WO2019011228A1 - 咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮类化合物及其应用 - Google Patents

咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮类化合物及其应用 Download PDF

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WO2019011228A1
WO2019011228A1 PCT/CN2018/095080 CN2018095080W WO2019011228A1 WO 2019011228 A1 WO2019011228 A1 WO 2019011228A1 CN 2018095080 W CN2018095080 W CN 2018095080W WO 2019011228 A1 WO2019011228 A1 WO 2019011228A1
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amino
phenyl
pyrimido
pyridazin
imidazo
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PCT/CN2018/095080
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English (en)
French (fr)
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蔡遂雄
田野
董志强
王晓珠
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上海瑛派药业有限公司
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Priority to US16/629,185 priority Critical patent/US11345710B2/en
Priority to CN201880046450.0A priority patent/CN110914277B/zh
Publication of WO2019011228A1 publication Critical patent/WO2019011228A1/zh

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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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D487/12—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 three hetero rings

Definitions

  • the invention belongs to the field of medicinal chemistry and relates to imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one compounds and applications thereof.
  • the process of growth and proliferation of eukaryotic cells involves the mother cell producing two identical daughter cells through mitosis of the cell chromosome by accurately replicating its genome including genetic information.
  • the cell proliferation and division process is called the cell cycle, which includes the entire process from the completion of one division to the completion of the next division.
  • the cell cycle includes four growth stages, a protein after mitosis, a large number of synthetic G1 phases such as RNA, a S phase of DNA synthesis replication, a G2 phase of preparation before mitosis, and a M phase of mitosis.
  • the cells decide to divide and proliferate through the cell cycle depending on the condition of the cell and the need, or stop. Cell proliferation and division must maintain the integrity and correctness of their genetic information. Whether to enter the next stage of the cell cycle until the completion of the entire cell cycle is ensured and completed by multiple checkpoints during the cell cycle.
  • Each cell cycle checkpoint consists of a very complex system and consists of multiple factors.
  • the checkpoint during the G1 period determines whether or not the cell enters the cell cycle by examining the state inside and outside the cell, thereby determining whether the cell enters S phase DNA synthesis.
  • the G1 checkpoint is a complex system that includes the famous CDK4/CDK6.
  • Another important checkpoint is the completion of DNA replication (S phase) in the cell into the cell growth phase (G2 phase), the so-called G2-M checkpoint. This checkpoint examines whether DNA is damaged or defective after DNA synthesis, thereby determining whether the cell undergoes mitosis (M phase) of the following chromosome segregation.
  • the cell cycle checkpoint at this stage includes the complex kinase Cdk1 complex including Cyclin-B-cdc2 (Nurse, P., 1990, Nature 344, 503-508).
  • Cdk1 Activation of Cdk1 leads to the initiation of mitosis, and its subsequent inactivation is accompanied by the completion of mitosis.
  • the activity of Cdk1 is regulated by cdc2 binding to Cyclin-A or Cyclin-B and its phosphorylation.
  • activation of the cyclin B-Cdk1 complex enables mitosis of cells (Lindqvist, A. et al., 2009, The Journal of cell biology 185, 193-202).
  • Cdc2 is maintained in an inactive state by phosphorylation prior to cell entry into mitosis. Its phosphorylation state is achieved by the tyrosine kinase Wee1 or the like. In addition, there are M phase cell cycle checkpoints.
  • Wee1 phosphorylates tyrosine 15 (Y15) on Cdk1 thereby inhibiting the activity of Cdk1 (McGowan, CH et al, 1993, The EMBO journal 12, 75-85; Parker, LL et al, 1992, Science 257, 1955-1957 ). Therefore, Wee1 is a key inhibitory regulator of Cdk1 activity and plays an important role in the G2-M phase of detection, ensuring that mitosis is entered without DNA damage after completion of DNA replication (O'Connell et al., 1997, The EMBO Journal 16,545-554). Loss or inactivation of Wee1 can lead to premature entry into mitosis, causing mitotic failure and cell death (Stumpff, J.
  • Some G1 phase cell cycle checkpoints of tumor cells have functional defects that rely on G2-M phase checkpoints to ensure cell cycle progression (Sancar, A. et al., 2004, Annual review of biochemistry 73, 39-85).
  • G2-M phase checkpoints to ensure cell cycle progression
  • loss of Wee1 expression or inhibition of Wee1 activity in these cancer cells leads to loss of G2-M checkpoint, making tumor cells very sensitive to DNA damage. This sensitization loses G1 checkpoint ability. It is particularly prominent in tumor cells (Wang, Y. et al., 2004, Cancer biology & therapy 3, 305-313).
  • inhibition of Wee1 activity can selectively cause cancer cells with defective cell cycle checkpoints to die; at the same time, it has little effect on normal cells with normal cell cycle checkpoints.
  • inhibitors of Wee1 are potentially targeted agents for the treatment of cancer and other cell proliferative disorders.
  • Wee1 inhibitors can be used in combination with anticancer drugs that cause DNA damage or inhibit DNA repair mechanisms, including the PARP inhibitor olaparib. Niraparib, Rucaparib, and Talazoparib; HDAC inhibitors vorinostat, romidepsin, pabisstat, and belistat, etc., are used to treat cancer or other cell proliferative disorders.
  • Wee1 inhibitors may also be combined with other anticancer drugs associated with cell division cell cycle checkpoints, including Chk1/2 inhibitors, CDK4/6 inhibitors such as Pabsini, ATM/ATR inhibitors, etc. Treat diseases such as cancer.
  • AZD1775 is the first Wee1 kinase inhibitor with single-agent anti-tumor activity in preclinical models.
  • Phase I clinical studies have demonstrated the efficacy of AZD1775 in monotherapy of patients with solid tumors carrying BRCA mutations, and confirmed the differentiation mechanism and DNA damage response by paired tumor biopsy to confirm its Wee1 kinase inhibition mechanism (J Clin Oncol, 2015, 33:3409-3415).
  • the efficacy of single drug in patients with advanced solid tumors and the combination with gemcitabine, cisplatin or carboplatin was studied, showing that it was at a certain dose.
  • WO2012161812 discloses the following tricyclic compounds as Wee1 kinase inhibitors.
  • X is N or CR 1 ;
  • Y is N or CR 2 ;
  • Z is O, S or NH;
  • R 1 and R 2 are H or C 1-6 alkyl;
  • R 3 is C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, aryl, or heteroaryl, etc.;
  • R 4 is phenyl, naphthyl, tetrahydronaphthyl, anthracenyl or indanyl, or 5-16 yuan A cyclic, bicyclic or tricyclic heterocyclic group or the like.
  • WO2005021551 discloses the following tetracyclic pyrimidine or pyridine compounds as protein kinase inhibitors.
  • X is N or CH;
  • Y is NH, N(CN), O or S;
  • L is a 4-atom chain consisting of C and N atoms;
  • R a is H, C 1-8 alkyl, CN, benzene Or a benzyl group;
  • R 1 and R 2 are independently a saturated or unsaturated 5-, 6-, or 7-membered monocyclic ring which may be substituted, or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring (containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein O and S atoms are not present simultaneously, and C atoms in the ring are replaced by 0, 1 or 2 oxy groups )Wait.
  • the present invention provides novel imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one compounds as kinase inhibitors, In particular, Wee1 kinase inhibitors.
  • the invention also provides pharmaceutical compositions comprising an effective amount of a compound of Formulas I, II and III for use in the treatment of cancer.
  • the pharmaceutical composition may also contain one or more pharmaceutically acceptable carriers or diluents for the treatment of cancer.
  • the pharmaceutical composition may further comprise at least one known anticancer drug or a pharmaceutically acceptable salt of the anticancer drug for treating cancer.
  • the invention also relates to a process for the preparation of the novel compounds of structural formulas I, II and III.
  • the present invention finds novel imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one compounds as kinase inhibitors, particularly Wee1 kinase inhibitor.
  • a compound useful in the present invention is a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof:
  • A is N or CR 6 ;
  • R 1 is hydrogen, a C 1 -C 8 alkyl group which may be substituted, a C 2 -C 8 alkenyl group which may be substituted, a C 3 -C 8 cycloalkyl group which may be substituted, an aryl group which may be substituted, a substituted heterocyclic group or a heteroaryl group which may be substituted;
  • R 2 is a carbocyclic group which may be substituted, a heterocyclic group which may be substituted, an aryl group which may be substituted, or a heteroaryl group which may be substituted;
  • R 3 -R 6 are independently hydrogen, halogen, amino group which may be substituted, alkoxy group which may be substituted, C 1 -C 10 alkyl group which may be substituted (such as haloalkyl, hydroxyalkyl, aminoalkyl and Carboxyalkyl), alkenyl, alkynyl, nitro, cyano, amido, hydroxy, decyl, acyloxy, azido, carboxy, ethylenedioxy, hydroxyamido or alkane which may be substituted Sulfur based.
  • A is N.
  • R 1 and R 2 are each an aryl group which may be substituted.
  • R 3 is hydrogen
  • R 4 and R 5 are hydrogen and a C 1 -C 6 alkyl group which may be substituted.
  • R 4 is hydrogen or unsubstituted C 1 -C 6 alkyl.
  • R 5 is hydrogen or C 1 -C 6 alkyl optionally substituted by hydroxy, such as hydroxy C 1 -C 6 alkyl.
  • R 6 is hydrogen
  • the substituent on R 1 is selected from any one, any two, any three or any of the following groups: halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogenated C 1 -C 6 alkyl.
  • R 1 is selected from C 2 -C 8 alkenyl and phenyl optionally substituted with from 1 to 4 substituents selected from halo and C 1 -C 6 alkyl.
  • R 1 is selected from phenyl optionally substituted with from 1 to 4 substituents selected from halo and C 1 -C 6 alkyl; in certain embodiments, substituents The number is 2; in certain embodiments, at least one substituent is in the ortho position; in certain embodiments, at least one substituent is a halogen; in certain embodiments, the substituent on the phenyl group is Two, two are in the ortho position, and at least one of them is a halogen.
  • R 1 is selected from C 2 -C 8 alkenyl groups which may be substituted.
  • the substituent of R 2 is selected from any one, any two, any three or any four of the following groups: a C 1 -C 6 alkyl group which may be substituted, a substituted oxy group, a halogen, and a heterocyclic group which may be substituted; preferably, the substituent on the group which may be substituted may be a group of 1 to 4 selected from the group consisting of C 1 -C 6 alkyl And -NR a R b , wherein R a and R b are each independently H and C 1 -C 6 alkyl; preferably, the heterocyclic group is selected from the group consisting of piperazinyl and piperidinyl.
  • the substituent of R 2 is any one, any two, any three or any four selected from the group consisting of: a piperazinyl group which may be substituted, which may be substituted Piperidinyl, C 1 -C 6 alkyl, halogen and C 1 -C 6 alkoxy; preferably, the substituent on the group which may be substituted may be from 1 to 4 groups selected from the group below : C 1 -C 6 alkyl and -NR a R b , wherein R a and R b are each independently H and C 1 -C 6 alkyl.
  • the piperazine group which may be substituted is piperazinyl which may be substituted with 1, 2 or 3 groups selected from C 1 -C 6 alkyl.
  • the piperazinyl group has at least one substituent at the para position, optionally having one or two substituents at the meta position.
  • the substitutable piperidinyl group is a piperidinyl group which may be substituted with one group selected from a C 1 -C 6 alkyl group and -NR a R b , wherein R a and R b are each independently H and C 1 -C 6 alkyl.
  • R 2 is selected from the group consisting of an optionally substituted phenyl group and an optionally substituted tetrahydroisoquinolyl group.
  • R 2 is selected from phenyl substituted with an optionally substituted piperazinyl, phenyl substituted with an optionally substituted piperidinyl, and optionally 1-3 C 1 -C 6 alkyl substituted tetrahydroisoquinolyl.
  • the piperazinyl is optionally substituted with from 1 to 3 substituents selected from C1- C6 alkyl.
  • the piperidinyl group is optionally substituted with one substituent selected from the group consisting of C 1 -C 6 alkyl and -NR a R b , wherein R a and R b are each independently It is H and C 1 -C 6 alkyl.
  • R 4 and R 5 are each independently selected from H and C 1 -C 6 alkyl which may be substituted.
  • R 4 and R 5 are H and a C 1 -C 6 alkane which may be substituted.
  • One of the preferred compounds of formula I of the invention is represented by a compound of formula II or a pharmaceutically acceptable salt or prodrug thereof:
  • R 3 -R 5 are as described in formula I;
  • Ar 1 and Ar 2 are each independently an aryl group which may be substituted, a heterocyclic group which may be substituted or a heteroaryl group which may be substituted;
  • R 3 is hydrogen
  • R 4 and R 5 are hydrogen and a C 1 -C 6 alkyl group which may be substituted.
  • Ar 1 and Ar 2 are each independently an aryl group which may be substituted, a heterocyclic group which may be substituted or a heteroaryl group which may be substituted; preferably, each of Ar 1 and Ar 2 Independently an aryl group which may be substituted, more preferred is a phenyl group which may be substituted.
  • the substituent on Ar 1 is any one, any two, any three or any four selected from the group consisting of halogen and C 1 -C 6 alkyl;
  • the number of substituents is two; in certain embodiments, at least one substituent is in the ortho position; in certain embodiments, at least one substituent is a halogen; in certain embodiments, There are two substituents on the phenyl group, both of which are in the ortho position, and at least one of them is a halogen.
  • Ar 1 is selected from phenyl optionally substituted with from 1 to 4 substituents selected from halo and C 1 -C 6 alkyl.
  • the substituent of Ar 2 is any one, any two, any three or any four selected from the group consisting of C 1 -C 6 alkyl groups; A substituted oxy group, a halogen, and a heterocyclic group which may be substituted.
  • the substituents on the groups which may be substituted may be from 1 to 4 groups selected from the group consisting of C 1 -C 6 alkyl and -NR a R b , wherein R a and R b are each independently H and C 1 -C 6 alkyl; preferably, the heterocyclic group is selected from the group consisting of piperazinyl and piperidinyl.
  • the substituent of Ar 2 is any one, any two, any three or any four selected from the group consisting of: a piperazinyl group which may be substituted, which may be substituted Piperidinyl, C 1 -C 6 alkyl, halogen and C 1 -C 6 alkoxy; preferably, the substituent on the group which may be substituted may be from 1 to 4 groups selected from the group below : C 1 -C 6 alkyl and -NR a R b , wherein R a and R b are each independently H and C 1 -C 6 alkyl.
  • the piperazine group which may be substituted is piperazinyl which may be substituted with 1, 2 or 3 groups selected from C 1 -C 6 alkyl.
  • the piperazinyl group has at least one substituent at the para position, optionally having one or two substituents at the meta position.
  • the substitutable piperidinyl group is a piperidinyl group which may be substituted with one group selected from a C 1 -C 6 alkyl group and -NR a R b , wherein R a and R b are each independently H and C 1 -C 6 alkyl.
  • Ar 2 is selected from the group consisting of an optionally substituted phenyl group and an optionally substituted tetrahydroisoquinolyl group.
  • Ar 2 is selected from the group consisting of: a phenyl group substituted with an optionally substituted piperazinyl group, a phenyl group substituted with an optionally substituted piperidinyl group, and optionally 1-3 C 1 -C 6 alkyl substituted tetrahydroisoquinolyl.
  • the piperazinyl is optionally substituted with from 1 to 3 substituents selected from C1- C6 alkyl.
  • the piperidinyl group is optionally substituted with one substituent selected from the group consisting of C 1 -C 6 alkyl and -NR a R b , wherein R a and R b are each independently It is H and C 1 -C 6 alkyl.
  • R 4 and R 5 are each independently selected from H and C 1 -C 6 alkyl which may be substituted; preferably, R 4 and R 5 are H and C 1 may be substituted - C 6 alkane.
  • R 1 or Ar 1 is selected from the group consisting of
  • R 2 or Ar 2 is selected from the group consisting of
  • R 1 or Ar 1 is selected from any of the following groups:
  • R 2 or Ar 2 is selected from any of the following groups:
  • the compound of Formula II has the structure of Formula III:
  • Ar 1 is selected from the group consisting of: phenyl substituted by 1 or 2 substituents selected from halogen and C 1 -C 6 alkyl;
  • Ar 2 is selected from the group consisting of: substituted phenyl, the substituent of which is selected from the group consisting of: halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy; optionally 1-3 selected from C 1 -C 6 alkane Substitudinally substituted piperazinyl; piperidinyl optionally substituted with 1 substituent selected from C 1 -C 6 alkyl and -NR a R b ; and 1-3 C 1 -C 6 An alkyl-substituted tetrahydroisoquinolyl group; wherein, R a and R b are each independently H or a C 1 -C 6 alkyl group.
  • Ar 1 is selected from the group consisting of: a phenyl group substituted with two substituents selected from a halogen and a C 1 -C 6 alkyl group;
  • Ar 2 is selected from the group consisting of: substituted phenyl, the substituent of which is selected from the group consisting of: halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy; optionally 1-3 selected from C 1 -C 6 alkane a substituted piperazinyl group; a piperidinyl group optionally substituted with one substituent selected from the group consisting of C 1 -C 6 alkyl and -NR a R b ; and optionally 1-3 C 1 - C 6 alkyl substituted tetrahydroisoquinolinyl.
  • R a and R b are each independently H or a C 1 -C 6 alkyl group.
  • Ar 1 is a disubstituted phenyl group in which two meta positions are each substituted with a substituent selected from a halogen and a C 1 -C 3 alkyl group, preferably, two substituents.
  • Ar 2 is a phenyl group substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy, optionally 1- 3 piperidinyl groups substituted with a substituent selected from C 1 -C 6 alkyl, piperidinyl optionally substituted by 1 substituent selected from C 1 -C 6 alkyl and -NR a R b ; A tetrahydroisoquinolinyl group optionally substituted with 1 to 3 substituents selected from C 1 -C 6 alkyl groups; wherein R a and R b are independently selected from H and C 1 -C 4 alkyl groups.
  • Ar 1 is preferably any of the following groups:
  • Ar 2 is preferably any of the following groups:
  • preferred compounds of Formula I, Formula II, and Formula III of the present invention include, but are not limited to:
  • alkyl refers to an alkyl group itself or a group having up to ten carbon atoms in a straight or branched chain.
  • Useful alkyl groups include straight or branched C 1 -C 10 alkyl groups, preferably C 1 -C 6 alkyl groups.
  • the alkyl group is a C 1 -C 4 alkyl group.
  • Typical C 1 -C 10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups which may be optionally substituted.
  • alkenyl means a straight or branched chain containing from 2 to 10 carbon atoms unless the carbon chain length is additionally limited, wherein at least one of the two carbon atoms in the chain contains a double bond; C 2 -C 6 alkenyl.
  • Typical alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.
  • alkynyl means a straight or branched chain containing from 2 to 10 carbon atoms unless the carbon chain length is additionally limited, wherein at least one of the two carbon atoms in the chain contains a hydrazone linkage; C 2 -C 6 alkynyl.
  • Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.
  • Useful alkoxy groups include those substituted by the above C 1 -C 10 alkyl group, preferably C 1 -C 6 alkyl group, such as methoxy, ethoxy, and the like.
  • the alkyl group in the alkoxy group may be optionally substituted.
  • Substituents for alkoxy groups include, but are not limited to, halogen, morpholinyl, amino groups including alkylamino and dialkylamino groups and carboxyl groups (including ester groups thereof).
  • Useful alkylthio groups include a thio group substituted by the above C 1 -C 10 alkyl group, preferably a C 1 -C 6 alkyl group, and the alkyl group in the alkylthio group may be optionally substituted. Also included are such alkylthio sulfoxides and sulfones.
  • Useful amino groups and optionally substituted amino groups include -NH 2 , -NHR' and -NR'R", wherein R' and R" are C 1 -C 10 alkyl groups which may be optionally substituted, cycloalkyl, aryl Base, heteroaryl or amino.
  • R' and R" together with N form a 5-8 membered heterocycle such as piperidine, or R' and R" and N together with other N or O form a 5-8 membered heterocycle such as piperazine.
  • the alkyl group and the heterocyclic ring may be optionally substituted.
  • the arylalkenyl, arylalkynyl, heteroaryl and heteroarylalkyl groups may be substituted by one or more (e.g.
  • substituents selected from the group consisting of halogens, hydroxy groups , carboxy, amino, nitro, cyano, C 1 -C 6 acylamino, C 1 -C 6 acyloxy, C 1 -C 6 alkoxy, aryloxy, alkylthio, C 1 -C 6 Alkyl, C 1 -C 6 acyl, C 6 -C 10 aryl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl (C 2 -C 6 )alkenyl, C 6 -C 10 aryl(C 2 -C 6 )alkynyl, saturated and unsaturated heterocyclic or heteroaryl, methylenedioxy, C 1- C 6 haloalkyl, C 6 -C 10 aryl(C 1 -C 6 )alkyl, C 1 -C 6 hydroxy
  • an alkyl group, an alkoxy group, an alkylthio group, an alkenyl group, an alkynyl group, a cycloalkyl group, a carbonyl group, a carbocyclic ring, and a heterocyclic ring may be one or more (for example, 1 , 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxy, carboxy, amino, nitro, cyano, C 1 -C 6 acylamino, C 1 -C 6 acyl, C 1 - C 6 acyloxy, C 1 -C 6 alkoxy, aryloxy, alkylthio, C 6 -C 10 aryl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2- C6 alkynyl, C 6 -C 10 aryl(C 2 -C 6 )alkenyl, C 6 -C 10 -C 10
  • aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, and heteroarylalkyl can be one or more (eg, 1, 2, 3 or 4) substituents selected from the group consisting of halogen, methylene dioxy, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, C 3 -C 8 cycloalkyl, C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl(C 1 -C 6 )alkyl, C 6 -C 10 aryl (C 2 -C 6 )alkenyl, C 6 -C 10 aryl(C 2 -C 6 )alkynyl, C 1 -C 6 hydroxyalkyl, nitro, amino, ureido, cyano, C 1 -C 6 acyla
  • the substituent is a heterocyclic group, an aryl group or a heteroaryl group
  • the number of the heterocyclic group, aryl or heteroaryl substituent is usually one.
