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WO2026003380A1 - Composés inhibiteurs de wrn - Google Patents

Composés inhibiteurs de wrn

Info

Publication number
WO2026003380A1
WO2026003380A1 PCT/EP2025/068557 EP2025068557W WO2026003380A1 WO 2026003380 A1 WO2026003380 A1 WO 2026003380A1 EP 2025068557 W EP2025068557 W EP 2025068557W WO 2026003380 A1 WO2026003380 A1 WO 2026003380A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
alkylene
heterocyclyl
carbocyclyl
optionally substituted
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/EP2025/068557
Other languages
English (en)
Inventor
Ulrich LÜCKING
Olivier Querolle
Andreas Goutopoulos
Luca IACOVINO
Zaixu Xu
Anika KUSTER
Marta MALATTIA
Nicolas Bocquet
Irena Konstantinova
Frank Zenke
Jason CLOCHARD
Anja STAMPFLI
Giacomo Rossetti
Marina GYSIN
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.)
Forx Therapeutics Ag
Original Assignee
Forx Therapeutics Ag
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
Priority claimed from PCT/EP2024/077789 external-priority patent/WO2025073792A1/fr
Application filed by Forx Therapeutics Ag filed Critical Forx Therapeutics Ag
Publication of WO2026003380A1 publication Critical patent/WO2026003380A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof.
  • the present invention further relates to the compound of formula (I) of the present invention for use in therapy.
  • Instant compounds are particularly useful as WRN inhibitors, and can be used in a method of treatment of cancer, in particular, the cancer is treatable by inhibition of WRN, and/or the cancer characterized by MSI-H and/or dMMR.
  • Cancer is a leading cause of death worldwide.
  • a limitation of prevailing therapeutic approaches, e.g. chemotherapy is that their cytotoxic effects are not restricted to cancer cells and adverse side effects can occur within normal tissues. Consequently, novel strategies are needed to better target cancer cells.
  • Synthetic lethality arises when a combination of genetic deficiencies (e.g. gene mutations, silencing or global genomic lesions) and/or molecular perturbations (e.g. gene expression knockout/knockdown, pharmacological inhibition/activation) corresponding to two or more genes impaired cell wellbeing, whereas presence of single deficiency/perturbation does not (Dobzhansky, T., Genetics 1946; 31 , 269-290, Huang et al., Nature Reviews Drug Discovery 2020; volume 19, pages 23-38).
  • genetic deficiencies e.g. gene mutations, silencing or global genomic lesions
  • molecular perturbations e.g. gene expression knockout/knockdown, pharmacological inhibition/activation
  • Microsatellite instability is a genomic lesion caused by defects in mismatch repair machinery (dMMR). MSI status is present in colorectal cancer, endometrial cancer, gastric cancer and other cancer types. Mutation or silencing of MMR genes, including MLH1 , MSH2, MSH6 and PMS2, abrogates cell’s ability to repair DNA mismatch mutations (Baudrin et al., Front. Oncol. 2018). As a consequence, tumor with MSI-H status carries higher mutation burden, disrupted microsatellite repeat sequences and extended TA dinucleotide repeat sequences across the genome (van Wietmarschen N. et al., Nature 2020; 586, pages 292-298).
  • MSI status can be assessed by molecular testing of certain microsatellites, next-generation sequencing of patient genome or by immunohistochemical evaluation of expression of certain MMR proteins. Tumors can be categorized into MSI high (MSI-H), MSI low (MSI-L) and MSS depending on the number of tested microsatellite showing instability. Based on a consensus NCI- Reference Panel (Bethesda, 1998), MSI can be assessed by molecular testing of five microsatellites - including two mononucleotides (BAT25 and BAT26) and three dinucleotides (D2S123, D5S346, D17S250).
  • Tumors are denoted as MSI-high (MSI-H) if two or more of the microsatellite markers show instability, MSI-low (MSI-L) if only one microsatellite marker shows instability, and MS-stable (MSS) if none of the five microsatellite markers show instability.
  • MSI-H MSI-high
  • MSI-L MSI-low
  • MSS MS-stable
  • tumors can be classified as a MSS neoplasms.
  • Document WO 2023/062575 discloses certain cyclic vinyl sulfone compounds as WRN inhibitors.
  • Documents WO 2024/010782 and WO 2024/010784 disclose certain covalent WRN inhibitors. Further covalent inhibitors of WRN are disclosed in document WO 2024/028169.
  • the compounds of the present invention show improved PK/PD properties compared to previously known WRN inhibitors. Furthermore, the compounds of the present invention show improved selectivity as covalent inhibitors against WRN protein.
  • the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I).
  • the present invention relates to a compound of formula (I) for use as a medicament.
  • the present invention relates to a compound of formula (I) for use in the treatment of cancer. It is preferred that the cancer is characterized by high microsatellite instability (MSI) and/or by defective DNA mismatch repair system (dMMR) in a patient.
  • MSI microsatellite instability
  • dMMR defective DNA mismatch repair system
  • the present invention relates to use of a compound of formula (I) in a manufacture of a medicament.
  • the present invention relates to use of a compound of formula (I) in a manufacture of a medicament for the treatment of cancer. It is preferred that the cancer is characterized by high microsatellite instability (MSI) and/or by defective DNA mismatch repair system (dMMR) in a patient.
  • MSI microsatellite instability
  • dMMR defective DNA mismatch repair system
  • the present invention relates to a method of treatment of cancer in a subject in need thereof, the method comprising the step of administering the compound of formula (I) to said subject.
  • a therapeutically effective amount of the compound of formula (I) is administered.
  • the cancer is characterized by high microsatellite instability (MSI) and/or by defective DNA mismatch repair system (dMMR) in a patient.
  • MSI microsatellite instability
  • dMMR defective DNA mismatch repair system
  • hydrogen is herein used to refer to protium, deuterium and/or tritium, preferably to protium. Accordingly, the term “non-hydrogen atom” refers to any atoms that is not hydrogen, i.e. that is not protium, deuterium or tritium.
  • hydrocarbon group refers to a group consisting of carbon atoms and hydrogen atoms.
  • alicyclic is used in connection with cyclic groups and denotes that the corresponding cyclic group is non-aromatic.
  • alkyl refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group which may be linear or branched. Accordingly, an “alkyl” group does not comprise any carbon-to-carbon double bond or any carbon-to-carbon triple bond.
