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WO2025172707A1 - Composés hétérocycliques modulant l'exonucléase 1 (exo1) - Google Patents

Composés hétérocycliques modulant l'exonucléase 1 (exo1)

Info

Publication number
WO2025172707A1
WO2025172707A1 PCT/GB2025/050273 GB2025050273W WO2025172707A1 WO 2025172707 A1 WO2025172707 A1 WO 2025172707A1 GB 2025050273 W GB2025050273 W GB 2025050273W WO 2025172707 A1 WO2025172707 A1 WO 2025172707A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydroxy
dione
pyrazine
pyridazino
methyl
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/GB2025/050273
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 WO2025172707A1 publication Critical patent/WO2025172707A1/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

Definitions

  • the present invention relates to compounds of formula (I), and stereoisomers, tautomers, N-ox- ides, or pharmaceutically acceptable salts thereof that are useful for modulating exonuclease 1 (EXO1).
  • the present invention further relates to compounds of the formula (I) for use as a medicament and to pharmaceutical compositions comprising said compounds.
  • the present invention relates to compounds of formula (I) and pharmaceutical compositions comprising said compounds for use in the treatment of cancer, preferably a cancer selected from the group consisting of hepatocellular carcinoma (HCC), glioma, colon cancer/colorectal cancer, in particular nonpolyposis colorectal cancer (HNPCC), breast cancer, ovarian cancer, lung cancer, pancreatic cancer, gastric tract cancer, cancer of the small intestine, oral cancer, and cervical cancer.
  • HCC hepatocellular carcinoma
  • glioma glioma
  • colon cancer/colorectal cancer in particular nonpolyposis colorectal cancer (HNPCC)
  • HNPCC nonpolyposis colorectal cancer
  • breast cancer ovarian cancer
  • lung cancer pancreatic cancer
  • gastric tract cancer cancer of the small intestine
  • oral cancer oral cancer
  • cervical cancer preferably a cancer selected from the group consisting of hepatocellular carcinoma (HCC), glioma, colon cancer/colorectal cancer
  • EXO1 participates in DNA replication and post-replication processes and DNA repair pathways, for example mismatch repair (MMR), translesion DNA synthesis (TLS), nucleotide excision repair (NER), double-strand break repair (DSBR), and checkpoint activation. Dysfunction of EXO1 could therefore lead to alterations in DNA repair processes, which in turn can lead to replication stress, genomic instability and consequently to the development of cancer.
  • MMR mismatch repair
  • TLS translesion DNA synthesis
  • NER nucleotide excision repair
  • DSBR double-strand break repair
  • checkpoint activation checkpoint activation
  • EXO1 has been investigated as a biomarker for the treatment of breast cancer. It was shown that increased EXO1 expression is associated with carcinogenesis and poor prognosis in breast cancer.
  • EXO1 As a backup for FEN1 , EXO1 also degrades a small percentage of such short 5'-flaps (Sun, H., Ma, L., Tsai, Y. F., Abeywardana, T., Shen, B., Zheng, L. (2023), Okazaki fragment maturation: DNA flap dynamics for cell proliferation and survival, Trends in Cell Biology, 33(3), 221-234).
  • EXO1 has proven to be an important protein in cancer research and is being investigated as a candidate gene for cancer therapies due to its increased expression in various tumours (Keijzers, G., Bakula, D., Petr, M. A., Madsen, N. G.
  • EXO1 is considered to be an important therapeutic target for cancer treatment I oncology drug discovery.
  • compounds modulating EXO1 may be useful for treating cancer, preferably a cancer selected from hepatocellular carcinoma (HCC), glioma, colon cancer/colorectal cancer, in particular nonpolyposis colorectal cancer (HNPCC), breast cancer, ovarian cancer, lung cancer, pancreatic cancer, gastric tract cancer, cancer of the small intestine, oral cancer, and cervical cancer.
  • HCC hepatocellular carcinoma
  • glioma glioma
  • colon cancer/colorectal cancer in particular nonpolyposis colorectal cancer (HNPCC)
  • HNPCC nonpolyposis colorectal cancer
  • breast cancer ovarian cancer
  • lung cancer pancreatic cancer
  • gastric tract cancer cancer of the small intestine
  • oral cancer oral cancer
  • cervical cancer preferably hepatocellular carcinoma (HCC), glioma, colon cancer/colorectal cancer, in particular nonpol
  • 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 EX01 , in particular that they inhibit EX01 .
  • 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 EX01 in an effective amount to individuals in need of such treatment.
  • the present invention therefore relates to a compound of formula (I) or a stereoisomer, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein
  • 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-rod rings 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 2 is Ci-C4-alkyl, phenyl, or a 5- or 6-membered aromatic 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 of the aforementioned aromatic rings is independently unsubstituted or substituted with one or more, same or different, substituents R Y1 ; or R 2 and R x , if present, together with the atoms by which they are connected form a fused 5- to 7-membered partially unsaturated carbocyclyl or 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 partially unsaturated rings is independently unsubsti
  • R 3 is a 5- or 6-membered aromatic carbocyclyl, carbocyclyl-Ci-C2-alkyl, heterocyclyl, or het- erocyclyl-Ci-C2-alkyl, or an 8- to 10-membered aromatic carbobicyclyl, carbobicyclyl-Ci- C2-alkyl, heterobicyclyl, or heterobicyclyl-Ci-C2-alkyl, 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 z ;
  • R 4 is H or Ci-C4-alkyl
  • R x is halogen or Ci-C 4 -alkyl
  • R Y1 is halogen or Ci-C 4 -alkyl
  • R Y2 is halogen or Ci-C 4 -alkyl
  • R z is halogen, Ci-C 4 -alkyl, or Ci-C 4 -haloalkyl
  • R N1 is H or Ci-C 4 -alkyl
  • R N2 is H or Ci-C 4 -alkyl.