  • aryl refers to a aryl group or as part of another group, and refers to a monocyclic, bicyclic or tricyclic aromatic group containing from 6 to 14 carbon atoms.
  • Useful aryl groups include C 6 -C 14 aryl groups, preferably C 6 -C 10 aryl groups.
  • Typical C 6 -C 14 aryl groups include phenyl, naphthyl, phenanthryl, anthryl, fluorenyl, fluorenyl, biphenyl, biphenylene and anthracenyl.
  • the "carbocyclic ring" referred to herein includes a cycloalkyl group and a partially saturated carbocyclic group.
  • Useful cycloalkyl groups are C 3 -C 8 cycloalkyl groups.
  • Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Useful saturated or partially saturated carbocyclic groups are the cycloalkyl and cycloalkenyl groups described above, such as cyclopentenyl, cycloheptenyl and cyclooctenyl.
  • Useful halogen or halogen groups include fluorine, chlorine, bromine and iodine.
  • Arylalkyl include any of the above C 6 -C 14 aryl-substituted C 1 -C 10 alkyl group used herein. Preferred arylalkyl groups are benzyl, phenethyl or naphthylmethyl.
  • arylalkenyl as used above includes any of a C 6 -C 14 aryl-substituted C 2 -C 10 alkenyl group.
  • arylalkynyl as used above includes any of a C 6 -C 14 aryl-substituted C 2 -C 10 alkynyl group.
  • aryloxy includes an oxy group substituted by any of the above C 6 -C 14 aryl groups, the aryl group of which may be optionally substituted.
  • Useful aryloxy groups include phenoxy and 4-methylphenoxy.
  • aryl alkoxy group includes C is any one of the above-described aryl group substituted with 1 -C 10 alkoxy group, an aryl group which may be optionally substituted.
  • Useful arylalkoxy groups include benzyloxy and phenylethoxy.
  • Useful haloalkyl groups include C 1 -C 10 alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms, preferably C 1 -C 6 alkyl groups, such as fluoromethyl, difluoromethyl, trifluoromethyl Base, pentafluoroethyl, 1,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl.
  • Useful acylamino is any C 1 -C 6 acyl (alkanoyl) attached to the amino nitrogen, such as acetylamino, chloroacetamido, propionylamino, butyrylamino, pentanoylamino and hexanoylamino, And an aryl-substituted C 1 -C 6 acylamino group such as a benzoylamino group and a pentafluorobenzoylamino group.
  • Useful acyl groups include C 1 -C 6 acyl groups such as acetyl.
  • acyloxy groups are any C 1 -C 6 acyl (alkanoyl) group attached to oxygen (-O-), such as formyloxy, acetoxy, propionyloxy, butyryloxy, valeryl Oxyl and hexanoyloxy.
  • heterocyclic ring refers to a saturated or partially saturated 3-7 membered monocyclic ring, or a 7-10 membered bicyclic ring system, which is selected from the group consisting of carbon atoms and from one to four of O, N, and S. It is composed of heteroatoms in which the hetero atom nitrogen and sulfur can be arbitrarily oxidized, and the nitrogen can also be arbitrarily quaternized, and includes the fusion of any heterocyclic ring defined above in the bicyclic ring system with the benzene ring. If the resulting compound is stable, then the carbon or nitrogen atom of the heterocycle can be substituted.
  • Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indanyl, isoindoline , quinuclidinyl, morpholinyl, heterochromyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetrahydroisoquinolinyl, tetronoyl and tetramoyl, these groups may be optionally substituted.
  • heteromatic ring means having 5 to 14 ring atoms and having 6, 10 or 14 ⁇ electrons are shared on the ring system. Further, the ring atom contained is a carbon atom and optionally 1-3 hetero atoms from oxygen, nitrogen, and sulfur.
  • Useful heteroaryl groups include thienyl (phenylthio), benzo[d]isothiazol-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thiazide, Furanyl, pyranyl, isobenzofuranyl, chromenyl, anthranilyl, phenoxanthiinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (including but not limited to 2-pyridine , 3-pyridyl and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, pyridazinyl, isodecyl, 3H-indenyl, fluorenyl, oxazolyl, fluorenyl, 4H-quinazinyl, isoquinolyl, quinolyl, pyridazinyl, naphthyridin
  • such a nitrogen atom may be in the form of an N-oxide such as a pyridyl N-oxide, a pyrazinyl N-oxide, and a pyrimidinyl N-oxide.
  • heteroaryloxy includes oxy groups substituted by any of the above heteroaryl groups, wherein the heteroaryl group may have a substituent.
  • Useful heteroaryloxy groups include pyridyloxy, pyrazinyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy and phenylthiooxy.
  • heteroarylalkoxy refers to any of the above C 1 -C 10 alkoxy groups substituted by any of the above heteroaryl groups, wherein the heteroaryl group may have a substituent.
  • stereoisomers including optical isomers.
  • the present invention includes all stereoisomers and racemic mixtures of such stereoisomers, as well as the individual enantiomers which can be separated according to methods well known to those skilled in the art.
  • Examples of pharmaceutically acceptable salts include inorganic and organic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, citrates, lactates, tartrates, maleates, fumarates, Mandelic acid salts and oxalates; and inorganic and organic base salts formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methylglucamine.
  • inorganic and organic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, citrates, lactates, tartrates, maleates, fumarates, Mandelic acid salts and oxalates
  • inorganic and organic base salts formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methylglucamine.
  • prodrugs of the compounds of the invention include simple esters of carboxylic acid containing compounds (e.g., esters obtained by condensation with a C 1 -C 4 alcohol according to methods known in the art); esters of hydroxyl containing compounds (e.g., based on A method known in the art is an ester obtained by condensation with a C 1 -C 4 carboxylic acid, a C 3 -C 6 diacid or an anhydride thereof such as succinic anhydride and fumaric anhydride; an imine of an amino group-containing compound (for example, according to the present invention)
  • a known method in the art is an imine obtained by condensation with a C 1 -C 4 aldehyde or a ketone); a carbamate of an amino group-containing compound, such as Leu et al.
  • the compounds of the invention can be prepared using methods known to those skilled in the art or by the novel methods of the invention.
  • the compounds of the invention having formula I can be prepared as shown in the reaction examples in Reaction Scheme 1.
  • N-tert-butoxycarbonyl-2-aminoacetaldehyde, 2,6-dichlorophenylhydrazine and sodium triacetoxyborohydride are reacted in dichloromethane at room temperature, then sodium cyanoborohydride is added at room temperature The reaction was continued to give the product (2-(2-(2,6-dichlorophenyl)indenyl)ethyl)carbamic acid tert-butyl ester.
  • the tert-butyl carbamate, diisopropylethylamine and benzyl chloroformate are reacted in dichloromethane at room temperature to give the product 1-(2-(tert-butoxycarbonylamino)ethyl)-2-( Benzyl 2,6-dichlorophenyl)hydrazinecarboxylate.
  • the benzyl hydrazinecarboxylate is dissolved in a hydrochloric acid dioxane solution and reacted at room temperature to obtain the product 1-(2-aminoethyl)-2-(2,6-dichlorophenyl)indolecarboxylic acid benzyl ester hydrochloride. salt.
  • the benzyl hydrazinecarboxylate is dissolved in trifluoroacetic acid to obtain a product of 2-methylthio-5-bromo-N-(2-(2-(2,6-dichlorophenyl)indenyl)ethyl).
  • - Pyrimidine-4-carboxamide The formamide and phosphorus pentachloride are reacted in dichloromethane at room temperature to give the product 2-(2-methylthio-5-bromopyrimidin-4-yl)-N-(2,6-dichlorobenzene Base 4,5-dihydro-1H-imidazol-1-amine.
  • the title compound 6-(2,6-dichloro) can be obtained by substituting tert-butyl (3-methyl-1-oxobutan-2-yl)carbamate for N-tert-butoxycarbonyl-2-aminoacetaldehyde.
  • the compound of the present invention can be produced as shown in the reaction examples in Reaction Scheme 2.
  • 2-Methylthio-5-bromopyrimidine-4-carboxylic acid and carbonyldiimidazole are heated in tetrahydrofuran, and then 2,2-dimethoxyethyl-1-amine is added to react at room temperature to obtain the product N-( 2,2-Dimethoxyethyl)-2-methylthio-5-bromopyrimidine-4-carboxamide.
  • N-(2,2-dimethoxyethyl)-2-methylthio-5-bromopyrimidine-4-carboxamide and dilute hydrochloric acid are heated in acetone to give the product N-(2-oxoethyl) )-2-methylthio-5-bromopyrimidine-4-carboxamide.
  • N-(2-oxoethyl)-2-methylthio-5-bromopyrimidine-4-carboxamide, 2,6-difluorophenylhydrazine and acetic acid are reacted in methanol at room temperature, then sodium cyanoborohydride is added Reaction at room temperature gave the product N-(2-(2-(2,6-difluorophenyl)indolyl)ethyl)-2-methylthio-5-bromopyrimidine-4-carboxamide.
  • the target compound 6-(2,6-dichlorophenyl)-2-((3-methyl-4-() can be obtained by substituting 2,6-dichlorophenylhydrazine for 2,6-difluorophenylhydrazine.
  • the target compound 6-(2-chloro-6-fluorophenyl)-2-((3-methyl-4-() can be obtained by substituting 2-chloro-6-fluorophenylhydrazine for 2,6-difluorophenylhydrazine.
  • the target compound 6-(2-fluoro-6-methylphenyl)-2-((3-methyl-4) can be obtained by substituting 2-fluoro-6-methylphenylhydrazine for 2,6-difluorophenylhydrazine.
  • the target compound 6 can be obtained by substituting 3-chloro-4-(4-(dimethylamino)piperidin-1-yl)aniline for 3-methyl-4-(4-methylpiperazin-1-yl)aniline -(2,6-dichlorophenyl)-2-((3-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)imidazo[1,2- b] Pyrimido[4,5-d]pyridazin-5(6H)-one.
  • the target compound 6-(2) can be obtained by substituting 3-fluoro-4-(1-methylpiperidin-4-yl)aniline for 3-methyl-4-(4-methylpiperazin-1-yl)aniline ,6-dichlorophenyl)-2-((3-fluoro-4-(1-methylpiperidin-4-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4, 5-d]pyridazine-5(6H)-one.
  • the compound of the present invention can be produced as shown in the reaction examples in Reaction Scheme 3.
  • 2-methylthio-5-(ethoxycarbonyl)pyrimidine-4-carboxylic acid and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate The ester is reacted in N,N-dimethylformamide at room temperature, then 2,2-dimethoxyethane-1-amine is added to continue the reaction at room temperature to give the product 2-methylthio-4-( Ethyl (2,2-dimethoxyethyl)carbamoyl)pyrimidine-5-carboxylate.
  • Ethyl 2-methylthio-4-((2,2-dimethoxyethyl)carbamoyl)pyrimidine-5-carboxylate and concentrated hydrochloric acid are heated in dichloromethane to give the product 2-methylthio.
  • 3-chloro-4-(4-methylpiperazin-1-yl)aniline can be used instead of 3-methyl-4-(4-methylpiperazin-1-yl)aniline to obtain the target compound 6- (2-bromo-6-chlorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimidine [4,5-d]pyridazine-5(6H)-one.
  • the target compound can be obtained by substituting 3-chloro-4-(4-(dimethylamino)piperidin-1-yl)aniline for 3-methyl-4-(4-methylpiperazin-1-yl)aniline 6-(2-Bromo-6-chlorophenyl)-2-((3-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)imidazo[1, 2-b]pyrimido[4,5-d]pyridazin-5(6H)-one.
  • the compound of the present invention can be produced as shown in the reaction examples in Reaction Scheme 4.
  • 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid, N,N-diisopropylethylamine, 2-(7-azobenzotriazole)-N,N,N',N '-Tetramethylurea hexafluorophosphate and aminoacetone hydrochloride are reacted in N,N-dimethylformamide at room temperature to give the product 5-bromo-2-(methylthio)-N-(2 -Oxopropyl)pyrimidine-4-carboxamide.
  • Trifluoromethanesulfonic anhydride and triphenylphosphine are reacted in dichloromethane at room temperature, followed by the addition of 5-bromo-N-(2-(2-(2,6-dichlorophenyl)indolyl)propyl) 2-(Methylthio)pyrimidine-4-carboxamide was reacted at 0 ° C to give the crude product 2-(5-bromo-2-(methylthio)pyrimidin-4-yl)-N-(2,6 -Dichlorophenyl)-5-methyl-4,5-dihydro-1H-imidazol-1-amine.
  • the ketone and m-chloroperoxybenzoic acid are reacted in dichloromethane at room temperature to give the crude intermediate, the crude product, 3-chloro-4-(4-methylpiperazin-1-yl)aniline and trifluoro
  • the acetic acid is heated in acetonitrile to give the title compound 6-(2,6-dichlorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino) 8-methylimidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one.
  • Formula I is a kinase inhibitor, particularly a Wee1 kinase inhibitor. Therefore, these compounds are useful for the treatment of Wee1-related diseases.
  • Weel-associated disease refers to a Weel-mediated disease, particularly a disease that benefits from the inhibition of Weel kinase activity, such as cancer.
  • the invention includes a method of administering to an animal an effective amount of a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment of a Wee1-related disease, such as cancer.
  • Such diseases which can be treated or prevented by the methods or pharmaceutical compositions of the invention include, but are not limited to, liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoid leukemia, multiple myeloma , neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain Cancer, malignant melanoma, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute granulocytes Leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma,
  • the invention also encompasses the use of, for the treatment or prevention of other diseases caused by abnormal Wee1 activity, such as neurological or neuropsychiatric diseases or conditions, such as depression.
  • an effective amount of the pharmaceutical formulation is administered to a patient having one or more of these symptoms.
  • the pharmaceutical preparations contain a therapeutically effective concentration of a compound of Formula I, Formula II or Formula III formulated for oral, intravenous, topical or topical administration for the treatment of cancer and other diseases.
  • the amount administered is an amount effective to ameliorate or eliminate one or more conditions.
  • an effective amount is an amount sufficient to ameliorate or in some way alleviate the symptoms associated with the disease.
  • Such doses can be administered as a single dose or can be administered according to an effective therapeutic regimen.
  • the amount administered may cure the disease, but administration is usually to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired improvement in symptoms.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt thereof, as a Wee1 inhibitor, and a pharmaceutically acceptable carrier.
  • Another embodiment of the invention relates to a pharmaceutical composition effective for treating cancer comprising a compound of Formula I, Formula II or Formula III as a Wee1 kinase inhibitor, or a pharmaceutically acceptable salt or prodrug thereof, and at least one Known anticancer drugs or pharmaceutically acceptable salts of anticancer drugs are used in combination.
  • anticancer drugs related to DNA damage and repair mechanisms including any of the compounds prepared in the PARP inhibitors Olapani, Niraparib, Rucaparib, Talazoparib, and PCT/CN2012/073362 ( This article is incorporated herein by reference in its entirety; HDAC inhibitors vorinostat, romidepsin, pabisstat, and belistat; And a combination of other anticancer drugs associated with cell division detection sites, including Chk1/2 inhibitors, CDK4/6 inhibitors such as Pabsini, ATM/ATR inhibitors, and the like.
  • anticancer drugs useful in combination therapy for cancer include, but are not limited to, alkylating agents such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, Cisplatin, mitomycin C, bleomycin and carboplatin; topoisomerase I inhibitors such as camptothecin, irinotecan and topotecan; topoisomerase II inhibitors such as doxorubicin, Epirubicin, aclarithromycin, mitoxantrone, methylhydroxy ellipticine and metoprolol; RNA/DNA antimetabolites such as 5-azacytidine, gemcitabine, 5-fluorouracil and methotrexate DNA; DNA antimetabolites such as 5-fluoro-2'-deoxyuridine, fludarabine, nairabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea
  • the compounds of the invention may be administered as a single pharmaceutical composition with at least one known anti-cancer drug.
  • the compounds of the invention may also be administered separately from at least one known anticancer drug.
  • the compound of the invention is administered at about the same time as at least one known anticancer drug, i.e., all drugs are administered simultaneously or sequentially, as long as the compound achieves a therapeutic concentration in the blood simultaneously.
  • the compound of the invention and at least one known anticancer drug are administered according to a respective dosage regimen as long as the compound reaches a therapeutic concentration in the blood.
  • Another embodiment of the present invention is a bioconjugate of the compound which is effective as a tumor suppressor and which is effective as a Wee1 inhibitor.
  • the bioconjugant capable of inhibiting tumors consists of the compound with at least one known medically active antibody, such as Herceptin or rituximab, or an auxin, such as DGF or NGF, or a cytokine, such as interleukin 2 Or 4, or any molecule that binds to the cell surface.
  • the antibody and other molecules are capable of delivering the compound to its target, making it an effective anticancer drug.
  • This bioconjugate can also increase the anticancer effect of medically active antibodies such as Herceptin or rituximab.
  • Another embodiment of the present invention relates to a pharmaceutical composition effective for inhibiting tumors, comprising a Wee1 inhibitor of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt or prodrug thereof, in combination with radiation therapy treatment.
  • the compounds of the invention may be administered at the same time or at different times with radiation therapy.
  • Another embodiment of the present invention is directed to a pharmaceutical composition effective for post-operative treatment of cancer comprising a Wee1 inhibitor of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt or prodrug thereof.
  • the invention further relates to a method of treating a cancer in a mammal by surgically removing the tumor and then treating the mammal with a pharmaceutical composition of the invention.
  • the pharmaceutical composition of the present invention includes all of the pharmaceutical preparations of the present invention in an amount effective to achieve their intended purpose. While the needs of each individual are different, one skilled in the art can determine the optimal dosage for each portion of the pharmaceutical formulation.
  • the compound, or a pharmaceutically acceptable salt thereof is orally administered to a mammal daily for a dose of from about 0.0025 to 50 mg/kg body weight. Preferably, however, it is about 0.01 to 10 mg/kg administered orally per kg. If a known anticancer drug is also administered, the dose should be effective to achieve its intended purpose.
  • the optimal dosage of these known anticancer drugs is well known to those skilled in the art.
  • the unit oral dose can include from about 0.01 to 50 mg, preferably from about 0.1 to 10 mg, of the compound of the invention.
  • the unit dose may be administered one or more times per day in one or more tablets, each tablet containing from about 0.1 to 50 mg, conveniently from about 0.25 to 10 mg of the compound of the invention or a solvate thereof.
  • the concentration of the compound of the present invention may be about 0.01 to 100 mg per gram of the carrier.
  • the compounds of the invention can be administered as unprocessed pharmaceuticals.
  • the compounds of the invention may also be administered as part of a suitable pharmaceutical formulation containing a pharmaceutically acceptable carrier, including excipients and auxiliaries.
  • a pharmaceutically acceptable carrier including excipients and auxiliaries.
  • These pharmaceutically acceptable carriers facilitate the processing of the compounds into pharmaceutically acceptable pharmaceutical preparations.
  • Preferred pharmaceutical preparations especially those of the oral and preferred modes of administration, such as tablets, troches and capsules, and solutions suitable for injection or oral administration, comprise from about 0.01% to about 99%, preferably from about 0.25%. Up to 75% of active compound and excipients.
  • non-toxic pharmaceutically acceptable salts of the compounds of the invention are non-toxic pharmaceutically acceptable salts of the compounds of the invention.
  • the acid addition salt is formed by mixing a non-toxic pharmaceutically acceptable acid solution and a solution of the compound of the present invention.
  • the acid is, for example, hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid and the like.
  • the base addition salt is formed by mixing a non-toxic pharmaceutically acceptable base solution and a solution of the compound of the present invention.
  • the base is, for example, sodium hydroxide, potassium hydroxide, hydrogen choline, sodium carbonate, trishydroxymethylaminomethane, N-methyl-glucosamine or the like.
  • the pharmaceutical preparation of the present invention can be administered to any mammal as long as they can obtain the therapeutic effect of the compound of the present invention.
  • the most important of these mammals are human and veterinary animals, although the invention is not intended to be so limited.
  • the pharmaceutical preparation of the present invention can be administered by any route to achieve its intended purpose.
  • it can be administered by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, nasal or topical routes.
  • parenteral subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, nasal or topical routes.
  • it can be administered orally.
  • the dosage of the drug will be determined by the age of the patient, the health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.
  • the pharmaceutical preparations of the invention can be made in a known manner. For example, it is manufactured by a conventional mixing, granulating, tableting, dissolving, or freeze drying process. In the manufacture of oral formulations, the mixture can be selectively milled by combining the solid adjuvant with the active compound. If necessary or necessary, after adding an appropriate amount of auxiliary agent, the mixture of particles is processed to obtain a tablet or tablet core.
