WO2025046148A1 - Nouveaux inhibiteurs de parg - Google Patents

Nouveaux inhibiteurs de parg Download PDF

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WO2025046148A1
WO2025046148A1 PCT/EP2024/074505 EP2024074505W WO2025046148A1 WO 2025046148 A1 WO2025046148 A1 WO 2025046148A1 EP 2024074505 W EP2024074505 W EP 2024074505W WO 2025046148 A1 WO2025046148 A1 WO 2025046148A1
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alkyl
alkylene
methylcyclopropyl
sulfamoyl
heterocycloalkyl
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Ulrich LÜCKING
Oliver QUEROLLE
Andreas Goutopoulos
Zaixu Xu
Luca IACOVINO
Alena FREUDENMANN
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Forx Therapeutics AG
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Forx Therapeutics AG
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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/195—Radicals derived from nitrogen analogues of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

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 PARG inhibitors, and can be used in a method of treatment of a proliferative disorder, preferably of cancer.
  • Cancer is a leading cause of death worldwide. Although progression-free survival and overall survival of cancer patients has improved over the past two decades, millions of cancer patients still have few therapeutic options and poor survival outcomes (Jemal et al., J. Natl. Cancer Inst. 2017, 109, 1975).
  • DRS DNA replication stress
  • DRS refers to the deregulation of DNA replication and cell cycle progression. DRS can be induced from endogenous or exogenous causes such as oncogene activation and chemotherapeutics, respectively (Zeman and Cimprich, Nat. Cell Biol. 2013, 16, 2). At the level of the replication fork, DRS leads to replication fork stalling, disengagement of the replisome and eventually collapse.
  • Poly(ADP)ribosylation is a transient and reversible post-translational modification that occurs at DNA damaged sites and is catalyzed by the poly (ADP-ribose) polymerase (PARP) family of proteins (Cohen and Chang, Nat. Chem. Biol. 2018, 14, 236). PARylation of various DNA repair proteins leads to their activation. Degradation of the poly(ADP) ribose chains is mediated primarily by the poly(ADP-ribose) glycohydrolase (PARG) protein. DNA damage dependent PARylation/dePARylation is a rapid and dynamic process which needs to be well regulated since imbalances between the two processes can lead to DNA damage.
  • PARP poly (ADP-ribose) polymerase
  • Human PARG encodes a 111 kDa protein of 976 amino acids. It contains a N-terminal regulatory domain, a catalytic domain and an ADP-ribose binding macrodomain. Five human PARG transcripts have been identified. Full length PARG is mostly nuclear; the smaller isoforms localize primarily to the cytoplasm. PARG functions primarily as an exo-hydrolase and it releases mainly mono(ADP-ribose) by hydrolyzing the a-O-glycosidic ribose-ribose bond in PAR. PARG can also act as an endo-hydrolase. PARG preferentially degrades long and linear PAR chains whereas its activity with small and branched PAR chains is significantly reduced (O’Sullivan et al., Nat. Commun. 2019, 10, 1182).
  • PARG is the dominant cellular PAR degrading enzyme, it cannot act on the terminal protein-ribose bond.
  • Additional hydrolases such as terminal ADP-ribose protein glycohydrolase (TARG1) and ADP-ribosylhydrolase 3 (ARH3) are also known to catalyze PAR-degradation.
  • TARG1 and ARH3 complete the reversal of PARylation by removing protein-bound mono(ADP-ribose) moieties (a) Fontana et al., Elife 2017, doi: 10.7554/eLife.28533; b) Rack et al., Genes Dev. 2020, 34, 263).
  • TARG1 is located in the nucleus and cytoplasm.
  • ARH3 is found primarily in the cytoplasm but it can also be found in the mitochondria and in the nucleus (Rack et al., Genes Dev. 2020, 34, 263).
  • PARG participates in DNA replication and in various DNA repair mechanisms including singlestrand break (SSB) repair and replication fork restart.
  • SSB singlestrand break
  • PARG inhibitors have shown synthetic lethal phenotype in cells with high levels of DRS caused by low expression of genes involved in DNA replication and/or replication fork stability (Pillay et al., Cancer Cell. 2019, 35, 519).
  • PARG inactivation, depletion or inhibition sensitizes cells to irradiation and to DNA damaging agents such as alkylating agents (e.g. temozolomide and methyl methanesulfonate) (a) Fujihara et al., Curr. Cancer Drug Targets 2009, 9, 953; b) Gogola et al., Cancer Cell 2018, 33, 1078; c) Houl et al., Nat Commun. 2019, 10, 5654).
  • alkylating agents e.g. temozolomide and methyl methanesulfonate
  • Certain compounds that are useful as PARG inhibitors are further disclosed in documents WO 2016/092326, WO 2016/097749 and WO 2021/055744. Further compounds particularly useful as PARG inhibitors are disclosed in documents WO 2024/074497 and WO 2023/183850.
  • the present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof. It is to be understood that through the present description the term “compound of formula (I)” preferably encompasses also a compound of formula (II), (III) and (IV), unless explicitly indicated to the contrary.
  • a further embodiment of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention relates to the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, for use in therapy.
  • the compounds of formula (I) are useful for treating a disease or disorder in which PARG activity is implicated.
  • the compounds of formula (I) are useful for a method of treating a proliferative disorder.
  • the proliferative disorder is cancer, preferably a human cancer.
  • 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 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 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 (- CH 2 -), ethylene (e.g., -CH2-CH2- or -CH(-CH 3 )-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH 2 -CH 3 )-, -CH 2 - CH(-CH 3 )-, or -CH(-CH 3 )-CH2-), or butylene (e.g., -CH2-CH2-CH2-).
  • alkylene preferably refers to C alkylene (including, in particular, linear CM 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 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 C2 alkynylene (including, in particular, linear C2 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, N, P and Si, 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) and/or one or more P 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.
  • heterocyclyl preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl.
  • 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.
  • 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
  • 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.
  • 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 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).
  • 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.
  • 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
  • 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).
  • ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S
  • 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.
  • 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
  • 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, N, P and Si, 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) and/or one or more P ring atoms (if present) may optionally be oxidized, further wherein one or more S ring atoms (
  • 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
  • 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 group
  • 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 may, e.g., refer to imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1 H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), tetrahydropyridinyl (e.g., 1 ,2,3,6-tetrahydropyridinyl), dihydropyridinyl (e.g., 1 ,2-dihydropyridinyl or 2,3-dihydropyridinyl), pyranyl (e.g., 2H-pyranyl or 4H-pyranyl), thiopyranyl (e.g., 2H-thiopyranyl or 4H-thiopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindolyl,
  • 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
  • heterocycloalkenyl refers to an unsaturated alicyclic (non-aromatic) 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, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group comprises at least one double bond between adjacent
  • 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 may, e.g., refer to imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1 H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), tetrahydropyridinyl (e.g., 1 ,2,3,6-tetrahydropyridinyl), dihydropyridinyl (e.g., 1 ,2- dihydropyridinyl or 2,3-dihydropyridinyl), pyranyl (e.g., 2H-pyranyl or 4H-pyranyl), thiopyranyl (e.g., 2H-thiopyranyl or 4H-thiopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindolyl,
  • 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
  • heterocycloalkenylene refers to a heterocycloalkenyl group, as defined hereinabove, as defined hereinabove, but having two points of attachment, i.e. a divalent unsaturated alicyclic (non-aromatic) 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, N, P and Si 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) and/or one or more P ring atoms (if
  • 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 heteroatomcontaining ring.
  • heterocycloalkenylene refers to a heterocycloalkenyl group, as defined hereinabove, as defined hereinabove, but having two points of attachment, i.e. a divalent unsaturated alicyclic (non-aromatic) 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, wherein one or more carbon ring atom
  • 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.
  • halogen refers to fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-I). As it is to be understood for the skilled person, the terms “halogen” and “halo” may be used interchangeably.
  • haloalkyl refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms which are selected independently from fluoro, chloro, bromo and iodo, and are preferably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group.
  • Haloalkyl may, e.g., refer to -CF 3 , -CHF 2I -CH 2 F, -CF 2 -CH 3 , -CH 2 -CF 3 , -CH 2 -CHF 2 , -CH 2 -CF 2 -CH 3 , -CH 2 -CF 2 -CF 3 , or -CH(CF 3 ) 2 .
  • a particularly preferred “haloalkyl” group is -CF 3 .
  • 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.
  • substituents such as, e.g., one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety.
  • the “optionally substituted” groups referred to in this specification carry preferably not more than two substituents and may, in particular, carry only one substituent.
  • the optional substituents are absent, i.e. that the corresponding groups are unsubstituted.
  • substituent groups comprised in the compounds of the present invention may be attached to the remainder of the respective compound via a number of different positions of the corresponding specific substituent group. Unless defined otherwise, the preferred attachment positions for the various specific substituent groups are as illustrated in the examples.
  • compositions comprising “a” compound of formula (I) can be interpreted as referring to a composition comprising “one or more” compounds of formula (I).
  • 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.
