Novel parc inhibitors

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present invention further relates to the compound of formula (I) of the present invention for use in therapy. Instant compounds are particularly useful as PARC inhibitors, and can be used in a method of treatment of a proliferative disorder, preferably of cancer.

Description

[0001] Novel PARG inhibitors

[0002] Field of the invention

[0003] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present invention further relates to the compound of formula (I) of the present invention for use in therapy. Instant compounds are particularly useful as PARG inhibitors, and can be used in a method of treatment of a proliferative disorder, preferably of cancer.

[0004] Background of the invention

[0005] 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).

[0006] 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).

[0007] 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.

[0008] 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).

[0009] 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).

[0010] 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.

[0011] 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).

[0012] 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).

[0013] Certain compounds that are useful as PARG inhibitors are further disclosed in documents WO 2016 / 092326, WO 2016 / 097749 and WO 2021 / 055744.

[0014] Document WO 2023 / 154913 further discloses certain sulfonamides and related compounds which are inhibitors of PARG and are useful in the treatment of cancer.

[0015] Document WO 2024 / 173453 discloses certain heteroaryl-substituted imidazopyridine compounds that are inhibitors of PARG, useful in the treatment of cancer.

[0016] Summary of the invention

[0017] 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.

[0018] The compound of the invention are potent and cell-permeable inhibitors of PARG, which makes them suitable for therapeutic applications against cancer. The inhibitors of PARG of the present invention show advantageous properties, including good hERG inhibition profile, good metabolic stability and good solubility, which further supports their therapeutic use in human subjects. Accordingly, the present invention is based, at least in part, on the surprising discovery of the present inventors that introduction of optionally substituted oxetane moiety in the compounds of formula (I) comprising imidazo[1 , 5-a] pyrid i ne core improves hERG inhibition properties (i.e., leads to reduced hERG inhibition), metabolic stability properties and solubility of the compounds.

[0019] In a first embodiment, the present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof.

[0020] A further embodiment of the present invention relates to a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.

[0021] 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.

[0022] The compounds of formula (I) are useful for treating a disease or disorder in which PARG activity is implicated.

[0023] 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.

[0024] Definitions

[0025] The following definitions apply throughout the present specification and the claims, unless specifically indicated otherwise.

[0026] 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.

[0027] The term “alicyclic” is used in connection with cyclic groups and denotes that the corresponding cyclic group is non-aromatic.

[0028] 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.

[0029] 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 C24 alkenyl.

[0030] 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.

[0031] 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.

[0032] 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).

[0033] 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).

[0034] 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.

[0035] 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, N, P and Si, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) and / or one or more P ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. 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 heteroatomcontaining ring. Unless defined otherwise, “heterocyclyl” preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl.

[0036] Preferably, 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.

[0037] 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.

[0038] 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).

[0039] 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., 1H-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, 0-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1 ,10]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 rath ieno[3,2-c]pyrid i 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.

[0040] 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).

[0041] 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).

[0042] 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, N, P and Si, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) and / or one or more P ring atoms (if present) may optionally be oxidized, further wherein one or more S ring atoms (if present) may be modified with =NH or =N (C1 -3 alkyl) 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.

[0043] Preferably, 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.

[0044] 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, N, P and Si, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) and / or one or more P ring atoms (if present) may optionally be oxidized, further wherein one or more S ring atoms (if present) may be modified with =NH or =N(CI-3 alkyl) 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.

[0045] Preferably, 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.

[0046] As used herein, the term “W-heterocycloalkyl” refers to the heterocycloalkyl groups as defined hereinabove wherein said heterocycloalkyl includes at least one nitrogen atom which serves as an attachment point of said heterocycloalkyl.

[0047] 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.

[0048] As used herein, the term “cycloalkenylene” refers to a cycloalkenyl group, as defined hereinabove, but having two points of attachment, i.e. a divalent unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said hydrocarbon ring group comprises one or more (e.g., one or two) carbon-to- carbon double bonds and does not comprise any carbon-to-carbon triple bond. 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, N, P and Si, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) and / or one or more P ring atoms (if present) may optionally be oxidized, wherein one or more S ring atoms (if present) may be modified with =NH or =N(CI-3 alkyl), 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, di hydrofuranyl, 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. Preferably, 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.

[0049] As used herein, the term “heterocycloalkenylene” refers to a heterocycloalkenyl group, as defined hereinabove, as defined hereinabove, but having two points of attachment, i.e. a divalent unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S, N, P and Si and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) and / or one or more P ring atoms (if present) may optionally be oxidized, wherein one or more S ring atoms (if present) may be modified with =NH or =N(C1 -3 alkyl), 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 heteroatomcontaining ring.

[0050] Preferably, the term “heterocycloalkenylene” refers to a heterocycloalkenyl group, as defined hereinabove, as defined hereinabove, but having two points of attachment, i.e. a divalent unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring 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.

[0051] As used herein, the term “halogen" refers to fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-I). As it is to be understood for the skilled person, the terms “halogen” and “halo” may be used interchangeably.

[0052] As used herein, the term “haloalkyl” refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms which are selected independently from fluoro, chloro, bromo and iodo, and are preferably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group. “Haloalkyl" may, e.g., refer to -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.

[0053] The terms “bond” and “covalent bond” are used herein synonymously, unless explicitly indicated otherwise or contradicted by context.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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).

[0058] 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.

[0059] 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.

[0060] 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).

[0061] Detailed description of the invention

[0062] 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.

[0063] In a first embodiment, the present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof.

[0064] In formula (I), R1 is -H, -CN, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1.2 alkylene)-OH or -(C1-2 alkylene)-O-(C1-2 alkyl).

[0065] R1 is preferably -CN, methyl, fluoromethyl, difluoromethyl or trifluoromethyl, more preferably R1 is methyl or fluoromethyl, even more preferably R1 is methyl. In an embodiment, wherein R1 is methyl, particularly preferred R1 is CD3. In an alternative embodiment, R1 is fluoromethyl. In again an alternative embodiment, R1 is -CN.

[0066] R2 is -H or -F. Preferably, R2 is -H.

[0067] R3 is selected from -H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and -CN, wherein said alkyl, said alkenyl, and said alkynyl are each optionally substituted with one or more groups independently selected from RS1.

[0068] Preferably, R3 is selected from -H, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, and -CN, wherein said alkyl, said alkenyl, and said alkynyl are each optionally substituted with one or more groups independently selected from RS1.

[0069] More preferably, R3 is selected from -H, C1-2 alkyl, and C1-2 haloalkyl wherein said alkyl is optionally substituted with one or more groups independently selected from RS1.

[0070] Even more preferably, R3 is selected from -H, and C1-2 alkyl, wherein said alkyl is optionally substituted with one or more groups independently selected from RS1. Particularly suitable C1-2 alkyl is methyl. However, C1-2 alkyl may also be ethyl. Accordingly, in one embodiment, R3 is -H. In one embodiment, R3 is methyl. In one embodiment, R3 is hydroxymethyl.

[0071] It is preferred that in R3 said alkyl, said alkenyl, and said alkynyl are not substituted.

[0072] Alternatively, R2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more groups independently selected from RS2. Preferably, said cyclopropyl is optionally substituted with one or more-F (fluoro groups).

[0073] It is however preferred that R2 and R3 do not form, together with the carbon atom to which they are attached, a cyclopropyl ring, and that R2 and Rsare as defined hereinabove.

[0074] In formula (I), X2 is C-Yc2-Rc2.

[0075] YC2is 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.

[0076] RC2 is selected from hydrogen, halogen, -OH, -NH2, -SH, -CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; wherein said alkyl, alkenyl, and alkynyl in X2 are each optionally substituted with one or more groups independently selected from RS1, and wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl in X2are 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-(CI-3 alkylene)-, -(C1-3 alkylene)-CONH-, -NHCO-(CI-3 alkylene)-, -(C1-3 alkylene)- NHCO-, -NH-(CI-3 alkylene)-, -(C1-3 alkylene)-NH-, -N(C1-5 alkyl)-, -0-(C1-3 alkylene)-, -(C1-3 alkylene)-O- , -SO2-(C1-3 alkylene)-, -(C1-3 alkylene)-SO2-, -CONH-, -NHCO-, -NH-, -0-, -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.

[0077] Preferably, Rc2 is selected from hydrogen, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2. More 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. Even 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 heterocycloalkyl, aryl and heteroaryl in X2 are each optionally substituted with one or more groups independently selected from RS2. Even more preferably, Rc2 is heterocycloalkyl, wherein said heterocycloalkyl, in X2 is optionally substituted with one or more groups independently selected from RS2.

[0078] Thus preferably, -Yc2-Rc2 is is selected from -O-C1-12 alkyl, -NH-C1-12 alkyl, -N(C1-5 alkyl)-C2-12 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-i2 alkynyl, -(C0-3 alkylene)-cycloalkyl, -CO-(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-CO- cycloalkyl, -CONH-(Co-3 alkylene)-cycloalkyl, (C0-3 alkylene)-CONH-cycloalkyl, -NHCO-(Co-3 alkylene)- cycloalkyl, -(C0-3 alkylene)-NHCO-cycloalkyl, -NH-(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-NH- cycloalkyl, -0-(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-O-cycloalkyl, -S02-(Co-3 alkylene)-cycloalkyl, - (C0-3 alkylene)-SO2-cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO- cycloalkyl, -SCb-cycloalkyl, -(C0-3 alkylene)-cycloalkenyl, -CO-(Co-3 alkylene)-cycloalkenyl, -(C0-3 alkylene)-CO-cycloalkenyl, -CONH-(Co-3 alkylene)-cycloalkenyl, (C0-3 alkylene)-CONH-cycloalkenyl, - NHCO-(Co-3 alkylene)-cycloalkenyl, -(C0-3 alkylene)-NHCO-cycloalkenyl, -NH-(Co-3 alkylene)- cycloalkenyl, -(C0-3 alkylene)-NH-cycloalkenyl, -0-(Co-3 alkylene)-cycloalkenyl, -(C0-3 alkylene)-O- cycloalkenyl, -S02-(Co-3 alkylene)-cycloalkenyl, -(C0-3 alkylene)-SO2-cycloalkenyl, -CONH-cycloalkenyl, - NHCO-cycloalkenyl, -NH-cycloalkenyl, -O-cycloalkenyl, -CO-cycloalkenyl, -SO2-cycloalkenyl, -(C0-3 alkylene)-heterocycloalkyl, -CO-(Co-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-CO-heterocycloalkyl, - CONH-(CO-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(Co-3 alkylene)- heterocycloalkyl, -(C0-3 alkylene)-NHCO-heterocycloalkyl, -NH-(Co-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-NH-heterocycloalkyl, -0-(Co-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-O- heterocycloalkyl, -S02-(Co-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-SO2-heterocycloalkyl, -CONH- heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO- heterocycloalkyl, -SO2-heterocycloalkyl, -(C0-3 alkylene)-heterocycloalkenyl, -CO-(Co-3 alkylene)- heterocycloalkenyl, -(C0-3 alkylene)-CO-heterocycloalkenyl, -CONH-(Co-3 alkylene)-heterocycloalkenyl, - (C0-3 alkylene)-CONH-heterocycloalkenyl, -NHCO-(Co-3 alkylene)-heterocycloalkenyl, -(C0-3 alkylene)- NHCO-heterocycloalkenyl, -NH-(Co-3 alkylene)-heterocycloalkenyl, -(C0-3 alkylene)-NH- heterocycloalkenyl, -0-(Co-3 alkylene)-heterocycloalkenyl, -(C0-3 alkylene)-O-heterocycloalkyl, -S02-(Co-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-(Co-3 alkylene)-aryl, -(C0-3 alkylene)-CO-aryl, -CONH-(Co-3 alkylene)-aryl, -(C0-3 alkylene)-CONH-aryl, -NHCO-(Co-3 alkylene)-aryl, -(C0-3 alkylene)-NHCO-aryl, -NH-(Co-3 alkylene)-aryl, - (C0-3 alkylene)-NH-aryl, -0-(Co-3 alkylene)-aryl, -(C0-3 alkylene)-O-aryl, -S02-(Co-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-(Co-3 alkylene)-heteroaryl, -(C0-3 alkylene)-CO-heteroaryl, -CONH-(Co-3 alkylene)- heteroaryl, -(C0-3 alkylene)-CONH-heteroaryl, -NHCO-(Co-3 alkylene)-heteroaryl, -(C0-3 alkylene)-NHCO- heteroaryl, -NH-(Co-3 alkylene)-heteroaryl, -(C0-3 alkylene)-NH-heteroaryl, -0-(Co-3 alkylene)-heteroaryl, - (C0-3 alkylene)-O-heteroaryl, -S02-(Co-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, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2.

