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WO2025172706A1 - Composés modulant l'endonucléase flap (fen1) - Google Patents

Composés modulant l'endonucléase flap (fen1)

Info

Publication number
WO2025172706A1
WO2025172706A1 PCT/GB2025/050272 GB2025050272W WO2025172706A1 WO 2025172706 A1 WO2025172706 A1 WO 2025172706A1 GB 2025050272 W GB2025050272 W GB 2025050272W WO 2025172706 A1 WO2025172706 A1 WO 2025172706A1
Authority
WO
WIPO (PCT)
Prior art keywords
dione
hydroxy
ethoxy
tetradeca
oxa
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/GB2025/050272
Other languages
English (en)
Inventor
Lars Burgdorf
Bernd Neff
Bruce Follows
Catherine Jorand-Lebrun
Christin RAKERS
Julien LEFRANC
Christoph GÖLDNER
Lizbeth Deselm
Roch Boivin
Xiaoling Chen
Owen Davis
Robert Heald
Samuel Mann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Artios Pharma Ltd
Original Assignee
Merck Patent GmbH
Artios Pharma Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH, Artios Pharma Ltd filed Critical Merck Patent GmbH
Publication of WO2025172706A1 publication Critical patent/WO2025172706A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • the above objects can be achieved by the compounds of formula (I) as defined herein (including stereoisomers, tautomers, /V-oxides, or pharmaceutically acceptable salts thereof) as well as pharmaceutical compositions comprising the same, and by the medical uses thereof.
  • the inventors of the present invention inter alia surprisingly found that the compounds of formula (I) as defined herein act as modulators of FEN1, in particular that they inhibit FEN1.
  • the compounds of formula (I) (including stereoisomers, tautomers, /V-oxides, or pharmaceutically acceptable salts thereof) as well as the pharmaceutical compositions comprising the same can be used as a medicament, in particular for the treatment of cancer, wherein the treatment preferably involves the administration of the compound of formula (I) as modulators of FEN1 in an effective amount to individuals in need of such treatment.
  • the compound is a compound of formula (IA) or (IB):
  • R 3 is Ci-C4-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy-Ci-C4-alkyl, phenyl, or a 3- to 6-membered saturated carbocyclyl-Ci-C2-alkyl or heterocyclyl-Ci-C2-alkyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized, and wherein each of the aforementioned groups is independently unsubstituted or substituted with one or more, preferably one, same or different substituents R Y ; and
  • the fused saturated heterocyclyl formed by R 4 and R 3 together with the atoms to which they are bonded is a morpholinyl of the following structure: wherein the wavy lines indicate the connections to the remainder of the molecule; and preferably the fused saturated heterocyclyl formed by R 4 and R 3 together with the atoms to which they are bonded is a morpholinyl of the following structure: wherein the wavy lines indicate the connections to the remainder of the molecule.
  • the present invention relates to a compound of formula (I) as defined herein or a pharmaceutical composition as defined herein for use in medicine.
  • the present invention relates to a compound of formula (I) as defined herein or a pharmaceutical composition as defined herein for use in the treatment of cancer, preferably for use in the treatment of a cancer selected from bladder cancer, breast cancer, colorectal cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer, gynaecological cancer, in particular ovarian cancer, and head and neck cancer.
  • a cancer selected from bladder cancer, breast cancer, colorectal cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer, gynaecological cancer, in particular ovarian cancer, and head and neck cancer.
  • the present invention relates to a compound of formula (I) or a stereoisomer, tautomer, A/-oxide, or pharmaceutically acceptable salt thereof.
  • the compound of formula (I) is a compound of formula
  • the compound of formula (IA) may be a compound of formula (IA*) or (IA**):
  • Y is O or S, in particular O.
  • R 1 is phenyl, a 5- or 6-membered aromatic heterocyclyl, or an 8- to 10-membered aromatic carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic and heterobicy-mann rings independently comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxi- dized, and wherein each of the aforementioned aromatic rings is independently unsubstituted or substituted with one or more, same or different, substituents R x .
  • R 1 is phenyl, a 6-membered aromatic heterocyclyl, or a 10-membered aromatic carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic and heterobicyclic rings independently comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each of the aforementioned aromatic rings is independently unsubstituted or substituted with one or more, same or different, substituents R x .
  • R 1 is phenyl, pyridinyl, naphtalenyl, quinolinyl, or isoquinolinyl, wherein each of the aforementioned aromatic rings is independently unsubstituted or substituted with one or more, same or different, substituents R x .