  • the term “comprising” (or “comprise”, “comprises”, “contain”, “contains”, or “containing”), unless explicitly indicated otherwise or contradicted by context, has the meaning of “containing, inter alia”, i.e., “containing, among further optional elements, ...’’. In addition thereto, this term also includes the narrower meanings of “consisting essentially of’ and “consisting of’.
  • a comprising B and C has the meaning of "A containing, inter alia, B and C”, wherein A may contain further optional elements (e.g., “A containing B, C and D” would also be encompassed), but this term also includes the meaning of “A consisting essentially of B and C” and the meaning of "A consisting of B and C” (i.e., no other components than B and C are comprised in A).
  • the present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof.
  • Ri is hydrogen, -CN, formyl, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-O-(Ci-2 alkyl).
  • R1 is preferably -CN, methyl, fluoromethyl, difluoromethyl, -(C1-2 alkylene)-OH or C2 alkenyl, more preferably R 1 is methyl or -CN. In an embodiment, wherein R1 is methyl, particularly preferred R1 is CD3. In an alternative embodiment, R1 is -CN.
  • R2 and R3 are each independently C1-2 alkyl or C1-2 haloalkyl, or R2 and R3 together with the carbon atom to which they are attached form C3-5 cycloalkyl or 4-5 membered heterocycloalkyl, wherein said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups selected from C1-2 alkyl (such as methyl), C1-2 haloalkyl (such as fluoromethyl) and -F.
  • R2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more methyl or -F, or oxetanyl optionally substituted with one or more methyl or -F.
  • R2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more -F.
  • R2 and R3 together with the carbon atom to which they are attached form cyclopropyl.
  • W is selected from -NHS(O) y -, wherein y is 1 or 2.
  • y is 2.
  • W is preferably -NHS(O)2-.
  • the left side of W, as defined herein is attached to the carbon atom that carries R1, R2 and R3, and the right side of W, as defined herein, is attached to the ring system shown in formula (I).
  • Xi and X3 are independently selected from the group consisting of N, CH, C(Ci-2 alkyl), C-CI and CF, preferably independently selected from the group consisting of N, CH, CF and CCI, more preferably independently selected from the group consisting of N, CH and CF.
  • Xi is CF or CH and X3 is CH, more preferably Xi and Xsare each CH.
  • X2 is C-Yc2-Rc2.
  • Y C2 is selected from a covalent bond, C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, cycloalkylene and heterocycloalkylene wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more groups independently selected from R S1 , and further wherein one or more - CH2- units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from -O-, -NH-, -N(CI-5 alkyl)-, -CO-, -S-, -SO-, and -SO2-, and wherein said cycloalkylene and heterocycloalkylene are each optionally substituted with one or more groups independently selected R S2 .
  • Rc2 is selected from hydrogen, halogen, -OH, -NH2, -SH, -CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; wherein said alkyl, alkenyl, and alkynyl in X2 are each optionally substituted with one or more groups independently selected from R S1 , and wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl in X2are each optionally substituted with one or more groups independently selected from R S2 .
  • Yc2 is selected from a covalent bond, -(C1-3 alkylene)-, -CO-(Ci-3 alkylene)-, (C1-3 alkylene)-CO-, -CONH-(CI-3 alkylene)-, -(C1-3 alkylene)-CONH-, -NHCO-(CI- 3 alkylene)-, -(C1.3 alkylene)- NHCO-, -NH-(CI- 3 alkylene)-, -(C1-3 alkylene)-NH-, -N(CI- 5 alkyl)-, -O-(Ci- 3 alkylene)-, -(C1-3 alkylene)-O- , -SO2-(Ci-3 alkylene)-, -(C1-3 alkylene)-SO2-, -CONH-, -NHCO-, -NH-, -O-, -CO- and -SO2-, wherein said alkylene, said alkenylene and said alky
  • Rc2 is selected from hydrogen, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from R S2 .
  • Rc2 is selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from R S2 .
  • Rc2 is selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl are each optionally substituted with one or more groups independently selected from R S2 .
  • Rc2 is selected from heterocycloalkyl, and heterocycloalkenyl wherein said heterocycloalkyl, and heterocycloalkenyl are each optionally substituted with one or more groups independently selected from R S2 .
  • Rc2 is heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more groups independently selected from R S2 .
  • X2 is C-Yc2-Rc2
  • -Yc2-Rc2 is is selected from -O-C1-12 alkyl, -NH-C1-12 alkyl, -N(Ci. 5 alkyl)-Ci-i2 alkyl, -O-C2-12 alkenyl, -NH-C2-12 alkenyl, -N(CI-5 alkyl)-C2-i2 alkenyl, -O-C2-12 alkynyl, -NH- C2-12 alkynyl, -N(CI-5 alkyl)-C2-i2 alkynyl, -(C0-3 alkylene)-cycloalkyl, -CO-(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-CO-cycloalkyl, -CONH-(Co-3 alkylene)-cycloalkyl, (C0-3 alkylene)-CONH-cycloalkyl, (C
  • -Yc2-Rc2 is selected from -(C0-3 alkylene)-heterocycloalkyl, -CO-(Co-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)-CO-heterocycloalkyl, -CONH-(Co-3 alkylene)heterocycloalkyl, -
  • -Yc2-Rc2 is selected from -(C0-3 alkylene)-heterocycloalkyl, -CONH- heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO- heterocycloalkyl, -SO2-heterocycloalkyl, -(C0-3 alkylene)-heterocycloalkenyl, -CONH-heterocycloalkenyl, - NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO- heterocycloalkenyl, -SO2-heterocycloalkenyl, -(C0-3 alkylene)aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -NHCO-
  • -Yc2-Rc2 is selected from -(C0-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)heterocycloalkenyl, -(C0-3 alkylene)aryl, and -(C0-3 alkylene)heteroaryl, wherein said heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from R S2 -.
  • -Yc2-Rc2 is selected from heterocycloalkyl, and heterocycloalkenyl, wherein said heterocycloalkyl, and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from R S2 .
  • -Yc2-Rc2 is heterocycloalkyl wherein said heterocycloalkyl is optionally substituted with one or more groups independently selected from R S2 .
  • X 4 , X 5 and X 6 are each independently selected from N and C-R x , wherein R x is selected from -H, C1-5 alkyl, C1-5 alkenyl, C1-5 alkynyl, -0(Ci-5 alkyl), -CN and Hal, wherein said alkyl, alkenyl and alkynyl group is optionally substituted with one or more groups independently selected from RS1.
  • R x is selected from -H, C1-2 alkyl, -0(Ci-2 alkyl), and Hal, wherein said alkyl group is optionally substituted with one or more groups independently selected from R S1 .
  • R x is selected from -H, C1-2 alkyl, and -0(Ci-2 alkyl), wherein said alkyl group is optionally substituted with one or more groups independently selected from R S1 .
  • R x is selected from -H, and C1-2 alkyl, wherein said alkyl group is optionally substituted with one or more groups independently selected from R S1 .
  • R x is selected from -H, and C1-2 alkyl. Particularly preferred C1.2 alkyl is methyl. However, in an alternative preferred embodiment, R x is -H.
  • not more than two of X 4 , X 5 and X 6 are N. More preferably, not more than one of X 4 , X 5 and X 6 is N. If two of X 4 , X 5 and X 6 are N, it is preferred that X 4 , and X 5 are each N, or that X 4 and X 6 are each N. If one of X 4 , X 5 and X 6 is N, it is preferred that X 4 or X 5 is N. If one of X 4 , X 5 and X 6 is N, it is particularly preferred that X 4 is N.
  • Y is -N(R N1 )-WCOVI.RCOVI.
  • RCOVI j S selected from , C2 alkenyl, and C2 alkynyl, wherein said alkenyl is optionally substituted with one or more optional substituents selected from CM alkyl, -COO-(Ci-4 alkyl), -CONH-(Ci- 4 alkyl), -(CM alkylene)N(Ci-4 alkyl)(CM alkyl), -(CM alkylene)-(W-heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, and said alkynyl is optionally substituted with an optional substituent selected from CM alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
  • Suitable cycloalkyl group is for example a cyclopropyl group.
  • Suitable aryl group is for example a phenyl group.
  • R C0V1 is selected from and C2 alkenyl, wherein said alkenyl is optionally substituted with one or more optional substituents selected from CM alkyl, -COO-(CM alkyl), -CONH-(Ci. 4 alkyl), -(CM alkylene)N(Ci-4 alkyl)(CM alkyl), -(CM alkylene)-(A/-heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3.
  • -W c °vi- is selected from -CO-, -SO- and -SO2-.
  • -W COV1 - is selected from -CO-, and - SO2-. More preferably, -W COV1 - is -CO-.
  • R N1 is selected from hydrogen and CM alkyl. Suitable CM alkyl is for example methyl or ethyl. Preferably, R N1 is hydrogen.
  • R S1 is selected from halogen, -CN, -OH, -O(Ci-5 alkyl), -O(Ci-5 haloalkyl), C1-5 haloalkyl, -SH, -S(Ci- 5 alkyl), -SO 2 (Ci.