  • a “C1-5 alkyl” denotes an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl).
  • alkyl preferably refers to C1-4 alkyl, more preferably to methyl or ethyl, and even more preferably to methyl.
  • alkenyl refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond.
  • C2-5 alkenyl denotes an alkenyl group having 2 to 5 carbon atoms.
  • Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1 -en-1-yl, prop-1 -en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., buta-1 ,3-dien-1-yl or buta-1 ,3- dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl).
  • alkenyl preferably refers to C2-4 alkenyl.
  • alkynyl refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds.
  • C2-5 alkynyl denotes an alkynyl group having 2 to 5 carbon atoms.
  • Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl.
  • alkynyl preferably refers to C2-4 alkynyl.
  • alkylene refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group which may be linear or branched.
  • a “C1-5 alkylene” denotes an alkylene group having 1 to 5 carbon atoms, and the term “C0-3 alkylene” indicates that a covalent bond (corresponding to the option “Co alkylene”) or a C1-3 alkylene is present.
  • Preferred exemplary alkylene groups are methylene (- CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH 3 )-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH 2 -CH 3 )-, -CH2- CH(-CH 3 )-, or -CH(-CH 3 )-CH2-), or butylene (e.g., -CH2-CH2-CH2-CH2-).
  • alkylene preferably refers to C1-4 alkylene (including, in particular, linear C1-4 alkylene), more preferably to methylene or ethylene, and even more preferably to methylene.
  • alkenylene refers to an alkenediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond.
  • a “C2- 5 alkenylene” denotes an alkenylene group having 2 to 5 carbon atoms.
  • alkenylene preferably refers to C2-4 alkenylene (including, in particular, linear C2-4 alkenylene).
  • alkynylene refers to an alkynediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds.
  • a “C2-5 alkynylene” denotes an alkynylene group having 2 to 5 carbon atoms.
  • alkynylene preferably refers to C24 alkynylene (including, in particular, linear C2-4 alkynylene).
  • carbocyclyl refers to a hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic.
  • “carbocyclyl” preferably refers to aryl, cycloalkyl or cycloalkenyl.
  • heterocyclyl refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic.
  • each heteroatom-containing ring comprised in said ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring.
  • heterocyclyl preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl.
  • aryl refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic).
  • Aryl may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1 ,2-dihydronaphthyl), tetralinyl (i.e., 1 ,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1 H-indenyl), anthracenyl, phenanthrenyl, 9H- fluorenyl, or azulenyl.
  • an “aryl” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.
  • arylene refers to an aryl group, as defined herein above, but having two points of attachment, i.e. a divalent aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic).
  • “Arylene” may, e.g., refer to phenylene (e.g., phen-1 ,2-diyl, phen-1 ,3-diyl, or phen-1 ,4-diyl), naphthylene (e.g., naphthalen-1 ,2-diyl, naphthalen-1 ,3-diyl, naphthalen-1 ,4-diyl, naphthalen-1 ,5-diyl, naphthalen-1 ,6- diyl, naphthalen-1 , 7-diyl, naphthalen-2,3-diyl, naphthalen-2,5-diyl, naphthalen-2,6-diyl, naphthalen-2,7- diyl, or naphthalen-2,8-diyl), 1 ,2-dihydronaphthylene, 1 ,2,3,4-tetrahydr
  • an “arylene” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenylene or naphthylene, and most preferably refers to phenylene (particularly phen- 1 ,4-diyl).
  • heteroaryl refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group).
  • aromatic ring group comprises one or more (such as, e.g., one, two, three
  • each heteroatom-containing ring comprised in said aromatic ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring.
  • Heteroaryl may, e.g., refer to thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1- benzopyranyl or 4H-1 -benzopyranyl), isochromenyl (e.g., 1 H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 1 H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3- pyridyl, or 4-pyridyl), pyr
  • heteroaryl preferably refers to a 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a “heteroaryl” refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.
  • heteroarylene refers to a heteroaryl group, as defined herein above, but having two points of attachment, i.e. a divalent aromatic ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i).
  • each heteroatom-containing ring comprised in said aromatic ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring.
  • Heteroarylene may, e.g., refer to thienylene (i.e., thiophenylene; e.g., thien-2,3-diyl, thien-2,4-diyl, or thien-2,5-diyl), benzo[b]thienylene, naphtho[2,3-b]thienylene, thianthrenylene, furylene (i.e., furanylene; e.g., furan-2,3-diyl, furan-2,4-diyl, or furan-2,5-diyl), benzofuranylene, isobenzofuranylene, chromanylene, chromenylene, isochromenylene, chromonylene, xanthenylene, phenoxathiinylene, pyrrolylene, imidazolylene, pyrazolylene, pyridylene (i.e., pyridinylene),
  • heteroarylene preferably refers to a divalent 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a “heteroarylene” refers to a divalent 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from 0, S, and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optional
  • a “heteroarylene”, including any of the specific heteroarylene groups described herein, may be attached through two carbon ring atoms, particularly through those two carbon ring atoms that have the greatest distance from one another (in terms of the number of ring atoms separating them by the shortest possible connection) within one single ring or within the entire ring system of the corresponding heteroarylene.
  • the term “cycloalkyl” refers to a saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings).
  • Cycloalkyl may, e.g., refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl.
  • cycloalkyl preferably refers to a C3-11 cycloalkyl, and more preferably refers to a C3-7 cycloalkyl.
  • a particularly preferred “cycloalkyl” is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g., cyclopropyl or cyclohexyl).
  • cycloalkylene refers to a cycloalkyl group, as defined herein above, but having two points of attachment, i.e. a divalent saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings).
  • Cycloalkylene may, e.g., refer to cyclopropylene (e.g., cyclopropan-1 , 1 -diyl or cyclopropan-1 ,2-diyl), cyclobutylene (e.g., cyclobutan-1 ,1-diyl, cyclobutan-1 ,2-diyl, or cyclobutan-1 ,3-diyl), cyclopentylene (e.g., cyclopentan-1,1 -diyl, cyclopentan-1 , 2-diyl, or cyclopentan-1 , 3-diyl), cyclohexylene (e.g., cyclohexan-1 , 1-diyl, cyclohexan-1, 2-diyl, cyclohexan-1, 3-diyl, or cyclohexan-1 ,4-diyl), cycloheptylene, de
  • cycloalkylene preferably refers to a C3-11 cycloalkylene, and more preferably refers to a C3-7 cycloalkylene.
