WO2018011570A1 - Composés de pyridopyrimidinone inhibant la wee -1 - Google Patents

Composés de pyridopyrimidinone inhibant la wee -1 Download PDF

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WO2018011570A1
WO2018011570A1 PCT/GB2017/052042 GB2017052042W WO2018011570A1 WO 2018011570 A1 WO2018011570 A1 WO 2018011570A1 GB 2017052042 W GB2017052042 W GB 2017052042W WO 2018011570 A1 WO2018011570 A1 WO 2018011570A1
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group
compound
amino
phenyl
dichlorophenyl
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PCT/GB2017/052042
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English (en)
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Frank Burkamp
James Samuel Shane Rountree
Adam Piotr TREDER
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Almac Discovery Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds that are useful as inhibitors of the activity of Wee-1 kinase.
  • the present invention also relates to pharmaceutical compositions comprising these compounds and to methods of using these compounds in the treatment of cancer and methods of treating cancer.
  • kinases have been identified as key regulators of the G2 checkpoint, namely Chk1 , Chk2 and Wee-1. Inhibitors for these kinases are currently being evaluated in clinical trials.
  • Wee-1 is a nuclear tyrosine kinase which negatively regulates entry into mitosis at the G2/M check-point by catalysing a phosphorylation of the cdc2 / cyclin B kinase complex.
  • the phosphorylation occurs on the tyrosine-15 residue and leads to the inactivation of the cdc2 / cyclin B complex, ultimately preventing mitosis.
  • Wee-1 function is intimately linked to that of Chk1 and Chk2 due to their phosphorylation and inactivation of cdc25 on serine- 216, as well as the reported activation of Wee-1 by Chk 1 & 2 (Ashwell et al., 2012, DNA Repair in Cancer Therapy, DOI: 10. 1016 B978-0-12-384999-1. 10010-1).
  • Wee-1 is downstream of the Chk family and is a crucial component of the checkpoint signalling cascade as it prevents cells from entering mitosis if lesions are detected (Do et al., Cell Cycle 2013 12 (19) 3159-3164).
  • chemosensitization upon Wee-1 inhibition include but are not limited to combination with irinotecan, topotecan or alkylating agent (temozolomide). Radiosensitization has also been demonstrated in multiple cancer types (Havelek R., et al. 2014 Biochem Biophys Res Commun., 24 (453), 569-75; Caretti V., et al. 2013 Mol Cancer Ther., 12 (2) 141-50; Bridges KA., et al. 201 1 Clin Cancer Res., 1 (17), 5638-48; PosthumaDeBoer J., et al. 2011 BMC Cancer., 29 (1 1 ) , 156) .
  • Chk-1 inhibitors Carrasa et al., 2012 Cell Cycle 1 : 11 (13):2507- 2517
  • Src inhibitors Cozzi et al., 2012, Cell Cycle 11 (5), 1-1 1
  • PARP inhibitor Karnak D., et al. 2014 Clin. Cancer Res., 1 (20), 5085-96
  • HSP90 inhibitor Likeshwar VB., 2012 Cell Cycle., 15 (11), 3722-3; Iwai A., et al.
  • Irradiation is known to increase phosphorylation of the Tyr15 and Thr14 residues of cdc2, leading to a radioresistant phenotype.
  • Inhibition of Wee-1 activity by small molecule inhibitors (Wang et ai, 2004, Cancer Biology and Therapy 3(3), 305-313), (Caretti et al., 2013 Mol Cancer Ther. 12 (2) 141-150) leads to a reduction in phosphorylation and radiosensitization, with the effect being more pronounced in p53 mutant cell lines.
  • kinase inhibitory effect for example a Wee-1 kinase inhibitory effect
  • WO2002/090360 WO2007/126122, US2007/0254892
  • WO2008/1 15742 WO2008/153207
  • WO2010/098367 US2012/0220572
  • WO2012/161812 Compounds having a kinase inhibitory effect, for example a Wee-1 kinase inhibitory effect, are described in WO2002/090360, WO2007/126122, US2007/0254892, WO2008/1 15742, WO2008/153207, WO2010/098367, US2012/0220572, WO2012/161812,
  • This compound is said to have a Wee-1 activity of less than 10 nM, and a CDC2 activity of more than 100nM but less than 1000 nM. Furthermore, WO2015/092431 , Example 18 (page 106), describes the synthesis of a
  • This compound is said to have a Wee-1 activity of less than 10 nM, and a CDC2 activity of more than 100nM but less than 1000 nM.
  • This compound is said to have a Wee-1 activity of less than 100 nM, and a CDC2 activity of less than 500 nM.
  • This compound is said to have a Wee-1 activity of less than 10 nM, and a CDC2 activity of less than 100 nM.
  • WO2013/013031 Example 174 (page 156), describes the synthesis of a compound having the formula:
  • This compound is said to have a Wee-1 activity of 0.1 nM.
  • Example 207 (page 163) describes the synthesis of a
  • This compound is said to have a Wee-1 activity of 0.1 nM.
  • This compound is said to have a Wee-1 activity of less than 10 nM.
  • R 1 is an optionally substituted aryl or heteroaryl group
  • R 2 is an optionally substituted alkyl group, an alkynyl group optionally substituted by one or more alkyl groups and/or one or more alkoxy groups, or a cyano group
  • R 3 is an optionally substituted alkyl group, a cycloalkyl group, an alkoxy group or a cycloalkoxy group
  • R 4 is a hydrogen atom, an alkyl group or a cycloalkyl group
  • X is a nitrogen atom or a CH-group
  • Y is a nitrogen atom or a CH-group
  • Z is a nitrogen atom or a CH-group
  • n is 1 when X is a nitrogen atom and n is 0 or 1 when X is a CH-group.
  • the present invention provides the compound of Formula (I), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, and at least one
  • the present invention provides a pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, and at least one pharmaceutically acceptable excipient.
  • the present invention provides the compound of Formula (I), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, or the pharmaceutical composition as described herein, for use in therapy.
  • the present invention provides the compound of Formula (I), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, or the pharmaceutical composition as described herein, for use as a medicament.
  • the present invention provides the compound of Formula (I), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, or the pharmaceutical composition as described herein, for use in treating or preventing cancer.
  • the present invention provides the use of the compound of Formula (I), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, or the pharmaceutical composition as described herein, for the manufacture of a medicament for treating or preventing cancer.
  • the present invention provides a method of treating or preventing cancer in a human or animal patient comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or N- oxide derivative thereof, or the pharmaceutical composition as described herein.
  • a compound of Formula (I) or a pharmaceutically acceptable salt or N- oxide derivative thereof, or the pharmaceutical composition as described herein.
  • Other preferred embodiments of the compounds according to the invention appear throughout the specification and in particular in the examples. Particularly preferred are those named compounds having greater activity as tested. Compounds having higher activity are more preferred over those having lower activity.
  • the present inventors have also surprisingly found that compounds of the present invention show an enhanced or similar kinetic solubility compared to known compounds.
  • the present inventors have also surprisingly found that compounds of the present invention show an enhanced or similar stability in human microsomes compared to known compounds.
  • the present inventors have surprisingly found that compounds of the present invention exhibit an enhanced or similar Wee-1 kinase inhibitory effect as well as displaying enhanced or comparable Wee-1 potency in cells, and/or an enhanced or similar kinetic solubility, and/or an enhanced or similar thermodynamic solubility, and/or an enhanced or similar stability in human microsomes, compared to known compounds.
  • the compounds of the present invention tend to show the advantageous effects discussed above due, at least in part, to the presence of a pyrido[4,3-d]pyrimidin-5-one (or a pyridazino[4,5-d]pyrimidin-6-one) in combination with an alkyl group, a cyano group or optionally substituted alkynyl group as R 2 , an optionally substituted alkyl group, a cycloalkyl group, an alkoxy group or a cycloalkoxy group as R 3 , a nitrogen atom or methine group as X, and a hydrogen atom, deuterium atom, an alkyl group or a cycloalkyl group as R 4 .
  • alkyl group (alone or in combination with another term(s)) means a straight-or branched-chain saturated hydrocarbyl substituent typically containing 1 to 15 carbon atoms, such as 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms.
  • a "C n alkyl' group refers to an aliphatic group containing n carbon atoms.
  • a C1-C10 alkyl group contains 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Attachment to the alkyl group occurs through a carbon atom.
  • substituents include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl (branched or unbranched), hexyl (branched or unbranched), heptyl (branched or unbranched), octyl (branched or unbranched), nonyl (branched or unbranched), and decyl (branched or unbranched).
