions of the above halo and alkyl.
  • haloalkoxy refers to an alkoxy group optionally substituted by halogen.
  • haloalkoxy includes the definitions of the above halo and alkoxy.
  • amino means -NH 2
  • alkylamino refers to at least one hydrogen atom is substituted with alkyl amino group, including but not limited to: -NHCH 3, -N (CH 3 ) 2, -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 .
  • aminoalkyl means that any one of the hydrogen atoms on the alkyl group is replaced by an amino group, including but not limited to: -CH 2 NH 2 , -CH 2 CH 2 NH 2 .
  • aminoalkyl and alkylamino embrace the definition of alkyl and amino as defined above.
  • aminocycloalkyl means that any one of the hydrogen atoms on the cycloalkyl group is replaced by an amino group, including but not limited to:
  • aminocycloalkyl includes the definitions of the above cycloalkyl and amino groups.
  • nitro refers to -NO 2 .
  • cyano refers to -CN.
  • mercapto refers to -SH.
  • Root temperature as used herein means 15-30 °C.
  • the isotope-substituted derivative includes an isotope-substituted derivative obtained by substituting any hydrogen atom of the formula I with 1-5 deuterium atoms, and an isotope obtained by substituting any carbon atom of the formula I with 1-3 carbon atoms and 14 atoms.
  • prodrug is meant that the compound is converted to the original active compound after metabolism in the body. Typically, the prodrug is inactive or less active than the active parent compound, but can provide convenient handling, administration or improved metabolic properties.
  • “Pharmaceutically acceptable salts” as described herein are discussed in Berge, et al., “Pharmaceutically acceptable salts", J. Pharm. Sci., 66, 1-19 (1977), and for pharmaceutical chemists It is apparent that the salts are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, and the like.
  • the compounds of the present invention may have an acidic group, a basic group or an amphoteric group, and typical pharmaceutically acceptable salts include those prepared by reacting a compound of the present invention with an acid, for example, hydrochloride, hydrobromic acid Salt, sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, Propionate, citrate, octanoate, formate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, suberate, Benzoate, methyl benzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, (D,L)-tartaric acid, citric acid, maleic acid, (D,
  • the pharmaceutically acceptable salt thereof may further include: an alkali metal salt such as a sodium or potassium salt; an alkaline earth metal salt such as a calcium or magnesium salt; an organic base salt such as ammonia and an alkane A salt formed from a base such as a hydroxyalkylamine, an amino acid (lysine, arginine) or N-methylglucamine.
  • an alkali metal salt such as a sodium or potassium salt
  • an alkaline earth metal salt such as a calcium or magnesium salt
  • an organic base salt such as ammonia and an alkane A salt formed from a base such as a hydroxyalkylamine, an amino acid (lysine, arginine) or N-methylglucamine.
  • “isomer” means that the compound of formula (I) of the present invention may have asymmetric centers and racemates, racemic mixtures and individual diastereomers, all of which include Stereoisomers, geometric isomers are all included in the present invention.
  • a compound of the formula I or a salt thereof, in stereoisomeric form is a single stereoisomer (enantiomer and diastereomer). Isomers) and mixtures thereof are included within the scope of the invention.
  • the invention also includes individual isomers of the compound or salt represented by Formula I, as well as mixtures with isomers in which one or more chiral centers are inverted.
  • the scope of the invention includes: mixtures of stereoisomers, as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures.
  • the invention includes mixtures of stereoisomers of all possible different combinations of all enantiomers and diastereomers.
  • the invention includes all combinations and subsets of stereoisomers of all the specific groups defined above.
  • the invention also includes geometric isomers of a compound of formula I or a salt thereof, including cis-isomers.
  • the reagents and starting materials used in the present invention are commercially available.
  • Figure 1 is a graph showing tumor volume changes of a compound 7-2-1 (15 mg/kg, 30 mg/kg, qd) and AZD1775 (60 mg/kg, bid) in a human lung cancer H1299 xenograft model.
  • the structures of all compounds of the invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
  • the 1 H NMR chemical shift ( ⁇ ) was recorded in PPM (10 -6 ).
  • NMR was performed on a Bruker AVANCE-400 spectrometer. Suitable solvents are deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), deuterated dimethyl sulfoxide (DMSO-d 6 ), and tetramethylsilane as internal standard (TMS).
  • All of the compounds of the present invention can be separated by high performance liquid chromatography, silica gel column chromatography, thin layer chromatography, or flash column chromatography.
  • High performance liquid chromatography was prepared using Shimadzu LC-20 preparative liquid chromatography column: waters xbridge Pre C18, 10 um, 19 mm x 250 mm.
  • Separation condition 1 Mobile phase A: 0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile; mobile phase B 40%, elution time: 20 minutes.
  • Separation condition 2 mobile phase A: 10 mmol/L aqueous ammonium hydrogencarbonate solution, mobile phase B: acetonitrile; gradient elution mobile phase B from 25% to 80%, elution time 30 minutes.
  • Separation condition 3 mobile phase A: 0.05% aqueous hydrochloric acid, mobile phase B: acetonitrile; gradient elution mobile phase B from 75% to 25%, elution time: 30 minutes.
  • Detection wavelength 214 nm & 254 nm; flow rate: 15.0 mL / minute.
  • Each of the compounds of the specific examples 37 to 75 of the present invention can be purified by prep-HPLC.
  • the compound obtained using the separation condition 1 is a trifluoroacetate salt
  • the compound obtained using the condition 2 is a free base
  • the compound obtained using the condition 3 is Hydrochloride.