[0079] More preferably, -Yc2-Rc2 is selected from -(C0-3 alkylene)-heterocycloalkyl, -CO-(Co-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)-CO-heterocycloalkyl, -CONH-(Co-3 alkylene)heterocycloalkyl, - (C0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(Co-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)-NHCO- heterocycloalkyl, -NH-(Co-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)-NH-heterocycloalkyl, -0-(Co-3 alkylene) heterocycloalkyl, (C0-3 alkylene)-O-heterocycloalkyl, -S02-(Co-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)-SO2-heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO2-heterocycloalkyl, -(C0-3 alkylene)-heterocycloalkenyl, - CO-(Co-a alkylene)heterocycloalkenyl, -(C0-3 alkylene)-CO-heterocycloalkenyl, -CONH-(Co-3 alkylene)heterocycloalkenyl, -(C0-3 alkylene)-CONH-heterocycloalkenyl, -NHCO-(Co-3 alkylene)heterocycloalkenyl, -(C0-3 alkylene)-NHCO-heterocycloalkenyl, -NH-(Co-3 alkylene)heterocycloalkenyl, -(C0-3 alkylene)-NH-heterocycloalkenyl, -0-(Co-3 alkylene) heterocycloalkenyl, (C0-3 alkylene)-O-heterocycloalkenyl, -S02-(Co-3 alkylene)heterocycloalkenyl, -(C0-3 alkylene)-SO2-heterocycloalkenyl, -CONH-heterocycloalkenyl, -NHCO-heterocycloalkenyl, -NH- heterocycloalkenyl, -O-heterocycloalkenyl, -CO-heterocycloalkenyl, -SO2-heterocycloalkenyl, -(C0-3 alkylene)aryl, -CO-(Co-3 alkylene)aryl, -(C0-3 alkylene)-CO-aryl, -CONH-(Co-3 alkylene)aryl, -(C0-3 alkylene)-CONH-aryl, -NHCO-(Co-3 alkylene)aryl, -(C0-3 alkylene)-NHCO-aryl, -NH-(Co-3 alkylene)aryl, - (C0-3 alkylene)-NH-aryl, -0-(Co-3 alkylene)aryl, -(C0-3 alkylene)-O-aryl, -S02-(Co-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-(Co-3 alkylene)heteroaryl, -(C0-3 alkylene)-CO-heteroaryl, -CONH-(Co-3 alkylene)heteroaryl, -(C0-3 alkylene)-CONH-heteroaryl, -NHCO-(Co-3 alkylene)heteroaryl, -(C0-3 alkylene)- NHCO-heteroaryl, -NH-(Co-3 alkylene)heteroaryl, -(C0-3 alkylene)-NH-heteroaryl, -0-(Co-3 alkylene)heteroaryl, -(C0-3 alkylene)-O-heteroaryl, -S02-(Co-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, heterocycloalkenyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2.

[0080] 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)-heterocycloalkenyl, -CONH-heterocycloalkenyl, - NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO- heterocycloalkenyl, -S02-heterocycloalkenyl, -(C0-3 alkylene)aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -0- aryl, -CO-aryl, -S02-aryl, -(C0-3 alkylene)heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH- heteroaryl, -O-heteroaryl, -CO-heteroaryl and -SO2-heteroaryl, (preferably -(C0.3 alkylene)- heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -0- heterocycloalkyl, -CO-heterocycloalkyl, -SO2-heterocycloalkyl, -(C0.3 alkylene)-heterocycloalkenyl, - CONH-heterocycloalkenyl, -NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, - CO-heterocycloalkenyl, and -SO2-heterocycloalkenyl), wherein said alkylene is optionally substituted with one or more groups independently selected from RS1, and wherein said heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2.

[0081] Even more preferably, -Yc2-Rc2 is selected from -(C0-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)heterocycloalkenyl, -(C0-3 alkylene)aryl, and -(C0-3 alkylene)heteroaryl, wherein said heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2.

[0082] Even more preferably, -Yc2-Rc2 is selected from heterocycloalkyl, and heterocycloalkenyl, wherein said heterocycloalkyl, and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from RS2.

[0083] In an embodiment of the compound of formula (I) wherein -Yc2-Rc2 is selected from heterocycloalkyl, and heterocycloalkenyl, wherein said heterocycloalkyl, and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from RS2, -Yc2-Rc2 is

[0084]

[0085] Even more preferably, -Yc2-Rc2 is heterocycloalkyl wherein said heterocycloalkyl is optionally substituted with one or more groups independently selected from RS2. Particularly preferred heterocycloalkyl moieties are described hereinabove.

[0086] In formula (I), R4 is YRS-RRS.

[0087] YRS is selected from a covalent bond, C1-4 alkylene, C2-4 alkenylene, and C2-4 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more groups independently selected from RS1and 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-, -COO-, -S-, -SO-, and -SO2-, preferably selected from -0- , -NH-, -N(C1-5 alkyl)-, -CO-, -S-, -SO-, and -SO2-. Preferably, YRS is selected from a covalent bond, C1-2 alkylene, -C0-(C1-2 alkylene)-, -(C1-2 alkylene)-CO-, -C0NH-(C1-2 alkylene)-, -(C1-2 alkylene)-CONH-, - NHC0-(C1-2 alkylene)-, -(C1-2 alkylene)-NHCO-, -NH-(C1-2 alkylene)-, -(C1-2 alkylene)-NH-, -0-(C1-2 alkylene)-, -(C1-2 alkylene)-O-, -SO2-(C1-2 alkylene)-, -(C1-2 alkylene)-S02-, -CONH-, -C0N(C1-5 alkyl)-, - NHCO-, -N(C1-5 alkyl)CO-, -NH-, -0-, -CO-, -COO- and -SO2-. C1-2 alkylene is herein preferably a -CH2- group.

[0088] RRS is selected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, cycloalkyl, cycloalkenyl heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. Preferably RRS is selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. More preferably, RRS is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. Even more preferably, RRS is selected from heterocycloalkyl, aryl, and heteroaryl. Even more preferably, RRS is selected from aryl and heteroaryl. Most preferably, RRS is heteroaryl. Said alkyl, alkenyl, or alkynyl is optionally substituted with one or more groups independently selected from RS1. Said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from RS2.

[0089] Preferably, YRS is selected from a covalent bond, C1-2 alkylene, -CO-(C1-2 alkylene)-, -(C1-2 alkylene)-CO-, -CONH-(CI-2 alkylene)-, -(C1-2 alkylene)-CONH-, -NHCO-(CI-2 alkylene)-, -(C1-2 alkylene)- NHCO-, -NH-(CI-2 alkylene)-, -(C1-2 alkylene)-NH-, -O-(C1-2 alkylene)-, -(C1-2 alkylene)-O-, -SO2-(C1-2 alkylene), -(C1-2 alkylene)-SO2-, -CONH-, -NHCO-, -NH-, -O-, -CO- and -SO2-, wherein said alkylene is optionally substituted with one or more groups independently selected from RS1.