  • a particularly preferred “cycloalkylene” is a divalent monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g., cyclopropylene or cyclohexylene).
  • heterocycloalkyl refers to a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group).
  • Heterocycloalkyl may, e.g., refer to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1 ,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1 ,3-dioxolanyl, tetrahydropyranyl, 1 ,4-dioxanyl, oxepany
  • heterocycloalkyl preferably refers to a 3 to 11 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, “heterocycloalkyl” refers to a 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms
  • heterocycloalkylene refers to a heterocycloalkyl group, as defined herein above, but having two points of attachment, i.e. a divalent saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo
  • each heteroatom-containing ring comprised in said saturated ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring.
  • Heterocycloalkylene may, e.g., refer to aziridinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, piperazinylene, azepanylene, diazepanylene (e.g., 1 ,4-diazepanylene), oxazolidinylene, isoxazolidinylene, thiazolidinylene, isothiazolidinylene, morpholinylene, thiomorpholinylene, oxazepanylene, oxiranylene, oxetanylene, tetrahydrofuranylene, 1 ,3-dioxolanylene, tetrahydropyranylene, 1 ,4-dioxanylene, oxepanylene, thiiranylene, thietanylene, tetrahydrothiophenylene (
  • heterocycloalkylene preferably refers to a divalent 3 to 11 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, “heterocycloalkylene” refers to a divalent 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N
  • W-heterocycloalkyl refers to the heterocycloalkyl groups as defined hereinabove wherein said heterocycloalkyl includes at least one nitrogen atom which serves as an attachment point of said heterocycloalkyl.
  • cycloalkenyl refers to an unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said hydrocarbon ring group comprises one or more (e.g., one or two) carbon-to-carbon double bonds and does not comprise any carbon-to-carbon triple bond.
  • Cycloalkenyl may, e.g., refer to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl.
  • cycloalkenyl preferably refers to a C3-11 cycloalkenyl, and more preferably refers to a C3-7 cycloalkenyl.
  • a particularly preferred “cycloalkenyl” is a monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and containing one or more (e.g., one or two; preferably one) carbon-to-carbon double bonds.
  • cycloalkenylene refers to a cycloalkenyl group, as defined hereinabove, but having two points of attachment, i.e. a divalent unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said hydrocarbon ring group comprises one or more (e.g., one or two) carbon-to- carbon double bonds and does not comprise any carbon-to-carbon triple bond.
  • a divalent unsaturated alicyclic (non-aromatic) hydrocarbon ring group including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.
  • each heteroatom-containing ring comprised in said unsaturated alicyclic ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring.
  • heterocycloalkenyl preferably refers to a 3 to 11 membered unsaturated alicyclic ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms; more preferably, “heterocycloalkenyl” refers to a 5 to 7 membered monocyclic unsaturated non-aromatic ring group containing one or more (e.g
  • the terms “optional”, “optionally” and “may” denote that the indicated feature may be present but can also be absent.
  • the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent.
  • the expression “X is optionally substituted with Y” (or “X may be substituted with Y”) means that X is either substituted with Y or is unsubstituted.
  • a component of a composition is indicated to be “optional”, the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.
  • the term “about” preferably refers to ⁇ 10% of the indicated numerical value, more preferably to ⁇ 5% of the indicated numerical value, and in particular to the exact numerical value indicated. If the term “about” is used in connection with the endpoints of a range, it preferably refers to the range from the lower endpoint -10% of its indicated numerical value to the upper endpoint +10% of its indicated numerical value, more preferably to the range from of the lower endpoint -5% to the upper endpoint +5%, and even more preferably to the range defined by the exact numerical values of the lower endpoint and the upper endpoint.
  • A is selected from aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl, cycloalkenyl, C2 alkynyl, -N(CI-5 alkyl)(Ci-5 alkyl) (such as -N(CH3)(CH(CH3)2)), C2-haloalkyl (such as - CF2CH3) and — (C1-2 haloalkylene)-cycloalkyl (such as -CF2-cyclopropyl), wherein said aryl, said heteroaryl, said heterocycloalkyl, said heterocycloalkenyl, said cycloalkyl and said cycloalkenyl are each optionally substituted with one or more R 1 , and wherein said C2 alkynyl is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, aryl (such as phenyl) or heteroaryl (such as thien-2-yl),
  • the scope of the invention embraces the compounds of formula (I) in any solvated form, including, e.g., solvates with water (i.e., as a hydrate) or solvates with organic solvents such as, e.g., methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile. All physical forms, including any amorphous or crystalline forms (i.e., polymorphs), of the compounds of formula (I) are also encompassed within the scope of the invention. It is to be understood that such solvates and physical forms of pharmaceutically acceptable salts of the compounds of the formula (I) are likewise embraced by the invention.
  • such prodrugs may preferably include for the compounds of formula (I) which comprise -OH moiety derivatives wherein said -OH moiety is turned into an -ORx moiety, wherein R x preferably comprises a moiety selected from -CO-, -CH2-O-CO, -CH2-O-CO-O-, and -CH(CH3)-O-COO-, more preferably wherein R x is selected from -CO-R y , -CH2-0-C0-R y , -CH2-0-C0-0-R y , and -CH(CH3)-0- COO-R y , wherein R y is preferably carbocyclyl, heterocyclyl, C1-5 alkyl, -NH-(CI-5 alkyl) or -S-(Ci-5 alkyl), wherein the said alkyl is optionally substituted with a group selected from halogen, -CN, -OH, C1-5 alkyl,
  • Said compounds or pharmaceutical compositions can also be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
  • sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules.
  • Sustained-release matrices include, e.g., polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D-(— )-3-hydroxybutyric acid.
  • Sustained-release pharmaceutical compositions also include liposomally entrapped compounds. The present invention thus also relates to liposomes containing a compound of the invention.
  • the MSI-H phenotype is associated with germline defects in the mismatch repair genes MLH1 , MSH2, MSH6, and PMS2, and is the primary phenotype observed in tumors from patients with HNPCC/Lynch syndrome.
  • a tumor is classified as MSI-H in IHC test if it shows a loss of protein expression for at least 1 of the above 4 mismatch repair genes.
  • Cells can be similarly classified as MSI-H using the tests described herein for tumors.