  • Flash column chromatography Flash column chromatography (Flash column chromatography) (flash system / Cheetah TM) using Agela Technologies MP200, supporting the use of a separation column for Flash columm Silica-CS (80g) , Cat No.CS140080-0.
  • Thin layer chromatography is Yantai Xinnuo Chemical Co., Ltd. with a coating thickness of 0.2 ⁇ 0.03 mm and a size of 20 ⁇ 20 cm.
  • Silica gel column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as a carrier.
  • the eluent or developing agent used in silica gel column chromatography, thin layer chromatography or flash column chromatography is selected from one or more selected from the group consisting of ethyl acetate, methanol, dichloromethane, petroleum ether and n-hexane. .
  • the hydrogen atmosphere described in the examples of the present invention is provided by a hydrogen balloon.
  • Step 1 5-Nitroindole (1 g, 6.2 mmol), dimethylaminochloroethane hydrochloride (1.3 g, 9.3 mmol) and anhydrous potassium carbonate (3.4 g, 25 mmol) of N,N- A mixture of dimethylformamide (DMF) (15 mL) was stirred at 70 ° C for 3 hours. The obtained mixture was cooled to room temperature, then poured into ice water (50 mL), and the mixture was evaporated. Filtration and concentrating, and the residue was purified mjjjjjjjj
  • Step 2 Compound 1.2 (700 mg, 3.0 mmol) was added to a mixture of palladium carbon (100 mg, 10%) in methanol (20 mL), and the reaction system was replaced with hydrogen three times, and the mixture was stirred at room temperature overnight under hydrogen atmosphere. The reaction solution was filtered through Celite to remove the catalyst, and the filtrate was concentrated to give 1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (comp. 1.3, 600 mg, yield: 98%) Oily. m/z: [M+H] + 204.0.
  • Step 1 To a solution of 5-nitroguanidine (4 g, 24.7 mmol) in DMF (100 mL) EtOAc (EtOAc) Stir at room temperature for 2 hours. The reaction solution was then cooled in an ice bath and then 2-bromoethanol (12.3 g, 98.4 mmol). The mixture was stirred at room temperature for 24 hours. The reaction was then diluted with EtOAc. EtOAc (EtOAc m. Compound 1.4 (2.1 g, yield: 41%) was obtained as a colorless oil.
  • Step 2 Dess-Martin reagent (6.2 g, 14.7 mmol) was added portionwise to a solution of compound 1.4 (1 g, 4.85 mmol) in dichloromethane (20 mL). The resulting mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was washed with EtOAc EtOAc (EtOAc m.
  • Step 3 After a drop of acetic acid was added to a solution of compound 1.5 (400 mg, 1.96 mmol) and azetidine (168 mg, 2.94 mmol) in methanol (10 mL), the reaction mixture was stirred at room temperature for 30 min. Sodium cyanoborohydride (369 mg, 5.88 mmol) was added portionwise to the reaction mixture. The resulting mixture was further stirred at room temperature for 1 hour. Then, the reaction mixture was concentrated to dryness.
  • Step 4 To a mixed solution of compound 1.6 (270 mg, 1.10 mmol) in ethyl acetate (5 mL) and tetrahydrofuran (5 mL) was added palladium carbon (50 mg, 10%), and the mixture was replaced with hydrogen three times, then the mixture was hydrogen The mixture was stirred at room temperature for 3 hours under an atmosphere. The reaction system was filtered through celite, and the filtrate was evaporated to drynessieldielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielie
  • Step 1 To a solution of 5-nitroindole (1.01 g, 6.2 mmol) in DMF (10.0 mL), NaCI (0.5 g, 60%, 12. The reaction system was stirred at room temperature for 30 minutes, and then 1-Boc-4-methanesulfonyloxypiperidine (1.72 g, 6.2 mmol) was added to the above reaction system, and the reaction mixture was stirred at 100 ° C for 12 hours. Then, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was combined and washed with EtOAc EtOAc (EtOAc m. Rate: 75%) is yellow oil. m/z: [M+H] + 346.0.
  • Step 2 A mixed solution of the compound 2.2 (0.85 g, 2.4 mmol) of trifluoroacetic acid (2.0 mL) and dichloromethane (4.0 mL) was stirred at room temperature for 1 hour, and then the reaction system was concentrated under reduced pressure to give Compound 2.3 (0.55 g, crude) is a yellow oil. m/z: [M+H] + 246.0.
  • Step 3 Compound 2.3 (0.50 g, 2.0 mmol), 37% formaldehyde (0.33 g, 4.0 mmol), triethylamine (0.1 mL), acetic acid (2 drops) of 1,2-dichloroethane (10 mL) The solution was stirred at room temperature for 1 hour. Then, sodium cyanoborohydride (0.39 g, 6.0 mmol) was added to the above reaction system, and the obtained mixture was further stirred at room temperature for 2 hr. The reaction was quenched with aqueous sodium hydroxide (1.0M). The organic phase was combined and washed with EtOAc EtOAc (EtOAc m. : 66%) is a yellow solid. m/z: [M+H] + 260.0.
  • Step 4 To a solution of compound 2.4 (0.35 g, 1.3 mmol) in methanol (10.0 mL) was added palladium carbon (0.05 g, 10%), and the reaction system was replaced with hydrogen three times, then the reaction system was stirred at room temperature under a hydrogen atmosphere. hour. Filtration and concentration under reduced pressure gave 1-(1-methylpiperidin-4-yl)-1H-indole-5-amine (Compound 2.5, 0.10 g, crude). m/z: [M+H] + 230.2.
