WO2023175185A1 - 2,4-dioxo-1,4-dihydroquinazoline derivatives as parg inhibitors for the treatment of cancer - Google Patents

2,4-dioxo-1,4-dihydroquinazoline derivatives as parg inhibitors for the treatment of cancer Download PDF

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WO2023175185A1
WO2023175185A1 PCT/EP2023/056969 EP2023056969W WO2023175185A1 WO 2023175185 A1 WO2023175185 A1 WO 2023175185A1 EP 2023056969 W EP2023056969 W EP 2023056969W WO 2023175185 A1 WO2023175185 A1 WO 2023175185A1
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alkyl
alkylene
heterocycloalkyl
heteroaryl
aryl
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PCT/EP2023/056969
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French (fr)
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Ulrich LÜCKING
Andreas Goutopoulos
Zaixu Xu
Sotirios Sotiriou
Luca IACOVINO
Alena FREUDENMANN
Olivier Querolle
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Forx Therapeutics Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C07D239/96—Two oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt or a prodrug 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, preferably as covalent 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
  • the present invention provides a compound of formula (I): or a pharmaceutically acceptable salt thereof.
  • compound of formula (I) preferably encompasses also an enantiomer, diastereoisomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystal form, pharmaceutically acceptable salt or a prodrug thereof.
  • 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 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 C2-4 alkenyl.
  • alkynyl refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds.
  • C2-5 alkynyl denotes an alkynyl group having 2 to 5 carbon atoms.
  • Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl.
  • alkynyl preferably refers to C2-4 alkynyl.
  • alkylene refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group which may be linear or branched.
  • a “C1-5 alkylene” denotes an alkylene group having 1 to 5 carbon atoms, and the term “C0-3 alkylene” indicates that a covalent bond (corresponding to the option “Co alkylene”) or a C1-3 alkylene is present.
  • Preferred exemplary alkylene groups are methylene (- CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH 3 )-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH 2 -CH 3 )-, -CH2- CH(-CH3)-, or -CH(-CH3)-CH2-), or butylene (e.g., -CH2-CH2-CH2-CH2-).
  • alkylene preferably refers to C1-4 alkylene (including, in particular, linear C1-4 alkylene), more preferably to methylene or ethylene, and even more preferably to methylene.
  • alkenylene refers to an alkenediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond.
  • a “C2- 5 alkenylene” denotes an alkenylene group having 2 to 5 carbon atoms.
  • alkenylene preferably refers to C2-4 alkenylene (including, in particular, linear C2-4 alkenylene).
  • alkynylene refers to an alkynediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds.
  • a “C2-5 alkynylene” denotes an alkynylene group having 2 to 5 carbon atoms.
  • alkynylene preferably refers to C2-4 alkynylene (including, in particular, linear C2-4 alkynylene).
  • carbocyclyl refers to a hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic.
  • “carbocyclyl” preferably refers to aryl, cycloalkyl or cycloalkenyl.
  • heterocyclyl refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic.
  • each heteroatom-containing ring comprised in said ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring.
  • heterocyclyl preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl.
  • aryl refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic).
  • Aryl may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1 ,2-dihydronaphthyl), tetralinyl (i.e., 1 ,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1 H-indenyl), anthracenyl, phenanthrenyl, 9H- fluorenyl, or azulenyl.
  • an “aryl” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.
  • arylene refers to an aryl group, as defined herein above, but having two points of attachment, i.e. a divalent aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic).
  • “Arylene” may, e.g., refer to phenylene (e.g., phen-1 ,2-diyl, phen-1 , 3-diyl, or phen-1 ,4-diyl), naphthylene (e.g., naphthalen-1 ,2-diyl, naphthalen-1 ,3-diyl, naphthalen-1 ,4-diyl, naphthalen-1 ,5-diyl, naphthalen-1 ,6- diyl, naphthalen-1 , 7-diyl, naphthalen-2, 3-diyl, naphthalen-2, 5-diyl, naphthalen-2, 6-diyl, naphthalen-2, 7- diyl, or naphthalen-2, 8-diyl), 1 ,2-dihydronaphthylene, 1 ,2,3,4-tetrahydronaph
  • 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 may, e.g., refer to cyclopropylene (e.g., cyclopropan-1 ,1 -diyl or cyclopropan-1 ,2-diyl), cyclobutylene (e.g., cyclobutan-1, 1 -diyl, cyclobutan-1 ,2-diyl, or cyclobutan-1 ,3-diyl), cyclopentylene (e.g., cyclopentan-1,1 -diyl, cyclopentan-1 , 2-diyl, or cyclopentan-1 , 3-diyl), cyclohexylene (e.g., cyclohexan-1 ,1-diyl, cyclohexan-1 , 2-diyl, cyclohexan-1 , 3-diyl, or cyclohexan-1 ,4-diyl), cycloheptylene
  • cycloalkylene preferably refers to a C3-11 cycloalkylene, and more preferably refers to a C3-7 cycloalkylene.
  • a particularly preferred “cycloalkylene” is a divalent monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g., cyclopropylene or cyclohexylene).
  • heterocycloalkyl refers to a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group).
  • 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
  • A/-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.
  • heterocycloalkylene refers to a heterocycloalkyl group, as defined herein above, but having two points of attachment, i.e. a divalent saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo
  • each heteroatom-containing ring comprised in said saturated ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring.
  • Heterocycloalkylene may, e.g., refer to aziridinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, piperazinylene, azepanylene, diazepanylene (e.g., 1 ,4-diazepanylene), oxazolidinylene, isoxazolidinylene, thiazolidinylene, isothiazolidinylene, morpholinylene, thiomorpholinylene, oxazepanylene, oxiranylene, oxetanylene, tetrahydrofuranylene, 1 ,3-dioxolanylene, tetrahydropyranylene, 1 ,4-dioxanylene, oxepanylene, thiiranylene, thietanylene, tetrahydrothiophenylene (
  • heterocycloalkylene preferably refers to a divalent 3 to 11 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, “heterocycloalkylene” refers to a divalent 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N
  • 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.
  • 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, oc
  • 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
  • halogen refers to fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-I).
  • haloalky I 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 2 , -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 “bond” and “covalent bond” are used herein synonymously, unless explicitly indicated otherwise or contradicted by context.
  • 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.
  • R oov is selected from C2 alkenyl, C2 alkynyl, -CH2CI, -CH2CN, and wherein said alkenyl is optionally substituted with one or more optional substituents selected from C1-4 alkyl, -COO-(Ci-4 alkyl), -CO-(Ci-4 alkyl), -CONH-(CI-4 alkyl), -OOC-(Ci-4 alkyl), -NHCO-(CI-4 alkyl), -(C1-4 alkylene)N(Ci-4 alkyl)(Ci-4 alkyl), -(C1-4 alkylene)-(/V-heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, said alkynyl is optionally substituted with an optional substituent selected from C1-4 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroary
  • Suitable cycloalkyl group is for example a cyclopropyl group.
  • Suitable aryl group is for example a phenyl group.
  • R cov is selected from C2 alkenyl, C2 alkynyl, -CH2Cl, -CH2CN, and wherein said alkenyl is optionally substituted with one or more optional substituents selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -OOC-(C1-4 alkyl), -NHCO-(C1-4 alkyl), -(C1-4 alkylene)N(C1-4 alkyl)(C1-4 alkyl), -(C1-4 alkylene)-(N-heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, preferably selected from C1-4 alky
  • R cov is selected from C2 alkenyl, C2 alkynyl, and -CH2Cl, wherein said alkenyl is optionally substituted with one or more optional substituents selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -OOC-(C1-4 alkyl), -NHCO-(C1-4 alkyl), -(C1-4 alkylene)N(C1-4 alkyl)(C1-4 alkyl), -(C1-4 alkylene)-(N-heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF 3 , preferably selected from C 1-4 alkyl, -COO-(C 1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -(C1-4
  • R cov is selected from C 2 alkenyl, and -CH 2 Cl, wherein said alkenyl is optionally substituted with one or more optional substituents selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -OOC-(C1-4 alkyl), -NHCO-(C1-4 alkyl), -(C1-4 alkylene)N(C1-4 alkyl)(C1-4 alkyl), -(C1-4 alkylene)-(N-heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, preferably selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -(C1-4 alkylene)N(C1-4 alkyl)(
  • R cov is C2 alkenyl, wherein said alkenyl is optionally substituted with one or more optional substituents selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -OOC-(C1-4 alkyl), -NHCO-(C1-4 alkyl), -(C1-4 alkylene)N(C1-4 alkyl)(C1-4 alkyl), -(C1-4 alkylene)-(N- heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, preferably selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -(C1-4 alkylene)N(C1-4 alkyl)(C1-4 alkyl), -(C
  • R cov is C2 alkenyl.
  • -W cov - is selected from -CO- and -SO2-. More preferably, -W cov - is -CO-.
  • -RN- is: - heterocycloalkylene comprising an N atom, wherein W cov is connected to RN through said N atom and wherein said heterocycloalkylene is optionally substituted with one or more optional substituents selected from -Hal, -(C0-2 alkylene)-CN, C1-2 alkyl and C1-2 haloalkyl; - -(C1-2 alkylene)-heterocycloalkylene, wherein said heterocycloalkylene comprises an N atom, wherein W cov is connected to RN through said N atom and wherein said heterocycloalkylene is optionally substituted with one or more optional substituents selected from -Hal, -(C0-2 alkylene)-CN, C1-2 alkyl
  • -RN- is heterocycloalkylene comprising an N atom, wherein W cov is connected to RN through said N atom and wherein said heterocycloalkylene is optionally substituted with one or more optional substituents selected from -Hal, -(C0-2 alkylene)-CN, C1-2 alkyl and C1-2 haloalkyl.
  • RN is selected from:
  • R 1 is hydrogen, chloro, fluoro, -CN, formyl, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-O-(C1-2 alkyl) (preferably R 1 is chloro, fluoro, -CN, formyl, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-O-(C1-2 alkyl)); and R 2 and R 3 are independently each C1-2 alkyl or C1-2 haloalkyl, or R2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more -F; or -CR 1 R 2 R 3 is bicyclo[1,1,1
  • R 1 is hydrogen, chloro, fluoro, -CN, formyl, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-O-(C1-2 alkyl) (preferably R 1 is chloro, fluoro, -CN, formyl, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-O-(C1-2 alkyl)); and R 2 and R 3 are independently each C1-2 alkyl or C1-2 haloalkyl, or R2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more -F.
  • R 1 is hydrogen, chloro, fluoro, -CN, formyl, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-O-(C1-2 alkyl) (preferably R 1 is chloro, fluoro, -CN, formyl, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-O-(C1-2 alkyl)); and R2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more -F.
  • R 1 is preferably -CN, methyl, fluoromethyl, difluoromethyl or trifluoromethyl, more preferably R 1 is methyl or fluoromethyl.
  • R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more -F.
  • W is selected from -NHS(O)y-, -S(O)yNH-, -NHS(O)(NH)-, -NHS(O)(N-C1-2 alkyl)-, -S(O)(NH)-NH- , -S(O)(N-C1-2 alkyl)-NH-, wherein y is 1 or 2.
  • y is 2.
  • W is selected from -NHS(O)2-, -S(O)2NH-, -NHS(O)(NH)-, and -S(O)(NH)-NH-. More preferably, W is selected from -NHS(O)2-, and -S(O)2NH-, even more preferably W is -NHS(O)2-.
  • W is selected from -NHS(O)2-, and -S(O)2NH-, even more preferably W is -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).
  • X1 and X3 are independently selected from the group consisting of N, CH, C(C1-2 alkyl), C-Cl and CF, preferably independently selected from the group consisting of N, CH and CF.
  • X1 is CF or CH and X3 is CH, more preferably X1 and X3 are each CH.
  • X2 is N or C-YC2-RC2, wherein 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(C1-5 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 ; and wherein R C2 is selected from hydrogen, halo, -OH, -NH2, -SH,
  • YC2 is selected from a covalent bond, -(C1-3 alkylene)-, -CO-(C1-3 alkylene)-, (C1-3 alkylene)-CO-, -CONH-(C1-3 alkylene)-, -(C1-3 alkylene)-CONH-, -NHCO-(C1-3 alkylene)-, -(C1-3 alkylene)- NHCO-, -NH-(C1-3 alkylene)-, -(C1-3 alkylene)-NH-, -N(C1-5 alkyl)-, -O-(C1-3 alkylene)-, -(C1-3 alkylene)-O- , -SO2-(C1-3 alkylene)-, -(C1-3 alkylene)-SO2-, -CONH-, -NHCO-, -NH-, -O-, -CO- and -SO2-, wherein said alkylene, said alkenylene and said alkynylene are each optional
  • C1-3 alkylene is herein preferably a -CH2- group.
  • RC2 is selected from hydrogen, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from R S2 .
  • RC2 is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in X 2 are each optionally substituted with one or more groups independently selected from R S2 .
  • RC2 is selected from heterocycloalkyl, aryl, and heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in X 2 are each 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(C1-5 alkyl)-C1-12 alkyl, -O-C2-12 alkenyl, -NH-C2-12 alkenyl, -N(C1-5 alkyl)-C2-12 alkenyl, -O-C2-12 alkynyl, - NH-C2-12 alkynyl, -N(C1-5 alkyl)-C2-12 alkynyl, -(C0-3 alkylene)-cycloalkyl, -CO-(C0-3 alkylene)-cycloalkyl, - (C0-3 alkylene)-CO-cycloalkyl, -CONH-(C0-3 alkylene)-cycloalkyl, (C0-3 alkylene)-CONH-cycloalkyl,
  • -YC2-RC2 is selected from -(C0-3 alkylene)-heterocycloalkyl, -CO-(C0-3 alkylene)heterocycloalkyl, -(C 0-3 alkylene)-CO-heterocycloalkyl, -CONH-(C 0-3 alkylene)heterocycloalkyl, - (C0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(C0-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)-NHCO- heterocycloalkyl, -NH-(C0-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)-NH-heterocycloalkyl, -O-(C0-3 alkylene) heterocycloalkyl, (C0-3 alkylene)-O-cycloalkyl, -SO2-(C0-3 alkylene)
  • -YC2-RC2 is selected from -(C0-3 alkylene)-heterocycloalkyl, -CONH- heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO- heterocycloalkyl, -SO2-heterocycloalkyl, -(C0-3 alkylene)aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO2-aryl, -(C0-3 alkylene)heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O- heteroaryl, -CO-heteroaryl and -SO2-heteroaryl, wherein said alkylene is optionally substituted
  • -YC2-RC2 is selected from -(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)aryl, and -(C0-3 alkylene)heteroaryl, wherein said heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from R S2. .
  • -YC2-RC2 is selected from heterocycloalkyl, aryl, and heteroaryl wherein said heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from R S2 .
  • -YC2-RC2 is selected from heterocycloalkyl and heteroaryl, wherein said heterocycloalkyl, and heteroaryl are each optionally substituted with one or more groups independently selected from R S2 . Even more preferably, -YC2-RC2 is heterocycloalkyl wherein said heterocycloalkyl is optionally substituted with one or more groups independently selected from R S2 .
  • the moiety represented with a partial formula is a moiety selected from wherein: R 7 is hydrogen, -CN, -Hal, or a moiety of the formula: wherein: L 71 is a bond or C1-5 alkylene optionally substituted with halo or oxo; L 72 is a bond, -O-, -S-, -SO-, -SO 2 -, -NH-, -N(C 1-6 alkyl)-, -CO-, -COO-, -OCO-, -CONH-, -CON(C 1- 6 alkyl)-, -NHCO-, N(C1-6 alkyl)CO-, -NHCONH-, -N(C1-6 alkyl)CONH-, -NHCON(C1-6 alkyl)-, N(C1-6 alkyl)CON(C1-6 alkyl)-, -SO2NH-, -SO2N(C1-6 alkyl)-, -NHSO
  • R 7 is a moiety of the formula: wherein: L 71 is a bond or C1-5 alkylene optionally substituted with halo or oxo; L 72 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, -N(C1-6 alkyl)-, -CO-, -COO-, -OCO-, -CONH-, -CON(C1- 6 alkyl)-, -NHCO-, N(C1-6 alkyl)CO-, -NHCONH-, -N(C1-6 alkyl)CONH-, -NHCON(C1-6 alkyl)-, N(C1-6 alkyl)CON(C1-6 alkyl)-, -SO2NH-, -SO2N(C1-6 alkyl)-, -NHSO2-, or -N(C1-6 alkyl)SO2-, and Q 7 is hydrogen, C1-6 alkyl, C2-6 alkeny
  • L 71 is a bond.
  • L 72 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, -N(C1-6 alkyl)-, -CO-, -COO-, -OCO-, -CONH- , -CON(C1-6 alkyl)-, -NHCO-, N(C1-6 alkyl)CO-, -NHCONH-, -N(C1-6 alkyl)CONH-, -NHCON(C1-6 alkyl)-, N(C 1-6 alkyl)CON(C 1-6 alkyl)-, -SO 2 NH-, or -NHSO 2 -, wherein said alkyl in is optionally substituted with one or more optional substituents selected from R S1 .
  • L 72 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, -CO-, -COO-, -OCO-, -CONH-, - SO2NH- or -NHSO2-. Even more preferably, L 72 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, or -CO-. Even more preferably, L 72 is a bond, -O-, or -S-. Even more preferably, L 72 is a bond. It is noted that in the case of two bivalent chemical groups attached to each other, e.g.
  • -L 71 -L 72 - if each of them is defined to be a chemical bond, it is to be understood that the whole moiety comprising two bivalent chemical groups attached to each other is a bond.
  • -L 71 - is a bond
  • -L 72 - is a bond
  • -L 71 -L 72 - is a bond
  • Q 7 is C2-6 alkynyl, -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-aryl, -(C0-2 alkylene)- heterocycloalkyl or -(C0-2 alkylene)-heteroaryl; wherein said alkynyl and alkylene are each optionally substituted with one or more optional substituents selected from R S1 ; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more optional substituents selected from R S2 .
  • Q 7 is -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-aryl, -(C0-2 alkylene)- heterocycloalkyl or -(C0-2 alkylene)-heteroaryl; wherein said alkylene is optionally substituted with one or more optional substituents selected from R S1 ; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more optional substituents selected from R S2 .
  • Q 7 is -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-heterocycloalkyl or -(C0-2 alkylene)-heteroaryl; wherein said alkylene is optionally substituted with one or more optional substituents selected from R S1 ; and wherein said cycloalkyl, heterocycloalkyl, and heteroaryl are each optionally substituted with one or more optional substituents selected from R S2 . It is to be understood that if L 71 is a bond and L 72 is a bond, then R 7 is preferably Q 7 .
  • R 7 is preferably Q 7 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(C0-2 alkylene)- cycloalkyl, -(C0-2 alkylene)-aryl, -(C0-2 alkylene)-heterocycloalkyl or -(C0-2 alkylene)-heteroaryl; wherein said alkyl, alkenyl, alkynyl, and alkylene in R 7 are each optionally substituted with one or more optional substituents selected from R S1 ; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in R 7 are each optionally substituted with one or more optional substituents selected from R S2 .
  • R 7 is C2-6 alkynyl, -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-aryl, -(C0-2 alkylene)-heterocycloalkyl or -(C0-2 alkylene)-heteroaryl; wherein said alkynyl and alkylene are each optionally substituted with one or more optional substituents selected from R S1 ; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more optional substituents selected from R S2 .
  • R 7 is -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-aryl, -(C0-2 alkylene)- heterocycloalkyl or -(C0-2 alkylene)-heteroaryl; wherein said alkylene is optionally substituted with one or more optional substituents selected from R S1 ; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more optional substituents selected from R S2 .
  • R 7 is -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-heterocycloalkyl or -(C0-2 alkylene)-heteroaryl; wherein said alkylene is optionally substituted with one or more optional substituents selected from R S1 ; and wherein said cycloalkyl, heterocycloalkyl, and heteroaryl are each optionally substituted with one or more optional substituents selected from R S2 .
  • R 8 is a moiety of the formula: wherein: L 81 is a bond, C1-5 alkylene optionally substituted with halo or oxo; L 82 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, -N(C1-6 alkyl)-, -CO-, -COO-, -OCO-, -CONH-, -CON(C1- 6 alkyl)-, -NHCO-, N(C1-6 alkyl)CO-, -NHCONH-, -N(C1-6 alkyl)CONH-, -NHCON(C1-6 alkyl)-, N(C1-6 alkyl)CON(C1-6 alkyl)-, -SO2NH-, -SO2N(C1-6 alkyl)-, -NHSO2-, or -N(C1-6 alkyl)SO2-; and Q 8 is hydrogen, -CN, C1-6 alkyl, C2
  • L 81 is -(C0-2 alkylene)-, wherein said alkylene is optionally substituted with one or more optional substituents selected from R S1 .
  • L 82 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, -CO-, -COO-, -OCO-, -CONH-, -SO2NH-, or -NHSO2-. More preferably, L 82 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, or -CO-. Even more preferably, L 82 is a bond, -O-, or -S-.
  • L 82 is a bond.
  • Q 8 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein said alkyl, alkenyl, and alkynyl are each optionally substituted with one or more optional substituents selected from R S1 ; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more optional substituents selected from R S2 .
  • Q 8 is C2-6 alkynyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein said alkynyl is optionally substituted with one or more optional substituents selected from R S1 ; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more optional substituents selected from R S2 .
  • Q 8 is cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more optional substituents selected from R S2 .
  • Q 8 is cycloalkyl, heterocycloalkyl or heteroaryl; wherein said cycloalkyl, heterocycloalkyl, and heteroaryl are each optionally substituted with one or more optional substituents selected from R S2 .
  • R 8 is preferably selected from -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-aryl, -(C0-2 alkylene)-heterocycloalkyl or -(C0-2 alkylene)-heteroaryl, wherein said alkylene is optionally substituted with one or more optional substituents selected from R S1 ; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in R 8 are each optionally substituted with one or more optional substituents selected from R S2 .
  • R 8 is selected from -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-heterocycloalkyl or -(C0-2 alkylene)-heteroaryl, wherein said alkylene is optionally substituted with one or more optional substituents selected from R S1 ; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in R 8 are each optionally substituted with one or more optional substituents selected from R S2 .
  • Particularly preferred -(C0-2 alkylene)- in R 8 is methylene.
  • R 8 is selected from - CH2-cycloalkyl, -CH2-aryl, -CH2-heterocycloalkyl or -CH2-heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in R 8 are each optionally substituted with one or more optional substituents selected from R S2 . More preferably R 8 is selected from -CH2-cycloalkyl, -CH2-heterocycloalkyl or -CH2-heteroaryl, wherein said cycloalkyl, heterocycloalkyl, and heteroaryl in R 8 are each optionally substituted with one or more optional substituents selected from R S2 .
  • L 81 is methylene
  • -L 82 is a covalent bond
  • Q 8 is cycloalkyl, aryl, heterocycloalkyl or heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in R 8 are each optionally substituted with one or more optional substituents selected from R S2 .
  • R 8 is methylene, -L 82 is a covalent bond, and Q 8 is cycloalkyl, heterocycloalkyl or heteroaryl, wherein said cycloalkyl, heterocycloalkyl, and heteroaryl in R 8 are each optionally substituted with one or more optional substituents selected from R S2 .
  • Particularly preferred R 8 is Preferably, the moiety represented with a partial formula Therein, R 8 is defined as defined hereinabove.
  • R S1 is selected from halogen, -CN, -OH, -O(C1-5 alkyl), -O(C1-5 haloalkyl), C1-5 haloalkyl, -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1- 5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -(N-heterocycloalkyl), -CO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -CO-(N-heterocycloalkyl), -NHCO-(C1-5 alkyl), -N(C1-5 alkyl),
  • R S1 is selected from halogen, -CN, -OH, -O(C1-5 alkyl), -O(C1-5 haloalkyl), C1-5 haloalkyl, -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1- 5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -(N-heterocycloalkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -CO-(N-heterocycloalkyl), -NHCO-(C1-5 alkyl), -N(C1-5 alkyl)-CO-(N-heterocyclo
  • R S1 is selected from halogen, -CN, -OH, -O(C1-5 alkyl), -O(C1-5 haloalkyl), C1-5 haloalkyl, -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), and -(N-heterocycloalkyl).
  • R S1 is selected from halogen, -CN, -OH, -SH, and -NH2.
  • R S2 is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(C1-5 alkyl), -O(C1- 5 haloalkyl), -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -(N-heterocycloalkyl), -CO(C1-5 alkyl), -CONH2, -CONH(C1- 5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -CO-(N-heterocycloalkyl), -(C1-5 alkylene)-CN,
  • R S2 is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(C1-5 alkyl), -O(C1-5 haloalkyl), -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1- 5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -(N-heterocycloalkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -CO-(N-heterocycloalkyl), -NHCO-(C1-5 alkyl), -N(C1-5 alkyl)-N(C
  • R S2 is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(C1-5 alkyl), -O(C1-5 haloalkyl), -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -(N-heterocycloalkyl), -(C1-5 alkylene)- CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-O(C1-5 alkyl), -(C1-5 alkylene)-O(C1-5 haloalkyl), -(C1-5 alkyl),
  • 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. Even more preferably, R S2 is selected from halogen, -CN, -OH, -SH, and -NH2.
  • -CR 1 R 2 R 3 is bicyclo[1,1,1]pent-1-yl.
  • RN is selected from:
  • X 2 is CH.
  • X1 is CF and X3 is CH.
  • -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(C1-5 alkyl), -O(C1-5 haloalkyl), -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -CO(C 1-5 alkyl), -CONH 2 , -CON
  • -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(C1-5 alkyl), -O(C1-5 haloalkyl), -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -CO(C1-5 alkyl),
  • -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(C1-5 alkyl), -O(C1-5 haloalkyl), -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -CO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), and -CON(C1- 5 alkyl)(C1-5 alkyl).
  • -YC2-RC2 is piperazinyl (preferably N-piperazinyl) optionally substituted (preferably N-substituted) with -CO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), and -CON(C1-5 alkyl)(C1-5 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(C1-5 alkyl)(C1-5 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-yl, 8-oxa-3-azabicy
  • R 7 is hydrogen, -CN, or -Hal.
  • R 7 is hydrogen.
  • the moiety represented with a partial formula p referably
  • R 8 is hydrogen, -CN, or -Hal.
  • R 8 is hydrogen.
  • the moiety represented with a partial formula is .
  • R 8 is -CH2C ⁇ CH.
  • the moiety represented with a partial formula s In a twelfth specific embodiment, R 8 is -CH2-cycloalkyl or -CO-cycloalkyl. Particularly preferred cycloalkyl is cyclopropyl.
  • -W cov -R is -CN.
  • -RN- is -(C1-6 alkylene)-NH- or -(C1-6 alkylene)-N(C1-2 alkyl)- , wherein W cov is connected to RN through said N atom in -(C1-6 alkylene)-NH- or -(C1-6 alkylene)-N(C1-2 alkyl)-, wherein said alkylene is optionally substituted with one or more optional substituents selected from -Hal and -CN.
  • C 1-6 alkylene is propylene or butylene.
  • a -W cov - is -CO- and R cov is C2 alkenyl, wherein said alkenyl is optionally substituted with one or more optional substituents selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -OOC-(C1-4 alkyl), -NHCO-(C1-4 alkyl), -(C1-4 alkylene)N(C1-4 alkyl)(C1-4 alkyl), -(C1-4 alkylene)-(N- heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, preferably selected from C1-4 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3,
  • -RN- is -(C1-2 alkylene)-heterocycloalkylene, wherein said heterocycloalkylene comprises an N atom, wherein W cov is connected to RN through said N atom and wherein said heterocycloalkylene is optionally substituted with one or more optional substituents selected from -Hal, -(C0-2 alkylene)-CN, C1-2 alkyl and C1-2 haloalkyl.
  • particularly preferred -RN- is .
  • -RN- is -(C0-2 alkylene)-cycloalkylene-(C0-2 alkylene)-NH- or - (C0-2 alkylene)-cycloalkylene-(C0-2 alkylene)-N(C1-2 alkyl)-, wherein W cov is connected to RN through said N atom in -(C0-2 alkylene)-cycloalkylene-(C0-2 alkylene)-NH- or -(C0-2 alkylene)-cycloalkylene-(C0-2 alkylene)-N(C1-2 alkyl)-, wherein said cycloalkylene is optionally substituted with one or more optional substituents selected from -Hal, -(C0-2 alkylene)-CN, C1-2 alkyl and C1-2 haloalkyl.
  • -RN- is particularly preferred .
  • R cov is .
  • W is -NHS(O)y-, wherein y is 1 or 2.
  • y is 2. It is to be understood that the left side of W as defined herein is attached to the carbon atom that carries R1, R2 and R3.
  • Preferred compound of formula (I) are selected from the following compounds or their pharmaceutically acceptable salts: , ,
  • 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”).
  • 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 O, 76 Br, 77 Br, 120 I and/or 124 I.
  • a positron-emitting isotope of the corresponding atom such as, e.g., 18 F, 11 C, 13 N, 15 O, 76 Br, 77 Br, 120 I and/or 124 I.
  • 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, (iii) 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
  • 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 -ORx 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-Ry, -CH2-O-CO-Ry, -CH2-O-CO-O-Ry, and -CH(CH3)-O- COO-Ry, wherein Ry is preferably carbocyclyl, heterocyclyl, C1-5 alkyl, -NH-(C1-5 alkyl) or -S-(C1-5 alkyl), wherein the said alkyl is optionally substituted with a group selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloal
  • 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., polyfethylene glycol), including polyfethylene 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-cyclodext
  • 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 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 thereof, as defined herein.
  • the present inventors have demonstrated that certain compounds of formula (I) as described herein are covalent inhibitors of PARG enzyme.
  • the compounds of the present invention are significantly more potent (i.e., exhibit lower ICso) against the wild-type PARG protein in comparison to its C872A mutant, which is not capable of covalently binding the compounds of the present invention.
  • the inhibition of PARG by the compounds of the present invention is time-dependent, leading to lower ICso values upon 2-hour incubation when compared to a shorter incubation of 15 minutes.
  • 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 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 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 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 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 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 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 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 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 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 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 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 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 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
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestagens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5oc-reductase such as finasteride;
  • antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
  • antiandrogens for example
  • 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-tetra
  • 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
  • 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 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 A.
  • the scheme can also be extended to the compounds of formula (I) wherein W is -S(O) y NH-, -NHS(O)(NH)-, -NHS(O)(NCH 3 )-, -S(O)(NH)-NH-, or -S(O)(NCH 3 )-NH- upon the corresponding functionalization of the bromide of compound 1.
  • compound 1 in which X 1 , X 2 , X 3 and R 7 are are as defined for formula (I) is reacted with benzyl mercaptan to give compound 2 in which X 1 , X 2 , X 3 and R 7 are are as defined for formula (I).
  • 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.
  • compound 2 in which X 1 , X 2 , X 3 and R 7 are are as defined for formula (I) is reacted with an bromide reagent to give compound 3 in which X 1 , X 2 , X 3 and R 7 are are as defined for formula (I).
  • This bromination can be carried out by treatment with NBS, Br2 etc., in MeCN, THF, dioxane, DMF etc. (see for example: Bentley et al; WO2011/138266). Preferred is the herein described use of NBS in MeCN.
  • the reactions are preferably run under an atmosphere of argon for 0.5 - 5 hours at 0 °C to room temperature.
  • compound 3 in which X 1 , X 2 , X 3 , R 7 are as defined for formula (I) is reacted with compound 4 in which R 8 is CN or a moiety of the formula -L 81 -L 82 -Q 8 to give compound 5.
  • the coupling reaction is catalyzed by palladium catalysts, e.g.
  • Pd(0) catalysts like tetrakis(triphenylphosphine) palladium(O) [Pd(PPh3)4], tris(di benzylideneacetone) di-palladium(O) [Pd2(dba)3], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)-palladium(ll) [Pd(PPh3)2Cl2], palladium(ll) acetate and triphenylphosphine or by [l,l'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • Pd(0) catalysts like tetrakis(triphenylphosphine) palladium(O) [Pd(PPh3)4], tris(di benzylideneacetone) di-palladium(O) [Pd2(dba)3]
  • Pd(ll) catalysts like dichlorobis(triphenylpho
  • the reaction is preferably carried out in a solvent like 1 ,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base like potassium carbonate, sodium carbonate, sodium bicarbonate or potassium phosphate, (see for example: Hall, Boronic Acids, 2005 Wiley VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527- 30991-8 and references cited therein).
  • the reaction is performed at temperatures ranging from room temperature to the boiling point of the respective solvent. Further on, the reaction can be performed at temperatures above the boiling point using pressure tubes and a microwave oven.
  • the reaction is preferably completed after 1 to 36 hours.
  • compound 5 in which X 1 , X 2 , X 3 R 7 and R 8 are as defined for formula (I) is reacted with chlorination reagent to give a sulfonyl chloride 6.
  • This sulfonyl chloride formation can be carried out by treatment with NCS, sulfonyl chloride, DCDMH, CI2 etc., in MeCN with equivalent acetic acid and water, (see for example: Sutton et al, WO 2021/055744).
  • the reactions are preferably run under an atmosphere of argon for 0.5 - 5 hours at 0 °C to room temperature.
  • compound 6 in which X 1 , X 2 , X 3 R 7 and R 8 are as defined for formula (I) is reacted with amine 7 in which R1, R 2 and R 3 are as defined for formula (I) to give compound 8 in which X 1 , X 2 , X 3 R 7 and R 8 are as defined for formula (I).
  • 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 at 0 °C to room temperature.
  • compound 8 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 7 and R 8 are as defined for the compound of formula (I) is reacted with compound 9 in which RN is as defined for formula (I) and LG is a leaving group such as HO-, CI-, Br-, I-, MsO- to give compound 10 which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 7 , R 8 and RN are as defined for formula (I).
  • This reaction is preferably carried out with Mitsunobu conditions when LG is HO-. Preferred is the herein described use of DIAD or DEAD etc.
  • compound 10 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 7 , R 8 and RN are as defined for formula (I) is reacted with compound 11 in which R oov and W oov are as defined for formula (I) and LG is leaving group such as HO-, Cl- or -O-W oov -R oov , to give compound A.
  • This condensation is preferably carried out in a basic condition using bases as triethyl amine, pyridine, di-/so-propylethylamine etc. with condensating agents such as HATU, EDCI/HOBt, T3P, GDI etc.
  • Scheme 2 illustrates a preferred synthetic approach to compounds of the general formula B.
  • the scheme can also be extended to the compounds of formula (I) wherein W is -S(O) y NH-, -NHS(O)(NH)-, -NHS(O)(NCH 3 )-, -S(O)(NH)-NH-, or -S(O)(NCH 3 )-NH-.
  • compound 12 in which X 1 , X 2 and X 3 are are as defined for formula (I) is reacted with chlorosulfonic acid to give compound 13 in which X 1 , X 2 and X 3 are are as defined for formula (I).
  • chlorosulfonic acid under an atmosphere of argon, (see for example: Adams et al, W02008070707).
  • the reactions are preferably run in an oil bath for 2-24 hours at 0-140°C.
  • compound 13 in which X 1 , X 2 and X 3 are as defined for formula (I) is reacted with amine 7 in which R1 , R 2 and R 3 are as defined for formula (I) to give compound 14 in which X 1 , X 2 , X 3 , R 1 , R 2 and R 3 as defined for formula (I).
  • 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 at 0 °C to room temperature.