  • R S1 is selected from halogen, -CN, -OH, -O(Ci-5 alkyl), -O(Ci-5 haloalkyl), C1-5 haloalkyl, -SH, -S(Ci- 5 alkyl), -S(Ci- 5 haloalkyl), -NH 2 , -NH(CI- 5 alkyl), -NH(Ci-s haloalkyl), -N(CI- 5 alkyl)(Ci- 5 alkyl), -N(CI-5 haloalkyl)(Ci-5 alkyl), -(/V-heterocycloalkyl), -CO(Ci-5 alkyl), -CONH 2 , -CONH(CI-5 alkyl), -CON(CI-5 alkyl)(Ci-5 alkyl), -CO-(/V-heterocycloalkyl), -NHCO-(CI-5 alkyl), -N
  • R S1 is selected from halogen, -CN, -OH, -O(Ci-5 alkyl), -O(Ci-5 haloalkyl), C1-5 haloalkyl, -SH, -S(Ci- 5 alkyl), -S(Ci- 5 haloalkyl), -NH 2 , -NH(CI- 5 alkyl), -NH(CI- 5 haloalkyl), -N(CI- 5 alkyl)(Ci- 5 alkyl), -N(CI-5 haloalkyl)(Ci- 5 alkyl), -(/V-heterocycloalkyl), -CONH 2 , -CONH(CI- 5 alkyl), -CON(CI- 5 alkyl)(Ci-5 alkyl), -CO-(/V-heterocycloalkyl), -NHCO-(CI- 5 alkyl), -N(CI- 5 alkyl)
  • R S1 is selected from halogen, -CN, -OH, -O(Ci-5 alkyl), -O(Ci-5 haloalkyl), C1-5 haloalkyl, -SH, -S(Ci-s alkyl), -S(Ci- 5 haloalkyl), -NH 2 , -NH(CI- 5 alkyl), -NH(CI- 5 haloalkyl), -N(CI- 5 alkyl)(Ci-5 alkyl), -N(CI-5 haloalkyl)(Ci-5 alkyl), and -(/V-heterocycloalkyl).
  • R S1 is selected from halogen, -CN, -OH, -SH, and -NH 2 .
  • R S2 is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(Ci-5 alkyl), - O(Ci- 5 haloalkyl), -SH, -S(Ci- 5 alkyl), -S(O)(Ci- 5 alkyl), -SO 2 (Ci-5 alkyl), -S(O)(NH)(CI- 5 alkyl), -S(O)(N-Ci- 3 alkyl)(Ci-5 alkyl), -S(O)(NH)-(/V-heterocycloalkyl), -S(O)(N-CI-3 alkyl)-(/V-heterocycloalkyl), -S(O)(NH)- (C1-5 alkylene)-(/V-heterocycloalkyl), -S(O)(N-CI-3 alkyl)-(Ci-(Ci-
  • R S2 is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(Ci-5 alkyl), -O(Ci-5 haloalkyl), -SH, -S(Ci- 5 alkyl), -S(Ci- 5 haloalkyl), -NH 2 , -NH(CI- 5 alkyl), -NH(Ci ⁇ haloalkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -N(CI-5 haloalkyl)(Ci-5 alkyl), -(/V-heterocycloalkyl), -CO(Ci-5 alkyl), -CONH2, -CONH(CI- 5 alkyl), -CON(Ci-s alkyl)(Ci- 5 alkyl), -CO-(/V-heterocycloalkyl), -NHCO-(Ci)
  • R S2 is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(Ci-5 alkyl), -O(Ci-5 haloalkyl), -SH, -S(Ci- 5 alkyl), -S(Ci- 5 haloalkyl), -NH 2 , -NH(CI- 5 alkyl), -NH(CI-5 haloalkyl), -N(CI- 5 alkyl)(Ci- 5 alkyl), -N(CI- 5 haloalkyl)(Ci- 5 alkyl), -(N- heterocycloalkyl), -CONH 2 , -CONH(CI- 5 alkyl), -CON(CI- 5 alkyl)(Ci- 5 alkyl), -CO-(N- heterocycloalkyl), -NHCO-(CI- 5 alkyl), -N(CI- 5 alkyl),
  • R S2 is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(Ci-5 alkyl), -O(Ci-5 haloalkyl), -SH, -S(Ci- 5 alkyl), -S(Ci- 5 haloalkyl), -NH 2 , -NH(CI- 5 alkyl), -NH(Ci ⁇ haloalkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -N(CI-5 haloalkyl)(Ci-5 alkyl), -(/V-heterocycloalkyl), -(C1.5 alkylene)- CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-O(Ci-5 alkyl), -(C1.5 alkylene)-O(Ci-5 haloalkyl), -(C1-5
  • R S2 is selected from halogen, -CN, -OH, -SH, -NH2, -(C1-5 alkylene)-CN, - (C1.5 alkylene)-OH, -(C1-5 alkylene)-SH, and -(C1-5 alkylene)-NH2.
  • R S2 is selected from halogen, -CN, -OH, -SH, and -NH2.
  • R1 is methyl.
  • One possible methyl group is CD3.
  • R1 is -CN.
  • Xi is CH and X3 is CH.
  • -Yc2-Rc2 is not H.
  • -Yc2-Rc2 is aryl, preferably -Yc2-Rc2 is phenyl, wherein said aryl (said phenyl) is optionally substituted with one or more groups independently selected from halogen, CN, OH, C1-5 alkyl, C1-5 haloalkyl, O(Ci-5 alkyl), -O(Ci-s haloalkyl), SH, S(Cis alkyl), S(Ci5 haloalkyl), NH 2 , NH(CI-5 alkyl), NH(CI- 5 haloalkyl), N(CI- 5 alkyl)(Ci- 5 alkyl), -N(CI- 5 haloalkyl)(Ci- 5 alkyl), -CO(Ci-5 alkyl), CONH 2 , CONH(CI- 5 alkyl), and CON(CI- 5 alkyl)(Ci- 5 alkyl)(Ci- 5 alkyl)(Ci
  • -Yc2-Rc2 is heteroaryl, preferably selected from imidazolyl, pyridazinyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and indazolyl, wherein said heteroaryl is optionally substituted with one or more groups independently selected from halogen, CN, OH, C1.5 alkyl, C1.5 haloalkyl, O(Ci- 5 alkyl), -O(Ci- 5 haloalkyl), SH, S(Ci 5 alkyl), S(Ci 5 haloalkyl), NH 2 , NH(CI- 5 alkyl), NH(CI- 5 haloalkyl), N(CI- 5 alkyl)(Ci- 5 alkyl), -N(CI- 5 haloalkyl)(Ci- 5 alkyl), -CO(Ci- 5 alkyl), CONH
  • -Yc2-Rc2 is heterocycloalkyl, preferably selected from morpholinyl, 1 ,1-dioxothiomorpholinyl, azetinyl, pyrrolidinyl, piperidinyl, 6-oxo- 1 ,6- dihydropyridinyl, or piperazinyl, wherein said heterocycloalkyl is optionally substituted with one or more groups independently selected from R S2 .
  • -Yc2-Rc2 is piperazinyl, optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(Ci-5 alkyl), -O(Ci- 5 haloalkyl), -SH, -S(Ci- 5 alkyl), -S(Ci-5 haloalkyl), -NH 2 , -NH(CI- 5 alkyl), -NH(CI-5 haloalkyl), -N(CI- 5 alkyl)(Ci- 5 alkyl), -N(CI- 5 haloalkyl)(Ci- 5 alkyl), -CO(Ci- 5 alkyl), -CONH2, -CONH(CI-5 alkyl), and -CON(CI-5 alkyl)(Ci-5 alkyl).
  • -Yc2-Rc2 is piperazinyl (preferably N-piperazinyl) optionally substituted (preferably N-substituted) with -CO(Ci-5 alkyl), -CONH2, -CONH(CI-5 alkyl), and -CON(CI-5 alkyl)(Ci-s alkyl).
  • -Yc2-Rc2 is piperazinyl (preferably N-piperazinyl) substituted (preferably N-substituted, preferably at a different N- atom than that attached to the ring system as shown in formula (I)), with -CON(CI-5 alkyl)(Ci-s alkyl), preferably with -CON(CH3)2.
  • -Yc2-Rc2 is heterocycloalkyl, wherein said heterocycle comprises a spiro ring system, optionally selected from 2-oxaspiro[3.5]non-6- en-7-yl, 2-oxaspiro[3.5]non-7-yl, 2-oxa-8-azaspiro[4.5]dec-8-yl, 9-oxa-3-azaspiro[5.5]undec-3-yl, 2-oxa-6- azaspiro[3.4]oct-6-yl, 1-oxa-7-azaspiro[3.5]non-7-yl, 1 -oxa-8-azaspiro[4.5]dec-8-yl, 6-oxa-2- azaspiro[3.3]hept-2-yl, 2,8-diazaspiro[4.5]dec-8-yl, 7-oxa-3-azabicyclo[3.3.0]oct-3-y
  • -Yc2-Rc2 is heterocycloalkenyl, wherein said heterocycloalkenyl is optionally substituted with one or more groups independently selected from R S2 .