  • Step 1 5 -Nitroindole (1.62 g, 10.0 mmol) and 4-tetrahydropyranyl methanesulfonate (3.6 g, 20.0 mmol) were dissolved in DMF (20 mL) then EtOAc (EtOAc) g, 20.0 mmol), and the mixture was stirred with EtOAc EtOAc. The residue was purified to silicagel eluting elut elut elut elut elut elut elut elut elut m/z: [M+H] + 247.3.
  • Step 2 Palladium carbon (50 mg, 10%) was added to a solution of the compound 2.14 (950 mg, 3.8 mmol) in methanol (30 mL), and the reaction system was replaced with hydrogen three times, and then stirred under a hydrogen atmosphere for 30 minutes. The mixture was filtered through celite, and the filtrate was evaporated evaporated evaporated. It is a brown oil. m/z: [M+H] + 217.2.
  • Step 1 Acetic anhydride (49.9 mg, 0.49 mmol) was added to a solution of compound 2.3 (0.1 g, 0.41 mmol) and triethylamine (82.4 mg, 0.82 mmol) in dichloromethane (5 mL). The reaction system was stirred at room temperature for 2 hours. After diluting with dichloromethane, the mixture was washed with EtOAc EtOAc.
  • Step 2 Using the synthesis of compound 2.5, step 4, using compound 4.1 (100 mg, 0.35 mmol) to give 1-(4-(5-amino-1H-indol-1-yl)piperidin-1-yl) The ketone (Compound 4.2, 80 mg, Yield: 89%) was a pale yellow solid.
  • Step 1 2,2,2-Trifluoroethyl trifluoromethanesulfonate (284 mg, 1.22 mmol) was added to compound 2.3 (0.1 g, 0.41 mmol) and triethylamine (124 mg, 1.22 mmol) of tetrahydrofuran (In a 10 mL) solution, the reaction system was stirred at 70 ° C overnight. After the reaction mixture was cooled to room temperature, the residue was evaporated tolululululululululululululululululululululululululululululululululu m/z: [M+H] + 288.2.
  • Step 2 Using the synthesis of compound 2.5, step 4, using compound 5.1 (95 mg, 0.29 mmol) to give 1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H- Indole-5-amine (Compound 5.2, 85 mg, Yield: 100%) was a pale yellow solid.
  • Step 2 A mixture of compound 6.1 (3.05 g, 8.1 mmol) in trifluoroacetic acid (4 mL) and dichloromethane (20 mL) was stirred at room temperature for 2 hr then quenched with saturated aqueous sodium hydrogen carbonate and diluted with water The resulting mixture was extracted with dichloromethane. The organic phase was combined and washed with EtOAc EtOAc (EtOAc m. , Yield: 49%) as a pale yellow solid. m/z: [M+H] + 278.2.
  • Step 3 Compound 6.2 (1.1 g, 4.0 mmol) and sodium methoxide (643 mg, 11.9 mmol) in ethanol (20 mL) was stirred at 55 ° C for 2 hr. Then, saturated brine was added to the reaction system, and the mixture was extracted with dichloromethane. The organic phase was combined, dried over anhydrous sodium sulfate m/z: [M+H] + 232.4.
  • Step 4 To a solution of the compound 6.3 (310 mg, 1.3 mmol) in DMF (20 mL) Methyl iodide (285 mg, 2.0 mmol) was stirred at room temperature for 30 min. It was then diluted with ethyl acetate (100 mL) and the organic phase was washed with brine. The organic phase was separated and dried over anhydrous sodium sulfate. m/z: [M+H] + 246.4.
  • Step 5 Palladium carbon (180 mg, 10%) was added to a solution of Compound 6.4 (358 mg) in methanol (15 mL). The reaction system was replaced with hydrogen three times and then stirred under a hydrogen atmosphere for 0.5 hour. The reaction mixture was filtered over EtOAc (EtOAc) m/z: [M+H] + 216.2.
  • Step 6 A solution of lithium tetrahydroaluminum in tetrahydrofuran (1.95 mL, 4.9 mmol, 2.5 M) was added dropwise to a solution of compound 6.5 (275 mg, 1.3 mmol) in methyl t-butyl ether (30 mL). The system was stirred at 60 ° C for 5 hours. The reaction was then quenched with EtOAc EtOAc (EtOAc)EtOAc. The organic phase was separated and dried over anhydrous sodium sulfate, filtered and evaporatedEtOAc. 248 mg, 3-step yield: 96%) as a red solid. m/z: [M+H] + 202.2.
  • Step 1 Isobutyl chloroformate (10.2 mL, 78 mmol) was added dropwise to monomethyl 1,1-cyclopropyldicarboxylate (10 g, 69.4 mmol) and triethylamine (10.8 mL) at -10 °C. A solution of 78 mmol) in tetrahydrofuran (200 mL) was stirred at -10 ° C for 1 hour. The reaction mixture was warmed to 0 ° C.
  • Step 2 Methanesulfonyl chloride (7.4 g, 64.5 mmol) was added dropwise to a solution of compound 7.1 (5.6 g, 43 mmol) and triethylamine (8.7 mL, 86 mmol) in dichloromethane (100 mL) The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. ) is a white solid.
  • Step 3 Compound 7.2 (10.7 g, 51.5 mmol) was added to a solution of 5-nitroindole (5.56 g, 34.3 mmol) and cesium carbonate (33.5 g, 103 mmol) in DMF (60 mL) The mixture was stirred at rt., and the mixture was evaporated to EtOAc EtOAc. Purification by silica gel column chromatography (EtOAc /EtOAcEtOAc m/z: [M+H] + 275.2.