[0090] Thus, preferably, R4 is selected from -(C0-2 alkylene)-cycloalkyl, -CO-(Co-2 alkylene)-cycloalkyl, - (C0-2 alkylene)-CO-cycloalkyl, -CONH-(Co-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-CONH-cycloalkyl, - NHCO-(CO-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-NHCO-cycloalkyl, -NH-(Co-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-NH-cycloalkyl, -0-(Co-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-O-cycloalkyl, -S02-(Co-2 alkylene)- cycloalkyl, -(C0-2 alkylene)-SO2-cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -0- cycloalkyl, -CO-cycloalkyl, -SO2-cycloalkyl, -(C0-2 alkylene)-cycloalkenyl, -CO-(Co-2 alkylene)- cycloalkenyl, -(C0-2 alkylene)-CO-cycloalkenyl, -CONH-(Co-2 alkylene)-cycloalkenyl, -(C0-2 alkylene)- CONH-cycloalkenyl, -NHCO-(Co-2 alkylene)-cycloalkenyl, -(C0-2 alkylene)-NHCO-cycloalkenyl, -NH-(Co-2 alkylene)-cycloalkenyl, -(C0-2 alkylene)-NH-cycloalkenyl, -0-(Co-2 alkylene)-cycloalkenyl, -(C0-2 alkylene)- O-cycloalkenyl, -S02-(Co-2 alkylene)-cycloalkenyl, -(C0-2 alkylene)-SO2-cycloalkenyl, -CONH- cycloalkenyl, -NHCO-cycloalkenyl, -NH-cycloalkenyl, -O-cycloalkenyl, -CO-cycloalkenyl, -SO2- cycloalkenyl,-(Co-2 alkylene)-heterocycloalkyl, -CO-(Co-2 alkylene)-heterocycloalkyl, -(C0-2 alkylene)-CO- heterocycloalkyl, -C0NH-(CQ-2 alkylene)-heterocycloalkyl, -(C0-2 alkylene)-CONH-heterocycloalkyl, - NHCO-(CO-2 alkylene)-heterocycloalkyl, -(C0-2 alkylene)-NHCO-heterocycloalkyl, -NH-(Co-2 alkylene)- heterocycloalkyl, -(C0-2 alkylene)-NH-heterocycloalkyl, -0-(Co-2 alkylene)-heterocycloalkyl, -(C0-2 alkylene)-O-heterocycloalkyl, -S02-(Co-2 alkylene)-heterocycloalkyl, -(C0-2 alkylene)-S02- heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -0- heterocycloalkyl, -CO-heterocycloalkyl, -S02-heterocycloalkyl,-(Co-2 alkylene)-heterocycloalkenyl, -CO- (C0-2 alkylene)-heterocycloalkenyl, -(C0-2 alkylene)-CO-heterocycloalkenyl, -CONH-(Co-2 alkylene)- heterocycloalkenyl, -(C0-2 alkylene)-CONH-heterocycloalkenyl, -NHCO-(Co-2 alkylene)- heterocycloalkenyl, -(C0-2 alkylene)-NHCO-heterocycloalkenyl, -NH-(Co-2 alkylene)-heterocycloalkenyl, - (C0-2 alkylene)-NH-heterocycloalkenyl, -0-(Co-2 alkylene)-heterocycloalkenyl, -(C0-2 alkylene)-O- heterocycloalkenyl, -S02-(Co-2 alkylene)-heterocycloalkenyl, -(C0-2 alkylene)-SO2-heterocycloalkenyl, - CONH-heterocycloalkenyl, -NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, - CO-heterocycloalkenyl, -SCk-heterocycloalkenyl, -(C0-2 alkylene)-aryl, -CO-(Co-2 alkylene)-aryl, -(C0-2 alkylene)-CO-aryl , -CONH-(Co-2 alkylene)-aryl, -(C0-2 alkylene)-CONH-aryl, -NHCO-(Co-2 alkylene)-aryl, - (C0-2 alkylene)-NHCO-aryl, -NH-(Co-2 alkylene)-aryl, -(C0-2 alkylene)-N H-aryl, -0-(Co-2 alkylene)-aryl, -(Co- 2 alkylene)-O-aryl, -S02-(Co-2 alkylene)-aryl, -(C0-2 alkylene)-SO2-aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO2-aryl, -(C0-2 alkylene)-heteroaryl, -CO-(Co-2 alkylene)-heteroaryl, -(C0-2 alkylene)- CO-heteroaryl, -CONH-(Co-2 alkylene)-heteroaryl, -(C0-2 alkylene)-CONH-heteroaryl, -NHCO-(Co-2 alkylene)-heteroaryl, -(C0-2 alkylene)-NHCO-heteroaryl, -NH-(Co-2 alkylene)-heteroaryl, -(C0-2 alkylene)- NH-heteroaryl, -0-(Co-2 alkylene)-heteroaryl, -(C0-2 alkylene)-O-heteroaryl, -S02-(Co-2 alkylene)- heteroaryl, -(C0-2 alkylene)-SO2-heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -0- heteroaryl , -CO-heteroaryl, and -SCfe-heteroaryl. Said alkylene is optionally substituted with one or more groups independently selected from RS1. Said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from RS2.

[0091] More preferably, R4 is selected from -(C0-2 alkylene)-cycloalkyl, -CO-(Co-2 alkylene)-cycloalkyl, - (C0-2 alkylene)-CO-cycloalkyl, -CONH-(Co-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-CONH-cycloalkyl, - NHCO-(CO-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-NHCO-cycloalkyl, -NH-(Co-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-NH-cycloalkyl, -0-(Co-2 alkylene)-cycloalkyl, -(C0-2 alkylene)-O-cycloalkyl, -S02-(Co-2 alkylene)- cycloalkyl, -(C0-2 alkylene)-SO2-cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -0- cycloalkyl, -CO-cycloalkyl, -SO2-cycloalkyl, -(C0-2 alkylene)-heterocycloalkyl, -CO-(Co-2 alkylene)- heterocycloalkyl, -(C0-2 alkylene)-CO-heterocycloalkyl, -CONH-(Co-2 alkylene)-heterocycloalkyl, -(C0-2 alkylene)-CONH-heterocycloalkyl, -NHCO-(Co-2 alkylene)-heterocycloalkyl, -(C0-2 alkylene)-NHCO- heterocycloalkyl, -NH-(Co-2 alkylene)-heterocycloalkyl, -(C0-2 alkylene)-NH-heterocycloalkyl, -0-(Co-2 alkylene)-heterocycloalkyl, -(C0-2 alkylene)-O-heterocycloalkyl, -S02-(Co-2 alkylene)-heterocycloalkyl, - (C0-2 alkylene)-SO2-heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH- heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO2-heterocycloalkyl, -(C0-2 alkylene)-aryl, - CO-(Co-2 alkylene)-aryl, -(C0-2 alkylene)-CO-aryl, -CONH-(Co-2 alkylene)-aryl, -(C0-2 alkylene)-CONH-aryl, -NHCO-(CO-2 alkylene)-aryl, -(C0-2 alkylene)-N HCO-aryl, -NH-(Co-2 alkylene)-aryl, -(C0-2 alkylene)-N H-aryl, -0-(Co-2 alkylene)-aryl, -(C0-2 alkylene)-O-aryl, -S02-(Co-2 alkylene)-aryl, -(C0-2 alkylene)-S02-aryl, - CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -S02-aryl, -(C0-2 alkylene)-heteroaryl, -CO-(Co-2 alkylene)-heteroaryl, -(C0-2 alkylene)-CO-heteroaryl, -CONH-(Co-2 alkylene)-heteroaryl, -(C0-2 alkylene)- CONH-heteroaryl, -NHCO-(Co-2 alkylene)-heteroaryl, -(C0-2 alkylene)-NHCO-heteroaryl, -NH-(Co-2 alkylene)-heteroaryl, -(C0-2 alkylene)-NH-heteroaryl, -0-(Co-2 alkylene)-heteroaryl, -(C0-2 alkylene)-O- heteroaryl, -S02-(Co-2 alkylene)-heteroaryl, -(C0-2 alkylene)-SO2-heteroaryl, -CONH-heteroaryl, -NHCO- heteroaryl , -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and -SO2-heteroaryl. Said alkylene is optionally substituted with one or more groups independently selected from RS1. Said cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from RS2.

[0092] Even more preferably, R4 is selected from -(C0-2 alkylene)-aryl, -CO-(Co-2 alkylene)-aryl, -(C0-2 alkylene)-CO-aryl, -CONH-(Co-2 alkylene)-aryl, -(C0-2 alkylene)-CONH-aryl, -NHCO-(Co-2 alkylene)-aryl, - (C0-2 alkylene)-NHCO-aryl, -NH-(Co-2 alkylene)-aryl, -(C0-2 alkylene)-N H-aryl, -0-(Co-2 alkylene)-aryl, -(Co- 2 alkylene)-O-aryl, -S02-(Co-2 alkylene)-aryl, -(C0-2 alkylene)-SO2-aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO2-aryl, -(C0-2 alkylene)-heteroaryl, -CO-(Co-2 alkylene)-heteroaryl, -(C0-2 alkylene)- CO-heteroaryl, -CONH-(Co-2 alkylene)-heteroaryl, -(C0-2 alkylene)-CONH-heteroaryl, -NHCO-(Co-2 alkylene)-heteroaryl, -(C0-2 alkylene)-NHCO-heteroaryl, -NH-(Co-2 alkylene)-heteroaryl, -(C0-2 alkylene)- NH-heteroaryl, -0-(Co-2 alkylene)-heteroaryl, -(C0-2 alkylene)-O-heteroaryl, -S02-(Co-2 alkylene)- heteroaryl, -(C0-2 alkylene)-SO2-heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -0- heteroaryl, -CO-heteroaryl, and -SO2-heteroaryl, wherein said alkylene is optionally substituted with one or more groups independently selected from RS1, and wherein said aryl or heteroaryl is optionally substituted with one or more groups independently selected from RS2.

[0093] More preferably, YRS is a covalent bond.

[0094] Thus accordingly, R4 is preferably selected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. More preferably, R4 is preferably selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. Even more preferably, R4 is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. Even more preferably, R4 is selected from aryl, and heteroaryl. Most preferably, R4 is heteroaryl. Said alkyl, alkenyl, or alkynyl is optionally substituted with one or more groups independently selected from RS1. Said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from RS2.

[0095] Preferably, R4 is a five membered heteroaryl, optionally substituted with one or more groups independently selected from RS2. More preferably, R4 is a five membered heteroaryl, 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), -SO(C1-5 alkyl), -SO(C1-5 haloalkyl), -SO2(C1-5 alkyl), -SO2(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(C1-5 haloalkyl), -N(CI-5alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), and -CON(C1-5 alkyl)(C1-5 alkyl). The said five membered heteroaryl is preferably selected from imidazolyl, isoxazolyl, pyrazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, thiazolyl, 1 ,2,4-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,4-thiadiazolyl, or 1 ,3,4- thiadiazolyl. More preferably, said five membered heteroaryl is 1 ,2,4-thiadiazolyl, optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(C1- 5 alkyl), -SH, -S(C1-5 alkyl), -NH2, -NH(C1-5 alkyl), -N(C1-5 alkyl)(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), and -CON(C1-5 alkyl)(C1-5 alkyl), preferably optionally substituted with C1-5 alkyl, C1-5 haloalkyl, -O(C1-5 alkyl), -SH, -S(C1-5 alkyl), more preferably optionally substituted with C1-5 alkyl, C1-5 haloalkyl, even more preferably optionally substituted with C1-5 haloalkyl, preferably selected from -CHF, -CHF2 and CF3, most preferably optionally substituted with -CHF2.

[0096] In formula (I), R5 is selected from -H, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, cyclopropyl, cyclobutyl, oxetanyl, and halogen (such as -F or -Cl).

[0097] Preferably R5 is selected from -H, C1-2 alkyl, C2alkenyl, C2alkynyl, C1-2 haloalkyl, cyclopropyl and halogen.

[0098] More preferably, R5 is selected from -H, -CH3, -CF3, cyclopropyl, -F and -Cl.

[0099] Even more preferably, R5 is -H.

[0100] In formula (I), RS1is 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-CI-3alkyl)(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), -(W-heterocycloalkyl), -CO(C1-5 alkyl), -CONH2, -CONH(CI-5alkyl), -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-s alkyl)CONH-(C1-5 alkyl), and -N(C1-5 alkyl)CON(C1-5 alkyl)(C1-5 alkyl).

[0101] Preferably, RS1is 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), -(A / -heterocycloalkyl), -CO(C1-5 alkyl), -CONH2, -CONH(CI-5alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -CO-(W-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(CI-5alkyl)CONH-(C1-5 alkyl), and -N(C1-5 alkyl)CON(C1-5 alkyl)(C1-5 alkyl).

[0102] More preferably, RS1is 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), -( / V-heterocycloalkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-s alkyl)(C1-5 alkyl), -CO-(W-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(CI-5alkyl)CONH-(C1-5 alkyl), and -N(C1-5 alkyl)CON(C1-5 alkyl)(C1-5 alkyl).