  • the compound is a compound of formula (IA):
  • R 1 is phenyl, or a 9- or 10-membered aromatic carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic and heterobicyclic rings 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, or a 9- or 10-membered aromatic carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic and heterobicyclic rings 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 ; and
  • R x is halogen or Ci-C2-alkyl.
  • R 1 is phenyl, wherein said phenyl is unsubstituted or substituted with one or more, same or different substituents R x .
  • R 2 is methyl, ethyl, or phenyl; or R 2 and R x , if present, together with the atoms by which they are connected form a fused 6- membered partially unsaturated carbocyclyl.
  • R 2 is methyl; or R 2 and R x , if present, together with the atoms by which they are connected form a fused 6- membered partially unsaturated carbocyclyl.
  • R 3 is a 6-membered aromatic carbocyclyl, carbocyclyl-Ci-alkyl, heterocyclyl, heterocyclyl- Ci-alkyl, or an 9- or 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 z ; wherein preferably
  • R 3 is a 6-membered aromatic carbocyclyl, carbocyclyl-Ci-alkyl, heterocyclyl, heterocyclyl- Ci-alkyl, or an 9- or 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 z ; wherein preferably
  • R z is F, CH 3 , or CF 3 .
  • R 4 is H.
  • R 5 is H or CH 3 .
  • R 5 is H.
  • the compound is a compound of formula (IA-2):
  • the compound according to formula (I) is selected from the group consisting of:
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of formula (I) as defined herein, and optionally a pharmaceutically acceptable carrier, diluent or excipient.
  • 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 hepatocellular carcinoma (HCC), glioma, colon cancer/colorectal cancer, in particular nonpolyposis colorectal cancer (HNPCC), breast cancer, ovarian cancer, lung cancer, pancreatic cancer, gastric tract cancer, cancer of the small intestine, oral cancer, and cervical cancer.
  • HCC hepatocellular carcinoma
  • glioma colon cancer/colorectal cancer
  • HNPCC nonpolyposis colorectal cancer
  • breast cancer ovarian cancer
  • lung cancer pancreatic cancer
  • gastric tract cancer cancer of the small intestine
  • oral cancer oral cancer
  • cervical cancer cervical cancer
  • the present invention relates to a compound of formula (I) or a stereoisomer, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein
  • 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-rod rings 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 2 is Ci-C4-alkyl, phenyl, or a 5- or 6-membered aromatic 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 of the aforementioned aromatic rings is independently unsubstituted or substituted with one or more, same or different, substituents R Y1 ; or R 2 and R x , if present, together with the atoms by which they are connected form a fused 5- to 7-membered partially unsaturated carbocyclyl or 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-oxi- dized, and wherein each substitutable atom in the aforementioned partially unsaturated rings is independently
  • R 3 is a 5- or 6-membered aromatic carbocyclyl, carbocyclyl-Ci-C2-alkyl, heterocyclyl, or het- erocyclyl-Ci-C2-alkyl, or an 8- to 10-membered aromatic carbobicyclyl, carbobicyclyl-Ci- C2-alkyl, heterobicyclyl, or heterobicyclyl-Ci-C2-alkyl, 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 z ;
  • R 4 is H or Ci-C4-alkyl
  • R x is halogen or Ci-C4-alkyl
  • R Y1 is halogen or Ci-C4-alkyl
  • R Y2 is halogen or Ci-C4-alkyl
  • R z is halogen, Ci-C4-alkyl, or Ci-C4-haloalkyl
  • R N1 is H or Ci-C4-alkyl
  • R N2 is H or Ci-C4-alkyl.
  • the compound is a compound of formula (IA):
  • the compound of formula (IA) may be a compound of formula (IA-1) or (IA-2):
  • the compound of formula (I) is a compound of formula (IA-1). In another preferred embodiment, the compound of formula (I) is a compound of formula (IA-2).
  • 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-rod rings 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, or a 9- or 10-membered aromatic carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic and heterobicyclic rings 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 ; wherein
  • R x is halogen or Ci-C2-alkyl.
  • R 1 is phenyl, or a 9- or 10-membered aromatic carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic and heterobicyclic rings 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 ; wherein
  • R x is Cl, F, or CH 3 .
  • R 1 is selected from the group consisting of wherein the wavy line in each case marks the connection to the remainder of the molecule.
  • R 1 is phenyl, wherein said phenyl is unsubstituted or substituted with one or more, same or different substituents R x ; and wherein preferably
  • R x is Cl or F.