  • Step 4 An aqueous solution (10 mL) of lithium hydroxide monohydrate (475 mg, 11.3 mmol) was added dropwise to a solution of Compound 7.3 (1.24 g, 4.5 mmol) in tetrahydrofuran (30 mL). The tetrahydrofuran was removed by concentration, and the aqueous phase was washed with a petroleum ether/ethyl acetate mixed solution (1/1), then adjusted to pH 3 with a saturated aqueous solution of citric acid, and the aqueous phase was extracted with ethyl acetate (10 mL ⁇ 3). The mixture was washed with EtOAc EtOAc m.
  • Step 6 Compound 7.5 (460 mg, 1.39 mmol) and palladium on carbon (100 mg, 10%). The reaction system was replaced with hydrogen three times, and then stirred under a hydrogen atmosphere for 2 hours. Filtration with celite, and the filtrate was concentrated under reduced pressure to give (1-((5-amino-1H-indol-1-yl)methyl)cyclopropyl)aminomethyl tert-butyl ester (Compound 7.6, 308 mg, Rate: 74%) as a brown solid. m/z: [M+H] + 302.2.
  • Step 1 Under ice-cooling conditions, sodium hydrogen (121 mg, 3.0 mmol, 60%) was added to a solution of compound 7.5 (500 mg, 1.5 mmol) in DMF (10 mL), and the reaction system was stirred for 0.5 hr. , the mixture was added to the above reaction system, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and the aqueous phase was extracted with ethyl acetate (20 mL ⁇ 3). The organic phase was concentrated, and the residue was purified mjjjjjjjj m/z: [M+H] + 290.2.
  • Step 2 A mixture of compound 7.7 (362 mg, 1.0 mmol) and palladium carbon (100 mg, 10%) in methanol (15 mL) was replaced with hydrogen three times and then stirred at room temperature for 2 hours under hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was evaporated to dryness (diethyldiaminediethyldiethyldiphenyl) (((5-amino-1H-indol-1-yl)methyl)cyclopropyl)(methyl)aminomethyl-tert-butyl ester ( Compound 7.8, 315 mg, yield: 100%) was obtained as a brown solid. m/z: [M+H] + 316.2.
  • Step 2 Compound 8.1 (4 g, 19.4 mmol), dimethylamine hydrochloride (2.4 g, 29.1 mmol), HATU (11.0 g, 29.1 mmol) and N,N-diisopropylethylamine (9.6 mL, 58.2 mmol) of a solution of DMF (50 mL) was stirred at room temperature for 3 hr, and then water (150 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (100 mL ⁇ 3). The mixture was dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated, evaporated. Yellow solid. m/z: [M+H] + 234.2.
  • 6-Bromo-2-aminonaphthalene 500 mg, 2.25 mmol
  • 1-methylpiperazine 270 mg, 2.7 mmol
  • cesium hydroxide hydrate 760 mg, 4.5 mmol
  • dimethyl sulfoxide 5.0 mL
  • the solution was stirred at 120 ° C for 20 hours, then the reaction system was cooled to room temperature, diluted with ice water (10 mL), and the aqueous phase was extracted with dichloromethane (20 mL ⁇ 2). Drying over sodium sulfate, filtration, EtOAc (EtOAc:EtOAc) 9.1, 70 mg, yield: 13%) was a brown solid.
  • EtOAc EtOAc
  • Step 1 2-Fluoro-4-nitrobenzonitrile (2 g, 12.0 mmol), ethyl decylacetate (1.37 g, 11.4 mmol) and triethylamine (5 mL, 36 mmol) were added to acetonitrile (30 mL). The system was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj
  • Step 2 A mixture of compound 10.1 (600 mg, 2.25 mmol), tert-butyl nitrite (349 mg, 3.38 mmol) and copper bromide (1 g, 4.51 mmol) in acetonitrile (20 mL) was stirred at 65 ° C for 16 h. The reaction solution was concentrated under reduced pressure and poured into water, filtered, and then filtered and evaporated to dryness to afford Compound 10.2 (600 mg, yield: 81%). m/z: [M+H] + 329.8.
  • Step 3 Compound 10.2 (600 mg, 1.82 mmol), 1-methylpiperazine (219 mg, 2.18 mmol), tris(dibenzylideneacetone) dipalladium (83 mg, 0.091 mmol), 1,1'-binaphthyl -2,2'-bisdiphenylphosphine (113 mg, 0.182 mmol) and cesium carbonate (1.18 g, 3.64 mmol) were added to toluene (15 mL), and the reaction was heated under reflux for 16 hours under nitrogen. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjj m/z: [M+H] + 349.8.
  • Step 4 Compound 10.3 (100 mg, 0.28 mmol) and palladium on carbon (50 mg, 10%) were added to ethyl acetate (15 mL). The reaction system was replaced with hydrogen three times, then stirred under a hydrogen atmosphere for 0.5 hour, using silicon. The reaction mixture was filtered through celite, and the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to give ethyl 6-amino-3-(4-methylpiperidin-1-yl)benzo[b]thiophene-2-carboxylate. (Compound 10.4, 90 mg, crude) was obtained as a brown oil. m/z: [M+H] + 319.8.
  • Step 1 Compound 10.1 (500 mg, 1.88 mmol) and lithium chloride (995 mg, 23.5 mmol) were added to dimethyl sulfoxide (10 mL), and the reaction was stirred at 160 ° C for 5 hours. After the reaction mixture was cooled, EtOAc (EtOAc m. Compound 10.5 (200 mg, yield: 55%) was obtained as a brown solid. m/z: [M+H] + 194.8.