  • alkynyl group (alone or in combination with another term(s)) means a straight-or branched-chain hydrocarbon substituent containing one or more triple bonds and typically 2 to 15 carbon atoms; such as 2 to 10, 2 to 8, 2 to 6 or 2 to 4 carbon atoms.
  • substituents include ethynyl, 1-propynyl, 3-propynyl, 1-butynyl, 3-butynyl and 4- butynyl.
  • cycloalkyi group (alone or in combination with another term(s)) means a saturated cyclic hydrocarbon substituent containing 3 to 14 carbon ring atoms.
  • a cycloalkyi may be a single carbon ring, which typically contains 3 to 8 carbon ring atoms and more typically 3 to 6 ring atoms. It is understood that attachment to a cycloalkyi group is via a ring atom of the cycloalkyi group.
  • single-ring cycloalkyls include cyclopropyl (cyclopropanyl), cyclobutyl (cyclobutanyl), cyclopentyl (cyclopentanyl), cyclohexyl
  • a cycloalkyi may alternatively be partly unsaturated or be polycyclic or contain more than one ring.
  • polycyclic cycloalkyls include bridged, fused, and spirocyclic cycloalkyls.
  • a spirocyclic cycloalkyi one atom is common to two different rings.
  • An example of a spirocyclic cycloalkyi is spiropentanyl.
  • the rings In a bridged cycloalkyi, the rings share at least two common non-adjacent atoms.
  • bridged cycloalkyls examples include bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl.
  • two or more rings may be fused together, such that two rings share one common bond.
  • two- or three-fused ring cycloalkyls include
  • tetrahydronaphthalenyl tetralinyl
  • indenyl indenyl
  • indanyl dihydroindenyl
  • decalinyl tetrahydronaphthalenyl
  • aryl group (alone or in combination with another term(s)) means an aromatic cycloalkyi containing from 6 to 14 carbon ring atoms, or 6 to 12, 6 to 10 or 6 to 8 carbon ring atoms.
  • An aryl may be monocyclic or polycyclic (i.e., may contain more than one ring). In the case of polycyclic aromatic rings, only one ring in the polycyclic system is required to be unsaturated while the remaining ring(s) may be saturated, partially saturated or unsaturated. Attachment to the aryl group occurs through a carbon atom contained in the ring.
  • aryl groups include phenyl, naphthyl, indenyl, indanyl, and
  • heterocyclyl group (alone or in combination with another term(s)) means a saturated (i.e. "heterocycloalkyl"), partially saturated (i.e. “heterocycloalkenyl”), or completely unsaturated (i.e. "heteroaryl”) ring structure containing a total of 3 to 14 ring atoms, wherein at least one of the ring atoms is a heteroatom (i.e. oxygen, nitrogen, or sulfur), with the remaining ring atoms being carbon atoms.
  • a heterocyclyl group may, for example, contain one, two, three, four or five heteroatoms. One or more attachments to the heterocyclyl group may occur either through a carbon atom and/or one or more heteroatoms that are contained in the ring.
  • a heterocyclyl may be a single-ring
  • a heterocyclyl group may be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms.
  • single-ring heterocyclyles include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl, oxazolidinyl, isoxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, isothiazolinyM oxo, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxadiazol
  • a heterocydyl group may alternatively be polycyclic (i.e., may contain more than one ring).
  • polycyclic heterocydyl groups include bridged, fused, and spirocyclic heterocydyl groups.
  • a spirocyclic heterocydyl group one atom is common to two different rings.
  • a bridged heterocydyl group the rings share at least two common non- adjacent atoms.
  • two or more rings may be fused together, such that two rings share one common bond.
  • fused ring heterocydyl groups containing two or three rings include indolizinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]- pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl.
  • fused-ring heterocydyl groups containing two or three rings include indolizinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]- pyridinyl, or pyrido[4,3-b]-pyr
  • heterocydyl groups include benzo-fused heterocydyl groups, such as indolyl, isoindolyl (isobenzazolyl, pseudoisoindolyl), indoleninyl (pseudoindolyl), isoindazolyl (benzpyrazolyl), benzazinyl (including quinolinyl (1-benzazinyl) or isoquinolinyl (2 -benzazinyl)),
  • phthalazinyl quinoxalinyl, benzodiazinyl (including cinnolinyl (1 ,2-benzodiazinyl) or quinazolinyl (1 ,3-benzodiazinyl)), benzopyranyl (including chromanyl or isochromanyl), benzoxazinyl, and benzisoxazinyl (including 1 ,2-benzisoxazinyl or 1 ,4-benzisoxazinyl).
  • heterocycloalkyl group (alone or in combination with another term(s)) means a saturated heterocydyl group.
  • heteroaryl group (alone or in combination with another term(s)) means an aromatic heterocydyl containing from 5 to 14 ring atoms.
  • a heteroaryl may be a single ring or 2 or 3 fused rings.
  • heteroaryl groups include 6-membered rings such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and 1 ,3,5-, 1 ,2,4- or 1 ,2,3-triazinyl; 5-membered rings such as imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1 ,2,3-, 1 ,2,4-, 1 ,2,5-, or 1 ,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused rings such as benzothiofuranyl, benzisoxazolyl, be
  • amino group refers to the -NH 2 group.
  • the amino group can be optionally substituted (a "substituted amino") with one or more substituents, which can be the same or different.
  • Amino group substituents may be, but are not limited to, an alkyl, alkanoyi, aryl and/or a heterocyclyl group.
  • alkoxy group refers to an -O-alkyl group.
  • the alkoxy group can refer to linear, branched, saturated or unsaturated hydrocarbon chains, including, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and pentoxy.
  • the alkoxy group can be optionally substituted (a "substituted alkoxy") with one or more substituents.
  • the term "cycloalkoxy group” refers to an -O-cycloalkyl group.
  • the cycloalkoxy group refers to cyclic, saturated or unsaturated, hydrocarbon chains, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl and cyclohexyl.
  • the cycloalkyl group can be optionally substituted (a "substituted cycloalkoxy") with one or more substituents.
  • the term "hydroxy" refers to an -OH group.
  • alkanoyi group refers to an organic acid group wherein the -OH of the carboxyl group has been replaced with another substituent.
  • alkanoyi groups include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group and a benzoyl group.
  • halo group refers to a group selected from chlorine, fluorine, bromine and iodine. Examples of halo groups include a chlorine atom (a chloro group) and a fluorine atom (a fluoro group).
  • alkyi, alkynyl, amino, amido, alkoxy, cycloalkyl, aryl, heterocyclyl group can be optionally substituted with one or more substituents, which can be the same or different.
  • a substituent can be attached through a carbon atom and/or a heteroatom in the alkyi, alkynyl, amino, amido, alkoxy, clyloalkyl, aryl, heterocyclyl group.
  • substituted alkyi includes but is not limited to alkyi, substituted alkyi, aralkyi, substituted aralkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halo, cyano, amino, amido, alkylamino, arylamino, carbocyclyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, nitro, thio, alkanoyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, alkylsulfonyl and arylsulfonyl. If a group (for example an alkyi group) is "optionally
  • Stereoisomers are known in the art to be molecules that have the same molecular formula and sequence of bonded atoms, but which differ in their spatial orientations of their atoms and / or groups.
  • the compounds of the present invention may possess tautomerism. Each tautomeric form is intended to fall within the scope of the invention.
  • the compounds of the present invention may be provided as a pro-drug. Prodrugs are transformed, generally in vivo, from one form to the active forms of the drugs described herein.
  • a prodrug may be formed by protecting any -N-H groups with a hydrolysable group that gives -NH on hydrolysis. Any -NH group within the compound may be protected as a physiological hydrolyzable amide.
  • a hydrogen atom may be 1 H, 2 H (deuterium) or 3 H (tritium).
  • the compounds of the present invention may be provided in the form of their pharmaceutically acceptable salts or as co-crystals.
  • the compounds may be provided having protonated amine groups.
  • pharmaceutically acceptable salt' refers to ionic compounds formed by the addition of an acid to a base.
  • pharmaceutically acceptable salts are generally chosen for their non-toxic, non-irritant characteristics.
  • co-crystaf refers to a multi- component molecular crystal, which may comprise non-ionic interactions.
  • compositions may be prepared by ion exchange chromatography or by reacting the free base or acidic form of a compound with
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Further reference is made to the number of literature sources that survey suitable pharmaceutically acceptable salts, for example the Handbook of pharmaceutical salts published by lUPAC.
  • the compounds of the present invention may sometimes exist as zwitterions, which are considered as part of the invention.
  • the present inventors have discovered that the compounds of the present invention are useful in the treatment of medical conditions associated with disordered cell growth, including, but not restricted to, cancer, in particular (but not restricted to) cancers associated with inactivation in the tumour suppressor gene p53.