  • compound 14 in which X 1 , X 2 , X 3 , R 1 , R 2 and R 3 are as defined for formula (I) is reacted with compound 15 in which R 7 is as defined for formula (I) to give compound 16 in which X 1 , X 2 , X 3 , R 1 , R 2 ,R 3 and R 7 are as defined for formula (I).
  • R 7 is as defined for formula (I)
  • the conditions for this reaction can be found in: McGonagle et al, WO2016/092326.
  • compound 16 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 and R 7 are as defined for formula (I) is reacted with compound 9 in which RN is as defined for formula (I) and LG is a leaving group such HO-, CI-, Br-, I-, MsO- to give compound 17 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 7 and RN are as defined for formula (I).
  • This reaction is preferably carried out with Mitsunobu conditions when LG is HO-. Preferred is the herein described use of DIAD or DEAD etc.
  • compound 17 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 7 and RN are as defined for formula (I) is reacted with compound 11 in which R oov and W oov are as defined for formula (I) and LG is leaving group such as HO-, Cl- or -O- W oov -R oov , to give a compound of formula B.
  • This condensation is preferably carried out in a basic condition using bases as triethyl amine, pyridine, di-/so-propylethylamine etc. with condensating agents such as HATU, EDCI/HOBt, T3P, GDI etc.
  • Scheme 3 illustrates a preferred synthetic approach to compounds of the general formula C. As it is to be understandable to the skilled person, the scheme can also be extended to the compounds of formula
  • W is -S(O) y NH-, -NHS(O)(NH)-, -NHS(O)(NCH 3 )-, -S(O)(NH)-NH-, or -S(O)(NCH 3 )-NH-.
  • compound 20 in which X 1 , X 2 and X 3 are as defined for formula (I) is reacted with amine 7 in which R1 , R 2 and R 3 are as defined for formula (I) to give compound 21 in which X 1 , X 2 , X 3 , R 1 , R 2 and R 3 are as defined for formula (I).
  • This reaction can be carried out under basic conditions, (see for example: Guo et al, WO2013/006394). Preferred is the herein described use of triethylamine, pyridine, di-/so-propylethylamine 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.
  • compound 21 in which X 1 , X 2 , X 3 , R 1 , R 2 and R 3 are as defined for formula (I) is reacted with amine 22 in which R 8 is as defined for formula (I) to give compound 23 in which X 1 , X 2 , X 3 , R 1 , R 2 ,R 3 and R 8 are as defined for formula (I).
  • R 8 is as defined for formula (I) to give compound 23 in which X 1 , X 2 , X 3 , R 1 , R 2 ,R 3 and R 8 are as defined for formula (I).
  • Preferred is the herein described use of triethylamine, di- /so-propylethylamine etc in DMF, acetonitrile or dioxane, (see for example: Liu et al, Eur. J. Med. Chem, 2021 , 222, 113565).
  • the reactions are preferably run under an atmosphere of argon for 2-24 hours
  • compound 23 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 and R 8 are as defined for formula (I) is converted to compound 24 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 and R 8 are as defined for formula (I).
  • This amide formation can be carried out with ammonium hydroxide or ammonium salt and base such as triethylamine, pyridine, di-/so-propylethylamine etc.
  • this amidation also can be conducted by an acyl chloride strategy.
  • the reactions are preferably run under an atmosphere of argon for 2-24 hours at room temperature.
  • compound 24 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 and R 8 are as defined for formula (I) is converted to compound 25 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 and R 8 are as defined for formula (I).
  • This cyclization is preferably carried out with GDI in the presence of base such as triethylamine, di-/so- propylethylamine etc. in DMF, NMP or DMA.
  • the reactions are preferably run for 0.5-16 hours at 80-120°C in a microwave oven or in an oil bath (see for example: Velaparthi et al, WO2021/133751).
  • This cyclization reaction can also be carried out with GDI in DMF, NMP or DMA etc. without base at 100 - 150°C, or with triphosgene and base in DCM, THF etc. at 0 °C to room temperature.
  • compound 25 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 and R 8 are as defined for formula (I) is reacted with compound 9 in which RN is as defined for formula (I) and LG is a leaving group such as HO- , CI-, Br-, I-, MsO- to give compound 26 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 8 and RN are as defined for formula (I).
  • This reaction is preferably carried out with Mitsunobu conditions when LG is HO-. Preferred is the herein described use of DIAD or DEAD etc.
  • compound 26 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 8 and RN are as defined for formula (I) is reacted with compound 11 in which R oov and W oov are as defined for formula (I) and LG is leaving group such as HO-, Cl- or -O-W oov -R oov , to give a compound of formula C.
  • This condensation is preferably carried out in a basic condition using bases as triethyl amine, pyridine, di-7so-propylethylamine etc. with condensating agents such as HATU, EDCI/HOBt, T3P, GDI etc.
  • Scheme 3.1 illustrates an alternative approach to compounds of the general formula 24.
  • compound 27 in which X 1 , X 2 and X 3 are as defined for formula (I) is reacted with chlorosulfonic acid to give compound 28 in which X 1 , X 2 and X 3 are as defined for formula (I).
  • chlorosulfonic acid under an atmosphere of argon (see for example: Adams et al, W02008070707).
  • the reactions are preferably run in an oil bath for 2-24 hours at 0-140°C.
  • compound 28 in which X 1 , X 2 and X 3 are as defined for formula (I) is reacted with amine 7 in which R1, R 2 and R 3 are as defined for formula (I) to give compound 29 in which X 1 , X 2 , X 3 , R 1 , R 2 and R 3 are as defined for formula (I).
  • This reaction can be carried out under basic conditions (see for example: Sari et al, Eur. J. Med. Chem., 2017, 138, 407 - 421). Preferred is the herein described use of triethylamine, pyridine, di-/so-propylethylamine 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.
  • compound 29 in which X 1 , X 2 , X 3 , R 1 , R 2 and R 3 are as defined for formula (I) is reacted with amine 22 in which R 8 is as defined for formula (I) to give compound 24 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 and R 8 are as defined for formula (I).
  • R 8 is as defined for formula (I) to give compound 24 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 and R 8 are as defined for formula (I).
  • the reactions are preferably run under an atmosphere of argon for 2-24 hours at 80-110°C in a microwave oven
  • compound 21 in which X 1 , X 2 , X 3 , R 1 , R 2 and R 3 are as defined for formula (I) is reacted with the protected compound 9a in which RN is as defined for formula (I) to give compound 30 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 and RN are as defined for formula (I).
  • This amide formation can be carried out with amine and base such as triethylamine, pyridine, di-/so-propylethylamine etc. in the presence of condensating agents such as HATU, EDCI/HOBt, T3P, GDI etc.in DCM or DMF.
  • this amide formation also can be conducted by an acyl chloride strategy (see for example: Shook et al, WO2019067864).
  • the reactions are preferably run under an atmosphere of argon for 2-24 hours at room temperature.
  • compound 30 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 and RN are as defined for formula (I) is reacted with amine 21 in which R 8 is as defined for the compound of formula (I) to give compound 31 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 8 and RN are as defined for formula (I).
  • R 8 is as defined for the compound of formula (I)
  • the reactions are preferably run under an atmosphere of argon for 2-24 hours at 80-110°C in a microwave oven or in an oil bath.
  • compound 31 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 8 and RN are as defined for formula (I) is converted to compound 26 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 8 and RN are as defined for formula (I).
  • This cyclization is preferably carried out with GDI in the presence of base such as triethylamine, di-/so- propylethylamine etc. in DMF, NMP or DMA.
  • the reactions are preferably run for 0.5 - 16 hours at 80- 120°C in a microwave oven or in an oil bath.
  • This cyclization also can be carried out with GDI in DMF, NMP or DMA etc. (see for example: Lisius et al, W02007004958) without base at 100-150°C, or with triphosgene and base in DCM, THF etc. at 0 °C to room temperature. Finally, the protecting group is removed to give compound 26.
  • Scheme 4 illustrates a preferred synthetic approach to compounds of the general formula D.
  • the scheme can also be extended to the compounds of formula (I) wherein W is -S(O) y NH-, -NHS(O)(NH)-, -NHS(O)(NCH 3 )-, -S(O)(NH)-NH-, or -S(O)(NCH 3 )-NH- upon the corresponding functionalization of the bromide of compound 35.
  • compound 32 in which X 1 , X 2 and X 3 are are as defined for formula (I) is reacted with compound 33 is as defined for formula (I) to give compound 34 in which X 1 , X 2 , X 3 and R 8 are as defined for formula (I). Reaction conditions for this conversion are described in the literature (McGonagle et al, WO2016/092326).
  • compound 34 in which X 1 , X 2 , X 3 and R 8 are are as defined for formula (I) is reacted with hydrazine hydrate to give compound 35 in which X 1 , X 2 , X 3 and R 8 are as defined for formula (I). Reaction conditions for this conversion are described in the literature (McGonagle et al, WO2016/092326).
  • compound 35 in which X 1 , X 2 , X 3 and R 8 are are as defined for formula (I) is reacted with benzyl mercaptan to give compound 36 in which X 1 , X 2 , X 3 and R 8 are are as defined for formula (I).
  • 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.
  • compound 36 in which X 1 , X 2 , X 3 and R 8 are are as defined for formula (I) is reacted with chlorination reagent to give sulfonyl chloride 37 in which X 1 , X 2 , X 3 and R 8 are are as defined for formula (I).
  • This sulfonyl chloride formation can be carried out by treatment with NCS, sulfonyl chloride, DCDMH, CI2 etc., in MeCN with equivalent acetic acid and water (see for example: Sutton et al, WO 2021/055744). Preferred is the herein described use of DCDMH in MeCN with equivalent acetic acid and water.
  • the reactions are preferably run under an atmosphere of argon for 0.5-5 hours at 0 °C to room temperature.
  • compound 37 in which X 1 , X 2 , X 3 and R 8 are as defined for formula (I) is reacted with amine 7 in which R1, R 2 and R 3 are as defined for formula (I) to give compound 38 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 and R 8 are as defined for formula (I).
  • 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 at 0 °C to room temperature.
  • compound 38 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 and R 8 are as defined for formula (I) is reacted with compound 9 in which R N is as defined for formula (I) and LG is a leaving group such as HO-, CI-, Br-, I-, MsO- to give compound 39 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 8 and R N are as defined for formula (I).
  • This reaction is preferably carried out with Mitsunobu conditions when LG is HO-. Preferred is the herein described use of DIAD or DEAD etc.
  • compound 39 in which X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 8 and R N are as defined for formula (I) is reacted with compound 11 in which R oov and W oov are as defined for formula (I) and LG is leaving group such as HO-, Cl- or -O-W oov -R oov Stamm to give compound D.
  • This condensation is preferably carried out under basic condition with bases such as triethylamine, pyridine, di-/so-propylethylamine etc. and with condensating agents such as HATU, EDCI/HOBt, T3P, GDI etc.
  • 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 C18 2.1X30 mm, 5 urn 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.
  • Method 2 SHIMADZU LCMS-2020 Kinetex EVO C18 2.1X30 mm, 5 urn at 40°C ;
  • Mobile Phase A: 0.025% NH3-H2O in water (v/v) , B: MeCN; flow rate held at 1 .5 mL/min; eluted with the mobile phase over 1.55 min employing UV detection at 220 nm and 254 nm.
  • Gradient information 0-0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-1 .20 min, held at 5% A-95% B; 1 .20-1 .21 min, returned to 95% A-5% B, 1.21-1 .55 min, held at 95% A-5% B.
  • Method 3 Agilent 1200 ⁇ G6110A Kinetex EVO C18 2.1X30 mm, 5 urn 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.
  • Method 4 SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X30 mm 5 urn at 50°C
  • A 0.0375% TFA in water (v/v); B: 0.01875% TFA in MeCN (v/v); flow rate held at 1 .5 mL/min; eluted with the mobile phase over 1.00 min employing UV detection at 220 nm and 254 nm.
  • Gradient information 0.01-0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-0.95 min, held at 5% A-95% B; 0.95-0.96 min, returned to 95% A-5% B, 0.96-1 .00 min, held at 95% A-5% B.
  • Method 5 SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X20 mm 2.6 urn at 50°C; Mobile Phase: A: 0.0375% TFA in water (v/v); B: 0.01875% TFA in MeCN (v/v); flow rate held at 2.0 mL/min; eluted with the mobile phase over 1.00 min employing UV detection at 220 nm and 254 nm. Gradient information: 0.01-0.60 min, ramped from 95% A-5% B to 5% A-95% B; 0.61-0.78 min, held at 5% A-95% B; 0.78-0.79 min, returned to 95% A-5% B, 0.79-0.80 min, held at 95% A-5% B.
  • Method 6 SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X30 mm 5 urn 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.
  • 1 H NMR spectra were acquired on a Bruker Avance IH spectrometer at 400 MHz using residual undeuterated solvent as reference. 1 H NMR signals are specified with their multiplicity / combined multiplicities as apparent from the spectrum; possible higher-order effects are not considered. Chemical shifts of the signals (5) are specified as ppm (parts per million).
  • N2 was bubbled through a solution of N-(1 -methylcyclopropyl)-1 -[(1 -methylcyclopropyl)methyl]-2,4- dioxo-quinazoline-6-sulfonamide (25 mg, 68.79 pmol) and PPha (36.09 mg, 137.58 pmol) in toluene (1.5 mL) for 5 min, then the solution was cooled to 0 °C. 4-Hydroxypiperidine-1 -carbonitrile (13.02 mg, 103.19 pmol) was added slowly, followed by DIAD (27.82 mg, 137.58 pmol, 26.75 pL).
  • reaction was warmed to 60 °C and stirred at 60 °C for 12 h under N2.
  • the reaction mixture was poured into water (30 mL), and extracted with EtOAc (30 mL; 2x). The combined organic layers were washed with brine (20 mL; 2x), dried over Na2SO4, filtered and the filtrate was concentrated to give a residue.
  • N2 was bubbled through a solution of A/-(1 -methylcyclopropyl)-1-[(1-methylcyclopropyl)methyl]-2,4- dioxo-quinazoline-6-sulfonamide (30 mg, 82.55 pmol) and PPha (43.30 mg, 165.10 pmol) in toluene (2 mL) for 5 min and then the solution was cooled to 0 °C.
  • Tert-butyl 3-hydroxyazetidine-1 -carboxylate 21 .45 mg, 123.82 pmol
  • DEAD 28.75 mg, 165.10 pmol, 30.01 pL).
  • the mixture was heated to 60 °C and stirred at 60 °C for 12 h under N2.
  • the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL; 2x). The combined organic layers were washed with brine (20 mL; 2x), dried over Na2SO4, filtered and the filtrate was concentrated.
  • the resulting solution turned to a suspension before it was extracted by EtOAc (200 mL; 2x).
  • the organic phase was collected and washed with brine (200 mL; 2x).
  • the organic phase was collected and dried over anhydrous Na2SO4.
  • the organic phase was filtered and concentrated under reduced pressure to give the product 2-fluoro-5-(/V-(1 -methylcyclopropyl)sulfamoyl)benzoic acid (11.0 g, 40.25 mmol, 64.03% yield) as a white solid.
  • the mixture was diluted with water (400 mL) and extracted with EtOAc (200 mL; 2x). The organic phase was washed with brine (200 mL; 2x). The organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • the residue was purified by reversed-phase flash (ISCO®; 330 g Flash Coulmn Welch Ultimate XB_C18 20-40pm; 120 A, Eluent of 8-50% ACN/H2O (0.1 % HCI condition) @ 100 mL/min). The resulting solution was concentrated in vacuum, and adjusted to pH>7 with sat. NaHCO3 solution. The solution was extracted with EtOAc (100 mL; 2x).
  • Example 14 3-(1-acryloylpiperidin-4-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2, 4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide
  • the material obtained was purified by preparative-HPLC (column: Phenomenex luna C18 150*25 mm*10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 32%-62%, 10 min) and lyophilized directly to give the product 3-(1-cyanoazetidin-3-yl)-1-(cyclopropylmethyl)-A/-(1- methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (7.1 mg, 16.12 pmol, 6.52% yield, 97.49% purity) as a white solid.
  • the residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 4%-37%, 11 min).
  • the product solution was basified with Na2COs (aq, sat., 30 mL) and extracted with DCM (30 mL, 2x).
  • the product solution was lyophilized to give the product N-(2-(1 -(cyclopropylmethyl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)-2,4- dioxo-1 , 4-d i hydroq ui nazol i n-3(2 H)-yl)ethyl )acry I ami de (12.56 mg, 28.13 umol, 30.16% yield, >99% purity) as a white solid.
  • the crude product was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 29%-59%, 10 min).
  • the product solution was lyophilized to give the product N-(2-(1- (cyclopropylmethyl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,4-dihydroquinazolin-3(2H)- yl)ethyl)-N-methylacrylamide (17.32 mg, 37.45 umol, 33.18% yield? 99% purity) as a white solid.
  • reaction mixture was heated to 50 °C and stirred for 16 h under nitrogen atmosphere.
  • the resulting mixture was concentrated under vacuum to give a residue which was purified by reversed-phase flash (ISCO®; 48 g Flash Coulmn: Spherical C18 20-45pm; 100 A, Eluent of 5-95% ACN/H2O (addition of 0.1 % formic acid) @ 80 mL/min).
  • the mixture was stirred at 95 °C for 16 h and concentrated under vacuum .
  • the crude product was purified by reversed-phase HPLC (ISCO®;48 g Flash Column Welch Ultimate XB_C18 20-40pm; 120 A, mobile phase: A: 0.1 % HCI in water, B: MeCN; B%: 5%-95%, 10 min).
  • the product solution was extracted with EtOAc (20 mL, 2x).
  • Exemplary compounds of formula (I) were tested in selected biological and/or physicochemical assays one or more times.
  • data are reported as either average values or as median values, wherein the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median value is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.
  • the in vitro pharmacological, pharmacokinetic and physicochemical properties of the compounds can be determined according to the following assays and methods.
  • Protein was purified by IMAC and SEC: frozen cell pellets (typically 40 g wet weight) were resuspended by homogenization in 5 volumes buffer A (25 mM Tris/HCI pH 8.0, 200 mM NaCI, 2 mM DTT), supplemented with 1 mg of DNase I from bovine pancreas (Sigma-Aldrich) and protease inhibitors (Roche CompleteTM EDTA-free protease inhibitor tablet), and lysed by passage through a Constant Systems BasicZ homogenizer.
  • buffer A 25 mM Tris/HCI pH 8.0, 200 mM NaCI, 2 mM DTT
  • protease inhibitors Roche CompleteTM EDTA-free protease inhibitor tablet
  • the lysate was clarified by centrifugation for 60 minutes at 25,000 g, 4°C, and the lysate supernatant was loaded onto 5 ml StrepTrap HP (Cytiva) pre-equilibrated with buffer A.
  • the column was washed with buffer A ( ⁇ 10 CV), then buffer B containing 1 M KCI ( ⁇ 5 CV), and then the protein was eluted with buffer A containing 2.5 mM d-Desthiobiotin. Pooled fractions containing 6HisTwinStrep-TEV-hPARG were incubated with TEV protease overnight at 4°C.
  • hPARG was separated from uncleaved material and Thrombin protease through gel filtration with Superdex75 sizing column (GE Healthcare) pre-equilibrated with SEC buffer (15 mM Tris/HCI pH 8.5, 100 mM NaCI, 2 mM DTT). Pooled fractions containing pure hPARG were concentrated using a 10 k MWCO spin concentrator (VivaSpin) to 10 mg/mL, and then either used immediately for crystallisation or snap-frozen in liquid nitrogen for storage at -80°C.
  • SEC buffer 15 mM Tris/HCI pH 8.5, 100 mM NaCI, 2 mM DTT.
  • Protein was purified by IMAC and SEC: frozen cell pellets (typically 40 g wet weight) were resuspended by homogenization in 5 volumes buffer A (25 mM Tris/HCI pH 8.0, 200 mM NaCI, 2 mM DTT), supplemented with 1 mg of DNase I from bovine pancreas (Sigma-Aldrich) and protease inhibitors (Roche CompleteTM EDTA-free protease inhibitor tablet), and lysed by passage through a Constant Systems BasicZ homogenizer.
  • buffer A 25 mM Tris/HCI pH 8.0, 200 mM NaCI, 2 mM DTT
  • protease inhibitors Roche CompleteTM EDTA-free protease inhibitor tablet
  • the lysate was clarified by centrifugation for 60 minutes at 25,000 g, 4°C, and the lysate supernatant was loaded onto 5 ml StrepTrap HP (Cytiva) pre-equilibrated with buffer A.
  • hPARG C872A was separated from uncleaved material and Thrombin protease through gel filtration with Superdex75 sizing column (GE Healthcare) preequilibrated with SEC buffer (15 mM Tris/HCI pH 8.5, 100 mM NaCI, 2 mM DTT). Pooled fractions containing pure hPARG C872A were concentrated using a 10 k MWCO spin concentrator (VivaSpin) to 10 mg/mL, and then snap-frozen in liquid nitrogen for storage at -80°C.
  • PARG enzyme as incubated with compound or vehicle (DMSO) for 15 minutes or 2 hours in a 384 well plate. After adding the PARG substrate ADP-ribose-pNP, the plate was read for absorbance intensity at 405 nm.
  • the vehicle (DMSO) with high absorbance intensity represents no inhibition of enzymatic reaction while the low control (no enzyme) with low absorbance intensity represents full inhibition of enzymatic reaction.
  • Substrate ADP-pNP, 800 pM, Jena Bioscience catalog # NU-955
  • Assay buffer 50 mM Tris-HCI pH 8.0, 100 mM NaCI, 2 mM DTT
  • the ability of compounds to inhibit PARG in response to DNA damage was assessed with U2OS cells pretreated with the compounds for 1 hour, following a 1 -hour treatment with or without the DNA alkylating agent temozolomide (TMZ).
  • TTZ DNA alkylating agent temozolomide
  • the cells were harvested and fixed in 70% ethanol, rehydrated with glucose and EDTA in PBS and subsequently blocked for 1 hour with PBS 1 % BSA and 0.01% Tween-20 (PBT).
  • PBT PBS 1 % BSA and 0.01% Tween-20
  • the cells were incubated for 2 hours at room temperature with a mouse monoclonal antibody against poly (ADP) ribose (PAR) polymer.
  • the cells were washed and incubated with an anti-mouse Alexa-488 conjugated secondary antibody for 1 hour at room temperature.
  • NCIH-460 as a PARG-inhibition sensitive cell line and U2OS as PARG-inhibition insensitive cell line were plated at 1000 cells/well and 2000 cells/well, respectively, in 96-well white plates with clear flat bottom. After 24 hours, the compounds were added with the Tecan digital dispenser (D300e) in duplicates. The outer wells of the plate were excluded. After 96 hours of incubation, 150 pl of the growth medium were removed and 50 pl of Cell Titer-Gio (Promega) were added per well. Following an incubation of 10 minutes, luminescence was read using a plate reader (Tecan). Averaged values of the samples were normalized to DMSO treated control samples. Curves were fit as % of the control vs. log of the compound concentration using a 4 parameter log-logistic function:
  • Table 2 Inhibition of PARG by compounds according to the present invention and cellular activity of compounds according to the present invention.
  • the ICso (inhibitory concentration at 50% of maximal effect) values are indicated in pM, empty space means that the corresponding compounds have not been tested in the respective assay.
  • IC50 in pM determined in PARG enzymatic assay (PARG C872A protein and 2 hours incubation) described under PARG enzymatic IC50 assay.
  • the Kinetic solubility assay employs the shake flask method followed by HPLC-UV analysis.
  • the kinetic solubility was measured according to the following protocol:
  • Test compounds and controls (10 mM in DMSO, 10 pL/tube) were added into the buffer (490 pL/well) which placed in a Minni-Uniprep filter.
  • the buffer was prepared as the customer’s requirement.
  • Caco-2 cells purchased from ATCC were seeded onto polyethylene membranes (PET) in 96- well BD Insert plates at 1 x 105 cells/ cm2, and refreshed medium every 4 ⁇ 5 days until to the
  • the quality of the monolayer is verified by measuring the Unidirectional (A ⁇ -B) permeability of fenoterol/nadolol (low permeability marker), propranolol/metopronolol (high permeability marker) and Bi-directional permeability of Digoxin (a P-glycoprotein substrate marker) in duplicate wells.
  • -Directions bi-directional transport including A >B and B >A; -Incubation time: single time point, 2hours;
  • MMS Microsome metabolic stability
  • the stability of the exemplary compounds was measured in the microsome metabolic stability assay as follows:
  • Test compounds will be incubated at 37°C with liver microsomes (pooled from multiple donors) at 1 pM in the presence of a NADPH regenerating system at 0.5 mg/ml microsomal protein.
  • Positive controls include Testosterone (3A4 substrate), Propafenone (2D6) and Diclofenac (2C9). They will be incubated with microsomes in the presence of a NADPH regenerating system.
  • int(mic) 0.693/half life/mg microsome protein per mLwt: 40 g/kg, 30 g/kg, 32 g/kg, 20 g/kg and 88 g/kg for rat, monkey, dog, human and mouse.
  • test compound is assessed based on peak area ratios of analyte/IS (no standard curve).

Abstract

The present invention relates to a compound of formula (I) or an enantiomer, diastereoisomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystal form 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, preferably as covalent PARG inhibitors, and can be used in a method of treatment of a proliferative disorder, preferably of cancer.

Description

2,4-DIOXO-1,4-DIHYDROQUINAZOLINE DERIVATIVES AS PARG INHIBITORS FOR THE TREATMENT OF CANCER
Field of the invention
The present invention relates to a compound of formula (I):
Figure imgf000002_0001
or a pharmaceutically acceptable salt or a prodrug 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, preferably as covalent PARG inhibitors, and can be used in a method of treatment of a proliferative disorder, preferably of cancer.
Background of the invention
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).
DNA replication stress (DRS) is a hallmark of cancer cells and a major source of genomic instability (a) Halazonetis et al., Science 2008, 319, 1352; b) Negrini et al., Nat. Rev. Mol. Cell Biol. 2010, 11 , 220). In broad terms, 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. Several DNA repair proteins are involved in replication fork stability, protection, and restart under DRS conditions (a) Costantino et al., Science 2014, 343, 88; b) Scully et al., Curr. Opin. Genet. Dev. 2021 71 , 154).
Poly(ADP)ribosylation (PARylation) 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.
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).
Although 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).
Genomic aberrations targeting tumor suppressor genes or oncogenes, often make cancer cells dependent on specific DNA repair pathways. For instance, it is well known that PARP inhibitors are particularly effective against tumors carrying mutations in the BRCA1 and BRCA2 genes (a) Bryant et al., Nature 2005, 434, 913; b) Farmer et al., Nature 2005, 434, 917). Targeting synthetic lethal interactions like the one between PARP and BRCA is an attractive novel therapeutic approach for cancer treatment.
PARG participates in DNA replication and in various DNA repair mechanisms including singlestrand break (SSB) repair and replication fork restart. 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). Moreover, 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).
Given the therapeutic potential of PARG inhibitors in cancer treatment, there is an increased need for the development of highly potent and selective PARG inhibitors beyond the ones that have already been described (a) James et al., ACS Chem. Biol. 2016, 11 , 3179; b) Waszkowycz et al., J. Med. Chem. 2018, 61 , 10767).
Certain compounds that are useful as PARG inhibitors are further disclosed in documents WO Summary of the invention
It was an objective technical problem of the present invention to provide compounds that are cell- permeable inhibitors of PARG. The technical problem of the present invention is solved by the embodiments described herein and as characterized by the claims.
Accordingly, in a first embodiment, the present invention provides a compound of formula (I):
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof. It is to be understood that the term “compound of formula (I)” preferably encompasses also an enantiomer, diastereoisomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystal form, pharmaceutically acceptable salt or a prodrug thereof.
A further embodiment of the present invention relates to a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In a further embodiment, 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. In a preferred embodiment of the present invention, the proliferative disorder is cancer, preferably a human cancer.
Definitions
The following definitions apply throughout the present specification and the claims, unless specifically indicated otherwise.
The term “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.
The term “hydrocarbon group” refers to a group consisting of carbon atoms and hydrogen atoms.
The term “alicyclic” is used in connection with cyclic groups and denotes that the corresponding cyclic group is non-aromatic.
As used herein, the term “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). Unless defined otherwise, the term “alkyl” preferably refers to C1-4 alkyl, more preferably to methyl or ethyl, and even more preferably to methyl.
As used herein, the term “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. The term “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). Unless defined otherwise, the term “alkenyl” preferably refers to C2-4 alkenyl.
As used herein, the term “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. The term “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. Unless defined otherwise, the term “alkynyl” preferably refers to C2-4 alkynyl.
As used herein, the term “alkylene” refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group which may be linear or branched. A “C1-5 alkylene” denotes an alkylene group having 1 to 5 carbon atoms, and the term “C0-3 alkylene” indicates that a covalent bond (corresponding to the option “Co alkylene”) or a C1-3 alkylene is present. Preferred exemplary alkylene groups are methylene (- CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, -CH2- CH(-CH3)-, or -CH(-CH3)-CH2-), or butylene (e.g., -CH2-CH2-CH2-CH2-). Unless defined otherwise, the term “alkylene” preferably refers to C1-4 alkylene (including, in particular, linear C1-4 alkylene), more preferably to methylene or ethylene, and even more preferably to methylene.
As used herein, the term “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. Unless defined otherwise, the term “alkenylene” preferably refers to C2-4 alkenylene (including, in particular, linear C2-4 alkenylene).
As used herein, the term “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. Unless defined otherwise, the term “alkynylene” preferably refers to C2-4 alkynylene (including, in particular, linear C2-4 alkynylene).
As used herein, the term “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. Unless defined otherwise, “carbocyclyl” preferably refers to aryl, cycloalkyl or cycloalkenyl.
As used herein, the term “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. For example, each heteroatom-containing ring comprised in said ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. Unless defined otherwise, “heterocyclyl” preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl.
As used herein, the term “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. Unless defined otherwise, 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.
As used herein, the term “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-tetrahydronaphthylene, indanylene, indenylene, anthracenylene, phenanthrenylene, 9H-fluorenylene, or azulenylene. Unless defined otherwise, 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).
As used herein, the term “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). For example, 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), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, p-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1 ,1 O]phenanthrolinyl, [1 ,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl (i.e., furazanyl), or 1 ,3,4-oxadiazolyl), thiadiazolyl (e.g., 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, or 1 ,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[1 ,5-a]pyrimidinyl (e.g., pyrazolo[1 ,5-a]pyrimidin-3-yl), 1 ,2-benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., 1 H-1 ,2,3-triazolyl, 2H-1 ,2,3-triazolyl, 1 H-1 ,2,4-triazolyl, or 4H-1 ,2,4-triazolyl), benzotriazolyl, 1 H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1,2,3-triazinyl, 1 ,2,4-triazinyl, or 1 ,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or 1 ,3-dihydrofuro[3,4- c]pyridinyl), imidazopyridinyl (e.g., imidazo[1 ,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1 ,3-benzodioxolyl, benzodioxanyl (e.g., 1 ,3-benzodioxanyl or 1 ,4-benzodioxanyl), or coumarinyl. Unless defined otherwise, the term “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.
As used herein, the term “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.e., to form an oxo group). For example, 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), pyrazinylene, pyrimidinylene, pyridazinylene, indolylene, isoindolylene, indazolylene, indolizinylene, purinylene, quinolylene, isoquinolylene, phthalazinylene, naphthyridinylene, quinoxalinylene, cinnolinylene, pteridinylene, carbazolylene, p-carbolinylene, phenanthridinylene, acridinylene, perimidinylene, phenanthrolinylene, phenazinylene, thiazolylene (e.g., thiazol-2,4-diyl, thiazol-2,5-diyl, or thiazol-4,5-diyl), isothiazolylene (e.g., isothiazol-3,4-diyl, isothiazol-3,5-diyl, or isothiazol-4,5-diyl), phenothiazinylene, oxazolylene (e.g., oxazol-2,4-diyl, oxazol-2,5-diyl, or oxazol-4,5-diyl), isoxazolylene (e.g., isoxazol-3,4-diyl, isoxazol-3,5-diyl, or isoxazol-4,5-diyl), oxadiazolylene (e.g., 1 ,2,4-oxadiazol-3,5-diyl, 1 ,2,5-oxadiazol-3,4-diyl, or 1,3,4- oxadiazol-2,5-diyl), thiadiazolylene (e.g., 1 ,2,4-thiadiazol-3,5-diyl, 1 ,2,5-thiadiazol-3,4-diyl, or 1,3,4- thiadiazol-2,5-diyl), phenoxazinylene, pyrazolo[1 ,5-a]pyrimidinylene, 1 ,2-benzoisoxazolylene, benzothiazolylene, benzothiadiazolylene, benzoxazolylene, benzisoxazolylene, benzimidazolylene, benzo[b]thiophenylene (i.e., benzothienylene), triazolylene (e.g., 1 H-1 ,2,3-triazolylene, 2H-1,2,3- triazolylene, 1 H-1 ,2,4-triazolylene, or 4H-1 ,2,4-triazolylene), benzotriazolylene, 1 H-tetrazolylene, 2H-tetrazolylene, triazinylene (e.g., 1 ,2,3-triazinylene, 1,2,4-triazinylene, or 1 ,3,5-triazinylene), furo[2,3- c]pyridinylene, dihydrofuropyridinylene (e.g., 2,3-dihydrofuro[2,3-c]pyridinylene or 1 ,3-dihydrofuro[3,4-c]pyridinylene), imidazopyridinylene (e.g., imidazo[1 ,2-a]pyridinylene or imidazo[3,2-a]pyridinylene), quinazolinylene, thienopyridinylene, tetrahydrothienopyridinylene (e.g., 4, 5, 6, 7-tetrahyd rothieno[3, 2-c]pyridi nylene) , dibenzofuranylene, 1 ,3-benzodioxolylene, benzodioxanylene (e.g., 1 ,3-benzodioxanylene or 1 ,4-benzodioxanylene), or coumarinylene. Unless defined otherwise, the term “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 optionally oxidized. A “heteroarylene”, including any of the specific heteroarylene groups described herein, may be attached through two carbon ring atoms, particularly through those two carbon ring atoms that have the greatest distance from one another (in terms of the number of ring atoms separating them by the shortest possible connection) within one single ring or within the entire ring system of the corresponding heteroarylene.
As used herein, the term “cycloalkyl” refers to a saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). “Cycloalkyl” may, e.g., refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl. Unless defined otherwise, “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).
As used herein, the term “cycloalkylene” refers to a cycloalkyl group, as defined herein above, but having two points of attachment, i.e. a divalent saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). “Cycloalkylene” may, e.g., refer to cyclopropylene (e.g., cyclopropan-1 ,1 -diyl or cyclopropan-1 ,2-diyl), cyclobutylene (e.g., cyclobutan-1, 1 -diyl, cyclobutan-1 ,2-diyl, or cyclobutan-1 ,3-diyl), cyclopentylene (e.g., cyclopentan-1,1 -diyl, cyclopentan-1 , 2-diyl, or cyclopentan-1 , 3-diyl), cyclohexylene (e.g., cyclohexan-1 ,1-diyl, cyclohexan-1 , 2-diyl, cyclohexan-1 , 3-diyl, or cyclohexan-1 ,4-diyl), cycloheptylene, decalinylene (i.e., decahydronaphthylene), or adamantylene. Unless defined otherwise, “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).
As used herein, the term “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). For example, 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, oxepanyl, thiiranyl, thietanyl, tetrahydrothiophenyl (i.e., thiolanyl), 1 ,3-dithiolanyl, thianyl, 1 ,1 -dioxothianyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless defined otherwise, “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 (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.