  • Suitable excipients are, in particular, fillers, such as sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, including Corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone.
  • fillers such as sugars such as lactose or sucrose, mannitol or sorbitol
  • cellulose preparations and/or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch pastes, including Corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or poly
  • a disintegrating agent such as the above-mentioned starch, and carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added.
  • Adjuvants are especially flow regulators and lubricants, for example, silica, talc, stearic acid or a salt thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • the tablet core can be provided with a suitable coating that is resistant to gastric juice. For this purpose, a concentrated sugar solution can be applied.
  • This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, a lacquer solution and a suitable organic solvent or solvent mixture.
  • a suitable cellulose solution such as cellulose acetate phthalic acid or hydroxypropyl methylcellulose phthalic acid can be used.
  • a dye or pigment can be added to the coating of the tablet or tablet core. For example, a combination for identifying or for characterizing the dosage of an active ingredient.
  • Other orally available pharmaceutical preparations include pressure-bonded capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the pressure-bonded capsules may contain the active compound in the form of granules mixed with a filler such as lactose; a binder such as starch; and/or a lubricant such as talc or magnesium stearate, and a stabilizer.
  • the active compound is preferably dissolved or suspended in a suitable liquid such as a fat or liquid paraffin, to which a stabilizer may be added.
  • Formulations suitable for parenteral administration include aqueous solutions of the active compounds, such as solutions of aqueous salts and basic solutions.
  • an oily injection suspension of the appropriate active compound may be employed.
  • Suitable lipophilic solvents or vehicles include oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides or polyethylene glycol 400, or hydrogenated castor oil, or cyclodextrin.
  • Aqueous injection suspensions may contain materials which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, and/or dextran. Suspension stabilizers may also be included.
  • the compounds of the invention are formulated for topical and parenteral use and for the treatment of skin cancer.
  • the external preparation of the present invention can be prepared into an oil, a cream, an emulsion, an ointment or the like by a preferably suitable carrier.
  • suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular alcohols (greater than C 12).
  • Preferred carriers are those in which the active ingredient is soluble.
  • Emulsifiers, stabilizers, humectants and antioxidants, as well as agents which impart color or aroma if desired, may also be included.
  • these external preparations may contain a transdermal penetration enhancer. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.
  • the cream is preferably formulated with a mineral oil, a mixture of self-emulsifying beeswax and water, and mixed with an active ingredient dissolved in a small amount of oil such as almond oil.
  • a typical example of a cream includes about 40 parts water, 20 parts beeswax, 40 parts mineral oil and 1 part almond oil.
  • the ointment can be formulated by mixing a vegetable oil containing an active ingredient such as almond oil and warm soft paraffin, and then cooling the mixture.
  • An example of a typical ointment includes about 30% by weight almond oil and 70% by weight white soft paraffin.
  • the invention also relates to the use of a compound of the invention for the manufacture of a medicament for the treatment of a clinical condition which is effective in inhibiting Wee1 activity.
  • These drugs may include the above pharmaceutical compositions.
  • N-(2,6-difluorophenyl)-2-(2-methylthio-5-bromopyrimidin-4-yl)-4,5-dihydro-1H-imidazol-1-amine N-(2-(2-(2,6-difluorophenyl)indolyl)ethyl)-2-methylsulfanyl-5-bromopyrimidine-4-carboxamide (6.0 g, at room temperature 14.4 mmol) was dissolved in anhydrous dichloromethane (200 mL), and phosphorus pentachloride (9.0 g, 43.2 mmol) was added portionwise.
  • Example 3 The following compounds of Examples 3 to 25 were prepared in analogy to the synthesis of Example 2 described, starting from 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid, 2,2-di. Methoxyethyl-1-amine, 2,6-disubstituted benzoquinone, cuprous cyanide and the corresponding substituted aniline or substituted tetrahydroisoquinolinamine.
  • Example 26 The intermediate of Example 26 below was first prepared using a synthetic procedure analogous to that described in Example 2h.
  • the starting material was 2-methylthio-6-(2,6-dichlorophenyl)imidazole.
  • This intermediate was reacted with dioxane hydrochloride at room temperature to afford the desired compound of Example 26.
  • Examples 27-45 were prepared in analogy to the synthetic procedure described in Example 2, starting from 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid, 2,2-di. Methoxyethyl-1-amine, 2,6-disubstituted benzoquinone, cuprous cyanide and the corresponding substituted aniline or substituted tetrahydroisoquinolinamine.
  • Example 47-50 The following compounds of Examples 47-50 were prepared in analogy to the synthesis of Example 46g described, starting from 2-methylthio-6-(2-bromo-6-chlorophenyl)imidazo[ 1,2-b]pyrimido[4,5-d]pyridazin-5-(6H)-one and the corresponding substituted aniline.
  • Example 51-55 The following compounds of Examples 51-55 were prepared in analogy to the synthesis of Example 2 described, starting from 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid, 2,2-di. Methoxyethyl-1-amine, 2,6-disubstituted benzoquinone, cuprous cyanide and the corresponding substituted aniline.
  • 6-(2,6-Dichlorophenyl)-8-methyl-2-(methylthio)imidazo[1,2-b]pyrimido[4,5-d]pyridazine-5 (6H )-ketone: 4-(1-((2,6-dichlorophenyl)amino)-5-methyl-1H-imidazol-2-yl)-2-(methylthio)pyrimidine at room temperature -5-carbonitrile (130 mg, 0.33 mmol) was added to a dioxyl chloride solution (4M, 40 mL). After the reaction mixture was stirred at 80 ° C for 15 h, it was reduced to 50 ° C, and water (10 mL) was added.
  • Example 58 and 59 were prepared in a similar manner to the synthesis of Example 2h described, starting from 6-(2,6-dichlorophenyl)-9-methyl-2-(A Thio)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one and 3-chloro-4-(4-methylpiperazin-1-yl)aniline .
  • Example 61 The compound of the following Example 61 was obtained by a synthetic procedure similar to that described in Example 60d.
  • the starting material was 6-(2,6-dichlorophenyl)-9-ethyl-2-(methylthio) Imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one and 3-methyl-4-(4-(dimethylamino)piperidin-1-yl )aniline.
  • Examples 62 and 63 were prepared in a similar manner to the ones described in Examples 1a-f and Examples 60b-d, starting from (3-methyl-1-oxobutane-2 -yl)-tert-butyl carbamate, 2,6-dichlorophenylhydrazine, 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid and 3-methyl-4-(4-(dimethylamino) Piperidin-1-yl)aniline.
  • Wie1 kinase (human) was added to a reaction solution containing 20 mM Tris/HCl pH 8.5, 0.2 mM EDTA, 500 ⁇ M LSNLYHQGKFLQTFCG SPLYRRR, 10 mM magnesium acetate and 10 ⁇ M [ ⁇ - 33 P]-ATP, followed by 50-fold concentration.
  • the reaction was initiated by the addition of a Mg/ATP mixture and after incubation for 40 minutes at room temperature, the phosphoric acid solution was added to a final concentration of 0.5% to quench the reaction.
  • Table 1 summarizes the Wee1 kinase inhibition data (% inhibition rate) of the compounds.
  • LoVo cells were trypsinized, centrifuged at 800 rpm for 5 min, the supernatant was discarded, resuspended in fresh medium, counted, and seeded at a density of 6000 cells per well to a 96-well cell culture plate and placed in a 37 ° C 5% CO 2 incubator. Cultivate overnight.
  • test substance including the test compound and reference compound AZD1775 mother liquor was serially diluted to 8 concentrations in DMSO at a ratio of 1:3 and 1:10 (the last concentration was DMSO negative control): 10 ⁇ M, 3.3 ⁇ M, 1 ⁇ M , 0.33 ⁇ M, 0.1 ⁇ M, 0.033 ⁇ M, 0.01 ⁇ M, 0 ⁇ M (final concentration of DMSO 1 ⁇ ).
  • DMSO negative control 10 ⁇ M, 3.3 ⁇ M, 1 ⁇ M , 0.33 ⁇ M, 0.1 ⁇ M, 0.033 ⁇ M, 0.01 ⁇ M, 0 ⁇ M (final concentration of DMSO 1 ⁇ ).
  • Add 5 ⁇ L of each concentration to 120 ⁇ L of Petri (25-fold dilution) and mix by shaking.
  • the cells were cultured overnight, the medium was removed, 195 ⁇ L of fresh medium was added to each well, and 5 ⁇ L of the diluted medium containing the corresponding concentration of the test substance was added, respectively, and then the plate was placed in a 37 ° C 5% CO 2 incubator. 3d.
  • the stock solution was removed, and 100 ⁇ L of fresh serum-free DMEM containing MTT (0.5 mg/mL) was added to each well, and the culture was continued. After 4 h, the stock solution was removed, 100 ⁇ L of DMSO was added to each well, and shaken for 10 min in the dark, and placed in a multi-function reader to read the absorbance (OD value) at a wavelength of 552/630/690 nm.
  • the data was analyzed by the software Graph Pad Prism 5.0, and the inhibitory activity of the compound on cell proliferation was plotted in terms of cell viability and compound concentration.
  • Table 2 summarizes the data inhibition (IC 50) of compounds on the growth of LoVo cells.
  • Example 1 2 3 4 7 9 IC 50 ( ⁇ m) 0.5241 0.4055 0.2362 0.3394 0.8311 0.2130
  • Example 11 12 13 14 15 16 IC 50 ( ⁇ m) 0.2660 0.8177 0.4878 0.8708 0.8316 0.4245
  • Example 17 18 19 20 twenty one twenty two IC 50 ( ⁇ m) 0.9020 0.5788 0.4079 0.3636 0.2590 0.1378
  • Example twenty three twenty four 25 26 27
  • Example 29 30 31 32 33 34 IC 50 ( ⁇ m) 0.2722 0.7787 0.8093 0.6794 0.3943 0.2364
  • Example 35 36 37 38 41 43 IC 50 ( ⁇ m) 0.3020 0.2057 0.2906 0.4155 0.2122 0.4756
  • Example 44 45 46 47 48 49 IC 50 ( ⁇ m) 0.3709 0.3331 0.2423 0.3703 0.2268 0.2722
  • Example 50 51 52 53 54 55 IC 50 ( ⁇ m) 0.3235 0.9979 0.7562 0.6420 0.6368 0.5605
  • Example 56 57 58 59 60 61
  • Example 62 AZD1775 IC 50 ( ⁇ m) 0.6202 0.1545
  • 6-(2,6-dichlorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2] was determined by MTT assay.
  • -b]pyrimido[4,5-d]pyridazin-5(6H)-one (Example 1) and its analogs have a good inhibitory effect on LoVo cell growth.
  • NCI-H1299 cells were trypsinized, centrifuged at 800 rpm for 5 min, the supernatant was discarded, resuspended in fresh wells, counted, and seeded at a density of 1000 cells per well to 96-well cell culture plates at 37 ° C 5% CO 2 . The incubator was cultured overnight.
  • test substance including the test compound and reference compound AZD1775 mother liquor was serially diluted to 8 concentrations in DMSO at a ratio of 1:3 and 1:10 (the last concentration was DMSO negative control): 10 ⁇ M, 3.3 ⁇ M, 1 ⁇ M , 0.33 ⁇ M, 0.1 ⁇ M, 0.033 ⁇ M, 0.01 ⁇ M, 0 ⁇ M (final concentration of DMSO 1 ⁇ ).
  • DMSO negative control 10 ⁇ M, 3.3 ⁇ M, 1 ⁇ M , 0.33 ⁇ M, 0.1 ⁇ M, 0.033 ⁇ M, 0.01 ⁇ M, 0 ⁇ M (final concentration of DMSO 1 ⁇ ).