  • the compound may have utility and activity as a single agent exploiting synthetic or contextual lethality relationships as well as in diseases including cancers with enhanced susceptibility to increased replicative stress and impaired cell cycle progression.
  • Wee1 inhibitors according to the invention may also be used in combination modalties including combinations with genotoxic agents, radiotherapy, targeted agents and immune-modulators including but not restricted to immune checkpoint inhibitors.
  • cancers include cardiac cancers, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, hematologic cancers, skin cancers and adrenal gland cancers, and cancers such as adrenal tumors, bile duct, bladder, blood, bone and connective tissue, brain and central nervous system, breast, cervical, colon and rectal (colorectal), endometrial, esophageal, gallbladder, head and neck, Hodgkin's Lymphoma,
  • hypopharangeal kidney, laryngeal, leukemias, liver, lung, lymphoma, mediastinal tumors, melanoma (malignant melanoma), mesothelioma, multiple myeloma, nasal cavity, nasopharyngeal, neuroendocrine tumors, non-Hodgkin's lymphoma, oral, oesophagus, oropharyngeal, ovarian, pancreas, paranasal sinus, parathyroid, penis, pituitary tumors, prostate, salivary gland, sarcoma, skin, spine, stomach, testicular, thyroid, urethra, uterine, vaginal and vulvar.
  • the cancer is selected from colon and rectal (colorectal) cancer, head and neck cancer, lung cancer, oesophagus cancer, ovarian cancer and pancreas cancer. More preferably, the cancer is colon and rectal (colorectal) cancer. Alternatively, preferably, the cancer is lung cancer, more preferably non-small cell lung cancer.
  • the compounds of the present invention are also useful in preparing a medicament that is useful in treating the diseases described above, in particular cancer.
  • the present invention is further directed to a method of inhibiting Wee-1 activity which comprises administering to a mammal, preferably a human, in need thereof a
  • the compounds of this invention may be administered to mammals, including humans, either alone or, in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • the present invention also includes within its scope the use of the compounds of the present invention in combination with a second or further drug in the treatment of cancer.
  • the second or further drug may be a drug that is already known in the art in the treatment of cancer.
  • the present invention also includes the use of the compounds of the invention in a regime including the step of radiotherapy.
  • the radiotherapy may be an ordinary method of treatment by x-ray, ⁇ -ray, neutron, a-particle, proton or electron beam irradiation.
  • the co- administration of compounds contained in this invention may lead to the potentiation of the radiation therapy, thus classifying them as radio-sensitizers.
  • cancers often become resistant to therapy.
  • the development of resistance may be delayed or overcome by the administration of a combination of drugs that includes the compounds of the present invention for example in cancers which are known to be resistant to DNA damaging agents, radiotherapy or any other form of treatment agents and modalities.
  • drugs that may be used in combination with the compounds of the present invention may target the same or a similar biological pathway to that targeted by the compounds of the present invention or may act on a different or unrelated pathway.
  • a variety of combination partners may be coadministered with the compounds of the present invention, for example genotoxic agents, targeted agents and immune-modulators.
  • the second active ingredient may include, but is not restricted to: alkylating agents, including cyclophosphamide, ifosfamide, thiotepa, melphalan, chloroethylnitrosourea and bendamustine; platinum derivatives, including cisplatin, oxaliplatin, carboplatin and satraplatin; antimitotic agents, including vinca alkaloids (vincristine, vinorelbine and vinblastine), taxanes (paclitaxel, docetaxel), epothilones and inhibitors of mitotic kinases including aurora and polo kinases;
  • alkylating agents including cyclophosphamide, ifosfamide, thiotepa, melphalan, chloroethylnitrosourea and bendamustine
  • platinum derivatives including cisplatin, oxaliplatin, carboplatin and satraplatin
  • antimitotic agents including
  • topoisomerase inhibitors including anthracyclines, epipodophyllotoxins, camptothecin and analogues of camptothecin; antimetabolites, including 5-fluorouracil, capecitabine, cytarabine, gemcitabine, 6-mercaptopurine, 6-thioguanine, fludarabine, methotrexate and premetrexed; targeted therapies, for example protein kinase inhibitors, including imatinib, gefitinib, sorafenib, sunitinib, erlotinib, dasatinib, and lapatinib; proteasome inhibitors, including bortezomib; histone deacetylase inhibitors, including valproate and SAHA; cell cycle and checkpoint inhibitors, including CDK4 / 6, CHK1 and CHK2; DNA-repair- modulators, including but not restricted to inhibitors of PARP, DNA-PK, ATM, ATR;
  • antiangiogenic drugs including bevacizumab
  • monoclonal antibodies including
  • trastuzumab trastuzumab, rituximab, alemtuzumab, tositumomab, cetuximab, panitumumab; conjugates of myoclonal antibodies, including Gemtuzumab ozogamicin, Ibritumomab tiuxetan;
  • hormonal therapies including antiestrogens (tamoxifen, raloxifen, anastrazole, letrozole, examestane) antiandrogens (flutamide, bicalutamide) and Luteinising Hormone analogues or antagonists.
  • the compounds of the present invention may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may be administered separately, sequentially, simultaneously, concurrently or may
  • the present invention provides a compound of Formula (I):
  • R 1 is an optionally substituted aryl or heteroaryl group
  • R 2 is an optionally substituted alkyl group, an alkynyl group optionally substituted by one or more alkyl groups and/or one or more alkoxy groups, or a cyano group;
  • R 3 is an optionally substituted alkyl group, a cycloalkyl group, an alkoxy group or a cycloalkoxy group;
  • R 4 is a hydrogen atom, an alkyl group or a cycloalkyl group
  • X is a nitrogen atom or a CH-group
  • Y is a nitrogen atom or a CH-group
  • Z is a nitrogen atom or a CH-group
  • n is 1 when X is a nitrogen atom and n is 0 or 1 when X is a CH-group.
  • R 1 is an optionally substituted aryl or heteroaryl group. Preferably, R 1 is a substituted aryl or heteroaryl group.
  • R 1 is optionally, independently substituted one or more times with a halo group, a hydroxy group, a cyano group, an amino group, a C C 6 alkyl group, a C 2 -C 6 alkenyl group, a C C 6 alkoxy group or a C C 6 alkoxy-CrC 6 alkyl group; and R 2 is an alkyl group, optionally, independently substituted one or more times with a halo group or C C 4 alkoxy group; or R 2 is an alkynyl group optionally, independently substituted one or more times with a C C 4 alkoxy group or a C C 4 alkyl group; or R 2 is a cyano group.
  • R 1 is optionally, independently substituted one or more times with a halo group, a C C 4 alkyl group, or a C C 4 alkoxy group
  • R 2 is an alkyl group, optionally, independently substituted one or more times with a halo group or a C1-C4 alkoxy group
  • R 2 is an alkynyl group, optionally, independently substituted one or more times with a C C 4 alkoxy group or a C C 4 alkyl group
  • R 2 is a cyano group.
  • R 1 is a group represented by the formula (a):
  • R 1a and R 1 b are each independently selected from the group consisting of a hydrogen atom, a halo group, a hydroxy group, a cyano group, an amino group, a C C 6 alkyl group, C 2 -C 6 alkenyl group, a C C 6 alkoxy group and a C C 6 alkoxy-CrC 6 alkyl group.
  • R 1 is a group represented by the formula (b):
  • R 1a and R 1 b are each independently selected from the group consisting of a hydrogen atom, a halo group, a hydroxy group, a cyano group, an amino group, a C C 6 alkyl group and a C C 6 alkoxy group.
  • R 1a is a hydrogen atom, a halo group, a cyano group, a methyl group or a methoxy group; and R 1 b is a halo group. More preferably, R 1a is a hydrogen atom, a methyl group or a halo group; and R 1 b is a halo group. More preferably, R 1a is a hydrogen atom, a methyl group or a halo group; and R 1 b is a chloro group.
  • R 1a is a hydrogen atom, a methyl group, a chloro group or a fluoro group; and R 1 b is a chloro group. More preferably, R 1a is a methyl group, a chloro group or a fluoro group; and R 1 b is a chloro group. Alternatively, preferably, R 1a is a hydrogen atom, a methyl group or a chloro group; and R 1 b is a chloro group. More preferably, R 1a is a methyl group or a chloro group; and R 1 b is a chloro group.
  • R 1 is a 2-chlorophenyl group, a 2-chloro-6-methylphenyl group, a 2-chloro-6- fluorophenyl group or a 2,6-dichlorophenyl group. Most preferably, R 1 is a 2,6- dichlorophenyl group.