As used herein, the term “A/-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.
As used herein, the term “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). For example, 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 (i.e., thiolanylene), 1 ,3-dithiolanylene, thianylene, 1 ,1-dioxothianylene, thiepanylene, decahydroquinolinylene, decahydroisoquinolinylene, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylene. Unless defined otherwise, “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 ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.
As used herein, the term “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. Unless defined otherwise, “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.
As used herein, the term “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 ring atoms and does not comprise any triple bond between adjacent ring atoms. For example, 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, octahydroquinolinyl (e.g., 1 ,2,3,4,4a,5,6,7-octahydroquinolinyl), or octahydroisoquinolinyl (e.g., 1 ,2,3,4,5,6,7,8-octahydroisoquinolinyl). Unless defined otherwise, “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., 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, 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.
As used herein, the term “halogen” refers to fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-I).
As used herein, the term “haloalky I” 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 -CF3, -CHF2, -CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3, or -CH(CF3)2. A particularly preferred “haloalkyl” group is -CF3. The terms “bond” and “covalent bond” are used herein synonymously, unless explicitly indicated otherwise or contradicted by context.
As used herein, the terms “optional”, “optionally” and “may” denote that the indicated feature may be present but can also be absent. Whenever the term “optional”, “optionally” or “may” is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, 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. Likewise, if 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.
Various groups are referred to as being “optionally substituted” in this specification. Generally, these groups may carry one or more 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. Unless defined otherwise, the “optionally substituted” groups referred to in this specification carry preferably not more than two substituents and may, in particular, carry only one substituent. Moreover, unless defined otherwise, it is preferred that the optional substituents are absent, i.e. that the corresponding groups are unsubstituted.
A skilled person will appreciate that the 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.
As used herein, unless explicitly indicated otherwise or contradicted by context, the terms “a”, “an” and “the” are used interchangeably with “one or more” and “at least one”. Thus, for example, a composition comprising “a” compound of formula (I) can be interpreted as referring to a composition comprising “one or more” compounds of formula (I).
It is to be understood that wherever numerical ranges are provided/disclosed herein, all values and subranges encompassed by the respective numerical range are meant to be encompassed within the scope of the invention. Accordingly, the present invention specifically and individually relates to each value that falls within a numerical range disclosed herein, as well as each subrange encompassed by a numerical range disclosed herein.
As used herein, 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.
As used herein, 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’. For example, the term “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).
Detailed description of the invention
The invention is described in detail in the following. It is to be understood that the present invention specifically relates to each and every combination of features and embodiments described herein, including any combination of general and/or preferred features/embodiments.
In a first embodiment, the present invention relates to a compound of formula (I):
Figure imgf000015_0001
or a pharmaceutically acceptable salt thereof.
In formula (I), Roov is selected from C2 alkenyl, C2 alkynyl, -CH2CI, -CH2CN, and
Figure imgf000015_0002
wherein said alkenyl is optionally substituted with one or more optional substituents selected from C1-4 alkyl, -COO-(Ci-4 alkyl), -CO-(Ci-4 alkyl), -CONH-(CI-4 alkyl), -OOC-(Ci-4 alkyl), -NHCO-(CI-4 alkyl), -(C1-4 alkylene)N(Ci-4 alkyl)(Ci-4 alkyl), -(C1-4 alkylene)-(/V-heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, said alkynyl is optionally substituted with an optional substituent selected from C1-4 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and the -CH2- group in said -CH2CI and the -CH2- group in said -CH2CN are each optionally substituted with one or more optional substituents selected from -Hal, C1-4 alkyl and -CF3, -Wcov- is selected from -CO-, -SO- and -SO2-; or -Wcov-Rcov is -CN. Suitable cycloalkyl group is for example a cyclopropyl group. Suitable aryl group is for example a phenyl group. Preferably, Rcov is selected from C2 alkenyl, C2 alkynyl, -CH2Cl, -CH2CN, and
Figure imgf000016_0001
wherein said alkenyl is optionally substituted with one or more optional substituents selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -OOC-(C1-4 alkyl), -NHCO-(C1-4 alkyl), -(C1-4 alkylene)N(C1-4 alkyl)(C1-4 alkyl), -(C1-4 alkylene)-(N-heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, preferably selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -(C1-4 alkylene)N(C1-4 alkyl)(C1-4 alkyl), -(C1-4 alkylene)-(N- heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, said alkynyl is optionally substituted with an optional substituent selected from C1-4 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and the -CH2- group in said -CH2Cl and the -CH2- group in said -CH2CN are each optionally substituted with one or more optional substituents selected from -Hal, C1-4 alkyl and -CF3, -Wcov- is selected from -CO-, -SO- and -SO2-. More preferably, Rcov is selected from C2 alkenyl, C2 alkynyl, and -CH2Cl, wherein said alkenyl is optionally substituted with one or more optional substituents selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -OOC-(C1-4 alkyl), -NHCO-(C1-4 alkyl), -(C1-4 alkylene)N(C1-4 alkyl)(C1-4 alkyl), -(C1-4 alkylene)-(N-heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, preferably selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -(C1-4 alkylene)N(C1-4 alkyl)(C1-4 alkyl), -(C1-4 alkylene)-(N- heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, more preferably selected from C1-4 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, said alkynyl is optionally substituted with an optional substituent selected from C1-4 alkyl, cycloalkyl, heterocycloalkyl, aryl phenyl and heteroaryl, preferably selected from C1-4 alkyl, cycloalkyl, and aryl and the -CH2- group in said -CH2Cl is optionally substituted with one or more optional substituents selected from -Hal, C1-4 alkyl and -CF3. More preferably, Rcov is selected from C2 alkenyl, and -CH2Cl, wherein said alkenyl is optionally substituted with one or more optional substituents selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -OOC-(C1-4 alkyl), -NHCO-(C1-4 alkyl), -(C1-4 alkylene)N(C1-4 alkyl)(C1-4 alkyl), -(C1-4 alkylene)-(N-heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, preferably selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -(C1-4 alkylene)N(C1-4 alkyl)(C1-4 alkyl), -(C1-4 alkylene)-(N- heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, more preferably selected from C1-4 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, and the -CH2- group in said -CH2Cl is optionally substituted with one or more optional substituents selected from -Hal, C1-4 alkyl and -CF3. Even more preferably, Rcov is C2 alkenyl, wherein said alkenyl is optionally substituted with one or more optional substituents selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -OOC-(C1-4 alkyl), -NHCO-(C1-4 alkyl), -(C1-4 alkylene)N(C1-4 alkyl)(C1-4 alkyl), -(C1-4 alkylene)-(N- heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, preferably selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -(C1-4 alkylene)N(C1-4 alkyl)(C1-4 alkyl), -(C1-4 alkylene)-(N-heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and - CF3, more preferably selected from C1-4 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3. Even more preferably, Rcov is C2 alkenyl. Preferably, -Wcov- is selected from -CO- and -SO2-. More preferably, -Wcov- is -CO-. In formula (I), -RN- is: - heterocycloalkylene comprising an N atom, wherein Wcov is connected to RN through said N atom and wherein said heterocycloalkylene is optionally substituted with one or more optional substituents selected from -Hal, -(C0-2 alkylene)-CN, C1-2 alkyl and C1-2 haloalkyl; - -(C1-2 alkylene)-heterocycloalkylene, wherein said heterocycloalkylene comprises an N atom, wherein Wcov is connected to RN through said N atom and wherein said heterocycloalkylene is optionally substituted with one or more optional substituents selected from -Hal, -(C0-2 alkylene)-CN, C1-2 alkyl and C1-2 haloalkyl; - -(C1-6 alkylene)-NH- or -(C1-6 alkylene)-N(C1-2 alkyl)-, wherein Wcov is connected to RN through said N atom in -(C1-6 alkylene)-NH- or -(C1-6 alkylene)-N(C1-2 alkyl)-, wherein said alkylene is optionally substituted with one or more optional substituents selected from -Hal and -CN; or - -(C0-2 alkylene)-cycloalkylene-(C0-2 alkylene)-NH- or -(C0-2 alkylene)-cycloalkylene-(C0-2 alkylene)-N(C1-2 alkyl)-, wherein Wcov is connected to RN through said N atom in -(C0-2 alkylene)- cycloalkylene-(C0-2 alkylene)-NH- or -(C0-2 alkylene)-cycloalkylene-(C0-2 alkylene)-N(C1-2 alkyl)-, wherein said cycloalkylene is optionally substituted with one or more optional substituents selected from -Hal, - (C0-2 alkylene)-CN, C1-2 alkyl and C1-2 haloalkyl. Preferably, in formula (I), -RN- is heterocycloalkylene comprising an N atom, wherein Wcov is connected to RN through said N atom and wherein said heterocycloalkylene is optionally substituted with one or more optional substituents selected from -Hal, -(C0-2 alkylene)-CN, C1-2 alkyl and C1-2 haloalkyl. More preferably, RN is selected from:
Figure imgf000018_0001
In formula (I), R1 is hydrogen, chloro, fluoro, -CN, formyl, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-O-(C1-2 alkyl) (preferably R1 is chloro, fluoro, -CN, formyl, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-O-(C1-2 alkyl)); and R2 and R3 are independently each C1-2 alkyl or C1-2 haloalkyl, or R2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more -F; or -CR1R2R3 is bicyclo[1,1,1]pent-1-yl. Preferably, R1 is hydrogen, chloro, fluoro, -CN, formyl, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-O-(C1-2 alkyl) (preferably R1 is chloro, fluoro, -CN, formyl, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-O-(C1-2 alkyl)); and R2 and R3 are independently each C1-2 alkyl or C1-2 haloalkyl, or R2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more -F. More preferably, R1 is hydrogen, chloro, fluoro, -CN, formyl, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-O-(C1-2 alkyl) (preferably R1 is chloro, fluoro, -CN, formyl, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-O-(C1-2 alkyl)); and R2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more -F. R1 is preferably -CN, methyl, fluoromethyl, difluoromethyl or trifluoromethyl, more preferably R1 is methyl or fluoromethyl. Preferably, R2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more -F. W is selected from -NHS(O)y-, -S(O)yNH-, -NHS(O)(NH)-, -NHS(O)(N-C1-2 alkyl)-, -S(O)(NH)-NH- , -S(O)(N-C1-2 alkyl)-NH-, wherein y is 1 or 2. Preferably, y is 2. Thus, in a preferred embodiment, W is selected from -NHS(O)2-, -S(O)2NH-, -NHS(O)(NH)-, and -S(O)(NH)-NH-. More preferably, W is selected from -NHS(O)2-, and -S(O)2NH-, even more preferably W is -NHS(O)2-. Preferably as understood herein, 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). X1 and X3 are independently selected from the group consisting of N, CH, C(C1-2 alkyl), C-Cl and CF, preferably independently selected from the group consisting of N, CH and CF. Preferably, X1 is CF or CH and X3 is CH, more preferably X1 and X3 are each CH. X2 is N or C-YC2-RC2, wherein YC2 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 RS1, 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(C1-5 alkyl)-, -CO-, -S-, -SO-, and -SO2-, and wherein said cycloalkylene and heterocycloalkylene are each optionally substituted with one or more groups independently selected RS2; and wherein RC2 is selected from hydrogen, halo, -OH, -NH2, -SH, -CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein said alkyl, alkenyl, and alkynyl in X2 are each optionally substituted with one or more groups independently selected from RS1, and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in X2 are each optionally substituted with one or more groups independently selected from RS2. Preferably, YC2 is selected from a covalent bond, -(C1-3 alkylene)-, -CO-(C1-3 alkylene)-, (C1-3 alkylene)-CO-, -CONH-(C1-3 alkylene)-, -(C1-3 alkylene)-CONH-, -NHCO-(C1-3 alkylene)-, -(C1-3 alkylene)- NHCO-, -NH-(C1-3 alkylene)-, -(C1-3 alkylene)-NH-, -N(C1-5 alkyl)-, -O-(C1-3 alkylene)-, -(C1-3 alkylene)-O- , -SO2-(C1-3 alkylene)-, -(C1-3 alkylene)-SO2-, -CONH-, -NHCO-, -NH-, -O-, -CO- and -SO2-, wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more groups independently selected from RS1. C1-3 alkylene is herein preferably a -CH2- group. Preferably, RC2 is selected from hydrogen, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2. More preferably, RC2 is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in X2 are each optionally substituted with one or more groups independently selected from RS2. Even more preferably, RC2 is selected from heterocycloalkyl, aryl, and heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in X2 are each optionally substituted with one or more groups independently selected from RS2. Thus preferably, if X2 is C-YC2-RC2, -YC2-RC2 is is selected from -O-C1-12 alkyl, -NH-C1-12 alkyl, - N(C1-5 alkyl)-C1-12 alkyl, -O-C2-12 alkenyl, -NH-C2-12 alkenyl, -N(C1-5 alkyl)-C2-12 alkenyl, -O-C2-12 alkynyl, - NH-C2-12 alkynyl, -N(C1-5 alkyl)-C2-12 alkynyl, -(C0-3 alkylene)-cycloalkyl, -CO-(C0-3 alkylene)-cycloalkyl, - (C0-3 alkylene)-CO-cycloalkyl, -CONH-(C0-3 alkylene)-cycloalkyl, (C0-3 alkylene)-CONH-cycloalkyl, - NHCO-(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-NHCO-cycloalkyl, -NH-(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-NH-cycloalkyl, -O-(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-O-cycloalkyl, -SO2-(C0-3 alkylene)- cycloalkyl, -(C0-3 alkylene)-SO2-cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O- cycloalkyl, -CO-cycloalkyl, -SO2-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -CO-(C0-3 alkylene)- heterocycloalkyl, -(C0-3 alkylene)-CO-heterocycloalkyl, -CONH-(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-NHCO- heterocycloalkyl, -NH-(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-NH-heterocycloalkyl, -O-(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-O-cycloalkyl, -SO2-(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-SO2-heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO2-heterocycloalkyl, -(C0-3 alkylene)-aryl, -CO-(C0-3 alkylene)-aryl, -(C0-3 alkylene)-CO-aryl, -CONH-(C0-3 alkylene)-aryl, -(C0-3 alkylene)-CONH-aryl, -NHCO- (C0-3 alkylene)-aryl, -(C0-3 alkylene)-NHCO-aryl, -NH-(C0-3 alkylene)-aryl, -(C0-3 alkylene)-NH-aryl, -O-(C0- 3 alkylene)-aryl, -(C0-3 alkylene)-O-aryl, -SO2-(C0-3 alkylene)-aryl, -(C0-3 alkylene)-SO2-aryl, -CONH-aryl, - NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO2-aryl, -(C0-3 alkylene)-heteroaryl, -CO-(C0-3 alkylene)- heteroaryl, -(C0-3 alkylene)-CO-heteroaryl, -CONH-(C0-3 alkylene)-heteroaryl, -(C0-3 alkylene)-CONH- heteroaryl, -NHCO-(C0-3 alkylene)-heteroaryl, -(C0-3 alkylene)-NHCO-heteroaryl, -NH-(C0-3 alkylene)- heteroaryl, -(C0-3 alkylene)-NH-heteroaryl, -O-(C0-3 alkylene)-heteroaryl, -(C0-3 alkylene)-O- heteroaryl, -SO2-(C0-3 alkylene)-heteroaryl, -(C0-3 alkylene)-SO2-heteroaryl, -CONH-heteroaryl, -NHCO- heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and -SO2-heteroaryl, wherein said alkylene is optionally substituted with one or more groups independently selected from RS1, and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2. More preferably, -YC2-RC2 is selected from -(C0-3 alkylene)-heterocycloalkyl, -CO-(C0-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)-CO-heterocycloalkyl, -CONH-(C0-3 alkylene)heterocycloalkyl, - (C0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(C0-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)-NHCO- heterocycloalkyl, -NH-(C0-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)-NH-heterocycloalkyl, -O-(C0-3 alkylene) heterocycloalkyl, (C0-3 alkylene)-O-cycloalkyl, -SO2-(C0-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)-SO2-heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO2-heterocycloalkyl, -(C0-3 alkylene)aryl, -CO-(C0-3 alkylene)aryl, -(C0-3 alkylene)-CO-aryl, -CONH-(C0-3 alkylene)aryl, -(C0-3 alkylene)-CONH-aryl, -NHCO- (C0-3 alkylene)aryl, -(C0-3 alkylene)-NHCO-aryl, -NH-(C0-3 alkylene)aryl, -(C0-3 alkylene)-NH-aryl, -O-(C0-3 alkylene)aryl, -(C0-3 alkylene)-O-aryl, -SO2-(C0-3 alkylene)aryl, -(C0-3 alkylene)-SO2-aryl, -CONH-aryl, - NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO2-aryl, -(C0-3 alkylene)heteroaryl, -CO-(C0-3 alkylene)heteroaryl, -(C0-3 alkylene)-CO-heteroaryl, -CONH-(C0-3 alkylene)heteroaryl, -(C0-3 alkylene)- CONH-heteroaryl, -NHCO-(C0-3 alkylene)heteroaryl, -(C0-3 alkylene)-NHCO-heteroaryl, -NH-(C0-3 alkylene)heteroaryl, -(C0-3 alkylene)-NH-heteroaryl, -O-(C0-3 alkylene)heteroaryl, -(C0-3 alkylene)-O- heteroaryl, -SO2-(C0-3 alkylene)heteroaryl, -(C0-3 alkylene)-SO2-heteroaryl, -CONH-heteroaryl, -NHCO- heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and -SO2-heteroaryl, wherein said alkylene is optionally substituted with one or more groups independently selected from RS1, and wherein said heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2. Even more preferably, -YC2-RC2 is selected from -(C0-3 alkylene)-heterocycloalkyl, -CONH- heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO- heterocycloalkyl, -SO2-heterocycloalkyl, -(C0-3 alkylene)aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO2-aryl, -(C0-3 alkylene)heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O- heteroaryl, -CO-heteroaryl and -SO2-heteroaryl, wherein said alkylene is optionally substituted with one or more groups independently selected from RS1, and wherein said heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2. Even more preferably, -YC2-RC2 is selected from -(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)aryl, and -(C0-3 alkylene)heteroaryl, wherein said heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2.. Even more preferably, -YC2-RC2 is selected from heterocycloalkyl, aryl, and heteroaryl wherein said heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2. Even more preferably -YC2-RC2 is selected from heterocycloalkyl and heteroaryl, wherein said heterocycloalkyl, and heteroaryl are each optionally substituted with one or more groups independently selected from RS2. Even more preferably, -YC2-RC2 is heterocycloalkyl wherein said heterocycloalkyl is optionally substituted with one or more groups independently selected from RS2. In formula (I), the moiety represented with a partial formula is a moiety selected
Figure imgf000022_0002
from
Figure imgf000022_0001
wherein: R7 is hydrogen, -CN, -Hal, or a moiety of the formula:
Figure imgf000022_0003
wherein: L71 is a bond or C1-5 alkylene optionally substituted with halo or oxo; L72 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, -N(C1-6 alkyl)-, -CO-, -COO-, -OCO-, -CONH-, -CON(C1- 6 alkyl)-, -NHCO-, N(C1-6 alkyl)CO-, -NHCONH-, -N(C1-6 alkyl)CONH-, -NHCON(C1-6 alkyl)-, N(C1-6 alkyl)CON(C1-6 alkyl)-, -SO2NH-, -SO2N(C1-6 alkyl)-, -NHSO2-, or -N(C1-6 alkyl)SO2-, and Q7 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)- aryl, -(C0-2 alkylene)-heterocycloalkyl or -(C0-2 alkylene)-heteroaryl; wherein said alkyl, alkenyl, alkynyl, and alkylene in R7 are each optionally substituted with one or more optional substituents selected from RS1; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in R7 are each optionally substituted with one or more optional substituents selected from RS2; R8 is hydrogen, -CN, -Hal, or a moiety of the formula:
Figure imgf000023_0001
wherein: L81 is a bond, C1-5 alkylene optionally substituted with halo or oxo; L82 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, -N(C1-6 alkyl)-, -CO-, -COO-, -OCO-, -CONH-, -CON(C1- 6 alkyl)-, -NHCO-, N(C1-6 alkyl)CO-, -NHCONH-, -N(C1-6 alkyl)CONH-, -NHCON(C1-6 alkyl)-, N(C1-6 alkyl)CON(C1-6 alkyl)-, -SO2NH-, -SO2N(C1-6 alkyl)-, -NHSO2-, or -N(C1-6 alkyl)SO2-; and Q8 is hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein said alkyl, alkenyl, alkynyl, and alkylene in R8 are each optionally substituted with one or more optional substituents selected from RS1; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in R8 are each optionally substituted with one or more optional substituents selected from RS2. Preferably, R7 is a moiety of the formula:
Figure imgf000023_0002
wherein: L71 is a bond or C1-5 alkylene optionally substituted with halo or oxo; L72 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, -N(C1-6 alkyl)-, -CO-, -COO-, -OCO-, -CONH-, -CON(C1- 6 alkyl)-, -NHCO-, N(C1-6 alkyl)CO-, -NHCONH-, -N(C1-6 alkyl)CONH-, -NHCON(C1-6 alkyl)-, N(C1-6 alkyl)CON(C1-6 alkyl)-, -SO2NH-, -SO2N(C1-6 alkyl)-, -NHSO2-, or -N(C1-6 alkyl)SO2-, and Q7 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)- aryl, -(C0-2 alkylene)-heterocycloalkyl or -(C0-2 alkylene)-heteroaryl; wherein said alkyl, alkenyl, alkynyl, and alkylene in R7 are each optionally substituted with one or more optional substituents selected from RS1; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in R7 are each optionally substituted with one or more optional substituents selected from RS2. Preferably, L71 is a bond. Preferably, L72 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, -N(C1-6 alkyl)-, -CO-, -COO-, -OCO-, -CONH- , -CON(C1-6 alkyl)-, -NHCO-, N(C1-6 alkyl)CO-, -NHCONH-, -N(C1-6 alkyl)CONH-, -NHCON(C1-6 alkyl)-, N(C1-6 alkyl)CON(C1-6 alkyl)-, -SO2NH-, or -NHSO2-, wherein said alkyl in is optionally substituted with one or more optional substituents selected from RS1. More preferably, L72 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, -CO-, -COO-, -OCO-, -CONH-, - SO2NH- or -NHSO2-. Even more preferably, L72 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, or -CO-. Even more preferably, L72 is a bond, -O-, or -S-. Even more preferably, L72 is a bond. It is noted that in the case of two bivalent chemical groups attached to each other, e.g. -L71-L72-, if each of them is defined to be a chemical bond, it is to be understood that the whole moiety comprising two bivalent chemical groups attached to each other is a bond. In other words, for example, is -L71- is a bond and -L72- is a bond, then -L71-L72- is a bond. Preferably, Q7 is C2-6 alkynyl, -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-aryl, -(C0-2 alkylene)- heterocycloalkyl or -(C0-2 alkylene)-heteroaryl; wherein said alkynyl and alkylene are each optionally substituted with one or more optional substituents selected from RS1; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more optional substituents selected from RS2. More preferably, Q7 is -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-aryl, -(C0-2 alkylene)- heterocycloalkyl or -(C0-2 alkylene)-heteroaryl; wherein said alkylene is optionally substituted with one or more optional substituents selected from RS1; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more optional substituents selected from RS2. Even more preferably, Q7 is -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-heterocycloalkyl or -(C0-2 alkylene)-heteroaryl; wherein said alkylene is optionally substituted with one or more optional substituents selected from RS1; and wherein said cycloalkyl, heterocycloalkyl, and heteroaryl are each optionally substituted with one or more optional substituents selected from RS2. It is to be understood that if L71 is a bond and L72 is a bond, then R7 is preferably Q7. Accordingly, R7 is preferably Q7 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(C0-2 alkylene)- cycloalkyl, -(C0-2 alkylene)-aryl, -(C0-2 alkylene)-heterocycloalkyl or -(C0-2 alkylene)-heteroaryl; wherein said alkyl, alkenyl, alkynyl, and alkylene in R7 are each optionally substituted with one or more optional substituents selected from RS1; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in R7 are each optionally substituted with one or more optional substituents selected from RS2. More preferably, R7 is C2-6 alkynyl, -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-aryl, -(C0-2 alkylene)-heterocycloalkyl or -(C0-2 alkylene)-heteroaryl; wherein said alkynyl and alkylene are each optionally substituted with one or more optional substituents selected from RS1; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more optional substituents selected from RS2. Even more preferably, R7 is -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-aryl, -(C0-2 alkylene)- heterocycloalkyl or -(C0-2 alkylene)-heteroaryl; wherein said alkylene is optionally substituted with one or more optional substituents selected from RS1; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more optional substituents selected from RS2. Even more preferably, R7 is -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-heterocycloalkyl or -(C0-2 alkylene)-heteroaryl; wherein said alkylene is optionally substituted with one or more optional substituents selected from RS1; and wherein said cycloalkyl, heterocycloalkyl, and heteroaryl are each optionally substituted with one or more optional substituents selected from RS2. Preferably R8 is a moiety of the formula:
Figure imgf000025_0001
wherein: L81 is a bond, C1-5 alkylene optionally substituted with halo or oxo; L82 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, -N(C1-6 alkyl)-, -CO-, -COO-, -OCO-, -CONH-, -CON(C1- 6 alkyl)-, -NHCO-, N(C1-6 alkyl)CO-, -NHCONH-, -N(C1-6 alkyl)CONH-, -NHCON(C1-6 alkyl)-, N(C1-6 alkyl)CON(C1-6 alkyl)-, -SO2NH-, -SO2N(C1-6 alkyl)-, -NHSO2-, or -N(C1-6 alkyl)SO2-; and Q8 is hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein said alkyl, alkenyl, alkynyl, and alkylene in R8 are each optionally substituted with one or more optional substituents selected from RS1; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in R8 are each optionally substituted with one or more optional substituents selected from RS2. Preferably, L81 is -(C0-2 alkylene)-, wherein said alkylene is optionally substituted with one or more optional substituents selected from RS1. Preferably, L82 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, -CO-, -COO-, -OCO-, -CONH-, -SO2NH-, or -NHSO2-. More preferably, L82 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, or -CO-. Even more preferably, L82 is a bond, -O-, or -S-. Even more preferably, L82 is a bond. Preferably, Q8 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein said alkyl, alkenyl, and alkynyl are each optionally substituted with one or more optional substituents selected from RS1; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more optional substituents selected from RS2. More preferably, Q8 is C2-6 alkynyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein said alkynyl is optionally substituted with one or more optional substituents selected from RS1; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more optional substituents selected from RS2. Even more preferably, Q8 is cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more optional substituents selected from RS2. Even more preferably, Q8 is cycloalkyl, heterocycloalkyl or heteroaryl; wherein said cycloalkyl, heterocycloalkyl, and heteroaryl are each optionally substituted with one or more optional substituents selected from RS2. Thus accordingly, R8 is preferably selected from -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-aryl, -(C0-2 alkylene)-heterocycloalkyl or -(C0-2 alkylene)-heteroaryl, wherein said alkylene is optionally substituted with one or more optional substituents selected from RS1; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in R8 are each optionally substituted with one or more optional substituents selected from RS2. More preferably, R8 is selected from -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-heterocycloalkyl or -(C0-2 alkylene)-heteroaryl, wherein said alkylene is optionally substituted with one or more optional substituents selected from RS1; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in R8 are each optionally substituted with one or more optional substituents selected from RS2. Particularly preferred -(C0-2 alkylene)- in R8 is methylene. Thus, preferably R8 is selected from - CH2-cycloalkyl, -CH2-aryl, -CH2-heterocycloalkyl or -CH2-heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in R8 are each optionally substituted with one or more optional substituents selected from RS2. More preferably R8 is selected from -CH2-cycloalkyl, -CH2-heterocycloalkyl or -CH2-heteroaryl, wherein said cycloalkyl, heterocycloalkyl, and heteroaryl in R8 are each optionally substituted with one or more optional substituents selected from RS2. In other words, preferably in R8 L81 is methylene, -L82 is a covalent bond, and Q8 is cycloalkyl, aryl, heterocycloalkyl or heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in R8 are each optionally substituted with one or more optional substituents selected from RS2. More preferably, in R8 L81 is methylene, -L82 is a covalent bond, and Q8 is cycloalkyl, heterocycloalkyl or heteroaryl, wherein said cycloalkyl, heterocycloalkyl, and heteroaryl in R8 are each optionally substituted with one or more optional substituents selected from RS2. Particularly preferred R8 is
Figure imgf000027_0001
Preferably, the moiety represented with a partial formula
Figure imgf000027_0002
Therein, R8 is defined as defined hereinabove. In formula (I), RS1 is selected from halogen, -CN, -OH, -O(C1-5 alkyl), -O(C1-5 haloalkyl), C1-5 haloalkyl, -SH, -S(C1-5 alkyl), -SO2(C1-5 alkyl), -S(O)(NH)(C1-5 alkyl), -S(O)(N-C1-3 alkyl)(C1-5 alkyl), -N=S(O)(C1-5 alkyl)(C1-5 alkyl), -S(C1-5 haloalkyl), -P(O)(C1-5 alkyl)(C1-5 alkyl), -P(O)(O-C1-5 alkyl) (O-C1-5 alkyl), -P(O)(O-C1-5 alkyl)(C1-5 alkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -(N-heterocycloalkyl), -CO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -CO-(N-heterocycloalkyl), -NHCO-(C1-5 alkyl), -N(C1-5 alkyl)-CO-(C1-5 alkyl), -NHCONH2, -NHCONH-(C1-5 alkyl), -NHCON(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 alkyl)CONH2, -N(C1-5 alkyl)CONH-(C1-5 alkyl), and -N(C1-5 alkyl)CON(C1-5 alkyl)(C1-5 alkyl). Preferably, RS1 is selected from halogen, -CN, -OH, -O(C1-5 alkyl), -O(C1-5 haloalkyl), C1-5 haloalkyl, -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1- 5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -(N-heterocycloalkyl), -CO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -CO-(N-heterocycloalkyl), -NHCO-(C1-5 alkyl), -N(C1-5 alkyl)-CO-(C1-5 alkyl), -NHCONH2, -NHCONH-(C1-5 alkyl), -NHCON(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 alkyl)CONH2, -N(C1-5 alkyl)CONH-(C1-5 alkyl), and -N(C1-5 alkyl)CON(C1-5 alkyl)(C1-5 alkyl). More preferably, RS1 is selected from halogen, -CN, -OH, -O(C1-5 alkyl), -O(C1-5 haloalkyl), C1-5 haloalkyl, -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1- 5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -(N-heterocycloalkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -CO-(N-heterocycloalkyl), -NHCO-(C1-5 alkyl), -N(C1-5 alkyl)-CO-(C1-5 alkyl), -NHCONH2, -NHCONH-(C1-5 alkyl), -NHCON(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 alkyl)CONH2, -N(C1-5 alkyl)CONH-(C1-5 alkyl), and -N(C1-5 alkyl)CON(C1-5 alkyl)(C1-5 alkyl). Even more preferably, RS1 is selected from halogen, -CN, -OH, -O(C1-5 alkyl), -O(C1-5 haloalkyl), C1-5 haloalkyl, -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), and -(N-heterocycloalkyl). Even more preferably, RS1 is selected from halogen, -CN, -OH, -SH, and -NH2. In formula (I), RS2 is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(C1-5 alkyl), - O(C1-5 haloalkyl), -SH, -S(C1-5 alkyl), -SO2(C1-5 alkyl), -S(O)(NH)(C1-5 alkyl), -S(O)(N-C1-3 alkyl)(C1-5 alkyl), -N=S(O)(C1-5 alkyl)(C1-5 alkyl), -S(C1-5 haloalkyl), -P(O)(C1-5 alkyl)(C1-5 alkyl), -P(O)(O-C1-5 alkyl)(O- C1-5 alkyl), -P(O)(O-C1-5 alkyl)(C1-5 alkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -(N-heterocycloalkyl), -CO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -CO-(N-heterocycloalkyl), -NHCO-(C1-5 alkyl), -N(C1-5 alkyl)-CO-(C1-5 alkyl), -NHCONH2, -NHCONH-(C1-5 alkyl), -NHCON(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 alkyl)CONH2, -N(C1-5 alkyl)CONH-(C1-5 alkyl), and -N(C1-5 alkyl)CON(C1-5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-O(C1-5 alkyl), -(C1-5 alkylene)-O(C1-5 haloalkyl), -(C1-5 alkylene)-SH, -(C1-5 alkylene)-S(C1-5 alkyl), -(C1-5 alkylene)-SO2(C1-5 alkyl), -(C1-5 alkylene)-S(O)(NH)(C1-5 alkyl), -(C1-5 alkylene)-S(O)(N-C1-3 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-N=S(O)(C1-5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)- S(C1-5 haloalkyl), -(C1-5 alkylene)-P(O)(C1-5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-P(O)(O-C1-5 alkyl)(O-C1-5 alkyl), -(C1-5 alkylene)-P(O)(O-C1-5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-NH2, -(C1-5 alkylene)-NH(C1-5 alkyl), - (C1-5 alkylene)-NH(C1-5 haloalkyl), -(C1-5 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-N(C1-5 alkyl)(C1- 5 haloalkyl), -(C1-5 alkylene)-(N-heterocycloalkyl), -(C1-5 alkylene)-N(C1-5 haloalkyl)(C1-5 alkyl), -(C1-5 alkylene)-CO(C1-5 alkyl), -(C1-5 alkylene)-CONH2, -(C1-5 alkylene)-CONH(C1-5 alkyl), -(C1-5 alkylene)-CON(C1-5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-CO-(N-heterocycloalkyl), -(C1-5 alkylene)-NHCO-(C1- 5 alkyl), -(C1-5 alkylene)-N(C1-5 alkyl)-CO-(C1-5 alkyl), -(C1-5 alkylene)-NHCONH2, -(C1-5 alkylene)-NHCONH-(C1-5 alkyl), -(C1-5 alkylene)-NHCON(C1-5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-N(C1-5 alkyl)CONH2, -(C1-5 alkylene)-N(C1-5 alkyl)CONH-(C1-5 alkyl), and -(C1-5 alkylene)-N(C1-5 alkyl)CON(C1-5 alkyl)(C1-5 alkyl). Preferably, RS2 is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(C1-5 alkyl), -O(C1- 5 haloalkyl), -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -(N-heterocycloalkyl), -CO(C1-5 alkyl), -CONH2, -CONH(C1- 5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -CO-(N-heterocycloalkyl), -(C1-5 alkylene)-CN, -(C1-5 alkylene)-OH, - (C1-5 alkylene)-O(C1-5 alkyl), -(C1-5 alkylene)-O(C1-5 haloalkyl), -(C1-5 alkylene)-SH, -(C1-5 alkylene)-S(C1-5 alkyl), -(C1-5 alkylene)-S(C1-5 haloalkyl), -(C1-5 alkylene)-NH2, -(C1-5 alkylene)-NH(C1-5 alkyl), -(C1-5 alkylene)-NH(C1-5 haloalkyl), -(C1-5 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-N(C1-5 alkyl)(C1-5 haloalkyl), -(C1-5 alkylene)-(N-heterocycloalkyl), -(C1-5 alkylene)-N(C1-5 haloalkyl)(C1-5 alkyl), -(C1-5 alkylene)-CO(C1-5 alkyl), -(C1-5 alkylene)-CONH2, -(C1-5 alkylene)-CONH(C1-5 alkyl), -(C1-5 alkylene)-CON(C1-5 alkyl)(C1-5 alkyl) -(C1-5 alkylene)-CO-(N-heterocycloalkyl), -(C1-5 alkylene)-NHCO-(C1- 5 alkyl), -(C1-5 alkylene)-N(C1-5 alkyl)-CO-(C1-5 alkyl), -(C1-5 alkylene)-NHCONH2, -(C1-5 alkylene)-NHCONH-(C1-5 alkyl), -(C1-5 alkylene)-NHCON(C1-5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-N(C1-5 alkyl)CONH2, -(C1-5 alkylene)-N(C1-5 alkyl)CONH-(C1-5 alkyl), and -(C1-5 alkylene)-N(C1-5 alkyl)CON(C1-5 alkyl)(C1-5 alkyl). More preferably, RS2 is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(C1-5 alkyl), -O(C1-5 haloalkyl), -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1- 5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -(N-heterocycloalkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -CO-(N-heterocycloalkyl), -NHCO-(C1-5 alkyl), -N(C1-5 alkyl)-CO-(C1-5 alkyl), -NHCONH2, -NHCONH-(C1-5 alkyl), -NHCON(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 alkyl)CONH2, -N(C1-5 alkyl)CONH-(C1-5 alkyl), -N(C1-5 alkyl)CON(C1-5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-O(C1-5 alkyl), -(C1-5 alkylene)-O(C1-5 haloalkyl), -(C1-5 alkylene)-SH, -(C1-5 alkylene)-S(C1-5 alkyl), -(C1-5 alkylene)-S(C1-5 haloalkyl), -(C1-5 alkylene)-NH2, -(C1-5 alkylene)-NH(C1-5 alkyl), -(C1-5 alkylene)-NH(C1-5 haloalkyl), -(C1-5 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-N(C1-5 alkyl)(C1-5 haloalkyl), -(C1-5 alkylene)-(N-heterocycloalkyl), -(C1-5 alkylene)-N(C1-5 haloalkyl)(C1-5 alkyl), -(C1-5 alkylene)-CONH2, -(C1-5 alkylene)-CONH(C1-5 alkyl), -(C1-5 alkylene)-CON(C1-5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-CO-(N-heterocycloalkyl), -(C1-5 alkylene)-NHCO-(C1-5 alkyl), -(C1-5 alkylene)-N(C1-5 alkyl)-CO- (C1-5 alkyl), -(C1-5 alkylene)-NHCONH2, -(C1-5 alkylene)-NHCONH-(C1-5 alkyl), -(C1-5 alkylene)-NHCON(C1- 5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-N(C1-5 alkyl)CONH2, -(C1-5 alkylene)-N(C1-5 alkyl)CONH-(C1-5 alkyl), and -(C1-5 alkylene)-N(C1-5 alkyl)CON(C1-5 alkyl)(C1-5 alkyl). Even more preferably, RS2 is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(C1-5 alkyl), -O(C1-5 haloalkyl), -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -(N-heterocycloalkyl), -(C1-5 alkylene)- CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-O(C1-5 alkyl), -(C1-5 alkylene)-O(C1-5 haloalkyl), -(C1-5 alkylene)-SH, -(C1-5 alkylene)-S(C1-5 alkyl), -(C1-5 alkylene)-S(C1-5 haloalkyl), -(C1-5 alkylene)-NH2, -(C1-5 alkylene)-NH(C1-5 alkyl), -(C1-5 alkylene)-NH(C1-5 haloalkyl), -(C1-5 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), -(C1- 5 alkylene)-N(C1-5 alkyl)(C1-5 haloalkyl), -(C1-5 alkylene)-(N-heterocycloalkyl), -(C1-5 alkylene)-N(C1-5 haloalkyl)(C1-5 alkyl), -(C1-5 alkylene)-CONH2, -(C1-5 alkylene)-CONH(C1-5 alkyl), -(C1-5 alkylene)-CON(C1- 5 alkyl)(C1-5 alkyl), and -(C1-5 alkylene)-CO-(N-heterocycloalkyl). Even more preferably, RS2 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. Even more preferably, RS2 is selected from halogen, -CN, -OH, -SH, and -NH2. In a first specific embodiment, -CR1R2R3 is bicyclo[1,1,1]pent-1-yl. In a second specific embodiment, RN is selected from:
Figure imgf000030_0001
In a third specific embodiment, X2 is CH. In a fourth specific embodiment, X1 is CF and X3 is CH. In a fifth specific embodiment, -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(C1-5 alkyl), -O(C1-5 haloalkyl), -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -CO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), and -CON(C1-5 alkyl)(C1-5 alkyl). In a sixth specific embodiment, -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(C1-5 alkyl), -O(C1-5 haloalkyl), -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -CO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), and -CON(C1-5 alkyl)(C1-5 alkyl). In a seventh specific embodiment, -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 RS2. More preferably, -YC2-RC2 is piperazinyl, optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(C1-5 alkyl), -O(C1-5 haloalkyl), -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -CO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), and -CON(C1- 5 alkyl)(C1-5 alkyl). Even more preferably, -YC2-RC2 is piperazinyl (preferably N-piperazinyl) optionally substituted (preferably N-substituted) with -CO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), and -CON(C1-5 alkyl)(C1-5 alkyl). Most preferably, -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(C1-5 alkyl)(C1-5 alkyl), preferably with -CON(CH3)2. In an eighth specific embodiment, -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-yl, 8-oxa-3-azabicyclo[4.3.0]non-3-yl, 2-oxa-6- azaspiro[3.5]non-6-yl, 7-oxo-3,6,8-triazabicyclo[4.3.0]non-3-yl, 3-pyrrolino[3,4-c]pyrazol-2-yl, 3,6- diazabicyclo[3.1.1]hept-3-yl, and 2,7-diazaspiro[3.5]non-7-yl. In a ninth specific embodiment, R7 is hydrogen, -CN, or -Hal. Preferably, R7 is hydrogen. In this ninth specific embodiment, the moiety represented with a partial formula
Figure imgf000031_0001
preferably
Figure imgf000031_0002
Figure imgf000031_0003
In a tenth specific embodiment, R8 is hydrogen, -CN, or -Hal. Preferably, R8 is hydrogen. In this tenth specific embodiment, the moiety represented with a partial formula
Figure imgf000032_0001
is
Figure imgf000032_0002
. In an eleventh specific embodiment, R8 is -CH2C≡CH. In this eleventh specific embodiment, the moiety represented with a partial formula
Figure imgf000032_0003
s In a twelfth specific embodiment, R8 is -CH2-cycloalkyl or -CO-cycloalkyl. Particularly preferred cycloalkyl is cyclopropyl. In this twelfth embodiment, the moiety represented with a partial formula (wherein preferred R7 is H) or
Figure imgf000032_0004
hirteenth specific embodiment, -Wcov-R is -CN.