  • R 1 is phenyl, wherein said phenyl is substituted with one substituent R x wherein the wavy line marks the connection to the remainder of the molecule.
  • R 1 is unsubstituted phenyl.
  • R x is Cl or F.
  • R 2 is Ci-C4-alkyl, phenyl, or a 5- or 6-membered aromatic 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 of the aforementioned aromatic rings is independently unsubstituted or substituted with one or more, same or different, substituents R Y1 ; or R 2 and R x , if present, together with the atoms by which they are connected form a fused 5- to 7-membered partially unsaturated carbocyclyl or 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-oxi- dized, and wherein each substitutable atom in the aforementioned partially unsaturated rings is independently
  • R Y1 is halogen or Ci-C4-alkyl
  • R Y2 is halogen or Ci-C4-alkyl.
  • R Y1 is Cl, F, or CH 3 ;
  • R Y2 is Cl, F, or CH 3 ;.
  • R 2 is methyl, ethyl, or phenyl; or R 2 and R x , if present, together with the atoms by which they are connected form a fused 6- membered partially unsaturated carbocyclyl.
  • R 2 and R x together with the atoms by which they are connected form a fused 6-membered partially unsaturated carbocyclyl is preferred in connection with the embodiment that R 1 is phenyl substituted with one substituent R x .
  • Said R x then together with R 2 and together with the atoms by which R 2 and R x are connected then forms the 6-membered partially unsaturated carbocylclyl.
  • the resulting moiety -CHR 1 R 2 thus preferably has the following structure:
  • R 2 is methyl; or R 2 and R x , if present, together with the atoms by which they are connected form a fused 6- membered partially unsaturated carbocyclyl;
  • R 2 is methyl
  • R 2 is methyl
  • R 3 is a 5- or 6-membered aromatic carbocyclyl, carbocyclyl-Ci-C2-alkyl, heterocyclyl, or het- erocyclyl-Ci-C2-alkyl, or an 8- to 10-membered aromatic carbobicyclyl, carbobicyclyl-Ci- C2-alkyl, heterobicyclyl, or heterobicyclyl-Ci-C2-alkyl, 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 z .
  • R 3 is a 6-membered aromatic carbocyclyl, carbocyclyl-Ci-alkyl, heterocyclyl, heterocyclyl- Ci-alkyl, or an 9- or 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 z .
  • R z is halogen, Ci-C4-alkyl, or Ci-C4-haloalkyl.
  • R z is halogen, Ci-C2-alkyl, or Ci-C2-haloalkyl.
  • R z is F, CH 3 , or CF 3 .
  • R 3 is a 6-membered aromatic carbocyclyl, carbocyclyl-Ci-alkyl, heterocyclyl, heterocyclyl-Ci- alkyl, or an 9- or 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 z ; wherein preferably
  • R z is F, CH 3 , or CF 3 .
  • R 4 is H or Ci-C4-alkyl.
  • R 4 is H or CH 3 .
  • R 4 is H.
  • R 4 is H.
  • R N1 is H or Ci-C4-alkyl
  • R N2 is H or Ci-C4-alkyl.
  • R 5 is H or CH 3 .
  • R 5 is H.
  • R 5 is H.
  • the compound according to formula (I) is selected from the group consisting of: 4-hydroxy-8-phenyl-6-[(1S)-1-phenylethyl]-3H,5H,6H,7H,8H-pyridazino[1 ,6-a]pyrazine-3,5-di- one; (8R)-4-hydroxy-8-phenyl-6-[(1S)-1-phenylethyl]-3H,5H,6H,7H,8H-pyridazino[1,6-a]pyrazine-3,5- dione;
  • 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 (8S)-4-hydroxy-8-phenyl-6-[(1S)-1-phenylethyl]-3H,5H,6H,7H,8H-pyridazino[1 ,6-a]pyrazine-3,5- dione;
  • 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), (IA-1) or (IA-2), and also covers a stereoisomer, tautomer, N-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.
  • the compounds according to the invention also include solvates, in particular hydrates of the compounds of formula (I).
  • hydrate in connection with the compounds of formula (I) refers to a compound of formula (I), which contains water or its constituent elements (i.e. H and OH).
  • a hydrate of the compounds of formula (I) is a compound of formula (I), which incorporates water molecules in the crystalline structure but does not alter the chemical structure of formula (I). It is to be understood that such hydrates of the compounds provided herein, particularly the compounds of the present invention, also include hydrates of pharmaceutically acceptable salts of the corresponding compounds.
  • Salts of the compounds according to the invention are preferably pharmaceutically acceptable salts, such as those containing counterions present in drug products listed in the US FDA Or- ange Book database. They can be formed in a customary manner, e.g., by reacting the compound with an acid of the anion in question, if the compounds according to the invention have a basic functionality, or by reacting acidic compounds according to the invention with a suitable base.
  • Suitable cationic counterions are in particular the ions of the alkali metals, preferably lithium, sodium and potassium, of the alkaline earth metals, preferably calcium, magnesium and barium, and of the transition metals, preferably manganese, copper, silver, zinc and iron, and also ammonium (NH 4 + ) and substituted ammonium in which one to four of the hydrogen atoms are replaced by Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci-C4-alkoxy, Ci-C4-alkoxy-Ci-C4-alkyl, hydroxy-Ci- C4-alkoxy-Ci-C4-alkyl, phenyl or benzyl.