  • Add 5 ⁇ L of each concentration to 120 ⁇ L of Petri (25-fold dilution) and mix by shaking.
  • the cells were cultured overnight, the medium was removed, 195 ⁇ L of fresh medium was added to each well, and 5 ⁇ L of the diluted medium containing the corresponding concentration of the test substance was added, respectively, and then the plate was placed in a 37 ° C 5% CO 2 incubator. 3d.
  • the stock solution was removed, and 100 ⁇ L of fresh serum-free DMEM containing MTT (0.5 mg/mL) was added to each well, and the culture was continued. After 4 h, the stock solution was removed, 100 ⁇ L of DMSO was added to each well, and shaken for 10 min in the dark, and placed in a multi-function reader to read the absorbance (OD value) at a wavelength of 552/630/690 nm.
  • the data was analyzed by the software Graph Pad Prism 5.0, and the inhibitory activity of the compound on cell proliferation was plotted in terms of cell viability and compound concentration.
  • Table 3 summarizes the data inhibition (IC 50) for Compound NCI-H1299 cell growth.
  • Example 1 2 3 4 7 9 IC 50 ( ⁇ m) 0.9163 0.6516 0.1785 0.3831 0.7810 0.2836
  • Example 11 12 13 14 15 16 IC 50 ( ⁇ m) 0.5554 0.4449 0.7379 0.5868 0.9044 0.3646
  • Example 17 18 19 20 twenty one twenty two IC 50 ( ⁇ m) 0.8020 1.080 0.7434 0.5973 0.5113 0.3755 Example twenty three twenty four 25 26 27 28 IC 50 ( ⁇ m) 0.5282 0.3276 0.2493 0.2685 0.4696 0.2953 Example 29 30 31 32 33 34 IC 50 ( ⁇ m) 0.4002 0.5082 0.6724 0.5146 0.2368 0.2194 Example 35 36 37 38 41 43 IC 50 ( ⁇ m) 0.1818 0.1350 0.1866 0.9781 0.1844 0.1754 Example 44 45 46 47 48 49 IC 50 ( ⁇ m) 0.1642 0.2703 0.2713 0.5622 0.2806 0.3372 Example 50 51 52 53 54 55 IC 50 ( ⁇ m) 0.5006 1.217 0.8090 0.8088 0.4186 0.6626 Example 56 57 58 59 60 61 IC 50 ( ⁇ m) 0.5402 0.1732 0.1510 0.2201 0.1606 0.1260 Example 62 AZD1775 IC 50 ( ⁇ m) 0.1973 0.1165
  • 6-(2,6-dichlorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2] was determined by MTT assay.
  • -b]pyrimido[4,5-d]pyridazin-5(6H)-one (Example 1) and its analogs have a good inhibitory effect on NCI H1299 cell growth.

Abstract

本发明提供咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮类化合物。具体而言，本发明提供式I的化合物，或其可药用盐或前药： (I) 其中A，R1-R5为本文所定义。式I的化合物是Wee1激酶抑制剂。因此，本发明的化合物可用于治疗由 Weel 活性异常而导致的疾病。

Description

咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮类化合物及其应用 技术领域
本发明属于药物化学领域，涉及咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮类化合物及其应用。
背景技术
真核细胞的生长、增殖的过程包括母细胞通过准确复制其包括遗传信息的基因组，通过细胞染色体的有丝***产生两个相同的子细胞。这种细胞的增殖、***过程被称为细胞周期(cell cycle)，这包括了细胞从一次***完成开始，到下一次***完成的整个过程。细胞周期包括四个生长阶段，有丝***后的蛋白质，RNA等大量合成的G1期，DNA合成复制的S期，有丝***前的准备阶段G2期和细胞进行有丝***的M期。细胞根据细胞状况和需要决定通过细胞周期进行***增殖，或停止。细胞增殖，***必须保持其遗传信息的完整和正确。是否进入细胞周期的下一阶段直至完成整个细胞周期是通过在细胞周期过程中的多个检验点(checkpoint)来保障并完成的。
在细胞周期的整个过程中有多个细胞周期检验点(cell cycle checkpoint)存在。每个细胞周期检验点都包括非常复杂的***和由多个因子组成。在G1期内的检验点通过检验细胞内外的状态来决定是否进入细胞周期，从而决定细胞是否进入S期DNA合成。G1检验点是个复杂的***，其中包括著名的CDK4/CDK6。另一个重要的检验点在细胞完成了DNA复制(S期)进入细胞生长期(G2期)，即所谓的G2-M检验点。这个检验点检验细胞合成DNA后是否有DNA损伤或缺损，从而决定细胞是否进行下面染色体分离的有丝***(M期)。这一阶段的细胞周期检验点包括了复杂的激酶Cdk1复合体包括Cyclin-B-cdc2(Nurse,P.,1990,Nature 344,503-508)。Cdk1的活化导致有丝***的起始，其随后的失活伴随着有丝***的完成。Cdk1的活性是通过cdc2结合细胞周期蛋白A(Cyclin-A)或细胞周期蛋白B(Cyclin-B)以及其磷酸化来调节的。比如，细胞周期蛋白B-Cdk1复合物的激活能使细胞有丝***(Lindqvist,A.等人,2009,The Journal of cell biology 185,193-202)。Cdc2在细胞进入有丝***前通过磷酸化维持在无活性的状态。其磷酸化状态是通过络氨酸激酶Wee1等来实现的。另外，还有M期细胞周期检验点。
Wee1磷酸化Cdk1上的酪氨酸15(Y15)从而抑制Cdk1的活性(McGowan,C.H.等人,1993,The EMBO journal 12,75-85；Parker,L.L.等人,1992,Science 257,1955-1957)。因此，Wee1是Cdk1活性的关键抑制性调节剂，在G2-M期检测点起重要作用，保证当DNA复制完成后在DNA没有损伤的情况下进入有丝***(O’Connell等人,1997,The EMBO journal 16,545-554)。Wee1的丧失或失活可以导致过早进入有丝***，引起有丝***的失败和细胞死亡(Stumpff,J.等人,2004,Curr Biol 14,2143-2148)。一些肿瘤细胞的G1期细胞周期检验点有功能缺陷，依赖G2-M期检测点来保障细胞周期的进行(Sancar,A.等人,2004,Annual review of biochemistry 73,39-85)。在这些癌细胞中由于p53蛋白功能的缺失，丧失Wee1表达或抑制Wee1的活性会导致G2-M期检验点的丧失，使肿瘤细胞对DNA损伤非常敏感，这个敏感化在丧失G1期检验点能力的肿瘤细胞中尤其突出(Wang,Y.等人,2004,Cancer biology&therapy 3,305-313)。
综上所述，抑制Wee1的活性可以选择性促使细胞周期检验点有缺陷的癌细胞死亡；同时，对细胞周期检验点正常的正常细胞则作用甚小。因此，Wee1的抑制剂有可能用于癌症及其它细胞增殖病症的治疗的靶向药物。
另外，由于抑制Wee1活性使细胞对DNA损伤的敏感度提高，Wee1抑制剂可以和造成DNA损伤或抑制DNA修复机制有关的抗癌药物联合使用，这包括和PARP抑制剂奥拉帕尼(olaparib)、Niraparib、Rucaparib和Talazoparib；HDAC抑制剂伏立诺他、罗咪地辛、帕比司他和贝利司他等等用于治疗癌症或其它细胞增殖病症。Wee1抑制剂还可能和其他与细胞***细胞周期检测点有关的抗癌药物的联合共用，包括Chk1/2抑制剂，CDK4/6抑制剂如帕博西尼，ATM/ATR抑制剂等等用于治疗癌症等病症。
Karnak等人(Clin Cancer Res,2014,20(9):5085-5096)的研究表明Wee1抑制剂AZD1775和PARP抑制剂olaparib联合使用可对放射治疗胰腺癌增敏。其结果证实了Wee1抑制剂和PARP抑制剂联合使用治疗胰腺癌可增敏放射疗效，支持了Wee1抑制使细胞对PARP抑制剂增敏的假设—通过抑制DNA修复和G2检验点功能对辐射治疗增敏，最终可导致未修复的损伤的DNA的积累直至细胞死亡。
另外，有报道(BMC Cancer,2015,15:462)将Wee1抑制剂MK1775和Chk1/2抑制剂AZD7762联合使用用于恶性黑素瘤细胞和异种移植模型中。结果显示，Wee1和Chk1/2抑制剂的联合使用可协同单一药物的抑制效果，从而降低肿瘤细胞的增殖能力及激活了细胞凋亡机制；在异种移植模型中二者的联合使用可更好地抑制肿瘤生长。
AZD1775是第一个在临床前模型中具有单药抗肿瘤活性的Wee1激酶抑制剂。I期临床研究显示出AZD1775对携带BRCA突变的实体瘤患者的单药疗效，并通过 配对肿瘤活检发现跟靶向有关的变化和DNA损伤应答证实了其Wee1激酶抑制机制(J Clin Oncol,2015,33:3409-3415)。在AZD1775总共入组200多名患者的一个临床I期中，研究了其在治疗晚期实体瘤患者的单药疗效和与吉西他滨、顺铂或卡铂联用的疗效，显示了其在一定的剂量下不管是单药还是与化药联用都是安全且可耐受的。在176例可评估疗效的患者中，94(53％)具有作为最佳应答的稳定疾病，以及17(10％)有部分应答。重要的是，AZD1775在TP53突变患者(n＝19)的应答率为21％，而在TP53野生型患者(n＝33)的应答率为12％，展现出其对TP53突变患者的巨大潜力(J Clin Oncol,2016Sep 6,pii:JCO675991)。
WO2012161812公开了以下三环化合物作为Wee1激酶抑制剂。其中，X是N或CR 1；Y是N或CR 2；Z是O、S或NH；R 1和R 2是H或C 1-6烷基；R 3是C 1-8烷基，C 2-8烯基，C 3-8环烷基，芳基，或杂芳基等；R 4是苯基，萘基，四氢萘基，茚基或茚满基，或5－16元单环、双环或三环杂环基等。
Figure PCTCN2018095080-appb-000001
WO2005021551公开了以下四环嘧啶或吡啶化合物作为蛋白激酶抑制剂。其中，X是N或CH；Y是NH，N(CN)，O或S；L是由C和N原子组成的4-原子链；R a是H，C 1-8烷基，CN，苯基或苄基；R 1和R 2独立是可被取代的饱和或不饱和的5-，6-，或7-元单环，或6-，7-，8-，9-，10-或11-元双环(包含0，1，2，3或4个选自N，O和S的原子，其中O和S原子不同时存在，环中的C原子被0，1或2个氧基取代)等。
Figure PCTCN2018095080-appb-000002
发明内容
如结构式I、II和III所示，本发明提供了新颖的咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮类化合物作为激酶抑制剂，特别是Wee1激酶抑制剂。
本发明还提供了包含一个有效量的式I、II和III化合物的药用组合物，用来治疗癌症。
在一具体实施例中，所述药用组合物还可含有一种或多种可药用载体或稀释剂，用来治疗癌症。
在一具体实施例中，所述药用组合物还可含有至少一种已知的抗癌药物或所述抗癌药物的可药用盐，用来治疗癌症。
本发明也涉及到结构式I、II和III的新颖化合物的制备方法。
具体实施方式
如式I、II和III所示，本发明发现新颖的咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮化合物作为激酶抑制剂，特别是Wee1激酶抑制剂。
应理解的是，本文所述的各实施方案的特征可任意组合，形成本文的技术方案；本文对各基团的定义适用于本文所述任一实施方案，例如，本文对烷基的取代基的定义适用于本文所述任一实施方案，除非该实施方案已清楚定义了烷基的取代基。
具体来说，可用于本发明的化合物是式I化合物或其可药用盐或前药：
Figure PCTCN2018095080-appb-000003
其中，A是N或CR 6；
R 1为氢，可被取代的C 1-C 8烷基，可被取代的C 2-C 8烯基，可被取代的C 3-C 8环烷基，可被取代的芳基，可被取代的杂环基或可被取代的杂芳基；
R 2为可被取代的碳环基，可被取代的杂环基，可被取代的芳基，或可被取代的杂芳基；
R 3-R 6独立为氢、卤素、可被取代的氨基、可被取代的烷氧基、可被取代的C 1-C 10烷基(如卤烷基、羟基烷基、氨基烷基和羧基烷基)、烯基、炔基、硝基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、羧基、亚乙基二氧基、羟基酰氨基或可被取代的烷硫基。
在一个或多个实施方案中，A是N。
在式I的前述各实施方案中，R 1和R 2分别为可被取代的芳基。
在式I的前述各实施方案中，R 3为氢。
在式I的前述各实施方案中，R 4和R 5为氢和可被取代的C 1-C 6烷基。
在式I的前述各实施方案中，R 4为氢或未被取代的C 1-C 6烷基。
在式I的前述各实施方案中，R 5为氢或任选被羟基取代的C 1-C 6烷基，如羟基C 1-C 6烷基。
在式I的前述各实施方案中，R 6为氢。
在式I的前述各实施方案中，R 1上的取代基选自以下基团中的任意一个、任意两个、任意三个或任意四个：卤素、C 1-C 6烷基、C 1-C 6烷氧基和卤代C 1-C 6烷基。
在式I的前述各实施方案中，R 1选自C 2-C 8烯基和任选地被1－4个选自卤素和C 1-C 6烷基的取代基取代的苯基。
在式I的前述各实施方案中，R 1选自任选地被1－4个选自卤素和C 1-C 6烷基的取代基取代的苯基；在某些实施方案中，取代基的数量为2个；在某些实施方案中，至少一个取代基位于邻位；在某些实施方案中，至少一个取代基为卤素；在某些实施方案中，该苯基上的取代基为2个，两个都位于邻位，且其中至少一个为卤素。
在式I的前述各实施方案中，R 1选自可被取代的C 2-C 8烯基。
在式I的前述各实施方案中，R 2的取代基选自以下基团中的任意一个、任意两个、任意三个或任意四个：可被取代的C 1-C 6烷基、可被取代的氧基、卤素和可被取代的杂环基；优选地，这些可被取代的基团上的取代基可以是1－4个选自以下的基团：C 1-C 6烷基和-NR aR b，其中，R a和R b各自独立为H和C 1-C 6烷基；优选地，所述杂环基选自哌嗪基和哌啶基。
在式I的前述各实施方案中，R 2的取代基为选自以下基团中的任意一个、任意两个、任意三个或任意四个：可被取代的哌嗪基、可被取代的哌啶基、C 1-C 6烷基、卤素和C 1-C 6烷氧基；优选地，所述可被取代的基团上的取代基可以是1－4个选自以下的基团：C 1-C 6烷基和-NR aR b，其中，R a和R b各自独立为H和C 1-C 6烷基。
在式I的前述各实施方案中，所述可被取代的哌嗪基为可被1、2或3个选自以下的基团取代的哌嗪基：C 1-C 6烷基。
在式I的前述各实施方案中，所述哌嗪基至少在对位上具有1个取代基，任选地在间位上具有一个或两个取代基。
在式I的前述各实施方案中，所述可被取代的哌啶基为可被1个选自C 1-C 6烷基和-NR aR b的基团取代的哌啶基，其中，R a和R b各自独立为H和C 1-C 6烷基。
在式I的前述各实施方案中，R 2选自任选取代的苯基和任选取代的四氢异喹啉基。
在式I的前述各实施方案中，R 2选自：被任选取代的哌嗪基取代的苯基，被任选取代的哌啶基取代的苯基和任选被1－3个C 1-C 6烷基取代的四氢异喹啉基。
在式I的前述各实施方案中，所述哌嗪基任选地被1－3个选自C 1-C 6烷基的取代基取代。
在式I的前述各实施方案中，所述哌啶基任选地被1个选自C 1-C 6烷基和-NR aR b的取代基取代，其中，R a和R b各自独立为H和C 1-C 6烷基。
在式I的前述各实施方案中，R 4和R 5各自独立选自H和可被取代的C 1-C 6烷基。优选地，R 4和R 5为H和可被取代的C 1-C 6烷。
本发明式I优选化合物的其中一组表示为式II化合物或其可药用盐或前药：
Figure PCTCN2018095080-appb-000004
其中，R 3-R 5如在式I中所述；
Ar 1和Ar 2各自独立为可被取代的芳基、可被取代的杂环基或可被取代的杂芳基；
在式II的一个或多个实施方案中，R 3为氢。
在式II的前述各实施方案中，R 4和R 5为氢和可被取代的C 1-C 6烷基。
在式II的前述各实施方案中，Ar 1和Ar 2各自独立为可被取代的芳基、可被取代的杂环基或可被取代的杂芳基；优选的，Ar 1和Ar 2各自独立为可被取代的芳基，更优选的是可被取代的苯基。
在式II的前述各实施方案中，Ar 1上的取代基为选自以下基团中的任意一个、任意两个、任意三个或任意四个：卤素和C 1-C 6烷基；在某些实施方案中，取代基的数量为2个；在某些实施方案中，至少一个取代基位于邻位；在某些实施方案中，至少一个取代基为卤素；在某些实施方案中，该苯基上的取代基为2个，两个都位于邻位，且其中至少一个为卤素。
在式II的前述各实施方案中，Ar 1选自任选地被1－4个选自卤素和C 1-C 6烷基的取代基取代的苯基。
在式II的前述各实施方案中，Ar 2的取代基为选自以下基团中的任意一个、任意两个、任意三个或任意四个：可被取代C 1-C 6烷基、可被取代的氧基、卤素和可被取代的杂环基。优选地，这些可被取代的基团上的取代基可以是1－4个选自以下的基团：C 1-C 6烷基和-NR aR b，其中，R a和R b各自独立为H和C 1-C 6烷基；优选地，所述杂环基选自哌嗪基和哌啶基。
在式II的前述各实施方案中，Ar 2的取代基为选自以下基团中的任意一个、任意两个、任意三个或任意四个：可被取代的哌嗪基、可被取代的哌啶基、C 1-C 6烷基、卤素和C 1-C 6烷氧基；优选地，所述可被取代的基团上的取代基可以是1－4个选自以下的基团：C 1-C 6烷基和-NR aR b，其中，R a和R b各自独立为H和C 1-C 6烷基。
在式II的前述各实施方案中，所述可被取代的哌嗪基为可被1、2或3个选自以下的基团取代的哌嗪基：C 1-C 6烷基。
在式II的前述各实施方案中，所述哌嗪基至少在对位上具有1个取代基，任选地在间位上具有一个或两个取代基。
在式II的前述各实施方案中，所述可被取代的哌啶基为可被1个选自C 1-C 6烷基和-NR aR b的基团取代的哌啶基，其中，R a和R b各自独立为H和C 1-C 6烷基。
在式II的前述各实施方案中，Ar 2选自任选取代的苯基和任选取代的四氢异喹啉基。
在式II的前述各实施方案中，Ar 2选自：被任选取代的哌嗪基取代的苯基，被任选取代的哌啶基取代的苯基和任选被1－3个C 1-C 6烷基取代的四氢异喹啉基。
在式II的前述各实施方案中，所述哌嗪基任选地被1－3个选自C 1-C 6烷基的取代基取代。
在式II的前述各实施方案中，所述哌啶基任选地被1个选自C 1-C 6烷基和-NR aR b的取代基取代，其中，R a和R b各自独立为H和C 1-C 6烷基。
在式II的前述各实施方案中，R 4和R 5各自独立选自H和可被取代的C 1-C 6烷基；优选地，R 4和R 5为H和可被取代的C 1-C 6烷。
在前述各实施方案中，R 1或Ar 1选自：
Figure PCTCN2018095080-appb-000005
在前述各实施方案中，R 2或Ar 2选自：
Figure PCTCN2018095080-appb-000006
Figure PCTCN2018095080-appb-000007
在前述各实施方案中，R 1或Ar 1选自以下任一基团：
Figure PCTCN2018095080-appb-000008
R 2或Ar 2选自以下任一基团：
Figure PCTCN2018095080-appb-000009
Figure PCTCN2018095080-appb-000010
在前述各实施方案中，式II的化合物具有下式III所示的结构：
Figure PCTCN2018095080-appb-000011
式中，
Ar 1选自：被1个或2个选自卤素和C 1-C 6烷基的取代基取代的苯基；和
Ar 2选自：取代的苯基，其取代基选自：卤素、C 1-C 6烷基和C 1-C 6烷氧基；任选被1－3个选自C 1-C 6烷基的取代基取代的哌嗪基；任选被1个选自C 1-C 6烷基和-NR aR b的取代基取代的哌啶基；和被1－3个C 1-C 6烷基取代的四氢异喹啉基；其中，R a和R b各自独立为H或C 1-C 6烷基。
在一个或多个实施方案中，式III中，
Ar 1选自：被两个选自卤素和C 1-C 6烷基的取代基取代的苯基；和
Ar 2选自：取代的苯基，其取代基选自：卤素、C 1-C 6烷基和C 1-C 6烷氧基；任选被1－3个选自C 1-C 6烷基的取代基取代的哌嗪基；任选被1个选自C 1-C 6烷基和-NR aR b的取代基取代的哌啶基；和任选被1－3个C 1-C 6烷基取代的四氢异喹啉基。其中，R a和R b各自独立为H或C 1-C 6烷基。
在一个或多个实施方案中，式III中，Ar 1为两个间位分别被选自卤素和C 1-C 3烷基的取代基取代的二取代苯基，优选地，两个取代基中至少一个为卤素；Ar 2为：被1、2或3个选自卤素、C 1-C 6烷基和C 1-C 6烷氧基的取代基取代的苯基，任选被1－3个选自C 1-C 6烷基的取代基取代的哌嗪基，任选被1个选自C 1-C 6烷基和-NR aR b的取代基取代的哌啶基；和任选被1－3个选自C 1-C 6烷基的取代基取代的四氢异喹啉基；其中，R a和R b独自选自H和C 1-C 4烷基。
在式III的前述各实施方案中，
Ar 1优选为以下任一基团：
Figure PCTCN2018095080-appb-000012
Ar 2优选为以下任一基团：
Figure PCTCN2018095080-appb-000013
在前述各实施方案中，本发明式I、式II和式III的优选化合物包括但不限于：
6-(2,6-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例1)；
6-(2,6-二氟苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例2)；
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例3)；
6-(2,6-二氯苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例4)；
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例5)；
6-(2,6-二氯苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例6)；
6-(2-氯-6-氟苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例7)；
6-(2-氯-6-氟苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例8)；
6-(2-氯-6-氟苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例9)；
6-(2-氯-6-氟苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例10)；
6-(2-氯-6-氟苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例11)；
6-(2-氯-6-氟苯基)-2-((2,4,4-三甲基-1,2,3,4-四氢异喹啉-7-基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例12)；
6-(2,6-二氟苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例13)；
6-(2-氟-6-甲基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例14)；
6-(2-氟-6-甲基苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例15)；