[0103] Even more preferably, RS1is 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(CI-5alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), and -( / V-heterocycloalkyl).

[0104] Even more preferably, RS1is selected from halogen, -CN, -OH, -SH, and -NH2.

[0105] In formula (I), RS2is 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(O)(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), -S(O)(C1-5 haloalkyl), -SO2(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(CI-S alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), - (A / -heterocycloalkyl), -CO(C1-5 alkyl), -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(CI-5alkyl)(C1-5 alkyl), -CO-(N-heterocycloalkyl), -NHCO-(C1-5 alkyl), -N(C1-5 alkyl)-CO-(C1-s alkyl), -NHCONH2, -NHCONH-(C1-5 alkyl), -NHCON(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 alkyl)CONH2, -N(CI-5alkyl)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)-S(O)(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)-S(O)(C1-5 haloalkyl), -(C1-5 alkylene)- S(O)2(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-s alkyl)(C1-5 haloalkyl), -(C1-5 alkylene)-( / V-heterocycloalkyl), -(C1-5 alkylene)-N(C1-5 haloalkyl)(C1-5 alkyl), - COO-(C1-5 alkylene)-N H2, -COO-(C1-5 alkylene)-NH(C1-5 alkyl), -COO-(C1-5 alkylene)-NH(C1-5 haloalkyl), - COO-(C1-5 alkylene)-N(C1-5 alkyl)(C1 -5 alkyl), -COO-(C1-5 alkylene)-N(C1-5 alkyl)(C1-5 haloalkyl), -COO-(C1. 5 alkylene)-(N-heterocycloalkyl), -COO-(C1-5 alkylene)-N(C1 -5 haloal kyl)(C1 -5 alkyl), -(C1-5 alkylene)-CO(C1- 5 alkyl), -(C1-5 alkylene)-COO(C1-5 alkyl), -(C1-5 alkylene)-COOH, -(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).

[0106] Preferably, RS2is 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(O)(C1-5 alkyl), -SO2(C1-5 alkyl), -S(O)(NH)(C1-5 alkyl), -S(O)(N-CI-3 alkyl)(C1-5 alkyl), -N=S(O)(C1-5 alkyl)(C1-5 alkyl), -S(C1-5 haloalkyl), -S(O)(C1-5 haloalkyl), -SO2(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), - (W-heterocycloalkyl), -CO(C1-5 alkyl), -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(CI-5alkyl)(C1-5 alkyl), -CO-(A / -heterocycloalkyl), -NHCO-(C1-5 alkyl), -N(C1-5 alkyl)-CO-(C1-s alkyl), -NHCONH2, -NHCONH-(C1-5 alkyl), -NHCON(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 alkyl)CONH2, -N(CI-5alkyl)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)-S(O)(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-C1-3alkyl)(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)-S(O)(C1-5 haloalkyl), -(C1-5 alkylene)- S(O)2(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-s alkyl), -(C1-5 alkylene)-NH(C1-5 haloalkyl), -(C1-5 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-N(C1-s alkyl)(C1-5 haloalkyl), -(C1-5 alkylene)-(A / -heterocycloalkyl), -(C1-5 alkylene)-N(C1-5 haloalkyl)(C1-5 alkyl), - (C1-5 alkylene)-CO(C1-5 alkyl), -(C1-5 alkylene)-COO(C1-5 alkyl), -(C1-5 alkylene)-COOH, -(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-( / \ / -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).

[0107] More preferably, RS2is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -0(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-CI-3alkyl)(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(CI-5alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -( / V-heterocycloalkyl), -CO(C1-5 alkyl), -CONH2, -CONH(CI-5alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -CO-(A / -heterocycloalkyl), -NHCO-(C1-5 alkyl), -N(C1-s alkyl)-C0-(C1-5 alkyl), -NHCONH2, -NHCONH-(C1-5 alkyl), -NHCON(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 alkyl)CONH2, -N(CI-5alkyl)C0NH-(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)-0(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-C1-3alkyl)(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-C1.5alkyl)(C1-5 alkyl), -(C1-5 alkylene)-N H2, -(C1-5 alkylene)-NH(C1-5 alkyl), - (C1-5 alkylene)-N H(C1 -5 haloalkyl), -(C1-5 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-N(C1-s alkyl)(C1- 5 haloalkyl), -(C1-5 alkylene)-(A / -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-(A / -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).

[0108] Even more preferably, RS2is 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(CI-5haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -( / V-heterocycloalkyl), -CO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -CO-(A / -heterocycloalkyl), -NHCO-(CI-5alkyl), -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)-N H(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)-( / V-heterocycloalkyl), -(C1-5 alkylene)-N(C1-s 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-(A / -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).

[0109] Still more preferably, RS2is 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(CI-5haloalkyl), -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-( / V- heterocycloalkyl), -NHCO-(C1-5 alkyl), -N(C1-5 alkyl)-CO-(C1-5 alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 alkyl)CONH2, -N(C1-5 alkyl)CONH-(C1-5 alkyl), -N(CI-5 alkyl)CON(C1-5 alkyl)(C1-5 alkyl), -(C1.5 alkylene)-CN, -(C1-5 alkylene)-OH, -(C1.5 alkylene)-O(C1-s 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)-( / V- 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).

[0110] Again more preferably, RS2is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(C1-s 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), -( / V-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)-( / V-heterocycloalkyl), -(C1-5 alkylene)-N(C1-s 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-( / V-heterocycloalkyl).

[0111] Again even more preferably, RS2is selected from halogen, -CN, -OH, -SH, -NH2, -(C1-5 alkylene)- CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-SH, and -(C1-5 alkylene)-NH2.

[0112] Most preferably, RS2is selected from halogen, -CN, -OH, -SH, and -NH2.

[0113] In a first specific embodiment, of the compound of formula (I), R1 is methyl. One possible methyl group is CD3.

[0114] In a second specific embodiment of the compound of formula (I), R1 is -CN.

[0115] In a third specific embodiment of the compound of formula (I), R2and R3 are both -H.

[0116] In a fourth specific embodiment of the compound of formula (I), the moietyR1is selected

[0117] In a fifth specific embodiment of the compound of formula (I), -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, 0(C1-5 alkyl), -0(C1-5 haloalkyl), SH, S(C15 alkyl), S(C15haloalkyl), NH2, NH(C1-5 alkyl), NH(C1-5 haloalkyl), N(C1-5 alkyl)(C1-5 alkyl), -N(CI-5haloalkyl)(C1-5 alkyl), -CO(C1-5 alkyl), CONH2, CONH(C1-5 alkyl), and CON(C1-5 alkyl)(C1-5 alkyl).

[0118] In a sixth specific embodiment of the compound of formula (I), -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, 0(C1-5 alkyl), -0(C1-5 haloalkyl), SH, S(C1s alkyl), S(C1s haloalkyl), NH2, NH(C1-5 alkyl), NH(C1-5 haloalkyl), N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -C0(C1-5 alkyl), CONH2, CONH(C1-5 alkyl), and CON(C1-5 alkyl)(C1-5 alkyl).

[0119] In a seventh specific embodiment of the compound of formula (I), -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(CI-5alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -CO(C1-5 alkyl), -CONH2, -C0NH(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 -C0(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.

[0120] In an eighth specific embodiment of the compound of formula (I), -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.

[0121] In a ninth specific embodiment of the compound of formula (I), -Yc2-Rc2 is heterocycloalkenyl, wherein said heterocycloalkenyl is optionally substituted with one or more groups independently selected from RS2. Preferably, in this eighth specific embodiment, -Yc2-Rc2 is oxacyclohexenyl or azacyclohexenyl, optionally substituted with one or more groups independently selected from RS2. More preferably, -Yc2- RC2 is azacyclohexenyl substituted (preferably N-substituted) with -CON(C1-5 alkyl)(C1-5 alkyl), preferably with -CON(CH3)2.

[0122] In a tenth specific embodiment of the compound of formula (I), -Yc2-Rc2 is selected from: optionally substituted with a methyl group.

[0123] In an eleventh specific embodiment of the compound of formula (I), -Yc2-Rc2 is selected from: l)

[0124] In a twelfth specific embodiment of the compound of formula In a thirteenth specific embodiment of the compound of formula preferably

[0125] In a fourteenth specific embodiment of the compound of formula preferably -Yc2-Rc2 is selected from more preferably -Yc2-Rc2 is

[0126] In a fifteenth specific embodiment of the compound of formula (I), -Yc2-Rc2 is In a sixteenth specific embodiment of the compound of formula (I), -Yc2-Rc2 is selected from In a seventeenth specific embodiment of the compound of formula (I), -Yc2-Rc2 is selected from

[0127] In an eighteenth specific embodiment of the compound of formula (I), R4 is a heteroaryl optionally substituted with one or more RS2, preferably selected from Most preferably, in this eighteenth embodiment,

[0128] In a nineteenth specific embodiment of the compound of formula (I), Rs is hydrogen.

[0129] It is to be understood that, in each of the specific embodiments of the compound of formula (I) as recited hereinabove, the definitions of any of R1, R2, R3, R4, Rs, and X2 which are not explicitly recited in the disclosure of said specific embodiments, are as in formula (I) hereinabove.

[0130] The compound of formula (I) may be a compound of formula (la): or a pharmaceutically acceptable salt thereof.

[0131] In formula (la), R1, R2, R3, R4, and X2 are defined as for formula (I), including any specific embodiment of the compound of formula (I). Preferably, in formula (la), the moiety preferably the moiety selected from: . Even more preferably, the moiety

[0132] Preferably, in formula (la), X2 is C-Yc2-Rc2, wherein -Yc2-Rc2 is selected from , and

[0133] . If -YC2-RC2 isH, then -Yc2-Rc2 is selected from HH, and , preferably is selected from , more preferably is H . Particularly preferred -Yc2-Rc2 isH, preferably selected from

[0134] Preferably, in formula (la), R4 is a heteroaryl optionally substituted with one or more RS2,

[0135] In an alternative embodiment of the compound of formula (la), X2 is C-Yc2-Rc2, wherein -Yc2-Rc2 embodiment of the compound of formula (la), R1, R2, R3, and R4, are as defined for formula (I) or formula (la).

[0136] The compound of formula (la) may be a compound of formula (lb):

[0137] or a pharmaceutically acceptable salt thereof.

[0138] In formula (lb), R1 , R2, R3, and X2 are defined as for formula (I) or for formula (la), including any specific embodiment of the compound of formula (I) or of formula (la).

[0139] Preferably, in formula (lb), the moiety selected from: Preferably the moiety , more preferably the moiety selected from: . Even more preferably, the moiety

[0140] Preferably, in formula (lb), X2 is C-Yc2-Rc2, wherein -Yc2-Rc2 is selected from , and

[0141] H. If -YC2-RC2 isH, then -Yc2-Rc2 is selected fromHand H

[0142]

[0143] In an alternative embodiment of the compound of formula (lb), X2 is C-Yc2-Rc2, wherein -Yc2-Rc2 embodiment of the compound of formula (lb), R1, R2, and R3, are as defined for formula (I), (la) or (lb).