  • substituted ammonium ions comprise methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trimethylammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2-hydroxy- ethylammonium, 2-(2-hydroxyethoxy)ethyl-ammonium, bis(2-hydroxyethyl)ammonium, benzyltrimethylammonium and benzyltriethylammonium, furthermore the cations of 1 ,4-piperazine, meglumine, benzathine and lysine.
  • Suitable anionic counterions are in particular chloride, bromide, hydrogensulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, phosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and the anions of Ci-C4-alkanoic acids, preferably formate, acetate, propionate and butyrate, furthermore lactate, gluconate, and the anions of poly acids such as succinate, oxalate, maleate, fumarate, malate, tartrate and citrate, furthermore sulfonate anions such as besylate (benzenesulfonate), tosylate (p-toluenesulfonate), napsylate (naphthalene-2-sulfonate), mesylate (methanesulfonate), esylate (ethanesulfonate), and ethanedisul
  • 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 mole- cule.
  • 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).
  • Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. See, for example, Poster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sei. 5(12):524- 527 (1984).
  • Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
  • the concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • substituted means that a hydrogen atom bonded to a designated atom is replaced with a specified substituent, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise indicated, a substituted atom may have one or more substituents and each substituent is independently selected.
  • substituted atom means that attached to the atom is a hydrogen, which can be replaced with a suitable substituent.
  • substituted when used in reference to a designated atom, means that attached to the atom is a hydrogen, which can be replaced with a suitable substituent.
  • substituents When it is referred to certain atoms or moieties being substituted with “one or more” substituents, the term “one or more” is intended to cover at least one substituent, e.g., 1 to 10 substituents, preferably 1 , 2, 3, 4, or 5 substituents, more preferably 1 , 2, or 3 substituents, most preferably 1 , or 2 substituents.
  • substituents e.g. 1 to 10 substituents, preferably 1 , 2, 3, 4, or 5 substituents, more preferably 1 , 2, or 3 substituents, most preferably 1 , or 2 substituents.
  • the organic moieties mentioned in the above definitions of the variables are - like the term halogen - collective terms for individual listings of the individual group members.
  • the prefix C n -C m indicates in each case the possible number of carbon atoms in the group.
  • 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.
  • alkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 6 carbon atoms, preferably 1 to 5 or 1 to 4 carbon atoms, more preferably 1 to 3 or 1 or 2 carbon atoms.
  • alkyl group examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, /so-butyl, terf-butyl, n-pentyl, 1 -methylbutyl, 2- methylbutyl, 3-methyl- butyl, 2,2-dimethylpropyl, 1 -ethylpropyl, n-hexyl, 1 ,1 -di methyl propyl, 1 ,2-dimethylpropyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1 -di methyl butyl, 1 ,2-dimethyl- butyl, 1 ,3-di methyl butyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2- ethylbut
  • haloalkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 4 carbon atoms, preferably 1 to 3 or 1 or 2 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms.
  • Preferred haloalkyl moieties are selected from Ci-C4-haloalkyl, more preferably from C1-C3- haloalkyl or Ci-C2-haloalkyl, in particular from Ci-C2-fluoroalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, 1 -fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.
  • alkoxy denotes in each case a straight-chain or branched alkyl group which is bonded via an oxygen atom to the remainder of the molecule and has usually from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom.
  • alkoxy group examples are methoxy, ethoxy, n-propoxy, /so-propoxy, n-butyloxy, 2-butyloxy, /so-bu- tyloxy, terf-butyloxy, and the like.
  • 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 terf-butyl.
  • alkoxy include methoxy, ethoxy, n-propoxy, iso -propoxy, n-butoxy, iso -butoxy, sec-butoxy, and terf-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.
  • carbocyclic or “carbocyclyl” covers phenyl and cycloalkyl, for example phenyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • 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 TT 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 norbornane), 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 norbornane
  • the carbobicycle is a fused carbobicycle, which is preferably aromatic, for example naphthalene.
  • carbocyclylalkyl refers to carbocyclyl as defined herein, which is bonded to the remainder of the molecule via an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon atom.
  • carbocyclylalkyl refers to phenylalkyl or cycloalkylalkyl, which refers to the corresponding groups being bonded to the remainder of the molecule via an alkyl group.
  • carbocyclylalkyl examples include benzyl (i.e., phenylmethyl), phenylethyl, cyclopropyl methyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl.
  • carbocyclyloxy denotes in each case a carbocyclyl as defined herein, which is bonded via an oxygen atom to the remainder of the molecule.
  • Examples of carbocyclyloxy include phenyloxy or cyclopropyloxy. The same applies to the terms “aryloxy” and “benzyloxy” referring to the corresponding groups, which are bonded to the remainder of the molecule via an oxygen atom.
  • heterocyclic or “heterocyclyl” includes, unless otherwise indicated, in general a 3- to 10-membered, preferably a 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6- membered, in particular 6-membered monocyclic ring.
  • the heterocycle 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.
  • the heterocycle typically comprises one or more, e.g.
  • the heterocycle is an aromatic heterocycle, preferably a 5- or 6-membered aromatic heterocycle comprising 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.