  • -Yc2-Rc2 is oxacyclohexenyl or azacyclohexenyl, optionally substituted with one or more groups independently selected from R S2 .
  • -Yc2- RC2 is azacyclohexenyl substituted (preferably N-substituted) with -CON(CI-5 alkyl)(Ci-5 alkyl), preferably with -CON(CH 3 ) 2 .
  • -Yc2-Rc2 is selected from: yl
  • X 4 is N and X 5 and X 6 are each independently C-R x . Further preferably, in this specific embodiment, X 5 and X 6 are each CH, X 5 and X 6 are CH and CCH3, respectively, X 5 and X 6 are CCH3 and CH, respectively, or X 5 and X 6 are each CCH3.
  • X 4 and X 6 are each N, and X 5 is C-R x . Further preferably, in this specific embodiment, X 5 is CH or CCH3.
  • X 4 , X 5 and X 6 are each independently C-R x , wherein R x is selected from -H, C1-5 alkyl, C1-5 alkenyl, C1-5 alkynyl, -O(Ci-5 alkyl), -CN and Hal, wherein said alkyl, alkenyl and alkynyl group is optionally substituted with one or more groups independently selected from R S1 .
  • R x is selected from -H, and C1-5 alkyl wherein said alkyl group is optionally substituted with one or more groups independently selected from R S1 . More preferably, R x is selected from -H, and C1-5 alkyl. Even more preferably, R x is -H. Accordingly, in this sixteenth specific embodiment, it is preferred that X 4 , X 5 and X 6 are each independently C-H.
  • R COV1 is
  • Y is selected from o o ,
  • R2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more methyl or -F.
  • R1 is selected from methyl and -CN, more preferably R1 is methyl.
  • R1 is -CN.
  • R2 and R3 together with the carbon atom to which they are attached form oxetanyl optionally substituted with one or more methyl or -F.
  • the compound comprises a moiety of formula 1 , preferably selected from defined herein, preferably R1 is selected from methyl and -CN, more preferably R1 is methyl. Alternatively, R1 is -CN.
  • the present invention relates to a compound of formula (II):
  • the present invention relates to a compound of formula (III): or a pharmaceutically acceptable salt thereof. It is to be understood that the definitions of any of R1, R2, R3, W, Xi, X2, X3, and Y are as in formula (I) hereinabove, including any of the specific embodiments of the compound of formula (I) recited hereinabove.
  • the present invention relates to a compound of formula (IV): or a pharmaceutically acceptable salt thereof. It is to be understood that the definitions of any of Ri, R2, R3, W, Xi, X2, X3, and Y are as in formula (I) hereinabove, including any of the specific embodiments of the compound of formula (I) recited hereinabove.
  • Exemplary preferred compounds of formula (I) are selected from the following compounds or their pharmaceutically acceptable salts:
  • a compound of formula (I) can preferably be selected from the compounds described in Table 2, or their pharmaceutically acceptable salts. Accordingly, a compound of formula (I) is preferably a compound selected from:
  • a compound of formula (I) is a compound selected from:
  • the present invention also relates to each of the intermediates described further below in the examples section of this specification, including any one of these intermediates in non-salt form or in the form of a salt (e.g., a pharmaceutically acceptable salt) of the respective compound.
  • a salt e.g., a pharmaceutically acceptable salt
  • Such intermediates can be used, in particular, in the synthesis of the compounds of formula (I).
  • the scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds of formula (I) which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation.
  • Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N- dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammoni
  • Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nic
  • Preferred pharmaceutically acceptable salts of the compounds of formula (I) include a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, and a phosphate salt.
  • a particularly preferred pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride salt.
  • the compound of formula (I), including any one of the specific compounds of formula (I) described herein, is in the form of a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, or a phosphate salt, and it is particularly preferred that the compound of formula (I) is in the form of a hydrochloride salt.
  • the present invention also specifically relates to the compound of formula (I), including any one of the specific compounds of formula (I) described herein, in non-salt form.
  • 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.
  • the compounds of formula (I) may exist in the form of different isomers, in particular stereoisomers (including, e.g., geometric isomers (or cis/trans isomers), enantiomers and diastereomers) or tautomers (including, in particular, prototropic tautomers, such as keto/enol tautomers or thione/thiol tautomers). All such isomers of the compounds of formula (I) are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form.
  • stereoisomers the invention embraces the isolated optical isomers of the compounds according to the invention as well as any mixtures thereof (including, in particular, racemic mixtures/racemates).
  • the racemates can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography.
  • the individual optical isomers can also be obtained from the racemates via salt formation with an optically active acid followed by crystallization.
  • the present invention further encompasses any tautomers of the compounds of formula (I). It will be understood that some compounds may exhibit tautomerism. In such cases, the formulae provided herein expressly depict only one of the possible tautomeric forms.
  • the formulae and chemical names as provided herein are intended to encompass any tautomeric form of the corresponding compound and not to be limited merely to the specific tautomeric form depicted by the drawing or identified by the name of the compound.
  • the scope of the invention also embraces compounds of formula (I), in which one or more atoms are replaced by a specific isotope of the corresponding atom.
  • the invention encompasses compounds of formula (I), in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e., 2 H; also referred to as “D”).
  • the invention also embraces compounds of formula (I) which are enriched in deuterium.
  • Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 ( 1 H) and about 0.0156 mol-% deuterium ( 2 H or D).
  • the content of deuterium in one or more hydrogen positions in the compounds of formula (I) can be increased using deuteration techniques known in the art.
  • a compound of formula (I) or a reactant or precursor to be used in the synthesis of the compound of formula (I) can be subjected to an H/D exchange reaction using, e.g., heavy water (D2O).
  • D2O heavy water
  • deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11 -12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014.
  • the content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy.
  • it is preferred that the compound of formula (I) is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or 1 H hydrogen atoms in the compounds of formula (I) is preferred.
  • the present invention also embraces compounds of formula (I), in which one or more atoms are replaced by a positron-emitting isotope of the corresponding atom, such as, e.g., 18 F, 11 C, 13 N, 15 0, 76 Br, 77 Br, 120 l and/or 124 l.
  • a positron-emitting isotope of the corresponding atom such as, e.g., 18 F, 11 C, 13 N, 15 0, 76 Br, 77 Br, 120 l and/or 124 l.
  • Such compounds can be used as tracers, trackers or imaging probes in positron emission tomography (PET).
  • the invention thus includes (I) compounds of formula (I), in which one or more fluorine atoms (or, e.g., all fluorine atoms) are replaced by 18 F atoms, (ii) compounds of formula (I), in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by 11 C atoms, (ill) compounds of formula (I), in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by 13 N atoms, (iv) compounds of formula (I), in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by 15 O atoms, (v) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by 76 Br atoms, (vi) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine
  • the present invention further embraces the prodrugs of the compounds of formula (I).
  • the term “prodrug” of the compound of formula (I) refers to a derivative of the compounds of formula (I) that upon administration to a subject becomes metabolized to the said compound of formula (I).
  • Said prodrugs of the compound of formula (I) may include modifications of -OH, -NH2, or -COOH group if present in the compound of formula (I), which preferably can be hydrolyzed to - OH, -NH2, or -COOH groups, respectively, e.g. upon administration to the subject.
  • such prodrugs may preferably include for the compounds of formula (I) which comprise -OH moiety derivatives wherein said -OH moiety is turned into an -OR X moiety, wherein Rx preferably comprises a moiety selected from -CO-, -CH2-O-CO, -CH2-O-CO-O-, and -CH(CH3)-O-COO-, more preferably wherein Rx is selected from -CO-R y , -CH2-O-CO-R y , -CH2-O-CO-O-R y , and -CH(CH3)-O- 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 al
  • such prodrugs may preferably include for the compounds of formula (I) which comprise -NH2 moiety derivatives wherein said -NH2 moiety is turned into -NHCOO-R y moiety, wherein R y is as defined hereinabove.
  • such prodrugs may preferably include for the compounds of formula (I) which comprise -COOH moiety derivatives wherein said -COOH group is turned into -COOR y moiety, wherein R y is as defined hereinabove.
  • groups that can be derivatized to yield prodrugs are known to the skilled person.
  • the compounds provided herein may be administered as compounds perse or may be formulated as medicaments.
  • the medicaments/pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and/or solubility enhancers.
  • the pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., polyethylene glycol), including polyethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, a non-ionic surfactant, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate (e.g., Kolliphor® HS 15, CAS 70142-34-6), a phospholipid, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, a cyclodextrin, a-cyclodextrin, p-cyclodextrin, y- cyclodextrin, hydroxyethyl-p-cyclodextrin
  • the pharmaceutical compositions may also comprise one or more preservatives, particularly one or more antimicrobial preservatives, such as, e.g., benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methyl-phenol or 4-chloro-3-methyl-phenol), benzalkonium chloride, benzethonium chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, thimerosal, or any combination thereof.