  • R 1 is phenyl, pyridine-4-yl, naphthalen-2-yl, quinolin-2-yl, quinolin-3-yl, quinolin-6-yl, quino- lin-7-yl, isoquinolin-3-yl, isoquinolin-6-yl, isoquinolin-7-yl, wherein each of the aforementioned aromatic rings is independently unsubstituted or substituted with one or more, same or different, substituents R x .
  • R x is halogen, CN, Ci-C4-alkyl, Ci-C4-alkoxy, or a 5- or 6-membered aromatic carbocyclyl, carbocyclyl-Ci-C2-alkyl, carbocyclyloxy, heterocyclyl, heterocyclyl-Ci-Cz-alkyl, or hetero- cyclyloxy, wherein the aforementioned heterocyclic rings independently of each other comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized.
  • R x is Cl, F, CN, Ci-C2-alkyl, Ci-C2-alkoxy, phenyl, benzyl, or phenoxy.
  • R x is Cl, F, CN, CH3, methoxy, phenyl, or phenoxy.
  • R 1 is phenyl, pyridine-4-yl, naphthalen-2-yl, quinolin-2-yl, quinolin-3-yl, quinolin-6-yl, quino- lin-7-yl, isoquinolin-3-yl, isoquinolin-6-yl, isoquinolin-7-yl, wherein each of the aforementioned aromatic rings is independently unsubstituted or substituted with one or more, same or different, substituents R x , wherein
  • R 2 is H, Ci-C4-alkyl, or Ci-C4-haloalkyl.
  • R 2 is H, Ci-C2-alkyl, or Ci-C2-haloalkyl
  • R 2 is C C2-alkyl, or C C2-haloalkyl.
  • R 2 is CH 3 or CF 3 .
  • R 2 is CH 3 or CF 3 .
  • R 3 is Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy-Ci-C4-alkyl, or a 3- to 7-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclyl-Ci-C2-alkyl, het- erocyclyl, or heterocyclyl-CrCz-alkyl, wherein the aforementioned heterocyclic rings independently comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different, substituents R Y ; and
  • R 4 is H; or R 4 and R 3 together with the atoms to which they are bonded form a fused 5- to 7-membered saturated heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S- atoms are independently oxidized or non-oxidized, and wherein each substitutable atom in the aforementioned heterocyclic rings is independently unsubstituted or substituted with one or more, same or different, substituents R z .
  • R 3 is Ci-C4-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy-Ci-C4-alkyl, phenyl, or a 3- to 6-membered saturated carbocyclyl-Ci-C2-alkyl or heterocyclyl-Ci-C2-alkyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each of the aforementioned groups is independently unsubstituted or substituted with one or more, preferably one, same or different substituents R Y ; and
  • R 4 is H; or R 4 and R 3 together with the atoms to which they are bonded form a fused 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein the aforementioned heterocyclic ring is independently unsubstituted or substituted with one or more, preferably one, same or different substituents R z .
  • R 3 is Ci-C4-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy-Ci-C4-alkyl, phenyl, or a 3- to 6-membered saturated carbocyclyl-Ci-C2-alkyl or heterocyclyl-Ci-C2-alkyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each of the aforementioned groups is independently unsubstituted or substituted with one or more, preferably one, same or different substituents R Y ; and
  • R 4 and R 3 together with the atoms to which they are bonded form a fused 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein the aforementioned heterocyclic ring is independently unsubstituted or substituted with one or more, preferably one, same or different substituents R z .
  • R 4 and R 3 together with the atoms to which they are bonded form a fused 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclic ring comprises in addition to the nitrogen atom to which R 3 is bonded one oxygen atom, wherein said nitrogen atom is independently oxidized or non-oxidized, and wherein the aforementioned heterocyclic ring is independently unsubstituted or substituted with one or more, preferably one, same or different substituents R z .
  • the heterocyclic ring is unsubstituted, i.e. that R z is absent.
  • the fused saturated heterocyclyl formed by R 4 and R 3 together with the atoms to which they are bonded is of the following structure: wherein the wavy lines indicate the connections to the remainder of the molecule.
  • the fused saturated heterocyclyl formed by R 4 and R 3 together with the atoms to which they are bonded is a morpholinyl of the following structure: wherein the wavy lines indicate the connections to the remainder of the molecule.