Figure imgf000032_0005
In a t cov In a fourteenth specific embodiment, -RN- is -(C1-6 alkylene)-NH- or -(C1-6 alkylene)-N(C1-2 alkyl)- , wherein Wcov is connected to RN through said N atom in -(C1-6 alkylene)-NH- or -(C1-6 alkylene)-N(C1-2 alkyl)-, wherein said alkylene is optionally substituted with one or more optional substituents selected from -Hal and -CN. Particularly preferred C1-6 alkylene is propylene or butylene. In this fourteenth embodiment, preferably -Wcov- is -CO- and Rcov is C2 alkenyl, wherein said alkenyl is optionally substituted with one or more optional substituents selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -OOC-(C1-4 alkyl), -NHCO-(C1-4 alkyl), -(C1-4 alkylene)N(C1-4 alkyl)(C1-4 alkyl), -(C1-4 alkylene)-(N- heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, preferably selected from C1-4 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3. More preferably, in this fourteenth embodiment, -Wcov-Rcov is -CO-CH=CH2. In a fifteenth specific embodiment, -RN- is -(C1-2 alkylene)-heterocycloalkylene, wherein said heterocycloalkylene comprises an N atom, wherein Wcov is connected to RN through said N atom and wherein said heterocycloalkylene is optionally substituted with one or more optional substituents selected from -Hal, -(C0-2 alkylene)-CN, C1-2 alkyl and C1-2 haloalkyl. In this fifteenth specific embodiment, particularly preferred -RN- is
Figure imgf000033_0001
. In a sixteenth specific embodiment, -RN- is -(C0-2 alkylene)-cycloalkylene-(C0-2 alkylene)-NH- or - (C0-2 alkylene)-cycloalkylene-(C0-2 alkylene)-N(C1-2 alkyl)-, wherein Wcov is connected to RN through said N atom in -(C0-2 alkylene)-cycloalkylene-(C0-2 alkylene)-NH- or -(C0-2 alkylene)-cycloalkylene-(C0-2 alkylene)-N(C1-2 alkyl)-, wherein said cycloalkylene is optionally substituted with one or more optional substituents selected from -Hal, -(C0-2 alkylene)-CN, C1-2 alkyl and C1-2 haloalkyl. In this sixteenth embodiment, particularly preferred -RN- is
Figure imgf000033_0002
. In a seventeenth specific embodiment, Rcov is
Figure imgf000033_0003
. In an eighteenth specific embodiment, W is -NHS(O)y-, wherein y is 1 or 2. Preferably, y is 2. It is to be understood that the left side of W as defined herein is attached to the carbon atom that carries R1, R2 and R3. Preferred compound of formula (I) are selected from the following compounds or their pharmaceutically acceptable salts: , ,
Figure imgf000033_0004
Figure imgf000034_0001
33
Figure imgf000035_0001
Further preferred compound of formula (I) are selected from the following compounds or their pharmaceutically acceptable salts:
Figure imgf000035_0002
Figure imgf000036_0001
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. 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, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. 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, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. 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. Accordingly, it is preferred that 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.
Moreover, 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.
Furthermore, 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. As for 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. For example, 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., 2H; also referred to as “D”). Accordingly, 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 (1H) and about 0.0156 mol-% deuterium (2H 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. For example, 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). Further suitable 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. Unless specifically indicated otherwise, it is preferred that the compound of formula (I) is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or 1H 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., 18F, 11C, 13N, 15O, 76Br, 77Br, 120I and/or 124I. 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 18F atoms, (ii) compounds of formula (I), in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by 11C atoms, (iii) compounds of formula (I), in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by 13N atoms, (iv) compounds of formula (I), in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by 15O atoms, (v) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by 76Br atoms, (vi) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by 77Br atoms, (vii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by 120I atoms, and (viii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by 124I atoms. In general, it is preferred that none of the atoms in the compounds of formula (I) are replaced by specific isotopes. The present invention further embraces the prodrugs of the compounds of formula (I). As preferably understood herein, 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. For example, as known to the skilled person, such prodrugs may preferably include for the compounds of formula (I) which comprise -OH moiety derivatives wherein said -OH moiety is turned into an -ORx moiety, wherein 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-Ry, -CH2-O-CO-Ry, -CH2-O-CO-O-Ry, and -CH(CH3)-O- COO-Ry, wherein Ry is preferably carbocyclyl, heterocyclyl, C1-5 alkyl, -NH-(C1-5 alkyl) or -S-(C1-5 alkyl), wherein the said alkyl is optionally substituted with a group selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(C1-5 alkyl), -O(C1-5 haloalkyl), -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), and -CON(C1-5 alkyl)(C1-5 alkyl), and wherein the said carbocyclyl and heterocyclyl are each optionally substituted with a group selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(C1-5 alkyl), -O(C1-5 haloalkyl), -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), and -CON(C1-5 alkyl)(C1-5 alkyl). Furthermore, for example, as known to the skilled person, such prodrugs may preferably include for the compounds of formula (I) which comprise -NH2 moiety derivatives wherein said -NH2 moiety is turned into -NHCOO-Ry moiety, wherein Ry is as defined hereinabove. Furthermore, for examples, as known to the skilled person, such prodrugs may preferably include for the compounds of formula (I) which comprise -COOH moiety derivatives wherein said -COOH group is turned into -COORy moiety, wherein Ry is as defined hereinabove. Further examples of groups that can be derivatized to yield prodrugs are known to the skilled person.
Pharmaceutical compositions
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., polyfethylene glycol), including polyfethylene 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, hydroxypropyl-p-cyclodextrin, hydroxyethyl-v-cyclodextrin, hydroxypropyl-y-cyclodextrin, dihydroxypropyl-p-cyclodextrin, sulfobutylether-p-cyclodextrin, sulfobutylether-Y-cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-p-cyclodextrin, diglucosyl-p-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-p-cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl-p-cyclodextrin, maltotriosyl-y-cyclodextrin, dimaltosyl-p-cyclodextrin, methyl-p-cyclodextrin, a carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, a vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.
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.
The pharmaceutical 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, 22nd 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.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or intracameral), rectal, or vaginal administration.
If said compounds or pharmaceutical compositions are administered parenterally, then 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. For 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. Preferred excipients in this regard include lactose, starch, a cellulose, or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, 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.
For oral administration, 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.
Alternatively, 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.
Said compounds or pharmaceutical compositions may also be administered by sustained release systems. Suitable examples of 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. For ophthalmic use, 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. Alternatively, they may be formulated in an ointment such as petrolatum.
It is also envisaged to prepare dry powder formulations of the compounds of formula (I) for pulmonary administration, particularly inhalation. Such dry powders 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.
For topical application to the skin, 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. Alternatively, 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. For each of the compounds or pharmaceutical compositions provided herein, it is particularly preferred that the respective compound or pharmaceutical composition is to be administered orally (particularly by oral ingestion).
Typically, 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 (of approximately 70 kg body weight) 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.
Therapeutic use
In one embodiment, the present invention relates to the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in therapy.
The present invention provides compounds that function as inhibitors of PARG. Thus, 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 thereof, as defined herein.
Without wishing to be bound by the theory, the present inventors have demonstrated that certain compounds of formula (I) as described herein are covalent inhibitors of PARG enzyme. As shown in Table 2, the compounds of the present invention are significantly more potent (i.e., exhibit lower ICso) against the wild-type PARG protein in comparison to its C872A mutant, which is not capable of covalently binding the compounds of the present invention. As further demonstrated in Table 2, the inhibition of PARG by the compounds of the present invention is time-dependent, leading to lower ICso values upon 2-hour incubation when compared to a shorter incubation of 15 minutes.
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 thereof, as defined herein.
In a further embodiment, 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 thereof, or a pharmaceutical composition as defined herein. In other words, in one embodiment 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.
In a further embodiment, 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 thereof, as defined herein. Thus, 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.
Thus, in a further embodiment, 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 thereof, or a pharmaceutical composition as defined herein. Preferably as disclosed herein, the proliferative disorder is cancer. Thus, 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 thereof, or a pharmaceutical composition as defined herein. In a particular embodiment, the cancer is human cancer.
In one embodiment, the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in treating a proliferative disorder. Preferably as disclosed herein, the proliferative disorder is cancer. Therefore, the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating cancer. In a particular embodiment, the cancer is human cancer.
In a further embodiment, the present invention relates to the compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, for use in the manufacture of a medicament for the treatment of a proliferative condition. In a preferred embodiment, the proliferative condition is cancer, more preferably a human cancer. Thus, preferably the present invention relates to the compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, for use in the manufacture of a medicament for the treatment of cancer, preferably for the treatment of human cancer.
In a further embodiment, the present invention relates to the compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, for use in the manufacture of a medicament for the inhibition of PARG enzyme activity. Preferably, the inhibition of PARG enzyme activity is selective inhibition of PARG enzyme activity over PARP1 or ARH3 enzyme activity. Thus, the present invention relates to the compound of formula (I), or a pharmaceutically acceptable salt 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 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.
As understood herein, the term "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. Examples of 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 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:
(i) other 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, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
(ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestagens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5oc-reductase such as finasteride;
(iii) 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. Chem., 2004, 47, 6658-6661 ) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase];
(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], 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. 54, pp1 1 -29); such 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 insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN107); inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (R1 15777) and lonafarnib (SCH66336)), inhibitors of cell signalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1 152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;
(v) 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 (Avastin™) 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 linomide, inhibitors of integrin av03 function and angiostatin)];
(vi) 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; (vii) an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan;
(viii) 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
(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.
In a particular embodiment, 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.
According to this aspect the present invention further relates to the compound of formula (I) or a pharmaceutically acceptable salt 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.
As understood herein, 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.
Examples
The following examples are merely illustrative of the present invention and should not be construed to limit the scope of the invention which is defined by the appended claims. The compounds described in this section are defined by their chemical formulae and their corresponding chemical names. In case of conflict between any chemical formula and the corresponding chemical name indicated herein, 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.
Synthesis of the compounds of formula (I)
The syntheses of embodiments A, B, C and D of the compounds of formula (I) according to the present invention are preferably carried out according to the general synthetic sequences as shown in Schemes 1-4.
In addition to said routes described below, also other routes may be used to synthesize the target compounds, in accordance with common general knowledge of a person skilled in the art of organic synthesis. The order of transformations exemplified in the following Schemes is therefore not intended to be limiting, and suitable synthesis steps from various schemes can be combined to form additional synthesis sequences. In addition, modification of any of the substituents can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protective groups, cleavage of protective groups, reduction or oxidation of functional groups, halogenation, metalation, metal-catalyzed coupling reactions, substitution or other reactions known to a person skilled in the art. These transformations include those which introduce a functionality allowing for further interconversion of substituents. Appropriate protective groups and their introduction and cleavage are well-known to a person skilled in the art (see for example: Greene's Protective Groups in Organic Synthesis; Editor: P.G.M. Wuts, 5th edition, Wiley 2014). Specific examples are described in the subsequent paragraphs. Further, it is possible that two or more successive steps may be performed without work-up being performed between said steps, e.g. a “one-pot” reaction, as it is well-known to a person skilled in the art.
Scheme 1
OH
Figure imgf000050_0001
Scheme 1 illustrates a preferred synthetic approach to compounds of the general formula A. As it is to be understandable to the skilled person, the scheme can also be extended to the compounds of formula (I) wherein W is -S(O)yNH-, -NHS(O)(NH)-, -NHS(O)(NCH3)-, -S(O)(NH)-NH-, or -S(O)(NCH3)-NH- upon the corresponding functionalization of the bromide of compound 1.
Figure imgf000050_0002
1 2
In the first step, compound 1 in which X1, X2, X3 and R7 are are as defined for formula (I) is reacted with benzyl mercaptan to give compound 2 in which X1, X2, X3 and R7 are are as defined for formula (I). 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’, 2nd edition.: de Meijere, Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004). Preferred is the herein described use of tris(dibenzylideneacetone) dipalladium(O), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and N-ethyl-N-isopropylpropan-2-amine in dioxane. 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.
Figure imgf000051_0001
In the second step, compound 2 in which X1, X2, X3 and R7 are are as defined for formula (I) is reacted with an bromide reagent to give compound 3 in which X1, X2, X3 and R7 are are as defined for formula (I). This bromination can be carried out by treatment with NBS, Br2 etc., in MeCN, THF, dioxane, DMF etc. (see for example: Bentley et al; WO2011/138266). Preferred is the herein described use of NBS in MeCN. The reactions are preferably run under an atmosphere of argon for 0.5 - 5 hours at 0 °C to room temperature.
Figure imgf000051_0002
In the third step, compound 3 in which X1, X2, X3, R7 are as defined for formula (I) is reacted with compound 4 in which R8 is CN or a moiety of the formula -L81-L82-Q8 to give compound 5. The coupling reaction is catalyzed by palladium catalysts, e.g. by Pd(0) catalysts like tetrakis(triphenylphosphine) palladium(O) [Pd(PPh3)4], tris(di benzylideneacetone) di-palladium(O) [Pd2(dba)3], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)-palladium(ll) [Pd(PPh3)2Cl2], palladium(ll) acetate and triphenylphosphine or by [l,l'-bis(diphenylphosphino)ferrocene]palladium dichloride. The reaction is preferably carried out in a solvent like 1 ,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base like potassium carbonate, sodium carbonate, sodium bicarbonate or potassium phosphate, (see for example: Hall, Boronic Acids, 2005 Wiley VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527- 30991-8 and references cited therein). The reaction is performed at temperatures ranging from room temperature to the boiling point of the respective solvent. Further on, the reaction can be performed at temperatures above the boiling point using pressure tubes and a microwave oven. The reaction is preferably completed after 1 to 36 hours.
Figure imgf000052_0001
In the fourth step, compound 5 in which X1, X2, X3 R7 and R8 are as defined for formula (I) is reacted with chlorination reagent to give a sulfonyl chloride 6. This sulfonyl chloride formation can be carried out by treatment with NCS, sulfonyl chloride, DCDMH, CI2 etc., in MeCN with equivalent acetic acid and water, (see for example: Sutton et al, WO 2021/055744). Preferred is the herein described use of DCDMH in MeCN with equivalent acetic acid and water. The reactions are preferably run under an atmosphere of argon for 0.5 - 5 hours at 0 °C to room temperature.
Figure imgf000052_0002
In the fifth step, compound 6 in which X1, X2, X3 R7 and R8 are as defined for formula (I) is reacted with amine 7 in which R1, R2 and R3 are as defined for formula (I) to give compound 8 in which X1, X2, X3 R7 and R8 are as defined for formula (I). 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 at 0 °C to room temperature.
Figure imgf000052_0003
In the sixth step, compound 8 in which X1, X2, X3, R1, R2, R3, R7 and R8 are as defined for the compound of formula (I) is reacted with compound 9 in which RN is as defined for formula (I) and LG is a leaving group such as HO-, CI-, Br-, I-, MsO- to give compound 10 which X1, X2, X3, R1, R2, R3, R7, R8 and RN are as defined for formula (I). This reaction is preferably carried out with Mitsunobu conditions when LG is HO-. Preferred is the herein described use of DIAD or DEAD etc. with PPha in toluene or THF or use of CMPB (Cas: 157141-27-0) in toluene, (see for example: Hubschwerlen et al, WO2013/21363). The reactions are preferably run under an atmosphere of argon for 1 - 24 hours at 0 - 120°C in a microwave oven or in an oil bath. When LG is halogen or sulphonate, this reaction is can be carried out under basic conditions. Preferred is the herein described use of K2CO3, NaH or t-BuOK etc. in THF or DMF under an atmosphere of argon for 0.5 - 24 hours at room temperature to 80 °C in a microwave oven or in an oil bath, (see for example: Ji et al, Bio. Med. Chem., 2014, 22, 3405 - 3413). If there is a protecting group on the N atom of RN which is supposed to be used for the connection to Woov the protecting group needs to be removed to give compound 10. The protecting groups can be Boc, Cbz, AcO etc. The deprotection conditions are known to a person skilled in the arts.
Figure imgf000053_0001
In the final step, compound 10 in which X1, X2, X3, R1, R2, R3, R7, R8 and RN are as defined for formula (I) is reacted with compound 11 in which Roov and Woov are as defined for formula (I) and LG is leaving group such as HO-, Cl- or -O-Woov-Roov, to give compound A. This condensation is preferably carried out in a basic condition using bases as triethyl amine, pyridine, di-/so-propylethylamine etc. with condensating agents such as HATU, EDCI/HOBt, T3P, GDI etc. in DCM or DMF when LG is HO-. The reactions are preferably run under an atmosphere of argon for 2-24 hours at room temperature, (see for example: Blake et W02020/131674). When LG is Cl- or -O-Woov-Roov the reaction can be carried out under basic conditions. Preferred is the herein described use of triethyl amine, pyridine, di-/so-propylethylamine etc. in DCM or THF under an atmosphere of argon for 2-24 hours at room temperature, (see for example: Flohr et al, WO2021/127397).
Scheme 2
Figure imgf000054_0001
B
Scheme 2 illustrates a preferred synthetic approach to compounds of the general formula B. As it is to be understandable to the skilled person, the scheme can also be extended to the compounds of formula (I) wherein W is -S(O)yNH-, -NHS(O)(NH)-, -NHS(O)(NCH3)-, -S(O)(NH)-NH-, or -S(O)(NCH3)-NH-.
Figure imgf000054_0002
12 13
In the first step, compound 12 in which X1, X2 and X3 are are as defined for formula (I) is reacted with chlorosulfonic acid to give compound 13 in which X1, X2 and X3 are are as defined for formula (I). Preferred is the herein described use of chlorosulfonic acid under an atmosphere of argon, (see for example: Adams et al, W02008070707). The reactions are preferably run in an oil bath for 2-24 hours at 0-140°C.
Figure imgf000054_0003
In the second step, compound 13 in which X1, X2 and X3 are as defined for formula (I) is reacted with amine 7 in which R1 , R2 and R3 are as defined for formula (I) to give compound 14 in which X1, X2, X3, R1, R2 and R3 as defined for formula (I). 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 at 0 °C to room temperature.
Figure imgf000055_0001
In the third step, compound 14 in which X1, X2, X3, R1, R2 and R3 are as defined for formula (I) is reacted with compound 15 in which R7 is as defined for formula (I) to give compound 16 in which X1, X2, X3, R1, R2,R3 and R7 are as defined for formula (I). The conditions for this reaction can be found in: McGonagle et al, WO2016/092326.
Figure imgf000055_0002
In the fourth step, compound 16 in which X1, X2, X3, R1, R2, R3 and R7 are as defined for formula (I) is reacted with compound 9 in which RN is as defined for formula (I) and LG is a leaving group such HO-, CI-, Br-, I-, MsO- to give compound 17 in which X1, X2, X3, R1, R2, R3, R7 and RN are as defined for formula (I). This reaction is preferably carried out with Mitsunobu conditions when LG is HO-. Preferred is the herein described use of DIAD or DEAD etc. with PPha in toluene or THF or the use of CMPB (Cas: 157141- 27-0) in toluene, (see for example: Hubschwerlen et al, WO2013/21363). The reactions are preferably run under an atmosphere of argon for 1 -24 hours at 0-120°C in a microwave oven or in an oil bath. When LG is halogen or sulphonate, this reaction is can be carried out under basic conditions. Preferred is the herein described use of K2CO3, NaH or t-BuOK etc. in THF or DMF under an atmosphere of argon for 0.5-24 hours at room temperature to 80 °C in a microwave oven or in an oil bath, (see for example: Ji et al, Bio. Med. Chem., 2014, 22, 3405 - 3413). ). If there is a protecting group on the N atom of RN which is supposed to be used for the connection to Woov the protecting group needs to be removed to give compound 17. The protecting groups can be Boc, Cbz, AcO etc. The deprotection conditions are known to a person skilled in the arts.
Figure imgf000056_0001
In the final step, compound 17 in which X1, X2, X3, R1, R2, R3, R7 and RN are as defined for formula (I) is reacted with compound 11 in which Roov and Woov are as defined for formula (I) and LG is leaving group such as HO-, Cl- or -O- Woov-Roov, to give a compound of formula B. This condensation is preferably carried out in a basic condition using bases as triethyl amine, pyridine, di-/so-propylethylamine etc. with condensating agents such as HATU, EDCI/HOBt, T3P, GDI etc. in DCM or DMF when LG is HO-. The reactions are preferably run under an atmosphere of argon for 2-24 hours at room temperature, (see for example: Blake et W02020/131674). When LG is Cl- or -0- Woov-Roov the reaction can be carried out under basic conditions. Preferred is the herein described use of triethylamine, pyridine, di-/so- propylethyl ami ne etc. in DCM or THF under an atmosphere of argon for 2-24 hours at room temperature, (see for example: Flohr et al, WO2021/127397).
Scheme 3
Figure imgf000057_0001
c
Scheme 3 illustrates a preferred synthetic approach to compounds of the general formula C. As it is to be understandable to the skilled person, the scheme can also be extended to the compounds of formula
(I) wherein W is -S(O)yNH-, -NHS(O)(NH)-, -NHS(O)(NCH3)-, -S(O)(NH)-NH-, or -S(O)(NCH3)-NH-.
Figure imgf000057_0002
In the first step, compound 20 in which X1, X2 and X3 are as defined for formula (I) is reacted with amine 7 in which R1 , R2 and R3 are as defined for formula (I) to give compound 21 in which X1, X2, X3, R1, R2 and R3 are as defined for formula (I). This reaction can be carried out under basic conditions, (see for example: Guo et al, WO2013/006394). Preferred is the herein described use of triethylamine, pyridine, di-/so-propylethylamine 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.
Figure imgf000058_0001
In the second step, compound 21 in which X1, X2, X3, R1, R2 and R3 are as defined for formula (I) is reacted with amine 22 in which R8 is as defined for formula (I) to give compound 23 in which X1, X2, X3, R1, R2,R3 and R8 are as defined for formula (I). Preferred is the herein described use of triethylamine, di- /so-propylethylamine etc in DMF, acetonitrile or dioxane, (see for example: Liu et al, Eur. J. Med. Chem,, 2021 , 222, 113565). The reactions are preferably run under an atmosphere of argon for 2-24 hours at 80- 110°C in a microwave oven or in an oil bath.
Figure imgf000058_0002
In the third step, compound 23 in which X1, X2, X3, R1, R2, R3 and R8 are as defined for formula (I) is converted to compound 24 in which X1, X2, X3, R1, R2, R3 and R8 are as defined for formula (I). This amide formation can be carried out with ammonium hydroxide or ammonium salt and base such as triethylamine, pyridine, di-/so-propylethylamine etc. in the presence of condensating agents such as HATU, EDCI/HOBt, T3P, GDI etc.in DCM or DMF (see for example: Weaver et al, W02020/257940). Moreover, this amidation also can be conducted by an acyl chloride strategy. The reactions are preferably run under an atmosphere of argon for 2-24 hours at room temperature.
Figure imgf000058_0003
In the fourth step, compound 24 in which X1, X2, X3, R1, R2, R3 and R8 are as defined for formula (I) is converted to compound 25 in which X1, X2, X3, R1, R2, R3 and R8 are as defined for formula (I). This cyclization is preferably carried out with GDI in the presence of base such as triethylamine, di-/so- propylethylamine etc. in DMF, NMP or DMA.The reactions are preferably run for 0.5-16 hours at 80-120°C in a microwave oven or in an oil bath (see for example: Velaparthi et al, WO2021/133751). This cyclization reaction can also be carried out with GDI in DMF, NMP or DMA etc. without base at 100 - 150°C, or with triphosgene and base in DCM, THF etc. at 0 °C to room temperature.
Figure imgf000059_0001
In the fifth step, compound 25 in which X1, X2, X3, R1, R2, R3 and R8 are as defined for formula (I) is reacted with compound 9 in which RN is as defined for formula (I) and LG is a leaving group such as HO- , CI-, Br-, I-, MsO- to give compound 26 in which X1, X2, X3, R1, R2, R3, R8 and RN are as defined for formula (I). This reaction is preferably carried out with Mitsunobu conditions when LG is HO-. Preferred is the herein described use of DIAD or DEAD etc. with PPha in toluene or THF or the use of CMPB (Cas: 157141-27-0) in toluene (see for example: Hubschwerlen et al, WO2013/21363). The reactions are preferably run under an atmosphere of argon for 1-24 hours at 0-120°C in a microwave oven or in an oil bath. When LG is halogen or sulphonate, this reaction is can be carried out under basic conditions. Preferred is the herein described use of K2CO3, NaH or t-BuOK etc. in THF or DMF under an atmosphere of argon for 0.5-24 hours at room temperature to 80 °C in a microwave oven or in an oil bath, (see for example: Ji et al, Bio. Med. Chem., 2014, 22, 3405 - 3413). If there is a protecting group on the N atom of RN which is supposed to be used for the connection to Woov the protecting group needs to be removed to give compound 26. The protecting groups can be Boc, Cbz, AcO etc. The deprotection conditions are known to a person skilled in the arts.
Figure imgf000059_0002
In the final step, compound 26 in which X1, X2, X3, R1, R2, R3, R8 and RN are as defined for formula (I) is reacted with compound 11 in which Roov and Woov are as defined for formula (I) and LG is leaving group such as HO-, Cl- or -O-Woov-Roov, to give a compound of formula C. This condensation is preferably carried out in a basic condition using bases as triethyl amine, pyridine, di-7so-propylethylamine etc. with condensating agents such as HATU, EDCI/HOBt, T3P, GDI etc. in DCM or DMF when LG is HO-. The reactions are preferably run under an atmosphere of argon for 2-24 hours at room temperature, (see for example: Blake et W02020/131674). When LG is Cl- or -O- Woov-Roov the reaction can be carried out under basic conditions. Preferred is the herein described use of triethylamine, pyridine, di-/so- propylethyl ami ne etc. in DCM or THF under an atmosphere of argon for 2-24 hours at room temperature, (see for example: Flohr et al, WO2021/127397).
Scheme 3.1
Figure imgf000060_0001
Scheme 3.1 illustrates an alternative approach to compounds of the general formula 24.
Figure imgf000060_0002
In the first step, compound 27 in which X1, X2 and X3 are as defined for formula (I) is reacted with chlorosulfonic acid to give compound 28 in which X1, X2 and X3 are as defined for formula (I). Preferred is the herein described use of chlorosulfonic acid under an atmosphere of argon (see for example: Adams et al, W02008070707). The reactions are preferably run in an oil bath for 2-24 hours at 0-140°C.
Figure imgf000060_0003
In the second step, compound 28 in which X1, X2 and X3 are as defined for formula (I) is reacted with amine 7 in which R1, R2 and R3 are as defined for formula (I) to give compound 29 in which X1, X2, X3, R1, R2 and R3 are as defined for formula (I). This reaction can be carried out under basic conditions (see for example: Sari et al, Eur. J. Med. Chem., 2017, 138, 407 - 421). Preferred is the herein described use of triethylamine, pyridine, di-/so-propylethylamine 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.
Figure imgf000061_0001
In the final step, compound 29 in which X1, X2, X3, R1, R2 and R3 are as defined for formula (I) is reacted with amine 22 in which R8 is as defined for formula (I) to give compound 24 in which X1, X2, X3, R1, R2, R3 and R8 are as defined for formula (I). Preferred is the herein described use of triethylamine, di- /so-propyl ethy lami ne etc in DMF, acetonitrile or dioxane (see for example: Putman et al, WO2016144792). The reactions are preferably run under an atmosphere of argon for 2-24 hours at 80-110°C in a microwave oven or in an oil bath.
Scheme 3.2
Figure imgf000061_0002
Scheme 3.2 illustrates an alternative approach to compounds of the general formula 26.
Figure imgf000062_0001
30
In the first step, compound 21 in which X1, X2, X3, R1, R2 and R3 are as defined for formula (I) is reacted with the protected compound 9a in which RN is as defined for formula (I) to give compound 30 in which X1, X2, X3, R1, R2, R3 and RN are as defined for formula (I). This amide formation can be carried out with amine and base such as triethylamine, pyridine, di-/so-propylethylamine etc. in the presence of condensating agents such as HATU, EDCI/HOBt, T3P, GDI etc.in DCM or DMF. Moreover, this amide formation also can be conducted by an acyl chloride strategy (see for example: Shook et al, WO2019067864). The reactions are preferably run under an atmosphere of argon for 2-24 hours at room temperature.
Figure imgf000062_0002
In the second step, compound 30 in which X1, X2, X3, R1, R2, R3 and RN are as defined for formula (I) is reacted with amine 21 in which R8 is as defined for the compound of formula (I) to give compound 31 in which X1, X2, X3, R1, R2, R3, R8 and RN are as defined for formula (I). Preferred is the herein described use of triethylamine, di-7so-propylethyl ami ne etc in DMF, acetonitrile or dioxane (see for example: Putman et al, WO2016144792). The reactions are preferably run under an atmosphere of argon for 2-24 hours at 80-110°C in a microwave oven or in an oil bath.