  • preservatives particularly one or more antimicrobial preservatives, such as, e.g., benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methyl-phenol or 4-chloro-3-methyl-phenol), benzalkonium chloride, benzethonium chloride, benzoic
  • compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in "Remington: The Science and Practice of Pharmacy”, Pharmaceutical Press, 22 nd edition.
  • the pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration.
  • Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets.
  • Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration.
  • Dosage forms for rectal and vaginal administration include suppositories and ovula.
  • Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by a metered inhaler.
  • Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.
  • the compounds of formula (I) or the above described pharmaceutical compositions comprising a compound of formula (I) may be administered to a subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection techniques or infusion techniques, and including, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for example, subcutaneously or intramuscularly), pulmonary (e
  • examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracardially, intracranially, intramuscularly or subcutaneously administering the compounds or pharmaceutical compositions, and/or by using infusion techniques.
  • parenteral administration the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • 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.
  • the tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine
  • disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glyco
  • Preferred excipients in this regard include lactose, starch, a cellulose, or high molecular weight polyethylene glycols.
  • the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • the compounds or pharmaceutical compositions are preferably administered by oral ingestion, particularly by swallowing.
  • the compounds or pharmaceutical compositions can thus be administered to pass through the mouth into the gastrointestinal tract, which can also be referred to as “oral-gastrointestinal” administration.
  • said compounds or pharmaceutical compositions can be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
  • the compounds of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch.
  • 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.
  • Said compounds or pharmaceutical compositions may also be administered by the pulmonary route, rectal routes, or the ocular route.
  • they can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzalkonium chloride.
  • they may be formulated in an ointment such as petrolatum.
  • dry powder formulations of the compounds of formula (I) for pulmonary administration may be prepared by spray drying under conditions which result in a substantially amorphous glassy or a substantially crystalline bioactive powder. Accordingly, dry powders of the compounds of the present invention can be made according to an emulsification/spray drying process.
  • said compounds or pharmaceutical compositions can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water.
  • they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol and water.
  • the present invention thus relates to the compounds or the pharmaceutical compositions provided herein, wherein the corresponding compound or pharmaceutical composition is to be administered by any one of: an oral route; topical route, including by transdermal, intranasal, ocular, buccal, or sublingual route; parenteral route using injection techniques or infusion techniques, including by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including by intravitreal, or intracameral route; rectal route; or vaginal route.
  • Preferred routes of administration are oral administration or parenteral administration.
  • a physician will determine the actual dosage which will be most suitable for an individual subject.
  • the specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy.
  • a proposed, yet non-limiting dose of the compounds according to the invention for oral administration to a human may be 0.05 to 2000 mg, preferably 0.1 mg to 1000 mg, of the active ingredient per unit dose.
  • the unit dose may be administered, e.g., 1 to 3 times per day.
  • the unit dose may also be administered 1 to 7 times per week, e.g., with not more than one administration per day. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient/subject as well as the severity of the condition to be treated. The precise dose and also the route of administration will ultimately be at the discretion of the attendant physician or veterinarian.
  • the present invention relates to the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
  • the present invention provides compounds that function as inhibitors of PARG.
  • the present invention provides a method of inhibiting PARG enzyme activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
  • the present invention also provides a method of selectively inhibiting PARG enzyme activity over PARP1 or ARH3 enzyme activity in vitro or in vivo.
  • the said method comprises the steps of contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
  • the present invention relates to the compound of formula (I), as disclosed herein, for use in a method of treating a disease or disorder in which PARG activity is implicated in a subject or patient in need of such treatment.
  • Said method of treatment comprises administering to said subject/patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.
  • the present invention relates to the compound of formula (I), as disclosed herein, for use in treating a disease or disorder in which PARG activity is implicated.
  • the present invention relates to a method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
  • the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof for use in of inhibiting cell proliferation, in vitro or in vivo.
  • the present invention relates to a method of treating a proliferative disorder in a subject or patient in need of such treatment.
  • the said method of treating a proliferative disorder in a subject or patient in need thereof comprises administering to said subject/patient a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.
  • the proliferative disorder is cancer.
  • the present invention relates to a method of treating cancer in a subject or patient in need thereof.
  • the said method of treating cancer in a subject or patient in need thereof comprises administering to said subject/patient a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.
  • the cancer is human cancer.
  • the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in treating a proliferative disorder.
  • the proliferative disorder is cancer. Therefore, the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in treating cancer.
  • the cancer is human cancer.
  • the present invention relates to the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, for use in the manufacture of a medicament for the treatment of a proliferative condition.
  • the proliferative condition is cancer, more preferably a human cancer.
  • the present invention relates to the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, for use in the manufacture of a medicament for the treatment of cancer, preferably for the treatment of human cancer.
  • the present invention relates to the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, for use in the manufacture of a medicament for the inhibition of PARG enzyme activity.
  • the inhibition of PARG enzyme activity is selective inhibition of PARG enzyme activity over PARP1 or ARH3 enzyme activity.
  • the present invention relates to the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, for use in the manufacture of a medicament for the selective inhibition of PARG enzyme activity over PARP1 or ARH3 enzyme activity.
  • the present invention further provides the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the manufacture of a medicament for the treatment of a disease or disorder in which PARG activity is implicated, as defined herein.
  • proliferative disorder are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo.
  • proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumours, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin.
  • the anti-proliferative effects of the compound of formula (I) of the present invention have particular application in the treatment of human cancers (by virtue of their inhibition of PARG enzyme activity).
  • the anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death).
  • the antiproliferative treatment with the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate 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
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341 ), N-(2-chloro-6- methylphenyl)-2- ⁇ 6-[4-(2- hydroxyethyl)piperazin-1 -yl]-2-methylpyrimidin-4-ylamino ⁇ thiazole- 5-carboxamide (dasatinib, BMS- 354825; J. Med.
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyr
  • 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-erbB 1 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 multidrug 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, hydrate or solvate 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 anti-tumour 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.
  • Scheme 1 illustrates a preferred synthetic approach to compounds of the general Formula (la) in which X2 is defined as being C-Yc2-Rc2, Y is defined as being -N(R N1 )-W COV1 -R COV1 , W is defined as being -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R 1 , R 2 and R 3 , and the right side of W, as defined herein, attached to the ring system shown in formula (la), and all the other variables are defined according to compound of Formula (la) in which X2 is defined as being C-Yc2-Rc2, Y is defined as being -N(R N1 )-W COV1 -R COV1 , W is defined as being -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R 1 , R 2 and R 3 , and the right
  • This reaction can be carried out under basic conditions (see for example: Sutton et al, WO 2021/055744). Preferred is the herein described use of trimethylamine, pyridine etc., in DCM, THF or DMF.
  • the reactions are preferably run under an atmosphere of argon for 0.5-24 hours at 0°C to room temperature.
  • the removal of the protecting group PG1 in formula 3 X 1 , X 3 , X 4 , X 5 and X 6 are as defined for the compound of Formula (I), PG1 and PG2 are protecting groups such as an acetyl group and W is -NHS(O)2- as defined in step 1 is performed under basic conditions to afford a compound of formula 4 (see for example: Muto Susumu et al, US2005/215645, 2005, A1). Preferred is the herein described use of NaOH, KOH etc., in a mixture solvent of water and MeOH. The reactions are preferably run under an atmosphere of argon for 0.5-24 hours at 0°C to room temperature.
  • PG2 is a protecting groups such as an acetyl group
  • W is -NHS(O)2- as defined in step 1
  • OTf triflate
  • This reaction can be carried out by treating with Tf2O or N,N-bis(trifluoromethylsulfonyl)aniline under basic conditions, (see for example: Fuchibe, Kohei et al, Organic Letters, 2015, vol. 17, # 5, p. 1126 - 1129).
  • Tf2O N,N-bis(trifluoromethylsulfonyl)aniline
  • Preferred is the herein described use of Tf2O in DCM with addition of triethylamine, pyridine, di-iso-propylethylamine etc.
  • the reactions are preferably run under an atmosphere of argon for 0.5-24 hours at 0°C to room temperature.
  • PG2 is a protecting groups such as an acetyl group and is -NHS(O)2- as defined in step 1 is coupled with various chemical moieties such as non-aromatic hetorocycles, hetaryl... to give a compound of formula 6 in which X 2 is defined as for the compound of Formula (I).
  • This coupling reaction can be carried out by a palladium-catalyzed cross-coupling reaction (see for example: a) Jiang, Buchwald in ‘Metal-Catalyzed CrossCoupling Reactions’, 2nd edition.: de Meijere, Diederich, Eds.: Wiley- VCH: Weinheim, Germany, 2004; b) Sutton et al, WO 2021/055744).
  • a carbon -nitrogen coupling preferred is the herein described use of cesium carbonate and Pd-PEPPSI-IPentCI o-picoline in dioxane.
  • the reactions are preferably run under an atmosphere of argon for 1-48 hours at 80-120°C in a microwave oven or in an oil bath.