  • the fused saturated heterocyclyl formed by R 4 and R 3 together with the atoms to which they are bonded is a morpholinyl of the following structure: wherein the wavy lines indicate the connections to the remainder of the molecule.
  • R 4 and R 3 together with the atoms to which they are bonded form a fused saturated heterocyclyl of the following structure
  • the compound according to formula (I) is selected from the group consisting of:
  • the compound according to formula (I) is selected from the group consisting of:
  • compound(s) of the present invention is to be understood as equivalent to the term “compound(s) according to the invention” and relates to the compounds of formula (I) as well as to compounds of formula (IA), (IB), (IA*), (IA**) and also covers a stereoisomer, tautomer, /V-ox- ide, or pharmaceutically acceptable salt thereof.
  • the compounds according to the invention may be amorphous or may exist in one or more different crystalline states (polymorphs), which may have different macroscopic properties such as stability or show different biological properties such as activities.
  • the present invention relates to amorphous and crystalline forms of compounds of formula (I), mixtures of different crystalline states of the compounds of formula (I), as well as amorphous or crystalline salts thereof.
  • Tautomers may be formed, if a substituent is present at the compound of formula (I), which allows for the formation of tautomers such as keto-enol tautomers, imine-enamine tautomers, am- ide-imidic acid tautomers or the like.
  • /V-oxide includes any compound of the present invention which has at least one tertiary nitrogen atom that is oxidized to an /V-oxide moiety.
  • the compounds according to the invention may have one or more centres of chirality, including axial chirality providing different stereoisomers.
  • the invention provides both, pure enantiomers or pure diastereomers, of the compounds according to the invention, and their mixtures, including racemic mixtures.
  • Suitable compounds according to the invention also include all possible geometrical stereoisomers (cis/trans isomers or E/Z isomers) and mixtures thereof.
  • E/Z- isomers may be present with respect to, e.g., an alkene, carbon-ni- trogen double-bond or amide group.
  • any formula or structure given herein, including compounds of formula (I), is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 CI and 125 l.
  • radioactive isotopes such as 3 H, 13 C and 14 C provide isotopically labelled compounds useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the disclosure includes compounds of formula (I) in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
  • Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME).
  • halo refers to fluoro, chloro, or bromo, particularly fluoro or chloro.
  • halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine, or bromine.
  • alkoxyalkyl refers to an alkoxy group as defined herein having usually from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, which is bonded via an alkyl group as defined herein having usually from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, to the remainder of the molecule.
  • alkyl group which is bonded via oxygen to a further alkyl group, which is then bonded to the remainder of the molecule.
  • alkoxyalkyl groups are methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, and the like.
  • Alkyl and alkoxy groups can be unbranched or branched, and examples of alkyl include but are not limited to methyl, ethyl, n- propyl, iso -propyl, n-butyl, iso -butyl, sec-butyl, and tert-butyl.
  • alkoxy include methoxy, ethoxy, r?-propoxy, iso -propoxy, n-butoxy, iso -butoxy, sec-butoxy, and tert-butoxy.
  • haloalkoxy denotes in each case a straight-chain or branched alkoxy group having from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms, in particular fluorine atoms.
  • Preferred haloalkoxy moieties include Ci-haloalkoxy, in particular Ci-fluoroalkoxy, such as trifluoromethoxy and the like.
  • hydroxyalkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably 1 to 2 carbon atoms, and being further substituted with 1 to 5, preferably with 1 to 2 hydroxy groups, in particular with 1 hydroxy group, wherein a hydroxy group is a OH group.
  • the one hydroxy group is terminating the straight-chain or branched alkyl group so that the hydroxy group is bonded to an alkyl bridge, which is bonded to the remainder of the molecule.
  • hydroxyalkyl group examples include hydroxymethyl, hydroxyethyl, n-hydroxypropyl, 2- hydroxypropyl, n-hydroxybutyl, 2-hydroxy butyl, 2-hydroxy-2-methylpropyl, and n-hydroxypentyl. Hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl, are preferred, in particular hydroxymethyl and hydroxyethyl.
  • carrier includes, unless otherwise indicated, in general a 3- to 10- membered monocyclic or bicyclic ring, preferably a 4- to 8-membered or a 3- to 6-membered or a 5- to 7-membered monocyclic or bicyclic ring, more preferably a 3-, 4-, 5- or 6-membered monocyclic ring, comprising 3 to 10, preferably 4 to 8 or 3 to 6 or 5 to 7, more preferably 3, 4, 5 or 6 carbon atoms.