Figure imgf000062_0003
In the final step, compound 31 in which X1, X2, X3, R1, R2, R3, R8 and RN are as defined for formula (I) is converted to compound 26 in which X1, X2, X3, R1, R2, R3, R8 and RN are as defined for formula (I). This cyclization is preferably carried out with GDI in the presence of base such as triethylamine, di-/so- propylethylamine etc. in DMF, NMP or DMA. The reactions are preferably run for 0.5 - 16 hours at 80- 120°C in a microwave oven or in an oil bath. This cyclization also can be carried out with GDI in DMF, NMP or DMA etc. (see for example: Lisius et al, W02007004958) without base at 100-150°C, or with triphosgene and base in DCM, THF etc. at 0 °C to room temperature. Finally, the protecting group is removed to give compound 26.
Scheme 4
Figure imgf000063_0001
Scheme 4 illustrates a preferred synthetic approach to compounds of the general formula D. As it is to be understandable to the skilled person, the scheme can also be extended to the compounds of formula (I) wherein W is -S(O)yNH-, -NHS(O)(NH)-, -NHS(O)(NCH3)-, -S(O)(NH)-NH-, or -S(O)(NCH3)-NH- upon the corresponding functionalization of the bromide of compound 35.
Figure imgf000063_0002
In the first step, compound 32 in which X1, X2 and X3 are are as defined for formula (I) is reacted with compound 33 is as defined for formula (I) to give compound 34 in which X1, X2, X3 and R8 are as defined for formula (I). Reaction conditions for this conversion are described in the literature (McGonagle et al, WO2016/092326).
Figure imgf000064_0001
In the second step, compound 34 in which X1, X2, X3 and R8 are are as defined for formula (I) is reacted with hydrazine hydrate to give compound 35 in which X1, X2, X3 and R8 are as defined for formula (I). Reaction conditions for this conversion are described in the literature (McGonagle et al, WO2016/092326).
Figure imgf000064_0002
In the third step, compound 35 in which X1, X2, X3 and R8are are as defined for formula (I) is reacted with benzyl mercaptan to give compound 36 in which X1, X2, X3 and R8 are are as defined for formula (I). 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’, 2nd edition.: de Meijere, Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004). Preferred is the herein described use of tris(dibenzylideneacetone) dipalladium(O), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and N-ethyl-N-isopropylpropan-2-amine in dioxane. 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.
Figure imgf000064_0003
In the fourth step, compound 36 in which X1, X2, X3 and R8 are are as defined for formula (I) is reacted with chlorination reagent to give sulfonyl chloride 37 in which X1, X2, X3 and R8 are are as defined for formula (I). This sulfonyl chloride formation can be carried out by treatment with NCS, sulfonyl chloride, DCDMH, CI2 etc., in MeCN with equivalent acetic acid and water (see for example: Sutton et al, WO 2021/055744). Preferred is the herein described use of DCDMH in MeCN with equivalent acetic acid and water. The reactions are preferably run under an atmosphere of argon for 0.5-5 hours at 0 °C to room temperature.
Figure imgf000065_0001
In the fifth step, compound 37 in which X1, X2, X3 and R8 are as defined for formula (I) is reacted with amine 7 in which R1, R2 and R3 are as defined for formula (I) to give compound 38 in which X1, X2, X3, R1, R2, R3 and R8 are as defined for formula (I). 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 at 0 °C to room temperature.
Figure imgf000065_0002
38 39
In the sixth step, compound 38 in which X1, X2, X3, R1, R2, R3 and R8 are as defined for formula (I) is reacted with compound 9 in which RN is as defined for formula (I) and LG is a leaving group such as HO-, CI-, Br-, I-, MsO- to give compound 39 in which X1, X2, X3, R1, R2, R3, R8 and RN are as defined for formula (I). This reaction is preferably carried out with Mitsunobu conditions when LG is HO-. Preferred is the herein described use of DIAD or DEAD etc. with PPha in toluene or THF or use of CMPB (Cas: 157141- 27-0) in toluene (see for example: Hubschwerlen et al, WO2013/21363). The reactions are preferably run under an atmosphere of argon for 1 -24 hours at 0-120°C in a microwave oven or in an oil bath. When LG is halogen or sulphonate, this reaction is can be carried out under basic conditions. Preferred is the herein described use of K2CO3, NaH or t-BuOK etc. in THF or DMF under an atmosphere of argon for 0.5-24 hours at room temperature to 80°C in a microwave oven or in an oil bath (see for example: Ji et al, Bio. Med. Chem., 2014, 22, 3405 - 3413). If there is a protecting group on the N atom of RN which is supposed to be used for the connection to Woov the protecting group needs to be removed to give compound 39. The protecting groups can be Boc, Cbz, AcO etc. The deprotection conditions are known to a person skilled in the arts.
Figure imgf000066_0001
In the final step, compound 39 in which X1, X2, X3, R1, R2, R3, R8 and RN are as defined for formula (I) is reacted with compound 11 in which Roov and Woov are as defined for formula (I) and LG is leaving group such as HO-, Cl- or -O-Woov-Roov„ to give compound D. This condensation is preferably carried out under basic condition with bases such as triethylamine, pyridine, di-/so-propylethylamine etc. and with condensating agents such as HATU, EDCI/HOBt, T3P, GDI etc. in DCM or DMF when LG is HO-. The reactions are preferably run under an atmosphere of argon for 2-24 hours at room temperature (see for example: Blake et W02020/131674). When LG is Cl- or -0- Woov-Roov, this reaction is can be carried out under basic conditions. Preferred is the herein described use of triethylamine, pyridine, di-/so- propylethylamine etc in DCM or THF under an atmosphere of argon for 2-24 hours at room temperature (see for example: Flohr et al, WO2021/127397).
Preparative examples
The compounds described in this section are defined by their chemical formulae and their corresponding chemical names. In case of conflict between any chemical formula and the corresponding chemical name indicated herein, 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.
General considerations
Abbreviations used in the descriptions that follow are: aq. (aqueous); br. (broad, 1H NMR signal); CDCh (deuterated chloroform); cHex (cyclohexane); CMPB (cyanomethylenetributylphosphorane); CUSO4.5H2O (copper sulfate pentahydrate); DCE (dichloroethane); d (doublet, 1H NMR signal); DCM (dichloromethane); DIAP (diisopropyl azodicarboxylate); DI PEA (di-/so-propylethylamine); DMAP (4- N- /V-dimethylaminopyridine), DME (1,2-dimethoxyethane), DMF (A/-A/-dimethylformamide); DMSO (dimethyl sulfoxide); ES (electrospray); EtOAc (ethyl acetate); EtOH (ethanol); h (hour(s)); 1H NMR (proton nuclear magnetic resonance spectroscopy); HCI (hydrogen chloride); HPLC (High Performance Liquid Chromatography), iPrOH (/so-propanol); K2CO3 (potassium phosphate); LiHMDS (Lithium Bis(trimethylsilyl)amide); m (multiplet, 1H NMR signal); mCPBA (mefa-chloroperoxybenzoic acid), MeCN (acetonitrile), MeOH (methanol); min (minute(s)); MS (mass spectrometry); MTBE (methyl ferf-butyl ether); Na2COs (sodium carbonate); NaHCOs (sodium hydrogencarbonate); Na2SO4 (sodium sulfate); NMR (nuclear magnetic resonance); PPha (triphenylphosphine); prep. TLC (preparative thin layer chromatography); q (quartet, 1 H NMR signal); quin (quintet, 1 H NMR signal); rac (racemic); RT (retention time); s (singlet, 1H NMR signal); sat. (saturated); SiO2 (silica); t (triplet, 1H NMR signal); TBAF (tetrabutyl ammonium fluoride); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran); UPLC (Ultra-High Performance Liquid Chromatography), UV (ultraviolet), wt-% (percent by weight).
General Procedure: All starting materials and solvents were obtained either from commercial sources or prepared according to literature references. Commercially available reagents and anhydrous solvents were used as supplied, without further purification. Unless otherwise stated all reactions were stirred. All air- and moisture-sensitive reactions were carried out in oven-dried (at 120°C) glassware under an inert atmosphere of nitrogen or argon. Compound names were generated using ChemDraw professional (Perkin Elmer). In some cases generally accepted names of commercially available reagents were used in place of ChemDraw generated names.
Reversed Phase HPLC conditions for LCMS Analysis of final compounds:
Method 1 : SHIMADZU LCMS-2020 Kinetex EVO C18 2.1X30 mm, 5 urn 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 2 : SHIMADZU LCMS-2020 Kinetex EVO C18 2.1X30 mm, 5 urn at 40°C ; Mobile Phase : A: 0.025% NH3-H2O in water (v/v) , B: MeCN; flow rate held at 1 .5 mL/min; eluted with the mobile phase over 1.55 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-1 .20 min, held at 5% A-95% B; 1 .20-1 .21 min, returned to 95% A-5% B, 1.21-1 .55 min, held at 95% A-5% B.
Method 3: Agilent 1200\G6110A Kinetex EVO C18 2.1X30 mm, 5 urn 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 4: SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X30 mm 5 urn 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: 0.01-0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-0.95 min, held at 5% A-95% B; 0.95-0.96 min, returned to 95% A-5% B, 0.96-1 .00 min, held at 95% A-5% B.
Method 5: SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X20 mm 2.6 urn at 50°C; Mobile Phase: A: 0.0375% TFA in water (v/v); B: 0.01875% TFA in MeCN (v/v); flow rate held at 2.0 mL/min; eluted with the mobile phase over 1.00 min employing UV detection at 220 nm and 254 nm. Gradient information: 0.01-0.60 min, ramped from 95% A-5% B to 5% A-95% B; 0.61-0.78 min, held at 5% A-95% B; 0.78-0.79 min, returned to 95% A-5% B, 0.79-0.80 min, held at 95% A-5% B.
Method 6: SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X30 mm 5 urn 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.
1H NMR Spectroscopy:
1H NMR spectra were acquired on a Bruker Avance IH spectrometer at 400 MHz using residual undeuterated solvent as reference. 1H 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).
Salt stoichiometry:
In the present text, in particular in the experimental section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown. Unless specified otherwise, suffixes to chemical names or structural formulae such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HO", "x CF3COOH", "x Na+", for example, are to be understood as not a stoichiometric specification, but solely as a salt form. This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates with (if defined) unknown stoichiometric composition.
Preparation of Intermediate 1.1
3-carbamoyl-4-fluorobenzenesulfonyl chloride
Figure imgf000069_0001
A solution of 2-fluorobenzamide (95.0 g, 682.83 mmol) in HSO3CI (477.4 g, 4.10 mol) was stirred at 140 °C for 2 h. LCMS showed that starting material remained. The mixture was stirred at 140 °C for another 1 hour. The mixture was carefully poured into ice (2 L) and filtered. The filter cake was dried under vacuum to give the product 3-carbamoyl-4-fluorobenzenesulfonyl chloride (150.0 g, 631 .22 mmol, 92.44% yield) as a white solid.
RT 0.376 min (Method 4); m/z 237.9 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 5 = 7.87 (dd, J = 6.8, 2.0 Hz, 1 H), 7.78 (s, 1 H), 7.72-7.67 (m, 1 H), 7.61 (s, 1 H), 7.21 (dd, J = 10.4, 8.4 Hz, 1 H).
Preparation of Intermediate 1 .2
2-fluoro-5-(N-(1-methylcyclopropyl)sulfamoyl)benzamide
Figure imgf000069_0002
To a solution of 1-methylcyclopropanamine (0.8 g, 11.25 mmol, HCI salt) and TEA (2.13 g, 21.09 mmol) in NMP (6 mL) at 0 °C was added dropwise a solution of 3-carbamoyl-4-fluorobenzenesulfonyl chloride (3.34 g, 14.06 mmol) in DCM (25 mL). The mixture was stirred at 20 °C for 16 h. The resulting mixture was distilled off under vacuum to give the NMP solution. The solution was diluted with water (20 mL), then adjusted with aq. HCI (1 N) to pH 5-6. The aqueous phase was extracted with EtOAc (100 mL, 2x). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the product 2-fluoro-5-(A/-(1- methylcyclopropyl)sulfamoyl)benzamide (1.3 g, 4.23 mmol, 30.07% yield, 88.55% purity) as a white solid.
RT 0.352 min (Method 4); m/z 273.0 (M+H)+ (ESI+); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.17 (s, 1 H), 8.06 (dd, J = 6.8, 2.4 Hz, 1 H), 7.94-7.89 (m, 2H), 7.87-7.83 (m, 1 H), 7.52 (t, J = 10.0 Hz, 1 H), 1 .07 (s, 3H), 0.63-0.57 (m, 2H), 0.43-0.37 (m, 2H).
Preparation of Intermediate 1 .3
1 -methylcyclopropane-1 -carboxamide
Figure imgf000069_0003
To a solution of 1 -methylcyclopropane-1 -carboxylic acid (22.0 g, 219.75 mmol) in DCM (220 mL) was added DMF (1 .61 g, 21 .97 mmol, 1 .69 mL). Then oxalyl dichloride (33.47 g, 263.70 mmol, 23.08 mL) was added dropwise to the mixture at 0°C under N2. The mixture was stirred at 20 °C for 2 h under N2. The mixture was concentrated in vacuum at 20 °C to give methylcyclopropanecarbonyl chloride (26.05 g, crude) which was used for next step without further purification. To a solution of methylcyclopropanecarbonyl chloride (26.05 g, crude) in THF (330 mL) was added NH3 H2O (82.50 g, 659.15 mmol, 90.66 mL, 28% purity) dropwise at 0 °C under N2. The mixture was stirred at 20 °C for 2 h under N2 before it was concentrated and filtered to give a solid which was dried under reduced pressure to give the product 1-methylcyclopropane-1 -carboxamide (14.8 g, 149.30 mmol, 67.95% yield) as a white solid.
1 HNMR (CDCI3, 400 MHz): 5 = 5.70 (s, 2H), 1 .34 (s, 3H), 1 .23-1 .20 (m, 2H), 0.64-0.60 (m, 2H).
Preparation of Intermediate 1 .4
(l-methylcyclopropyl)methanamine
Figure imgf000070_0001
To a solution of 1-methylcyclopropane-1 -carboxamide (14.8 g, 149.30 mmol) in THF (200 mL) at 0 °C was added dropwise BH3THF (1 M, 328.46 mL). The mixture was stirred at 20 °C for 16 h. To the mixture was added MeOH (50 mL) and aqueous HCI solution (1 N, 50 mL) drop-wise at 20°C. Then the mixture was heated to 50°C and stirred for 0.5 h. The mixture was concentrated under vacuum to give the crude product. The crude product was triturated with EtOAc (200 mL) at 20 °C for 10 min and filtered. The filter cake was dried under vacuum to give the product (l-methylcyclopropyl)methanamine (23.0 g, crude, HCI salt) as a white solid.
1 HNMR (DMSO-cfe, 400 MHz): 5 = 6.54 (s, 2H), 2.67 (s, 2H), 1.10 (s, 3H), 0.51-0.57 (m, 2H), 0.32- 0.38 (m, 2H).
Preparation of Intermediate 1 .5
2-(((1 -methylcyclopropyl)methyl)amino)-5-(N-(1 -methylcyc lopropyl) su Ifamoyl) benzamide
Figure imgf000070_0002
To a solution of 2-fluoro-5-[(1 -methylcyclopropyl)sulfamoyl]benzamide (1.4 g, 5.14 mmol) in MeCN (15 mL) was added DI PEA (3.99 g, 30.85 mmol) and (l-methylcyclopropyl)methanamine (2.03 g, 16.71 mmol, HCI salt). The mixture was stirred at 85 °C for 16 h. To the mixture was added (1- methylcyclopropyl)methanamine (1.63 g, 13.37 mmol, HCI salt) and DIPEA (1.99 g, 15.42 mmol). The mixture was stirred at 100 °C for 48 h. To the mixture was added (l-methylcyclopropyl)methanamine (1.88 g, 15.42 mmol) and DIPEA (3.32 g, 25.71 mmol). The mixture was stirred at 100 °C for 16 h. To the mixture was added potassium carbonate (7.11 g, 51.41 mmol). The mixture was stirred at 100 °C for 16 h. To the mixture was added K2CO3 (2 g, 14.47 mmol). The mixture was stirred at 100 °C for 8 h. The reaction mixture was adjusted to pH<6 with aqueous HCI solution (1 N). The mixture was extracted with EtOAc (100 mL, 2x). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was triturated with petroleum ether/ ethyl acetate 10:1 (30 mL) at 20 °C for 10 min. The mixture was filtered and the filter cake was dried under reduced pressure to give the product 2-(((1- methylcyclopropyl)methyl)amino)-5-(A/-(1-methylcyclopropyl)sulfamoyl) benzamide (1.28 g, 3.56 mmol, 69.16% yield, 93.96% purity) as a white solid.
RT 0.524 min (method 4); m/z 338.1 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 8.73 (s, 1 H), 8.19-8.03 (m, 1 H), 7.87 (d, J= 2.0 Hz, 1 H), 7.57 (dd, J= 8.8, 1.6 Hz, 1 H), 7.52 (s, 1 H), 7.30 (s, 1 H), 6.77 (d, J = 9.2 Hz, 1 H), 3.05 (d, J = 3.6 Hz, 2H), 1 .11 (s, 3H), 1 .05 (s, 3H), 0.62- 0.57 (m, 2H), 0.47-0.42 (m, 2H), 0.37-0.31 (m, 4H).
Preparation of Intermediate 1 .6
N-(1-methylcyclopropyl)-1 -((1 -methylcyclopropyl)methyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-6- sulfonamide
Figure imgf000071_0001
To a solution of 2-(((1-methylcyclopropyl)methyl)amino)-5-(A/-(1- methylcyclopropyl)sulfamoyl)benzamide (1.8 g, 5.33 mmol) in 1-methylpyrrolidin-2-one (20 mL) was added 1 ,1 ’-carbonyldiimidazole (6.92 g, 42.67 mmol). The mixture was stirred at 130 °C for 3 h before it was poured into aqueous HCI solution (400 mL, 1 N) and extracted with EtOAc (200 mL, 2x). The combined organic layers were washed with brine (200 mL, 2x), dried over with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the product A/-(1 -methylcyclopropyl)- 1 - ((1 -methylcyclopropyl)methyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (1.7 g, 4.36 mmol, 81.65% yield, 93.12% purity) as a yellow solid.
RT 0.372 min (method 5); m/z 364.1 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 5 = 11.85 (s, 1 H), 8.35 (d, J= 2.4 Hz, 1 H), 8.16 (s, 1 H), 8.03 (dd, J= 8.8, 2.4 Hz, 1 H) 7.72 (d, J= 9.2 Hz, 1 H), 4.12 (s, 2H), 1.07 (s, 3H), 1.02 (s, 3H), 0.62-0.57 (m, 2H), 0.56-0.52 (m, 2H), 0.41-0.36 (m, 2H), 0.32-0.27 (m, 2H).
Preparation of Intermediate 1 .7 Tert-butyl 3-(1-((1-methylcyclopropyl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,4- dihydroquinazolin-3(2H)-yl)azetidine-1-carboxylate
Figure imgf000072_0001
To the mixture of N-(1-methylcyclopropyl)-1 -((1 -methylcyclopropyl)methyl)-2,4-dioxo-1 ,2,3,4- tetrahyd roq ui nazoli ne-6-sulfonamide (500 mg, 1 .38 mmol) in toluene (5 mL) was added PPha (541 .27 mg, 2.06 mmol) and tert-butyl 3-hydroxyazetidine-1 -carboxylate (238.30 mg, 1.38 mmol) at 0°C under N2. DIAD (668.73 p L, 3.44 mmol) was added slowly at 0°C under N2. The mixture was stirred at 60 °C for 16 h under N2. The mixture was cooled to room temperature, quenched by H2O (30 mL) and extracted with EtOAc (30 mL; 3x). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250*50 mm*15 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 58%-88%,10 min). The resulting solution was concentrated under reduced pressure to remove most of MeCN, then it was neutralized with NaOH (1 M) to pH=8, and extracted with EtOAc (100 mL; 3x). The combined organic layers were washed with brine (100 mL; 2x), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the product tert-butyl 3-(1 -((1-methylcyclopropyl)methyl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,4- dihydroquinazolin-3(2H)-yl)azetidine-1 -carboxylate (550 mg, 1.06 mmol, 77.08% yield) as a yellow oil.
RT 1.014 min (method 1); m/z 519.3 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 8.39 (d, J= 2.4 Hz, 1 H), 8.20 (s, 1 H), 8.05 (dd, J = 8.8, 2.0 Hz, 1 H), 7.74 (d, J = 9.2 Hz, 1 H), 5.39-5.27 (m, 1 H), 4.37-4.23 (m, 2H), 4.18 (s, 2H), 4.13-4.05 (m, 2H), 1.41 (s, 9H), 1.07 (s, 3H), 1.06 (s, 3H), 0.66-0.50 (m, 4H), 0.45- 0.22 (m, 4H).
Preparation of Intermediate 1 .8
3-(azetidin-3-yl)-N-(1-methylcyclopropyl)-1-((1-methylcyclopropyl)methyl)-2, 4-dioxo-1, 2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000072_0002
To a mixture of tert-butyl 3-(1-((1-methylcyclopropyl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)- 2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)azetidine-1-carboxylate (550 mg, 1.06 mmol) in DCM (3 mL) was added TFA (2 mL, 27.01 mmol). The mixture was stirred at 20 °C for 1 h. To the reaction mixture was added MTBE (30 mL), then the mixture was stirred at 0 °C for 20 min. Some solid was separated out, filtered, and the cake was dried under reduced pressure to give the product 3-(azetidin-3-yl)-N-(1 - methylcyclopropyl)-1-((1-methylcyclopropyl)methyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-6- sulfonamide (250 mg, 597.36 pmol, 56.33% yield) as a white solid.
RT 0.591 min (method 1); m/z 419.0 (M+H)+ (ESI*).
Preparation of Example 1
3-(1 -(2-chloroacetyl) azeti di n-3-y l)-N-(1 -methylcyc lopropyl) - 1 -((1 -methylcyclopropyl) methyl) -2, 4- dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide
Figure imgf000073_0001
To a mixture of 3-(azetidin-3-yl)-N-(1-methylcyclopropyl)-1-((1-methylcyclopropyl)methyl)-2,4-dioxo- 1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (50 mg, 93.89 pmol, TFA salt) in DCM (1 mL) was added DIPEA (49.06 pL, 281.67 pmol) and 2-chloroacetyl chloride (10.60 mg, 93.89 pmol). The mixture was stirred at 20 °C for 2 h before it was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 28%-58%,10 min) and lyophilized directly to give the product 3-(1-(2- chloroacetyl)azetidin-3-yl)-N-(1-methylcyclopropyl)-1-((1-methylcyclopropyl)methyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-6-sulfonamide (7.87 mg, 15.74 pmol, 16.76% yield, 99% purity) as a yellow solid.
RT 0.698 min (method 1); m/z 495.1 (M+H)+ (ESH); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.47-8.34
(m, 1 H), 8.21 (s, 1 H), 8.06 (dd, J = 8.8, 2.0 Hz, 1 H), 7.75 (d, J = 9.2 Hz, 1 H), 5.44 (t, J = 6.8 Hz, 1 H), 4.69- 4.56 (m, 1 H), 4.54-4.43 (m, 1 H), 4.34 (dd, J = 10.0, 6.0 Hz, 1 H), 4.27-4.09 (m, 5H), 1.08 (d, J = 5.6 Hz, 6H), 0.66-0.52 (m, 4H), 0.45-0.26 (m, 4H).
Preparation of Example 2
3-(1 -acryloyl azetidin-3-yl)-N-(1 -methylcyclop ropyl)-1 -((1 -methylcyclopropyl)methyl)-2, 4-dioxo-
1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide
Figure imgf000073_0002
To a mixture of 3-(azetidin-3-yl)-N-(1-methylcyclopropyl)-1-((1-methylcyclopropyl)methyl)-2,4-dioxo- 1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (50 mg, 93.89 pmol, TFA salt) and acrylic anhydride (11.84 mg, 93.89 pmol) in DCM (0.5 mL) was added DIPEA (36.40 mg, 281.67 pmol). The mixture was stirred at 20 °C for 2 h before it was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 30%-60%,10 min) and lyophilized directly to give the product 3-(1- acryloylazetidin-3-yl)-N-(1-methylcyclopropyl)-1-((1 -methylcyclopropyl)methyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide (9.8 mg, 18.71 pmol, 19.93% yield, 99% purity, FA salt) as a white solid.
RT 0.692 min (method 1); m/z 473.1 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.49 (s, 1 H), 8.40 (d, J = 2.4 Hz, 1 H), 8.28-8.14 (m, 1 H), 8.05 (dd, J = 8.8, 2.4 Hz, 1 H), 7.74 (d, J = 9.2 Hz, 1 H), 6.35 (dd, J = 16.8, 10.4 Hz, 1 H), 6.13 (dd, J = 16.8, 2.4 Hz, 1 H), 5.76-5.62 (m, 1 H), 5.56-5.42 (m, 1 H), 4.67- 4.57 (m, 1 H), 4.56-4.45 (m, 1 H), 4.35 (dd, J = 10.0, 6.8 Hz, 1 H), 4.25-4.12 (m, 3H), 1.07 (d, J = 6.0 Hz, 6H), 0.64-0.52 (m, 4H), 0.45-0.36 (m, 2H), 0.35-0.26 (m, 2H).
Preparation of Intermediate 3.1
4-hydroxypiperidine-1-carbonitrile
Figure imgf000074_0001
To a mixture of piperidin-4-ol (600 mg, 5.93 mmol) and NaHCOs (1.50 g, 17.80 mmol, 692.15 pL) in DMF (20 mL) was added cyanogen bromide (565.49 mg, 5.34 mmol) and the mixture was stirred at 20 °C for 12 h. The mixture was poured into water (80 mL) and extracted with DCM (50 mL; 2x). The combined organic layers were washed with brine (20 mL; 2x), dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was triturated with MTBE (30 mL) for 15 min, then it was filtrated, the solid was collected to give the product 4- hydroxy pi perid i ne- 1 -carbonitrile (620 mg, 4.91 mmol, 82.85% yield) as a yellow solid.
1 HNMR (CDCh, 400 MHz): 5 = 3.90-3.77 (m, 1 H), 3.46-3.35 (m, 2H), 3.08-2.99 (m, 2H), 1.94-1.83 (m, 2H), 1.65-1.58 (m, 2H).
Preparation of Example 3
3-(1-cyanopiperidin-4-yl)-N-(1-methylcyclopropyl)-1-((1-methylcyclopropyl)methyl)-2,4-dioxo-
1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide
Figure imgf000075_0001
N2 was bubbled through a solution of N-(1 -methylcyclopropyl)-1 -[(1 -methylcyclopropyl)methyl]-2,4- dioxo-quinazoline-6-sulfonamide (25 mg, 68.79 pmol) and PPha (36.09 mg, 137.58 pmol) in toluene (1.5 mL) for 5 min, then the solution was cooled to 0 °C. 4-Hydroxypiperidine-1 -carbonitrile (13.02 mg, 103.19 pmol) was added slowly, followed by DIAD (27.82 mg, 137.58 pmol, 26.75 pL). After that, the reaction was warmed to 60 °C and stirred at 60 °C for 12 h under N2. The reaction mixture was poured into water (30 mL), and extracted with EtOAc (30 mL; 2x). The combined organic layers were washed with brine (20 mL; 2x), dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 pm; mobile phase: A: 0.1 % FA in water, B: MeCN ;B%: 42%-72%,10 min) and lyophilized directly to give the product 3-(1- cyanopiperidin-3-yl)-N-(1-methylcyclopropyl)-1-((1-methylcyclopropyl)methyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide (12 mg, 25.19 pmol, 36.62% yield, 99% purity) as a white solid.
RT 0.924 min (method 1); m/z 472.2 (M+H)+ (ESI*); 1 HNMR (DMSO- de, 400 MHz): 5 = 8.51 (s, 1 H), 8.41 (d, J= 2.0 Hz, 1 H), 8.21 (s, 1 H), 8.07-8.01 (m, 1 H), 7.73 (d, J= 9.2 Hz, 1 H), 5.02-4.89 (m, 1 H), 4.19 (s, 2H), 3.51-3.45 (m, 2H), 3.23-3.14 (m, 2H), 2.72-2.61 (m, 2H), 1.68 (d, J = 11.2 Hz, 2H), 1.09 (s, 3H), 1.05 (s, 3H), 0.65-0.53 (m, 4H), 0.44-0.37 (m, 2H), 0.34-0.26 (m, 2H).
Preparation of Intermediate 4.1
3-hydroxypyrrolidine-1-carbonitrile
Figure imgf000075_0002
To a solution of pyrrolidin-3-ol (500 mg, 5.74 mmol, 462.96 pL) and NaHCOs (1.21 g, 14.35 mmol, 558.02 pL) in DMF (8 mL) and H2O (2 mL) was added cyanogen bromide (607.91 mg, 5.74 mmol) and the mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL; 2x). The combined organic layers were washed with brine (20 mL; 2x), dried over Na2SO4, filtered and the filtrate was concentrated to give the product 3-hydroxypyrrolidine-1 -carbonitrile (250 mg, crude) as a yellow oil.
1 HNMR (DMSO- de, 400 MHz): 5 = 4.51 (br, 1 H), 3.69-3.60 (m, 1 H), 3.58-3.47 (m, 2H), 3.42-3.35 (m, 1 H), 2.03-1.95 (m, 2H), 1.75 (s, 1 H). Preparation of Example 4
3-(1 -cyanopyrroli di n-3-y l)-N-(1 -methylcyclop ropy I)- 1 -((1 -methylcyclopropyl)methyl)-2, 4-dioxo- 1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide
Figure imgf000076_0001
To a solution of /V-(1-methylcyclopropyl)-1-[(1-methylcyclopropyl)methyl]-2,4-dioxo-quinazoline-6- sulfonamide (80 mg, 220.12 pmol), 3-hydroxypyrrolidine-1 -carbonitrile (29.62 mg, 264.15 pmol) and PPha (127.02 mg, 484.27 pmol) in toluene (3 mL) was added DIAD (97.93 mg, 484.27 pmol, 94.16 pL) at O °C under N2. The mixture was stirred at 0 °C for 0.5 h before it was heated to 50 °C and stirred at 50 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge 150*25 mm* 5 pm; mobile phase: 10 mM aqueous solution of NH4HCO3, B: MeCN; B%: 38%-68%, 7 min) and lyophilized directly to give the product 3-(1- cyanopyrrolidin-3-yl)-N-(1-methylcyclopropyl)-1 -((1-methylcyclopropyl)methyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide (12 mg, 25.70 pmol, 11.68% yield, 98% purity) as a white solid.
RT 0.834 min (method 2); m/z 458.1 (M+H)+ (ESI*); 1 HNMR (DMSO- de, 400 MHz): 5 = 8.42 (d, J = 2.4 Hz, 1 H), 8.20 (br, 1 H), 8.09-8.02 (m, 1 H), 7.74 (d, J= 9.2 Hz, 1 H), 5.76-5.64 (m, 1 H), 4.19 (s, 2H), 3.78-3.68 (m, 1 H), 3.68-3.59 (m, 2H), 3.53-3.44 (m, 1 H), 2.34-2.27 (m, 1 H), 2.25-2.14 (m, 1 H), 1.08 (s, 3H), 1.06 (s, 3H), 0.62-0.54 (m, 4H), 0.42-0.38 (m, 2H), 0.33-0.27 (m, 2H).
Preparation of Intermediate 5.1 tert-butyl 3-(1-((1-methylcyclopropyl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl) -2,4-dioxo-1 ,4- dihydroquinazolin-3(2H)-yl)azetidine-1-carboxylate
Figure imgf000076_0002
N2 was bubbled through a solution of A/-(1 -methylcyclopropyl)-1-[(1-methylcyclopropyl)methyl]-2,4- dioxo-quinazoline-6-sulfonamide (30 mg, 82.55 pmol) and PPha (43.30 mg, 165.10 pmol) in toluene (2 mL) for 5 min and then the solution was cooled to 0 °C. Tert-butyl 3-hydroxyazetidine-1 -carboxylate (21 .45 mg, 123.82 pmol) was added followed by DEAD (28.75 mg, 165.10 pmol, 30.01 pL). The mixture was heated to 60 °C and stirred at 60 °C for 12 h under N2. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL; 2x). The combined organic layers were washed with brine (20 mL; 2x), dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by preparative TLC to give the product tert-butyl 3-(1-((1-methylcyclopropyl)methyl)-6-(N-(1- methylcyclopropyl)sulfamoy l)-2,4-dioxo- 1 , 4-d i hydroqui nazol i n-3(2 H)-yl)azeti di ne- 1 -carboxylate (620 mg, 4.91 mmol, 82.85% yield) as yellow oil.
RT 0.993 min (method 1); m/z 519.3 (M+H)+ (ESI*);
Preparation of Intermediate 5.2
3-(azetidin-3-yl)-N-(1-methylcyclopropyl)-1-((1-methylcyclopropyl)methyl)-2, 4-dioxo-1, 2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000077_0001
To a solution of tert-butyl 3-[1 -[(1 -methylcyclopropyl)methyl]-6-[(1 -methylcyclopropyl)sulfamoyl]-2,4- dioxo-quinazolin-3-yl]azetidine-1 -carboxylate (70 mg, 134.97 pmol) in DCM (2 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL) and the mixture was stirred at 20 °C for 1 h. The mixture was concentrated and the crude product was triturated with MTBE (30 mL) for 15 min to give the product 3-(azetidin-3-yl)-N-(1- methylcyclopropyl)-1-((1-methylcyclopropyl)methyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-6- sulfonamide (70 mg, 131.45 pmol, 97.39% yield, TFA salt) as a yellow solid which was directly used for next step.
Preparation of Example 5
3-(1 -cyanoazetid i n-3-yl)- N-( 1 -methylcyclop ropy I)- 1 -((1 -methylcyclopropyl)methyl)-2, 4-dioxo- 1 ,2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000077_0002
To a solution of 3-(azetidin-3-yl)-N-(1-methylcyclopropyl)-1-[(1-methylcyclopropyl)methyl]-2,4-dioxo- quinazoline-6-sulfonamide (70 mg, 131.45 pmol, TFA salt) and cyanogen bromide (15.32 mg, 144.59 pmol, 10.64 pL) in DMF (1 .5 mL) was added DIPEA (84.94 mg, 657.24 pmol, 114.48 pL) and the mixture was stirred at 20 °C for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL; 2x). The combined organic layers were washed with brine (20 mL; 2x), dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25 mm*4 pm; mobile phase: A: 0.1 % TFA in water, B: MeCN; B%: 39%-69%, 10 min) and lyophilized directly to give the product 3-(1 -cyanoazetidin-3-yl)-N-(1 -methylcyclopropyl)-1 -((1 - methylcyclopropyl)methyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (8 mg, 18.04 pmol, 13.72% yield) as off-white solid.
RT 0.899 min (method 1); m/z 444.2 (M+H)+ (ESI*); 1HNMR (DMSO-de, 400 MHz): 5 = 8.39 (d, J = 2.4 Hz, 1 H), 8.21 (s, 1 H), 8.10-8.03 (m, 1 H), 7.75 (d, J = 8.8 Hz, 1 H), 5.29-5.20 (m, 1 H), 4.60-4.51 (m, 2H), 4.43-4.36 (m, 2H), 4.19 (s, 2H), 1.08 (d, J= 4.8 Hz, 6H), 0.62-0.54 (m, 4H), 0.42-0.38 (m, 2H), 0.34- 0.28 (m, 2H).