  • This deprotection can be carried out under acidic conditions (see for example: Yamazaki, Yukari et al, Chemistry Letters, 2020, vol. 49, # 2, p. 133 - 136).
  • the reactions are preferably run under an atmosphere of argon for 0.5-24 hours at room temperature to the boiling point of the solvent.
  • a compound of formula 7 in which X 1 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 and R 3 are as defined for the compound of formula (I) and W is -NHS(O)2- as defined in step 1 is reacted with formula 8 in which R N1 is CM alkyl and LG1 is a leaving group such as CI-, Br-, I-, MsO- or aldehyde to give a compound of formula 9.
  • the alkylation is preferably carried out in basic conditions using preferentially deprotonating agents or bases such as NaH, K2CO3 or CS2CO3 etc.in suitable solvents such as for example DCM, DMF or THF (see for example: Sankaranarayananv et al, US2004106802), under an atmosphere of argon for 3-24 hours at a temperature ranged betweenO °C to 80 °C.
  • suitable solvents such as for example DCM, DMF or THF (see for example: Sankaranarayananv et al, US2004106802)
  • this reaction is preferably carried out in the presence of a suitable reducing agent such as for example sodium cyanoborohydride or sodium triacetoxyborohydride, in the presence of acetic acid (cat.), molecular sieve, in a suitable solvent such as MeOH, DCE, /-PrOH ect, preferably under an atmosphere of argon for 12-24 hours at room temperature to 80 °C(see for example: Ong et al, US2013203686).
  • a suitable reducing agent such as for example sodium cyanoborohydride or sodium triacetoxyborohydride
  • acetic acid cat.
  • a suitable solvent such as MeOH, DCE, /-PrOH ect
  • a compound of formula 9 in which X 1 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 and R 3 are as defined for the compound of formula (I), W is -NHS(O)2- as defined in step 1 , is reacted with a compound of formula 10 in which Rcovi.wcovi j S defined for the compound of formula (I) and LG2 is leaving group such as HO-, CI-, -0- W ⁇ -R 00 1 , MeO-, to give a compound of Formula (la).
  • this amidation reaction is preferably carried in the presence of a suitable base such as for example triethylamine, pyridine, di-iso-propylethylamine etc, in the presence of a suitable condensating agent such as HATU, EDCI/HOBt, T3P, CDI etc. in a suitable solvent such as for example DCM or DMF, preferably under an atmosphere of argon for 2 - 24 hours at room temperature (see for example: Blake et WO2020/131674).
  • a suitable base such as for example triethylamine, pyridine, di-iso-propylethylamine etc
  • a suitable condensating agent such as HATU, EDCI/HOBt, T3P, CDI etc.
  • a suitable solvent such as for example DCM or DMF
  • this reaction is carried out in of the presence of a suitable base such as triethylamine, pyridine, di-iso-propylethylamine etc in a suitable solvent such as for example DCM or THF under an atmosphere of argon for 2-24 hours at a temperature ranged between 0 °C and 50 °C (see for example: Lyeret al, Chem. Communications, 2018, 54, 11021 - 11024).
  • a suitable base such as triethylamine, pyridine, di-iso-propylethylamine etc
  • a suitable solvent such as for example DCM or THF
  • the reaction can be performed in the presence of a deprotonating agent such as LiHMDS in a suitable solvent such as THF under an atmosphere of argon for 0.5-24 hours at a temperature ranged between 0 °C and 50 °C (see for example: Bosch, Liu is et al, Tetrahedron Letters, 2011 , vol. 52, # 7, p. 753 - 756).
  • a deprotonating agent such as LiHMDS
  • THF a suitable solvent
  • argon argon
  • Scheme 2 illustrates a preferred synthetic approach to compounds of the general Formula (lb) in which X 2 is defined as CH, Y is defined as being -N(R N1 )-W C0V1 -R C0V1 , W is defined as being -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R 1 , R 2 and R 3 , and the right side of W, as defined herein, attached to the ring system shown in Formula (lb), and all the other variables are defined according to compound of Formula (I)
  • a compound of formula 11 in which X 1 , X 3 , X 4 , X 5 and X 6 are as defined for the compound of formula (I) is reacted with benzyl mercaptan to give a compound of formula 12.
  • This coupling reaction can be carried out by a palladium-catalyzed C-S cross-coupling reaction (see for example: Jiang, Buchwald in ‘Metal-Catalyzed Cross-Coupling Reactions’, 2 nd edition.: de Meijere, Diederich, Eds.: Wiley- VCH: Weinheim, Germany, 2004).
  • the reactions are preferably run under an atmosphere of argon for 1 - 48 hours at 80 - 100°C in a microwave oven or in an oil bath.
  • a compound of formula 12 in which X 1 , X 3 , X 4 , X 5 and X 6 are as defined for the compound of formula (I) is reacted with a chlorinating reagent to give a sulfonyl chloride of formula 13.
  • This sulfonyl chloride formation can be carried out by treatment with W-chlorosuccinimide (NCS), sulfonyl chloride, 1 ,3-dichloro-5,5-dimethylhydantoin (DCDMH), Ch etc., in MeCN with equivalent acetic acid and water, (see for example: Sutton et al, WO 2021/055744).
  • PCS W-chlorosuccinimide
  • DCDMH 1 ,3-dichloro-5,5-dimethylhydantoin
  • Ch etc. in MeCN with equivalent acetic acid and water, (see for example: Sutton et al, WO 2021/055744
  • a compound of formula 13 in which X 1 , X 3 , X 4 , X 5 and X 6 are as defined for the compound of Formula (I) is reacted with an amine of formula 2 in which R 1 , R 2 , R 3 are defined as for compound of Formula (I) to give a compound of formula 14 in which W is -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R 1 , R 2 and R 3 , and the right side of W, as defined herein, attached to the ring system shown in compound of formula 14.
  • This reaction can be carried out under basic conditions (see for example: Guo et al, WO2013/006394). Preferred is the herein described use of trimethylamine, pyridine etc., in DCM, THF or DMF.
  • the reactions are preferably run under an atmosphere of argon for 0.5 - 24 hours from 0 °C to room temperature.
  • This reaction can be carried out by Buchwald coupling with Tert-Butylcarbamate (NH2B0C) or benzophenone imine (HNCPI12), followed by cleavage of the protecting groups (see for example: Xiang, Zheng et al, Journal of Organic Chemistry, 2011 , vol. 76, # 15, p. 6367 - 6371).
  • Preferred Buchwald coupling condition is the herein described use of NH2B0C, Xantphos, Pd2(dba)3 in dioxane.
  • the reactions are preferably run under an atmosphere of argon for 0.5 - 24 hours from 80 °C to 120 °C in a microwave oven or in an oil bath.
  • Preferred protecting group cleavage conditions are the herein described use of HCI/dioxane, TFA/DCM, ect.
  • the reactions are preferably run under an atmosphere of argon for 0.5 - 24 hours at 0 °C to room temperature.
  • a compound of formula 15 in which X 1 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 and R 3 are as defined for the compound of formula (I) and W is -NHS(O)2- as defined in step 3, is reacted with a compound of formula 8 in which R N1 is C1-4 alkyl and LG1 is a leaving group such as CI-, Br-, I-, MsO- or aldehyde to give a compound of formula 16.
  • the alkylation is preferably carried out in basic conditions using preferentially deprotonating agents or bases such as NaH, K2CO3 or CS2CO3 etc.in suitable solvents such as for example DCM, DMF or THF (see for example: Sankaranarayananv et al, US2004106802), under an atmosphere of argon for 3-24 hours at a temperature ranged between 0 °C to 80 °C.
  • suitable solvents such as for example DCM, DMF or THF (see for example: Sankaranarayananv et al, US2004106802)
  • this reaction is preferably carried out in the presence of a suitable reducing agent such as for example sodium cyanoborohydride or sodium triacetoxyborohydride, in the presence of acetic acid (cat.), molecular sieve, in a suitable solvent such as MeOH, DCE, /-PrOH ect, preferably under an atmosphere of argon for 12-24 hours at room temperature to 80 °C (see for example: Ong et al, US2013203686).
  • a suitable reducing agent such as for example sodium cyanoborohydride or sodium triacetoxyborohydride
  • acetic acid cat.
  • a suitable solvent such as MeOH, DCE, /-PrOH ect
  • this amidation reaction is preferably carried in the presence of a suitable base such as for example triethylamine, pyridine, di-iso- propylethylamine etc, in the presence of a suitable condensating agent such as HATU, EDCI/HOBt, T3P, CDI etc. in a suitable solvent such as for example DCM or DMF, preferably under an atmosphere of argon for 2 - 24 hours at room temperature (see for example: Blake et WO2020/131674).
  • a suitable base such as for example triethylamine, pyridine, di-iso- propylethylamine etc
  • a suitable condensating agent such as HATU, EDCI/HOBt, T3P, CDI etc.