[0144] The compound of formula (lb) may be a compound of formula (Ic): or a pharmaceutically acceptable salt thereof.

[0145] In formula (Ic), X2 is defined as for formula (I), for formula (la), or for formula (lb), including any specific embodiment of the compound of formula (I), (la) or (lb).

[0146] Preferably, in formula (Ic), X2 is C-Yc2-Rc2, wherein -Yc2-Rc2 is selected from Most preferably, in the compound of formula (Ic), -Yc2-Rc2 is

[0147] In an alternative embodiment of the compound of formula (Ic), X2 is C-Yc2-Rc2, wherein -Yc2-Rc2

[0148] Exemplary preferred compounds of formula (I) are selected from the following compounds or their pharmaceutically acceptable salts:

[0149]

[0150] In case of the following compound: compound is the compound obtainable in the purification of racemic 3-(5-(d ifl uoromethyl)-1 ,3 ,4-thiad iazol- 2-yl)-8-(5-(methoxymethyl)-3,3-dimethylpiperazin-1 -yl)-N-(3-methyloxetan-3-yl)imidazo[1 ,5-a]pyridine-6- sulfonamide (i.e., the mixture of its enantiomers) by preparative SFC (column: Chiralpak AS (250mm*30mm,10pm); mobile phase: A: CO2, B: MeOH(0.1 % NH3H2O); Gradient elution:0% to 20% B, 10 mins, SFC Method 47) which is characterized by higher retention time (in other words, the compound that is present in the second peak obtained in purification according to the provided protocol).

[0151] the indicator “trans” indicates that preferably two substituents of the six-membered ring are present on the opposite sides of the ring (i.e., are in trans configuration with respect to each other).

[0152] Preferably, exemplary preferred compounds of formula (I) are selected from the following compounds or their pharmaceutically acceptable salts: Particularly preferred compound of formula (I) is pharmaceutically acceptable salt.

[0153] In one embodiment, the compound of formula pharmaceutically acceptable salt.

[0154] In one embodiment, the compound of formula its pharmaceutically acceptable salt.

[0155] In one embodiment, the compound of formula pharmaceutically acceptable salt. It is to be understood that whenever reference is made to formula (I), it includes any preferred definition of the compound of formula (I), as well as any example of the compound of formula (I), as well as examples and definitions of the compounds of formula (la), (lb) or (Ic).

[0156] 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).

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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 or1H hydrogen atoms in the compounds of formula (I) is preferred.

[0162] 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,150,76Br,77Br,120l and / or124l. 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 by18F atoms, (ii) compounds of formula (I), in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by11C atoms, (iii) compounds of formula (I), in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by13N atoms, (iv) compounds of formula (I), in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by15O atoms, (v) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by78Br atoms, (vi) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by77Br atoms, (vii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by120l atoms, and (viii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by124l atoms. In general, it is preferred that none of the atoms in the compounds of formula (I) are replaced by specific isotopes.

[0163] 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 -ORXmoiety, wherein Rx preferably comprises a moiety selected from -CO-, -CH2-O-CO, -CH2-O-CO-O-, and -CH(CH3)-O-COO-, more preferably wherein Rxis selected from -CO-Ry, -CFb-O-CO-Ry, -CFb-O-CO-O-Ry, and -CH(CH3)-O- COO-Ry, wherein Ryis preferably carbocyclyl, heterocyclyl, C1-5 alkyl, -NH-(C1-5 alkyl) or -S-(C1-s 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(CI-5alkyl), -NH(C1-5 haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -CONH2, -CONH(CI-5alkyl), 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, -0(C1-5 alkyl), -O(C1-5 haloalkyl), -SH, -S(C1-5 alkyl), -S(C1-5 haloalkyl), -NH2, -NH(C1-5 alkyl), -NH(CI-5haloalkyl), -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-Rymoiety, wherein Ryis 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 -COORymoiety, wherein Ryis as defined hereinabove. Further examples of groups that can be derivatized to yield prodrugs are known to the skilled person.

[0164] Pharmaceutical compositions

[0165] 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.

[0166] The pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., polyethylene glycol), including polyethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e-9-. 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-y-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.

[0167] 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.

[0168] 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, 22ndedition. 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.

[0169] 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 / peri pheral ly 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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).

[0180] 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.

[0181] 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 / su bject 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.

[0182] Therapeutic use

[0183] In one embodiment, the present invention relates to the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0184] 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), ora pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0185] The present invention also provides a method of selectively inhibiting PARG enzyme activity over PARP1 or ARH3 enzyme activity in vitro or in vivo. The said method comprises the steps of contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0186] 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, hydrate or solvate 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.

[0187] 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, hydrate or solvate 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.

[0188] 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, hydrate or solvate 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, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. In a particular embodiment, the cancer is human cancer.

[0189] In one embodiment, the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in treating a proliferative disorder. 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, hydrate or solvate thereof for use in treating cancer. In a particular embodiment, the cancer is human cancer.

[0190] In a further embodiment, the present invention relates to the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, for use in the manufacture of a medicament for the treatment of a proliferative condition. 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, hydrate or solvate thereof, as defined herein, for use in the manufacture of a medicament for the treatment of cancer, preferably for the treatment of human cancer.

[0191] In a further embodiment, the present invention relates to the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, for use in the manufacture of a medicament for the inhibition of PARG enzyme activity. 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, hydrate or solvate thereof, as defined herein, for use in the manufacture of a medicament for the selective inhibition of PARG enzyme activity over PARP1 or ARH3 enzyme activity.

[0192] The present invention further provides the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the manufacture of a medicament for the treatment of a disease or disorder in which PARG activity is implicated, as defined herein. 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.

[0193] Preferably, the proliferative disorder, as referred to herein, is cancer. The cancer to be treated in accordance with the present invention may be a solid cancer or a hematological cancer. Preferably, the cancer is selected from lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, large cell lung carcinoma, lung adenocarcinoma, including also lung adenocarcinoma with EGFR mutation AE746- A750, or squamous cell carcinoma of the lung), renal cancer (or kidney cancer; e.g., renal carcinoma), gastrointestinal cancer, stomach cancer, colorectal cancer (e.g., colorectal carcinoma), colon cancer, anal cancer, genitourinary cancer, bladder cancer, liver cancer (e.g., hepatocellular carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), cervical cancer, endometrial cancer, vaginal cancer, vulvar cancer, ovarian cancer (e.g., ovarian carcinoma), uterine cancer, prostate cancer (e.g., hormone-refractory prostate cancer), testicular cancer, biliary tract cancer, hepatobiliary cancer, neuroblastoma, brain cancer (e.g., glioblastoma), breast cancer (e.g., triple-negative breast cancer, breast cancer having a BRCA1 and / or BRCA2 gene mutation, or breast adenocarcinoma), head and / or neck cancer (e.g., head and neck squamous cell carcinoma), skin cancer, melanoma, Merkelcell cancer (e.g., Merkel-cell carcinoma), epidermoid cancer, squamous cell cancer (or squamous cell carcinoma; including, e.g., oral squamous cell carcinoma / squamous-cell mouth carcinoma, squamouscell skin cancer, squamous-cell lung carcinoma, squamous-cell thyroid carcinoma, squamous-cell esophageal carcinoma, or squamous-cell vaginal carcinoma), bone cancer (e.g., osteosarcoma or osteogenic sarcoma), fibrosarcoma, Ewing’s sarcoma, malignant mesothelioma, esophageal cancer, laryngeal cancer, mouth cancer, thymoma, neuroendocrine cancer (e.g., neuroendocrine carcinoma), goblet cell cancer (e.g., goblet cell carcinoid), hematological cancer, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia), lymphoma (e.g., Hodgkin lymphoma or non-Hodgkin lymphoma, such as, e.g., follicular lymphoma or diffuse large B-cell lymphoma), and multiple myeloma. Moreover, the cancer to be treated (including any one of the aforementioned specific types of cancer) may also be a chemoresistant and / or a metastatic cancer. According to the present invention, the cancer may be characterized by a reduction or absence of BRCA1 and / or BRCA2 gene expression, the absence or mutation of BRCA1 and / or BRCA2 genes, or reduced function of BRCA1 and / or BRCA2 proteins.

[0194] According to the present invention, the cancer may be selected from breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, colorectal cancer, gastric cancer, skin cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, esophageal cancer, kidney cancer, colorectal cancer, stomach cancer, thyroid cancer, lymphoma, leukemia, melanoma, uterine cancer, mantle cell lymphoma, renal cell carcinoma, appendicle cancer, hematologic cancer, MYH-related polyposis, gallbladder cancer, bile duct cancer, testicular cancer, bone cancer, and head and neck cancer.

[0195] Preferably, the cancer is selected from gastric, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin cancer. More preferably, the cancer is selected from lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin cancer. Alternatively, in one embodiment, the cancer is selected from ovarian, gastric, and breast cancer. Accordingly, in one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is breast cancer.

[0196] 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).

[0197] The antiproliferative treatment with the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined hereinbefore, may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:-

[0198] (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;

[0199] (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];

[0200] (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-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 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;

[0201] (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 ovp3 function and angiostatin)];

[0202] (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;

[0203] (viii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;

[0204] (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

[0205] (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.

[0206] 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.

[0207] According to this aspect the present invention further relates to the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, for use in the treatment of a cancer (for example a cancer involving a solid tumour) in combination with another anti-tumour agent. The anti-tumour agent is preferably selected from the anti-tumour agents as listed hereinabove.

[0208] 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.

[0209] Examples

[0210] 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.

[0211] Synthesis of the compounds of formula (I)

[0212] The syntheses of preferred embodiments of the compounds of formula (I) according to the present invention are preferably carried out per analogy to the synthesis of Example 1 .

[0213] 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 Examples 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, metallation, 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. It is further understood to the skilled person that a reaction can lead to side product(s) which, when appropriate, can be used for the preparation of compounds of formula (I) using similar procedures as reported in the general schemes hereinbelow, or reported in the specific examples hereinbelow.

[0214] Scheme 1

[0215]

[0216] Scheme 1 illustrates a preferred synthetic approach to compounds of the general formula (I) in which Rs is Hydrogen (H).

[0217] In the first step, the cyano group of a compound of formula 1 is reduced to give a compound of formula 2. The reaction is preferably carried out in THF in the presence of a reducing agent like BH3.THF, BHg.MejS, PtO2 / H2, sodium tetrahydroborate etc., (see for example: Long et al, WO 2018 / 71535). The reaction is performed at temperatures ranging from 20-40°C. The reaction is preferably completed after 0.5-24 hours. In the second step, a compound of formula 2 is reacted with ethyl 2-chloro-2-oxoacetate 3 under basic conditions to give a compound of formula 4. The acylation is preferably carried out in a polar aprotic solvent like DCM, dioxane or THF, in the presence of a base like trimethylamine or N-ethyl-N- isopropylpropan-2-amine (see for example: Blaquiere et al, WO 2015 / 25025). The reaction is performed at temperatures ranging from -5° C to room temperature. The reaction is preferably completed after 1- 24 hours.