  • the carbocycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Huckel rule for aromaticity is not fulfilled, whereas aromatic means that the Huckel (4n + 2) rule is fulfilled. Also “aryls” are covered by the term “carbocycles”.
  • aryl or “aromatic carbocycle” refers to aromatic carbocyclic rings based on carbon atoms as ring members, preferably 6-membered aromatic carbocyclic rings based on carbon atoms as ring members. A preferred example is phenyl. Unless otherwise indicated, the term “aryl” further covers “aromatic carbobicycles” as defined herein.
  • cycloalkyl denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 or from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are preferred.
  • carbobicycle includes in general 6 to 14-membered, preferably 7- to 12-membered or 8- to 10-membered, more preferably 9- or 10-membered bicyclic rings comprising 6 to 14, preferably 7 to 12 or 8 to 10, more preferably 9 or 10 carbon atoms.
  • the carbobicycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Huckel rule for aromaticity is not fulfilled, whereas aromatic means that the Huckel (4n + 2) rule is fulfilled.
  • aromatic in connection with the carbobicyclic ring means that both rings of the bicylic moiety are aromatic, so that, e.g., 8 IT electrons are present in case of a 10-membered aromatic carbobicyclic ring.
  • carrier or “carbobicyclyl”, unless otherwise indicated, may therefore cover inter alia bicycloalkyl, bicycloalkenyl, as well as bicyclic aromatic groups, for example bicyclohexane (decalin), bicycloheptane (such as norbomane), bicyclooctane (such as bicyclo[2.2.2]octane, bicyclo[3.2.1]octane or bicyclo[4.2.0]octane), bicyclononane (such as bicy- clo[3.3.1]nonane or bicyclo[4.3.0]nonane ), bicyclodecane (such as bicyclo[4.4.0]decane), bicycloundecane (such as bicyclo[3.3.3]undecane), norbornene, naphthalene and the like.
  • bicyclohexane decalin
  • bicycloheptane such as norbomane
  • Saturated heterocycles include, unless otherwise indicated, in general 3- to 10-membered, preferably 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6-membered monocyclic rings comprising 3 to 10, preferably 4 to 8 or 5 to 7, more preferably 5 or 6 atoms comprising at least one heteroatom, such as pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, tetrahydropyran, dioxane, morpholine or piperazine.
  • heteroatoms such as pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, tetrahydropyran, dioxane, morpholine or piperazine.
  • heterocyclic or “heterobicyclyl” includes, unless otherwise indicated, in general 6 to 14-membered, preferably 7- to 12-membered or 8- to 10-membered, more preferably 8- or 9- membered bicyclic rings.
  • the heterobicycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and 5 partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Huckel rule for aromaticity is not fulfilled, whereas aromatic means that the Huckel (4n + 2) rule is fulfilled.
  • aromatic it is sufficient if one of the two rings of the bicyclic moieties is aromatic, while the other is non-aromatic.
  • the heterobicycle typically comprises one or more, e.g., 1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO2.
  • the remaining ring members are carbon atoms.
  • heterobicycles include but are not limited to: benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadiazolyl, benzothiadia- zolyl, benzoxazinyl, quinolinyl, isoquinolinyl, purinyl, 1,8-naphthyridyl, pteridyl, pyrido[3,2-d]py- rimidyl, pyridoimidazolyl, triethylenediamine or quinuclidine and the like.
  • heteroaryl or “aromatic heterocycle” or “aromatic heterocyclic ring” or “hetaryl” or “heterocyclyl” includes monocyclic 5- or 6-membered aromatic heterocycles comprising as ring members 1, 2, 3 or 4 heteroatoms selected from N, O and S, where S-atoms as ring members may be present as S, SO or SO2.
  • 5- or 6-membered aromatic heterocycles include pyridyl (also referred to as pyridinyl), i.e. 2-, 3-, or 4-pyridyl, pyrimidinyl, i.e.
  • the terms “carbocyclylalkyl” and “heterocyclylalkyl” as well as the terms “arylalkyl”, “cycloalkylalkyl”, “hetarylalkyl”, and the like refer to the corresponding groups, which are bonded to the remainder of the molecule via an alkyl, preferably via a Ci-C2-alkyl group.
  • Preferred examples include benzyl (i.e. phenylmethyl), cyclohexylmethyl, pyridinylmethyl, and pi- peridinomethyl.