  • a tumor is classified as MSI-H using IHC to determine the expression level of the MMR proteins MLH1 , MSH2, MSH6, and/or PMS2 in both tumor tissue and normal tissue, wherein the tumor is classified as MSI-H if there is a loss of protein expression for at least one of the MMR proteins in the tumor tissue relative to the normal tissue.
  • the loss of protein expression is a decrease of at least 20% (such as a decrease of 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more).
  • the cancer to be treated in accordance with the present invention may be a solid cancer or a hematological cancer.
  • the cancer is selected from lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, large cell lung carcinoma, lung adenocarcinoma, including also lung adenocarcinoma with EGFR mutation AE746-A750, or squamous cell carcinoma of the lung), renal cancer (or kidney cancer; e.g., renal carcinoma), gastrointestinal cancer, stomach cancer, colorectal cancer (e.g., colorectal carcinoma), colon cancer, anal cancer, genitourinary cancer, bladder cancer, liver cancer (e.g., hepatocellular carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), cervical cancer, endometrial cancer, vaginal cancer, vulvar cancer, ovarian cancer (e.g., ovarian carcinoma), uterine cancer
  • the antiproliferative treatment i.e. the treatment of cancer
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumour agents:-
  • antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblast
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro- 4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the epidermal growth factor family; inhibitors of
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU1 1248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5- yloxy)-6-methoxy-7-(3-pyrrolidin-1 - ylpropoxy)quinazoline (AZD2171 ; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications W097/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example li
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01 Z92224, WO 02/04434 and WO 02/08213;
  • an endothelin receptor antagonist for example zibotentan (ZD4054) or atrasentan;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • (ix) gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi- drug resistance gene therapy; and
  • GDEPT gene-directed enzyme pro-drug therapy
  • (x) immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of formula (I) of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • the present invention further relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of a cancer (for example a cancer involving a solid tumour) in combination with another anti-tumour agent.
  • the antitumour agent is preferably selected from the anti-tumour agents as listed hereinabove.
  • the term “combination” refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.
  • the syntheses of the compounds of formula (I) according to the present invention are preferably carried out according to the general synthetic sequences as shown in Scheme 1 .
  • routes described below also other routes may be used to synthesize the target compounds, in accordance with common general knowledge of a person skilled in the art of organic synthesis.
  • the order of transformations exemplified in the following Schemes is therefore not intended to be limiting, and suitable synthesis steps from various schemes can be combined to form additional synthesis sequences.
  • modification of any of the substituents can be achieved before and/or after the exemplified transformations.
  • compound 3 is prepared via cross-coupling reactions of suitably functionalized building blocks 1 and 2.
  • Formation of a C-C bond between A (1) and B-X (2) can be e.g. achieved by the cross-coupling of an aryl, heteroaryl, alkyl, or vinyl boronic acid, borate ester, or borane 1 with an aryl or heteroaryl halide or tritiate 2 using a variety of palladium catalysts (Suzuki reaction; see e.g. B. S. Kadu, Catal. Sci. Technol., 2021 ,11 , 1186-1221).
  • the formation of a carbon-carbon bond between a terminal alkyne 1 and an aryl or heteroaryl halide 2 can be achieved employing palladium catalysts as well as copper co-catalysts (Sonogashira coupling, see e.g. I. Kanwal et al, Catalysts 2020, 10(4), 443).
  • formation of a C-N can be achieved via the palladium-catalyzed coupling reactions of amines 1 with aryl and heteroaryl halides 2 (Buchwald-Hartwig coupling, see e.g. R. Dorel et al, Angew. Chem. Int. Ed. 2019, 58, 171 18).
  • cross-coupling of A-B-X (3) and Y (4) can be achieved by various methods known of a person skilled in the art of organic synthesis, including e.g. a) coupling of carboxylic acids (3) and amines (4) (amide bond formation; see e.g. E. Massolo et al, Eur. J. Org. Chem. 2020, 4641), b) coupling of sulfonyl chlorides (3) and amines (4) (sulfonamide bond formation: see e.g. A. Kolaczek et al, CHEMIK 2014, 68, 620) or c) coupling of amines (3) and halides (4) (amine alkylation: see e.g. R. N Salvatoreet al, Tetrahedron 2001 , 7785).
  • ferf-BuBrettPhos-Pd-G3 [(2-di-ferf- butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1 ,1 '-biphenyl)-2-(2'-amino-1 ,1 '-biphenyl)]palladium(ll) methanesulfonate); tBuXPhos Pd G3 (methanesulfonato(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-1 ,1 biphenyl)(2'-amino-1 ,1'-biphenyl-2-yl)palladium(ll)); TBDMSCI orTBSCI (tert-buty
  • Method 1 SHIMADZU LCMS-2020 Kinetex EVO C18 2.1X30mm, 5pm at 50°C; Mobile Phase: A: 0.0375% TFA in water (v/v); B: 0.01875% TFA in MeCN (v/v); flow rate held at 1.5 mL/min; eluted with the mobile phase over 1 .55 min employing UV detection at 220 nm and 254 nm. Gradient information: 0- 0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-1 .20 min, held at 5% A-95% B; 1 .20-1 .21 min, returned to 95% A-5% B, 1.21-1 .55 min, held at 95% A-5% B.
  • Method 2 SHIMADZU LCMS-2020 Kinetex EVO C18 2.1X30mm, 5pm at 40°C ;
  • Mobile Phase A: 0.025% NHs- W in water (v/v); B: MeCN; flow rate held at 1 .5 mL/min; eluted with the mobile phase over 1 .55 min employing UV detection at 220 nm and 254 nm.
  • Gradient information 0-0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-1 .20 min, held at 5% A-95% B; 1 .20-1.21 min, returned to 95% A-5% B, 1 .21-1 .55 min, held at 95% A-5% B.
  • Method 3 SHIMADZU LCMS-2020 Kinetex EVO C18 2.1X30mm,5pm at 50°C; Mobile Phase: A: 0.0375% TFA in water (v/v); B: 0.01875% TFA in MeCN (v/v); flow rate held at 2.0 mL/min; eluted with the mobile phase over 0.80 min employing UV detection at 220 nm and 254 nm. Gradient information: 0- 0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-1 .20 min, held at 5% A-95% B; 1 .20-1 .21 min, returned to 95% A-5% B, 1.21-1 .55 min, held at 95% A-5% B.