6-(2-氯-6-甲基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例16)；
6-(2-氯-6-甲基苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例17)；
6-(2,6-二氟苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例18)；
6-(2,6-二氟苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例19)；
6-(2,6-二氟苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例20)；
6-(2-氯-6-氟苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例21)；
6-(2-氯-6-氟苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例22)；
6-(2-氯-6-氟苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例23)；
6-(2-氯-6-氟苯基)-2-((3-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例24)；
6-(2-氯-6-氟苯基)-2-((3-氟-5-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例25)；
6-(2,6-二氯苯基)-2-((3-甲基-4-(哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例26)；
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例27)；
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例28)；
6-(2,6-二氯苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例29)；
6-(2,6-二氯苯基)-2-((4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例30)；
6-(2,6-二氯苯基)-2-((3-氟-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例31)；
6-(2,6-二氯苯基)-2-((3-氯-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例32)；
6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例33)；
6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-4-异丙基-3,5-二甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例34)；
6-(2,6-二氯苯基)-2-((3-氯-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例35)；
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例36)；
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例37)；
6-(2,6-二氯苯基)-2-((3-氯-5-甲氧基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例38)；
6-(2,6-二氯苯基)-2-((3-氟-4-(1-甲基哌啶-4-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例39)；
6-(2,6-二氯苯基)-2-((3-氯-4-(1-甲基哌啶-4-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例40)；
6-(2,6-二氯苯基)-2-((3-甲基-4-(1-甲基哌啶-4-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例41)；
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(1-甲基哌啶-4-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例42)；
6-(2,6-二氯苯基)-2-((2,4,4,5-四甲基-1,2,3,4-四氢异喹啉-7-基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例43)；
6-(2,6-二氯苯基)-2-((2,5-二甲基-1,2,3,4-四氢异喹啉-7-基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例44)；
6-(2-溴-6-氟苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例45)；
6-(2-溴-6-氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例46)；
6-(2-溴-6-氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例47)；
6-(2-溴-6-氯苯基)-2-((3-氯-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例48)；
6-(2-溴-6-氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例49)；
6-(2-溴-6-氯苯基)-2-((3-氟-5-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例50)；
6-(2-氟-6-甲基苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例51)；
6-(2-氟-6-甲基苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例52)；
6-(2-氯-6-甲基苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例53)；
6-(2-氯-6-甲基苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例54)；
6-(2-氯-6-甲基苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例55)；
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例56)；
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-9-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例57)；
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-9-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例58)；
6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-9-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例59)；
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-9-乙基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例60)；
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-9-乙基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例61)；
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-9-异丙基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例62)；
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-9-(羟基甲基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例63)；
6-烯丙基-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例64)；
或其可药用盐或前药。
本文所用“烷基”是指烷基本身或是直链或支链高达十个碳原子的基团。有用的烷基包括直链或支链C 1-C 10烷基，优选C 1-C 6烷基。在某些实施方案中，烷基为C 1-C 4烷基。典型的C 1-C 10烷基包括可被任意取代的甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、3-戊基、己基和辛基。
本文所用“烯基”是指直链或支链含有2－10个碳原子，除非碳链长度被另外限制，其中至少是链中的两个碳原子之间含有一个双键的基团；优选C 2-C 6烯基。典型的链烯基包括乙烯基、1-丙烯基、2-丙烯基、2-甲基-1-丙烯基、1-丁烯基和2-丁烯基。
本文所用“炔基”是指直链或支链含有2－10个碳原子，除非碳链长度被另外限制，其中至少是链中的两个碳原子之间含有一个叁键的基团；优选C 2-C 6炔基。典型的炔基包括乙炔基、1-丙炔基、1-甲基-2-丙炔基、2-丙炔基、1-丁炔基和2-丁炔基。
有用的烷氧基包括被上述C 1-C 10烷基、优选C 1-C 6烷基取代的氧基，例如甲氧基、乙氧基等。烷氧基中的烷基可被任意取代。烷氧基的取代基包括但不限于卤素、吗啉基、氨基，所述氨基包括烷氨基和二烷氨基以及羧基(包括其酯基)。
有用的烷硫基包括被上述C 1-C 10烷基、优选C 1-C 6烷基取代的硫基，烷硫基中的烷基可被任意取代。同时还包括这类烷硫基的亚砜和砜。
有用的氨基和可被任意取代的氨基包括-NH 2、-NHR’和-NR’R”，其中R’和R”是可被任意取代的C 1-C 10烷基，环烷基，芳基，杂芳基或氨基。或者R’和R”与N一起形成5－8员杂环例如哌啶，或者R’和R”与N以及与其它N或O一起形成5－8员杂环例如哌嗪。所述烷基和杂环可被任意取代。
本文中，除非另有说明，当被取代时，烷基、烷氧基、烷硫基、烯基、炔基、环烷基、羰基、碳环和杂环、芳基、芳基烷基、芳基链烯基、芳基炔基、杂芳基和杂芳基烷基可被一个或多个(例如1、2、3或4个)选自以下基团的取代基取代：卤素、羟基、羧基、氨基、硝基、氰基、C 1-C 6酰氨基、C 1-C 6酰氧基、C 1-C 6烷氧基、芳氧基、烷硫基、C 1-C 6烷基、C 1-C 6酰基、C 6-C 10芳基、C 3-C 8环烷基、C 2-C 6链烯基、C 2-C 6炔基、C 6-C 10芳基(C 2-C 6)链烯基、C 6-C 10芳基(C 2-C 6)炔基、饱和和不饱和的杂环基或杂芳基、亚甲基二氧基、C 1-C 6卤代烷基、C 6-C 10芳基(C 1-C 6)烷基、C 1-C 6羟烷基、脲基、巯基、叠氮基、羰基、二(C 1-C 10烷基)氨基、烷磺酰基、氨磺酰基、二烷基氨磺酰基和烷基亚磺酰基等。其中取代基本身也可被任意取代。
除非另有说明，当被取代时，优选地，烷基、烷氧基、烷硫基、烯基、炔基、环烷基、羰基、碳环和杂环可被一个或多个(例如1、2、3或4个)选自以下基团的取代基取代：卤素、羟基、羧基、氨基、硝基、氰基、C 1-C 6酰氨基、C 1-C 6酰基、C 1-C 6酰氧基、C 1-C 6烷氧基、芳氧基、烷硫基、C 6-C 10芳基、C 3-C 8环烷基、C 2-C 6链烯基、C 2-C 6炔基、C 6-C 10芳基(C 2-C 6)链烯基、C 6-C 10芳基(C 2-C 6)炔基、饱和和不饱和的杂环基或杂芳基。
除非另有说明，当被取代时，芳基、芳基烷基、芳基链烯基、芳基炔基、杂芳基和杂芳基烷基可被一个或多个(例如1、2、3或4个)选自以下基团的取代基取代：卤素、亚甲基二氧基、C 1-C 6卤代烷基、C 6-C 10芳基、C 3-C 8环烷基、C 1-C 6烷基、 C 2-C 6链烯基、C 2-C 6炔基、C 6-C 10芳基(C 1-C 6)烷基、C 6-C 10芳基(C 2-C 6)链烯基、C 6-C 10芳基(C 2-C 6)炔基、C 1-C 6羟基烷基、硝基、氨基、脲基、氰基、C 1-C 6酰基氨基、羟基、巯基、C 1-C 6酰氧基、叠氮基、C 1-C 6烷氧基、羰基、羧基、二(C 1-C 10烷基)氨基、烷基磺酰基、氨基磺酰基、二烷基氨基磺酰基或烷基亚磺酰基。
应理解的是，本文各实施方案中，当取代基为杂环基、芳基或杂芳基时，该杂环基、芳基或杂芳基取代基的数量通常为1个。
本文所用“芳基”是指芳基本身或是作为其它基团的一部分，指含有6到14个碳原子的单环、双环或三环芳族基团。
有用的芳基包括C 6-C 14芳基，优选的是C 6-C 10芳基。典型的C 6-C 14芳基包括苯基、萘基、菲基、蒽基、茚基、薁基、联苯、亚联苯基和茀基。
这里所指“碳环”包括环烷基和部分饱和的碳环基团。有用的环烷基是C 3-C 8环烷基。典型的环烷基包括环丙基、环丁基、环戊基、环己基和环庚基。
有用的饱和的或是部分饱和的碳环基团是上面所描述的环烷基和环烯基，例如环戊烯基、环庚烯基和环辛烯基。
有用的卤素或卤素基团包括氟、氯、溴和碘。
本文所用“芳基烷基”包括被任一上述C 6-C 14芳基取代的C 1-C 10烷基。优选的芳基烷基是苄基、苯乙基或萘甲基。
本文所用“芳基烯基”包括被任一上述C 6-C 14芳基取代的C 2-C 10烯基。
本文所用“芳基炔基”包括被任一上述C 6-C 14芳基取代的C 2-C 10炔基。
本文所用“芳氧基”包括被任一上述C 6-C 14芳基取代的氧基，其芳基可被任意取代。有用的芳氧基包括苯氧基和4-甲基苯氧基。
本文所用“芳基烷氧基”包括被任一上述芳基取代的C 1-C 10烷氧基，其芳基可被任意取代。有用的芳基烷氧基包括苄氧基和苯基乙氧基。
有用的卤代烷基包括被一个或多个氟、氯、溴或碘原子取代的C 1-C 10烷基，优选C 1-C 6烷基，例如氟甲基、二氟甲基、三氟甲基、五氟乙基、1,1-二氟乙基、氯甲基、氯氟甲基和三氯甲基。
有用的酰基氨基(酰氨基)是连接在氨基氮上的任何C 1-C 6酰基(烷酰基)，例如乙酰氨基、氯乙酰氨基、丙酰氨基、丁酰氨基、戊酰氨基和己酰氨基，以及芳基取代的C 1-C 6酰基氨基，例如苯甲酰氨基和五氟苯甲酰氨基。有用的酰基包括C 1-C 6酰基，如乙酰基。
有用的酰氧基是连接在氧(-O-)上的任何C 1-C 6酰基(烷酰基)，例如甲酰氧基、乙酰氧基、丙酰氧基、丁酰氧基、戊酰氧基和己酰氧基。
本文所用杂环(杂环基)是指饱和或部分饱和的3－7员单环，或7－10员双环体系，它是由碳原子和从O、N、S中任选1－4个杂原子组成的，其中杂原子氮和硫都可以被任意氧化，氮也可以任意季铵化，并且包括双环体系中上述定义的任意杂环与苯环的融合。如果产生的化合物是稳定的话，那么杂环的碳原子或氮原子可被取代。
有用的饱和或部分饱和杂环基团包括四氢呋喃基、吡喃基、哌啶基、哌嗪基、吡咯烷基、咪唑烷基、咪唑啉基、二氢吲哚基、异二氢吲哚基、奎宁环基、吗啉基、异色满基、色满基、吡唑烷基、吡唑啉基、四氢异喹啉基、tetronoyl和tetramoyl，这些基团可被任意取代。
本文所用“杂芳环”是指含有5－14个环原子，并且有6个，10个或14个π电子在环体系上共用。而且所含环原子是碳原子和从氧、氮、硫中任选的1－3个杂原子。
有用的杂芳基包括噻吩基(苯硫基)、苯并[d]异噻唑-3-基、苯并[b]噻吩基、萘并[2,3-b]噻吩基、噻蒽基、呋喃基、吡喃基、异苯并呋喃基、色烯基、夹氧蒽基、噻吩恶基(phenoxanthiinyl)、吡咯基、咪唑基、吡唑基、吡啶基(包括但不限制于2-吡啶基、3-吡啶基和4-吡啶基)、吡嗪基、嘧啶基、哒嗪基、吲嗪基、异吲哚基、3H-吲哚基、吲哚基、吲唑基、嘌呤基、4H-喹嗪基、异喹啉基、喹啉基、酞嗪基、萘啶基、喹唑啉基、噌啉基、蝶啶基、咔唑基、β-咔啉基、菲啶基、吖啶基、萘嵌间二氮(杂)苯基、菲咯啉基、吩嗪基、异噻唑基、吩噻嗪基、异恶唑基、呋咱基、吩恶嗪基、1,4-二氢喹喔啉-2,3-二酮、7-氨基异香豆素、吡啶并[1,2-a]嘧啶-4-酮、四氢化五员[c]吡唑-3-基、吡唑[1,5-a]嘧啶基、苯并异恶唑基如1,2-苯并异恶唑-3-基、苯并咪唑基、2-羟吲哚基、噻重氮基和2-氧代苯并咪唑基。当杂芳基在环中含有氮原子时，这样的氮原子可以呈N-氧化物形式，例如吡啶基N-氧化物、吡嗪基N-氧化物和嘧啶基N-氧化物。
本文所用“杂芳氧基”包括被任一上述杂芳基取代的氧基，其中杂芳基上可有取代基。有用的杂芳氧基包括吡啶氧基、吡嗪氧基、吡咯氧基、吡唑氧基、咪唑氧基和苯硫基氧基。
本文所用“杂芳基烷氧基”是指被任一上述杂芳基取代的任一上述C 1-C 10烷氧基，其中杂芳基上可有取代基。
一些本发明化合物可能作为立体异构体，包括旋光异构体存在。本发明包括所有立体异构体和这样的立体异构体的外消旋混合物，以及可以根据本领域技术人员众所周知的方法分离出来的单独的对映体。
可药用盐的例子包括无机和有机酸盐，例如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐和草酸盐；以及与碱例如钠羟基、三(羟基甲基)氨基甲烷(TRIS，氨丁三醇)和N-甲基葡糖胺形成的无机和有机碱盐。
本发明化合物的前药的实施例包括含有羧酸的化合物的简单酯(例如依据本领域已知方法通过与C 1-C 4醇缩合而获得的酯)；含有羟基的化合物的酯(例如依据本领域已知方法通过与C 1-C 4羧酸、C 3-C 6二酸或其酸酐例如琥珀酸酐和富马酸酐缩合而获得的酯)；含有氨基的化合物的亚胺(例如依据本领域已知方法通过与C 1-C 4醛或酮缩合而获得的亚胺)；含有氨基的化合物的氨基甲酸酯，例如Leu等人(J.Med.Chem.42:3623-3628(1999))和Greenwald等人(J.Med.Chem.42:3657-3667(1999))描述的那些酯；含有醇的化合物的醛缩醇或酮缩醇(例如依据本领域已知方法通过与氯甲基甲基醚或氯甲基乙基醚缩合而获得的那些缩醇)。
本发明化合物可使用本领域技术人员已知的方法或本发明新方法制得。具体来说，具有式Ⅰ的本发明化合物可如反应方案1中的反应实施例所示制得。N-叔丁氧羰基-2-氨基乙醛、2,6-二氯苯肼和三乙酰氧基硼氢化钠在二氯甲烷中在室温下反应，然后加入氰基硼氢化钠，在室温下继续反应，得到产物(2-(2-(2,6-二氯苯基)肼基)乙基)氨基甲酸叔丁酯。该氨基甲酸叔丁酯、二异丙基乙胺和氯甲酸苄酯在二氯甲烷中，在室温下反应，得到产物1-(2-(叔丁氧羰基氨基)乙基)-2-(2,6-二氯苯基)肼甲酸苄酯。该肼甲酸苄酯溶于盐酸二氧六环溶液中，在室温下反应，得到产物1-(2-氨基乙基)-2-(2,6-二氯苯基)肼甲酸苄酯盐酸盐。该肼甲酸苄酯盐酸盐、二异丙基乙胺和5-溴-2-(甲硫基)嘧啶-4-甲酰氯的二氯甲烷溶液在N,N-二甲基甲酰胺中，在0℃下反应，得到产物1-(2-(2-甲硫基-5-溴嘧啶-4-甲酰氨基)乙基)-2-(2,6-二氯苯基)肼甲酸苄酯。该肼甲酸苄酯溶于三氟乙酸中加热反应，得到产物2-甲硫基-5-溴-N-(2-(2-(2,6-二氯苯基)肼基)乙基)-嘧啶-4-甲酰胺。该甲酰胺和五氯化磷在二氯甲烷中，在室温下反应，得到产物2-(2-甲硫基-5-溴嘧啶-4-基)-N-(2,6-二氯苯基)-4,5-二氢-1H-咪唑-1-胺。该4,5-二氢-1H-咪唑-1-胺和氰化亚铜在N,N-二甲基甲酰胺中加热反应，得到产物2-(2-甲硫基-5-氰基嘧啶-4-基)-N-(2,6-二氯苯基)-1H-咪唑-1-胺。该1H-咪唑-1-胺在盐酸二氧六环溶液中加热反应，得到产物2-甲硫基-6-(2,6-二氯苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。2-甲硫基-6-(2,6-二氯苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮和间氯过氧苯甲酸在二氯甲烷中，在室温下反应，得到中间粗产物2-甲亚磺酰基-6-(2,6-二氯苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮和2-甲磺酰基-6-(2,6-二氯苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。该粗产物、4-(4-甲基哌嗪-1-基)苯胺和三氟乙酸在乙腈中，在室温下反应，得到目标化合物6-(2,6-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。
反应方案1
Figure PCTCN2018095080-appb-000014
其它相关化合物可用类似方法制得。例如，用(1-氧代丁-2-基)氨基甲酸叔丁基酯替代N-叔丁氧羰基-2-氨基乙醛可制得目标化合物6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-9-乙基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。用(3-甲基-1-氧代丁烷-2-基)氨基甲酸叔丁酯替代N-叔丁氧羰基-2-氨基乙醛可制得目标化合物6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-9-异丙基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。
本发明化合物可如反应方案2中的反应实施例所示制得。2-甲硫基-5-溴嘧啶-4-甲酸和羰基二咪唑在四氢呋喃中加热反应，然后加入2,2-二甲氧基乙基-1-胺在室温下反应，得到产物N-(2,2-二甲氧基乙基)-2-甲硫基-5-溴嘧啶-4-甲酰胺。N-(2,2-二甲氧基乙基)-2-甲硫基-5-溴嘧啶-4-甲酰胺和稀盐酸在丙酮中加热反应，得到产物N-(2-氧代乙基)-2-甲硫基-5-溴嘧啶-4-甲酰胺。N-(2-氧代乙基)-2-甲硫基-5-溴嘧啶-4-甲酰胺、2,6-二氟苯肼和醋酸在甲醇中室温反应，然后加入氰基硼氢化钠在室温下反应，得到产物N-(2-(2-(2,6-二氟苯基)肼基)乙基)-2-甲硫基-5-溴嘧啶-4-甲酰胺。N-(2-(2-(2,6-二氟苯基)肼基)乙基)-2-甲硫基-5-溴嘧啶-4-甲酰胺和五氯化磷在无水二氯甲烷中在室温下反应，得到产物N-(2,6-二氯苯基)-2-(2-甲硫基-5-溴嘧啶-4-基)-4,5-二氢-1H-咪唑-1-胺。N-(2,6-二氯苯基)-2-(2-甲硫基-5-溴嘧啶-4-基)-4,5-二氢-1H-咪唑-1-胺和二氧化锰在二氯甲烷中在室温下 反应，得到产物N-(2,6-二氟苯基)-2-(2-甲硫基-5-溴嘧啶-4-基)-1H-咪唑-1-胺。N-(2,6-二氟苯基)-2-(2-甲硫基-5-溴嘧啶-4-基)-1H-咪唑-1-胺和氰化亚铜在1,4-二氧六环中加热反应，得到产物2-甲硫基-4-(1-((2,6-二氟苯基)氨基)-1H-咪唑并-2-基)嘧啶-5-甲腈。2-甲硫基-4-(1-((2,6-二氟苯基)氨基)-1H-咪唑并-2-基)嘧啶-5-甲腈和盐酸二氧六环溶液在加热下反应，然后加入水，加热反应，得到产物2-甲硫基-6-(2,6-二氟苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。2-甲硫基-6-(2,6-二氟苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮和间氯过氧苯甲酸在无水二氯甲烷中在室温下反应，得到中间体粗产物，该粗产物、3-甲基-4-(4-甲基哌嗪-1-基)苯胺和三氟乙酸在乙腈中，在室温下反应，得到目标化合物6-(2,6-二氟苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。
反应方案2
Figure PCTCN2018095080-appb-000015
其它相关化合物可用类似方法制得。例如，用2,6-二氯苯肼替代2,6-二氟苯肼可制得目标化合物6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。用2-氯-6-氟苯肼替代2,6-二氟苯肼可制得目标化合物6-(2-氯-6-氟苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。用2-氟-6-甲基苯肼替代2,6-二氟苯肼可制得目标化合物6-(2-氟-6-甲基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。用2,4,4-三甲基-1,2,3,4-四氢异喹啉-7-胺替代3-甲基-4-(4-甲基哌嗪-1-基)苯胺可制得目标化合物6-(2-氯-6-氟苯基)-2-((2,4,4-三甲基-1,2,3,4-四氢异喹啉-7-基)氨基)咪唑并[1,2-b]嘧 啶并[4,5-d]哒嗪-5(6H)-酮。用4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯胺替代3-甲基-4-(4-甲基哌嗪-1-基)苯胺可制得目标化合物6-(2,6-二氯苯基)-2-((4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。用3-氯-4-(4-(二甲氨基)哌啶-1-基)苯胺替代3-甲基-4-(4-甲基哌嗪-1-基)苯胺可制得目标化合物6-(2,6-二氯苯基)-2-((3-氯-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。用3-氟-4-(1-甲基哌啶-4-基)苯胺替代3-甲基-4-(4-甲基哌嗪-1-基)苯胺可制得目标化合物6-(2,6-二氯苯基)-2-((3-氟-4-(1-甲基哌啶-4-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。