Preparation of Intermediate 6.1
2-fl uoro-5- (N-(1 -methyl cyclop ropyl )s ulfamoyl) ben zoic acid
Figure imgf000078_0001
To a solution of 1-methylcyclopropanamine (6.76 g, 62.86 mmol, HCI salt) in DCM (150 mL) at -5 °C was added TEA (15.90 g, 157.15 mmol, 21.87 mL). Then 5-chlorosulfonyl-2-fluoro-benzoic acid (15 g, 62.86 mmol) was added in batches and stirred at -5 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved with saturated aq. NaHCOs (400 mL) and the solution was washed with EtOAc (200 mL; 2x). The aqueous phase was collected and it was adjusted to pH=6 with aq. HCI (1 N). The resulting solution turned to a suspension before it was extracted by EtOAc (200 mL; 2x). The organic phase was collected and washed with brine (200 mL; 2x). The organic phase was collected and dried over anhydrous Na2SO4. The organic phase was filtered and concentrated under reduced pressure to give the product 2-fluoro-5-(/V-(1 -methylcyclopropyl)sulfamoyl)benzoic acid (11.0 g, 40.25 mmol, 64.03% yield) as a white solid.
RT 0.261 min (method 4); m/z 274.0 (M+H)+ (ESI*); 1 HNMR (DMSO-d6, 400 MHz): 5 = 13.75 (s, 1 H), 8.28 (dd, J = 6.8, 2.4 Hz, 1 H), 8.22 (s, 1 H), 8.02 (m, 1 H), 7.55 (dd, J = 10.4, 9.2 Hz, 1 H), 1.06 (s, 3H), 0.61-0.58 (m, 2H), 0.42-0.39 (m, 2H).
Preparation of Intermediate 6.2
2-((cyclopropylmethyl)amino)-5-(N-(1-methylcyclopropyl)sulfamoyl)benzoic acid
Figure imgf000079_0001
To a solution of 2-fluoro-5-(A/-(1 -methylcyclopropyl)sulfamoyl)benzoic acid (5.0 g, 18.30 mmol) in MeCN (50 mL) was added DIPEA (3.55 g, 27.44 mmol) and cyclopropylmethanamine (1.43 g, 20.13 mmol). The mixture was stirred at 85 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was taken up with aq. NaHCOs (400 mL) and extracted with EtOAc (200 mL; 2x). The aqueous phase was adjust to pH<6 with HCI solution (aq., 1 N). The aqueous phase was extracted with EtOAc (200 mL; 2x). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the product 2-((cyclopropylmethyl)amino)-5-(A/-(1 -methylcyclopropyl)sulfamoyl)benzoic acid (4.86 g, 14.98 mmol, 81 .87% yield) as a white solid.
RT 0.407 min (Method 6); m/z 325.0 (M+H)* (ESI*); 1 HNMR (DMSO-de, 400 MHz): 5 = 13.16 (s, 1 H), 8.29 (dd, J = 6.8, 2.4 Hz, 1 H), 8.23 (s, 1 H), 8.03 (m, 1 H), 7.71 (s, 1 H), 7.56 (dd, J = 10.4, 9.2 Hz, 1 H), 3.13 (d, J= 7.2 Hz, 2H), 1.11-1.08 (m, 1 H),1 .07 (s, 3H), 0.62-0.58 (m, 4H), 0.43-0.39 (m, 2H), 0.37- 0.32 (m, 2H)
Preparation of Intermediate 6.3
2-((cyclopropylmethyl)amino)-5-(N-(1-methylcyclopropyl)sulfamoyl)benzamide
Figure imgf000079_0002
To a solution of 2-((cyclopropylmethyl)amino)-5-(N-(1 -methylcyclopropyl)sulfamoyl)benzoic acid (4.3 g, 13.26 mmol) and DIPEA (8.57 g, 66.28 mmol, 11.54 mL) in DMF (43 mL) was added HATU (6.05 g, 15.91 mmol). The mixture was stirred at 20 °C for 0.5 h. After 0.5 h, NH4CI (2.13 g, 39.77 mmol) was added and the mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (400 mL) and extracted with EtOAc (200 mL; 2x). The organic phase was washed with brine (200 mL; 2x). The organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase flash (ISCO®; 330 g Flash Coulmn Welch Ultimate XB_C18 20-40pm; 120 A, Eluent of 8-50% ACN/H2O (0.1 % HCI condition) @ 100 mL/min). The resulting solution was concentrated in vacuum, and adjusted to pH>7 with sat. NaHCO3 solution. The solution was extracted with EtOAc (100 mL; 2x). The organic phase was washed with brine (100 mL; 2x). The organic phase was dried over with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the product 2-(cyclopropylmethylamino)-5-[(1- methylcyclopropyl)sulfamoyl]benzamide (1.9 g, 5.87 mmol, 44.28% yield) as a yellow solid.
RT 0.490 min (method 4); m/z 324.0 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.60 (t, J = 4.8 Hz, 1 H), 8.05 (s, 1 H), 7.98 (d, J = 2.4 Hz, 1 H), 7.58 (dd, J = 9.2, 2.4 Hz, 1 H), 7.52 (s, 1 H) 7.30 (s, 1 H), 6.78 (d, J = 8.8 Hz, 1 H), 3.05 (dd, J = 6.4, 5.2 Hz, 2H), 1 .13-1 .07 (m, 1 H), 1 .05 (s, 3H), 0.63-0.56 (m, 2H), 0.54-0.47 (m, 2H), 0.35-0.30 (m, 2H), 0.28-0.21 (m, 2H).
Preparation of Intermediate 6.4
1 -(cycl op ropy I methyl)- N-( 1 -methylcyc lopropyl) -2,4-d ioxo- 1 , 2, 3, 4-tetrahyd roq u i n azoli ne-6- sulfonamide
Figure imgf000080_0001
To a solution of 2-(cyclopropylmethylamino)-5-[(1-methylcyclopropyl)sulfamoyl]benzamide (1.3 g, 4.02 mmol) in 1 -methylpyrrolidin-2-one (15 mL) was added di(1 H-imidazol-1 -yl)methanone (5.21 g, 32.16 mmol).The mixture was stirred at 130 °C for 3 h. The mixture was partitioned between aq. HCI (1 N, 400 mL) and EtOAc (200 mL; 2x). The aqueous phase was extracted with EtOAc (200 mL; 2x). The combined organic phase was washed with brine (200 mL; 2x). The organic phase was dried over with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the product 1- (cyclopropylmethyl)-A/- (1 -methylcyclopropyl)-2, 4-d ioxo- 1 ,2, 3, 4-tetrahy dro qui nazol i ne-6-s ulfonam ide (1 .4 g, 4 mmol, 100% yield) as a yellow solid.
RT 0.347 min (Method 6); m/z 350.0 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 5 = 11.85 (s, 1 H), 8.37 (d, J = 2.4 Hz, 1 H), 8.17 (s, 1 H), 8.05 (dd, J = 8.8, 2.0 Hz, 1 H), 7.77 (d, J = 8.8 Hz, 1 H), 4.01 (d, J = 6.8 Hz, 2H), 1.27-1.16 (m, 1 H), 1.08 (s, 3H), 0.65-0.56 (m, 2H), 0.50-0.42 (m, 4H), 0.42-0.38 (m, 2H).
Preparation of Intermediate 6.5 tert-butyl 3-(1-(cyclopropylmethyl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,2- dihydroquinazolin-3(4H)-yl)azetidine-1-carboxylate
Figure imgf000080_0002
To a solution of 1-(cyclopropylmethyl)-A/-(1-methylcyclopropyl)-2,4-dioxo-1, 2,3,4- tetrahydroquinazoline-6-sulfonamide (200 mg, 572.40 pmol) in THF (5 mL) at 0°C was added tert-butyl 3-hydroxyazetidine-1 -carboxylate (99.15 mg, 572.40 pmol) and PPha (300.27 mg, 1.14 mmol). The mixture was degassed with N2 three times before DIAD (231.49 mg, 1.14 mmol) was added slowly over 5 min. The mixture was heated to 50 °C and stirred for 12 h. The mixture was concentrated under reduced pressure. The residue was taken up with water (150 mL) and extracted with EtOAc (50 mL; 2x). The combined organic phase was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase flash (ISCO®; 100 g Flash Column Welch Ultimate XB_C18 20-40 pm; 120 A, Eluent of 5-50% ACN/H2O (0.1 % HCOOH condition) @ 70 mL/min). The resulting solution was concentrated in vacuum and adjusted to pH>7 with sat. NaHCOs solution. The aqueous phase was extracted with EtOAc (100 mL; 2x). The organic phase was washed with brine (100 mL; 2x). The organic phase was dried over with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the product tert-butyl 3-(1 -(cyclopropylmethyl)-6-(/V-(1-methylcyclopropyl)sulfamoyl)-2,4- dioxo-1 ,2-dihydroquinazolin-3(4H)-yl)azetidine-1-carboxylate (176 mg, 348.79 pmol, 51.9 % yield, 85.2% purity) as a white solid.
RT 0.625 min (method 4); m/z 505.3 (M+H)+ (ESI +); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.40 (d, J = 2.4 Hz, 1 H), 8.20 (s, 1 H), 8.06 (dd, J= 8.8, 2.4 Hz, 1 H), 7.77 (d, J= 9.2 Hz, 1 H), 5.37-5.27 (m, 1 H), 4.29 (s, 2H), 4.11-4.06 (m, 2H), 1.40 (s, 9H), 1.25 (m, 1 H), 1.08 (s, 3H), 0.64-0.57 (m, 2H), 0.52-0.45 (m, 4H), 0.42-0.38 (m, 2H).
Preparation of Intermediate 6.6
3-(azetidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000081_0001
To a solution of tert-butyl 3-(1-(cyclopropylmethyl)-6-(A/-(1-methylcyclopropyl)sulfamoyl)-2,4-dioxo- 1 ,2-dihydroquinazolin-3(4H)-yl)azetidine-1 -carboxylate (50 mg, 99.09 pmol) in DCM (2 mL) was added TFA (308.00 mg, 2.70 mmol, 0.2 mL). The mixture was stirred at 20 °C for 48 h. The mixture was concentrated under reduced pressure to give the product 3-(azetidin-3-yl)-1-(cyclopropylmethyl)-A/-(1 - methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (50 mg, 38.82 pmol, 39.18% yield, 40.26% purity, TFA salt) as a yellow waxy solid.
RT 0.287 min (method 5); m/z 404.1 (M+H)+ (ESI*); Preparation of Example 6
3-(1-(2-chloroacetyl)azetidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000082_0001
To a solution of 3-(azetidin-3-yl)-1-(cyclopropylmethyl)-A/-(1-methylcyclopropyl)-2,4-dioxo-1, 2,3,4- tetrahydroquinazoline-6-sulfonamide (40 mg, 77.14 pmol, TFA) in THF (1.2 mL) and H2O (0.5 mL) was added K2CO3 (21.32 mg, 154.29 pmol). The mixture was cooled to 0 °C and 2-chloroacetyl chloride (13.07 mg, 115.72 pmol) was added. The mixture was stirred at 0 °C for 15 min. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL; 2x). The organic phase was washed with brine (20 mL; 2x). The organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (column: Phenomenex luna C18 150*25 mm*10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 36%-66%, 8 min) and lyophilized directly to give the product (8 mg). HNMR showed that the product still contained impurities. The impure product was purified by preparative-TLC (petroleum ether : EtOAc = 2:1) to give the product 3-(1-(2-chloroacetyl)azetidin-3-yl)-1-(cyclopropylmethyl)-A/-(1-methylcyclopropyl)-2,4- dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (4.11 mg, 8.37 pmol, 10.85% yield, 97.97% purity) as a white solid.
RT 0.391 min (method 5); m/z 481 .1 (M+H)+ (ESI +); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.41 (d, J = 1.6 Hz, 1 H), 8.20 (s, 1 H), 8.07 (dd, J = 8.8, 2.4 Hz, 1 H), 7.78 (d, J = 8.8 Hz, 1 H), 5.46 (m, 1 H) 4.67-4.59 (m, 1 H), 4.53-4.44 (m, 1 H), 4.35 (m, 1 H), 4.19 (m, 1 H), 4.16 (s, 2H), 4.07 (d, J = 6.8 Hz, 2H), 1 .23 (s, 1 H), 1.08 (s, 3H), 0.60 (m, 2H), 0.45-0.53 (m, 4H), 0.37-0.43 (m, 2H).
Preparation of Example 7
3-(1-acryloyl azetidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000082_0002
To a solution of 3-(azetidin-3-yl)-1-(cyclopropylmethyl)-A/-(1-methylcyclopropyl)-2,4-dioxo-1, 2,3,4- tetrahydroquinazoline-6-sulfonamide (50 mg, 96.43 pmol, TFA salt) in THF (1.5 mL) and H2O (0.3 mL) was added NaHCOs (72.91 mg, 867.88 pmol). The mixture was cooled to 0°C and prop-2-enoyl chloride (13.09 mg, 144.65 pmol) was added. The mixture was stirred at 5 °C for 30 min. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (5 mL; 2x). The combined organic phase was washed with brine (5 mL; 2x). The organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative- HPLC (column: Phenomenex luna C18 150*25 mm* 10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 10%-60%, 10 min) and lyophilized directly to give the product 3-(1 -acryloylazetidin-3-yl)- 1-(cyclopropylmethyl)-N-(1 -methylcyclopropyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (4.02 mg, 8.67 pmol, 8.99% yield, 98.86% purity) as a white solid.
RT 0.498 min (method 4); m/z 459.1 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.70 (d, J = 2.0 Hz, 1 H), 8.16 (dd, J= 8.8, 2.4 Hz, 1 H), 7.43 (d, J = 8.8 Hz, 1 H), 6.43-6.33 (m, 1 H), 6.28-6.19 (m, 1 H), 5.71 (dd, J = 10.4, 1.6 Hz, 1 H), 5.65-5.50 (m, 1 H), 5.09 (s, 1 H), 4.75 (m, 1 H), 4.61-4.52 (m, 2H), 4.47 (m, 1 H), 4.09 (d, J= 7.2 Hz, 2H), 1.27 (s, 3H), 1.21 (m, 1 H), 0.86-0.74 (m, 2H), 0.66-0.58 (m, 2H), 0.57-0.47 (m, 4H).
Preparation of Intermediate 8.1 tert-butyl 3-(1-(cyclopropylmethyl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,2- dihydroquinazolin-3(4H)-yl)-2-methylazetidine-1 -carboxylate
Figure imgf000083_0001
To a solution of 1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide (250 mg, 715.50 pmol) in toluene (6 mL) was added 2-(tributyl-A5- phosphanylidene)acetonitrile (207.23 mg, 858.60 pmol) and tert-butyl 3-hydroxy-2-methyl-azetidine-1 - carboxylate (133.97 mg, 715.50 pmol). The mixture was stirred at 100 °C for 16 h. Then the mixture was cooled to 20 °C and 2-(tributyl-A5-phosphanylidene)acetonitrile (207.23 mg, 858.60 pmol) was added. The mixture was degassed and purged with N2 for three times and stirred at 100 °C for 16 h. The mixture was cooled to 20 °C and 2-(tributyl-A5-phosphanylidene)acetonitrile (259.03 mg, 1.07 mmol) was added. The mixture was degassed with N2 for 3 times and stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-40% EtOAc /Petroleum ethergradient @ 20 mL/min) and concentrated under vacuum to give the product tert-butyl 3-(1-(cyclopropylmethyl)-6-(/V-(1- methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,2-dihydroquinazolin-3(4H)-yl)-2 methylazetidine-1 -carboxylate (200 mg, 356.77 pmol, 49.86% yield, 92.52% purity) as a brown oil.
RT 0.488 min (method 6); m/z 519.2 (M+H)+ (ESI +); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.40 (d, J = 2.4 Hz, 1 H), 8.20 (s, 1 H), 8.06 (dd, J = 8.8, 2.4 Hz, 1 H), 7.76 (d, J = 9.2 Hz, 1 H), 4.85-4.95 (m, 1 H), 4.63- 4.74 (m, 1 H), 4.05 (m, 1 H), 4.03 (d, J = 7.2 Hz, 2H), 3.83-3.80 (m, 1 H), 1 .40 (s, 9H), 1 .24 (s, 1 H), 1 .09- 1.07 (m, 3H), 0.61-0.58 (m, 2H), 0.51-0.46 (m, 4H), 0.42-0.38 (m, 2H).
Preparation of Intermediate 8.2
1-(cyclopropylmethyl)-3-(2-methylazetidin-3-yl)-N-(1-methylcyclopropyl)-2,4-dioxo-1, 2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000084_0001
To a solution of 3-(1-(cyclopropylmethyl)-6-(/V-(1-methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,2- dihydroquinazolin-3(4H)-yl)-2-methylazetidine-1 -carboxylate (90 mg, 173.54 pmol) in DCM (1 mL) at O°C was added 2,6-lutidine (185.95 mg, 1.74 mmol) and TMSOTf (231.42 mg, 1.04 mmol). The mixture was stirred at 20 °C for 1 h before it was diluted with brine (4 mL) and extracted with DCM (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (column: Phenomenex luna C18 150*25 mm*10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 7%-37%, 10 min) and lyophilized directly to give the product 1-(cyclopropylmethyl)-3-(2-methylazetidin-3-yl)-A/-(1- methylcyclopropyl)-2,4-dioxo-1,2,3,4 tetrahydroquinazoline-6-sulfonamide(18.14 mg, 42.74 pmol, 24.63% yield, 98.6% purity, FA salt) as a white solid.
RT 0.408 min (method 4); m/z 419.1 (M+H)+ (ESI*); 1HNMR (DMSO-de, 400 MHz): 5 = 8.45-8.38 (m, 1 H), 8.37 (s, 1 H), 8.08-8.06 (m, 1 H), 7.79-7.77 (m, 1 H), 5.10-5.0 (m, 0.3H), 4.95-4.90 (m, 0.7H), 4.769-4.65 (m, 0.7H), 4.45-4.35 (m, 0.3H), 4.15-4.10 (m, 2H) 4.08-4.05 (m, 2H), 3.97-3.99 (m, 0.3H), 3.88-3.86 (m, 0.7H), 1.46 (d, J = 6.4 Hz, 2H), 1.30-1.22 (m, 2H), 1.08 (s, 3H), 0.60-0.56 (m, 2H), 0.50- 0.46 (m, 4H), 0.41-0.40 (m, 2H).
Preparation of Examples 8 and 9
Cis or Trans 3-(1-acryloyl-2-methylazetidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4- dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide Trans or Cis 3-(1-acryloyl-2-methylazetidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4- dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide
Figure imgf000085_0001
To a solution of 1-(cyclopropylmethyl)-3-(2-methylazetidin-3-yl)-A/-(1 -methylcyclopropyl)-2,4-dioxo- 1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (50 mg, 119.47 pmol) in THF (0.4 mL) and H2O (0.4 mL) at 0 °C was added NaHCOs (108.40 mg, 1.29 mmol) and prop-2-enoyl chloride (25.95 mg, 286.73 pmol). The mixture was stirred at 0 °C for 20 min before it was diluted with H2O (10 mL) and extracted with EtOAc (5 mL; 2x). The combined organic phase was washed with brine (5 mL, 2x). The organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (column: Phenomenex luna C18 150*25 mm*10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 32%-63%, 10 min) and lyophilized directly to give the products Cis or Trans 3-(1-acryloyl-2-methylazetidin-3-yl)-1- (cyclopropylmethyl)-A/-(1-methylcyclopropyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (2.04 mg, 4.32 pmol, 3.01 % yield, 99.99% purity) as a white solid and Trans or Cis 3-(1-acryloyl-2- methyl azetid i n-3-yl)- 1 -(cyclopropyl methyl)- A/- (1 -methylcyclopropyl )-2, 4-d ioxo- 1 ,2,3,4- tetrahydroquinazoline-6-sulfonamide (5.91 mg, 12.51 pmol, 8.72% yield, 99.99% purity) as a white solid.
Cis or Trans 3-(1-acryloyl-2-methylazetidin-3-yl)-1-(cyclopropylmethyl)-A/-(1-methylcyclopropyl)-2,4- dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide:
RT 0.507 min (method 4); m/z 473.1 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.39 (d, J = 2.0 Hz, 1 H), 8.22 (s, 1 H), 8.08 (dd, J= 9.2, 2.4 Hz, 1 H), 7.80 (d, J= 8.8 Hz, 1 H), 6.44-6.27 (m, 1 H), 6.12 (m, 1 H), 5.66 (d, J = 10.0 Hz, 1 H), 5.24-5.13 (m, 1 H), 4.98-4.91 (m, 1 H), 4.74-4.62 (m, 1 H), 4.53 -4.18 (m, 1 H), 4.06 (d, J = 5.6 Hz, 2H), 1.27 (dd, J = 12.8, 6.4 Hz, 3H), 1.24-1.18 (m, 1 H), 1.10 (s, 3H), 0.63- 0.59 (m, 2H), 0.52-0.45 (m, 4H), 0.43-0.38 (m, 2H).
Trans or Cis 3-(1-acryloyl-2-methylazetidin-3-yl)-1-(cyclopropylmethyl)-A/-(1-methylcyclopropyl)-2,4- dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide:
RT 0.514 min (method 4); m/z 473.4 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.41 (s, 1 H), 8.20 (s, 1 H), 8.06 (dd, J = 8.8, 2.4 Hz, 1 H), 7.77 (d, J = 8.8 Hz, 1 H), 6.25-6.39 (m, 1 H), 6.09-6.20 (m, 1 H), 5.72-5.65 (m, 1 H), 5.06 (s, 1 H), 5.00-4.82 (m, 1 H), 4.54-4.41 (m, 1 H), 4.30-4.07 (m, 1 H), 4.06 (d, J= 6.8 Hz, 2H), 1.55-1.45 (m, 3H), 1.26-1.18 (m, 1 H), 1.08 (s, 3H), 0.62-0.57 (m, 2H), 0.51-0.45 (m, 4H), 0.42- 0.38 (m, 2H).
Preparation of Example 10
3-(1-(2-chloroacetyl)-2-methylazetidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4- dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide
Figure imgf000086_0001
To a solution of 1-(cyclopropylmethyl)-3-(2-methylazetidin-3-yl)-A/-(1 -methylcyclopropyl)-2,4-dioxo- 1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (55 mg, 131.42 pmol) in H2O (0.4 mL) and THF (0.4 mL) at 0 °C was added NaHCOs (99.36 mg, 1.18 mmol) and 2-chloroacetyl chloride (29.69 mg, 262.84 pmol). The mixture was stirred at 0 °C for 10 min. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (5 mL; 2x). The combined organic phase was washed with brine (5 mL; 2x). The organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC column (Phenomenex luna C18 150*25 mm* 10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 33%-63%, 10 min) and lyophilized directly to give the product 3-(1 -(2-chloroacetyl)-2-methylazetidin-3-yl)-1 -(cyclopropylmethyl)- N-(1 -methylcyclopropyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (5.21 mg, 9.96 pmol, 7.58% yield, 94.65% purity) as a white solid
RT 0.520 min (method 4); m/z 495.4 (M+H)+ (ESI +); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.41 (d, J = 1 .6 Hz, 1 H), 8.21 (s, 1 H), 8.07 (dd, J = 8.8, 2.4 Hz, 1 H), 7.78 (d, J = 8.8 Hz, 1 H), 5.18-4.72 (m, 2H), 4.56- 4.09 (s, 4H), 4.06 (d, J = 6.8 Hz, 2H), 1.58-1.42 (m, 3H), 1.23 (m, 1 H), 1.08 (s, 3H), 0.62-0.58 (m, 2H), 0.53- 0.44 (m, 4H), 0.42-0.37 (m, 2H).
Preparation of Intermediate 11.1 tert-butyl 3-(1-(cyclopropylmethyl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,4- dihydroquinazolin-3(2H)-yl)pyrrolidine-1 -carboxylate
Figure imgf000086_0002
To a mixture of 1 -(cyclopropylmethyl)-A/-(1 -methylcyclopropyl)-2,4-dioxo-quinazoline-6-sulfonamide (50 mg, 143.10 pmol) in THF (2 mL) was added tert-butyl 3-hydroxypyrrolidine-1-carboxylate (26.79 mg, 143.10 pmol) and PPha (112.60 mg, 429.30 pmol). The reaction mixture was degassed with N2 three times, then DIAD (86.81 mg, 429.30 pmol, 83.47 pL) was added to the mixture. The mixture was heated to 50°C and stirred for 16 h. The mixture was concentrated under vacuum to give the residue. The residue was dissolved with DMF (0.5 mL), purified by preparative HPLC( column: Phenomenex luna C18 150*25 mm*10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 36%-66%, 10 min) and lyophilized directly to give the product tert-butyl 3-[1-(cyclopropylmethyl)-6-[(1 - methylcyclopropyl)sulfamoyl]-2,4-dioxo-quinazolin-3-yl]pyrrolidine-1-carboxylate (30 mg, 56.11 pmol, 39.21 % yield, 97% purity) as a white solid.
RT 0.604 min (method 4); m/z 463.0 (M-t-Bu+H)+ (ESI*)
Preparation of Intermediate 11 .2
1 -(cycl op ropy I methyl)- N-( 1 -methylcyc lopropyl) -2,4-d ioxo-3-(pyrrol i di n-3-y I)- 1 ,2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000087_0001
To a mixture of tert-butyl 3-[1-(cyclopropylmethyl)-6-[(1-methylcyclopropyl)sulfamoyl]-2,4-dioxo- quinazolin-3-yl]pyrrolidine-1 -carboxylate (30 mg, 57.85 pmol) in DCM (1 mL) was added TFA (0.1 mL) at 0°C. The mixture was warmed to 20°C and stirred for 1 h. The mixture was concentrated under vacuum to give the product 1 -(cyclopropylmethyl)-N-(l -methylcyclopropyl)-2,4-dioxo-3-pyrrolidin-3-yl-quinazoline- 6-sulfonamide (21 mg, 45.40 pmol, 78.48% yield, TFA) as a white solid.
RT 0.398 min (method 4); m/z 419 (M+H)+ (ESI*);
Preparation of Example 11
3-(1-(2-chloroacetyl)pyrrolidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo-
1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide
Figure imgf000087_0002
To a mixture of 1-(cyclopropylmethyl)-A/-(1-methylcyclopropyl)-2,4-dioxo-3-pyrrolidin-3-yl- quinazoline-6-sulfonamide (21 mg, 50.18 pmol, TFA) in THF (1 mL)and H2O (1 mL) was added K2CO3 (13.87 mg, 100.36 pmol) and 2-chloroacetyl chloride (5.67 mg, 50.18 pmol, 3.99 pL) at O°C. The mixture was warmed to 20°C and stirred for 1 h. The mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL; 2x). The combined organic phase was dried over Na2SO4 and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC(column: Phenomenex luna C18 150*25 mm*10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 40%-70%, 10 min) and lyophilized directly to give the product 3-(1-(2-chloroacetyl)pyrrolidin-3-yl)-1-(cyclopropylmethyl)-N-(1- methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (2.93 mg, 5.86 pmol, 11.68% yield, 99% purity) as a white solid.
RT 0.511 min (method 4); m/z 495 (M+H)+ (ESI*); 1 HNMR (400 MHz DMSO- de) 5 = 8.43 (s, 1 H), 8.21 (s, 1 H), 8.07 (d, J = 8.8 Hz, 1 H), 7.78 (dd, J = 4.2, 8.8 Hz, 1 H), 5.73-5.63 (m, 1 H), 4.37-4.27 (m, 2H), 4.07 (d, J = 3.8 Hz, 2H), 3.90-3.84 (m, 1 H), 3.77-3.54 (m, 2H), 3.50-3.37 (m, 1 H), 2.38-2.06 (m, 2H), 1 .28- 1.18 (m, 1 H), 1.09 (s, 3H), 0.61 (s, 2H), 0.50 (d, J = 9.0 Hz, 4H), 0.43-0.37 (m, 2H).
Preparation of Example 12
3-(1-acryloylpyrrolidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2, 4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000088_0001
To a mixture of 1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo-3-(pyrrolidin-3-yl)-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide (20 mg, 47.79 pmol, TFA salt) in THF (1 mL) and H2O (1 mL) was added K2CO3 (13.21 mg, 95.58 pmol) and prop-2-enoyl chloride (6.49 mg, 71.68 pmol, 5.84 pL) at 0°C. The mixture was warmed to 20°C and stirred for 1 h. The mixture was concentrated under vacuum and extracted with EtOAc (10 mL; 2x). The combined organic phase was dried over Na2SO4 and concentrated under vacuum to give a residue, which was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 pm; mobile phase: A: 0.225% formic acid in water; B%: 40%-70%, 10 min) and lyophilized directly to give the product 3-(1-acryloylpyrrolidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)- 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (2 mg, 4.19 pmol, 8.77% yield, FA salt) as a white solid.
RT 0.501 min (method 4); m/z 473.1 (M+H)+ (ESI*); 1 HNMR (400 MHz DMSO-de): 8.46 (s, 1 H), 8.42 (s, 1 H), 8.20 (s, 1 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.82-7.70 (m, 1 H), 6.74-6.43 (m, 1 H), 6.20-6.12 (m, 1 H), 5.77-5.60 (m, 2H), 4.06 (d, J = 6.4 Hz, 2H), 3.96-2.88 (m, 1 H), 3.78-3.62 (m, 2H), 3.50-3.41 (m, 1 H), 2.30-2.05 (m, 2H), 1.22-1. 25(m, 1 H), 1.09 (s, 3H), 0.66-0.58 (m, 2H), 0.53-0.46 (m, 4H), 0.43 - 0.36 (m, 2H)
Preparation of Intermediate 13.1 tert-butyl4-(1-(cyclopropylmethyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,2- dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate
Figure imgf000089_0001
To a solution of 1 -(cyclopropylmethyl)-A/-(1 -methylcyclopropyl)-2,4-dioxo-quinazoline-6-sulfonamide (50 mg, 143.10 pmol) in THF (2 mL) was added tert-butyl 4-hydroxypiperidine-1 -carboxylate (28.80 mg, 143.10 pmol) and PPha (112.60 mg, 429.30 pmol). The reaction mixture was cooled to 0°C and degassed with N2 three times before DIAD (86.7 mg, 429.30 pmol) was added slowly at 0°C.The mixture was heated to 50°C and stirred for 16 h. The mixture was concentrated under vacuum to give a residue, which was dissolved with DMF (0.4mL) and purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 36%-66%, 10 min) and lyophilized directly to give the product tert-butyl 4-[1-(cyclopropylmethyl)-6-[(1- methylcyclopropyl)sulfamoyl]-2,4-dioxo-quinazolin-3-yl]piperidine-1 -carboxylate (18 mg, 33.62 pmol, 23.50% yield, 99.5% purity) as a white solid.
RT 0.624 min (method 4); m/z 477.1 (M-f-Bu+H)+ (ESI*);
Preparation of intermediate 13.2
1 -(cycl op ropy I methyl)- N-( 1 -methylcyc lopropyl) -2,4-d ioxo-3-(p iperid i n-4-yl )- 1 ,2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000089_0002
To a mixture of tert-butyl-4-[1-(cyclopropylmethyl)-6-[(1-methylcyclopropyl)sulfamoyl]-2,4-dioxo- quinazolin-3-yl]piperidine-1 -carboxylate (60 mg, 112.64 pmol) in DCM (2 mL) at 0°C was added TFA (25.69 mg, 225.29 pmol, 16.68 pL). The mixture was warmed to 20°C and stirred for 1 h. The mixture was concentrated under vacuum to give the product 1 -(cyclopropylmethyl)-N-(l -methylcyclopropyl)-2,4- dioxo-3-(4-piperidyl)quinazoline-6-sulfonamide (40 mg, 90.63 pmol, 80.46% yield, 98% purity, TFA salt) as a white solid.
RT 0.403 min (method 4); 433.1 (M+H)+ (ESI*)
Preparation of Example 13
3-(1-(2-chloroacetyl)piperidin-4-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo-
1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide
Figure imgf000090_0001
To a mixture of 1-(cyclopropylmethyl)-/V-(1-methylcyclopropyl)-2,4-dioxo-3-(4-piperidyl)quinazoline- 6-sulfonamide (20 mg, 46.24 pmol, TFA salt) in THF (1 mL) and H2O (1 mL) was added K2CO3 (12.78 mg, 92.48 pmol) and 2-chloroacetyl chloride (5.22 mg, 46.24 pmol, 3.68 pL, 1 eq) at 0°C. The mixture was warmed to 20°C and stirred for 1 h. The mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuum to give a residue, which was purified by preparative HPLC ( column: Phenomenex luna C18 150*25 mm*10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 33%-63%, 8 min) and lyophilized directly to give the product 3-(1-(2-chloroacetyl)piperidin-4-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo- 1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (2.38 mg, 4.49 pmol, 9.71 % yield, 96% purity) as a white solid.
RT 0.528 min (method 4); m/z 509.1 (M+H)+ (ESI+); 1 HNMR (400 MHz, DMSO- de) 5 = 8.43 (s, 1 H), 8.21 (s, 1 H), 8.07 (d, J= 8.8 Hz, 1 H), 7.78 (dd, J= 4.2, 8.8 Hz, 1 H), 5.94-5.44 (m, 1 H), 4.39-4.25 (m, 3H), 4.39 (d, J= 3.8 Hz, 2H), 4.04(d, J= 6.8 Hz, 1 H), 3.17-3.13 (m, 1 H), 2.74-2.67 (m, 1 H), 2.42- 2.32 (m,2H), 1.70 (br, 2H), 1.23-1.08 (m, 1 H), 1.09 (s, 3H), 0.59 (s, 2H), 0.48 (d, J= 9.0 Hz, 4H), 0.39- 0.37 (m, 2H).
Preparation of Example 14 3-(1-acryloylpiperidin-4-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2, 4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000091_0001
To a mixture of 1-(cyclopropylmethyl)-A/-(1-methylcyclopropyl)-2,4-dioxo-3-(piperidin-4-yl)-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide (20 mg, 46.24 pmol) in THF (1 mL) and H2O (1 mL) at 0 °C was added K2CO3 (12.78 mg, 92.48 pmol) and prop-2-enoyl chloride (4.19 mg, 46.24 pmol, 3.77 pL). The mixture was warmed to 20°C and stirred for 1 h. The mixture was quenched with water (10 mL), extracted with EtOAc (10 mL) and separated. The organic phase was dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 30%-60%, 8 min) and lyophilized directly to give the product 3-(1 -acryloylpiperidin-4-yl)-1 -(cyclopropylmethyl)-N-(l - methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (1.53 mg, 3.11 pmol, 6.73% yield, 99% purity) as a white solid
RT 0.517 min (method 4); m/z 487.1 (M+H)+ (ESI*); 1 HNMR (400 MHz DMSO-de) 5 = 8.41 (s, 1 H), 8.24 (s, 1 H), 8.05 (d, J= 8.4 Hz, 1 H), 7.75 (d, J= 8.4 Hz, 1 H), 6.92-6.78 (dd, J= 8.0 Hz, J= 4.0 Hz, 1 H), 6.12 (d, J = 12.6 Hz, 1 H), 5.70 (d, J = 6.4 Hz, 1 H), 5.09-5.04 (m, 1 H), 4.64 (d, J= 2.0 Hz, 1 H), 4.11 (d, J = 2.0 Hz, 1 H), 4.04 (d, J = 4.0 Hz, 2H), 3.28-3.12 (m, 2H), 2.73-2.67 (m, 1 H), 2.34-2.33 (m, 1 H), 1.79- 1.71 (m, 2H), 1.26-1.21 (m, 1 H), 1.08 (s, 3H), 0.62-0.65 (m, 2H), 0.52-0.42 (m, 4H), 0.40-4.38 (m, 2H).