  • Step 2 Compound 10.5 (200 mg, 1.03 mmol), nitrogen mustard hydrochloride (297 mg, 1.54 mmol) and potassium carbonate (569 mg, 4.12 mmol) were added to tert-butanol (15 mL). Stir at °C for 3 hours. The reaction mixture was filtered, and then evaporated, evaporated, mjjjjjjj m/z: [M+H] + 277.8.
  • Step 3 Compound 10.6 (40 mg, 0.144 mmol), iron powder (40 mg, 0.72 mmol), ammonium chloride (39 mg, 0.72 mmol) and water (1 mL) were added to ethanol (15 mL) and the reaction was heated to reflux for 2 hours. . The reaction solution was then cooled to room temperature, filtered, and the filtrate was concentrated. The residue was washed with methylene chloride and methanol (10/1), and concentrated to give 3-(4-methylpiperazin-1-yl)benzene. And [b]thiophene-6-amine (compound 10.7, 34 mg, yield: 95%) was a dark brown liquid. m/z: [M+H] + 247.8.
  • Step 2 A solution of the compound 11.1 (82 mg, 0.28 mmol) and palladium carbon (40 mg, 10%) in methanol (10.0 mL) was replaced with hydrogen three times and then stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and then filtered and evaporated to ethyldiamine. %) is a brown solid.
  • Step 2 Palladium carbon (50 mg, 10%) was added to a solution of the compound 12.1 (760 mg, 2.9 mmol) in methanol (30 mL), and the reaction system was replaced with hydrogen three times, and then stirred under a hydrogen atmosphere for 30 minutes. The mixture was filtered through celite, and the filtrate was evaporated to dryness to give 3-(1-methylpiperidin-4-yl)-1H-indole-6-amine (Compound 12.2, 510 mg, yield: 77%) Brown oil. m/z: [M+H] + 230.2.
  • Step 2 To a suspension of compound 13.1 (1.76 g, 7.33 mmol) in acetic anhydride (20 mL) was added sodium acetate (2.39 g, 29.2 mmol), and the reaction was stirred at 130 ° C for 4 hours, then cooled to The reaction was quenched with EtOAc (EtOAc m. After the residue was cooled, a yellow solid was crystallised, filtered, and filtered, washed with petroleum ether and dried in vacuo to give compound 13.2 (1.05 g, yield: 55%) as a brown solid. m/z: [M+H] + 263.4.
  • Step 3 Compound 13.2 (200 mg, 0.76 mmol), 1-methylpiperazine (305 mg, 3.05 mmol) was dissolved in acetic acid (5 mL), and the reaction was subjected to microwave reaction at 150 ° C for 0.5 hour. The reaction mixture was concentrated under reduced vacuolululululululululululululululululululu m/z: [M+H] + 303.4.
  • Step 4 To a solution of the compound 13.3 (20 mg, 0.07 mmol) in methanol (5OmL), EtOAc (5 mg) was applied, and the system was replaced with hydrogen for 3 times and then stirred at room temperature for 1 hour under a hydrogen atmosphere. Filtration and concentration of the filtrate under reduced pressure gave 3-(4-methylpiperazin-1-yl)-1H-indole-6-amine (Compound 13.4, 16 mg, yield: 89%) as a brown solid. m/z: [M+H] + 231.2.
  • Step 1 To a solution of the compound 13.3 (110 mg, 0.36 mmol) in methanol (10.0 mL) was added triethylamine (120 mg, 1.10 mmol), and the reaction mixture was stirred at 80 ° C for 3 hours. The reaction system was concentrated under reduced pressure to give compound 13.5 (yield: yield: 100%). m/z: [M+H] + 261.4.
  • Step 2 To a solution of the compound 13.5 (94 mg, 0.36 mmol) in tetrahydrofuran (5.0 mL), sodium hydrogen (60%, 20 mg, 0.47 mmol) was added portionwise, and the reaction system was stirred at 0 ° C for 0.5 hour. Methyl iodide (80 mg, 0.54 mmol) was then stirred at 0 °C for 1 hour. The reaction system was concentrated under reduced pressure. EtOAc m. m/z: [M+H] + 275.4.
  • Step 3 Raney nickel (20 mg) was added to a solution of the compound 13.6 (45 mg, 0.16 mmol) in methanol (5.0 mL), and the reaction system was replaced with hydrogen three times, and then stirred for 1 hour under a hydrogen atmosphere. Filtration and concentration of the filtrate under reduced pressure gave 1-methyl-3-(4-methylpiperazin-1-yl)-1H-indole-6-amine (Compound 13.7, 40 mg, yield: 100%) as a brown solid. . m/z: [M+H] + 245.2.
  • Step 1 To a solution of 6-nitroguanidine (500 mg, 3.1 mmol) in toluene (10.0 mL) was added 2-bromopyridine (410 mg, 2.6 mmol) and cuprous iodide (25 mg, 0.13 mmol). Potassium phosphate (1.32 g, 6.2 mmol), N,N'-dimethylethylenediamine (55 mg, 0.63 mmol), then the reaction was stirred at 110 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj m/z: [M+H] + 240.2.
  • Step 2 Raney nickel (20 mg) was added to a solution of the compound 14.1 (130 mg, 0.54 mmol) in methanol (10.0 mL), and the reaction system was replaced with hydrogen for 3 times, and then stirred for 1 hour under a hydrogen atmosphere. Filtration and concentration of the filtrate under reduced pressure gave 1-(pyridin-2-yl)-1H-indole-5-amine (Compound 14.2, 113 mg, yield: 99%) as a brown solid. m/z: [M+H] + 210.3.