本发明化合物可如反应方案3中的反应实施例所示制得。2-甲硫基-5-(乙氧羰基)嘧啶-4-甲酸和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯在N,N-二甲基甲酰胺中在室温下反应，然后加入2,2-二甲氧基乙烷-1-胺在室温下继续反应，得到产物2-甲硫基-4-((2,2-二甲氧基乙基)氨基甲酰基)嘧啶-5-甲酸乙酯。2-甲硫基-4-((2,2-二甲氧基乙基)氨基甲酰基)嘧啶-5-甲酸乙酯和浓盐酸在二氯甲烷中加热反应，得到产物2-甲硫基-4-((2-氧代乙基)氨基甲酰基)嘧啶-5-甲酸乙酯。2-甲硫基-4-((2-氧代乙基)氨基甲酰基)嘧啶-5-甲酸乙酯和2-溴-6-氯苯肼在甲醇中在室温下反应，然后加入氰基硼氢化钠加热继续反应，得到产物2-甲硫基-4-((2-(2-(2-溴-6-氯苯基)肼基)乙基)氨基甲酰基)嘧啶-5-甲酸乙酯。2-甲硫基-4-((2-(2-(2-溴-6-氯苯基)肼基)乙基)氨基甲酰基)嘧啶-5-甲酸乙酯和五氯化磷在二氯甲烷中在室温下反应，得到产物2-甲硫基-4-(1-((2-溴-6-氯苯基)氨基)-4,5-二氢-1H-咪唑-2-基)嘧啶-5-甲酸乙酯。2-甲硫基-4-(1-((2-溴-6-氯苯基)氨基)-4,5-二氢-1H-咪唑-2-基)嘧啶-5-甲酸乙酯和二氧化锰在1,4-二氧六环中加热反应，得到产物2-甲硫基-4-(1-((2-溴-6-氯苯基)氨基)-1H-咪唑-2-基)嘧啶-5-甲酸乙酯。2-甲硫基-4-(1-((2-溴-6-氯苯基)氨基)-1H-咪唑-2-基)嘧啶-5-甲酸乙酯和1,8-二氮杂二环[5.4.0]十一碳-7-烯在二氯甲烷中在0℃下反应，得到产物2-甲硫基-6-(2-溴-6-氯苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。2-甲硫基-6-(2-溴-6-氯苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮和间氯过氧苯甲酸在二氯甲烷中在室温下反应，得到中间体粗产物，该粗产物、3-甲基-4-(4-甲基哌嗪-1-基)苯胺和三氟乙酸在乙腈中在室温下反应，得到目标化合物6-(2-溴-6-氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。
反应方案3
Figure PCTCN2018095080-appb-000016
其它相关化合物可用类似方法制得。例如，用3-氯-4-(4-甲基哌嗪-1-基)苯胺替代3-甲基-4-(4-甲基哌嗪-1-基)苯胺可制得目标化合物6-(2-溴-6-氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。用3-氯-4-(4-(二甲基氨基)哌啶-1-基)苯胺替代3-甲基-4-(4-甲基哌嗪-1-基)苯胺可制得目标化合物6-(2-溴-6-氯苯基)-2-((3-氯-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。用3-氟-5-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯胺替代3-甲基-4-(4-甲基哌嗪-1-基)苯胺可制得目标化合物6-(2-溴-6-氯苯基)-2-((3-氟-5-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。
本发明化合物可如反应方案4中的反应实施例所示制得。5-溴-2-(甲硫基)嘧啶-4-甲酸、N,N-二异丙基乙胺、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和氨基丙酮盐酸盐在N,N-二甲基甲酰胺中在室温下反应，得到产物5-溴-2-(甲硫基)-N-(2-氧代丙基)嘧啶-4-甲酰胺。5-溴-2-(甲硫基)-N-(2-氧代丙基)嘧啶-4-甲酰胺、2,6-二氯苯肼盐酸盐、醋酸和醋酸硼氢化钠在1,2-二氯乙烷中在室温下反应，得到产物5-溴-N-(2-(2-(2,6-二氯苯基)亚肼基)丙基)-2-(甲硫基)嘧啶-4-甲酰胺。5-溴-N-(2-(2-(2,6-二氯苯基)亚肼基)丙基)-2-(甲硫基)嘧啶-4-甲酰胺和硼氢化钠在二氯甲烷和甲醇的混合溶剂中在室温下反应，得到产物5-溴-N-(2-(2-(2,6-二氯苯基)肼基)丙基)-2-(甲硫基)嘧啶-4-甲酰胺。三氟甲磺酸酐和三苯基膦在二氯甲烷中在室温下反应，然后加入5-溴-N-(2-(2-(2,6-二氯苯基)肼基)丙基)-2-(甲硫基)嘧啶-4-甲酰胺在0℃下反应，得到粗产物2-(5-溴-2-(甲硫基)嘧啶-4-基)-N-(2,6-二氯苯基)-5-甲基-4,5-二氢-1H-咪唑-1-胺。该粗产物和二氧化锰在二氯甲烷中在室温下反应，得到产物2-(5-溴-2-(甲硫基)嘧啶-4-基)-N-(2,6-二氯苯基)-5-甲基-1H- 咪唑-1-胺。2-(5-溴-2-(甲硫基)嘧啶-4-基)-N-(2,6-二氯苯基)-5-甲基-1H-咪唑-1-胺和氰化亚铜在1,4-二氧六环中加热反应，得到产物4-(1-((2,6-二氯苯基)氨基)-5-甲基-1H-咪唑-2-基)-2-(甲硫基)嘧啶-5-甲腈。4-(1-((2,6-二氯苯基)氨基)-5-甲基-1H-咪唑-2-基)-2-(甲硫基)嘧啶-5-甲腈和盐酸二氧六环溶液加热反应，得到产物6-(2,6-二氯苯基)-8-甲基-2-(甲硫基)咪唑[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。6-(2,6-二氯苯基)-8-甲基-2-(甲硫基)咪唑[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮和间氯过氧苯甲酸在二氯甲烷中在室温下反应，得到中间体粗产物，该粗产物、3-氯-4-(4-甲基哌嗪-1-基)苯胺和三氟乙酸在乙腈中加热反应，得到目标化合物6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮。
反应方案4
Figure PCTCN2018095080-appb-000017
本发明的一个重要方面是发现了式I(包括本文所述的式II和式III化合物)是激酶抑制剂，特别是Wee1激酶抑制剂。因此，这些化合物可用于治疗Wee1相关疾病。本文所述的“Weel相关疾病”是指Weel介导的疾病，尤其是受益于Weel激酶活性被抑制的疾病，例如癌症。
因此，本发明包括给动物施用有效量的式I、式II或式III化合物或其可药用盐或前药的治疗方法，该治疗方法可用于治疗Wee1相关疾病，例如癌症。可由本发明的方法或药物组合物治疗或预防的这类疾病包括但不限于肝癌、黑素瘤、霍奇金病、非霍奇金淋巴瘤、急性淋巴白血病、慢性淋巴白血病、多发性骨髓瘤、成神经细胞瘤、 乳腺癌、卵巢癌、肺癌、维尔姆斯瘤、子***、睾丸癌、软组织肉瘤、原发性巨球蛋白血症、膀胱癌、慢性粒细胞白血病、原发性脑癌、恶性黑素瘤、小细胞肺癌、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌症、绒毛膜癌、蕈樣肉芽腫、头颈癌、骨原性肉瘤、胰腺癌、急性粒细胞白血病、毛细胞白血病、横纹肌肉瘤、卡波西肉瘤、泌尿生殖***肿瘤病、甲状腺癌、食管癌、恶性高钙血症、子宫颈增生症、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多症、肾上腺皮质癌、皮肤癌和***癌。
本发明也包括用于治疗或预防因Wee1活性异常而引起的其他疾病，例如神经病学或神经精神疾病或病症，例如抑郁症。
在实施本发明治疗方法时，给有一种或多种这些症状的病人施用有效量的药物制剂。所述药物制剂含有有效治疗浓度的式I、式II或式III化合物，被配制成用于口服、静脉注射、局部或外用给药的形式，用于治疗癌症和其他疾病。给药量是有效地改善或消除一个或多个病症的药量。对于特定疾病的治疗，有效量是足以改善或以某些方式减轻与疾病有关的症状的药量。这样的药量可作为单一剂量施用，或者可依据有效的治疗方案给药。给药量也许可治愈疾病，但是给药通常是为了改善疾病的症状。一般需要反复给药来实现所需的症状改善。
因此，在另一个实施方案中，本发明提供了一种药用组合物，其中含有作为Wee1抑制剂的式I、式II或式III化合物或其可药用盐与可药用载体。
本发明另一个实施方案涉及能有效地治疗癌症的药用组合物，其中包含作为Wee1激酶抑制剂的式I、式II或式III化合物，或其可药用盐或前药，与至少一种已知的抗癌药物或抗癌药物的可药用盐联合共用。特别是和其他与DNA损伤和修复机理有关的抗癌药物的联合共用，包括PARP抑制剂奥拉帕尼、Niraparib、Rucaparib、Talazoparib和PCT/CN2012/073362实施例中所制备的任一种化合物(本文将其全部内容以引用的方式纳入本文)；HDAC抑制剂伏立诺他、罗咪地辛、帕比司他和贝利司他；等等。以及和其他与细胞***检测点有关的抗癌药物的联合共用，包括Chk1/2抑制剂，CDK4/6抑制剂如帕博西尼，ATM/ATR抑制剂等等。其他可用于抗癌联合治疗的已知抗癌药物包括但不限于烷化剂例如白消安、马法兰、苯丁酸氮芥、环磷酰胺、异环磷酰胺、替莫唑胺、苯达莫司汀、顺铂、丝裂霉素C、博莱霉素和卡铂；拓扑异构酶Ⅰ抑制剂例如喜树碱、伊立替康和托泊替康；拓扑异构酶Ⅱ抑制剂例如阿霉素、表阿霉素、阿克拉霉素、米托蒽醌、甲基羟基玫瑰树碱和铭托泊普；RNA/DNA抗代谢物例如5-氮杂胞苷、吉西他滨、5-氟尿嘧啶和甲氨蝶呤；DNA抗代谢物例如5-氟-2′-去氧尿苷、氟达拉滨，奈拉滨、阿糖胞苷、普拉曲沙、培美曲塞、羟基脲和硫代鸟嘌呤；抗有丝***剂例如秋水仙碱、长春碱、长春新碱、长春瑞滨、紫杉醇，伊沙匹隆、卡巴他赛和多西他赛；抗体例如单抗，帕尼单抗、耐措妥珠单抗、纳武单抗、派姆单抗、雷莫芦单抗、贝伐珠单 抗、帕妥珠单抗、曲妥珠单抗、西妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、利妥昔单抗、阿仑单抗、替伊莫单抗、托西莫单抗、本妥昔单抗、达雷木单抗、埃罗妥珠单抗、T-DM1、Ofatumumab、Dinutuximab、Blinatumomab、易普利姆玛、阿瓦斯丁、赫赛汀和美罗华；激酶抑制剂例如伊马替尼、吉非替尼、厄洛替尼、奥斯替尼、阿法替尼、赛立替尼、艾乐替尼、克唑替尼、埃罗替尼、拉帕替尼、索拉非尼、瑞格非尼、维罗非尼、达拉非尼、阿柏西普、舒尼替尼、尼罗替尼、达沙替尼、博舒替尼、普拉替尼、依鲁替尼、卡博替尼、乐伐替尼、凡德他尼、曲美替尼、卡比替尼、阿昔替尼、替西罗莫司、Idelalisib、帕唑帕尼、特癌适和依维莫司。其他可用于抗癌组合治疗的已知抗癌药物包括他莫昔芬、来曲唑、氟维司群、米托胍腙、奥曲肽、视黄酸、砒霜、唑来膦酸、硼替佐米、卡非佐米、Ixazomib、维莫德吉、索尼德吉、狄诺塞麦、萨力多胺、来那度胺、Venetoclax、Aldesleukin(重组人白介素-2)和Sipueucel-T(***癌治疗疫苗)。
在实施本发明的方法时，本发明化合物与至少一种已知的抗癌药物可作为单一的药用组合物一起给药。另外，本发明化合物也可与至少一种已知抗癌药分开给药。在一个实施方案，本发明化合物和至少一种已知的抗癌药差不多同时给药，即所有的药物同时施用或陆续施用，只要化合物在血液中同时达到治疗浓度即可。在另外一个实施方案，本发明的化合物和至少一种已知的抗癌药根据各自的剂量方案给药，只要化合物在血液中达到治疗浓度即可。
本发明的另一个实施方案，是一种由所述化合物组成的能有效的抑制肿瘤的，作为Wee1抑制剂的生物耦合物。这个能抑制肿瘤的生物耦合物由所述化合物与至少一种已知的有医疗作用的抗体，如赫赛汀或美罗华，或生长素，如DGF或NGF，或细胞激素，如白细胞介素2或4，或任意能与细胞表面结合的分子组成。该抗体与其他分子能把所述化合物递送到其靶点，使之成为有效的抗癌药物。此生物耦合物也可以提高有医疗作用的抗体，如赫赛汀或美罗华的抗癌效果。
本发明的另一实施例涉及一种能有效的抑制肿瘤的药用组合物，包含式I、式II或式III所示的Wee1抑制剂，或其可用药盐或前药，与放射疗法联合治疗。在此实施例，本发明化合物与放射治疗可在相同时间或不同时间给药。
本发明的另一实施例涉及一种能有效的用于癌症手术后治疗的药用组合物，包含式I、式II或式III所示的Wee1抑制剂，或其可用药盐或前药。本发明还涉及用手术切除肿瘤，然后用本发明的药用组合物治疗该哺乳动物的癌症的治疗方法。
本发明的药用组合物包括所有本发明化合物的含有量能有效地实现其预期目标的药品制剂。虽然每个人的需求各不相同，本领域技术人员可确定药品制剂中每个部分的最佳剂量。一般情况下，所述化合物，或其可用药盐，对哺乳动物每天口服给药，药量按照约0.0025到50毫克/公斤体重。但最好是每公斤口服给药约0.01到10毫克/公 斤。如果也施用一个已知的抗癌药物，其剂量应可有效地实现其预期的目的。这些已知的抗癌药物的最佳剂量是本领域技术人员所熟知的。
单位口服剂量可以包括约0.01到50毫克，最好是约0.1到10毫克的本发明化合物。单位剂量可给予一次或多次，每天为一片或多片，每片含有约0.1到50毫克，合宜地约0.25到10毫克的本发明化合物或其溶剂化物。
在外用制剂中，本发明化合物的浓度可以是每克载体约0.01到100毫克。
本发明化合物可作为未加工药品给药。本发明化合物也可以作为含有可药用载体(包括辅料和助剂)的一个合适的药物制剂的一部分给药。这些可药用载体有利于把化合物加工成可药用的药物制剂。优选的药物制剂，特别是那些口服的和优选的给药方式类型，如片剂，锭剂和胶囊，以及适合于注射或口服的溶液，包含约0.01％到99％，最好从约0.25％到75％的活性化合物以及辅料。
本发明的范围也包括本发明化合物的无毒性可药用盐。酸加成盐由混合一个无毒性可药用酸溶液和本发明的化合物溶液而形成。所述酸例如盐酸，富马酸，马来酸，琥珀酸，乙酸，柠檬酸，酒石酸，碳酸，磷酸，草酸等。碱加成盐由混合一个无毒性可药用碱溶液和本发明的化合物溶液而形成。所述碱例如氢氧化钠，氢氧化钾，氢胆碱，碳酸钠，三羟甲基氨基甲烷，N-甲基-葡萄糖胺等。
本发明的药物制剂可以给予任何哺乳动物，只要他们能获得本发明化合物的治疗效果。在这些哺乳动物中最为重要的是人类和兽医动物，虽然本发明不打算如此受限。
本发明的药物制剂可通过任何途径给药以达到其预期目的。例如，可以通过肠外，皮下，静脉，肌肉，腹腔内，透皮，口腔，鞘内，颅内，鼻腔或外用途径给药。作为替代或并行地，可以通过口服给药。药的剂量将根据病人的年龄，健康与体重，并行治疗的种类，治疗的频率，以及所需治疗效益来决定。
本发明的药物制剂可用已知的方式制造。例如，由传统的混合，制粒，制锭，溶解，或冷冻干燥过程制造。制造口服制剂时，可结合固体辅料和活性化合物，选择性研磨混合物。如果需要或必要时加入适量助剂后，加工颗粒混合物，获得片剂或锭剂芯。
合适的辅料特别是填料，例如糖类如乳糖或蔗糖，甘露醇或山梨醇；纤维素制剂和/或钙磷酸盐，例如磷酸三钙或磷酸氢钙；以及粘结剂，例如淀粉糊，包括玉米淀粉，小麦淀粉，大米淀粉，马铃薯淀粉，明胶，黄芪胶，甲基纤维素，羟丙基甲基纤维素，羧甲基纤维素钠，和/或聚乙烯吡咯烷酮。如果需要，可增加崩解剂，比如上面提到的淀粉，以及羧甲基淀粉，交联聚乙烯吡咯烷酮，琼脂，或褐藻酸或其盐，如海藻酸钠。辅助剂特别是流动调节剂和润滑剂，例如，硅石，滑石，硬脂酸或其盐，如硬脂酸 镁或硬脂酸钙，和/或聚乙二醇。如果需要，可以给锭剂核芯提供可以抵抗胃液的合适包衣。为此，可以应用浓缩糖类溶液。这个溶液可以含有***树胶，滑石，聚乙烯吡咯烷酮，聚乙二醇和/或二氧化钛，漆溶液和合适的有机溶剂或溶剂混合物。为了制备耐胃液的包衣，可使用适当的纤维素溶液，例如醋酸纤维素邻苯二甲酸或羟丙基甲基纤维素邻苯二甲酸。可向药片或锭剂核芯的包衣加入染料或色素。例如，用于识别或为了表征活性成分剂量的组合。
其他可口服的药物制剂包括明胶制成的压接式胶囊，以及用明胶和甘油或山梨醇等增塑剂制成的密封软胶囊。该压接式胶囊可含有颗粒形式的活性化合物，与填料例如乳糖；粘结剂例如淀粉；和/或润滑剂例如滑石粉或硬脂酸镁，以及稳定剂混合而成。在软胶囊，活性化合物最好是溶解或悬浮在适当的液体例如油脂或液体石蜡中，其中可加入稳定剂。
合适于肠外给药的制剂包括活性化合物的水溶液，如水溶性盐的溶液和碱性溶液。此外，可施用适当的活性化合物的油性注射悬浮液。合适的亲脂性溶剂或载体包括油脂例如香油，合成脂肪酸酯例如油酸乙酯或甘油三酯或聚乙二醇400，或氢化蓖麻油，或环糊精。水性注射悬浮液可含有增加悬浮液黏度的物质，例如羧甲基纤维素钠，山梨醇，和/或葡聚糖。也可以含有悬浮稳定剂。
按照本发明的一个方面，本发明的化合物采用外用和肠外配方，并用于治疗皮肤癌。
本发明的外用制剂可通过优选合适的载体来制成油剂，霜剂，乳液剂，药膏等。合适的载体包括植物或矿物油，白矿油(白软石蜡)，支链脂肪或油脂，动物脂肪和高分子醇(大于C 12)。优选的载体是活性成分能溶解在其中的那些载体。也可包括乳化剂，稳定剂，保湿剂和抗氧化剂，以及如果需要的话，给予颜色或香味的试剂。此外，这些外用制剂可包含透皮渗透增强剂。这种增强剂的例子可参见美国专利号3,989,816和4,444,762。
霜剂优选用矿物油，自乳化蜂蜡和水的混合物配制，与溶解于少量油例如杏仁油的活性成分混合而成。一个典型的霜剂例子包括约40份水，20份蜂蜡，40份矿物油和1份杏仁油。
药膏可以这样配制，将含有活性成分的植物油例如杏仁油和温热的软石蜡混合，然后使该混合物冷却。一个典型的药膏例子包括约30％重量的杏仁油和70％重量的白软石蜡。
本发明也涉及应用本发明的化合物制备治疗对抑制Wee1活性有效果的临床病症的药物。这些药物可包括上述药用组合物。
下列实施例是举例说明，而不是限制本发明的方法和制剂。其他对于本领域技术人员来说是显而易见的，和在临床治疗中通常会遇到的对各种条件和参数的适当修改和改进，都在本发明的精神和范围内。
实施例
一般性说明
所用试剂均是商品品质，溶剂均按照标准方法干燥纯化。使用电喷雾的单四级杆质谱仪(平台Ⅱ，安捷伦6110)分析质谱样品。使用Brücker Ascend 400核磁仪在400MHz记录 1H NMR光谱，化学位移记录为以TMS作为内标(0.00ppm)从低场始以ppm为单位，耦合常数J值以Hz为单位。
实施例1
6-(2,6-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮
a)(2-(2-(2,6-二氯苯基)肼基)乙基)氨基甲酸叔丁酯：将N-叔丁氧羰基-2-氨基乙醛(15.5g，97.4mmol)溶于二氯甲烷(300mL)中，依次加入2,6-二氯苯肼(15.7g，88.7mmol)和三乙酰氧基硼氢化钠(37g，174.5mmol)。反应液在室温下搅拌反应过夜后，继续加入氰基硼氢化钠(11g，175mmol)，加入完毕后，反应液在室温下搅拌反应3h。碳酸氢钠水溶液(300mL)加入到反应体系中，分出有机相，水相用二氯甲烷(150mL×2)萃取。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗产物。柱层析分离纯化(硅胶，石油醚:乙酸乙酯＝6:1为洗脱剂)得到目标化合物(12.5g，44％收率，黄色固体)。LC-MS(ESI):m/z(M+H) +320.72。
b)1-(2-(叔丁氧羰基氨基)乙基)-2-(2,6-二氯苯基)肼甲酸苄酯：将(2-(2-(2,6-二氯苯基)肼基)乙基)氨基甲酸叔丁酯(10g，31.2mmol)溶于二氯甲烷(100mL)中，依次加入二异丙基乙胺(16.5mL，93.6mmol)和氯甲酸苄酯(5.8mL，40.5mmol)。反应液在室温下搅拌2h后，将碳酸氢钠水溶液(100mL)加入到反应体系中，分出有机相，水相用二氯甲烷(50mL×2)萃取。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗产物。柱层析分离纯化(硅胶，石油醚:乙酸乙酯＝8:1为洗脱剂)，得到目标化合物(13.8g，97％收率，黄色固体)。LC-MS(ESI):(M+H) +454.30。
c)1-(2-氨基乙基)-2-(2,6-二氯苯基)肼甲酸苄酯盐酸盐：将1-(2-(叔丁氧羰基氨基)乙基)-2-(2,6-二氯苯基)肼甲酸苄酯(13.8g，30.4mmol)溶于盐酸二氧六环溶液(4N， 130mL)中。反应混合物在室温下搅拌反应3h后，减压除去溶剂，得到目标化合物(11.8g，100％收率，黄色固体)。LC-MS(ESI):m/z(M+H) +353.98。
d)1-(2-(2-甲硫基-5-溴嘧啶-4-甲酰氨基)乙基)-2-(2,6-二氯苯基)肼甲酸苄酯：将1-(2-氨基乙基)-2-(2,6-二氯苯基)肼甲酸苄酯盐酸盐(10.5g，26.9mmol)溶于N,N-二甲基甲酰胺(100mL)中，加入二异丙基乙胺(13mL，134.5mmol)。将反应混合物冷却至0℃后，慢慢滴加5-溴-2-(甲硫基)嘧啶-4-甲酰氯(6g，22.4mmol)的二氯甲烷(80mL)溶液，滴加完毕后，反应液在0℃下搅拌反应45min后，将饱和碳酸氢钠水溶液(100mL)加入到反应体系中，分出有机相，水相用二氯甲烷(50mL×2)萃取。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗产物。柱层析分离纯化(硅胶，石油醚:乙酸乙酯＝4:1为洗脱剂)，得到目标化合物(10.2g，77.7％收率，黄色固体)。LC-MS(ESI):(M+H) +584.34。
e)2-甲硫基-5-溴-N-(2-(2-(2,6-二氯苯基)肼基)乙基)-嘧啶-4-甲酰胺：将1-(2-(2-甲硫基-5-溴嘧啶-4-甲酰氨基)乙基)-2-(2,6-二氯苯基)肼甲酸苄酯(10.2g，17.4mmol)溶于三氟乙酸(110mL)中，反应混合物在65℃下搅拌反应2h后，减压浓缩，加入二氯甲烷(200mL)溶解后，缓慢加入饱和碳酸氢钠水溶液(100mL)，分出有机相，水相用二氯甲烷(50mL×2)萃取。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗产物。柱层析分离纯化(硅胶，石油醚:乙酸乙酯＝4:1为洗脱剂)得到目标化合物(6.1g，77.6％收率，黄色固体)。LC-MS(ESI):m/z(M+H) +450.47。 1H NMR(400MHz,CDCl 3)δ8.76(s,1H),8.05(br s,1H),7.28–7.26(m,1H),7.25–7.24(m,1H),6.92–6.86(m,1H),5.84(br s,1H),3.60–3.55(m,2H),2.99(t,J＝5.4Hz,2H),2.57(s,3H)。
f)2-(2-甲硫基-5-溴嘧啶-4-基)-N-(2,6-二氯苯基)-4,5-二氢-1H-咪唑-1-胺的制备：将2-甲硫基-5-溴-N-(2-(2-(2,6-二氯苯基)肼基)乙基)-嘧啶-4-甲酰胺(1g，2.21mmol)溶于二氯甲烷(50mL)中，反应液冷却至0℃后，慢慢加入五氯化磷(922mg，4.43mmol)。反应液在室温下搅拌1h后，冷却至0℃，慢慢加入到甲醇(50mL)中。在0℃下搅拌15min后，加入饱和碳酸氢钠水溶液(100mL)，分出有机相，水相用二氯甲烷(50mL×2)萃取。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗产物。柱层析分离纯化(硅胶，石油醚:乙酸乙酯＝2:1为洗脱剂)得到目标化合物(550mg，57.3％收率，黄色固体)。LC-MS(ESI):m/z(M+H) +432.05。
g)2-(2-甲硫基-5-氰基嘧啶-4-基)-N-(2,6-二氯苯基)-1H-咪唑-1-胺的制备：将2-(2-甲硫基-5-溴嘧啶-4-基)-N-(2,6-二氯苯基)-4,5-二氢-1H-咪唑-1-胺(300mg，0.69mmol)和氰化亚铜((123mg，1.38mmol)溶于N,N-二甲基甲酰胺(10mL)中，反应液在120℃下搅拌反应3h后，冷却至室温。加入氨水(30mL)和乙酸乙酯(20mL)，分出有机 相，水相用乙酸乙酯(50mL×2)萃取。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗产物。柱层析分离纯化(硅胶，二氯甲烷:甲醇＝10:1为洗脱剂)得到目标化合物(150mg，57.5％收率，黄色固体)。LC-MS(ESI):m/z(M+H) +377.10。
h)2-甲硫基-6-(2,6-二氯苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮的制备：将2-(2-甲硫基-5-氰基嘧啶-4-基)-N-(2,6-二氯苯基)-1H-咪唑-1-胺(50mg，0.13mmol)加入到盐酸二氧六环溶液(4N，10mL)中，反应液在80℃下搅拌反应2d后，冷却至室温，减压浓缩除去有机溶剂，加入碳酸氢钠水溶液(10mL)和乙酸乙酯(10mL)，分出有机相，水相用乙酸乙酯(5mL×2)萃取。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗产物。柱层析分离纯化(硅胶，二氯甲烷:甲醇＝10:1为洗脱剂)得到目标化合物(30mg，59.9％收率，黄色固体)。LC-MS(ESI):m/z(M+H) +378.30。
i)2-甲磺酰基-6-(2,6-二氯苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮的制备：将2-甲硫基-6-(2,6-二氯苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(30毫克，0.079毫摩尔)溶于二氯甲烷(3毫升)中，加入间氯过氧苯甲酸(85％，18毫克，0.089毫摩尔)。反应液在室温下搅拌反应2小时后，减压浓缩得到粗产物直接用于下步反应。LC-MS(ESI):m/z(M+H) +410.08。