  • aryloxy and benzyloxy refer to the corresponding groups, which are bonded to the remainder of the molecule via an oxygen atom.
  • Preferred examples include phenyloxy and phenylmethyloxy (i.e. benzyloxy).
  • cancer pertains to a disease characterized by the rapid and uncontrolled growth of abnormal cells that can spread locally or through the bloodstream and lymphatic system.
  • Various cancers including colorectal, gastric, endometrial, prostate, adrenocortical, uterine, cervical, oesophageal, breast, kidney, and ovarian cancer, among others, are described herein.
  • the terms “tumour”, “tumor” and “cancer” are used interchangeably and encompass both solid and liquid tumours, including diffuse or circulating tumours.
  • the terms “tumour” and “cancer” include premalignant, as well as malignant cancers and tumours.
  • FEN1 modulator or “FEN1 inhibitor” refers to a compound that modulates or inhibits flap endonuclease (FEN1).
  • medicine as used herein is intended to be a generic term inclusive of prescription and non-prescription medications.
  • the compound for use in medicine should be understood as being useful in maintaining health or promoting recovery from a disease, preferably cancer.
  • medicine includes medicine in any form, including, without limitation, e.g., pills, salves, creams, powders, ointments, capsules, injectable medications, drops, vitamins and suppositories.
  • the scope of this invention is not limited by the type, form or dosage of the medicine.
  • a “pharmaceutical composition” is a compound of the invention or a pharmaceutically acceptable salt thereof, along with at least one pharmaceutically acceptable carrier, prepared for oral or parenteral administration.
  • a “pharmaceutically acceptable carrier” includes substances used in the preparation or use of pharmaceutical compositions, such as diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, and more.
  • pharmaceutically acceptable excipient refers to compounds commonly comprised in pharmaceutical compositions, which are known to the skilled person. Typically, a pharmaceutically acceptable excipient can be defined as being pharmaceutically inactive.
  • a “therapeutically effective amount” of a compound refers to an amount that, when administered to a subject, achieves a biological or medical response, such as the reduction of enzyme or protein activity or the alleviation, mitigation, or prevention of symptoms, disease progression, or the disease itself.
  • compositions may be solid or liquid dosage forms or may have an intermediate, e.g. gel-like character depending inter alia on the route of administration.
  • the dosage form according to the invention may be formulated for topical application.
  • Suitable pharmaceutical application forms for such an application may be a topical nasal spray, sublingual administration forms and controlled and/or sustained release skin patches.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compound of formula (I) may be administered to a patient in an amount of about 0.001 mg to about 5000 mg per day, preferably of about 0.01 mg to about 1000 mg per day, more preferably of about 0.05 mg to about 250 mg per day, which is the effective amount.
  • effective amount means an amount of compound that, when administered to a mammal in need of such treatment, is sufficient to treat or prevent a particular disease or condition.
  • the compounds according to the present invention are suitable for use in medicine.
  • the compounds of the present invention are useful for (partially) modulating FEN1.
  • the compounds according to the present invention are particularly suitable for use in the treatment of a disease associated with modulating FEN1, in particular a proliferative disorder such as cancer or pre- cancerous syndromes.
  • the present invention relates to a compound of formula (I) as defined herein or a pharmaceutical composition as defined herein for use in medicine.
  • the compound of the present invention or a pharmaceutical composition comprising the same is for use in the treatment of a disease selected from the group consisting of cancer or pre-cancerous syndromes.
  • said cancer is selected from the group consisting of bladder, breast, colorectal, gastric, liver, lung, pancreatic, prostate, gynaecological cancer, in particular ovarian cancer, and head and neck cancer.
  • the present invention relates to methods of treatment comprising the administration of a compound of formula (I) as defined herein or a pharmaceutical composition comprising the same as defined herein to a human or animal body.
  • the present invention relates to methods of treating diseases that can be addressed by FEN1 modulation, with a particular emphasis on cancers such as bladder, breast, colorectal, gastric, liver, lung, pancreatic, prostate, gynaecological cancer, in particular ovarian cancer, as well as head and neck cancer.
  • the invention further relates to the manufacture of a medicament for the treatment of diseases that can be addressed by FEN1 modulation, with a particular emphasis on cancers such as bladder, breast, colorectal, gastric, liver, lung, pancreatic, prostate, gynaecological cancer, in particular ovarian cancer, as well as head and neck cancer.