  • Method 4 SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X20 mm 2.6 pm at 50°C; Mobile Phase: A: 0.0375% TFA in water (v/v); B: 0.01875% TFA in MeCN (v/v); flow rate held at 2.0 mL/min; eluted with the mobile phase over 1.00 min employing UV detection at 220 nm and 254 nm. Gradient information: 0.01-0.60 min, ramped from 95% A-5% B to 5% A-95% B; 0.61-0.78 min, held at 5% A-95% B; 0.78-0.79 min, returned to 95% A-5% B, 0.79-0.80 min, held at 95% A-5% B.
  • Method 5 SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X30 mm 5 pm at 50°C
  • A 0.0375% TFA in water (v/v); B: 0.01875% TFA in MeCN (v/v); flow rate held at 1 .5 mL/min; eluted with the mobile phase over 1.00 min employing UV detection at 220 nm and 254 nm.
  • Gradient information 0.01-0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-0.95 min, held at 5% A-95% B; 0.95-0.96 min, returned to 95% A-5% B, 0.96-1.00 min, held at 95% A-5% B.
  • Method 6 SHIMADZU LCMS-2020 Kinetex® HALO C18 3.0X30mm, 5 pm at 50°C; Mobile Phase: A: 0.0375% TFA in water (v/v); B: 0.01875% TFA in MeCN (v/v); flow rate held at 1 .5 mL/min; eluted with the mobile phase over 1 .05 min employing UV detection at 220 nm and 254 nm. Gradient information: 0- 0.80 min, ramped from 50% A-50% B to 0% A-100% B; 0.80-1 .05 min, held at 50% A-50% B.
  • Method 7 SHIMADZU LCMS-2020 HALO C18 3.0X30 mm, 5 pm at 50 °C, Mobile Phase: A: 0.0375% TFA in water (v/v); B: 0.01875% TFA in Acetonitrile (v/v); flow rate held at 1.5 mL/min; eluted with the mobile phase over 1 .05 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-0.50 min, ramped from 95% A-5% B to 5% A-95% B; 0.50-0.80 min, held at 5% A-95% B; 0.80-0.81 min, returned to 95% A-5% B, 0.81-1.05 min, held at 95% A-5% B.
  • Method 9 SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X30 mm, 5 pm at 40°CMobile Phase: A: water; B: MeCN; flow rate held at 1.5 mL/min; eluted with the mobile phase over 1.55 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-1.20 min, held at 5% A-95% B; 1.20-1.21 min, returned to 95% A-5% B, 1.21-1.55 min, held at 95% A-5% B.
  • Method 10 SHIMADZU LCMS-2020 Waters Xselect HSS T3, 3.5 pm, 4.6*50mm at 40°C; Mobile Phase: A: 0.0375% TFA in water (v/v); B: 0.01875% TFA in MeCN (v/v); flow rate held at 1.5 mL/min; eluted with the mobile phase over 5.20 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-3.50 min, ramped from 95% A-5% B to 5% A-95% B; 3.50-4.80 min, held at 5% A-95% B; 4.80-4.81 min, returned to 95% A-5% B; 4.81-5.20 min, held at 95% A-5% B
  • Method 11 SHIMADZU LCMS-2020 HALO C18 3.0X30mm,5pm at 50 °C; Mobile Phase: A: 0.0375% TFA in water (v/v); B: 0.01875% TFA in MeCN (v/v); flow rate held at 1.5 mL/min; eluted with the mobile phase over 3.00 min employing UV detection at 220 nm and 254 nm. Gradient information: 0- 2.10 min, ramped from 95% A-5% B to 5% A-95% B; 2. 10-2.80 min, held at 5% A-95% B; 2.80-2.81 min, returned to 95% A-5% B, 2.81-3.00 min, held at 95% A-5% B.
  • Method 12 SHIMADZU LCMS-2020 HALO C18 3.0X30 mm, 5 pm at 50 °C, Mobile Phase: A: 0.0375% TFA in water (v/v); B: 0.01875% TFA in Acetonitrile (v/v); flow rate held at 2 mL/min; eluted with the mobile phase over 1 .05 min employing UV detection at 220 nm and 254 nm. Gradient information: 0- 0.40 min, ramped from 95% A-5% B to 5% A-95% B; 0.40-0.75 min, held at 5% A-95% B; 0.75-0.76 min, returned to 95% A-5% B, 0.76-1 .05 min, held at 95% A-5% B.
  • Method 13 SHIMADZU LCMS-2020 HALO C18 3.0X30 mm, 5 pm at 50°C
  • Mobile Phase A: 0.04% TFA in water (v/v); B: 0.02% TFA in MeCN (v/v); flow rate held at 1 .5 mL/min; eluted with the mobile phase over 1 .00 min employing UV detection at 220 nm and 254 nm.
  • Gradient information 0.01-0.50 min, ramped from 95% A-5% B to 5% A-95% B; 0.50-0.80 min, held at 5% A-95% B; 0.80-0.81 min, returned to 95% A-5% B, 0.81-1 .00 min, held at 95% A-5% B.
  • Method 14 SHIMADZU LCMS-2020 HALO C18 3.0X30 mm, 5 pm at 50°C
  • Mobile Phase A: 10mmol/L NH4HCO3 in water; B: MeCN; flow rate held at 1.5 mL/min; eluted with the mobile phase over 2.20 min employing UV detection at 220 nm and 254 nm.
  • Gradient information 0-1.50 min, ramped from 95% A-5% B to 5% A-95% B; 1 .50-1 .90 min, held at 5% A-95% B; 1 .90-1 .91 min, returned to 95% A-5% B, 1.91-2.20 min, held at 95% A-5% B.