  • R 2 is an optionally substituted alkyl group, an alkynyl group optionally substituted by one or more alkyl groups and/or one or more alkoxy groups, or a cyano group.
  • R 2 is a methyl group, a methyl group substituted by one or more fluoro groups, an alkynyl group optionally substituted by one or more alkyl groups and/or one or more alkoxy groups, or a cyano group. More preferably R 2 is a methyl group, a difluoromethyl group, an alkynyl group optionally substituted by one or more alkyl groups and/or one or more alkoxy groups, or a cyano group. More preferably still, R 2 is a methyl group, a difluoromethyl group, an alkynyl group optionally substituted by an alkoxy group, or a cyano group.
  • R 2 is an alkynyl group optionally substituted by one or more alkyl groups and/or one or more alkoxy groups.
  • R 2 is an alkynyl group optionally substituted by one or more methyl groups and/or one or more alkoxy groups. More preferably, R 2 is an alkynyl group optionally substituted by one or more methyl groups and/or one or more methoxy groups. More preferably, R 2 is an alkynyl group substituted by one or more methyl groups and/or one or more methoxy groups.
  • R 2 is an alkynyl group optionally substituted by an alkoxy group. More preferably, R 2 is an alkynyl group substituted by an alkoxy group. Most preferably, the alkynyl group is substituted by a methoxy group.
  • the alkynyl group is a C 2 -C 6 alkynyl group, more preferably a C 2 -C 5 alkynyl group, more preferably a C 2 -C 4 alkynyl group, more preferably a C 2 -C 3 alkynyl group, most preferably a C 3 alkynyl group.
  • R 2 is an alkynyl group
  • the alkynyl group is represented by formulc
  • R 2 is a methyl group or a methyl group substituted by one or more fluoro groups. More preferably, R 2 is a methyl group or a difluoromethyl group (-CHF 2 ). Most preferably, R 2 is an unsubstituted methyl group. Alternatively, preferably, R 2 is a difluoromethyl group.
  • R 2 is a cyano group.
  • R 3 is an optionally substituted alkyi group, a cycloalkyi group, an alkoxy group or a cycloalkoxy group.
  • R 3 is an optionally substituted alkyi group.
  • the alkyi group is a Ci-C 6 alkyi group, more preferably a C C 5 alkyi group, more preferably a C C 4 alkyi group, more preferably a C C 3 alkyi group, more preferably a C C 2 alkyi group.
  • R 3 is an optionally substituted methyl group.
  • R 3 is an unsubstituted alkyi group or an alkyi group substituted by a hydroxy group and/or one or more halo groups. More preferably, R 3 is an unsubstituted alkyi group or an alkyi group substituted by a hydroxy group and/or one or more fluoro groups. More preferably, R 3 is an unsubstituted C C 2 alkyi group or a C C 2 alkyi group substituted by a hydroxy group and/or one or more fluoro groups. Most preferably, R 3 is an unsubstituted methyl group or a methyl group substituted by a hydroxy group and/or a CF 3 group.
  • R 3 is an alkyi group, a cycloalkyi group, an alkoxy group or a cycloalkoxy group.
  • R 3 is an unsubstituted alkyi group.
  • the unsubstituted alkyi group is a C C 6 alkyi group, more preferably a C C 5 alkyi group, more preferably a C C 4 alkyi group, more preferably a C C 3 alkyi group, more preferably a C C 2 alkyi group.
  • R 3 is a methyl group.
  • R 3 is a cycloalkoxy group.
  • the cycloalkoxy group is a C 3 -C 6 cycloalkoxy group, more preferably a C 3 -C 5 cycloalkoxy group, more preferably a C 3 -C 4 cycloalkoxy group, more preferably a C 3 cycloalkoxy group.
  • R 3 is a cycloalkyl group.
  • the cycloalkyl group is a C 3 - C 6 alkyi group, more preferably a C 3 -C 5 alkyi group, more preferably a C 3 -C 4 alkyi group.
  • R 3 is a cyclopropyl group. More preferably, R 3 is an alkoxy group. Preferably, the alkoxy group is a C C 6 alkoxy group, more preferably a C C 5 alkoxy group, more preferably a C C 4 alkoxy group, more preferably a C C 3 alkoxy group, more preferably a C C 2 alkoxy group. Most preferably, R 3 is a methoxy group. In one preferable embodiment, R 3 is an unsubstituted methyl group, a methyl group substituted by a hydroxy group and/or a CF 3 group, or a C 3 cycloalkoxy group.
  • R 4 is a hydrogen atom (for example a hydrogen atom or a deuterium atom), an alkyi group or a cycloalkyl group.
  • R 4 is a hydrogen atom ( 1 H), a deuterium atom ( 2 H), an alkyi group or a cycloalkyl group.
  • R 4 is an alkyi group.
  • the alkyi group is a C C 6 alkyi group, more preferably a C C 5 alkyi group, more preferably a C C 4 alkyi group, more preferably a Ci-C 3 alkyi group, more preferably a C C 2 alkyi group.
  • the alkyi group is a methyl group.
  • the methyl group is unsubstituted.
  • R 4 is a cycloalkyl group.
  • the cycloalkyl group is a C 3 -C 6 cycloalkyl group, more preferably a C 3 -C 5 cycloalkyl group, more preferably a C 3 -C 4 cycloalkyl group.
  • the cycloalkyl group is a cyclopropyl group.
  • the cycloalkyl group is unsubstituted.
  • R 4 is a hydrogen atom.
  • R 4 is a deuterium atom.
  • R 4 is a hydrogen atom or an alkyi group. More preferably, R 4 is a hydrogen atom or a C C 6 alkyi group. More preferably, R 4 is a hydrogen atom or a C C 4 alkyi group. More preferably, R 4 is a hydrogen atom or a C C 3 alkyi group. More preferably, R 4 is a hydrogen atom or a C C 2 alkyi group. More preferably, R 4 is a hydrogen atom or a methyl group. More preferably, R 4 is a hydrogen atom. Alternatively, preferably, R 4 is a methyl group.
  • X is a nitrogen atom or a CH-group.
  • X is a nitrogen atom.
  • X is a CH-group.
  • R 3 is an alkyl group, preferably a methyl group.
  • X is a nitrogen atom and R 3 is an alkoxy group. More preferably still, X is a nitrogen atom and R 3 is a methoxy group.
  • Y is a nitrogen atom or a CH-group.
  • Y is a CH-group.
  • Y is a nitrogen atom.
  • Z is a nitrogen atom or a CH-group.
  • Z is a CH-group.
  • Z is a nitrogen atom.
  • n When X is a nitrogen atom, n is 1. When X is a CH-group, n is 0 or 1. Preferably, when X is a CH-group, n is 1. Alternatively, preferably, when X is a CH-group, n is 0.
  • X is a nitrogen atom or a CH-group and n is 1.
  • X is a nitrogen atom or a CH-group, and n is 1 when X is a nitrogen atom and 0 when X is a CH-group.
  • R 1 is a 2,6-dichlorophenyl group
  • R 2 is a methyl group, an alkynyl group substituted by an alkoxy group, or a cyano group
  • R 3 is an alkoxy group
  • R 4 is a hydrogen atom or an alkyl group
  • X is a nitrogen atom
  • Y is a nitrogen atom or a CH-group
  • Z is a CH-group
  • n is 1.
  • R 1 is a 2,6-dichlorophenyl group
  • R 2 is a methyl group, an alkynyl group substituted by an alkoxy group, or a cyano group
  • R 3 is a methoxy group
  • R 4 is a hydrogen atom or a methyl group
  • X is a nitrogen atom
  • Y is a CH- group
  • Z is a CH-group
  • n is 1.
  • R 1 is a 2,6-dichlorophenyl group
  • R 2 is a methyl group
  • R 3 is a methoxy group
  • R 4 is a hydrogen atom or a methyl group
  • X is a nitrogen atom
  • Y is a CH-group
  • Z is a CH-group
  • n is 1.
  • R 1 is a 2,6-dichlorophenyl group
  • R 2 is an alkynyl group substituted by an alkoxy group
  • R 3 is a methoxy group
  • R 4 is a hydrogen atom or a methyl group
  • X is a nitrogen atom
  • Y is a CH-group
  • Z is a CH-group
  • n is 1.
  • R 1 is a 2,6-dichlorophenyl group
  • R 2 is a cyano group
  • R 3 is a methoxy group
  • R 4 is a hydrogen atom or a methyl group
  • X is a nitrogen atom
  • Y is a CH-group
  • Z is a CH-group
  • n is 1.