[0218] In the third step, a compound of formula 4 is converted to a compound of formula 5. The cyclization is preferably carried out in the presence of dehydration reagents like trichlorophosphate, phosphorus pentoxide and trichlorophosphate, pyridine and trifluoroacetic anhydride etc., in 1 ,2-dichloro-ethane, toluene or under neat conditions. The reaction is performed at temperatures ranging from 70-140°C. The reaction is preferably completed after 1-24 hours.

[0219] In the fourth step, a compound of formula 5 is converted to a compound of formula 6 by several synthetic steps. If R4 is 2-(difluoromethyl)-1 ,3,4-thiadiazole, a compound of formula 5 is reacted with hydrazine hydrate to produce a hydrazide. This hydrazide formation can be carried out under neutral conditions (see for example: Dong et al, J. Med. Chem. 2020, 63, 3028). The hydrazide formation is preferably performed in EtOH and the reactions are preferably run for 1 -24 hours at 50-100°C with heating or microwave conditions. The hydrazide is then reacted with ethyl 2,2-difluoroacetate to produce a di-acyl hydrazine. This reaction can be carried out by basic condition, preferred is the herein described use of DBU in EtOH, THF, or DMF. The reactions are preferably run for 0.5-24 hours at room temperature to 100°C in a microwave oven or in an oil bath. Finally, the di-acyl hydrazine is cyclized by treatment with oxygen / sulfur exchange reagents to a compound of formula 6, in which R4 is 2-(difluoromethyl)-1 ,3,4- thiadiazole group (see for example: Brunet et al, W02020 / 127974). Preferred is the herein described use of Lawessons reagent in toluene or THF. The reactions are preferably run for 0.5-24 hours at 50-130°C.

[0220] In the fifth step, a compound of formula 6 in which R4 is as defined for the compound of formula (I) is reacted with benzyl mercaptan to give a compound of formula 7. 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’, 2ndedition.: 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.

[0221] In the sixth step, a compound of formula 7 in which R4 is as defined for the compound of formula (I) is reacted with chlorination reagent to give a sulfonyl chloride of formula 8. This sulfonyl chloride formation can be carried out by treatment with NCS, sulfonyl chloride, 1 ,3-dichloro-5,5-dimethyl- imidazolidine-2, 4-dione (DCDMH), CI2 etc., with equivalent amount of acetic acid and water and, or alternatively, in MeCN. (see for example: Sutton et al, WO 2021 / 055744). Preferred is the herein described use of DCDMH with equivalent acetic acid and water, or alternatively in MeCN. The reactions are preferably run under an atmosphere of argon for 0.5-5 hours at 0°C to room temperature.

[0222] In the seventh step, a compound of formula 8 in which R4 is as defined for the compound of formula

[0223] (I) is reacted with an amine of formula 9 in which R1 , R2 and R3 are as defined for the compound of formula (I) to give a compound of formula 10. This reaction can be carried out under basic conditions (see for example: Sutton et al, WO 2021 / 055744). Preferred is the herein described use of trimethylamine; diisopropylamine, 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.

[0224] In the final step, a compound of formula 10 in which Ri, R2, R3 and R4 are as defined for the compound of formula (I) is coupled with chemical moieties such as for example amines to give a compound of formula (I), in which X2 is defined as for the compound of formula (I). In case of amine, this coupling reaction can be carried out by a palladium-catalyzed C-N cross-coupling reaction (see for example: a) Jiang, Buchwald in 'Metal-Catalyzed Cross-Coupling Reactions’, 2ndedition.: de Meijere, Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004; b) Sutton et al, WO 2021 / 055744). Preferred is the herein described use of cesium carbonate and Pd-PEPPSI-I Hept Cl in dioxane. The reactions are preferably run under an atmosphere of argon for 1-48 hours at 80-120°C in a microwave oven or in an oil bath. Preferred is also the herein described use of cesium carbonate RuPhos-Pd-G3, Ruphos in dioxane or palladium acetate, Ruphos, tert-butyl alcohol sodium in THF. The reactions are preferably run under an atmosphere of argon for 1-24 hours at 70-130°C in a microwave oven or in an oil bath.

[0225] Scheme 2

[0226]

[0227] Scheme 2 illustrates a preferred synthetic approach to compounds of the general formula (I) in which R5 is not a Hydrogen (H). Compound 7 is obtainable according to Scheme 1 shown hereinabove.

[0228] In the first step, a compound of formula 7 in which R4 is as defined for the compound of formula (I) is reacted with an iodide reagent to give a compound of formula 11 . This iodination can be carried out by treatment with NIS, h etc., in MeCN, THF, dioxane, DMF etc. (see for example: Bentley et al; WO 2011 / 138266). Preferred is the herein described use of NIS in MeCN. The reactions are preferably run under an atmosphere of argon for 0.5-5 hours at 0°C to room temperature.

[0229] In the second step, a compound of formula 11 in which R4 is as defined for the compound of formula (I) is reacted with chlorination reagent to give a sulfonyl chloride of formula 12. This sulfonyl chloride formation can be carried out by treatment with NCS, sulfonyl chloride, 1 ,3-dichloro-5,5-dimethyl- imidazolidine-2, 4-dione (DCDMH), CI2 etc., with equivalent amount of acetic acid and water and, eventually, in MeCN. (see for example: Sutton et al, WO 2021 / 055744). Preferred is the herein described use of DCDMH with equivalent acetic acid and water, eventually in MeCN. The reactions are preferably run under an atmosphere of argon for 0.5-5 hours at 0°C to room temperature.

[0230] In the third step, a compound of formula 12 in which R4 is as defined for the compound of formula (I) is reacted with an amine of formula 9 in which R1 , R2 and R3 are as defined for the compound of formula (I) to give a compound of formula 13. This reaction can be carried out under basic conditions (see for example: Sutton et al, WO 2021 / 055744). Preferred is the herein described use of trimethylamine, diisopropylamine, 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.

[0231] In the fourth step, the iodide of a compound of formula 13 in which R1, R2, R3 and R4 are as defined for the compound of formula (I) reacts with different chemical moieties such as boronic esters;, boronic acids, alkyne compounds, organozinc reagents to give a compound of formula 14 in which R5, defined as for the compound of formula (I), is not H. The reaction is preferably carried out in THF, dioxane or DMF, eventually in the presence of a suitable catalyst such as for example Pd(0) catalysts like tetrakis(triphenylphosphine) palladium(O) [Pd(PPh3)4], tris(dibenzylideneacetone) 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, with or without water and, eventually in the presence of a base like potassium carbonate, sodium carbonate, sodium bicarbonate or potassium phosphate, (see for example for Suzuki couplings: 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. The reaction is preferably completed after 1 to 36 hours.

[0232] In the final step, a compound of formula 14 in which R-i, R2, R3, R4 and R5 are as defined for the compound of formula (I) is coupled with chemical moieties such as for example amines to give a compound of formula (I), in which X2 is defined as for the compound of formula (I). In case of amine, this coupling reaction can be carried out by a palladium-catalyzed C-N cross-coupling reaction (see for example: a) Jiang, Buchwald in ‘Metal-Catalyzed Cross-Coupling Reactions’, 2ndedition.: de Meijere, Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004; b) Sutton et al, WO 2021 / 055744). Preferred is the herein described use of cesium carbonate and Pd-PEPPSI-I Hept Cl in dioxane. The reactions are preferably run under an atmosphere of argon for 1-48 hours at 80-120°C in a microwave oven or in an oil bath. Preferred is also the herein described use of cesium carbonate RuPhos-Pd-G3, Ruphos in dioxane or palladium acetate, Ruphos, tert-butyl alcohol sodium in THF. The reactions are preferably run under an atmosphere of argon for 1-24 hours at 70-130°C in a microwave oven or in an oil bath.

[0233] Preparation of compounds

[0234] General considerations

[0235] Abbreviations used in the descriptions that follow are: AcOH (acetic acid); aq. (aqueous); Ar (Argon); Atm (atmosphere); BH3.THF (boran tetrahydrofuran complex); br. (broad,1H NMR signal); B0C2O (d i-te rt-buty I d icarbonate) ; (Cataxium APdGs (M esy late[(di ( 1 -adamantyl)-n-butylphosphine)-2-(2'-amino- 1 ,1'-biphenyl)]palladium(ll)); (CDCI3 (deuterated chloroform); cHex (cyclohexane); CMPB ( Cyanomethylene trimethylphosphorane); CS2CO3 (cesium carbonate); Cui (copper iodide); DABCO ((1 ,4-diazabicyclo[2.2.2]octane)); DAST (diethylaminosulfur trifluoride);DBU (1 ,8- Diazabicyclo(5.4.0)undec-7-ene); DCE (dichloroethane); d (doublet,1H NMR signal); DCM (dichloromethane); DIBAL-H (diisobutyl aluminium hydride); DIPEA or DIEA (di-zso-propylethylamine); DMAP (4- N-N-dimethylaminopyridine), DME (1 ,2-dimethoxyethane), DMEDA (dimethylethylenediamine ); DMF (A / -A / -dimethylformamide); DMSO (dimethyl sulfoxide); DPPA (diphenylphosphoride azide);dtbbpy (Bis(1 ,1-dimethylethyl)-2,2'-bipyridine); ES (electrospray); EtOAc or EA (ethyl acetate); EtOH (ethanol); h (hour(s)); FA (formic acid); HATU (1-[Bis(dimethylamino)methylene]- 1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); HFIP ( Hexafluoroisopropanol);1H NMR (proton nuclear magnetic resonance spectroscopy); HPLC (High Performance Liquid Chromatography), iPrOH ( / so-propanol); K2CO3 (potassium carbonate); K3PO4 (tripotassium phosphate); lr[dF(CF3)(dtbbpy)PFe ((4,4'-Di-t-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl- kN)phenyl-kC]iridium(lll) hexafluorophosphate); LiOH (lithium hydroxide); m (multiplet,1H NMR signal); mCPBA (meta-chloroperoxybenzoic acid), MeCN (acetonitrile), MeOH (methanol); min (minute(s)); Mg(OTf)2 (Magnesium trifluoromethanesulfonate); Mn02 (Manganese (IV) oxide); MS (mass spectrometry); MTBE (methyl tert-butyl ether); NaBH4 (sodium borohydride); NaHCOs (sodium hydrogenocarbonate); Na2S2d3 (sodium thiosulfate); NCS (N-chlorosuccinimide); NH3 (ammonia); NH4CI (ammonium fluoride); Ni&2 (nickel dichloride); NIS (N-lodosuccinimide); NMP (N-methylpyrrolidone); NMR (nuclear magnetic resonance); Pd / C (palladium on charcoal); Pd2dba3 (tris(dibenzylideneacetone)dipalladium ); Pd(dppf)CI2 (1 ,1 -Bis(diphenylphosphino)ferrocene dichloropalladium ); Pd(Ph3)2Ch (Bis(triphenylphosphine)palladium(l I) dichloride ); PE (petroleum ether); Pd-PEPPSI-IPentCI o-picoline ([1 ,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]- dichloro-(2-methylpyridin-1-ium-1 -yl)palladium; Pd(OH)2 (palladium hydroxide); Pd(Phs)4 (Palladium- tetrakis(triphenylphosphine)); Phl(OAc)2 ((Diacetoxyiodo)benzene)); P(tBu)s (Tri-tert-butylphosphine ); Py (pyridine); q (quartet, 1 H NMR signal); quin (quintet, 1 H NMR signal); rac (racemic); RT (retention time); s (singlet,1H NMR signal); sat. (saturated); t (triplet,1H NMR signal); TBAF (tetrabutylammonium fluoride); tert-BuBrettPhos-Pd-G3 ([(2-Di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1 ,1'-biphenyl)-2- (2'-amino-1 ,T-biphenyl)]palladium(ll) methanesulfonate); tBuXPhos Pd G3 (Methanesulfonato(2-di-t- butylphosphino-2',4',6'-tri-i-propyl-1 ,1'-biphenyl)(2'-amino-1 ,1,-biphenyl-2-yl)palladium(ll))TBDMSCI or TBSCI (tert-butyldimethylsilyl chloride); tBuOH (tert-butanol); TEA (triethylamine) ; TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran); TLC (thin layer chromatography); TMSCHN2 (Trimethylsilyldiazomethane); TMSCN (trimethylsilyl cyanide); TMSOTf (Trimethylsilyl trifluoromethanesulfonate ); TTMSS (trimethylsilane); UPLC (Ultra-High Performance Liquid Chromatography), UV (ultraviolet), wt-% (percent by weight); Xantphos (4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene); Xantphos Pd G4 (Methanesulfonato[9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene](2'-methylamino-1 ,T-biphenyl-2-yl)palladium(ll)).