  • Method 15 SHIMADZU LCMS 2020 XBridge C18 2.1X50 mm, 5 m at 50 °C; Mobile Phase: A: 10mmol/L NH4HCO3 in water (v/v); B: MeCN; flow rate held at 1.5 mL/min; eluted with the mobile phase over 2.2 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-0.1.5 min, ramped from 95 A-5% B to 5% A-95% B; 1 .50-1 .90 min, held at 5% A-95% B; 1 .900-1 .91 min, returned to 95% A- 5% B, 1.91-2.2 min, held at 95% A-5% B
  • Method 16 SHIMADZU LCMS 2020 XBridge C18 2.1X50 mm, 5 pm at 50 °C; Mobile Phase: A: 10mmol/L NH4HCO3 in water (v/v); B: MeCN; flow rate held at 0.8 mL/min; eluted with the mobile phase over 4 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-2.60 min, ramped from 95 A-5% B to 5% A-95% B; 2.60-3.60 min, held at 5% A-95% B; 3.60-3.61 min, returned to 95% A-5% B, 3.61-4.00 min, held at 95% A-5% B
  • Phase A: 0.025% NH3-H2O in water (v/v); B: MeCN; flow rate held at 1.5 mL/min; eluted with the mobile phase over 0.40 min employing UV detection at 220 nm. Gradient information: 0-0.40 min, ramped from 10% A-90% B to 10% A-90% B;
  • SFC Method 3 ColummChiralpak I G-3 50*4.6 mm I.D., 3pm; Mobile phase: Phase A for CO2, and Phase B for MeOH+ACN with 0.05% DEA additive; Gradient elution: 60% B in CO2, Flow rate: 3 mL/min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar.
  • SFC Method 4 ColummChiralcel OJ-3 50*4.6mm I. D.
  • SFC Method 36 Column: Chiralpak AS-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) from 5% to 40% in CO2; Flow rate: 3 mL/min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar SFC Method 37: Column: Chiralpak IG-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for MeOH (0.05% DEA); Gradient elution: 60% MeOH (0.05% DEA) in CO2; Flow rate: 3 mL/min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.
  • SFC Method 49 Column: Chiralcel OD-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for IPA (0.05% DEA), Gradient elution: B from 10% to 60% in CO2, Flow rate: 4 mL/min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar.
  • SFC Method 50 Column: Chiralpak AD-3 50x4.6mm I.D., 3um Mobile phase: Phase A for CO2, and Phase B for EtOH(0.05%DEA); Gradient elution: B in CO2 from 10% to 60%; Flow rate: 4mL/min; Detector: PDA; Column Temp: 35C;Back Pressure: 100Bar.
  • 1 H NMR spectra were acquired on a Bruker Avance IH spectrometer at 400 MHz using residual undeuterated solvent as reference. 1 H NMR signals are specified with their multiplicity / combined multiplicities as apparent from the spectrum; possible higher-order effects are not considered. Chemical shifts of the signals (5) are specified as ppm (parts per million).
  • reaction mixture was cooled to room temperature, diluted with H2O and extracted with EtOAc or DCM (3x). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative-HPLC or phase chromatographic column to give the corresponding product.
  • the filtrate was purified by column chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent Petroleum ether/Ethyl acetate gradient from 60/40 to 0/100 @ 40 mL/min) to give the product tert-butyl(((diethoxyphosphoryl)methyl)(methyl)(oxo)- X 6 -sulfaneylidene)carbamate (1000 mg, 3.04 mmol, 77.43 % yield) as yellow oil.
  • ISCO 12 g SepaFlash Silica Flash Column, Eluent Petroleum ether/Ethyl acetate gradient from 60/40 to 0/100 @ 40 mL/min
  • tert-butyl (((diethoxyphosphoryl)methyl)(methyl)(oxo)-X 6 -sulfaneylidene)carbamate 400 mg, 1.21 mmol
  • THF 8 mL
  • tert-butyl (S)-(1-cyclopropyl-2-oxoethyl)carbamate 290 mg, 1.46 mmol
  • K2CO3 420 mg, 3.04 mmol
  • Example 32a, 32b, 32c and 32d are single stereoisomers, as outlined in the following.
  • Fraction A (140 mg, 0.321 mmol) was further purified by preparative SFC (column: DAICEL CHIRALPAK IC(250 mm*30 mm, 10 pm); mobile phase: A for CO2, B for /-PrOH/ACN(2:1); Gradient elution: 40% B in CO2, 4 mins) to afford 2 solutions which were concentrated separately under vacuum (30 °C) to give the respective products (it is noted that the stereochemistry has been assigned arbitrarily):
  • Example 32a N-((S or R,E)-1-cyclopropyl-3-((R or S)-S-methylsulfonimidoyl)allyl)-2-(1 ,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (60 mg, 0.137 mmol, 99.39% purity,) as colorless gum.
  • Example 32b N-((S or R,E)-1-cyclopropyl-3-((S or R)-S-methylsulfonimidoyl)allyl)-2-(1 ,1 - difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (51 mg, 0.115 mmol, 99.07% purity,) as colorless gum.
  • Fraction B (140 mg, 0.321 mmol) was further purified by preparative SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10 pm; mobile phase: A for CO2, B for /-PrOH; Gradient elution: 30% B in CO2, 2.6 mins) to afford 2 solutions which were concentrated separately under vacuum (30 °C) to give the respective products:
  • Example 32c N-((R or S,E)-1 -cyclopropyl-3-((R or S)-S-methylsulfonimidoyl)allyl)-2-(1 ,1- difl uoroethyl)-4-p henoxypyrimidi ne-5-carboxamide (56 mg, 0.124 mmol, 97.57% purity,) as colorless gum.
  • Example 32d N-((R or S,E)-1-cyclopropyl-3-((S or R)-S-methylsulfonimidoyl)allyl)-2-(1 , 1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (59 mg, 0.133 mmol, 98.74% purity,) as colorless gum.
  • Example 33a N-((S or R,E)-1-cyclopropyl-3-((R or S)-N,S-dimethylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide (85 mg, 0.184 mmol, 96.89% purity,) as colorless gum.
  • Example 33b N-((S or R,E)-1-cyclopropyl-3-((S or R)-N,S-dimethylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide (71 mg, 0.155 mmol, 98.73% purity) as a white solid.
  • Example 33d N-((R or S,E)-1-cyclopropyl-3-((S or R)-N,S-dimethylsulfonimidoyl)allyl)-2-(1 ,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (65 mg, 0.141 mmol, 98.53% purity) as a white solid.
  • reaction mixture was warmed to 0 °C, stirred for 3 h under N2, then diluted with EtOAc (30 mL) and quenched with NH4CI (aq., sat., 30 mL) at 0 °C.
  • the mixture was slowly warmed to 20 °C while stirring.
  • the aqueous layer was extracted with EtOAc (50 mL; 3x).
  • the combined organic layer was washed with brine (50 mL; 3x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum.