  • aromatic heterocycles are provided below in connection with the definition of “hetaryl”.
  • Hetaryls or “heteroaryls” are covered by the term “heterocycles”.
  • the saturated or partially or fully unsaturated heterocycles usually comprise 1 , 2, 3, 4 or 5, 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.
  • 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.
  • carbocyclylalkyl as well as the term “cycloalkylalkyl”, 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.
  • 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.
  • EXO1 modulator or “EXO1 inhibitor” refers to a compound that modulates or inhibits exonuclease 1 (EXO1).
  • 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.
  • a "subject” can be a human, primate, dog, rabbit, guinea pig, pig, rat, or mouse, depending on the context.
  • Treatment refers to alleviating or mitigating a disease or disorder or reducing symptoms.
  • the term “treatment” is to be understood as also including the option of “prophylaxis”.
  • Prevent involves prophylactic treatment or delaying the onset or progression of a disease.
  • a subject is "in need of” treatment if they would benefit from it biologically, medically, or in terms of quality of life.
  • a pharmaceutical composition according to the present invention may be formulated for oral, buccal, nasal, rectal, topical, transdermal or parenteral application.
  • Preferred non-parenteral routes include mucosal (e.g., oral, vaginal, nasal, cervical, etc.) routes, of which the oral application may be preferred.
  • Preferred parenteral routes include but, are not limited to, one or more of subcutaneous, intravenous, intra-muscular, intraarterial, intradermal, intrathecal and epidural administrations.
  • Preferably administration is by subcutaneous, intra-tumoral or peri-tumoral routes. Particularly preferred is intratumoral administration.
  • the compound according to formula (I) should be applied in pharmaceutically effective amounts, for example in the amounts as set out herein below.
  • a pharmaceutical composition of the present invention may also be designated as formulation or dosage form.
  • a compound of formula (I) may also be designated in the following as (pharmaceutically) active agent or active compound.
  • 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.
  • inventive dosage forms can comprise various pharmaceutically acceptable excipients which will be selected depending on which functionality is to be achieved for the dosage form.
  • a “pharmaceutically acceptable excipient” in the meaning of the present invention can be any substance used for the preparation of pharmaceutical dosage forms, including coating materials, film-forming materials, fillers, disintegrating agents, release-modifying materials, carrier materials, diluents, binding agents and other adjuvants.
  • Typical pharmaceutically acceptable excipients include substances like sucrose, mannitol, sorbitol, starch and starch derivatives, lactose, and lubricating agents such as magnesium stearate, disintegrants and buffering agents.
  • carrier denotes pharmaceutically acceptable organic or inorganic carrier substances with which the active ingredient is combined to facilitate the application.
  • suitable pharmaceutically acceptable carriers include, for instance, water, aqueous salt solutions, alcohols, oils, preferably vegetable oils, propylene glycol, polyoxyethelene sorbitans, polyethylene-polypropylene block co-polymers such as poloxamer 188 or poloxamer 407, polyethylene glycols such as polyethylene glycol 200, 300, 400, 600, etc., gelatin, lactose, amylose, magnesium stearate, surfactants, perfume oil, fatty acid monoglycerides, diglycerides and triglycerides, polyoxyethylated medium or long chain fatty acids such as ricinoleic acid, and polyoxyethylated fatty acid mono-, di, and triglycerides such as capric or caprilic acids, petroethral fatty acid esters, hydroxymethyl celluloses such as hydroxymethyl
  • the compounds of the present invention are administered in a pharmaceutical composition comprising of lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]- based or poly anhydride-based nanoparticles or microparticles, nanoporous particle-supported lipid bilayers and as a conjugate with an antibody.
  • a pharmaceutical composition comprising of lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]- based or poly anhydride-based nanoparticles or microparticles, nanoporous particle-supported lipid bilayers and as a conjugate with an antibody.
  • compositions can be sterile and, if desired, mixed with auxiliary agents, like lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not del- eteriously react with the active compound.
  • auxiliary agents like lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not del- eteriously react with the active compound.
  • carrier also covers an antibody that delivers the compound of formula (I).
  • liquid dosage forms can include pharmaceutically acceptable emulsions, solutions, suspensions and syrups containing inert diluents commonly used in the art such as water.
  • These dosage forms may contain e.g. microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer and sweeteners/flavoring agents.
  • suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants.
  • Pharmaceutical formulations for parenteral administration are particularly preferred and include aqueous solutions of the compounds of formula (I) in water-soluble form.
  • suspensions of the compounds of formula (I) may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • Particularly preferred dosage forms are injectable preparations of a compound of formula (I).
  • sterile injectable aqueous or oleaginous suspensions can for example be formulated according to the known art using suitable dispersing agents, wetting agents and/or suspending agents.
  • a sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • the acceptable vehicles and solvents that can be used are water and isotonic sodium chloride solution. Sterile oils are also conventionally used as solvent or suspending medium.
  • Preferred applications for injectable preparations comprising the compounds of the present invention are intravenous, intratumoral and peritumoral administration.