  • Step 3 A mixture of compound 15.2 (210 mg, 0.77 mmol) and palladium carbon (60 mg, 5%) in methanol (15 mL) was replaced with hydrogen three times. The reaction system was then stirred at room temperature for 1 hour under a hydrogen atmosphere. The solution was filtered, and the filtrate was concentrated under reduced pressure to give 1-methyl-4-(4-methylpiperazin-1-yl)-1H-indole-6-amine (Compound 15.3, 205 mg, yield: 100%) solid.
  • Step 1 N-Bromosuccinimide (2.12 g, 12 mmol) was added to a solution of 7-nitroquinoline (1.74 g, 10 mmol) in acetic acid (20 mL). The reaction system was then stirred at 80 ° C for 2 hours. After the reaction mixture was cooled to room temperature and stood still for 2 hr, a white precipitate was obtained, which was filtered and washed with petroleum ether and dried in vacuo to afford compound 16.1 (2.10 g, yield: 84%) as white solid.
  • Step 2 Compound 16.1 (2.1 g, 8.33 mmol) was dissolved in dimethyl sulfoxide (20 mL), followed by 1-methylpiperazine (0.9 g, 9 mmol), potassium carbonate (2.2 g, 16 mmol) and iodine Cuprous (152 mg, 0.8 mmol). After the reaction system was replaced with nitrogen for 3 times, it was stirred at 120 ° C for 3 hours under a nitrogen atmosphere, and then the reaction liquid was poured into ice water, and the aqueous phase was extracted with ethyl acetate (20 mL ⁇ 3), and the organic phase was combined, followed by water, The mixture was washed with EtOAc EtOAc EtOAc.
  • Step 3 Compound 16.2 (540 mg, 1.99 mmol) and Raney nickel (60 mg) were taken in methanol (15 mL). The reaction system was replaced with hydrogen three times. The reaction system was then stirred at room temperature for 1 hour under a hydrogen atmosphere. Filtration and concentration of the filtrate gave 3-(4-methylpiperazin-1-yl)quinolin-7-amine (Compound 16.3, 480 mg, yield: 100%) as a brown solid.
  • Step 1 2-Chloro-6-nitroquinoline (300 mg, 1.44 mmol) was added to a solution of 1-methylpiperazine (5 mL) in ethanol (20 mL). The reaction solution was cooled to room temperature, concentrated, evaporated, evaporated, evaporated.
  • Step 2 Compound 16.4 (100 mg, 0.367 mmol), palladium carbon (30 mg, 10%) was added to methanol (15 mL), and the reaction system was replaced with hydrogen three times, and then stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction liquid was filtered, and the filtrate was evaporated to dryness, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Step 2 Raney nickel (20 mg) was added to a solution of the compound 17.1 (73 mg, 0.33 mmol) in methanol (5 mL), and the reaction system was replaced with hydrogen three times, and then stirred for 1 hour under a hydrogen atmosphere. Filtration and concentration of the filtrate under reduced pressure gave 1-(oxetane-3-yl)-1H-indole-6-amine (Compound 17.2, 60 mg, yield: 95%) as a yellow solid. m/z: [M+H] + 189.2.
  • step 1 The 3-iodooxetane in step 1 was replaced with methyl iodide using the synthesis of compound 17.2 to give 1-methyl-1H-indol-6-amine (compound 17.3). m/z: [M+H] + 147.2.
  • Step 1 4-Bromo-6-nitro-1H-indole (200 mg, 0.83 mmol), cyclopropylboronic acid (143 mg, 1.66 mmol), sodium carbonate (176 mg, 1.66 mmol), copper acetate (151 mg, 0.83)
  • a solution of 2,2-bipyridine (130 mg, 0.83 mmol) in dichloromethane (5 mL) was evaporated.
  • the reaction was then cooled to room temperature and diluted with dichloromethane and the organic phase was washed with water. The organic phase was separated, dried and evaporated tolululululululululululululululu
  • Steps 2 & 3 using the synthesis of Compound 15.3, Step 2 and Step 3, using compound 18.1 to give 1-cyclopropyl-4-(4-methylpiperazin-1-yl)-1H-indole-6-amine ( Compound 18.3) was a brown solid.
  • Step 1 A suspension of 4-bromo-6-nitro-1H-indole (300 mg, 1.24 mmol), bromoethanol (467 mg, 3.73 mmol) and potassium carbonate (176 mg, 1.66 mmol) in DMF (10 mL) Stir at 100 ° C overnight. Then, the reaction system was cooled to room temperature, poured into ice water, and the aqueous phase was extracted with ethyl acetate, and the organic phase was washed successively with water and brine. The organic phase was separated, dried and purified mjjjjjjjjjjj
  • Steps 2 & 3 Using the synthesis of Compound 15.3 Step 2 and Step 3, the compound 19.1 is reacted to give 2-(6-amino-4-(4-methylpiperazin-1-yl)-1H-indol-1-yl. Ethanol (Compound 19.3) is a brown solid.