j)6-(2,6-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮的制备：将2-甲磺酰基-6-(2,6-二氯苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(32.4mg，0.079mmol)和4-(4-甲基哌嗪-1-基)苯胺(23mg，0.12mmol)溶于乙腈(3mL)中，加入三氟乙酸(0.05mL)。反应液在室温下搅拌反应过夜后，减压除去有机溶剂得到粗产品。用制备液相色谱(C18柱，0-100％乙腈/水为流动相)分离纯化，得到目标化合物(7mg，17.1％收率，黄色固体)。
实施例2
6-(2,6-二氟苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮
a)N-(2,2-二甲氧基乙基)-2-甲硫基-5-溴嘧啶-4-甲酰胺的制备：在室温下，向2-甲硫基-5-溴嘧啶-4-甲酸(40.0g，160.6mmol)的四氢呋喃(200mL)溶液中加入羰基二咪唑(33.8g，208.8mmol)。置换氮气后，该反应液在60℃下搅拌反应2h后，降温到0℃下。将2,2-二甲氧基乙基-1-胺(22.0g，208.8mmol)慢慢加入，置换氮气后，该反应液在室温下搅拌反应过夜。加入水(100mL)，在室温下搅拌30min后过滤，滤饼用*** 洗涤两次，减压干燥得到目标化合物(43.0g，80％收率，黄色固体)。LC-MS(ESI):m/z(M+H) +336.21。
b)N-(2-氧代乙基)-2-甲硫基-5-溴嘧啶-4-甲酰胺的制备：在室温下，将N-(2,2-二甲氧基乙基)-2-甲硫基-5-溴嘧啶-4-甲酰胺(15.0g，44.7mmol)和稀盐酸(1M，100mL)加入到丙酮(100mL)中，置换氮气1次。反应混合物在50℃下搅拌反应4h后，冷却至室温。减压浓缩除去有机溶剂得到目标产物(10.6g，81％收率，白色固体)。LC-MS(ESI):m/z(M+H) +289.92。
c)N-(2-(2-(2,6-二氟苯基)肼基)乙基)-2-甲硫基-5-溴嘧啶-4-甲酰胺的制备：在室温下，将N-(2-氧代乙基)-2-甲硫基-5-溴嘧啶-4-甲酰胺(8g，27.7mmol)，2,6-二氟苯肼(4.8g，33.2mmol)和醋酸(7mL)依次加入到甲醇(200mL)中。反应混合物在室温下搅拌反应1h后，将氰基硼氢化钠(1.8g，27.7mmol)缓慢加入。反应混合物在室温下搅拌反应1h后减压浓缩除去有机溶剂得到粗产品。将粗品溶于二氯甲烷(50mL)中，加入碳酸氢钠饱和水溶液(100mL)分液萃取，水相用二氯甲烷(50mL×2)萃取。合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩除去有机溶剂得到粗产物。经柱层析分离纯化(硅胶，石油醚:乙酸乙酯＝1:1)得到目标产物(13.1g，90％收率，黄色固体)。LC-MS(ESI):m/z(M+H) +418.06。
d)N-(2,6-二氟苯基)-2-(2-甲硫基-5-溴嘧啶-4-基)-4,5-二氢-1H-咪唑-1-胺的制备：在室温下，将N-(2-(2-(2,6-二氟苯基)肼基)乙基)-2-甲硫基-5-溴嘧啶-4-甲酰胺(6.0g，14.4mmol)溶于无水二氯甲烷(200mL)中，分批加入五氯化磷(9.0g，43.2mmol)。反应混合物在室温下搅拌反应4h后，将反应液缓慢加入到冰甲醇(100mL)和碳酸氢钠固体(10g)的混合溶液中，搅拌10min后过滤，滤液旋干得到粗产物，直接用于下一步反应。LC-MS(ESI):m/z(M+H) +400.06。
e)N-(2,6-二氟苯基)-2-(2-甲硫基-5-溴嘧啶-4-基)-1H-咪唑-1-胺的制备：在室温下，将N-(2,6-二氟苯基)-2-(2-甲硫基-5-溴嘧啶-4-基)-4,5-二氢-1H-咪唑-1-胺(上一步粗品)和二氧化锰(6.5g，72.0mmol)加入到二氯甲烷(200mL)中。反应混合物在室温下搅拌反应20h后，过滤除去二氧化锰，减压浓缩除去有机溶剂得到粗产物。经柱层析分离纯化(硅胶，石油醚:乙酸乙酯＝1:1)得到目标化合物(2.5g，44％收率(两步)，红色油状物)。LC-MS(ESI):m/z(M+H) +398.06。
f)2-甲硫基-4-(1-((2,6-二氟苯基)氨基)-1H-咪唑并-2-基)嘧啶-5-甲腈的制备：在室温下，将N-(2,6-二氟苯基)-2-(2-甲硫基-5-溴嘧啶-4-基)-1H-咪唑-1-胺(4.5g，11.4mmol)和氰化亚铜(2.1g，27.8mmol)加入到1,4-二氧六环(30mL)中。反应混合物在80℃下搅拌反应20h后，冷却至室温。将反应液倒入水(100mL)中，用乙酸乙酯(50mL×3)萃取。合并有机相，用饱和食盐水洗，无水硫酸钠干燥，减压除去溶剂得到粗产物。 经柱层析分离纯化(硅胶，石油醚:乙酸乙酯＝1:1)得到目标产物(2.0g，50％收率，黄色固体)。LC-MS(ESI):m/z(M+H) +345.00。
g)2-甲硫基-6-(2,6-二氟苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮的制备：在室温下，将2-甲硫基-4-(1-((2,6-二氟苯基)氨基)-1H-咪唑并-2-基)嘧啶-5-甲腈(2.0g，5.8mmol)加入到盐酸二氧六环溶液(4M，20mL)中。反应混合物在80℃下搅拌反应15h后，降至50℃，加入水(10mL)。反应混合物在50℃下搅拌反应2h后，冷却至室温。减压浓缩除去有机溶剂，加入乙酸乙酯(50mL)和饱和碳酸氢钠水溶液(20mL)分液萃取，水相用乙酸乙酯(15mL×2)萃取，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，减压除去有机溶剂得到目标产物(1.5g，74％收率，黄色固体)。LC-MS(ESI):m/z(M+H) +346.00。 1H NMR(400MHz,CDCl 3):δ9.36(s,1H),7.72–7.63(m,1H),7.51(d,J＝1.0Hz,1H),7.26–7.22(m,2H),7.01–6.98(m,1H),2.77(s,3H)。
h)6-(2,6-二氟苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮的制备：将2-甲硫基-6-(2,6-二氟苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(80mg，0.22mmol)溶于无水二氯甲烷(3mL)中。在0℃下，将间氯过氧苯甲酸(58mg，0.33mmol)加入到反应体系中，加入完毕后，将反应液温度升至室温，在室温下搅拌反应1h后，减压浓缩除去有机溶剂得到粗产品。将该粗产品溶于乙腈(5mL)中，将3-甲基-4-(4-甲基哌嗪-1-基)苯胺(67mg，0.33mmol)和三氟乙酸(2滴)加入到反应体系中。将反应液升至室温并在室温下搅拌反应1h后，用饱和碳酸氢钠水溶液将反应液pH值调至7-8。加入二氯甲烷(50mL)和水(30mL)分液，水相用二氯甲烷(30mL×2)萃取，合并有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩除去有机溶剂得到粗产品。用制备液相色谱(C18柱，0-100％乙腈/水为流动相)分离纯化得到目标化合物(57mg，51.8％收率，黄色固体)。
应用类似于所描述的实施例2的合成方法制得下述实施例3—25的化合物，起始原料为5-溴-2-(甲硫基)嘧啶-4-甲酸、2,2-二甲氧基乙基-1-胺、2,6-二取代苯肼、氰化亚铜和相应的取代苯胺或取代四氢异喹啉胺。
应用类似于所描述的实施例2h的合成方法制得首先制得下述实施例26的中间体，起始原料为2-甲硫基-6-(2,6-二氯苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮和4-(4-氨基-2-甲基苯基)哌嗪-1-甲酸叔丁酯。该中间体和盐酸二氧六环在室温下反应，脱保护得到实施例26的目标化合物。
应用类似于所描述的实施例2的合成方法制得下述实施例27—45的化合物，起始原料为5-溴-2-(甲硫基)嘧啶-4-甲酸、2,2-二甲氧基乙基-1-胺、2,6-二取代苯肼、氰化亚铜和相应的取代苯胺或取代四氢异喹啉胺。
Figure PCTCN2018095080-appb-000018
Figure PCTCN2018095080-appb-000019
Figure PCTCN2018095080-appb-000020
Figure PCTCN2018095080-appb-000021
Figure PCTCN2018095080-appb-000022
Figure PCTCN2018095080-appb-000023
Figure PCTCN2018095080-appb-000024
Figure PCTCN2018095080-appb-000025
实施例46
6-(2-溴-6-氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮
a)2-甲硫基-4-((2,2-二甲氧基乙基)氨基甲酰基)嘧啶-5-甲酸乙酯：将2-甲硫基-5-(乙氧羰基)嘧啶-4-甲酸(700mg，2.9mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.7g，4.3mmol)。反应混合物在室温下搅拌反应30min后，加入2,2-二甲氧基乙烷-1-胺(914mg，8.7mmol)。反应混合物继续在室温下搅拌反应1h。向反应混合物中加入乙酸乙酯(100mL)和水(50mL)，分出有机相，水相用乙酸乙酯(100mL)萃取，合并有机相，无水硫酸钠干燥、减压浓缩除去有机溶剂得到粗品。经柱层析分离纯化(硅胶，二氯甲烷:甲醇＝20:1)得 到目标化合物(900毫克，收率93％，黄色固体)。LC-MS(ESI):m/z(M+H) +330.10。
b)2-甲硫基-4-((2-氧代乙基)氨基甲酰基)嘧啶-5-甲酸乙酯：将2-甲硫基-4-((2,2-二甲氧基乙基)氨基甲酰基)嘧啶-5-甲酸乙酯(900mg，2.7mmol)溶于二氯甲烷(9mL)中，加入浓盐酸(9mL)。反应混合物在50℃下搅拌反应3h后，冷却至室温。向反应液中加入水(10mL)，分出有机相，水相用二氯甲烷(10mL×2)萃取，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，减压浓缩除去有机溶剂得到粗品，直接用于下一步反应。LC-MS(ESI):m/z(M+H) +284.06。
c)2-甲硫基-4-((2-(2-(2-溴-6-氯苯基)肼基)乙基)氨基甲酰基)嘧啶-5-甲酸乙酯：将2-甲硫基-4-((2-氧代乙基)氨基甲酰基)嘧啶-5-甲酸乙酯(400mg，1.4mmol)溶于甲醇(10mL)中，加入2-溴-6-氯苯肼(309mg，1.4mmol)。反应混合物在室温下搅拌半小时后，加入氰基硼氢化钠(86.8mg，1.4mmol)。反应混合物在40℃下搅拌反应8h。向反应液中加入二氯甲烷(20mL)和水(20mL)，分出有机相，水相用二氯甲烷(20mL)萃取一次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，减压浓缩除去有机溶剂得到粗品。柱层析分离纯化(二氯甲烷:甲醇＝10:1)得到目标化合物(600mg，收率88％，黄色固体)。LC-MS(ESI):m/z(M+H) +488.79。
d)2-甲硫基-4-(1-((2-溴-6-氯苯基)氨基)-4,5-二氢-1H-咪唑-2-基)嘧啶-5-甲酸乙酯：将2-甲硫基-4-((2-(2-(2-溴-6-氯苯基)肼基)乙基)氨基甲酰基)嘧啶-5-甲酸乙酯(600mg，1.2mmol)溶于二氯甲烷(10mL)中，在0℃下加入五氯化磷(374mg，1.8mmol)。反应混合物在室温下搅拌反应30min后，降至0℃。依次加入甲醇(10mL)和碳酸氢钠固体(600mg)淬灭反应，过滤，减压浓缩除去有机溶剂得到粗品(650mg)，直接用于下一步反应。LC-MS(ESI):m/z(M+H) +470.77。
e)2-甲硫基-4-(1-((2-溴-6-氯苯基)氨基)-1H-咪唑-2-基)嘧啶-5-甲酸乙酯：在室温下，将2-甲硫基-4-(1-((2-溴-6-氯苯基)氨基)-4,5-二氢-1H-咪唑-2-基)嘧啶-5-甲酸乙酯(650mg，粗品，等当量)溶于1,4-二氧六环(20mL)中，加入二氧化锰(522mg，6.0mmol)。反应混合物在50℃下搅拌反应2h后，冷却至室温，过滤减压浓缩除去有机溶剂得到黄色粗品(600mg)，直接用于下一步反应。LC-MS(ESI):m/z(M+H) +468.75。
f)2-甲硫基-6-(2-溴-6-氯苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮：在0℃下，将2-甲硫基-4-(1-((2-溴-6-氯苯基)氨基)-1H-咪唑-2-基)嘧啶-5-甲酸乙酯(600mg，粗品，等当量)溶于二氯甲烷(20mL)中，加入1,8-二氮杂二环[5.4.0]十一碳-7-烯(146mg，0.96mmol)。反应混合物在0℃下搅拌反应5min。加入水(10mL)，分出有机相，水相用二氯甲烷(10mL)萃取，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，减压浓缩除去有机溶剂得到粗品。经柱层析分离纯化(硅胶，二氯甲烷:甲醇＝10:1)得到目标化合物(380毫克，三步收率75％，黄色固体)。LC-MS(ESI):m/z(M+H) +422.69。 1H  NMR(400MHz,CDCl 3):δ9.38(s,1H),7.79(dd,J＝8.1,1.3Hz,1H),7.67(dd,J＝8.2,1.3Hz,1H),7.52–7.48(m,2H),6.81(d,J＝1.2Hz,1H),2.78(s,3H)。
g)6-(2-溴-6-氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮：将2-甲硫基-6-(2-溴-6-氯苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(50mg,0.12mmol)溶于无水二氯甲烷(20mL)中。在0℃下，将间氯过氧苯甲酸(31mg，0.18mmol)加入到反应体系中，加入完毕后，将反应液温度升至室温，在室温下搅拌反应5min后，减压浓缩除去有机溶剂得到粗产品。将该粗产品溶于乙腈(20mL)中，将3-甲基-4-(4-甲基哌嗪-1-基)苯胺(24.6mg，0.12mmol)和三氟乙酸(0.05mL)加入到反应体系中。将反应液升至室温并在室温下搅拌反应过夜，用饱和碳酸氢钠水溶液将反应液pH值调至7-8。加入二氯甲烷(20mL)和水(10mL)分液萃取，水相用二氯甲烷(15mL×2)萃取，合并有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩除去有机溶剂得到粗产品。用制备液相色谱(C18柱，0-100％乙腈/水为流动相)分离纯化得到目标化合物(10mg，27％收率，黄色固体)。
应用类似于所描述的实施例46g的合成方法制得下述实施例47—50的化合物，起始原料为2-甲硫基-6-(2-溴-6-氯苯基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5-(6H)-酮和相应的取代苯胺。
Figure PCTCN2018095080-appb-000026
Figure PCTCN2018095080-appb-000027
Figure PCTCN2018095080-appb-000028
应用类似于所描述的实施例2的合成方法制得下述实施例51—55的化合物，起始原料为5-溴-2-(甲硫基)嘧啶-4-甲酸、2,2-二甲氧基乙基-1-胺、2,6-二取代苯肼、氰化亚铜和相应的取代苯胺。
Figure PCTCN2018095080-appb-000029
Figure PCTCN2018095080-appb-000030
Figure PCTCN2018095080-appb-000031
实施例56
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮
a)5-溴-2-(甲硫基)-N-(2-氧代丙基)嘧啶-4-甲酰胺：在室温下，向5-溴-2-(甲硫基)嘧啶-4-甲酸(24.4g，98.5mmol)的N,N-二甲基甲酰胺(80.0mL)溶液中加入N,N-二异丙基乙胺(31.9g，246.3mmol)，搅拌1min，然后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(46.9g，123.2mmol)，搅拌1min，最后加入氨基丙酮盐酸盐(6.0g，82.1mmol)。置换氮气后，该反应液在室温下搅拌4h，反应液加入到500mL水中，用二氯甲烷萃取3次，水相用二氯甲烷萃取2次，有机相用盐水洗，减压浓缩除去有机溶剂得到粗产物。经柱层析分离纯化(硅胶，乙酸乙酯:石油醚＝0％-50％)得到目标产物(9.0g，36％收率，黄色固体)。LC-MS(ESI):m/z(M+H) +303.89。
b)5-溴-N-(2-(2-(2,6-二氯苯基)亚肼基)丙基)-2-(甲硫基)嘧啶-4-甲酰胺：在室温下，将5-溴-2-(甲硫基)-N-(2-氧代丙基)嘧啶-4-甲酰胺(2.2g，7.2mmol)，2,6-二氯苯肼盐酸盐(1.5g，7.2mmol)和醋酸(4mL)，醋酸硼氢化钠(2.2mg，10.0mmol)依次加入到1,2-二氯乙烷(50mL)中。反应混合物在室温下搅拌反应3h后，减压浓缩除去有机溶剂得到的粗产品。将粗品溶于二氯甲烷(50mL)中，加入碳酸氢钠饱和水溶液(100mL)分液萃取，水相用二氯甲烷(30mL×2)萃取。合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩除去有机溶剂得到粗产物，直接用于下一步反应。LC-MS(ESI):m/z(M+H) +461.97。
c)5-溴-N-(2-(2-(2,6-二氯苯基)肼基)丙基)-2-(甲硫基)嘧啶-4-甲酰胺：在室温下，将5-溴-N-(2-(2-(2,6-二氯苯基)亚肼基)丙基)-2-(甲硫基)嘧啶-4-甲酰胺(4.0g，8.7mmol)溶于二氯甲烷(20mL)和甲醇(150mL)混合液中，加入硼氢化钠(1.5g，39.1mmol)。 反应混合物在室温下搅拌反应3h后，旋干反应液并用二氯甲烷(50mL)溶解，加入饱和碳酸氢钠水溶液(100mL)分液，水相用二氯甲烷(30mL×2)萃取。合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩除去有机溶剂，得到粗产物，经柱层析分离纯化(硅胶，乙酸乙酯:石油醚＝0％-50％)得到目标产物(1.8g，45％收率，黄色固体)。LC-MS(ESI):m/z(M+H) +463.97。
d)2-(5-溴-2-(甲硫基)嘧啶-4-基)-N-(2,6-二氯苯基)-5-甲基-4,5-二氢-1H-咪唑-1-胺：在室温下，将三氟甲磺酸酐(610mg，2.16mmol)溶于二氯甲烷(10mL)中，0℃下加入三苯基膦(566mg，2.16mmol)。反应混合物在该温度下搅拌反应30min后，将5-溴-N-(2-(2-(2,6-二氯苯基)肼基)丙基)-2-(甲硫基)嘧啶-4-甲酰胺用二氯甲烷(5mL)溶解并加入到反应液中，反应液继续在0℃下搅拌2h，向反应液中加入碳酸氢钠固体，搅拌2min，过滤，滤液直接用于下一步反应。LC-MS(ESI):m/z(M+H) +465.92。
e)2-(5-溴-2-(甲硫基)嘧啶-4-基)-N-(2,6-二氯苯基)-5-甲基-1H-咪唑-1-胺：在室温下，将2-(5-溴-2-(甲硫基)嘧啶-4-基)-N-(2,6-二氯苯基)-5-甲基-4,5-二氢-1H-咪唑-1-胺(粗品滤液)和二氧化锰(2.0g，10.0mmol)加入到二氯甲烷(20mL)中。反应混合物在室温下搅拌反应10h后，过滤除去二氧化锰，减压浓缩除去有机溶剂得到粗产物。经柱层析分离纯化(硅胶，乙酸乙酯:石油醚＝0％-50％)得到目标化合物(含50％三苯基氧膦)(500mg，40％收率，黄色固体)。LC-MS(ESI):m/z(M+H) +463.97。
f)4-(1-((2,6-二氯苯基)氨基)-5-甲基-1H-咪唑-2-基)-2-(甲硫基)嘧啶-5-甲腈：在室温下，将2-(5-溴-2-(甲硫基)嘧啶-4-基)-N-(2,6-二氯苯基)-5-甲基-1H-咪唑-1-胺(1.0g，2.3mmol)和氰化亚铜(414mg，4.6mmol)加入到1,4-二氧六环(15mL)中。反应混合物在80℃下搅拌反应20h后，冷却至室温。将反应液倒入氨水(15mL)和饱和氯化铵水溶液(85mL)中，用乙酸乙酯(50mL×3)萃取。合并有机相，用饱和食盐水洗，无水硫酸钠干燥，减压除去溶剂得到粗产物。经柱层析分离纯化(硅胶，乙酸乙酯:石油醚＝0％-50％)得到目标产物(140mg，15％收率，黄色固体)。LC-MS(ESI):m/z(M+H) +391.01。
g)6-(2,6-二氯苯基)-8-甲基-2-(甲硫基)咪唑[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮：在室温下，将4-(1-((2,6-二氯苯基)氨基)-5-甲基-1H-咪唑-2-基)-2-(甲硫基)嘧啶-5-甲腈(130mg，0.33mmol)加入到盐酸二氧六环溶液(4M，40mL)中。反应混合物在80℃下搅拌反应15h后，降至50℃，加入水(10mL)。反应混合物在50℃下搅拌反应2h后，冷却至室温。减压浓缩除去有机溶剂，加入乙酸乙酯(20mL)和水(10mL)分液萃取，水相用乙酸乙酯(15mL×2)萃取，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，减压除去溶剂得到目标产物(100mg，77％收率，黄色固体)。LC-MS(ESI):m/z(M+H) +392.01。
h)6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮：将6-(2,6-二氯苯基)-8-甲基-2-(甲硫基)咪唑[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(100mg，0.256mmol)溶于无水二氯甲烷(3mL)中。在0℃下，将间氯过氧苯甲酸(53mg，0.307mmol)加入到反应体系中，加入完毕后，将反应液温度升至室温，在室温下搅拌反应1h后，减压浓缩除去有机溶剂得到粗产品。将该粗产品溶于乙腈(5mL)中，将3-氯-4-(4-甲基哌嗪-1-基)苯胺(70mg，0.307mmol)和三氟乙酸(2滴)加入到反应体系中。将反应液升至50℃并在50℃下搅拌反应5h后，用饱和碳酸氢钠水溶液将反应液pH值调至7-8。加入二氯甲烷(50mL)和水(30mL)分液，水相用二氯甲烷(30mL×2)萃取，合并有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩除去有机溶剂得到粗产品。用制备液相色谱(C18柱，0-100％乙腈/水为流动相)分离纯化得到目标化合物(89mg，64％收率，黄色固体)。
实施例57
6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-9-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮
a)2-(5-溴-2-(甲硫基)嘧啶-4-基)-N-(2,6-二氯苯基)-4-甲基-1H-咪唑-1-胺：应用类似于所描述的实施例2a-e的合成方法制得，起始原料为5-溴-2-(甲硫基)嘧啶-4-甲酸、1,1-二甲氧基-2-丙胺、2,6-二氯苯肼。
b)6-(2,6-二氯苯基)-9-甲基-2-(甲硫基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮：在室温下，将2-(5-溴-2-(甲硫基)嘧啶-4-基)-N-(2,6-二氯苯基)-4-甲基-1H-咪唑-1-胺(0.7g，1.57mmol)和醋酸钯(0.071g，0.314mmol)加入到N,N-二甲基甲酰胺(10mL)中。反应混合物在60℃下搅拌反应20h后，冷却至室温。减压除去溶剂得到粗产物。经柱层析分离纯化(硅胶，乙酸乙酯:石油醚＝0％-50％)得到目标产物(0.3g，48.7％收率，黄色固体)。LC-MS(ESI):m/z(M+H) +392.01。
c)6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-9-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮：应用类似于所描述的实施例2h的合成方法制得，起始原料为6-(2,6-二氯苯基)-9-甲基-2-(甲硫基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮和3-氯-4-(4-甲基哌嗪-1-基)苯胺。
下述实施例58和59的化合物应用类似于所描述的实施例2h的合成方法制得，起始原料为6-(2,6-二氯苯基)-9-甲基-2-(甲硫基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮和3-氯-4-(4-甲基哌嗪-1-基)苯胺。
实施例60
6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-9-乙基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮
a)2-(5-溴-2-(甲硫基)嘧啶-4-基)-N-(2,6-二氯苯基)-4-乙基-4,5-二氢-1H-咪唑-1-胺：应用类似于所描述的实施例1a和1c-f的合成方法制得，起始原料为(1-氧代丁-2-基)氨基甲酸叔丁基酯、2,6-二氯苯肼和5-溴-2-(甲硫基)嘧啶-4-甲酸。
b)2-(5-溴-2-(甲硫基)嘧啶-4-基)-N-(2,6-二氯苯基)-4-乙基-1H-咪唑-1-胺：应用类似于所描述的实施例2e的合成方法制得，起始原料为2-(5-溴-2-(甲硫基)嘧啶-4-基)-N-(2,6-二氯苯基)-4-乙基-4,5-二氢-1H-咪唑-1-胺。