  • Suppositories for rectal administration of a compound of formula (I) can be prepared by e.g. mixing the compound with a suitable non-irritating excipient such as cocoa butter, synthetic triglycerides and polyethylene glycols which are solid at room temperature but liquid at rectal temperature such that they will melt in the rectum and release the compound according to formula (I) from said suppositories.
  • a suitable non-irritating excipient such as cocoa butter, synthetic triglycerides and polyethylene glycols which are solid at room temperature but liquid at rectal temperature such that they will melt in the rectum and release the compound according to formula (I) from said suppositories.
  • the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro- tetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro- tetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro- tetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Oral dosage forms may be liquid or solid and include e.g. tablets, troches, pills, capsules, powders, effervescent formulations, dragees and granules.
  • Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellu- lose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the oral dosage forms may be formulated to ensure an immediate release of the compound of formula (I) or a sustained release of the compound of formula (I).
  • a solid dosage form may comprise a film coating.
  • the inventive dosage form may be in the form of a so-called film tablet.
  • a capsule of the invention may be a two-piece hard gelatin capsule, a two-piece hydroxypropylmethylcellulose capsule, a two-piece capsule made of vegetable or plant-based cellulose, or a two-piece capsule made of polysaccharide.
  • 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.
  • compositions may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy.
  • the methods can include the step of bringing the compounds into association with a carrier, which constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • Liquid dose units are vials or ampoules.
  • Solid dose units are tablets, capsules and suppositories.
  • 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 EXO1.
  • the compounds according to the present invention are particularly suitable for use in the treatment of a disease associated with modulating EXO1 , 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 hepatocellular carcinoma (HCC), glioma, colon cancer/colorectal cancer, in particular nonpolyposis colorectal cancer (HNPCC), breast, ovarian, lung, pancreatic, gastric tract cancer, cancer of the small intestine, oral cancer, cervical 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 EXO1 modulation, with a particular emphasis on cancers such as hepatocellular carcinoma (HCC), glioma, colon cancer/colorectal cancer, in particular nonpolyposis colorectal cancer (HNPCC), breast, ovarian, lung, pancreatic, gastric tract cancer, cancer of the small intestine, oral cancer, and cervical cancer.
  • HCC hepatocellular carcinoma
  • glioma glioma
  • colon cancer/colorectal cancer in particular nonpolyposis colorectal cancer
  • HNPCC nonpolyposis colorectal cancer
  • the invention further relates to the manufacture of a medicament for the treatment of diseases that can be addressed by EXO1 modulation, with a particular emphasis on cancers such as hepatocellular carcinoma (HCC), glioma, colon cancer/colorectal cancer, in particular nonpolyposis colorectal cancer (HNPCC), breast, ovarian, lung, pancreatic, gastric tract cancer, cancer of the small intestine, oral cancer, and cervical cancer.
  • HCC hepatocellular carcinoma
  • glioma glioma
  • colon cancer/colorectal cancer in particular nonpolyposis colorectal cancer (HNPCC)
  • HNPCC nonpolyposis colorectal 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 routes described in the literature.
  • the microwave chemistry is performed on a single mode microwave reactor EmrysTM Opti- miser from Personal Chemistry.
  • Preparative column chromatography was performed with a Teledyne-lsco CombiFlash EZ Prep (column: Redi Sep Rf C-18, 360 g, eluent: gradient Water+0,1 % HCOOH --> ACN+0,1% HCOOH, flow-rate: 150 ml/min, detection: UV 214nm) or Biotage Isolera Prime or preparative HPLC.
  • Preparative HPLC was performed on an Agilent 1200. Column: Chromolith prep RP 18e Merck KGaA; C18 silica gel; mobile phase: 0.1 % formic acid in water / 0.1 % formic acid in acetonitrile; 10% to 50% gradient in 10 min; detector UV 254 nm.
  • Mass spectrum LC/MS Waters ZMD (ESI) or Hewlett Packard System of the HP 1100 series (Ion source: Electrospray (positive mode) or Waters Acquity H Class SQD; Scan: 100-1000 m/z; Fragmentation-voltage: 60 V; Gas-temperature: 300°C, DAD: 220 nm. Flow rate: 2.4 ml/Min. The used splitter reduced the flow rate after the DAD for the MS to 0,75ml/Min; Column: Chromolith Speed ROD RP-18e 50-4.6; Solvent: LiChrosolv-quality from the company Merck KGaA or as mentioned in the method. LCMS data provided in the examples are given with retention time, purity and/or mass in m/z.
  • LCMS method 0 Column: HALO C18, 2 pm, 3.0 x 30 mm, Column Oven: 40C; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; Flow rate: 1.5 mL/min; Gradient: 5%B to 100%B in 2.0 min, hold 0.5 min; 254nm.
  • Scheme B Synthesis routes and typical conditions to key aminoethanol intermediate ;
  • Route B1 a) Alcohol oxidation to an aldehyde with e.g. MnO2 in DCM at RT over night; b) Oxirane introduction with iodotrimethyl-h-sulfanone and NaH in THF at RT for 2 hours; c) Epoxide opening with NaCIO4 in ACN at 60 °C for 48 hours;
  • Route B2 d) Heck coupling conditions, for example a vinyl ether with 1 ,1'-Bis(diphenylphosphino)ferrocene, Pd(ll) acetate, triethylamine, ethylene glycol; Hal is halogen; e) Bromination with e.g.