[0236] 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. Organic solutions were routinely dried over anhydrous sodium sulfate. Column chromatography was performed on pre-packed silica (100-1000 mesh, 40-63 pm) cartridges using the amount indicated. 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.

[0237] Analytical Methods

[0238] Reverse Phase HPLC conditions for the LCMS analysis of compounds

[0239] Method 1 : SHIMADZU LCMS-2020 Kinetex EVO C18 2.1X30mm,5um at 50°C; Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 1 .5 mL / min; eluted with the mobile phase over 1 .55 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-1.20 min, held at 5% A-95% B; 1.20-1.21 min, returned to 95% A-5% B, 1 .21-1 .55 min, held at 95% A-5% B.

[0240] Method 2: SHIMADZU LCMS-2020 Kinetex EVO C182.1X30mm,5um at 40°C;Mobile Phase:

[0241] 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.

[0242] Method 3: Agilent 1200\G6110A Kinetex EVO C18 2.1X30mm,5um 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.

[0243] Method 6: SHIMADZU LCMS-2020 Kinetex® HALO C18 3.0X30mm, 5um, 5 urn at 50°C; Mobile

[0244] Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 1.5 mL / min; eluted with the mobile phase over 1.05 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-0.80 min, ramped from 50% A-50% B to 0% A-100% B; 0.80-1 .05 min, held at 50% A-50% B.

[0245] Methods for SFC analysis of compounds:

[0246] SFC Method 13: Column: Chiralpak AD-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for IPA (0.05% DEA); Gradient elution: IPA (0.05% DEA) in CO2 from 5% to 40%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar. SFC Method 26: Column: Chiralpak AD-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) from 20% to 60% in CO2; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0247] SFC Method 41 : Column: Chiralpak AS-3 50*4.6mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for MeOH (0.05% DEA); Gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0248] SFC Method 45: Column: Chiralpak ID-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for IPA(0.05% DEA); Gradient elution: IPA (0.05 % DEA) in CO2 from 5% to 40%, Flow rate: 3mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar.

[0249] SFC Method 46: Column: Chiralpak ID-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for IPA(0.05% DEA); Gradient elution: IPA (0.05 % DEA) in CO2 from 20% to 60%, Flow rate: 3mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar.

[0250] 1H NMR Spectroscopy

[0251] 1H NMR spectra were acquired on a Bruker Avance III spectrometer at 400 MHz using residual undeuterated solvent as reference.

[0252] Preparation of Intermediate 1.1

[0253] (5-bromo-3-chloropyridin-2-yl)methanamine

[0254] To a mixture of 5-bromo-3-chloropicolinonitrile (2.0 g, 9.20 mmol) in THF (10 mL) under ice-water cooling was added BH3 THF (1 M, 11 .04 mL) over 5 min. The mixture was stirred at 0°C for 30 min before it was warmed to 20°C and stirred for another 30 min at this temperature. The mixture was cooled to 0°C and quenched with dropwise addition of MeOH (10 mL) over 5 min. The mixture was heated to 70°C and stirred for 30 min at this temperature. The reaction was concentrated under vacuum to give the crude product (2.2 g) as a light brown solid. The crude product was dissolved in HCI (aq. 2M, 20 mL), washed with DCM (20 mL; 2x) and the aqueous phase was finally concentrated under vacuum to give the product (5-bromo-3-chloro-2-pyridyl)methanamine (1 .5 g, 4.07 mmol, 44.26% yield, 70% purity, HCI salt) as a light brown solid.

[0255] RT 0.18 min (LCMS method 2); m / z 222.9 (M+H)+(ESP),1H NMR (400 MHz, DMSO-d6) δ = 8.78 (d, J = 2.0 Hz, 1 H), 8.69 (br, 3H), 8.47 (d, J = 2.0 Hz, 1 H), 4.24 (d, J = 6.2 Hz, 2H).

[0256] Preparation of Intermediate 1.2

[0257] Ethyl 2-(((5-bromo-3-chloropyridin-2-yl)methyl)amino)-2-oxoacetate

[0258] To a mixture of (5-bromo-3-chloro-2-pyridyl)methanamine (1.5 g, 5.82 mmol, HCI salt) in DCM (30 mL) under ice-water cooling was added DIPEA (2.25 g, 17.45 mmol). Then, ethyl 2-chloro-2-oxoacetate (952.77 mg, 6.98 mmol) was added over 5 min and the mixture was stirred at 0°C for 30 min. The mixture was warmed to 20°C and stirred for 30 min at this temperature. The mixture was quenched with aqueous NaHCOa solution (50 mL) and extracted with DCM (50 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE: EtOAc=10:1 to 1 :1) to give the product ethyl 2-(((5-bromo-3-chloropyridin-2- yl)methyl)amino)-2-oxoacetate (1300 mg, 3.64 mmol, 62.57% yield, 65.6% purity) as a white solid.

[0259] RT 0.61 min (LCMS method 1); m / z 322.8 (M+H)+(ESI+). The product was used without further purification in the next step.

[0260] Preparation of Intermediate 1.3

[0261] Ethyl 6-bromo-8-chloroimidazo[1 ,5-a]pyrid i ne-3-carboxylate

[0262] To a mixture of ethyl ethyl 2-(((5-bromo-3-chloropyridin-2-yl)methyl)amino)-2-oxoacetate (1300 mg, 4.04 mmol) in POCh (15 mL) under ice water cooling was added phosphorus pentoxide (2.87 g, 20.21 mmol). The mixture was heated to 110°C and stirred for 5 h at this temperature. The mixture was cooled to 25°C and concentrated under vacuum to give a residue. The residue was dissolved in EtOAc (50 mL) and washed with water (30 mL) and an aqueous NaHCOa solution (30 mL). Then it was was finally concentrated under vacuum to give a residue. The residue was purified by column chromatography on silica gel (PE: EtOAc=10:1 to 3:1) to give the product ethyl 6-bromo-8-chloroimidazo[1 ,5-a]pyridine-3- carboxylate (900 mg, 2.97 mmol, 73.34% yield) as a white solid.

[0263] RT 0.718 min (LCMS method 1), m / z 304.8(M+H)+(ESP),1H NMR (400 MHz, CDC / 3) δ = 9.47 (s, 1 H), 7.77 (s, 1 H), 7.20 (s, 1 H), 4.65-4.42 (m, 2H), 1 .57-1 .42 (m, 3H).

[0264] Preparation of Intermediate 1.4

[0265] 6-bromo-8-chloroimidazo[1 ,5-a]pyridine-3-carbohydrazide

[0266] To a mixture of ethyl 6-bromo-8-chloroimidazo[1 ,5-a]pyridine-3-carboxylate (900 mg, 2.97 mmol) in EtOH (20 mL) was added NH2NH2 H2O (1.48 g, 29.65 mmol, 98%). The mixture was heated to 80°C and stirred for 2 h at this temperature. The reaction was cooled to 25°C and the precipitated solid was separated off. The crude product was triturated with EtOH (5 mL) to give 6-bromo-8-chloroimidazo[1 ,5- a]pyridine-3-carbohydrazide (650 mg, 2.25 mmol, 75.72% yield) as a white solid.

[0267] RT 0.56 min (method 1); m / z 290.8 (M+H)+(ESI+);1H NMR (400 MHz, DMSO-d6) δ ) = 10.02 (s, 1 H), 9.50 (s, 1 H), 7.72 (s, 1 H), 7.51 (s, 1 H), 4.58 (d, J = 4.0 Hz, 2H).

[0268] Preparation of Intermediate 1.5

[0269] 6-bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1 ,5-a]pyridine-3-carbohydrazide

[0270] To a mixture of 6-bromo-8-chloroimidazo[1 ,5-a]pyridine-3-carbohydrazide (650 mg, 2.25 mmol) in EtOH (20 mL) was added ethyl 2,2-difluoroacetate (3.10 g, 22.45 mmol) and DBU (683.58 mg, 4.49 mmol). The mixture was heated to 100°C stirred for 16 h at this temperature. The mixture was cooled to 25°C and concentrated under vacuum. The residue was dissolved with DCM (50 mL), washed with an aqueous NH4CI solution (30 mL; 2x) and concentrated under vacuum to give the crude product. The crude product was purified by column chromatography on silica gel (PE / EtOAc=1 : 1 to MeOH: EtOAc=1 : 10) to give the product 6-bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1 ,5-a]pyridine-3-carbohydrazide (650 mg, 1.56 mmol, 69.32% yield, 88% purity) as a white solid.

[0271] RT 0.62 min (LCMS method 1); m / z 368.8 (M+H)+(ESI+);1H NMR (400 MHz, DMSO-d6) δ = 10.95 (br, 2H), 9.44 (s, 1 H), 7.81 (s, 1 H), 7.59 (s, 1 H), 6.38 (t, J = 53.2, 1 H).