  • a suitable solvent such as for example DCM or DMF
  • the reaction can be performed in the presence of a deprotonating agent such as LiHMDS in a suitable solvent such as THF under an atmosphere of argon for 0.5-24 hours at a temperature ranged between 0 °C and 50 °C (see for example: Bosch, Lluis et al, Tetrahedron Letters, 2011 , vol. 52, # 7, p. 753 - 756).
  • a deprotonating agent such as LiHMDS
  • THF a suitable solvent
  • argon argon
  • Scheme 3 illustrates a preferred synthetic approach to compounds of the general Formula (le) in which X2 is defined as being C-Yc2-Rc2, X 4 as being N, X 6 as being C-R x , wherein R x is selected from C1- 5 alkyl, X 5 as being CH, Y is defined as being -N(R N1 )-W C0V1 -R C0V1 , W is defined as being -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R 1 , R 2 and R 3 , and the right side of W, as defined herein, attached to the ring system shown in Formula (le), and all the other variables are defined according to compound of Formula (I)
  • the methyl group in a compound of formula 22 in which X 1 , X 3 are defined as for the compound of Formula (I) is converted to aldehyde moiety.
  • This reaction can be carried out in the presence of DMF-DMA, followed by treatment with sodium periodate (NalO4) (see for example: Vetelino, Michael G. et al, Tetrahedron Letters, 1994, vol. 35, # 2, p. 219 - 222), or in the presence of azobisisobutyronitrile (AIBN), N-bromosuccinimide (NBS), followed by treatment with N- methylmorpholine-N-oxide (NMO) (see for example: Wallace, Debra J.
  • the nitro (NO2) moiety in a compound of formula 23 in which X 1 , X 3 are defined as for the compound of Formula (I) is converted to an amino (NH2) group.
  • This reduction can be carried out in the presence of Fe and NH4CI in EtOH - (see for example: Altevogt, Luca et al, Synlett, 2020, vol. 31 , # 12, p. 1177 - 1181), Preferred is the herein described use of Fe powder and NH4CI in EtOH.
  • the reactions are preferably run under an atmosphere of nitrogen for 0.5 - 24 hours at 50 °C to 100 °C.
  • a compound of formula 24 in which X 1 , X 3 are defined as for the compound of Formula (I) is reacted with an alkyl cyanide R-CN to give a compound of formula 25 in which X 6 is defined as being C-R x , wherein R x is selected from C1.5 alkyl and X 5 is defined as being CH.
  • the reaction are carried out in the presence of a suitable alkyl cyanide, in the presence of a suitable base such as potassium tert-butylate, f-BuOK in a suitable solvent such as DMSO preferably under an atmosphere of nitrogen for 0.5 - 24 hours at 0 °C to 50 °C. (see for example: Beesu, Mallesh et al, Journal of Medicinal Chemistry, 2015, vol. 58, # 19, p. 7833 - 7849).
  • a compound of formula 25 in which X 1 , X 3 , X 5 and X 6 are defined as in the third step is reacted with benzyl mercaptan to give a compound of formula 26.
  • This nucleophilic aromatic substitution reaction is carried out in the presence benzyl mercaptan, optionally in the presence of a suitable base such as for example cesium carbonate in a suitable solvent such as for example DMF.
  • the reaction is preferably run under an atmosphere of argon for 1 - 48 hours at 50 - 100°C in a microwave oven or in an oil bath (see for example: Diane Harris Boschelli et al, US2003/212276, 2003, A1).
  • amino (NH2) group in a compound of formula 26 in which X 1 , X 3 , X 5 and X 6 are defined are defined as in the fourth step is protected by a suitable protecting group PG2 such as for example Boc, Cbz ...
  • PG2 such as for example Boc, Cbz ...
  • This protection can be carried out for example in the presence of di-tert-butyl- dicarbonate (BOC2O), in presence of 4-dimethylaminopyridine (DMAP), in the presence of a suitable base such as diisopropylamine (DIPEA), in a suitable solvent such as dichloromethane (DCM).
  • the reaction is preferably run under an atmosphere of argon for 1 - 48 hours at 0 - 50°C (see for example: Abengozar, Alberto et al, European Journal of Organic Chemistry, 2015, vol. 2015, # 19, p. 4214 - 4223).
  • a compound of formula 27 in which X 1 , X 3 , X 5 ,X 6 and PG2are defined are defined as in the fifth step reacts with a chlorinating reagent to give a sulfonyl chloride of formula 28.
  • This sulfonyl chloride formation can be carried out by treatment with NCS, sulfonyl chloride, DCDMH, CI2 etc., in MeCN with 1 to 5 equivalent (s) of acetic acid and water, (see for example: Sutton et al, WO 2021/055744).
  • DCDMH as chlorinating reagent.
  • a compound of formula 28 in which X 1 , X 3 , X 5 ,X 6 and PG2 are defined are defined as in the sixth step reacts with an amine of formula 2 in which R 1 , R 2 and R 3 are as defined for the compound of Formula (I) to give a compound of formula 9 in which W is defined as being -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R 1 , R 2 and R 3 , and the right side of W, as defined herein, attached to the ring system shown in compound of formula 29.
  • the reaction can be carried out under basic conditions (see for example: Sutton et al, WO 2021/055744). Preferred is the herein described use of trimethylamine, pyridine etc., in DCM, THF or DMF.
  • the reactions are preferably run under an atmosphere of argon for 0.5-24 hours at 0°C to room temperature.
  • a compound of formula 29 in which X 1 , X 3 , X 5 ,X 6 , W and PG2 are defined are defined as in the seventh step, R 1 , R 2 and R 3 are as defined for the compound of Formula (I) is coupled with various chemical moieties such as non-aromatic hetorocycles, hetaryl... to give a compound of formula 30 in which X 2 is restricted C-Yc2-Rc2 defined as for the compound of Formula (I).
  • This coupling reaction can be carried out by a palladium-catalyzed cross-coupling reaction (see for example: a) Jiang, Buchwald in ‘Metal-Catalyzed CrossCoupling Reactions’, 2nd edition.: de Meijere, Diederich, Eds.: Wiley- VCH: Weinheim, Germany, 2004; b) Sutton et al, WO 2021/055744).
  • a carbon -nitrogen coupling preferred is the herein described use of cesium carbonate and Pd-PEPPSI-IPentCI o-picoline in dioxane.
  • the reactions are preferably run under an atmosphere of argon for 1-48 hours at 80-120°C in a microwave oven or in an oil bath.
  • the protecting group PG2 in a compound of formula 30 in which X 1 , X 3 , X 5 ,X 6 , W and PG2 are defined are defined as in the eighth step, R 1 , R 2 and R 3 are as defined for the compound of Formula (I) is cleaved to give an amino (NH2) group.
  • This deprotection can be carried out under acidic conditions (see for example: Yamazaki, Yukari et al, Chemistry Letters, 2020, vol. 49, # 2, p. 133 - 136).
  • the reactions are preferably run under an atmosphere of argon for 0.5-24 hours at room temperature to the boiling point of the solvent.
  • Scheme 4 illustrates a preferred synthetic approach to compounds of the general Formula (Ig) in which X 2 is defined as being CH, X 4 is defined as being N, Y is defined as being N(R N1 )-W COV1 -RCOV1 , W is defined as being -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R 1 , R 2 and R 3 , and the right side of W, as defined herein, attached to the ring system shown in Formula (Ig), and all the other variables are defined according to compound of Formula (I).
  • This reaction can be carried out by Buchwald coupling with Tert-Butylcarbamate (NH2B0C) or benzophenone imine (HNCPh2), followed by cleavage of the protecting groups (see for example: Xiang, Zheng et al, Journal of Organic Chemistry, 2011 , vol. 76, # 15, p. 6367 - 6371).
  • Preferred Buchwald coupling condition is the herein described use of NH2B0C, Xantphos, Pd2(dba)s in dioxane.
  • the reactions are preferably run under an atmosphere of argon for 0.5 - 24 hours from 80 °C to 120 °C in a microwave oven or in an oil bath.
  • Preferred protecting group cleavage conditions are the herein described use of HCI/dioxane, TFA/DCM, ect.
  • the reactions are preferably run under an atmosphere of argon for 0.5 - 24 hours at 0 °C to room temperature.
  • the strategy for converting a compound of formula 36 to a compound of Formula (Ig) is similar as the final step of Scheme 1 or Scheme 2.
  • Scheme 5 illustrates a preferred synthetic approach to compounds of the general Formula (Ih) in which X2 is defined as being C-Yc2-Rc2, X 5 is defined as being N, Y is defined as being -N(R N1 )-W COV1 - Rcov ⁇ w is defined as being -NHS(O)2- with preferably as understood herein, the leftside of W, as defined herein, attached to the carbon atom that carries R 1 , R 2 and R 3 , and the right side of W, as defined herein, attached to the ring system shown in Formula (Ih), and all the other variables are defined according to compound of Formula (I)
  • an amino (NH2) group in a compound of formula 37 in which X 1 , X 3 , X 4 and X 6 are defined as for the compound of Formula (I) is protected by a protecting group PG2 such as Boc, Cbz ...