  • Step 1 To a solution of 4-bromo-6-nitro-1H-indole (200 mg, 0.83 mmol) and di-di-di-butyl-di- butyl ester (271 mg, 1.24 mmol) in dichloromethane (10 mL) Aminopyridine (10 mg, 0.083 mmol), and the reaction was stirred at room temperature for 1 hour. Then, the reaction mixture was concentrated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal
  • Step 2 Compound 20.1 (140 mg, 0.41 mmol), palladium acetate (4.6 mg, 0.02 mmol), 1-methylpiperazine (41 mg, 0.41 mmol), cesium carbonate (200 mg, 0.62 mmol) and 2-dicyclohexyl
  • a mixture of phosphorus-2',6'-diisopropoxy-1,1'-biphenyl (19.3 mg, 0.04 mmol) in 1,4-dioxane (10 mL) was replaced with nitrogen three times and then reacted The system was heated to 110 ° C and stirred for 2 hours. The reaction system was cooled to room temperature and then filtered over Celite. The filter cake was washed with ethyl acetate. The filtrate was concentrated. (110 mg, yield: 74%) was obtained as a brown solid. m/z: [M+H] + 361.2.
  • Step 3 using the synthesis method of the compound 15.3 step 3, using the compound 20.2 to obtain 6-amino-4-(4-methylpiperazin-1-yl)-1H-indole-1-carboxylic acid tert-butyl ester (compound) 20.3) is a brown solid.
  • Step 1 Iron powder (2.2 g, 39.2 mmol) was added to a solution of compound 15.1 (2 g, 7.84 mmol) and ammonium chloride (629 mg, 11.8 mmol) in acetic acid (20 mL). The reaction mixture was filtered with EtOAc (EtOAc). Brown solid. m/z: [M+H] + 225.0.
  • Step 3 a solution of n-butyllithium in tetrahydrofuran (2.5 M, 2.5 mL, 6.28 mmol) was added dropwise to a solution of compound 21.2 (680 mg, 2.09 mmol) in anhydrous tetrahydrofuran (20 mL). After stirring at -78 ° C for 1 hour, a solution of 1-methyl-4-piperidone (284 mg, 2.50 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise to the above reaction mixture, and stirring was continued at this temperature. After 2 hours, the reaction was quenched with EtOAc EtOAc EtOAc. (268 mg, yield: 36%) was a brown liquid. m/z: [M+H] + 360.0.
  • Step 4 Compound 21.3 (268 mg, 0.75 mmol) was dissolved in EtOAc (EtOAc) (EtOAc) It is a brown solid. m/z: [M+H] + 242.0.
  • Step 1 Compound 1-1 (222 mg, 1.0 mmol), Compound 1-2 (215 mg, 1.0 mmol), cuprous iodide (191 mg, 1.0 mmol), anhydrous potassium carbonate (276 mg, 2.0 mmol) and N N-Dimethylethylenediamine (88 mg, 1 mmol) was added to 1,4-dioxane (20 mL), and the mixture was warmed to 100 ° C and stirred overnight. The reaction system was then cooled to room temperature, and the reaction mixture was filtered. EtOAcjjjjjjjjjjj %) is a brown solid. m/z: [M+H] + 358.2.
  • Step 2 m-Chloroperoxybenzoic acid (68 mg, 0.34 mmol) was added to a solution of Compound 1-3 (120 mg, 0.34 mmol) in dichloromethane (10 mL). Dichloromethane was removed to give 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylsulfinyl)-1H-pyrazole[3 , 4-d]pyrimidin-3(2H)-one (Compound 1-4, 125 mg, Yield: 100%) was obtained as a white solid. m/z: [M+H] + 374.2.
  • Trifluoroacetic acid (2 mL) was added dropwise to a solution of Compound 2-1 (130 mg, 0.21 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 2 hr. 1) Purification to give 2-allyl-6-((1-((1-aminocyclopropyl)methyl)-1H-indol-5-yl)amino)-1-(6-(2-hydroxyl) Prop-2-yl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one trifluoroacetate (Compound 1-1-2, 46.7 mg, Rate: 36%) is a yellow solid.
  • the compound 2-2 is reacted to obtain 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(( 1-((1-(Methylamino)cyclopropyl)methyl)-1H-indol-5-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)- Ketone trifluoroacetate (Compound 1-1-3).
  • Step 1 Add ferrocene dichloride to a solution of compound 1-1-1 (210 mg, 0.41 mmol) and ammonium formate (52 mg, 0.82 mmol) in 1,4-dioxane (10 mL) at room temperature. Palladium (34 mg, 0.041 mmol) was replaced with nitrogen three times, then the reaction was slowly warmed to 100 ° C and stirred overnight. The reaction mixture was cooled to room temperature, filtered, and the filtered cake was washed with EtOAc. ) is a brown solid.
  • Step 2 To a solution of Compound 2-1 (110 mg, 0.233 mmol) in DMF (5 mL) H, propylpropyl bromide (94 mg, 0.7 mmol) was added and the mixture was stirred at room temperature overnight. Then, the reaction liquid was cooled to 0 ° C, and the reaction was quenched with ice water. The solution was extracted with dichloromethane (5 mL ⁇ 3).
  • the Wee1 enzyme catalysis test is carried out using the ATP-Glo Max luminescence detection kinase kit (Promega). Kinase activity was assessed by quantitative detection of the amount of ATP retained in the solution following the kinase reaction. The luminescent signal in the test is proportional to the amount of ATP and inversely proportional to the kinase activity.
  • the concentration of the compound in the test ranged from 0.5 nM to 30 ⁇ M. The compound was dissolved in 10% DMSO, and 5 ⁇ L of the solution was added to 50 ⁇ L of the reaction, and the concentration of DMSO in the final reaction was 1%. The reaction was carried out at 30 ° C for 50 minutes.