  • the filtrate was directly purified by preparative HPLC (column: Waters xbridge 150*25 mm 10 m; mobile phase: A: 10mM NH4HCO3 in water; B: ACN; B%: 35%-65%, 9.00 min; flow rate: 25.00 mL/min) and lyophilized to give the product (E)-N-(1 -cyclopropyl-3-fluoro-3-(S-methylsulfonimidoyl)allyl)-2-(1 , 1 - difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (11 mg, 0.0234 mmol, 32.80 % yield) as an off-white solid.
  • Peak B (90 mg, 0.198 mmol) was further purified by preparative SFC (column: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 pm); mobile phase: A for CO2; A for IPA; Gradient elution: 20% B in CO2, 3.80 mins) to afford 2 solutions which were concentrated separately under vacuum (30 °C) to give the corresponding products:
  • Example 1 a N-((S or R,E)-1-cyclopropyl-3-fluoro-3-((S or R)-S-methylsulfonimidoyl)allyl)-2-(1 ,1 - difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (14 mg, 0.0312 mmol, 100% purity) as an off-white solid.
  • Example 1 b N-((S or R,E)-1-cyclopropyl-3-fluoro-3-((R or S)-S-methylsulfonimidoyl)allyl)-2-(1 ,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (42 mg, 0.0915 mmol, 100% purity,) as a white solid.
  • Peak A (90 mg, 0.198 mmol) was further purified by preparative SFC (column: DAICEL CHIRALCEL OJ(250 mm*30 mm, 10 pm);mobile phase: A for CO2; B for IPA; Gradient elution: 30% B in CO2, 4.60 mins) to give the corresponding products:
  • Example 1c N-((R or S,E)-1-cyclopropyl-3-fluoro-3-(( R or S)-S-methylsulfonimidoyl)allyl)-2-(1 ,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (15 mg, 0.0334 mmol, 100% purity) as a yellow solid.
  • Example 1 d N-((R or S,E)-1-cyclopropyl-3-fluoro-3-(( S or R)-S-methylsulfonimidoyl)allyl)-2-(1 ,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (50 mg, 0.109 mmol, 100% purity) as a white solid.
  • Exemplary compounds of formula (I) were tested in selected biological and/or physicochemical assays one or more times.
  • data are reported as either average values or as median values, wherein the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median value is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.
  • the in vitro pharmacological, pharmacokinetic and physicochemical properties of the compounds can be determined according to the following assays and methods.
  • WRN (amino acid 517-1093, L1074F isoform) was purchased from CRELUX GmbH, Planegg, Germany. WRN was produced in a Sf21 expression system, purified, and stored and frozen in 50 mM HEPES / NaOH, 500 mM NaCI, 5% Glycerol and 0.5 mM TCEP, pH 7.5.
  • the forked DNA was prepared by mixing the two DNA strands in a 1 :1.8 ratio of OLIGOB-FLU (FAM(fluorescein)-GAACGA ACA CAT CGG GTA CGT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TT) (SEQ ID NO.: 1) to OLIGOA-BHQ1 (TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT CGT ACC CGA TGT GTT CGT TC-BHQ1 ) (SEQ ID NO.: 2) in DNA-annealing buffer (10 mM Tris/HCI pH 7.5, 50 mM NaCI & 1 mM EDTA, pH 8.0). The mixture is heated to 95 °C and cooled down to 35 °C at a rate of 5°C per minute in a Roche LightCycler® 96 System.
  • a continuous, fluorescence-based helicase assay was set up to measure ATP-coupled unwinding of a forked DNA substrate by WRN (517-1093, L1074F isoform). Fluorescently labelled forked DNA was used as a DNA substrate, the DNA sequences were described by Sommers et al. 2019 (doi: 10.1371 /journal. pone.0210525), with different fluorescent dyes. WRN mediated separation of the forked DNA leads to an increase in fluorescence. ssDNA complementary to the quenching strand, oligo-block (GAA CGA ACA CAT CGG GTA CG) (SEQ ID NO.: 3), is included in 10-fold excess to prevent reannealing of the forked DNA. Labelled DNA was purchased from IDT (Integrated DNA Technologies, Inc.) and ssDNA oligo-block from Microsynth AG.
  • a typical reaction consists of 30 pL of 1 nM WRN in 25 mM Tris/HCI pH 7.5, 100 mM NaCI, 1 mM DTT, 0.01 % TWEEN-20, 0.025 mg/mL BSA, 0.1 mM forked DNA substrate, 1 mM Oligo-BLOCK and 0.5 mM Mg-ATP in a 384 well black plate (Thermo Scientific).
  • IC50s were determined by pre-incubating compounds (10 mM DMSO stock solutions) with WRN in a 12-point custom dilution series to a final DMSO concentration of 1 %.
  • Compounds and WRN were pre-incubated for 2 or 6 hours at room temperature, before the addition of forked DNA, ssDNA oligo-block, and Mg-ATP to initiate the reaction.
  • Fluorescence (Ex: 485 nm, Em: 535 nm, gain 66, 5 flashes per measurement) was measured on a Tecan Spark plate reader for 45 minutes, in 60 seconds intervals at 27.5°C. All points were measured in triplicate.
  • the colon carcinoma cell lines HCT116 and SW48 both microsatellite instability- high and WRN- inhibition sensitive cell lines
  • SW620 microsatellite stable and WRN-inhibition insensitive cell line
  • HCT116 were cultured in growth medium composed of McCoy's 5A (Modified) Medium (ThermoFisher Scientific Cat# 16600082), 1x Penicillin-Streptomycin (ThermoFisher Scientific Cat# 15140163), and 10% fetal bovine serum (ThermoFisher Scientific Cat#A5256801).
  • SW48 and SW620 were cultured in growth medium composed of Leibovitz's L-15 Medium (ThermoFisher Scientific Cat#11415056), 1x Penicillin-Streptomycin and 10% fetal bovine serum.
  • HCT 116, SW48 and SW620 were plated at 1500 cells/well, 2000 cel Is/well and 2000 cells/well, respectively, in 96-well black plates with clear flat bottom (Huberlab #.655 983), in a volume of 200 pL per well.
  • the outer wells of the plate were filled with DPBS (ThermoFisher Scientific Cat#14190250) to compensate evaporation mediated effects in the plate periphery.
  • the compounds were dispensed with the Tecan digital dispenser (D300e), starting at 20 pM for a 8-point dose curve at 1 :4 dilution, in duplicates.