  • R 1 is a 2,6-dichlorophenyl group
  • R 2 is a methyl group
  • R 3 is a methoxy group
  • R 4 is a hydrogen atom or a methyl group
  • X is a nitrogen atom
  • Y is a nitrogen atom
  • Z is a CH-group
  • n is 1.
  • R 1 is a 2,6-dichlorophenyl group
  • R 2 is a methyl group, an alkynyl group substituted by an alkoxy group, or a cyano group
  • R 3 is an optionally substituted alkyl group, a cycloalkyi group, an alkoxy group or a cycloalkoxy group
  • R 4 is a hydrogen atom, a deuterium atom, an alkyl group or a cycloalkyi group
  • X is a CH-group
  • Y is a nitrogen atom or a CH-group
  • Z is a nitrogen atom or a CH-group
  • n is 0 or 1.
  • R 1 is a 2,6-dichlorophenyl group
  • R 2 is a methyl group, an alkynyl group substituted by an alkoxy group, or a cyano group
  • R 3 is an optionally substituted alkyl group
  • R 4 is a hydrogen atom or an alkyl group
  • X is a CH- group
  • Y is a nitrogen atom or a CH-group
  • Z is a CH-group
  • n is 0 or 1.
  • R 1 is a 2,6-dichlorophenyl group
  • R 2 is a methyl group, an alkynyl group substituted by an alkoxy group, or a cyano group
  • R 3 is a methyl group or a methyl group substituted by a hydroxy group and/or a -CF 3 group
  • R 4 is a hydrogen atom or a methyl group
  • X is a CH-group
  • Y is a CH-group
  • Z is a CH-group
  • n is 1.
  • R 1 is a 2,6-dichlorophenyl group
  • R 2 is a methyl group
  • R 3 is a methyl group or a methyl group substituted by a hydroxy group and/or a -CF 3 group
  • R 4 is a hydrogen atom or a methyl group
  • X is a CH-group
  • Y is a CH- group
  • Z is a CH-group
  • n is 1.
  • R 1 is a 2,6-dichlorophenyl group
  • R 2 is an alkynyl group substituted by an alkoxy group
  • R 3 is a methyl group or a methyl group substituted by a hydroxy group and/or a -CF 3 group
  • R 4 is a hydrogen atom or a methyl group
  • X is a CH-group
  • Y is a CH-group
  • Z is a CH-group
  • n is 1.
  • R 1 is a 2,6-dichlorophenyl group
  • R 2 is a cyano group
  • R 3 is a methyl group or a methyl group substituted by a hydroxy group and/or a -CF 3 group
  • R 4 is a hydrogen atom or a methyl group
  • X is a CH-group
  • Y is a CH- group
  • Z is a CH-group
  • n is 1.
  • R 1 is a 2,6-dichlorophenyl group
  • R 2 is a methyl group
  • R 3 is a methyl group or a methoxy group
  • R 4 is a hydrogen atom or a methyl group
  • X is a CH-group or a nitrogen atom
  • Y is a nitrogen atom
  • Z is a CH-group
  • n is 1.
  • R 1 is a 2,6-dichlorophenyl group
  • R 2 is a methyl group
  • R 3 is a methoxy group
  • R 4 is a hydrogen atom or a methyl group
  • X is a nitrogen atom
  • Y is a nitrogen atom
  • Z is a CH-group
  • n is 1.
  • the compound of Formula (I) is selected from the following:
  • the compound of Formula (I) is selected from the following:
  • the present invention provides a compound of Formula (III):
  • R 1 , R 3 , R 4 , X, Y and Z are as described above with regard to the compound of Formula (I), and R 2a and R 2b are independently selected from the group consisting of a hydrogen atom and a fluoro group.
  • R 2a and R 2b is a hydrogen atom or each of R 2a and R 2b is a fluoro group. More preferably, each of R 2a and R 2b is a hydrogen atom.
  • R 10 is C1-C4 alkyl
  • R 1 , R 3 , R 4 , X, Y and Z are as described above with regard to the compound of Formula (I).
  • the present invention provides a compound of Formula (IVa):
  • the present invention provides a compound of Formula (V):
  • the present invention provides a compound of Formula (VI):
  • the present invention provides a compound of Formula (VII):
  • Suitable pharmaceutically acceptable excipients would be known by the person skilled in the art, for example, fats, water, physiological saline, alcohol (e.g., ethanol), glycerol, polyols, aqueous glucose solution, extending agent, disintegrating agent, binder, lubricant, wetting agent, stabilizer, emulsifier, dispersant, preservative, sweetener, colorant, seasoning agent or aromatizer, concentrating agent, diluent, buffer substance, solvent or solubilizing agent, chemical for achieving storage effect, salt for modifying osmotic pressure, coating agent or antioxidant, saccharides such as lactose or glucose; starch of corn, wheat or rice; fatty acids such as stearic acid; inorganic salts such as magnesium metasilicate aluminate or anhydrous calcium phosphate; synthetic polymers such as polyvinylpyrrolidone or polyalkylene glycol; alcohols such as stearyl alcohol or benzyl alcohol;
  • a pharmaceutical composition comprising the compound of any of Formulae (I), (II), (III), (IV), (IVa), (V), (VI) or (VII), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition further comprises an anti-cancer agent, for example as a combination therapy as described herein.
  • a suitable anti-cancer agent may be any one or more of a genotoxic agent, a targeted agent and an immune-modulator.
  • the cancer is selected from colon and rectal (colorectal) cancer, head and neck cancer, lung cancer, oesophagus cancer, ovarian cancer and pancreas cancer. More preferably, the cancer is colon and rectal (colorectal) cancer. Alternatively, preferably, the cancer is lung cancer, more preferably non-small cell lung cancer.
  • the cancer is selected from colon and rectal (colorectal) cancer, head and neck cancer, lung cancer, oesophagus cancer, ovarian cancer and pancreas cancer. More preferably, the cancer is colon and rectal (colorectal) cancer. Alternatively, preferably, the cancer is lung cancer, more preferably non-small cell lung cancer.
  • a method of treating or preventing cancer in a human or animal patient comprising administering to a patient in need thereof an effective amount of a compound of any of Formulae (I), (II), (III), (IV), (IVa), (V), (VI) or (VII), or a
  • the cancer is selected from colon and rectal (colorectal) cancer, head and neck cancer, lung cancer, oesophagus cancer, ovarian cancer and pancreas cancer. More preferably, the cancer is colon and rectal (colorectal) cancer. Alternatively, preferably, the cancer is lung cancer, more preferably non-small cell lung cancer.
  • the compounds of the present invention have an IC 50 value for Wee-1 kinase of about 0.1 nM to about 1 ,000 nM, more preferably from about 0.1 nM to about 500 nM, or from about 0.1 nM to about 300 nM, or from about 0.1 nM to about 100 nM, or from about 0.1 nM to about 50 nM, or from about 0.1 nM to about 30 nM, or from about 0.1 nM to about 15 nM, or from about 0.1 nM to about 10 nM, or from about 0.1 nM to about 5 nM, or from about 0.1 nM to about 2 nM, or from about 0.1 nM to about 1 nM, or, preferably, less than 10nM, more preferably less than 5 nM, more preferably less than 2 nM, most preferably less than 1 nM.
  • Biotage KP-Sil SNAP cartridge columns (10-340 g) were used along with the stated solvent system and an appropriate solvent gradient depending on compound polarity (determined by TLC analysis). In the case of more polar and basic compounds, Biotage KP-NH SNAP cartridge columns (1 1 g) were used.
  • LCMS Liquid Chromatography Mass Spectrometry
  • Method A The system consists of an Agilent Technologies 6130 quadrupole mass spectrometer linked to an Agilent Technologies 1290 Infinity LC system with UV diode array detector and autosampler.
  • the spectrometer consists of an electrospray ionization source operating in positive and negative ion mode.
  • LCMS experiments were performed on each sample submitted using the following conditions: LC Column: Agilent Eclipse Plus C18 RRHD 1.8 micron 50 x 2.1 mm maintained at 40°C. Mobile phases: A) 0.1 % (v/v) formic acid in water; B) 0.1 % (v/v) formic acid in acetonitrile.
  • Method B The system consists of an Agilent Technologies 6140 single quadrupole mass spectrometer linked to an Agilent Technologies 1290 Infinity LC system with UV diode array detector and autosampler.
  • the spectrometer consists of a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode.
  • LCMS experiments were performed on each sample submitted using the following conditions: LC Column: Zorbax Eclipse Plus C18 RRHD 1.8 micron 50 x 2.1 mm maintained at 40°C. Mobile phases: A) 0.1 % (v/v) formic acid in water; B) 0.1 % (v/v) formic acid in acetonitrile.