  • cancers such as bladder, breast, colorectal, gastric, liver, lung, pancreatic, prostate, gynaecological cancer, in particular ovarian cancer, as well as head and neck cancer.
  • the compounds according to the present invention are administered in combination with antibodies, radiotherapy, surgical therapy, immunotherapy, chemotherapy, toxin therapy, gene therapy, or any other therapy known to those of ordinary skill in the art for treatment of a particular disease. This is particularly relevant in connection with the treatment of cancer.
  • the compounds described herein may be prepared using the following methods and schemes.
  • the sequence of reactions is an illustrative example. Swapping steps is possible and reaction conditions can be easily adapted. Unless specified otherwise, all starting materials used are commercially available or can be synthesised analogously to the described intermediates or to routes described in the literature.
  • Route B1 a) Protecting group introduction, e.g. N,O-Bis(trimethylsilyl)-acetamide and 2-(Trime- thylsilyl)ethoxymethyl chloride in tert-Butyl methyl ether at RT for 4 hours; b) amide coupling with typical acid activation conditions like HATU, thionylchlorid, BOP; c) Chlorination with e.g. thionylchlorid in DCM at RT for 45 min; d) cyclisation with e.g. Li Br in Dioxane at 130 °C for 1.5 hours; e) chlorination with e.g.
  • protecting group introduction e.g. benzyl via benzylbromid, a base like triethylamine and a solvent like DMF at 75 °C for 2 hours or via Mitsunobu conditions, alternative protecting group can be, but not limited to Pivaloyl; g) aromatic nucleophilic halogen displacement under basic conditions, e.g. with Potassium tert-bu- tylate or NaH; h) removal of protecting group, condition dependent on selected protecting group, for benzyl, e.g., LiCI is suitable, but not limited to it.
  • Route B2 i) basic ester saponification, e.g. with NaOH at 75°C for 1 h; j) amide coupling with typical acid activation conditions like HATU, thionylchlorid, BOP; k) ring closing via converting the alcohol into a leaving group, like SOCh; I) Benzyl protecting group removal, e.g. under acidic conditions with TFA; m) protecting group introduction, e.g. benzyl via benzylbromid, a base like triethylamine and a solvent like DMF at 75 °C for 2 hours or via Mitsunobu conditions, alternative protecting group can be, but not limited to Pivaloyl; n) chlorination with e.g.
  • NCS at 50°C for 3 h.
  • aromatic nucleophilic halogen displacement under basic conditions e.g. with Potassium tert-butylate or NaH;
  • removal of protecting group, condition dependent on selected protecting group, for benzyl, e.g., LiCI is suitable, but not limited to it.
  • Channel B p-Toluenesulfonyl azide solution, 11-15 % (w/w) in toluene (99.7 ml; 50 mmol; 1 eq.)
  • Channel D Trimethylphosphine solution, 1.0 M in THF (100 ml; 100 mmol; 2 eq.)
  • the final product stream was collected in a flask that contains 100 ml of water equipped with a stir bar. The mixture was stirred for 1h at RT to quench the trimethylphospine, diluted with EtOAc and washed with water and brine.
  • LCMS LC-MS, Agilent 1200 Series, Chromolith HR RP-18e 50-4,6; 3.3ml/min; solvent A: Water + 0.1% TFA; solvent B: Acetonitrile + 0.1% TFA; 220 nm; 0 to 2,0 min: 1 %B to 99%B; 2,0 to 2,5 min. 99%B): purity 43.5 %, Rt 1 .39 and 1.437 min (E/Z mixture), [M+Na] + 287.0 m/z.
  • LCMS LC-MS, Agilent 1200 Series, Chromolith HR RP-18e 50-4,6; 3.3ml/min; solvent A: Water + 0.1% TFA; solvent B: Acetonitrile + 0.1% TFA; 220 nm; 0 to 2,0 min: 1 %B to 99%B; 2,0 to 2,5 min. 99%B): purity 100 %, Rt 1.82 min, [M+Na] + 381.1 m/z.
  • the stream of A was pumped through reactor 1 (2ml volume) at 60°C for pre-heating the reagent.
  • the output of reactor 1 and stream B were mixed in a T-mixer and pumped at 60°C through the reactors 2-4 (in series, 30 ml total volume). Total flow: 1.0 ml/min.
  • the final product stream was manually collected in a flask. The collected product solution was cooled in an ice bath and acidified to pH 2 by adding hydrogen chloride solution (4 M in dioxane).