Preparation of Example 15
3-(1 -cyanoazetid i n-3-yl)- 1 -(cyclopropyl methyl)-N-(1 -methylcyc lopropyl) -2, 4-d ioxo- 1 ,2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000091_0002
To a mixture of 3-(azetidin-3-yl)-1-(cyclopropylmethyl)-/V-(1-methylcyclopropyl)-2,4-dioxo-1, 2,3,4- tetrahydroquinazoline-6-sulfonamide (100 mg, 247.23 pmol) and DIPEA (159.76 mg, 1.24 mmol) in DMF (1 mL) was added cyanogen bromide (28.81 mg, 271 .95 pmol). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated in vacuum. The residue was first purified by prep-TLC (petroleum ether: EtOAc = 2:1). The material obtained was purified by preparative-HPLC (column: Phenomenex luna C18 150*25 mm*10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 32%-62%, 10 min) and lyophilized directly to give the product 3-(1-cyanoazetidin-3-yl)-1-(cyclopropylmethyl)-A/-(1- methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (7.1 mg, 16.12 pmol, 6.52% yield, 97.49% purity) as a white solid.
RT 0.534 min (method 4); m/z 430.1 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.40 (d, J = 2.0 Hz, 1 H), 8.22 (s, 1 H), 8.07 (dd, J= 8.8, 2.4 Hz, 1 H), 7.79 (d, J= 8.8 Hz, 1 H), 5.31-5.22 (m, 1 H), 4.57 (t, J= 8.0 Hz, 2H), 4.39 (t, J= 8.0 Hz, 2H), 4.06 (d, J= 6.8 Hz, 2H), 1.26-1.19 (m, 1 H), 1.08 (s, 3H), 0.62- 0.58 (m, 2H), 0.51-0.46 (m, 4H), 0.43-0.38 (m, 2H).
Preparation of Intermediate 16.1
2-chloro-2-fluoroacetyl chloride
Figure imgf000092_0001
To a solution of ethyl 2-chloro-2-fluoroacetate (4 g, 28.46 mmol) in chlorosulfonic acid (5 mL) was added benzene-1 , 2-dicarbo nyl chloride (11 .56 g, 56.92 mmol). The mixture was stirred at 120 °C for 4 h in a still connected to an dry ice-cooled receiver, and the product was collected in the dry ice-cooled receiver to give the product 2-chl oro-2-fl uoroacetyl chloride (1 .5 g, 11 .46 mmol, 40.25% yield) as a fuming colorless liquid which was used in the next step.
Preparation of Example 16
3-(1-(2-chloro-2-fluoroacetyl)azetidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4- dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide
Figure imgf000092_0002
To a mixture of 3-(azetidin-3-yl)-1-(cyclopropylmethyl)-A/-(1-methylcyclopropyl)-2,4-dioxo-1, 2,3,4- tetrahydroquinazoline-6-sulfonamide (50 mg, 123.61 pmol) and NaHCOs (103.84 mg, 1.24 mmol) in THF (0.5 mL) and H2O (0.5 mL) was added 2-chloro-2-fl uoro-acetyl chloride (48.56 mg, 370.83 pmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 10 min. 2-chloro-2-fluoro-acetyl chloride (48.55 mg, 370.83 pmol) was added to the mixture dropwise at 0 °C and stirred for 10 min. The mixture was poured into water (10 mL). The aqueous phase was extracted with EtOAc (5 mL, 2x). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue, which was purified by preparative-HPLC (column: Phenomenex luna C18 150*25 mm*10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 47%-77%, 10.5 min) and lyophilized directly to give the product 3-(1 -(2-chloro-2-fluoroacetyl)azetidin-3-yl)-1 - (cyclopropylmethyl)-A/-(1-methylcyclopropyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (5.12 mg, 10.19 pmol, 8.24% yield, 99.26% purity) as a white solid.
RT 0.519 min (method 4); m/z 499.0 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.41 (s, 1 H), 8.21 (s, 1 H), 8.07 (dd, J = 8.8, 2.0 Hz, 1 H), 7.78 (d, J = 9.2 Hz, 1 H), 6.98 (dd, J = 48.4, 4.8 Hz, 1 H), 5.50- 5.62 (m, 1 H), 4.64-4.82 (m, 1 H), 4.41-4.63 (m, 2H), 4.22-4.32 (m, 1 H), 4.07 (d, J= 6.8 Hz, 2H), 1.21-1.24 (m, 1 H), 1.08 (s, 3H), 0.57-0.62 (m, 2H), 0.46-0.52 (m, 4H), 0.38-0.42 (m, 2H).
Preparation of Example 17
1-(cyclopropylmethyl)-3-(1-(2-fluoroacryloyl)azetidin-3-yl)-N-(1-methylcyclopropyl)-2,4-dioxo-
1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide
Figure imgf000093_0001
To a mixture of 3-(azetidin-3-yl)-1-(cyclopropylmethyl)-/V-(1-methylcyclopropyl)-2,4-dioxo-1, 2,3,4- tetrahydroquinazoline-6-sulfonamide (50 mg, 123.61 pmol), 2-fluoroprop-2-enoic acid (12.24 mg, 135.97 pmol) and DIEA (31 .95 mg, 247.22 pmol) in DMF (0.5 mL) was added T3P (94.39 mg, 148.33 pmol, 50% purity). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated in vacuum to give a residue, which was purified by preparative-HPLC (column: Phenomenex luna Cis 150*25 mm*10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 32%-62%, 10 min) to give the product 1- (cyclopropylmethyl)-3-(1-(2-fluoroacryloyl)azetidin-3-yl)-A/-(1-methylcyclopropyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-6-sulfonamide (10.77 mg, 22.44 pmol, 18.15% yield, 99.28% purity) as a white solid.
RT 0.517 min (method 4); m/z 477.0 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.41 (d, J = 2.0 Hz, 1 H), 8.21 (s, 1 H), 8.07 (dd, J = 8.8, 1 .6 Hz, 1 H), 7.78 (d, J = 8.8 Hz, 1 H), 5.40-5.60 (m, 2H), 5.30 (dd, J = 16.8, 3.6 Hz, 1 H), 4.56-4.82 (m, 2H), 4.19-4.47 (m, 2H), 4.07 (d, J = 6.8 Hz, 2H), 1.18-1.27 (m, 1 H), 1.08 (s, 3H), 0.57-0.63 (m, 2H), 0.44-0.52 (m, 4H), 0.37-0.42 (m, 2H).
Preparation of Intermediate 18.1 tert-butyl 3-(2-fluoro-5-(N-(1-methylcyclopropyl)sulfamoyl)benzamido)-3-methylazetidine-1- carboxylate
Figure imgf000094_0001
To a solution of 2-fluoro-5-[(1 -methylcyclopropyl)sulfamoyl] benzoic acid (690.39 mg, 2.53 mmol) and HATU (1.25 g, 3.28 mmol) in DMF (20 mL) was added DIPEA (816.25 mg, 6.32 mmol, 1.10 mL). The mixture was stirred at 20 °C for 15 min before tert-butyl 3-amino-3-methyl-azetidine-1-carboxylate (447 mg, 2.40 mmol) was added and the mixture was stirred at 20 °C for 12 h. The mixture was poured into water (30 ml) and extracted with EtOAc (20 mL; 2x). The combined organic layers were washed with brine (10 mL; 2x), dried over Na2SO4, filtered and the filtrate was concentrated to give the product tert-b uty I 3- (2-fl uoro-5-(N-( 1 -methylcyclopropyl)sulfamoyl)benzamido)-3-methylazetidine-1 -carboxylate (1.12 g, crude) as a yellow solid which was directly used for next step without purification.
RT 0.895 min (method 1); m/z 386.2 (M+H)+ (ESI*)
Preparation of Intermediate 18.2 tert-butyl 3-(2-((cyclopropylmethyl)amino)-5-(N-(1-methylcyclopropyl)sulfamoyl)benzamido)-3- methyl azetid i ne- 1 -carboxylate
Figure imgf000094_0002
To a solution of tert-butyl 3-[[2-fluoro-5-[(1 -methylcyclopropyl)sulfamoyl]benzoyl]amino]-3-methyl- azetidine-1 -carboxylate (1.12 g, 2.54 mmol) in MeCN (15 mL) was added DI PEA (983.54 mg, 7.61 mmol, 1 .33 mL) and cyclopropyl methanamine (216.50 mg, 3.04 mmol). The mixture was stirred at 85 °C for 24 hr. The mixture was poured into water (50 ml) and extracted with EtOAc (40 mL; 2x). The combined organic layers were washed with brine (30 mL; 2x), dried over Na2SO4, filtered and the filtrate was concentrated. The residue was triturated with petroleum ether (50 ml) for 15 min to give the product tertbutyl 3-(2-((cyclopropylmethyl)amino)-5-(N-(1-methylcyclopropyl)sulfamoyl)benzamido)-3- methylazetidine-1 -carboxylate (1 .2 g, 2.28 mmol, 89.69% yield, 93.4% purity) as a yellow solid.
RT 0.913 min (method 1); m/z 437.2 (M-56+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.94 (s, 1 H), 8.32 (s, 1 H), 7.97 (d, J = 2.0 Hz, 1 H), 7.58-7.66 ( m, 2H), 6.82 (d, J = 9.2 Hz, 1 H), 4.02-4.06 (m, 2H), 3.71-3.78 (m, 2H), 3.03-3.08 (m, 2H), 1.55 (s, 3H), 1.39 (s, 9H), 1.25 (s, 1 H), 1.07 (s, 3H), 0.58-0.62 (m, 2H), 0.50-0.54 (m, 2H), 0.35 (d, J= 2.0 Hz, 2H), 0.26 (dd, J= 4.8, 1.2 Hz, 2H).
Preparation of Intermediate 18.3 tert-butyl 3-(1-(cyclopropylmethyl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,4- dihydroquinazolin-3(2H)-yl)-3-methylazetidine-1 -carboxylate
Figure imgf000095_0001
To a solution of tert-butyl 3-[[2-(cyclopropylmethylamino)-5-[(1- methylcyclopropyl)sulfamoyl]benzoyl]amino]-3-methyl-azetidine-1-carboxylate (1.1 g, 2.23 mmol) in DMF (15 mL) was added GDI (2.17 g, 13.40 mmol) and DIEA (1.73 g, 13.40 mmol, 2.33 mL). The mixture was stirred at 130 °C for 12 h. The mixture was quenched by the addition of aq. citric acid (40 mL, 10%) and extracted with EtOAc (50 mL; 2x). The combined organic layers were washed with brine (50 mL; 2x), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethylacetate/Petroleum ethergradient @ 50 mL/min) to give the product tert-butyl 3-(1- (cyclopropylmethyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,4-dihydroquinazolin-3(2H)-yl)-3- methylazetidine-1 -carboxylate (800 mg, 1 .43 mmol, 64.25% yield, 93% purity) as a yellow solid.
RT 0.900 min (method 1); m/z 519.3 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.36 (d, J = 2.4 Hz, 1 H), 8.22 (s, 1 H), 8.06 (dd, J= 9.2, 2.25 Hz, 1 H), 7.78 (d, J= 9.2 Hz, 1 H), 4.10-4.17 (m, 2H), 4.03 (d, J= 7.2 Hz, 2H), 3.78 (d, J= 8.0 Hz, 2H), 1.65 (s, 3H), 1.34 (s, 9H), 1.16-1.20 (m, 1 H), 1.09 (s, 3H), 0.58-0.64 (m, 2H), 0.44-0.52 (m, 4H), 0.37-0.44 ( m, 2H).
Preparation of Intermediate 18.4
1-(cyclopropylmethyl)-3-(3-methylazetidin-3-yl)-N-(1-methylcyclopropyl)-2,4-dioxo-1, 2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000095_0002
To a solution of tert-butyl 3-[1-(cyclopropylmethyl)-6-[(1-methylcyclopropyl)sulfamoyl]-2,4-dioxo- quinazolin-3-yl]-3-methyl-azetidine-1-carboxylate (800 mg, 1.54 mmol) in DCM (8 mL) was added TFA (6.16 g, 54.02 mmol, 4.00 mL) at 0 °C. The mixture was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure to give a residue, which was triturated with MTBE (20 ml) for 15 min to give the product 1-(cyclopropylmethyl)-3-(3-methylazetidin-3-yl)-N-(1-methylcyclopropyl)-2,4- dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide(360 mg, 860.20 pmol, 55.76% yield, 100% purity) as a white solid.
RT 0.679 min (method 1); m/z 419.2 (M+H)+ (ESI*); 1HNMR (DMSO- de, 400 MHz): 5 = 8.42-8.59 (m, 1 H), 7.92-8.04 (m, 1 H), 7.17-7.26 (m, 1 H), 5.61 (s, 1 H), 3.86-3.95 (m, 2H), 3.70-3.83 (m, 4H), 1.72- 1.85 (m, 1 H), 1.50 (s, 3H), 1.17 (s, 3H), 1.06-1.13 (m, 1 H), 0.68-0.76 (m, 2H), 0.50 (d, J= 8.0 Hz, 2H), 0.39-0.47 (m, 4H).
Preparation of Example 18
3-(1-(2-chloroacetyl)-3-methylazetidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4- dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide
Figure imgf000096_0001
To a solution of 1-(cyclopropylmethyl)-3-(3-methylazetidin-3-yl)-N-(1 -methylcyclopropyl)-2,4-dioxo- quinazoline-6-sulfonamide (25 mg, 46.95 pmol, TFA) in DCM (1 mL) was added TEA (19.00 mg, 187.78 pmol, 26.14 pL) followed by dropwise addition of 2-chloroacetyl chloride (6.36 mg, 56.33 pmol, 4.48 pL) at 0 °C. The mixture was stirred at 0 °C for 30 min .The mixture was poured into water (30 ml) and extracted with EtOAc (20 mL; 2x). The combined organic layers were washed with brine (10 mL; 2x), dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 20%-50%, 10 min) and lyophilized to give impure product. This impure product was further purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 pm; mobile phase: A: 10 mM aqueous solution of NH4HCO3, B: MeCN; B%: 37%-67%, 10 min) to give the product 3-(1-(2- chloroacetyl)-3-methylazetidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-6-sulfonamide(7. 89 mg, 14.14 pmol, 30.12% yield, 100% purity) as a white solid.
RT 0.737 min (method 1); m/z 495.2 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.29-8.34 (m, 1 H), 8.10-8.17 (m, 1 H), 7.93 (dd, J= 8.8, 2.32 Hz, 1 H), 7.59-7.66 (m, 1 H), 4.71-4.77 (m,1 H), 4.25- 4.33 (m, 3H), 4.04 (d, J = 15.6 Hz, 1 H), 3.94 (d, J= 6.8 Hz, 2H), 3.75 (d, J = 15.6 Hz, 1 H), 1.56 (s, 3H), 1.14-1.21 (m, 1 H) 1.09 (s, 3H), 0.59-0.64 (m, 2H), 0.46 (d, J= 7.2 Hz, 2H), 0.33-0.43 (m, 4H).
Preparation of Example 19 3-(1-acryloyl-3-methylazetidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo-
1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide
Figure imgf000097_0001
To a solution of 1-(cyclopropylmethyl)-3-(3-methylazetidin-3-yl)-N-(1 -methylcyclopropyl)-2,4-dioxo- quinazoline-6-sulfonamide (20 mg, 37.56 pmol, TFA salt) in DCM (1 mL) at 0°C was added TEA (15.20 mg, 150.23 pmol, 20.91 pL) followed by the dropwise addition of prop-2-enoyl chloride (4.08 mg, 45.07 pmol, 3.67 pL).The mixture was stirred at 0°C for 30 min. The mixture was poured into water (30 mL) and extracted with EtOAc (20 mL, 2x). The combined organic layers were washed with brine (10 mL, 2x), dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 mm* 5 pm; mobile phase: A: 10 mM aqueous solution of NH4HCO3, B: MeCN; B%: 40%-70%, 10 min), and lyophilized to give the product 3-(1-acryloyl-3- methylazetidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide (6.72 mg, 14.22 pmol, 37.86% yield, 100% purity) as a white solid.
RT 0.756 min (method 1); m/z 473.2 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 5 = 8.29-8.35 (m, 1 H), 8.06-8.24 ( m, 1 H), 7.93 (dd, J= 8.8, 2.32 Hz, 1 H), 7.63 (d, J= 9.2Hz, 1 H), 6.11-6.20 (m, 1 H), 5.99-6.10 (m, 1 H), 5.83 (dd, J = 11 .2, 1 .71 Hz, 1 H), 4.74 (d, J = 11 ,2Hz, 1 H), 4.23 (d, J = 11 .2 Hz, 1 H), 4.04 (d, J = 15.6 Hz, 1 H), 3.95 (d, J= 6.8Hz, 2H), 3.77 (d, J = 15.6 Hz, 1 H), 1.59 (s, 3H), 1.13-1.22 (m, 1 H), 1.09 (s, 3H), 0.57-0.66 (m, 2H) 0.28-0.52 (m, 6H).
Preparation of Intermediate 20.1
Tert-butyl (2-(1 -((1 -methylcyclopropyl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,4- dihydroquinazolin-3(2H)-yl)ethyl)carbamate
Figure imgf000097_0002
To a solution of A/-(1 -methylcyclopropyl)-1-((1-methylcyclopropyl)methyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide (300 mg, 825.47 pmol), tert-butyl N-(2-hydroxyethyl)carbamate (146.37 mg, 908.0 umol, 140.74 pL) and PPha (346.42 mg, 1.32 mmol) in toluene (8 mL) was added DIAD (267.07 mg, 1 .32 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h, then heated to 50 °C and stirred for 12 h at this temperature. The resulting mixture was poured into water (50 ml) and extracted with EtOAc (50 mL, 2x). The combined organic layers were washed with brine (10 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=20/1 to 3:1) to give the product tert-butyl (2-(1-((1- methylcyclopropyl)methyl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,4-dihydroquinazolin-3(2H)- yl)ethyl)carbamate (350 mg, 690.86 umol, 83.7% yield) as yellow oil.
RT 0.963 min (method 1); m/z 407.2 (M-Boc+H)+ (ESI*).
Preparation of Intermediate 20.2
3-(2-ami noethy l)-N- (1 -methylcycl op ropy I)- 1 -((1 -methylcyclop ropyl) methyl) -2, 4-d ioxo- 1 ,2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000098_0001
To a solution of tert-butyl (2-(1-((1-methylcyclopropyl)methyl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)- 2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)ethyl)carbamate (350 mg, 690.86 pmol) in DCM (4 mL) was added TFA (3.08 g, 27.0 mmol, 2 mL). The mixture was stirred at 20 °C for 1 h and then, concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 4%-37%, 11 min). The product solution was basified with Na2COs (aq, sat., 30 mL) and extracted with DCM (30 mL, 2x). The combined organic layers were washed with brine (10 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated to give the product 3-(2-aminoethyl)-N-(1-methylcyclopropyl)-1-((1- methylcyclopropyl)methyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (250 mg, 597.36 pmol, 56.33% yield) as a white solid.
RT 0.580 min (method 1); m/z 407.1 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 8.41 (d, J= 2.0 Hz, 1 H), 8.35 (br, 1 H), 8.26 (dd, J = 2.0, 9.2 Hz, 1 H), 7.78 (d, J = 9.2 Hz, 1 H), 4.25 - 4.07 (m, 4H), 1 .08 (s, 3H), 1.06 (s, 3H), 0.63 - 0.55 (m, 4H), 0.43 - 0.37 (m, 2H), 0.33 - 0.27 (m, 2H).
Preparation of Example 20
3-(2-cyanamidoethyl)-N-(1-methylcyclopropyl)-1-((1-methylcyclopropyl)methyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000099_0001
To a solution of 3-(2-aminoethyl)-N-(1 -methylcyclopropyl)-1-[(1 -methylcyclopropyl)methyl]-2,4- dioxo-quinazoline-6-sulfonamide (50 mg, 112.88 pmol) and DIPEA (43.76 mg, 338.63 umol, 58.98 pL) in DMF (1 mL) was added cyanic bromide (13.33 mg, 125.88 umol)and the mixture was stirred at 0 °C for 1 h. Then, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL, 2x). The combined organic layers were washed with brine (10 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge 150*25mm 10pm; mobile phase: A: 10 mmol/L NH4HCO3 in water, B: MeCN; B%: 32%-64%, 10 min) to give the product 3-(2-cyanamidoethyl)-N-(1-methylcyclopropyl)-1-((1-methylcyclopropyl)methyl)-2,4- dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (12 mg, 26.70 umol, 23.65% yield, 96% purity) as a white solid.
RT 0.869 min (method 1); m/z 432.2 (M+H)+ (ESI*); 1 HNMR (DMSO-de, 400 MHz): 8.43 (d, J = 2.4 Hz, 1 H), 8.25 (br, 1 H), 8.21 (dd, J= 2.4, 9.2 Hz, 1 H), 7.78 (d, J = 9.2 Hz, 1 H), 6.89 (br, 1 H), 4.21 (s, 2H), 4.12 (t, J= 6.0 Hz, 2H), 3.21 (t, J = 6.0 Hz, 2H), 1.09 (s, 3H), 1.05 (s, 3H), 0.63 - 0.55 (m, 4H), 0.43 - 0.38 (m, 2H), 0.32 - 0.28 (m, 2H).
Preparation of Example 21 and Example 22
Cis or Trans-3-(1-cyano-2-methylazetidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4- dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide and
Trans or Cis-3-(1-cyano-2-methylazetidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4- dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide
Figure imgf000099_0002
To a solution of 1 -(cyclopropylmethyl)-3-(2-methylazetidin-3-yl)-N-(1 -methylcyclopropyl)-2,4-dioxo- 1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (100 mg, 238.94 pmol) and DIEA (148.40 mg, 1.15 mmol, 0.2 mL) in DMF (1 mL) was added cyanogen bromide (28 mg, 264.35 pmol). The mixture was stirred at 20 °C for 2 h under N2. Then, it was diluted with H2O (10 mL) and extracted with ethyl acetate (5 mL, 3x). The combined organic layers were washed with brine (5 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 39%-69%, 10min) to give product 1 solution and product 2 solution. The solutions containing each compound were lyophilized to give the product cis or trans-3-(1-cyano-2-methylazetidin-3-yl)-1- (cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (5.45 mg, 12.29 umol, 5.14% yield, 99% purity) as a white solid and the product Trans or Cis-3-(1-cyano- 2-methylazetidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide (15.18 mg, 34.22 umol, 14.32% yield, >99% purity) as a white solid
Cis or Trans-3-(1-cyano-2-methylazetidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4- dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide
RT 0.518 min (method 4); m/z 444.1 (M+H)+ (ESI +); 1 H NMR (DMSO-de, 400 MHz): 8.37 (d, J = 2.4 Hz, 1 H), 8.22 (br, 1 H), 8.08 (dd, J = 8.8, 2.4 Hz, 1 H), 7.80 (d, J = 8.8 Hz, 1 H), 5.07 (q, J = 8.0 Hz, 1 H), 4.78-4.68 (m, 2H), 4.41 (t, J = 8.0 Hz, 1 H), 4.05 (d, J = 6.8 Hz, 2H), 1.34 (d, J = 6.4 Hz, 3H), 1.26-1.19 (m, 1 H), 1.10 (s, 3H), 0.63-0.58 (m, 2H), 0.51-0.44 (m, 4H), 0.43-0.39 (m, 2H).
Trans or Cis-3-(1-cyano-2-methylazetidin-3-yl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4- dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide
RT 0.526 min (method 3); m/z 444.1 (M+H)+ (ESI*);1 H NMR (DMSO-de, 400 MHz): 8.41 (d, J = 2.4 Hz, 1 H), 8.21 (s, 1 H), 8.07 (dd, J = 8.8, 2.4 Hz, 1 H), 7.78 (d, J = 8.8 Hz, 1 H), 5.04 - 4.90 (m, 2H), 4.52- 4.43 (t, J = 7.6 Hz, 1 H), 4.26 (t, J = 7.6 Hz, 1 H), 4.06 (d, J = 6.8 Hz, 2H), 1.50 (d, J = 6.0 Hz, 3H),1.28- 1.18 (m, 1 H), 1.08 (s, 3H), 0.62-0.57 (m, 2H), 0.45-0.51 (m, 4H), 0.42-0.38 (m, 2H).
Preparation of Intermediate 23.1 tert-butyl (2-(1-(cyclopropylmethyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,4- dihydroquinazolin-3(2H)-yl)ethyl)carbamate
Figure imgf000100_0001
To a solution of 1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide (100 mg, 286.20 pmol) in THF (3 mL) was added tert-butyl N-(2- hydroxyethyl)carbamate (46.14 mg, 286.20 pmol) and PPha (150.13 mg, 572.40 pmol). The mixture was degassed, purged with N2 (3x) and DIAD (115.74 mg, 572.40 pmol) was added at 0 °C. The resulting mixture was stirred at 50 °C for 16 h and concentrated under reduced pressure to remove solvent. The resulting residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate= 1 :1) to give the product tert-butyl (2-(1-(cyclopropylmethyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,4- dihydroquinazolin-3(2H)-yl)ethyl)carbamate (80 mg, 162.41 umol, 56.75% yield) as a white solid.
RT 0.533 min (method 4); m/z 393.0 (M-100+H)+ (ESI+);1H NMR (DMSO-de, 400 MHz): 8.42 (d, J = 2.0 Hz, 1 H), 8.19 (br, 1 H), 8.05 (dd, J= 8.4, 2.0 Hz, 1 H), 7.76 (d, J= 8.4 Hz, 1 H), 6.82 (br, t, J= 5.6 Hz, 1 H), 4.09- 4.01 (m, 4H), 3.23 (q, J = 5.6 Hz, 2H), 1.25 (s, 9H), 1.23-1.21 (m, 1 H), 1.10 (s, 3H), 0.63-0.58 (m, 2H), 0.52-0.46 (m, 4H), 0.42-0.38 (m, 2H)
Preparation of Intermediate 23.2
3-(2-aminoethyl)-1 -(cyclopropylmethyl)-N-(l -methylcyclopropyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000101_0001
To a solution of HCI/dioxane (4N, 1 .22 mL) was added tert-butyl (2-(1-(cyclopropylmethyl)-6-(N-(1- methylcyclopropyl)sulfamoyl)-2,4-dioxo- 1 ,4-di hydroq ui nazol i n-3(2H)-yl)ethyl)carbamate (80 mg, 162.41 pmol) and then the mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the product 3-(2-aminoethyl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)- 2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (80 mg, crude, HCI salt) as a white solid.
RT 0.366 min (method 3); m/z 392.9 (M+H)+ (ESI +); 1 H NMR (DMSO-de, 400 MHz): 8.43 (d, J = 2.0 Hz, 1 H), 8.26 (br, 1 H), 8.10 (dd, J = 8.8, 2.0 Hz, 1 H), 7.94 (br, 3H), 7.82 (d, J = 8.8 Hz, 1 H), 4.21 (t, J = 6.0 Hz, 2H), 4.08 (d, J = 6.8 Hz, 2H), 3.10 (br, 2H), 1.28-1.20 (m, 1 H), 1.09 (s, 3H), 0.63-0.58 (m, 2H), 0.53-0.46 (m, 4H), 0.43-0.38 (m, 2H).
Preparation of Example 23
N-(2-( 1 -(cyclopropyl methyl )-6-(N- (1 -methylcyc lopropyl) su Ifamoy l)-2 , 4-d ioxo- 1 ,4- dihydroquinazolin-3(2H)-yl)ethyl)acryl amide
Figure imgf000102_0001
To a solution of 3-(2-aminoethyl)-1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo- 1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (40 mg, 93.25 umol, HCI salt) in THF (0.5 mL) was added NaHCOs (70.51 mg, 839.29 pmol) and H2O (0.5 mL), followed by the addition of prop-2-enoyl chloride (9.28 mg, 102.58 pmol) at 0 °C. The mixture was stirred at 0 °C for 10 min, then diluted with H2O (10 mL) and extracted with ethyl acetate (5 mL, 3x). The combined organic layer was washed with brine (5 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product which was purified by reversed-phase HPLC (column: Phenomenex luna C18 150*25 mm* 10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN: B%: 29%-59%, 10 min). The product solution was lyophilized to give the product N-(2-(1 -(cyclopropylmethyl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)-2,4- dioxo-1 , 4-d i hydroq ui nazol i n-3(2 H)-yl)ethyl )acry I ami de (12.56 mg, 28.13 umol, 30.16% yield, >99% purity) as a white solid.
RT 0.458 min (method 4); m/z 447.0 (M+H)+ (ESI +); 1 H NMR (DMSO-de, 400 MHz): 8.42 (d, J = 2.4 Hz, 1 H), 8.23-8.11 (m, 2H), 8.06 (dd, J = 9.2, 2.4 Hz, 1 H), 7.77 (d, J = 9.2 Hz, 1 H), 6.14-6.02 (m, 1 H), 6.01-5.94 (m, 1 H), 5.56-5.47 (m, 1 H), 4.12- 4.02(m, 4 H), 3.44 (m, 2H), 1.27-1.17 (m, 1 H), 1.13 (s, 3H), 0.65-0.57 (m, 2H), 0.51-0.44 (m, 4H), 0.42-0.38 (m, 2H).
Preparation of Intermediate 24.1 tert-butyl (2-(1-(cyclopropylmethyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,4- dihydroquinazolin-3(2H)-yl)ethyl)(methyl)carbamate
Figure imgf000102_0002
To a solution of 1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide (100 mg, 286.20 pmol) in THF (3 mL) was added PPha (150.13 mg, 572.40 pmol) and tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (100.30 mg, 572.40 pmol). The mixture was degassed and purged with N2 (3x). Then, DIAD (115.74 mg, 572.40 pmol) was added at 0 °C and the reaction mixture was stirred at 50 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate= 1 :1) to give the product tert-butyl (2-(1-(cyclopropylmethyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-2,4- dioxo-1 ,4-dihydroquinazolin-3(2H)-yl)ethyl)(methyl)carbamate (110 mg, 217.13 umol, 75.87% yield) as a white solid.
RT 0.549 min (method 4); m/z 407.0 (M+H-Boc)+ (ESI*); 1H NMR (DMSO-de, 400 MHz): 8.44 (d, J= 2.0 Hz, 1 H), 8.24 (br, 1 H), 8.08 (dd, J = 8.8, 2.0 Hz, 1 H), 7.82 (d, J = 9.2 Hz, 1 H), 4.12-4.10 (m, 2H), 4.08-4.06 (m, 2H), 3.53-3.51 (m, 2H), 2.80 (s, 3H), 1.26-1.21 (m, 1 H), 1.08 (s, 3H), 1.00 (s, 9H), 0.61- 0.58 (m, 2H), 0.48-0.46 (m, 4H), 0.40-0.38 (m, 2H) Preparation of Intermediate 24.2
1-(cyclopropylmethyl)-3-(2-(methylamino)ethyl)-N-(1 -methylcyclopropyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000103_0001
To a solution of HCI/dioxane (4N, 2 mL) was added tert-butyl (2-(1-(cyclopropylmethyl)-6-(N-(1- methylcyclopropyl)sulfamoy l)-2,4-dioxo- 1 , 4-d i hydroqui nazol i n-3(2 H)-yl)ethy I) (methyl)carbamate (110 mg, 217.13 pmol). The mixture was stirred at 20 °C for 0.5 h and concentrated under reduced pressure to give the product 1-(cyclopropylmethyl)-3-(2-(methylamino)ethyl)-N-(1-methylcyclopropyl)-2,4-dioxo- 1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (90 mg, 203.18 umol, 93.58% yield, HCI salt) as a white solid.
RT 0.303 min (method 5); m/z 407.2 (M+H)+ (ESI*);1 H NMR (DMSO-de, 400 MHz): 8.59 (br, 2H) 8.43 (d, J = 2.4 Hz, 1 H), 8.24 (br, 1 H), 8.11 (dd, J = 8.8, 2.0 Hz, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 4.25 (t, J = 5.2 Hz, 2H), 4.09 (d, J = 6.8 Hz, 2H), 3.22 (br, 2H), 2.57 (s, 3H), 1.30-1.20 (m, 1 H), 1.10 (s, 3H), 0.66- 0.56 (m, 2H), 0.55-0.46 (m, 4H), 0.44-0.38 (m, 2H)
Preparation of Example 24
N-(2-( 1 -(cyclopropyl methyl )-6-(N- (1 -methylcyc lopropyl) su Ifamoy l)-2 , 4-d ioxo- 1 ,4- dihydroquinazolin-3(2H)-yl)ethyl)-N-methyl acrylamide
Figure imgf000104_0001
To a solution of 1-(cyclopropylmethyl)-3-[2-(methylamino)ethyl]-N-(1-methylcyclopropyl)-2,4-dioxo- quinazoline-6-sulfonamide (50 mg, 112.88 umol, HCI salt) in THF (0.5 mL) and H2O (0.5 mL) was added
NaHCOs (85.35 mg, 1 .02 mmol) followed by addition of prop-2-enoyl chloride (20.43 mg, 225.75 pmol) at 0 °C. The mixture was stirred at 0 °C for 10 min, diluted with water (10 mL) and extracted with ethyl acetate (5 mL, 3x). The combined organic layer was washed with brine (5 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 29%-59%, 10 min). The product solution was lyophilized to give the product N-(2-(1- (cyclopropylmethyl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,4-dihydroquinazolin-3(2H)- yl)ethyl)-N-methylacrylamide (17.32 mg, 37.45 umol, 33.18% yield? 99% purity) as a white solid.
RT 0.478 min (method 4); m/z 460.9 (M+H)+ (ESI*);1 H NMR (DMSO-ofe, 400 MHz): 8.45-8.34 (m, 1 H), 8.23-8.15 (m, 1 H), 8.10-8.02 (m, 1 H), 7.86-7.72 (m, 1 H), 6.65-6.50 (m, 1 H), 6.65-6.50 (m, 1 H), 5.58- 5.27 (m, 1 H), 4.19-4.12 (m, 2H), 4.06 (d, J= 6.8 Hz, 2H), 3.72-3.60 (m, 2H), 3.11-2.88 (m, 3H), 1.26-1.16 (m, 1 H), 1.07 (s, 3H), 0.62-0.55 (m, 2H), 0.52-0.43 (m, 4H), 0.42-0.35 (m, 2H)
Preparation of Intermediate 25.1 tert-butyl (R)-3-(1-(cyclopropylmethyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-2,4-dioxo-1,4- dihydroquinazolin-3(2H)-yl)pyrrolidine-1-carboxylate
Figure imgf000104_0002
To a mixture of tert-butyl (S)-3-hydroxypyrrolidine-1 -carboxylate (53.59 mg, 286.20 umol,) in THF (4 mL) was added 1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide (100 mg, 286.20 pmol) and PPha (150.14 mg, 572.40 pmol). The reaction mixture was degassed with N2 (3x). Then.DIAD (115.75 mg, 572.40 umol, 111 .29 pL) was added. The reaction mixture was heated to 50 °C and stirred for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum to give a residue which was purified by reversed-phase flash (ISCO®; 48 g Flash Coulmn: Spherical C18 20-45pm; 100 A, Eluent of 5-95% ACN/H2O (addition of 0.1 % formic acid) @ 80 mL/min). The fraction containing the product was concentrated under vacuum to give the product tert-butyl (R)-3-(1-(cyclopropylmethyl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,4- dihydroquinazolin-3(2H)-yl)pyrrolidine-1 -carboxylate (70 mg, 128.22 umol, 44.80% yield, 95% purity) as a white solid.