  • PG2 such as Boc, Cbz ...
  • This protection can be carried out for example in the presence of di-tert-butyl-dicarbonate (BOC2O), in presence of 4-dimethylaminopyridine (DMAP), in the presence of a suitable base such as diisopropylamine (DIPEA), in a suitable solvent such as dichloromethane (DCM).
  • the reaction is preferably run under an atmosphere of argon for 1 - 48 hours at 0 - 50°C (see for example: Abengbzar, Alberto et al, European Journal of Organic Chemistry, 2015, vol. 2015, # 19, p. 4214 - 4223).
  • a compound of formula 38 in which X 1 , X 3 , X 4 and X 6 are defined as for the compound of Formula (I) and in which PG2 is defined in step 1 is reacted with benzyl mercaptan to give a compound of formula 39.
  • This coupling reaction can be carried out by a palladium-catalyzed C-S crosscoupling reaction (see for example: Jiang, Buchwald in ‘Metal-Catalyzed Cross-Coupling Reactions’, 2 nd edition.: de Meijere, Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004).
  • the reactions are preferably run under an atmosphere of argon for 1 - 48 hours at 80 - 100°C in a microwave oven or in an oil bath.
  • a compound of formula 39 in which X 1 , X 3 , X 4 and X 6 are as defined for the compound of formula (I), and in which PG2 is defined in step 1 is reacted with q chlorinating reagent to give a sulfonyl chloride compound of formula 40.
  • This sulfonyl chloride formation can be carried out by treatment with W-chlorosuccinimide (NCS), sulfonyl chloride, 1 ,3-dichloro-5,5-dimethylhydantoin (DCDMH), CI2 etc., in MeCN with equivalent acetic acid and water, (see for example: Sutton et al, WO 2021/055744).
  • This deprotection can be carried out under acidic conditions (see for example: Yamazaki, Yukari et al, Chemistry Letters, 2020, vol. 49, # 2, p. 133 - 136).
  • the reactions are preferably run under an atmosphere of argon for 0.5-24 hours at room temperature to the boiling point of the solvent.
  • Scheme 6 illustrates a preferred synthetic approach to compounds of the general Formula (li) in which X 2 is defined as being CH, X 5 is defined as being N, Y is defined as being -N(R N1 )-W C0V1 -R C0V1
  • W is defined as being -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R 1 , R 2 and R 3 , and the right side of W, as defined herein, attached to the ring system shown in Formula (li), and all the other variables are defined according to compound of Formula (I).
  • the reactions are preferably run under an atmosphere of argon for 1 - 48 hours at 80 - 100°C in a microwave oven or in an oil bath.
  • This sulfonyl chloride formation can be carried out by treatment with NCS, sulfonyl chloride, DCDMH, CI2 etc., in MeCN with 1 to 5 equivalent (s) of acetic acid and water (see for example: Sutton et al, WO 2021/055744).
  • Preferred chlorinating reagent is the herein described use of DCDMH.
  • the reactions are preferably run under an atmosphere of argon for 0.5 - 5 hours at 0 °C to room temperature.
  • This reaction can be carried out under basic conditions (see for example: Sutton et al, WO 2021/055744). Preferred is the herein described use of trimethylamine, pyridine etc., in DCM, THF or DMF.
  • the reactions are preferably run under an atmosphere of argon for 0.5-24 hours at 0°C to room temperature.
  • This reaction can be carried out by Buchwald coupling with Tert-Butylcarbamate (NH2B0C) or benzophenone imine (HNCPI12), followed by cleavage of the protecting groups (see for example: Xiang, Zheng et al, Journal of Organic Chemistry, 2011 , vol. 76, # 15, p. 6367 - 6371).
  • Preferred Buchwald coupling condition is the herein described use of NH2B0C, Xantphos, Pd2(dba)s in dioxane.
  • the reactions are preferably run under an atmosphere of argon for 0.5 - 24 hours from 80 °C to 120 °C in a microwave oven or in an oil bath.
  • Preferred protecting group cleavage conditions are the herein described use of HCI/dioxane, TFA/DCM, ect.
  • the reactions are preferably run under an atmosphere of argon for 0.5 - 24 hours at 0 °C to room temperature.
  • the compounds described in this section are defined by their chemical formulae and their corresponding chemical names.
  • the present invention relates to both the compound defined by the chemical formula and the compound defined by the chemical name, and particularly relates to the compound defined by the chemical formula.
  • Method 1 SHIMADZU LCMS-2020 Kinetex EVO C182.1X30 mm, 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 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 3 Agilent 1200 ⁇ G6110A Kinetex EVO C18 2.1X30 mm, 5 m 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 1.5.0 mL/min; eluted with the mobile phase over 0.80 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; 0.80-1 .20 min, held at 5% A-95% B; 1.20-1 .21 min, returned to 95% A-5% B, 1.21-1.50 min, held at 95% A-5% B.
  • Method 6 SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X30 mm 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 1.00 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; 0.60-0.78 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 8 SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X30mm,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 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 11 SHIMADZU LCMS-2020 Shim-pack Scepter C18-1202.1 x33 mm, 5 pm at40°C; Mobile Phase: A: 10 mM NH ⁇ HCOa in water; B: Acetonitrile; flow rate held at 1.7 mL/min; eluted with the mobile phase over 1.00 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-0.70 min, ramped from 95% A-5% B to 5% A-95% B; 0.70-0.90 min, held at 5% A-95% B; 0.90-0.91 min, returned to 95% A-5% B, 0.91-1.00 min, held at 95% A-5% B.
  • Method 12 SHIMADZU LCMS-2020 Kinetex® EVO C183.0x50mm, 2.6 pm at 50°C; Mobile Phase: A: 0.04% TFA in water (v/v); B: 0.02% TFA in Acetonitrile (v/v); flow rate held at 0.9 mL/min; eluted with the mobile phase over 4.00 min employing UV detection at 220 nm and 254 nm. Gradient information: 0- 3.40 min, ramped from 95% A-5% B to 5% A-95% B; 3.40-3.70 min, held at 5% A-95% B; 3.70-3.71 min, returned to 95% A-5% B, 3.71-4.00 min, held at 95% A-5% B.
  • 1 H NMR spectra were acquired on a Bruker Avance III 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).
  • 6-(benzylthio)-3-chloroisoquinoline To a solution of 6-bromo-3-chloroisoquinoline (1 g, 4.12 mmol) in dioxane (10 mL) was added phenylmethanethiol (563.40 mg, 4.54 mmol), Xantphos (477.21 mg, 824.74 pmol), Pd2(dba)s (377.62 mg, 412.37 mol) and DIPEA (1 .07 g, 8.25 mmol). The mixture was degassed, purged with N2 (3x) andstirred at 90°C for 2 h under N2. The resulting mixture was filtered and the filtrate was concentrated under vacuum.
  • Example 4 4-(6-(bicyclo[1 .1 .0]butane-1 -carboxamido)-3-(N-(1 -methylcyclopropyl)sulfamoyl)naphthalen-1 -yl)- N,N-dimethylpiperazine-1-carboxamide
  • reaction mixture was warmed slowly to 20°C then, stirred at 20 °C for 1 h under N2, quenched with NH4CI (aq., sat., 5 mL) and extracted with EtOAc (5 mL, 2x). The combined organic layer was washed with water (3 mL; 3x), dried over anhydrous Na2SO4 and concentrated under vacuum.
  • reaction mixture was warmed slowly to 20°C then, stirred at 20 °C for 1 h under N2;, quenched with NH4CI (aq., sat., 5 mL) and extracted with EtOAc (5 mL, 2x). The combined organic layer was washed with water (3 mL; 3x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum.
  • the aqueous layer was extracted with ethyl acetate (10 mL, 2x). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum.
  • the impure residue was further purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 pm; mobile phase: A: 0.225% formic acid in water,, B: MeCN; B%: 23%- 53%, 10 min) and lyophilized directly to give the product N-(7-(N-(1 -methylcyclopropyl)sulfamoyl)quinolin- 2-yl)acrylamide formate (4.46 mg, 11.70 pmol, 1.16% yield, 99% purity, FA salt) as a white solid.
  • reaction mixture was degassed under vacuum, purged with N2 (3x) and stirred at 100 °C for 1 h under N2.
  • the mixture was then cooled to room temperature, diluted with H2O (10 mL) and extracted with EtOAc (10 mL, 2x). The combined organic layer was washed with brine (2 mL, 3x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum.
  • reaction mixture was stirred at 0 °C for 1 h, then quenched with aqeous NH4CI (sat., 5 mL) and extracted with ethyl acetate (10 mL; 3x). The combined organic layer was washed with brine (2 mL; 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum.

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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 présents composés sont particulièrement utiles en tant qu'inhibiteurs de PARC, et peuvent être utilisés dans une méthode de traitement d'un désordre prolifératif, de préférence du cancer.
PCT/EP2024/074505 2023-09-01 2024-09-02 Nouveaux inhibiteurs de parg Pending WO2025046148A1 (fr)

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