  • Scheme C Synthesis route and typical conditions to 4-hydroxy-6,8-substituted-7,8-dihydro-3H- pyrazino[1 ,2-b]pyridazine-3,5(6H)-dione a) Protecting group introduction, e.g. N,O-Bis(trimethylsilyl)-acetamide and 2-(trimethylsilyl)eth- oxymethyl chloride in tert-butyl methyl ether at RT for 4 hours; b) amide coupling with typical acid activation conditions like HATLI, thion coyl chloride, BOP; c) Chlorination with e.g. thionyl chloride in DCM at RT for 45 min; d) Cyclisa stion with e.g. LiBr in dioxane at 130 °C for 1.5 hours.
  • a) Protecting group introduction e.g. N,O-Bis(trimethylsilyl)-acetamide and 2-(
  • 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.
  • Channel A Solution of tert-butoxy bis(dimethylamino)methane (13.5 g; 77.4 mmol; 3 eq.) in 10 ml tetra hydrofuran, filled up with tetrahydrofuran to 50 ml (about 1.5 M tert-butoxy bis(dimethyla- mino)methane).
  • Channel B Solution of ethyl (2E)-4-(benzyloxy)-2-( ⁇ [(tert-butoxy)carbonyl]amino ⁇ imino)-3-oxobu- tanoate (9.4 g; 25.8 mmol; 1 eq.) in 30 ml tetrahydrofuran, filled up with tetra hydrofuran to 50 ml (about 0.5 M of ethyl (2E)-4-(benzyloxy)-2-( ⁇ [(tert-butoxy)carbonyl]amino ⁇ imino)-3-oxobuta- noate).
  • 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.
  • Amino alcohol intermediates were synthesised according to route B1 or route B2 of scheme B, as described for 1-(1-methyl-1 H-indazol-4-yl)-2- ⁇ [(1S)-1-phenylethyl]amino ⁇ ethan-1-ol in the following.
  • 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 96.2%, Rt 0.43 min., [M+H] + calc.: 295.17, found: 295.95m/z.
  • N,O-bis(trimethylsilyl)-acetamide (52.1 ml; 212.4 mmol; 2.2 eq.) was added to a suspension of ethyl 5-(benzyloxy)-4-oxo-1 ,4-dihydropyridazine-3-carboxylate hydrochloride (30 g; 96 mmol; 1 eq.) in tert-butyl methyl ether (500 ml) and the mixture was stirred for 30 min. at RT. To the resulting solution, 2-(trimethylsilyl)ethoxymethyl chloride (25.6 ml; 144.8 mmol; 1.5 eq.) was added and the mixture was stirred for 4h at RT.
  • reaction mixture was quenched with saturated NaHCOs-solution to pH 4-5 and the phases were separated.
  • aqueous sodium hydroxide solution (1 M) (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 aqueous HCI (2 M).
  • HATLI 38 g; 100 mmol; 1.15 eq.
  • N-ethyl di-isopropyl amine 44.7 ml; 3 eq.
  • 5-(benzyloxy)-4-oxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -1 ,4-dihydropyridazine- 3-carboxylic acid 33 g; 1 eq.
  • dichloromethane 600 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+H] + 672.2 ; Rt 2.053 min.
  • Lithium bromide (3.3 ml; 131 mmol; 1.5 eq.) was added to a solution of 5-(benzyloxy)-N-[2- chloro-2-(1-methyl-1 H-indazol-4-yl)ethyl]-4-oxo-N-[(1S)-1-phenylethyl]-1- ⁇ [2-(trimethylsilyl)eth- oxy]methyl ⁇ -1 ,4-dihydropyridazine-3-carboxamide (95 g; 87.6; 1 eq.) in 1 ,4-dioxane (600 ml) and the mixture was heated to 130°C for 1.5h. After cooling to RT, the solvent was removed in vacuo.
  • Example 14 The fractions containing Example 14 were combined and the ACN was evaporated in vacuo. To the aqueous residue was added saturated NaHCOs solution and the product was extracted with DCM. The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The solid residue was triturated with ether, filtered and dried in vacuo at 50°C to give (8S)-4-hy- droxy-8-(1-methyl-1 H-indazol-4-yl)-6-[(1S)-1-phenylethyl]-3H,5H,6H,7H,8H-pyridazino[1 ,6-a]py- razine-3, 5-dione as beige solid (8.96 g).
  • 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): [M+H] + 416.1 ; purity 100 %, Rt 1.365 min.
  • Example 15 The fractions containing Example 15 were combined and the ACN was removed in vacuo. To the aqueous residue was added saturated NaHCCh solution and the product was extracted with DCM. The separated organic layer was dried over Na2SC>4 and concentrated in vacuo. The residue was triturated with ether, filtered and dried in vacuo at 50°C to give (8R)-4-hydroxy-8-(1- methyl-1 H-indazol-4-yl)-6-[(1S)-1-phenylethyl]-3H,5H,6H,7H,8H-pyridazino[1 ,6-a]pyrazine-3,5- dione as a beige solid (6.37 g).
  • Example 14 and Example 15 can be achieved as described above.