  • LCMS LC-MS, Agilent 1200 Series, Chromolith HR RP-18e 50-4,6; 3.3ml/min; solvent A: Water + 0.1% TFA; solvent B: Acetonitrile + 0.1% TFA; 220 nm; 0 to 2,0 min: 1 %B to 99%B; 2,0 to 2,5 min. 99%B): purity 96.4 %, Rt 1.12 min., [M+Na] + 297.0 m/z.
  • reaction mixture was quenched with sat. NaHCO3-solution to pH 4-5 and the phases were separated.
  • Sodium hydroxide solution c(NaOH) 1 mol/l (1 N) (193 ml; 193 mmol; 2 eq.) and the mixture was stirred at RT.
  • the phases were separated.
  • the aqueous layer was acidified to pH 2-3 by adding 2-N HCI.
  • LCMS (Agilent 1200 Series, Chromolith HR RP-18e 50-4,6; 3.3ml/min; solvent A: Water + 0.1% TFA; solvent B: Acetonitrile + 0.1% TFA; 220 nm; 0 to 2,0 min: 1%B to 99%B; 2,0 to 2,5 min. 99%B): [M+Na] 494.1 m/z, purity 93 %, Rt 1.771 min.
  • Lithiumbromide (12 g) was added to a solution of 5-(benzyloxy)-3-[(3R)-3-(chloromethyl)mor- pholine-4-carbonyl]-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -1 ,4-dihydropyridazin-4-one (89 g) in Dioxane (600 ml) and the mixture was heated to 130°C in a Buchi 1 I Uniclave pressure reactor. After cooling to RT the reaction mixtures of both batches were combined. The precipitated product was collected by filtration and rinsed with Dioxane (500 ml) and THF (300 ml).
  • LCMS (Agilent 1200 Series, Chromolith HR RP-18e 50-4,6; 3.3ml/min; solvent A: Water + 0.1% TFA; solvent B: Acetonitrile + 0.1% TFA; 220 nm; 0 to 2,0 min: 1%B to 99%B; 2,0 to 2,5 min. 99%B): [M+Na] 238.1 m/z, purity 98.9 %, Rt 0.745 min.
  • LCMS (Agilent 1200 Series, Chromolith HR RP-18e 50-4,6; 3.3ml/min; solvent A: Water + 0.1% TFA; solvent B: Acetonitrile + 0.1% TFA; 220 nm; 0 to 2,0 min: 1%B to 99%B; 2,0 to 2,5 min. 99%B): purity 95.9 %, Rt 1.28 min; [M+H] 362.1 m/z.
  • LCMS (Agilent 1200 Series, Chromolith HR RP-18e 50-4,6; 3.3ml/min; solvent A: Water + 0.1% TFA; solvent B: Acetonitrile + 0.1% TFA; 220 nm; 0 to 2,0 min: 1%B to 99%B; 2,0 to 2,5 min. 99%B): purity 30.1 %, Rt 1.74 min., [M+H - C12H10CI] 344.1 m/z and purity 23.4 %, Rt 1.97 min., [M+H - C12H10CI] 254.1 m/z.
  • LCMS (Agilent 1200 Series, Chromolith HR RP-18e 50-4,6; 3.3ml/min; solvent A: Water + 0.1% TFA; solvent B: Acetonitrile + 0.1% TFA; 220 nm; 0 to 2,0 min: 1%B to 99%B; 2,0 to 2,5 min. 99%B): purity 97.0%, Rt 1.56 min., [M+H - C12H10CI] 254.1 m/z.
  • Example 17 via benzoyl protecting group route: (3S)-13-[(1S)-1-(7-chloronaphthalen-2-yl)ethoxy]-11-hydroxy-5-oxa-1 ,8,14-triazatricy- clo[8.4.0.0 3 ’ 8 ]]tetradeca-10, 13-diene-9, 12-dione
  • LCMS (Agilent 1200 Series, Chromolith HR RP-18e 50-4,6; 3.3ml/min; solvent A: Water + 0.1% TFA; solvent B: Acetonitrile + 0.1% TFA; 220 nm; 0 to 2,0 min: 1%B to 99%B; 2,0 to 2,5 min.
  • Stereoinformation regarding the stereocenter at position 1 is assigned arbitrarily in both the structural formula and the IUPAC name.
  • BIOLOGICAL DATA FEN1 nuclease assay - determination of FEN1 inhibition (IC50 FEN1):
  • the IC50 values were determined by a biochemical FEN1 nuclease assay.