  • the final concentration of DMSO was normalized to the highest compound concentration and a maximum of 0.1 %..
  • Plasma Animal or human plasma were purchased from BiolVT or other qualified suppliers.
  • Propantheline is used as control compound in CD-1 mouse and human plasma.
  • Enalapril, bisacodyl, and procaine are used as control compounds in SD rat, beagle dog, and cynomolgus monkey plasma, respectively.
  • Frozen plasma was thawed under cold water for 10 to 20 minutes, and then centrifuged at 3220*g for 5 minutes.
  • test compound or control compounds working solutions were mixed with 98.0 pL of blank plasma from animal and human in corresponding time points TO, T 10, T30, T60, and T120 in duplicate, respectively. Incubate all sample plates in a water bath at 37.0°C. The final concentration of test compound and control compounds was 2.00 pM in the incubation system.
  • Concentrations of test compounds and positive controls in the samples are determined by using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.
  • T1/2 value is reported in table 4 for selected examples. As evidenced by the data in Table 4, Examples 32, 32d, 33 and 33d show an improved in vitro stability in human plasma in comparison to Reference Example 1
  • the Kinetic solubility assay employs the shake flask method followed by HPLC-UV analysis.
  • the kinetic solubility was measured according to the following protocol:
  • Test compounds and controls (10 mM in DMSO, 10 pL/tube) were added into the buffer (490 pL/well) which were placed in a Mini-UniPrep filter.
  • the buffer was prepared as the customer’s requirement.
  • test compound concentration of the filtrate were determined using HPLC-UV.
  • Caco-2 cells purchased from ATCC were seeded onto polyethylene membranes (PET) in 96- well BD insert plates at 1 x 105 cells/cm 2 , and refreshed medium every 4 ⁇ 5 days until to the 21 st to 28 th day for confluent cell monolayer formation.
  • PET polyethylene membranes
  • the quality of the monolayer was verified by measuring the unidirectional (A— >B) permeability of fenoterol/nadolol (low permeability marker), propranolol/metopronolol (high permeability marker) and bi-directional permeability of digoxin (a P-glycoprotein substrate marker) in duplicate wells.
  • n 2;
  • bi-directional transport including A ⁇ B and B ⁇ A;
  • Animal or human liver microsomes were purchased from Xenotech or Corning and stored in a freezer (lower than -60°C) before use.
  • Control compounds Testosterone, diclofenac and propafenone.
  • a total of two sample plates with 96-well format were prepared for incubation, labeled as 'Incubation' T60 and 'Incubation' NCF60.
  • Empty 'Incubation' T60 and NCF60 plates were pre-warmed for 10 min minutes. Liver microsomes were diluted to 0.56 mg/mL in 100 mM phosphate buffer. Microsome working solutions (0.56 mg/mL) were transferred (445 uL) into pre-warmed 'Incubation' T60 and NCF60 plates, followed by incubation for 10 min at 37°C with constant shaking.
  • Liver microsomes (54 pL) were transferred to a Blank60 plate, followed by the addition of 6 pL NAPDH cofactor and 180 pL stop solution (acetonitrile containing internal standards) into each well.
  • Stop solution 180 pL
  • NAPDH cofactor 6 pL
  • NAPDH cofactor 44 pL was added to the 'Incubation' T60 plate.
  • the plate was incubated at 37°C for 60 min while shaking. At 5, 15, 30, 45, and 60 min, 180 pL stop solution was added to the 'Quenching' plates, samples were mixed once, and 60 pL was serially transferred from 'Incubation' T60 plate per time point.
  • the final concentration was 1 pM for test compounds, testosterone, diclofenac and propafenone, 0.5 mg/mL for animal or human liver microsomes, 0.01 % (v/v) for DMSO and 0.99% (v/v) for acetonitrile.
  • CLint(liver) CLmt(rnic) x mg microsomal protein/g liver weight x g liver weight/kg body weight
  • hepatic intrinsic clearance and hepatic clearance can be calculated by the following formula.
  • Animal or human hepatocytes were purchased from BioreclamationIVT or RILD.
  • Cryopreserved hepatocytes were thawed, isolated, and suspended in Williams’ Medium E, then diluted with pre-incubated Williams’ Medium E to a final concentration of 0.510x106 cells/mL.
  • a corresponding quenching plate was prepared by adding 125 pL/well of acetonitrile containing 200 ng/mL tolbutamide and 200 ng/mL labetalol as internal standards (stop solution), and 25 pL/well of the incubation sample were transferred to this plate after shaking for 1 minute to ensure homogeneity.
  • MC plates (TO-MC and T90-MC) were prepared by adding everything except for Williams’ Medium E at the corresponding time-points.
  • the plates were then sealed and shaken for 10 minutes prior to centrifugation at 4000 rpm and 4°C for 20 minutes. 80 pL/well of the resulting supernatant were diluted with 240 pL/well of pure water and sealed and shaken for 10 minutes prior to LC-MS/MS analysis.
  • CLmt (liver) CLmt (hep) x liver weight (g/kg body weight) x hepatocellularity
  • hepatic intrinsic clearance and hepatic clearance can be calculated by the following formula.
  • example 32d shows a longer half-life (T1/2) and a reduced plasma clearance (CL) after iv application as well as improved exposure (AUG) and bioavailability after oral application in comparison to reference example 1.
  • ABPP Activity-based protein profiling
  • HCT 116 cells were treated with either DMSO or compound 32d (1 pM) for 2 hours, followed by treatment with a cysteine reactive, isotopically labeled probe.
  • Samples (quadruplicates) were merged, trypsinized and enriched for proteomic analysis.
  • the isotopically labelled probe allows quantification of specific cysteine engagement in the compound treated samples (measured as decreased enrichment over the DMSO sample).

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Abstract

La présente invention concerne un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci. La présente invention concerne en outre le composé de formule (I) de la présente invention destiné à être utilisé en thérapie. Les composés de l'invention sont particulièrement utiles en tant qu'inhibiteurs de WRN, et peuvent être utilisés dans une méthode de traitement du cancer, en particulier, le cancer pouvant être traité par inhibition de WRN, et/ou le cancer caractérisé par MSI-H et/ou dMMR.
PCT/EP2025/068557 2024-06-28 2025-06-30 Composés inhibiteurs de wrn Pending WO2026003380A1 (fr)

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