  • the 50 ⁇ L reaction mixture contained 40 mM Tris, pH 7.4, 10 mM MgCl 2 , 0.1 mg/ml BSA, 2 mM DTT, 0.1 mg/ml Poly(Lys, Tyr) substrate, 10 ⁇ M ATP and Wee1.
  • 50 ⁇ L of ATP-Glo Max luminescence assay kinase assay solution (Promega) was added and incubated for 15 minutes at room temperature. The luminescent signal was measured using a microplate reader.
  • a known Wee1 inhibitor was added as a positive control. Luminance data was analyzed using Graphpad software.
  • Non-linear regression analysis was used to plot the % activity value and the corresponding series compound concentration dose-effect curve.
  • IC 50 values determined by the concentration causing half-maximal percentage activity.
  • cellular assays are used to assess the biological activity of a compound. This trial was conducted using the human colon adenocarcinoma cell line WiDr. The activity of a specific Wee1 inhibitor was evaluated using the p-CDK1Y15 ELISA assay. The detailed test method is described as follows:
  • WiDr cells were cultured in Dulbecco's Modified Eagle's medium containing 10% FBS at 37 ° C and 5% CO 2 .
  • the compound concentration ranged from 0.5 nM to 30 ⁇ M.
  • the compound was diluted and added to a 24-well plate and incubated with the cells for 24 hours.
  • DMSO was used as a negative control.
  • a known Wee1 inhibitor was added as a positive control in some experiments.
  • the manufacturer's instructions in the p-CDK1Y15 assay, cells were lysed and subjected to a colorimetric ELISA kit test to determine the amount of p-CDK1Y15. The optical density is measured using a spectrophotometer. OD data analysis using Graphpad Software, curve fitting to obtain IC 50 values of the compounds.
  • the biological activity of the compound is evaluated using a cell test method.
  • MG63 ATCC CRL-1427
  • a human osteosarcoma cell line cultured in a 96-well plate of Dulbecco's Modified Eagle's medium, supplemented with 10% fetal bovine serum and 1% (v/v) L-glutamine, cultured at 37 °C and 5% CO 2 .
  • Compound concentrations ranged from 4.5 nM to 30 [mu]M.
  • the Wee1 inhibitor stock solution was dissolved in DMSO and added to the indicated concentration medium and incubated for 72 hours. Negative control cells were treated only with vehicle. In some experiments, a known Wee1 inhibitor was added as a positive control.
  • Cell viability was measured using Cell Counting Kit-8 (CCK-8, Sigma-Aldrich) under the direction of the product specification. Using Graphpad software for data analysis, and IC 50 values obtained compound and the fitted curve.
  • Example 4 In vivo pharmacodynamic experiment of human lung cancer H1299 xenograft tumor model
  • mice BALB/c nude mice, 24, 7-8 weeks, 16-21 g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • H1299 cell line (5 ⁇ 10 6 cells/cell) was inoculated subcutaneously into the right side of the experimental mice.
  • the inoculation amount of each mouse was 0.1 mL of PBS: Matrigel (volume ratio 1:1), and the tumor was observed regularly.
  • the growth condition was randomized according to tumor size and mouse body weight when the tumor grew to about 100 mm 3 , and was administered according to the administration schedule (Table 1). During the whole experiment, the body weight and tumor were measured 2 to 3 times per week. size.
  • the tumor volume change curves of the four experimental groups are shown in Figure 1.
  • the results show that compared to the positive control AZD1775, the present compound 7-2-1 is in the case of lower doses and longer dosing intervals in human lung cancer.
  • the H1299 xenograft model also showed better tumor inhibition.
  • the positive control in Biological Examples 1, 2, 3 and 4 of the present invention is AZD1775, chemical name: 2-allyl-1-(6-(2-hydroxyprop-2-yl)pyridin-2-yl) -6-((4-(4-Methylpiperazin-1-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (2-allyl- 1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazolo[3,4-d ] pyrimidin-3 (2H)-one), the synthesis method can be referred to WO2007126122A1 Example 9.

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Abstract

L'invention concerne un dérivé de pyrazolo[3,4-d]pyrimidin-3-one tel que représenté par la formule (I) ou (I') et/ou un sel pharmaceutiquement acceptable de celui-ci, une composition comprenant le composé tel que représenté par la formule (I) ou (I') et/ou un sel pharmaceutiquement acceptable de celle-ci, son procédé de préparation, son utilisation en tant qu'inhibiteur de Wee1 et son utilisation en tant que sensibilisateur dans une chimiothérapie ou une radiothérapie de cancers. Le composé peut inhiber de manière efficace les voies de signalisation Wee1 et associées et présente de bons effets en termes de traitement et/ou de soulagement de cancers.
PCT/CN2018/101290 2017-08-24 2018-08-20 Dérivé de pyrazolo[3,4-d]pyrimidin-3-one, composition pharmaceutique et utilisation associée Ceased WO2019037678A1 (fr)

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JP7614255B2 (ja) 2018-03-09 2025-01-15 リキュリウム アイピー ホールディングス リミテッド ライアビリティー カンパニー 置換１，２－ジヒドロ－３Ｈ－ピラゾロ［３，４－ｄ］ピリミジン－３－オン
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EP4069240A4 (fr) * 2019-12-20 2023-12-20 Recurium IP Holdings, LLC Associations
CN115867551A (zh) * 2020-05-15 2023-03-28 里科瑞尔姆Ip控股有限责任公司 单一疗法和组合疗法
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WO2023072301A1 (fr) * 2021-11-01 2023-05-04 正大天晴药业集团股份有限公司 Composé pyrazolo[3,4-d]pyrimidin-3-one et son utilisation médicale
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