  • Table 1 were prepared according to Scheme C and the procedures described for Example 14 and Example 15 above using the appropriate aminoethanol intermediate, wherein the aminoethanol intermediate is prepared from the appropriate starting materials according to Scheme B and the procedures described above for amino alcohol intermediate 1-(1- methyl-1 H-indazol-4-yl)-2- ⁇ [(1S)-1-phenylethyl]amino ⁇ ethan-1-ol.
  • ⁇ tereoinformation regarding the stereocenter at position 8 is assigned arbitrarily in both the structural formula and the IUPAC name.
  • Example 38 and Example 39 were prepared from 4-hydroxy-6-[(1S)-1-phenylethyl]-8-(pyridin-2- yl)-3H,5H,6H,7H,8H-pyridazino[1,6-a]pyrazine-3, 5-dione (mixture of Example 5 and Example 6 before chromatographic separation) as described in the following.
  • Example 38 and Example 39 (8S)-4-hydroxy-2-methyl-6-[(1S)-1-phenylethyl]-8-(pyridin-2-yl)- 3H,5H,6H,7H,8H-pyridazino[1 ,6-a]pyrazine-3, 5-dione and (8R)-4-hydroxy-2-methyl-6-[(1S)-1- phenylethyl]-8-(pyridin-2-yl)-3H,5H,6H,7H,8H-pyridazino[1 ,6-a]pyrazine-3, 5-dione (stereocenter at 8 position arbitrarily assigned).
  • Example 39 (8R)-4-hydroxy-2-methyl-6-[(1S)-1-phenylethyl]-8-(pyridin-2-yl)-3H,5H,6H,7H,8H- pyridazino[1 ,6-a]pyrazine-3, 5-dione (10.70 mg;).
  • EXO1 nuclease assay - determination of EXO1 inhibition (IC50 EXO1):
  • EXO1 (Exonuclease 1) exhibits both 5' to 3' exonuclease as well as endonuclease activity.
  • a mixture of EXO1 protein and the test substance were incubated at different concentrations with addition of fluorescently labelled 5’ pseudo Y DNA substrate. Cleavage of a FAM I BHQ1 dual labelled pseudo Y DNA substrate released the fluorescently tagged oligonucleotide causing an increase in fluorescent signal that is proportional to the amount of product generated.
  • the enzymatic EXO1 assay was carried out as Fluorescence Intensity (Fl) based 384- well assay.
  • Purified human recombinant EXO1 human EXO1 , full length, UniProt ID Q9UQ84, expressed in E. coli
  • the assay buffer comprised 20 mM TRIS pH 7.5, 5 % (v/v) Glycerol, 5 mM MgCI2, 1 mM DTT, 0.01 % (v/v) IGEPAL® CA-630.
  • test-substance solutions were dispensed into the microtitre plates using a Hummingbird capillary pipettor (Hummingbird Nano). Reactions were initiated by the addition of FAM I BHQ1 dual labelled pseudo Y DNA substrate (generated by annealing of oligo 1 : CTAAGTTCGTCAGGATTCCACACAG-[FAM], oligo 2: CGCTATGACTGTTAGAATGCT-[BHQ]- GGAATCCTGACGAACTTAG (Integrated DNA Technologies)) in assay buffer. The pharmacologically relevant assay volume was 5 pl. The final concentrations in the assay during incubation of the reaction mixture were 1 .2 - 1 .6 nM EXO1 and 40 nM DNA substrate.
  • IC50 half-maximum inhibitory concentration
  • FAM Carboxyfluorescein
  • TRIS Tris(hydroxymethyl)aminomethane
  • MgCh magnesium chloride
  • DTT dithiothreitol
  • EDTA ethylenediamine tetraacetate
  • EXO1 IC50 A: IC50 ⁇ 100 nm; B: 100 nM ⁇ IC50 ⁇ 1000 nM; C: 1000 nM ⁇ IC50 ⁇ 10000 nM;

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Abstract

La présente invention concerne des composés de formule (I) et des stéréoisomères, tautomères, N-oxides, et des sels pharmaceutiquement acceptables de ceux-ci qui sont utiles pour moduler l'exonucléase 1 (EXO1). 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/GB2025/050273 2024-02-13 2025-02-13 Composés hétérocycliques modulant l'exonucléase 1 (exo1) Pending WO2025172707A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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 (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DAI, Y.TANG, Z.YANG, Z.ZHANG, L.DENG, Q.ZHANG, XYU, Y.LIU, X.ZHU, J.: "EXO1 overexpression is associated with poor prognosis of hepatocellular carcinoma patients", CELL CYCLE, vol. 17, no. 19-20, 2018, pages 2386 - 2397
KEIJZERS, G., BAKULA, D., PETR, M. A., MADSEN, N. G. K., TEKLU, A., MKRTCHYAN, G., OSBORNE, B., SCHEIBYE-KNUDSEN, M.: "Human exonuclease 1 (EXO1) regulatory functions in DNA replication with putative roles in cancer", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 20, no. 1, 2018, pages 74
LIU, J.ZHANG, J.: "Elevated EXO1 expression is associated with breast carcinogenesis and poor prognosis", ANNALS OF TRANSLATIONAL MEDICINE, vol. 9, no. 2, 2021
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

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