  • the system consisted of an Agilent Technologies 6120 single quadrupole mass
  • the mass spectrometer linked to an Agilent Technologies 1200 Preparative LC system with Multiple Wavelength detector and autosampler.
  • the mass spectrometer used a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. Fraction collection was mass-triggered (multimode positive and negative ion). Purification experiments, unless otherwise stated, were performed under basic conditions at an appropriate solvent gradient that was typically determined by the retention time found using HPLC Method A. In cases were the basic conditions were unsuccessful, acidic conditions were employed.
  • 6-(2,6-Dichlorophenyl)-8-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one was prepared according to the previously reported procedure contained in WO 2014/167347 [Page 54, Example 2, Step 2].
  • the reaction vessel was sealed and heated under microwave conditions (CEM Explorer/Discover) at 100 °C (80 W ceiling) for 15 mins.
  • the reaction mixture was partitioned between brine / water (25 ml, 1 : 1) and diethyl ether (20 ml).
  • the aqueous was separated and extracted with diethyl ether (3 x 10 ml).
  • the combined diethyl ether fractions were washed with brine / water (4 x 6 ml, 1 :1), dried (phase separator) and the solvent was removed in vacuo.
  • the resulting residue was purified by flash chromatography (0-25% EtOAc in cyclohexane) to afford the title compound (156.4 mg, 64 %)
  • reaction mixture was allowed to cool to RT, and was loaded onto a KP-NH column and purified by flash chromatography (0-100%, EtOAc in cyclohexane) to give the A/-Boc protected product.
  • the material was dissolved in DCM (2.0 ml_) and TFA (2.0 ml_, 26.0 mmol) was added. The resultant solution was stirred at RT under nitrogen. After 30 min, the solvents were removed in vacuo and the remaining residue was partitioned between DCM and saturated sodium bicarbonate (aq) solution.
  • the reaction mixture was partitioned between brine/water (65 ml, 1 : 1) and diethyl ether (30 ml). The mixture was filtered through a sinter funnel. The aqueous phase was separated and extracted with diethyl ether (2 x 20 ml). The combined diethyl ether fractions were washed with brine/water (4 x 20 ml, 1 : 1), dried (phase separator) and reduced in vacuo. The resulting residue was purified by flash chromatography (0-15% EtOAc in cyclohexane) to afford the title compound.
  • the Boc-protected amine (0.132 mmol) was dissolved in DCM (3 mL) and TFA (0.8 mL) was added at r.t. whilst stirring. Stirring was continued for 60-90 min (as indicated by HPLC analysis) and the solvent was removed in vacuo. The residue was re-dissolved in DCM (2 mL) and the solution was applied to a 2 g SCX cartridge (prewashed with DCM / MeOH (5: 1)); the compound was left to adsorb for 5 min. and the cartridge was washed with 2 column lengths of DCM / MeOH (5: 1).
  • Example 1 6-(2,6-Dichlorophenyl)-2-((3-methyl-4-(piperazin-1-yl)phenyl)amino)-5-oxo-5,6- dihvdropyrido[4,3-dlpyrimidine-8-carbonitrile
  • Step 1 (6-(2, 6-dichlorophenyl)-2-(methylthio)-5-oxo-5, 6-dihydropyrido[4,3-d]pyrimidin-8- carbonitrile:
  • Step 2 tert-butyl 4-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3- d]pyrimidin-2-yl)amino)-2-methylphenyl)piperazine-1-carboxylate:
  • the flask was flushed with nitrogen and the suspension was heated at 90°C for 90 min.
  • the flask was left cooling to r.t. overnight and the solid was filtered off using a phase separation cartridge.
  • the solid was washed with I PA / diethyl ether (1 :1 ; 10 mL) followed by petrol ether (10 mL) and dried on the frit to obtain the target compound (84 mg; 29%) as a bright yellow solid.
  • Step 3 6-(2, 6-Dichlorophenyl)-2-((3-methyl-4-(piperazin- 1-yl)phenyl)amino)-5-oxo-5, 6- dihydropyrido[4,3-d]pyrimidine-8-carbonitrile tert-butyl 4-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2- yl)amino)-2-methylphenyl)piperazine-1-carboxylate (80mg; 0.132 mmol) was reacted according to General Procedure D to yield the target compound (44 mg; 66%) as a bright yellow solid.
  • Step 1 (R)-tert-butyl 4-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3- d]pyrimidin-2-yl)amino)-2-methylphenyl)-2-methylpiperazine-1-carboxylate ⁇ 6-(2,6-dichlorophenyl)-2-(methylthio)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin
  • Step 2 (R)-6-(2, 6-Dichlorophenyl)-2-((3-methyl-4-(3-methylpiperazin- 1-yl)phenyl)amino)-5- oxo-5, 6-dihydropyrido[4, 3-d]pyrimidine-8-carbonitrile
  • Step 1 8-Bromo-6-(2,6-dichlorophenyl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-5(6H)-o 6-(2,6-dichlorophenyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one (WO 2014/167347 [Page 51 , Example 1 , Step 2].; 3.5 g; 10.35 mmol) was suspended in dry acetonitrile (40 mL) at 85°C. NBS (2.76 g; 15.52 mmol) was added in three portions and the mixture was left stirring for 2.5 hours.
  • Step 2 tert-butyl 4-(4-((8-bromo-6-(2,6-dichlorophenyl)-5-oxo-5,6-dih
  • Step 3 tert-butyl 4-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3- d]pyrimidin-2-yl)amino)-2-methoxyphenyl)piperazine-1-carboxylate: tert-butyl 4-(4-((8-bromo-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2- yl)amino)-2-methoxyphenyl)piperazine-1-carboxylate (0.10 g; 0.148 mmol) was reacted according to General Procedure C to yield the target compound (80 mg; 87 %) after flash chromatography (0 to 60 % EtOAc in cyclohexane) using a 40 g Grace cartridge.
  • Step 1 (R)-tert-butyl 4-(4-((8-bromo-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3- d]pyrimidin-2-yl)amino)-2-methoxyphenyl)-2-methylpiperazine-1-carboxylate:
  • WO2015/038417 were suspended in I PA (5 ml_) at r.t. using a reaction tube.
  • Step 2 tert-butyl 4-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3- d]pyrimidin-2-yl)amino)-2-methoxyphenyl)-2-methylpiperazine-1-carboxylate:
  • Step 3 (f?)-6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(3-methylpiperazin-1-yl)phenyl)amino)- 5-0X0-5, 6-dihydropyrido[4,3-d]pyrimidine-8-carbonitrile tert-butyl 4-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2- yl)amino)-2-methoxyphenyl)-2-methylpiperazine-1-carboxylate (0.08 g; 0.126 mmol) was reacted according to General Procedure D to yield the target compound (60 mg; 89 %) as a yellow solid after trituration with diethyl ether.
  • Step 1 (6-(2,6-dichlorophenyl)-8-(3-methoxyprop-1-yn-1-yl)-2-(methylthio)pyrido[4,3- d]pyrimidin-5(6H)-one: Copper(l) iodide (2.85 mg, 0.015 mmol) and bis(triphenylphosphie)palladium(ll) chloride (21.03 mg, 0.030 mmol) were added to a pre-degassed, stirring solution of Intermediate B (250 mg, 0.599 mmol), 3-methoxyprop-1-yne (84 mg, 1.199 mmol) and tetrabutylammoium iodide (443 mg, 1.199 mmol) in triethylamine (0.501 ml, 3.60 mmol) / DMF (2.5 ml) using a microwave vial.
  • Intermediate B 250 mg, 0.599 mmol
  • 3-methoxyprop-1-yne 84
  • the reaction vessel was sealed and heated under microwave conditions (CEM Explorer/Discover) at 100 °C (80 W ceiling) for 15 mins.
  • the reaction mixture was partitioned between brine / water (25 ml, 1 :1) and diethyl ether (20 ml).
  • the aqueous was separated and extracted with diethyl ether (3 x 10 ml).
  • the combined diethyl ether fractions were washed with brine / water (4 x 6 ml, 1 :1), dried (phase separator) and the solvent was removed in vacuo.