  • FEN1 Flexible Endonuclease 1
  • a mixture of FEN1 protein and the test substance were incubated at different concentrations with addition of fluorescently labelled 5’ Flap DNA substrate.
  • Cleavage of the FAM / BHQ1 dual labelled 5’ Flap DNA substrate released the fluorescently tagged 5’ Flap causing an increase in fluorescent signal that is proportional to the amount of product generated.
  • a single nucleotide 3’ flap was included in the substrate as this has been shown to be important for FEN1 substrate binding and cleavage.
  • the final concentrations in the assay during incubation of the reaction mixture were 0.03 - 0.04 nM FEN1 and 40 nM DNA substrate. After 60 min at room temperature, reactions were quenched by the addition of 3 pl of stop buffer (270 mM EDTA, 45 mM TRIS pH 7.5). The plates were analysed in a plate reader (PheraStar FSX, BMG LabTech) measuring fluorescence at 520 nm following excitation at 485 nm. The amount of product generated is directly proportional to the amounts of light emitted, i.e. the relative fluorescence units (RFU) at 520 nm. The measurement data were processed by means of the Genedata Screener software. In particular, IC50 values were determined by fitting a dose-response curve to the data points using nonlinear regression analysis.

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Abstract

La présente invention concerne des composés de formule (I) et des stéréoisomères, des tautomères, des N-oxides, ou des sels pharmaceutiquement acceptables de ceux-ci qui sont utiles pour moduler l'endonucléase de FLAP (FEN1). La présente invention concerne en outre les composés de formule (I) destinés à être utilisés en tant que médicament et une composition pharmaceutique comprenant lesdits composés.
PCT/GB2025/050272 2024-02-13 2025-02-13 Composés modulant l'endonucléase flap (fen1) Pending WO2025172706A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006014647A2 (fr) * 2004-07-21 2006-02-09 Athersys, Inc. N-hydroxy-imides servant d'inhibiteurs de la flap-endonuclease et leurs utilisations
WO2017051251A1 (fr) * 2015-09-25 2017-03-30 Ludwig Institute For Cancer Research Ltd Dérivés de 3-hydroxy-quinazoline-2,4-dione et leur utilisation comme modulateurs de nucléase
WO2019067442A1 (fr) * 2017-09-26 2019-04-04 Ideaya Biosciences, Inc. Composés de dihydrothiéno [3,2-b] pyridine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006014647A2 (fr) * 2004-07-21 2006-02-09 Athersys, Inc. N-hydroxy-imides servant d'inhibiteurs de la flap-endonuclease et leurs utilisations
WO2017051251A1 (fr) * 2015-09-25 2017-03-30 Ludwig Institute For Cancer Research Ltd Dérivés de 3-hydroxy-quinazoline-2,4-dione et leur utilisation comme modulateurs de nucléase
WO2019067442A1 (fr) * 2017-09-26 2019-04-04 Ideaya Biosciences, Inc. Composés de dihydrothiéno [3,2-b] pyridine

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Title
GUO, E.ISHII, Y.MUELLER, J.SRIVATSAN, A.GAHMAN, T.PUTNAM, C. D.WANG, J. Y. J.KOLODNER, R. D.: "FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 117, no. 32, 2020, pages 19415 - 19424
MENGWASSER, K. E.ADEYEMI, R. O.LENG, Y.CHOI, M. Y.CLAIRMONT, C.D'ANDREA, A. D.ELLEDGE, S. J.: "Genetic screens reveal FEN1 and APEX2 as BRCA2 synthetic lethal targets", MOLECULAR CELL, vol. 73, no. 5, 2019, pages 885 - 899
POSTER: "Deuterium Isotope Effects in Studies of Drug Metabolism", TRENDS PHARMACOL. SEI., vol. 5, no. 12, 1984, pages 524 - 527
SUN, H.MA, L.TSAI, Y. F.ABEYWARDANA, T.SHEN, B.ZHENG, L.: "Okazaki fragment maturation: DNA flap dynamics for cell proliferation and survival", TRENDS IN CELL BIOLOGY, vol. 33, no. 3, 2023, pages 221 - 234
WARD, T. A., MCHUGH, P. J., DURANT, S.T.: "Small molecule inhibitors uncover synthetic genetic interactions of human flap endonuclease 1 (FEN1) with DNA damage response genes", PLOS ONE, vol. 12, no. 6, 2017, pages 0179278

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