RT 0.605 min (method 4); m/z 463.1 (M-tBu+H)+ (ESI*);
Preparation of Intermediate 25.2
(R)-1 -(cyclop ropyl methyl)-N- (1 -methylcyclopropyl)-2, 4-d ioxo-3-(pyrrol id i n-3-yl)- 1 ,2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000105_0001
To a mixture of tert-butyl (R)-3-(1-(cyclopropylmethyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-2,4- dioxo-1 ,4-dihydroquinazolin-3(2H)-yl)pyrrolidine-1-carboxylate (70 mg, 134.97 pmol) in dioxane (2 mL) was added HCI/dioxane (4N, 2 mL).The mixture was warmed to 20 °C, stirred for 2 h and concentrated under vacuum to give the product (R)-1 -(cyclopropylmethyl)-N-(l -methylcyclopropyl)-2,4-dioxo-3- (pyrrolidin-3-yl)-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (28 mg, 58.47 umol, 43.32% yield, 95% purity, HCI salt) as an off-white solid
RT 0.384 min (method 4); m/z 419.0 (M+H)+ (ESI*); 1H NMR (DMSO-de, 400 MHz): 9.49 (br, 1 H), 8.83-8.68 (m, 1 H), 8.43 (d, J = 2.0 Hz, 1 H), 8.26 (s, 1 H), 8.09 (dd, J = 8.8, 2.0 Hz, 1 H), 7.81 (d, J = 8.8 Hz, 1 H), 5.83-5.73 (m, 1 H), 4.08 (d, J= 6.8, 2H), 3.47-3.36 (m, 3H), 3.24-3.17 (m, 1 H), 2.33-2.24 (m, 2H), 1.31-1.20 (m, 1 H), 1.09 (s, 3H), 0.64-0.57 (m, 2H), 0.53-0.47 (m, 4H), 0.42-0.38 (m, 2H)
Preparation of Example 25
(R)-3-(1 -acryloy Ipyrroli di n-3-y I)- 1 -(cyclopropyl methyl)-N-(1 -methylcyclop ropyl)-2, 4-dioxo- 1 ,2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000105_0002
To a mixture of (R)-1 -(cyclopropylmethyl)-N-(l -methylcyclopropyl)-2,4-dioxo-3-(pyrrolidin-3-yl)- 1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (28 mg, 61.54 umol, HCI salt) in THF (2 mL) and H2O (2 mL) was added K2CO3 (17.01 mg, 123.09 pmol) followed by acryloyl chloride (8.36 mg, 92.31 umol, 7.53 pL) at 0 °C. The mixture was warmed to 20 °C and stirred for 1 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL, 3x). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 32%-62%, 10 min) and lyophilized directly to give the product (R)-3-(1 -acryloylpyrrolidin-3-yl)-1- (cyclopropylmethyl)-N- (1 -methyl cyclopropyl)-2, 4-d ioxo- 1 , 2, 3,4-tetrahydroq u i n azoli ne-6-s ulfo namide (13 mg, 26.96 umol, 43.81 % yield, 98% purity) as a white solid.
RT 0.494 min (method 4); m/z 473.1 (M+H)+ (ESI*); 1H NMR 8.43-8.41 (m, 1 H), 8.21 (br, 1 H), 8.21-8.04 (m, 1 H), 7.77 (dd, J= 8.8, 4.0 Hz, 1 H), 6.72-6.42 (m, 1 H), 6.18-6.10 (m, 1 H), 5.76-5.59 (m, 2H), 4.06 (d, J = 6.4 Hz, 2H), 3.97-3.85 (m, 1 H), 3.81-3.61 (m, 2H), 3.52-3.42 (m, 1 H), 2.48-2.38 (m, 1 H), 2.30-2.09 (m, 1 H), 1.27-1.17 (m, 1 H), 1.09 (s, 3H), 0.63-0.57 (m, 2H), 0.52-0.43 (m, 4H), 0.42-0.38 (m, 2H).
Preparation of Intermediate 26.1 tert-butyl 3-(1-(cyclopropylmethyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-2,4-dioxo-1,4- dihydroquinazolin-3(2H)-yl)pyrrolidine-1 -carboxylate
Figure imgf000106_0001
To a mixture of 1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-6-sulfonamide (150 mg, 429.30 pmol) and tert-butyl 3-hydroxypyrrolidine-1- carboxylate (80.38 mg, 429.30 pmol) in toluene (1 .5 mL) was added CMBP (259.03 mg, 1 .07 mmol). The mixture was stirred at 95 °C for 16 h and concentrated under vacuum .The crude product was purified by reversed-phase HPLC (ISCO®;48 g Flash Column Welch Ultimate XB_C18 20-40pm; 120 A, mobile phase: A: 0.1 % HCI in water, B: MeCN; B%: 5%-95%, 10 min). The product solution was extracted with EtOAc (20 mL, 2x). The combined organic layer was washed with brine (40 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give the product tert-butyl 3-(1 -(cyclopropylmethyl)- 6-(N-(1-methylcyclopropyl)sulfamoyl)-2,4-dioxo-1 ,4-dihydroquinazolin-3(2H)-yl)pyrrolidine-1 -carboxylate (120 mg, 231.38 umol, 53.90% yield) as a white solid.
RT 0.492 min (method 5), m/z, 541 .0(M+Na)+ (ESI*).
Preparation of Intermediate 26.2
1 -(cycl op ropy I methyl)- N-( 1 -methylcyc lopropyl) -2,4-d ioxo-3-(pyrrol i di n-3-y I)- 1 ,2,3,4- tetrahydroquinazoline-6-sulfonamide
Figure imgf000107_0001
To a solution of HCI/dioxane (4N, 2 mL) was added tert-butyl 3-(1-(cyclopropylmethyl)-6-(N-(1- methylcyclopropyl)sulfamoyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)pyrrolidine-1-carboxylate (120 mg, 231.38 pmol). Then, the mixture was stirred at 20°C for 1 h and concentrated under vacuum. The resulting residue was dissolved in NaHCOs (aq., sat., 10 mL) and the solution was extracted with EtOAc (5 mL, 2x). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the product 1-(cyclopropylmethyl)-N-(1- methylcyclopropyl)-2,4-dioxo-3-(pyrrolidin-3-yl)-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (88 mg, 210.27 umol, 90.88% yield) as a yellow solid.
RT 0.429 min (method), m/z, 419.1 (M+H)+ (ESI*).
Preparation of Intermediate 26.3
Methyl bicyclo[1 .1 .0]butane-1 -carboxylate
Figure imgf000107_0002
To a solution of methyl 3-chlorocyclobutanecarboxylate (100 mg, 673.01 pmol) in THF (1.2 mL) was added dropwise a solution of LiHMDS in THF (1 M, 807.61 pL) at 0°C under N2 atmosphere. The mixture was stirred at 0°C for 1 h. The resulting yellow solution of methyl bicyclo[1.1.0]butane-1 - carboxylate (theoretical quantity: 75 mg, 2 mL, 336.5 pmol/mL) was used directly in the next step without further purification.
Preparation of Example 26
3-(1-(bicyclo[1.1.0]butane-1-carbonyl)pyrrolidin-3-yl)-1-(cyclopropylmethyl)-N-(1- methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide
Figure imgf000107_0003
To a solution of 1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2,4-dioxo-3-(pyrrolidin-3-yl)-1 ,2,3,4- tetrahydroquinazoline-6-sulfonamide (88 mg, 210.27 pmol) and a solution of methyl bicyclo[1.1.0]butane- 1 -carboxylate (theoretical quantity: 47.15 mg, 420.54 umol, 1.2 mL) in THF (0.5 mL) was added dropwise at 0°C a solution of LiHMDS in THF (1 M, 630.81 pL). The mixture was stirred at 40°C for 1 h, poured into NH4CI (aq., sat., 15 mL) and extracted with EtOAc (5 mL, 2x). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 mm*10 pm; mobile phase: A: 10 mM aqueous solution of NH4HCO3 in water, B: MeCN; B%: 28%-58%, 8 min) and lyophilized directly to give the product 3-(1-(bicyclo[1.1.0]butane-1 -carbonyl)pyrrolidin-3-yl)-1-(cyclopropylmethyl)-N-(1- methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (7.94 mg, 14.65 umol, 6.97% yield, 92% purity) as a white solid.
RT 0.304 min (method 5), m/z, 419.1 (M+H)+ (ESH); 1 H NMR (DMSO-de, 400 MHz): 8.42 (d, J = 2.0 Hz, 1 H), 8.19 (br, 1 H), 8.06 (dd, J = 2.0, 8.8 Hz, 1 H), 7.77 (d, J = 8.8 Hz, 1 H), 5.73 - 5.56 (m, 1 H), 4.06 (d, J = 6.8 Hz, 2H), 4.03 - 3.95 (m, 1 H), 3.81 - 3.65 (m, 2H), 3.50 - 3.38 (m, 1 H), 2.46 - 2.37 (m, 1 H), 2.28 - 2.14 (m, 3H), 2.07 (s, 1 H), 1.27 - 1.18 (m, 1 H), 1.11 - 1.04 (m, 4H), 1.00 (m, 1 H), 0.63 - 0.58 (m, 2H), 0.52 - 0.45 (m, 4H), 0.42 - 0.37 (m, 2H).
Compounds listed in the table below were prepared accordingly to closely related compounds and starting from the corresponding intermediates.
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Ill
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
The following Table 1 provides an overview on the compounds described in the example section:
Table 1
Figure imgf000129_0002
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Biological evaluation of the exemplary compounds
Exemplary compounds of formula (I) were tested in selected biological and/or physicochemical assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median value is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values. The in vitro pharmacological, pharmacokinetic and physicochemical properties of the compounds can be determined according to the following assays and methods.
PARG protein expression and purification
A codon optimized gene encoding human PARG (448-976 [H446G, L447S, L473S, N479S, S802A, R81 1 K, M841 I, S858P, 1916T, T924D, D927K, C963S, A967T]) was synthesized by Genscript, and cloned into pET15b (Ncol/BamHI) with an N-terminal, Thrombin protease cleavable 6His-TwinStrep tag. Expression of the protein in E. coli BL21 (DE3) was induced by addition of 0.2 mM IPTG to a shake flask culture grown to GD600=0.8 at 37°C. Growth was allowed to continue at 30°C for a further 20 hours before harvesting by centrifugation and storage of the cell pellet at -80°C.
Protein was purified by IMAC and SEC: frozen cell pellets (typically 40 g wet weight) were resuspended by homogenization in 5 volumes buffer A (25 mM Tris/HCI pH 8.0, 200 mM NaCI, 2 mM DTT), supplemented with 1 mg of DNase I from bovine pancreas (Sigma-Aldrich) and protease inhibitors (Roche Complete™ EDTA-free protease inhibitor tablet), and lysed by passage through a Constant Systems BasicZ homogenizer. The lysate was clarified by centrifugation for 60 minutes at 25,000 g, 4°C, and the lysate supernatant was loaded onto 5 ml StrepTrap HP (Cytiva) pre-equilibrated with buffer A. The column was washed with buffer A (~ 10 CV), then buffer B containing 1 M KCI (~5 CV), and then the protein was eluted with buffer A containing 2.5 mM d-Desthiobiotin. Pooled fractions containing 6HisTwinStrep-TEV-hPARG were incubated with TEV protease overnight at 4°C. hPARG was separated from uncleaved material and Thrombin protease through gel filtration with Superdex75 sizing column (GE Healthcare) pre-equilibrated with SEC buffer (15 mM Tris/HCI pH 8.5, 100 mM NaCI, 2 mM DTT). Pooled fractions containing pure hPARG were concentrated using a 10 k MWCO spin concentrator (VivaSpin) to 10 mg/mL, and then either used immediately for crystallisation or snap-frozen in liquid nitrogen for storage at -80°C.
PARG C872A protein expression and purification
A codon optimized gene encoding human PARG C872A (448-976 [L473S, N479S, S802A, R81 1 K, M8411, S858P, C872A, 1916T, T924D, D927K, C963S, A967T]) was synthesized by Genscript, and cloned into pET15b (Ncol/BamHI) with an N-terminal, Thrombin protease cleavable 6His-TwinStrep tag. Expression of the protein in E. coli BL21 (DE3) was induced by addition of 0.2 mM IPTG to a shake flask culture grown to GD600 = 0.8 at 37°C. Growth was allowed to continue at 30°C for a further 20 hours before harvesting by centrifugation and storage of the cell pellet at -80°C.
Protein was purified by IMAC and SEC: frozen cell pellets (typically 40 g wet weight) were resuspended by homogenization in 5 volumes buffer A (25 mM Tris/HCI pH 8.0, 200 mM NaCI, 2 mM DTT), supplemented with 1 mg of DNase I from bovine pancreas (Sigma-Aldrich) and protease inhibitors (Roche Complete™ EDTA-free protease inhibitor tablet), and lysed by passage through a Constant Systems BasicZ homogenizer. The lysate was clarified by centrifugation for 60 minutes at 25,000 g, 4°C, and the lysate supernatant was loaded onto 5 ml StrepTrap HP (Cytiva) pre-equilibrated with buffer A.
The column was washed with buffer A (~10 CV), then buffer B containing 1 M KCI (~5 CV), and then the protein was eluted with buffer A containing 2.5 mM d-Desthiobiotin. Pooled fractions were incubated with TEV protease overnight at 4°C. hPARG C872A was separated from uncleaved material and Thrombin protease through gel filtration with Superdex75 sizing column (GE Healthcare) preequilibrated with SEC buffer (15 mM Tris/HCI pH 8.5, 100 mM NaCI, 2 mM DTT). Pooled fractions containing pure hPARG C872A were concentrated using a 10 k MWCO spin concentrator (VivaSpin) to 10 mg/mL, and then snap-frozen in liquid nitrogen for storage at -80°C.
PARG enzymatic I Cso assay
PARG enzyme as incubated with compound or vehicle (DMSO) for 15 minutes or 2 hours in a 384 well plate. After adding the PARG substrate ADP-ribose-pNP, the plate was read for absorbance intensity at 405 nm. The vehicle (DMSO) with high absorbance intensity represents no inhibition of enzymatic reaction while the low control (no enzyme) with low absorbance intensity represents full inhibition of enzymatic reaction.
Materials: hPARG: Peak Protein, 30 nM
Substrate: ADP-pNP, 800 pM, Jena Bioscience catalog # NU-955
Reaction time: 60 minutes
Assay buffer: 50 mM Tris-HCI pH 8.0, 100 mM NaCI, 2 mM DTT
Temperature: 30 °C
Total volume: 30 pL
Controls:
• 0% inhibition control: DMSO
• 100% inhibition control: No enzyme
The protocol that was used for enzyme reaction and detection is as follows:
1. Transfer 100 nL of the final concentration of test compounds or vehicle (DMSO) to the appropriate wells of a microtiter plate.
2. Centrifuge the plate at 1000 rpm for 1 minute.
3. Transfer 14.6 pL of 2x final concentration of enzyme in assay buffer or assay buffer alone to the appropriate wells.
4. Centrifuge the plate at 1000 rpm for 1 minute.
5. Incubate the plate at room temperature for 15 minutes.
6. Transfer 15.4 pL of 2x substrate in assay buffer to all the test wells.
7. Centrifuge the plate at 1000 rpm for 1 minute.
8. Read the plate on a plate reader (e.g., Spark Tecan).
The Absorbance ICso value of compounds of Formula (I) in Examples 1 to 96 are provided in Table 2 below.
Cellular PAR chain assay
The ability of compounds to inhibit PARG in response to DNA damage, was assessed with U2OS cells pretreated with the compounds for 1 hour, following a 1 -hour treatment with or without the DNA alkylating agent temozolomide (TMZ). The cells were harvested and fixed in 70% ethanol, rehydrated with glucose and EDTA in PBS and subsequently blocked for 1 hour with PBS 1 % BSA and 0.01% Tween-20 (PBT). The cells were incubated for 2 hours at room temperature with a mouse monoclonal antibody against poly (ADP) ribose (PAR) polymer. The cells were washed and incubated with an anti-mouse Alexa-488 conjugated secondary antibody for 1 hour at room temperature. Propidium iodide staining was used to determine DNA content in the cells (staining at 4°C overnight). The fluorescence intensity of the cells was assessed by flow cytometry (Cytoflex from Beckmann) and the percentage of PAR chain positive cells (gated in relation to TMZ+DMSO treated control) was determined. PAR chain positive cells % were fit against the concentration of the compound using a 4 parameter log-logistic function, generating PAR chain ECso values:
Figure imgf000151_0001
The PAR chain ECso value for compounds of Formula (I) in Examples 1 to 96 are provided in Table 2 below.
Cellular Viability Assay
NCIH-460 as a PARG-inhibition sensitive cell line and U2OS as PARG-inhibition insensitive cell line were plated at 1000 cells/well and 2000 cells/well, respectively, in 96-well white plates with clear flat bottom. After 24 hours, the compounds were added with the Tecan digital dispenser (D300e) in duplicates. The outer wells of the plate were excluded. After 96 hours of incubation, 150 pl of the growth medium were removed and 50 pl of Cell Titer-Gio (Promega) were added per well. Following an incubation of 10 minutes, luminescence was read using a plate reader (Tecan). Averaged values of the samples were normalized to DMSO treated control samples. Curves were fit as % of the control vs. log of the compound concentration using a 4 parameter log-logistic function:
Figure imgf000152_0001
The PARGi (NCIH-460 and U2OS) cellular viability ECso values for compounds of Formula (I) in Examples 1 to 96 are provided in Table 2 below.
Table 2: Inhibition of PARG by compounds according to the present invention and cellular activity of compounds according to the present invention. The ICso (inhibitory concentration at 50% of maximal effect) values are indicated in pM, empty space means that the corresponding compounds have not been tested in the respective assay.
(T) Example number
@ Structure
(3) IC50 in pM determined in PARG enzymatic assay (PARG protein and 15 mn incubation) described under PARG enzymatic IC50 assay
(4) IC50 in pM determined in PARG enzymatic assay (PARG protein and 2 hours incubation) described under PARG enzymatic IC50 assay.
(5) IC50 in pM determined in PARG enzymatic assay (PARG C872A protein and 2 hours incubation) described under PARG enzymatic IC50 assay.
(6) EC50 in pM determined in cellular assay as described under Cellular PAR chain assay (conditions with treatment of TMZ).
(7) EC50 in pM determined in cellular assay as described under Cellular PAR chain assay (conditions without treatment of TMZ).
(8) EC50 in pM determined in NCIH-460 cells as described under Cellular viability assay.
(9) EC50 in pM determined in U2OS cells as described under Cellular viability assay.
Figure imgf000152_0002
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Further assays
Kinetic solubility assay
The Kinetic solubility assay employs the shake flask method followed by HPLC-UV analysis. For exemplary compounds, the kinetic solubility was measured according to the following protocol:
1) Samples were weighed and dissolved in 100% DMSO to make a stock solution of 10 mM. About 100 pL of stock solution is needed to cover this assay.
2) Test compounds and controls (10 mM in DMSO, 10 pL/tube) were added into the buffer (490 pL/well) which placed in a Minni-Uniprep filter. The buffer was prepared as the customer’s requirement.
3) Vortex the kinetic solubility samples for 2 minutes.
4) Incubate and shake the solubility solutions on an orbital shaker for 24 hr at room temperature
5) Transfer 200 pL each of solubility solution into 96-deep well for analysis when the samples were directly filtered by the syringeless filter device
6) Determine the test compound concentration of the filtrate using HPLC-UV.
7) Injected three UV standard solutions into HPLC from low to high concentration, followed by testing of the K.S. supernatant. Testing samples are injected in duplicate.
Bidirectional permeability in Caco2
The bidirectional permeability in Caco-2 cells assay was performed for the exemplary compounds of formula (I) according to the following protocol:
1. Caco-2 cells purchased from ATCC were seeded onto polyethylene membranes (PET) in 96- well BD Insert plates at 1 x 105 cells/ cm2, and refreshed medium every 4~5 days until to the
21 st to 28th day for confluent cell monolayer formation.
2. The integrity of the monolayer is verified by performing Lucifer yellow rejection assay.
3. The quality of the monolayer is verified by measuring the Unidirectional (A^-B) permeability of fenoterol/nadolol (low permeability marker), propranolol/metopronolol (high permeability marker) and Bi-directional permeability of Digoxin (a P-glycoprotein substrate marker) in duplicate wells.
4. Standard assay conditions for test compounds:
-Test concentration: 2 pM (DMSO<1 %);
-Replicates: n=2;
-Directions: bi-directional transport including A >B and B >A; -Incubation time: single time point, 2hours;
-Transport buffer: HBSS containing 10 mM HEPES, pH7.40±0.05;
-Incubation condition: 37±1 °C, 5% CO2, relatively saturated humidity.
5. Spike dosing solution and mix with transport buffer and Stop Solution (containing an appropriate internal standard (IS)) as TO sample.
6. At the end of incubation, sample solutions from both donor and receiver wells and mix with Stop Solution immediately.
7. All samples including TO samples, donor samples and receiver samples are analyzed using LC/MS/MS. Concentrations of test compound are expressed as peak area ratio of analytes versus IS without a standard curve.
Microsome metabolic stability (MMS) assay
The stability of the exemplary compounds was measured in the microsome metabolic stability assay as follows:
1) Test compounds will be incubated at 37°C with liver microsomes (pooled from multiple donors) at 1 pM in the presence of a NADPH regenerating system at 0.5 mg/ml microsomal protein.
2) Positive controls include Testosterone (3A4 substrate), Propafenone (2D6) and Diclofenac (2C9). They will be incubated with microsomes in the presence of a NADPH regenerating system.
3) Time samples (0, 5, 15, 30, 45 and 60 minutes) will be removed, immediately mixed with cold acetonitrile containing internal standard (IS). Test compound incubated with microsomes without NADPH regenerating system for 60min will be also included.
4) Single point for each test condition (n=1).
5) Samples will be analyzed by LC/MS/MS; disappearance of test compound will be assessed base on peak area ratios of analyte/IS(no standard curve).
6) An excel data summary, calculated intrinsic clearance and t1/2 values will be provided.
7) Using the following equation to calculate the microsome clearance:
, int(mic) = 0.693/half life/mg microsome protein per mLwt: 40 g/kg, 30 g/kg, 32 g/kg, 20 g/kg and 88 g/kg for rat, monkey, dog, human and mouse.CLint(mic) to calculate the whole the liver clearance: microsomal protein / g liver weight: 45 mg/g for 5 speciesint(liver) = CLint(mic) * mg microsomal protein/g liver weight * g liver weight/kg body weight .
In vitro metabolic stability of test compounds in CD-1 mouse, SD rat, beagle dog, cynomolqus monkey and human cryopreserved hepatocytes
1. Test compound (at 1 pM) is incubated with cryopreserved hepatocytes (0.5 x 106 cells per mL) in duplicates (n=2) at 37°C using 96-well plate format.
2) Time points are 0, 15, 30, 60 and 90 minutes in separate plates and medium control samples without cells at 0 and 90 minutes are also incubated. At each time point the reaction will be stopped by adding organic solution containing internal standard (IS).
3. Positive controls 7-ethoxycoumarin and 7-hydroxycoumarin are included in parallel.
4. Samples are analyzed by LC-MS/MS. Disappearance of test compound is assessed based on peak area ratios of analyte/IS (no standard curve).

Claims

Claims 1. A compound of formula (I):
Figure imgf000158_0001
wherein: Rcov is selected from C2 alkenyl, C2 alkynyl, -CH2Cl, CH2CN, and
Figure imgf000158_0002
, wherein said alkenyl is optionally substituted with one or more optional substituents selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -OOC- C1-4 alkyl), -NHCO-(C1-4 alkyl),-(C1-4 alkylene)N(C1-4 alkyl)(C1-4 alkyl), -(C1-4 alkylene)-(N-heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, wherein said alkynyl is optionally substituted with an optional substituent selected from C1-4 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the -CH2- group in said -CH2Cl and the -CH2- group in said -CH2CN are each optionally substituted with one or more optional substituents selected from -Hal, C1-4 alkyl and -CF3; -Wcov- is selected from -CO-, -SO- and -SO2-; or -Wcov-Rcov is -CN; -RN- is heterocycloalkylene comprising an N atom, wherein Wcov is connected to RN through said N atom and wherein said heterocycloalkylene is optionally substituted with one or more optional substituents selected from -Hal, -(C0-2 alkylene)-CN, C1-2 alkyl and C1-2 haloalkyl; R1 is hydrogen, chloro, fluoro, -CN, formyl, (C1-2)alkyl, (C2)alkenyl, (C2)alkynyl, (C1-2)haloalkyl, -(C1- 2 alkylene)-OH or -(C1-2 alkylene)-O-(C1-2 alkyl); R2 and R3 are independently each (C1-2)alkyl or (C1-2)haloalkyl, or R2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more - F; or -CR1R2R3 is bicyclo[1,1,1]pent-1-yl; W is selected from -NHS(O)y-, -S(O)yNH-, -NHS(O)(NH)-, -NHS(O)(N-C1-2 alkyl)-, -S(O)(NH)-NH-, -S(O)(N-C1-2 alkyl)-NH-, wherein y is 1 or 2; X1 and X3 are independently selected from the group consisting of N, CH, and CF; X2 is N or C-YC2-RC2, wherein YC2 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 RS1, 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(C1-5 alkyl)-, -CO-, -S-, -SO-, and -SO2-, and wherein said cycloalkylene and heterocycloalkylene are each optionally substituted with one or more groups independently selected RS2; and wherein RC2 is selected from hydrogen, halo, -OH, -NH2, -SH, -CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein said alkyl, alkenyl, and alkynyl in X2 are each optionally substituted with one or more groups independently selected from RS1, and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in X2 are each optionally substituted with one or more groups independently selected from RS2; and the moiety represented with a partial formula
Figure imgf000160_0001
is a moiety selected from
Figure imgf000160_0002
wherein: R7 is s hydrogen, -CN, -Hal, or a moiety of the formula -L71-L72-Q7 wherein: L71 is a bond or C1-5 alkylene optionally substituted with halo or oxo; L72 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, -N(C1-6 alkyl)-, -CO-, -COO-, -OCO-, -CONH- , -CON(C1-6 alkyl)-, -NHCO-, N(C1-6 alkyl)CO-, -NHCONH-, -N(C1-6 alkyl)CONH-, - NHCON(C1-6 alkyl)-, N(C1-6 alkyl)CON(C1-6 alkyl)-, -SO2NH-, -SO2N(C1-6 alkyl)-, - NHSO2-, or -N(C1-6 alkyl)SO2-, and Q7 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(C0-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-aryl, -(C0-2 alkylene)-heterocycloalkyl or -(C0-2 alkylene)-heteroaryl; wherein said alkyl, alkenyl, alkynyl, and alkylene in R7 are each optionally substituted with one or more optional substituents selected from RS1; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in R7 are each optionally substituted with one or more optional substituents selected from RS2; R8 is hydrogen, -CN, -Hal, or a moiety of the formula: -L81-L82-Q8 wherein: L81 is a bond, C1-5 alkylene optionally substituted with halo or oxo; L82 is a bond, -O-, -S-, -SO-, -SO2-, -NH-, -N(C1-6 alkyl)-, -CO-, -COO-, -OCO-, -CONH- , -CON(C1-6 alkyl)-, -NHCO-, N(C1-6 alkyl)CO-, -NHCONH-, -N(C1-6 alkyl)CONH-, - NHCON(C1-6 alkyl)-, N(C1-6 alkyl)CON(C1-6 alkyl)-, -SO2NH-, -SO2N(C1-6 alkyl)-, - NHSO2-, or -N(C1-6 alkyl)SO2-; and Q8 is hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein said alkyl, alkenyl, alkynyl, and alkylene in R8 are each optionally substituted with one or more optional substituents selected from RS1; and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl in R8 are each optionally substituted with one or more optional substituents selected from RS2; wherein RS1 is selected from halogen, -CN, -OH, -O(C1-5 alkyl), -O(C1-5 haloalkyl), C1-5 haloalkyl, -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -(N-heterocycloalkyl), -CO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -CO-(N-heterocycloalkyl), -NHCO- (C1-5 alkyl), -N(C1-5 alkyl)-CO-(C1-5 alkyl), -NHCONH2, -NHCONH-(C1-5 alkyl), -NHCON(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 alkyl)CONH2, -N(C1-5 alkyl)CONH-(C1-5 alkyl), and -N(C1-5 alkyl)CON(C1-5 alkyl)(C1-5 alkyl), and wherein RS2 is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(C1-5 alkyl), -O(C1-5 haloalkyl), -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -(N-heterocycloalkyl), -CO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -CO-(N-heterocycloalkyl), -(C1-5 alkylene)-CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-O(C1-5 alkyl), -(C1-5 alkylene)-O(C1-5 haloalkyl), -(C1-5 alkylene)-SH, -(C1-5 alkylene)-S(C1-5 alkyl), -(C1-5 alkylene)-S(C1-5 haloalkyl), -(C1-5 alkylene)-NH2, -(C1-5 alkylene)-NH(C1-5 alkyl), -(C1-5 alkylene)-NH(C1-5 haloalkyl), -(C1-5 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-N(C1-5 alkyl)(C1-5 haloalkyl), -(C1-5 alkylene)-(N- heterocycloalkyl), -(C1-5 alkylene)-N(C1-5 haloalkyl)(C1-5 alkyl), -(C1-5 alkylene)-CO(C1-5 alkyl), -(C1- 5 alkylene)-CONH2, -(C1-5 alkylene)-CONH(C1-5 alkyl), -(C1-5 alkylene)-CON(C1-5 alkyl)(C1-5 alkyl) - (C1-5 alkylene)-CO-(N-heterocycloalkyl), -(C1-5 alkylene)-NHCO-(C1-5 alkyl), -(C1-5 alkylene)-N(C1-5 alkyl)-CO-(C1-5 alkyl), -(C1-5 alkylene)-NHCONH2, -(C1-5 alkylene)-NHCONH-(C1-5 alkyl), -(C1-5 alkylene)-NHCON(C1-5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-N(C1-5 alkyl)CONH2, -(C1-5 alkylene)-N(C1- 5 alkyl)CONH-(C1-5 alkyl), and -(C1-5 alkylene)-N(C1-5 alkyl)CON(C1-5 alkyl)(C1-5 alkyl); or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein Rcov is C2 alkenyl, wherein said alkenyl is optionally substituted with one or more optional substituents selected from C1-4 alkyl, -COO-(C1-4 alkyl), -CO-(C1-4 alkyl), -CONH-(C1-4 alkyl), -OOC-(C1-4 alkyl), -NHCO-(C1-4 alkyl), -(C1-4 alkylene)N(C1-4 alkyl)(C1-4 alkyl), - (C1-4 alkylene)-(N-heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and - CF3.
3. The compound of claim 1 or 2, wherein Rcov is C2 alkenyl.
4. The claim of any one of claims 1 to 3, wherein Wcov is -CO-.
5. The compound of any one of claims 1 to 4, wherein R1 is methyl or fluoromethyl. 161
6. The compound of any one of claims 1 to 5, wherein R2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more -F.
7. The compound of any one of claims 1 to 6, wherein W is -NHS(O)2-, preferably wherein the left side of W as defined herein is attached to the carbon atom that carries R1, R2 and R3.
8. The compound of any one of claims 1 to 7, wherein X1 is CF or CH and X3 is CH, preferably wherein X1 and X3 are each CH.
9. The compound of any one of claims 1 to 8, wherein wherein X2 is C-YC2-RC2, wherein -YC2-RC2 is selected from -O-C1-12 alkyl, -NH-C1-12 alkyl, -N(C1-5 alkyl)-C1-12 alkyl, -O-C2-12 alkenyl, -NH-C2-12 alkenyl, -N(C1-5 alkyl)-C2-12 alkenyl, -O-C2-12 alkynyl, -NH-C2-12 alkynyl, -N(C1-5 alkyl)-C2-12 alkynyl, -(C0-3 alkylene)-cycloalkyl, -CO-(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-CO-cycloalkyl, -CONH- (C0-3 alkylene)-cycloalkyl, (C0-3 alkylene)-CONH-cycloalkyl, -NHCO-(C0-3 alkylene)-cycloalkyl, -(C0- 3 alkylene)-NHCO-cycloalkyl, -NH-(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-NH-cycloalkyl, -O-(C0- 3 alkylene)-cycloalkyl, -(C0-3 alkylene)-O-cycloalkyl, -SO2-(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-SO2-cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, - CO-cycloalkyl, -SO2-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -CO-(C0-3 alkylene)- heterocycloalkyl, -(C0-3 alkylene)-CO-heterocycloalkyl, -CONH-(C0-3 alkylene)-heterocycloalkyl, - (C0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)- NHCO-heterocycloalkyl, -NH-(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-NH- heterocycloalkyl, -O-(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-O-cycloalkyl, -SO2-(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-SO2-heterocycloalkyl, -CONH-heterocycloalkyl, - NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO2- heterocycloalkyl, -(C0-3 alkylene)-aryl, -CO-(C0-3 alkylene)-aryl, -(C0-3 alkylene)-CO-aryl, -CONH- (C0-3 alkylene)-aryl, -(C0-3 alkylene)-CONH-aryl, -NHCO-(C0-3 alkylene)-aryl, -(C0-3 alkylene)- NHCO-aryl, -NH-(C0-3 alkylene)-aryl, -(C0-3 alkylene)-NH-aryl, -O-(C0-3 alkylene)-aryl, -(C0-3 alkylene)-O-aryl, -SO2-(C0-3 alkylene)-aryl, -(C0-3 alkylene)-SO2-aryl, -CONH-aryl, -NHCO-aryl, - NH-aryl, -O-aryl, -CO-aryl, -SO2-aryl, -(C0-3 alkylene)-heteroaryl, -CO-(C0-3 alkylene)-heteroaryl, - (C0-3 alkylene)-CO-heteroaryl, -CONH-(C0-3 alkylene)-heteroaryl, -(C0-3 alkylene)-CONH- heteroaryl, -NHCO-(C0-3 alkylene)-heteroaryl, -(C0-3 alkylene)-NHCO-heteroaryl, -NH-(C0-3 alkylene)-heteroaryl, -(C0-3 alkylene)-NH-heteroaryl, -O-(C0-3 alkylene)-heteroaryl, -(C0-3 alkylene)- O-heteroaryl, -SO2-(C0-3 alkylene)-heteroaryl, -(C0-3 alkylene)-SO2-heteroaryl, -CONH-heteroaryl, - NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and -SO2-heteroaryl, wherein said alkylene is optionally substituted with one or more groups independently selected from RS1, and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2. The compound of any one of claims 1 to 8, wherein X2 is CH. The compound of any one of claims 1 to 10, wherein the moiety represented with a partial formula
Figure imgf000164_0001
The compound of claim 11 , wherein R8 is a moiety of the formula -L81-L82-Q8. The compound of claim 12, wherein L81 is methylene, -L82 is a covalent bond, and wherein Q8 is cycloalkyl, aryl, heterocycloalkyl or heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more optional substituents selected from RS2. The compound of any one of claims 1 to 13, wherein RN is selected from:
Figure imgf000164_0002
A pharmaceutical composition comprising the compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier. The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of claim 15, for use in therapy. The compound for use or the pharmaceutical composition for use of claim 16, for use in a method of treating a disease or disorder in which PARG activity is implicated. The compound for use or the pharmaceutical composition for use of claim 16, for use in a method of treating a proliferative disorder, preferably wherein the proliferative disorder is cancer, preferably a human cancer.
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