  • the resulting residue was purified by flash chromatography (0-25% EtOAc in cyclohexane) to afford the title compound (156.4 mg, 64 %)
  • Step 2 tert-butyl 4-(4-((6-(2,6-dichlorophenyl)-8-(3-methoxyprop-1-yn-1-yl)-5-oxo-5,6- dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-2-methoxyph
  • Step 3 6-(2, 6-dichlorophenyl)-2-((3-methoxy-4-(piperazin- 1-yl)phenyl)amino)-8-(3- methoxyprop- 1-yn-1 -yl) pyridof 4, 3-d]pyrimidin-5( 6H) -one:
  • Step 1 ⁇ R)-tert- butyl 4-(4-((6-(2,6-dichlorophenyl)-8-(3-methoxyprop-1-yn-1-yl)-5-oxo-5,6- dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-2-methoxyphenyl)-2-methylpi
  • Step 1 tert-butyl 4-(4-((6-(2,6-dichlorophenyl)-8-(3-methoxyprop-1-yn-1-yl)-5-oxo-5,6- dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-2-methylphenyl) ⁇ iperazin
  • Step 2 6-(2,6-dichlorophenyl)- 8-(3-methoxyprop-1-yn-1-yl)-2-((3-methyl-4-(piperazin-1- yl)phenyl)amino)pyrido[4,3-d]pyrimidin-5(6H)-one
  • Example 8 6-(2,6-Dichlorophenyl)-8-methyl-2-((3-methyl-4-(piperazin-1- yl)phenyl)amino)pyrido[4,3-dlpyrimidin-5(6H)-one
  • Step 1 tert-Butyl 4-(2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate 1-Bromo-2-methyl-4-nitrobenzene (1 g, 4.63 mmol), and te/f-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (1.86 g, 6.02 mmol) were suspended in 1 ,4-dioxane (32 ml_) and 2M sodium carbonate solution (5.32 ml_, 10.65 mmol) was added.
  • Step 2 tert-Butyl 4-(4-amino-2-methylphenyl)piperidine-1-carboxylate
  • Example 1 2-((3-Cvclopropoxy-4-(piperazin-1-yl)phenyl)amino)-6-(2,6-dichlorophenyl)-5- oxo-5,6-dihvdropyrido[4,3-dlpyrimidine-8-carbonitrile
  • reaction mixture was chilled to RT and filtered through Celite (washed with EtOAc).
  • product as purified by flash chromatography (10-50 % EtOAc in cyclohexane) and the product containing fractions were concentrated in vacuo to yield the target compound as a yellow oil that solidified upon storage (129 mg, 61 %).
  • Step 4 tert-Butyl 4-[4-Amino-2-(cyclopropoxy)phenyl]piperazine-1-carboxylate
  • Step 5 2-((3-Cyclopropoxy-4-(piperazin- 1-yl)phenyl)amino)-6-(2, 6-dichlorophenyl)-5-oxo- 5, 6-dihydropyrido[4, 3-d]pyrimidine-8-carbonitrile
  • Example 12 6-(2-chloro-6-methylphenyl)-8-(difluoromethyl)-2-((3-methoxy-4-(piperazin-1- yl)phenyl)amino)pyrido[4,3-dlpyrimidin-5(6H)-one
  • Step 1 6-(2-Chloro-6-methy ⁇ henyl)-2-methylsulfanyl-5-oxo ⁇ yrido[4,3-d]pyrimidin carbaldehyde
  • Phosphoryltrichloride (3.73 mL, 39.9 mmol) was added to DMF (18.52 mL, 239 mmol) at 0°C and the mixture was warmed up to RT and stirred for 30 min. The resulting solution was added to a solution of A/-(2-chloro-6-methylphenyl)-4-methyl-2-(methylthio)pyrimidine- 5-carboxamide (1.227 g, 3.99 mmol) in DMF (20 mL) at 0°C and the mixture was warmed to RT and subsequently stirred at 90°C for 15h.
  • the mixture was cooled to RT and partitioned between MTBE (200 mL) and water / sat. brine (100mL / 100mL) and the mixture was neutralised with sat. sodium
  • Step 2 6-(2-Chloro-6-methyl ⁇ henyl)-8-(difluoromethyl)-2-methylsulfan 3- d]pyrimidin-5-one
  • 6-(2-chloro-6-methyl-phenyl)-2-methylsulfanyl-5-oxo-pyrido[4,3-d]pyrimidine-8- carbaldehyde (315 mg, 0.91 mmol) was dissolved in DCM (6 mL) and the flask was flushed with N 2.
  • XtalFluor-E (313 mg, 1.34 mmol) was added followed by TEA*3HF (0.3 ml, 1.82 mmol). The reaction mixture was stirred overnight at RT. Additional 600 mg of XTalFluor-E was added followed by 0.6 ml of TEA*3HF. The reaction mixture was stirred for 5h at RT.
  • 6-(2-Chloro-6-methyl-phenyl)-8-(difluoromethyl)-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-5- one (50 mg, 0.136 mmol) was dissolved in DCM (2 mL) and mCPBA (37 mg, 0.150 mmol) was added. The reaction mixture was stirred for 30 min at RT. Then the reaction mixture was diluted to 10 mL with DCM and washed with aqueous sodium thiosulfate solution. The organic layer was separated, dried (anh. MgS0 4 ) and evaporated under reduced pressure.
  • the product was washed with 20% MeOH/DCM and eluted with 20% 7N NH 3 MeOH /DCM.
  • the product containing fractions were evaporated under reduced pressure and lyophilised (ACN/water), yielding the target compound as a yellow solid (41 mg, 71 %).
  • Example 13 rac-6-(2,6-Dichlorophenyl)-8-(3-methoxyprop-1-vn-1-yl)-2-((3-methyl-4- (pyrrolidin-3-yl)phenyl)amino)pyrido[4,3-dlpyrimidin-5(6H)-one
  • Step 1 tert-Butyl 3-(trifluoromethylsulfonyloxy)-2,5-dihydropyrrole-1-carboxylate
  • i-/V-Boc-3-pyrrolidinone 1000 mg, 5.40 mmol was dissolved in THF (10 mL) and chilled to -78 °C. 1 M LHMDS in THF (9.99 mmol, 9.99 mL) was added slowly (within approx. 10-15 min). The reaction mixture was stirred for 30 min. Next 1 , 1 , 1-Trifluoro-N-phenyl-N- (trifluoromethyl)sulfonylmethanesulfonamide (2141 mg, 5.99 mmol in THF (20 mL) was added slowly (30 min). The reaction mixture was stirred for an additional 30 min at -78 °C.
  • Step 2 tert-Butyl 3-(2-methyl-4-nitro-phenyl)-2,5-dihydropyrrole-1-carboxylate
  • Step 4 rac-6-(2, 6-dichlorophenyl)-8-(3-methoxyprop- 1-yn- 1-yl)-2-((3-methyl-4-(pyrrolidin-3- yl)phenyl)amino)pyrido[4, 3-d]pyrimidin-5( 6H)-one
  • Example 14 rac-6-(2,6-Dichlorophenyl)-2-((3-methyl-4-(pyrrolidin-3-yl)phenyl)arriino)-5- oxo-5,6-dihvdropyrido[4,3-dlpyrimidine-8-carbonitrile
  • the orange suspension was poured into aqu. sat. sodium hydrogencarbonate solution / DCM (100ml_ / 200 ml_) and extracted into DCM twice (100 ml_ each).
  • the combined organic phases were washed with sat. sodium hydrogencarbonate solution followed by sat. brine and dried over K 2 C0 3 .
  • the solid was filtered off and the solvent was removed in vacuo to obtain the target compound as an orange liquid which was taken on as such.
  • Step 2 tert-Butyl 3-(4-amino-2-methoxy-phenyl)-2,5-dihydropyrrole-1-carboxylate te/f-Butyl 3-(trifluoromethylsulfonyloxy)-2,5-dihydropyrrole-1-carboxylate (1840 mg, 5.80 mmol) (Obtained according to Example 13, Step 1) was dissolved in 1 ,4-dioxane (16 ml_), AcOK (1770 mg, 18.04 mmol), bis(pinacolato)diboron (1635 mg, 6.44 mmol), dppf (96 mg, 0.174 mmol) and Pd(dppf)CI 2 DCM (142 mg, 0.174 mmol) were added.
  • the reaction mixture was intensively stirred at 90 °C overnight under nitrogen and subsequently cooled to RT and diluted with EtOAc (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2x 100 mL). The combined organic extracts were dried (anh. MgS0 4 ) and evaporated under reduced pressure. The product was purified by flash chromatography (10-50 % EtOAc in cyclohexane), yielding the target compound as a yellowish oil (1660 mg, 98 %).