c)6-(2,6-二氯苯基)-9-乙基-2-(甲硫基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮：在室温下，将2-(5-溴-2-(甲硫基)嘧啶-4-基)-N-(2,6-二氯苯基)-4-乙基-1H-咪唑-1-胺(0.9g，1.96mmol)，碳酸铯(1.9g，5.88mmol)，1,3-双(二苯基磷烷基)丙烷(323mg，0.78mmol)和醋酸钯(88mg，0.39mmol)加入到二氧六环(10mL)中。反应混合物在60℃一氧化碳气球保护下，搅拌反应20h后，冷却至室温。减压除去溶剂得到粗产物。经柱层析分离纯化(硅胶，乙酸乙酯:石油醚＝0％-50％)得到目标产物(0.3g，48.7％收率，黄色固体)。LC-MS(ESI):m/z(M+H) +392.01。
d)6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-9-乙基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮：应用类似于所描述的实施例2h的合成方法制得，起始原料为6-(2,6-二氯苯基)-9-乙基-2-(甲硫基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮和3-甲基-4-(4-甲基哌嗪-1-基)苯胺。
下述实施例61的化合物应用类似于所描述的实施例60d的合成方法制得，起始原料为6-(2,6-二氯苯基)-9-乙基-2-(甲硫基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮和3-甲基-4-(4-(二甲氨基)哌啶-1-基)苯胺。
下述实施例62和63的化合物应用类似于所描述的实施例1a-f和实施例60b-d的合成方法制得，起始原料为(3-甲基-1-氧代丁烷-2-基)氨基甲酸叔丁酯，2,6-二氯苯肼，5-溴-2-(甲硫基)嘧啶-4-甲酸和3-甲基-4-(4-(二甲氨基)哌啶-1-基)苯胺。
Figure PCTCN2018095080-appb-000032
Figure PCTCN2018095080-appb-000033
Figure PCTCN2018095080-appb-000034
实施例64
6-烯丙基-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮
应用类似于所描述的实施例2的合成方法制得。M.W.458.57。
实施例65
应用Wee1激酶(人源)检测法测定6-(2,6-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮与其相似物对Wee1激酶的酶活性的抑制效应
在含20mM Tris/HCl pH 8.5，0.2mM EDTA，500μM LSNLYHQGKFLQTFCG SPLYRRR，10mM醋酸镁和10μM[γ- 33P]-ATP的反应液中加入Wee1激酶(人源)孵育，而后加入50倍浓度的溶于100％DMSO中的待测化合物储液至终浓度1/0.1/0.01μM，混匀。加入Mg/ATP混合物启动反应，在室温下孵育40分钟后，加入磷酸溶液至终浓度0.5％淬灭反应。取10μL反应液滴到P30滤纸上用0.425％磷酸溶液洗4次之后用甲醇洗1次，干燥，液闪计数。每个化合物样品一式二份重复。实验阴性对照为缺少Wee1酶的所有组成部分，阳性为加入30％磷酸终止反应。在相同实验条件下对Wee1抑制剂AZD1775在10/0.01μM下进行了检测。
表1汇总了化合物的Wee1激酶抑制数据(抑制率％)。
表1. 6-(2,6-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮对Wee1激酶活性的抑制效应
Figure PCTCN2018095080-appb-000035
因此，经Wee1激酶(人源)检测法测定，6-(2,6-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例1)与其相似物对Wee1激酶酶活性有好的抑制效应。
实施例66
应用MTT检测法测定6-(2,6-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮与其相似物对LoVo细胞增长的抑制作用
将新复苏的LoVo细胞培养传代至第三代后，且生长状态良好、融合度90％左右，开始用于实验。用胰酶消化LoVo细胞，800rpm离心5min，弃上清，用新鲜培基重悬，并计数，以6000个细胞每孔密度接种至96孔细胞培养板，置于37℃5％CO 2培养箱培养过夜。受试物(包括待测化合物和参考化合物AZD1775)母液用DMSO按1:3和1:10比例分别进行连续系列稀释至8个浓度(最后一个浓度为DMSO阴性对照)：10μM，3.3μM，1μM，0.33μM，0.1μM，0.033μM，0.01μM，0μM(DMSO终浓度为1‰)。每个浓度取5μL加入到120μL培基(25倍稀释)，振荡混匀。取培养过夜的细胞，除去培养基，每孔加入195μL新鲜培基，再分别加入5μL稀释好的含相应浓度受试物的培基，随后将培养板置于37℃5％CO 2培养箱培养3d。除去原液，每孔加100μL含MTT(0.5mg/mL)的新鲜无血清DMEM培基后，继续培养。4h后除去原液，每孔加入100μL DMSO，避光震荡10min，置于多功能读数仪读取552/630/690nm波长的吸光值(OD值)。用软件Graph Pad Prism 5.0分析数据，化合物对细胞增值的抑制活性以细胞存活率和化合物浓度为坐标绘图。IC 50值以S形剂量反应曲线方程拟合，曲线方程为：Y＝100/(1+10^(LogC-LogIC 50))，其中C是化合物浓度。
表2汇总了化合物对LoVo细胞增长的抑制作用数据(IC 50)。
表2. 6-(2,6-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮对LoVo细胞增长的抑制作用
实施例 1 2 3 4 7 9
IC 50(μm) 0.5241 0.4055 0.2362 0.3394 0.8311 0.2130
实施例 11 12 13 14 15 16
IC 50(μm) 0.2660 0.8177 0.4878 0.8708 0.8316 0.4245
实施例 17 18 19 20 21 22
IC 50(μm) 0.9020 0.5788 0.4079 0.3636 0.2590 0.1378
实施例 23 24 25 26 27 28
IC 50(μm) 0.1946 0.3588 0.1438 0.2013 0.3695 0.2665
实施例 29 30 31 32 33 34
IC 50(μm) 0.2722 0.7787 0.8093 0.6794 0.3943 0.2364
实施例 35 36 37 38 41 43
IC 50(μm) 0.3020 0.2057 0.2906 0.4155 0.2122 0.4756
实施例 44 45 46 47 48 49
IC 50(μm) 0.3709 0.3331 0.2423 0.3703 0.2268 0.2722
实施例 50 51 52 53 54 55
IC 50(μm) 0.3235 0.9979 0.7562 0.6420 0.6368 0.5605
实施例 56 57 58 59 60 61
IC 50(μm) 0.4338 0.2693 0.2421 0.2848 0.3254 0.3516
实施例 62 AZD1775        
IC 50(μm) 0.6202 0.1545        
因此，经MTT检测法测定，6-(2,6-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例1)与其相似物对LoVo细胞增长有好的抑制作用。
实施例67
应用MTT检测法测定6-(2,6-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮与其相似物对NCI-H1299细胞增长的抑制作用
将新复苏的NCI-H1299细胞培养传代至第三代后，且生长状态良好、融合度90％左右，开始用于实验。用胰酶消化NCI-H1299细胞，800rpm离心5min，弃上清，用新鲜培基重悬，并计数，以1000个细胞每孔密度接种至96孔细胞培养板，置于37℃5％CO 2培养箱培养过夜。受试物(包括待测化合物和参考化合物AZD1775)母液用DMSO按1:3和1:10比例分别进行连续系列稀释至8个浓度(最后一个浓度为DMSO阴性对照)：10μM，3.3μM，1μM，0.33μM，0.1μM，0.033μM，0.01μM，0μM(DMSO终浓度为1‰)。每个浓度取5μL加入到120μL培基(25倍稀释)，振荡混匀。取培养过夜的细胞，除去培养基，每孔加入195μL新鲜培基，再分别加入5μL稀释好的含相应浓度受试物的培基，随后将培养板置于37℃5％CO 2培养箱培养3d。除去原液，每孔加100μL含MTT(0.5mg/mL)的新鲜无血清DMEM培基后，继续培养。4h后除去原液，每孔加入100μL DMSO，避光震荡10min，置于多功能读数仪读取552/630/690nm波长的吸光值(OD值)。用软件Graph Pad Prism 5.0分析数据，化合物对细胞增值的抑制活性以细胞存活率和化合物浓度为坐标绘图。IC 50值以S形剂量反应曲线方程拟合，曲线方程为：Y＝100/(1+10^(LogC-LogIC 50))，其中C是化合物浓度。
表3汇总了化合物对NCI-H1299细胞增长的抑制作用数据(IC 50)。
表3. 6-(2,6-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮对NCI-H1299细胞增长的抑制作用
实施例 1 2 3 4 7 9
IC 50(μm) 0.9163 0.6516 0.1785 0.3831 0.7810 0.2836
实施例 11 12 13 14 15 16
IC 50(μm) 0.5554 0.4449 0.7379 0.5868 0.9044 0.3646
实施例 17 18 19 20 21 22
IC 50(μm) 0.8020 1.080 0.7434 0.5973 0.5113 0.3755
实施例 23 24 25 26 27 28
IC 50(μm) 0.5282 0.3276 0.2493 0.2685 0.4696 0.2953
实施例 29 30 31 32 33 34
IC 50(μm) 0.4002 0.5082 0.6724 0.5146 0.2368 0.2194
实施例 35 36 37 38 41 43
IC 50(μm) 0.1818 0.1350 0.1866 0.9781 0.1844 0.1754
实施例 44 45 46 47 48 49
IC 50(μm) 0.1642 0.2703 0.2713 0.5622 0.2806 0.3372
实施例 50 51 52 53 54 55
IC 50(μm) 0.5006 1.217 0.8090 0.8088 0.4186 0.6626
实施例 56 57 58 59 60 61
IC 50(μm) 0.5402 0.1732 0.1510 0.2201 0.1606 0.1260
实施例 62 AZD1775        
IC 50(μm) 0.1973 0.1165        
因此，经MTT检测法测定，6-(2,6-二氯苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮(实施例1)与其相似物对NCI H1299细胞增长有好的抑制作用。
虽然已经充分地描述了本发明，但是本领域技术人员应当理解，可在不影响本发明范围或其任何实施方案的情况下，在广泛且等同的条件、制剂和其它参数范围内进行相同实施。本文所引用的所有专利、专利申请和出版物都全文引入本文以供参考。

Claims (10)

  1. 式I的化合物，或其可药用盐或前药：
    Figure PCTCN2018095080-appb-100001
    其中，A是N或CR 6；
    R 1为可被取代的C 1-C 8烷基，可被取代的C 2-C 8烯基，可被取代的C 3-C 8环烷基，可被取代的芳基，或可被取代的杂芳基；
    R 2为可被取代的杂环基，可被取代的芳基，或可被取代的杂芳基；
    R 3-R 6独立为氢、卤素、可被取代的氨基、可被取代的烷氧基、可被取代的C 1-C 10烷基(如卤烷基、羟基烷基、氨基烷基和羧基烷基)、烯基、炔基、硝基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、羧基、亚乙基二氧基，羟基酰氨基或可被取代的烷硫基。
  2. 权利要求1的化合物，其中A是N，R 1和R 2为可被取代的芳基，R 3-R 5为氢；
    优选地，R 1选自任选地被1－4个选自卤素和C 1-C 6烷基的取代基取代的苯基；
    优选地，R 2选自：可被取代的苯基和四氢异喹啉基；优选地，R 2的取代基选自以下基团中的任意一个、任意两个、任意三个或任意四个：可被取代的C 1-C 6烷基、可被取代的氧基、卤素和可被取代的杂环基；优选地，这些可被取代的取代基上的取代基团为1－4个选自以下的基团：C 1-C 6烷基和-NR aR b，其中，R a和R b各自独立为H和C 1-C 6烷基；优选地，所述杂环基选自哌嗪基和哌啶基。
  3. 权利要求1的化合物，其中为式II的化合物，或其可药用盐或前药:
    Figure PCTCN2018095080-appb-100002
    其中，R 3-R 5独立为氢、卤素、可被取代的氨基、可被取代的烷氧基、可被取代的C 1-10烷基(如卤烷基、羟基烷基、氨基烷基和羧基烷基)、烯基、炔基、硝基、氰基、酰这基、羟基、巯基、酰氧基、叠氮基、羧基、亚乙基二氧基，羟基酰氨基或可被取代的烷硫基。
    Ar 1和Ar 2为可被取代的芳基或可被取代的杂芳基。
  4. 权利要求3的化合物，其中R 3-R 5各自独立为氢或可被取代的C 1-6烷基，Ar 1和Ar 2各自独立为可被取代的苯基；
    优选地，R 1选自任选地被1－4个选自卤素和C 1-C 6烷基的取代基取代的苯基；
    优选地，R 2选自被任选取代的哌嗪基取代的苯基和被任选取代的哌啶基取代的苯基；优选地，所述哌嗪基任选地被1－3个选自C 1-C 6烷基的取代基取代，所述哌啶基任选地被1个选自C 1-C 6烷基和-NR aR b的取代基取代，其中，R a和R b各自独立为H和C 1-C 6烷基。
  5. 权利要求1的化合物，其中所述化合物选自：
    6-(2-氯-6-氟苯基)-2-((2,4,4-三甲基-1,2,3,4-四氢异喹啉-7-基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氟苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氯-6-氟苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氯-6-氟苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氯-6-氟苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氯-6-氟苯基)-2-((2,4,4-三甲基-1,2,3,4-四氢异喹啉-7-基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氟苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氟-6-甲基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氟-6-甲基苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氯-6-甲基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氯-6-甲基苯基)-2-((3,5-二甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氟苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氟苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氟苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氯-6-氟苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氯-6-氟苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氯-6-氟苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氯-6-氟苯基)-2-((3-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氯-6-氟苯基)-2-(3-氟-5-甲基-(4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-甲基-4-(哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-氟-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-氯-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-3,4,5-三甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-甲基-4-((3S,5R)-4-异丙基-3,5-二甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-氯-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-氯-5-甲氧基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-氟-4-(1-甲基哌啶-4-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-氯-4-(1-甲基哌啶-4-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-甲基-4-(1-甲基哌啶-4-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(1-甲基哌啶-4-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((2,4,4,5-四甲基-1,2,3,4-四氢异喹啉-7-基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((2,5-二甲基-1,2,3,4-四氢异喹啉-7-基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-溴-6-氟苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-溴-6-氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-溴-6-氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-溴-6-氯苯基)-2-((3-氯-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-溴-6-氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-溴-6-氯苯基)-2-((3-氟-5-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氟-6-甲基苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氟-6-甲基苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氯-6-甲基苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氯-6-甲基苯基)-2-((3-氟-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2-氯-6-甲基苯基)-2-((3-氯-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-8-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-氯-4-(4-甲基哌嗪-1-基)苯基)氨基)-9-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-9-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-氟-5-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-9-甲基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-9-乙基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-9-乙基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-9-异丙基咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-(2,6-二氯苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)-9-(羟基甲基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    6-烯丙基-2-((3-甲基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮；
    或其可药用盐或前药。
  6. 权利要求1～5中任一项所述的化合物在制备治疗或预防Wee1介导的疾病的药物中的用途。
  7. 权利要求6的用途，其中所述疾病是癌症；优选地，所述癌症选自肝癌、黑素瘤、霍奇金病、非霍奇金淋巴瘤、急性淋巴白血病、慢性淋巴白血病、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、肺癌、维尔姆斯瘤、子***、睾丸癌、软组织肉瘤、慢性淋巴细胞白血病、原发性巨球蛋白血症、膀胱癌、慢性粒细胞白血病、原发性脑癌、恶性黑素瘤、小细胞肺癌、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌症、恶性黑素瘤、绒毛膜癌、蕈樣肉芽腫、头颈癌、骨原性肉瘤、胰腺癌、急性粒细胞白血病、毛细胞白血病、横纹肌肉瘤、卡波西肉瘤、泌尿生殖***肿瘤、甲状腺癌、食管癌、恶性高钙血症、子宫颈增生症、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多症、肾上腺皮质癌、皮肤癌和***癌。
  8. 一种药用组合物，包括权利要求1～5中任一项所述的化合物与可药用载体。
  9. 权利要求8的药用组合物，其中所述组合物还含有至少一种已知的抗癌药物，或所述抗癌药物的可药用盐。
  10. 权利要求8或9的药用组合物，其中，所述组合物还含有至少一种选自下组的抗癌药物：白消安、马法兰、苯丁酸氮芥、环磷酰胺、异环磷酰胺、替莫唑胺、苯达莫司汀、顺铂、丝裂霉素C、博莱霉素、卡铂、喜树碱、伊立替康、托泊替康、阿霉素、表阿霉素、阿克拉霉素、米托蒽醌、甲基羟基玫瑰树碱、铭托泊普、5-氮杂胞苷、吉西他滨、5-氟尿嘧啶、甲氨蝶呤、5-氟-2'-去氧尿苷、氟达拉滨、奈拉滨、阿糖胞苷、普拉曲沙、培美曲塞、羟基脲、硫代鸟嘌呤、秋水仙碱、长春碱、长春新碱、长春瑞滨、紫杉醇、伊沙匹隆、卡巴他赛、多西他赛、单抗、帕尼单抗、耐措妥珠单抗、纳武单抗、派姆单抗、雷莫芦单抗、贝伐珠单抗、帕妥珠单抗、曲妥珠单抗、西妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、利妥昔单抗、阿仑单抗、替伊莫单抗、托西莫单抗、本妥昔单抗、达雷木单抗、埃罗妥珠单抗、T-DM1、Ofatumumab、Dinutuximab、Blinatumomab、易普利姆玛、阿瓦斯丁、赫赛汀、美罗华、伊马替尼、吉非替尼、厄洛替尼、奥斯替尼、阿法替尼、赛立替尼、艾乐替尼、克唑替尼、埃罗替尼、拉帕替尼、索拉非尼、舒尼替尼、尼罗替尼、达沙替尼、帕唑帕尼、特癌适、依维莫司、伏立诺他、罗咪地辛、帕比司他、贝利司他、他莫昔芬、来曲唑、氟维司群、米托胍腙、奥曲肽、视黄酸、砒霜、唑来膦酸、硼替佐米、卡非佐米、Ixazomib、维莫德吉、索尼德吉、狄诺塞麦、萨力多胺、来那度胺、Venetoclax、Aldesleukin(重组人白介素-2)、Sipueucel-T(***癌治疗疫苗)、帕博西尼、奥拉帕尼、Niraparib、Rucaparib和Talazoparib。
PCT/CN2018/095080 2017-07-10 2018-07-10 咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮类化合物及其应用 WO2019011228A1 (zh)

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