  • Example 17 6-(2,6-Dichlorophenyl)-2-[3-methoxy-4-[(3R)-3-methylpiperazin-1-yl1anilino1-8- methyl-pyrimido[4,5-dlpyridazin-5-one
  • Example 18 6-(2,6-Dichlorophenyl)-2-(3-methoxy-4-piperazin-1-yl-anilino)-8-methyl- pyrimido[4,5-dlpyridazin-5-one
  • Example 19 6-(2,6-dichlorophenyl)-5-oxo-2-((4-(piperidin-4-yl)-3-(2,2,2-trifluoro-1- hvdroxyethyl)phenyl)amino)-5,6-dihydropyrido[4,3-dlpyrimidine-8-carbonitrile
  • Step 1 rac-1-(2-Bromo-5-nitrophenyl)-2, 2, 2-trifluoroethan- 1-ol 2-Bromo-5-nitro-benzaldehyde (2.00 mg, 8.69 mmol) was dissolved in THF (25 mL) under nitrogen and the flask was chilled in an ice bath. (Trifluoromethyl)trimethylsilane (1.8 mL, 12.17 mmol) was added followed by 1 M tetrabutylammonium fluoride in THF (0.3 mL, 0.304 mmol). The reaction mixture was stirred for 1 h at 0 °C. Then 1 mL of 1 M
  • reaction mixture was cooled to RT and filtered through Celite.
  • Celite was washed with EtOAc.
  • the combined filtrates were evaporated under reduced pressure.
  • the residue was purified by flash chromatography (20-50% EtOAc in cyclohexane), yielding the title compound as a clear oil that solidified upon storage (340 mg. 73 %).
  • Example 20 6-(2,6-Dichlorophenyl)-5-oxo-2-((4-(piperidin-4-yl)-3-(2,2,2- trifluoroethyl)phenyl)amino -5,6-dihydropyrido[4,3-dlpyrimidine-8-carbonitrile
  • Example 21 rac-6-(2,6-Dichlorophenyl)-8-(3-methoxyprop-1-vn-1-yl)-2-((4-(piperidin-4-yl)- 3-(2,2,2-trifluoro-1-hvdroxyethyl)phenyl)amino)pyrido[4,3-dlpyrimidin-5(6H)-one
  • Example 22 6-(2,6-Dichlorophenyl)-8-(3-methoxyprop-1-vn-1-yl)-2-((4-(piperidin-4-yl)-3- (2,2,2-trifluoroethyl)phenyl)amino)pyrido[4,3-dlpyrimidin-5(6H)-one
  • Example 24 6-(2-Chloro-6-fluorophenyl)-2-((3-methoxy-4-(piperazin-1-yl)phenyl)amino)-5- oxo-5,6-dihvdropyrido[4,3-dlpyrimidine-8-carbonitrile
  • Step 1 tert-butyl 4-(4-((8-cyano-6-(2, 6-dichlorophenyl)-5-oxo-5, 6-dihydropyrido[4,3- d]pyrimidin-2-yl)amino)-2-(hydroxymethyl)phenyl)piperazine-1 -carboxylate:
  • Example 9 shows that in the presence of the methyl-group on the pyridone- core the methoxy-group on the benzene results in an improved kinetic solubility compared to the methyl-analogue (example 8), whereas in the absence of the methyl-group on the pyridone, the kinetic solubility is similar (examples 13 and 14 of WO2014/167347
  • Table 2 shows that exemplary compounds of the present invention display an enhanced Wee-1 kinase inhibitory effect (Wee-1 IC 50 value), an enhanced Wee-1 potency in cells (pCDC2 value), similar kinetic solubility (KSol value), and a similar stability in human microsomes (HLM), compared to Example 13 of WO 2014/167347.
  • Table 3 Comparison of alkynyl analogues
  • Table 3 shows the importance of an alkoxy group as R 3 , a nitrogen atom as X, and a methoxymethylalkynyl group as R 2 in order for the compound to exhibit both good activity and good solubility.
  • Table 4 Comparison of cyano-analogues
  • Table 4 shows the importance of an alkoxy group as R 3 , a nitrogen atom as X, and a cyano group as R 2 in order for the compound to exhibit both good activity and good solubility.
  • Table 5 Examples 10 to 28
  • Table 5 shows the Wee-1 kinase inhibitory effect and Wee-1 potency in cells of Examples 10 to 28.

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Abstract

L'invention concerne des composés utiles comme inhibiteurs de l'activité de la kinase Wee-1. La présente invention concerne également des compositions pharmaceutiques comprenant ces composés, et des méthodes d'utilisation de ces composés dans le traitement du cancer, ainsi que des méthodes de traitement du cancer.
PCT/GB2017/052042 2016-07-12 2017-07-12 Composés de pyridopyrimidinone inhibant la wee -1 WO2018011570A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018183891A1 (fr) 2017-03-31 2018-10-04 Cascadian Therapeutics Combinaisons d'inhibiteurs de chk1 et wee1
WO2020192581A1 (fr) 2019-03-22 2020-10-01 首药控股(北京)有限公司 Inhibiteur de wee1 ainsi que sa préparation et son utilisation
US10807994B2 (en) 2017-10-09 2020-10-20 Nuvation Bio Inc. Heterocyclic compounds and uses thereof
WO2021254389A1 (fr) 2020-06-17 2021-12-23 微境生物医药科技(上海)有限公司 Dérivé de pyrazolo[3,4-d]pyrimidine-3-cétone utilisé en tant qu'inhibiteur de wee-1
US11299493B2 (en) 2017-10-09 2022-04-12 Nuvation Bio Inc. Heterocyclic compounds and uses thereof
US11332473B2 (en) 2019-04-09 2022-05-17 Nuvation Bio Inc. Substituted pyrazolo[3,4-d]pyrimidines as Wee1 inhibitors
WO2022228511A1 (fr) 2021-04-30 2022-11-03 微境生物医药科技(上海)有限公司 Composé à cycle fusionné utilisé comme inhibiteur de wee-1, son procédé de préparation et son utilisation
WO2022256680A1 (fr) * 2021-06-04 2022-12-08 Atrin Pharmaceuticals Dérivés de pyridopyrimidine utiles en tant qu'inhibiteurs de kinase wee1
WO2023010354A1 (fr) * 2021-08-04 2023-02-09 四川大学华西医院 Composé à petites molécules ayant une activité inhibitrice de l'egfr, son procédé de préparation et son utilisation
WO2023138362A1 (fr) 2022-01-18 2023-07-27 江苏天士力帝益药业有限公司 Inhibiteur de wee1, sa préparation et son utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013126656A1 (fr) * 2012-02-23 2013-08-29 Abbvie Inc. Dérivés de pyridopyrimidinone inhibiteurs de kinases
WO2014167347A1 (fr) * 2013-04-11 2014-10-16 Almac Discovery Limited Dérivés 2-aminopyrido[4,3-d]pyrimidin-5-one et leur utilisation comme inhibiteurs de wee-1

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013126656A1 (fr) * 2012-02-23 2013-08-29 Abbvie Inc. Dérivés de pyridopyrimidinone inhibiteurs de kinases
WO2014167347A1 (fr) * 2013-04-11 2014-10-16 Almac Discovery Limited Dérivés 2-aminopyrido[4,3-d]pyrimidin-5-one et leur utilisation comme inhibiteurs de wee-1

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018183891A1 (fr) 2017-03-31 2018-10-04 Cascadian Therapeutics Combinaisons d'inhibiteurs de chk1 et wee1
US10807994B2 (en) 2017-10-09 2020-10-20 Nuvation Bio Inc. Heterocyclic compounds and uses thereof
US11299493B2 (en) 2017-10-09 2022-04-12 Nuvation Bio Inc. Heterocyclic compounds and uses thereof
WO2020192581A1 (fr) 2019-03-22 2020-10-01 首药控股(北京)有限公司 Inhibiteur de wee1 ainsi que sa préparation et son utilisation
US11332473B2 (en) 2019-04-09 2022-05-17 Nuvation Bio Inc. Substituted pyrazolo[3,4-d]pyrimidines as Wee1 inhibitors
WO2021254389A1 (fr) 2020-06-17 2021-12-23 微境生物医药科技(上海)有限公司 Dérivé de pyrazolo[3,4-d]pyrimidine-3-cétone utilisé en tant qu'inhibiteur de wee-1
WO2022228511A1 (fr) 2021-04-30 2022-11-03 微境生物医药科技(上海)有限公司 Composé à cycle fusionné utilisé comme inhibiteur de wee-1, son procédé de préparation et son utilisation
WO2022256680A1 (fr) * 2021-06-04 2022-12-08 Atrin Pharmaceuticals Dérivés de pyridopyrimidine utiles en tant qu'inhibiteurs de kinase wee1
WO2023010354A1 (fr) * 2021-08-04 2023-02-09 四川大学华西医院 Composé à petites molécules ayant une activité inhibitrice de l'egfr, son procédé de préparation et son utilisation
WO2023138362A1 (fr) 2022-01-18 2023-07-27 江苏天士力帝益药业有限公司 Inhibiteur de wee1, sa préparation et son utilisation

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