[0272] Preparation of Intermediate 1.6

[0273] 2-(6-bromo-8-chloroimidazo[1 ,5-a]pyridin-3-yl)-5-(difluoromethyl)-1 ,3,4-thiadiazole

[0274] To a mixture of 6-bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1 ,5-a]pyridine-3-carbohydrazide (550 mg, 1 .50 mmol) in toluene (20 mL) was added Lawessons reagent (665.80 mg, 1 .65 mmol) under a N2 atmosphere. The reaction was heated to 120°C and stirred for 2 h at this temperature. The reaction was cooled to 25°C and concentrated under vacuum. The residue was triturated with MeOH (10 mL) at 70°C for 1 h, filtered and the cake was collected, and dried under vacuum to give the product 2-(6-bromo- 8-chloroimidazo[1 ,5-a]pyridin-3-yl)-5-(difluoromethyl)-1 ,3,4-thiadiazole (530 mg, 1.45 mmol, 96.88% yield) as a light yellow solid.

[0275] RT 0.806 min (LCMS method 1); m / z 366.8 (M+H)+(ESI+);1H NMR (400 MHz, DMSO-cfe) δ = 9.62 (s, 1 H), 8.64 (s, 1 H), 8.09 (s, 1 H), 7.70 (t, J = 53.2, 1 H).

[0276] Preparation of Intermediate 1.7

[0277] 2-(6-(benzylthio)-8-chloroimidazo[1 ,5-a]pyridin-3-yl)-5-(difluoromethyl)-1 ,3,4-thiadiazole

[0278] To a mixture of 2-(6-bromo-8-chloroimidazo[1 ,5-a]pyridin-3-yl)-5-(difluoromethyl)-1 ,3,4-thiadiazole (450 mg, 1.23 mmol) and phenylmethanethiol (168.17 mg, 1.35 mmol) in dioxane (10 mL) which was degassed with nitrogen for 2 min was added Pd2(dba)3 (112.72 mg, 123.09 pmol), Xantphos (71 .22 mg, 123.09 pmol) and DIEA (477.26 mg, 3.69 mmol) under nitrogen. The mixture was heated to 90°C and stirred for 16 h at this temperature. The mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE: EtOAc=20:1 to 5:1) to give the product 2-(6- (benzylthio)-8-chloroimidazo[1 ,5-a]pyridin-3-yl)-5-(difluoromethyl)-1 ,3,4-thiadiazole (250 mg, 489.15 pmol, 39.74% yield, 80% purity) as a light yellow solid.

[0279] RT 0.99 min (LCMS method 1); m / z 409.0 (M+H)+(ESP);1H NMR (400 MHz, CDC / 3) δ = 9.35 (s, 1 H), 7.69 - 7.67 (m, 1 H), 7.39 - 7.28 (m, 2H), 7.25 - 7.12 (m, 3H), 7.05 (t, J = 53.2, 1 H), 7.00 (s, 1 H), 6.90 (s, 1 H), 4.10 (s, 2H)

[0280] Preparation of intermediate 1.8 1 ,3-dichloro-5,5-dimethyl-imidazolidine-2, 4-dione

[0281] AcOH, H2O, 0 °C, 0.5 h

[0282] To a mixture of 2-(6-(benzylthio)-8-chloroimidazo[1 ,5-a]pyridin-3-yl)-5-(difluoromethyl)-1 ,3,4- thiadiazole (5.00 g, 12.2 mmol) in AcOH (50 mL, 874 mmol) and water (50 mL) was added 1 ,3-dichloro- 5, 5-dimethyl-imidazolidine-2, 4-dione (7.23 g, 36.7 mmol) in batches over 10 min at 0°C. The reaction mixture was then stirred at 0 °C for 0.5 h, poured into ice-water (100 mL), filtered and the filter cake was collected. The filter cake was dissolved in DCM (50 mL) and washed with ice water (50 mL, 3x). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give the product 8- chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)imidazo[1 ,5-a]pyridine-6-sulfonyl chloride (3.00 g, 7.79 mmol, 63.69% yield) as a light yellow solid. The crude product was used for the next step directly.

[0283] RT 0.605 min (LCMS method 1); m / z 384.9 (M+H)+(ESI+)

[0284] Preparation of Intermediate 1.9

[0285] 8-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)imidazo[1 ,5- a]pyridine-6-sulfonamide

[0286] To a solution of 3-methyloxetan-3-amine (271.0 mg, 3.12 mmol) in DCM (6 mL) was added DIEA (1.4 mL, 7.79 mmol) at -5 °C., Then, 8-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)imidazo[1 ,5- a]pyridine-6-sulfonyl chloride (300 mg, 0.779 mmol) in DCM (3 mL) was added dropwise and the mixture was stirred at -5 °C for 50 min. The reaction mixture was poured into water (10 mL), then extracted with DCM (30 mL, 2x). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by reverse-phase flash chromatography (ISCO®; 25 g Flash Column Welch Ultimate XB_C18 20-45 pm; 100 A, mobile phase: A: 0.05% Ammonia v / v in water, B: MeCN; B%: 0%-100% @ 60mL / min) and lyophilized directly to give product 8-chloro-3-(5-(difl uoromethyl)- 1 ,3,4-thiad iazol-2-yl)-N-(3-methyloxetan-3-yl) imidazo [1 ,5-a] pyridine-6-sulfonamide (300 mg, 0.779 mmol, 86.9% yield) as a yellow solid. RT 0.528 min (LCMS method 1); m / z 436.0 (M-H)+(ESI+);1H NMR (CDCI3, 400 MHz): 10.13 (s, 1 H), 7.92 (s, 1 H), 7.40 (s, 1 H), 7.09 (t, J = 53.6 Hz, 1 H), 5.55 (s, 1 H), 4.82 (d, J = 7.0 Hz, 2H), 4.46 (d, J = 7.0 Hz, 2H), 1.74 (s, 3H)

[0287] Preparation of Example 1

[0288] 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1 -yl)-N-(3- methyloxetan-3-yl)imidazo[1 ,5-a]pyridine-6-sulfonamide

[0289] To a mixture of 8-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3- yl)imidazo[1 ,5-a]pyridine-6-sulfonamide (30 mg, 0.0680 mmol) in 1 ,4-dioxane (0.5 mL) was added (2S,6S)-2,6-dimethylpiperazine (31.1 mg, 0.272 mmol), CS2CO3 (66.5 mg, 0.204 mmol) and Pd-PEPPSI- IPent Cl o-picoline (3.0 mg, 0.0034 mmol) at 25°C under N2. The reaction mixture was stirred at 90°C for 2 h, then, quenched with water (20 mL) and extracted with EtOAc (30 mL, 2x). The combined organic layer was washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by preparative-HPLC (column: Waters Xbridge 150*25 mm* 5 urn; mobile phase: A: 10 mmol NH4.HCO3 in water, B: MeCN; B%: 30%-50%, 10 min) and then lyophilized directly to give the product 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(3- methyloxetan-3-yl)imidazo[1 ,5-a]pyridine-6-sulfonamide (2.7 mg, purity: 100%, 0.0052 mmol, 7.58% yield) as a yellow solid.

[0290] RT 0.495 min (LCMS method 1); m / z 514.2 (M+H)+(ESI+); 1H NMR (MeOD, 400 MHz): 9.81 (s, 1 H), 7.84 (s, 1 H), 7.32(t, J = 53.2 Hz, 1 H), 6.76 (s, 1 H), 4.82 (dd, J = 6.4, 2.4 Hz, 2H), 4.33 (d, J = 6.8 Hz, 2H), 3.53 - 3.44 (m, 2H), 3.37 (dd, J = 12.0, 2.4 Hz, 2H), 3.14 (dd, J = 12.0, 6.4 Hz, 2H), 1 .63 (s, 3 H), 1.37 (d, J = 6.8 Hz, 6H).

[0291] Preparation of Example 2

[0292] 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-((2S,6S)-2,6-dimethylmorpholino)-N-(3-methyloxetan- 3-yl)imidazo[1 ,5-a]pyridine-6-sulfonamide

[0293] To a solution of 8-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)- imidazo [1 ,5-a]-pyridine-6-sulfonamide (40 mg, 0.0918 mmol) in 1 ,4-dioxane (2 mL) was added CS2CO3 (150 mg, 0.459 mmol), (2S,6S)-2,6-dimethylmorpholine (42 mg, 0.367 mmol) and Pd-PEPPSI-IPent Cl (24 mg, 0.0275 mmol). The mixture was degassed with N2 (3x) and stirred at 90 °C for 0.5 h. The resulting mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL, 2x). The combined organic layers were washed with brine (60 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 mmol NH4.HCO3 in water, B: MeCN; B%: 30%-50%, 8 min) and then lyophilized directly to give the product 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-((2S,6S)-2,6- dimethylmorpholino)-N-(3-methyloxetan-3-yl)imidazo[1 ,5-a]pyridine-6-sulfonamide (21.09 mg, 0.0410 mmol, 44.66% yield) as a yellow solid.

[0294] RT 0.933 min (LCMS method 1); m / z 515.3 (M+H)+(ESI+);1H NMR (DMSO-d6, 400 MHz): 9.56 (s, 1 H), 8.63 (br, 1 H), 7.92 (s, 1 H), 7.67 (t, J = 53.2 Hz, 1 H), 6.68 (s, 1 H), 4.63 (t, J = 6.8 Hz, 2H), 4.25-4.11 (m, 4H), 3.34-2.90 (m, 2H), 3.14-3.09 ( m, 2H), 1 .49 (s, 3H), 1 .31 (d, J = 6.4 Hz, 6H)

[0295] Preparation of Example 3

[0296] (S)-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-8-(3,3,5-trimethylpiperazin-

[0297] 1 -yl)i m idazo[ 1 ,5-a]py rid I ne-6-su Ifonam ide

[0298] To a solution of 8-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3- yl)imidazo[1 ,5-a]pyridine-6-sulfonamide (20 mg, 0.0459 mmol) in DMF (0.5 mL) were added CS2CO3 (45 mg, 0.138 mmol), Pd-PEPPSI-IPent Cl o-picoline (2-methylpyridine) (3.9 mg, 0.00459 mmol) and (S)- 2,2,6-trimethylpiperazine (12 mg, 0.0918 mmol). The mixture was degassed with N2 (3x) and stirred at 90 °C for 0.5 h. After cooling, the resulting mixture was filtrated. The filtrate was purified by preparative-HPLC (column: Phenomenex luna C18 150*25 mm* 10 pm; mobile phase: A: 10 mmol / L NH4HCO3 in water, B: MeCN; B%: 30%-60%, 9 min) and then lyophilized directly to give the product (S)-3-(5-(difluoromethyl)- 1 ,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-8-(3,3,5-trimethylpiperazin-1 -yl)imidazo[1 ,5-a]pyridine-6- sulfonamide (7.7 mg, 0.0145 mmol, 31 .55 % yield) as a yellow solid.

[0299] RT 0.429 min (LCMS method 6); m / z 528.2 (M+H)+(ESP); RT 1.258 min (SFC Method 46); ee: 90.29%;1H NMR (400 MHz, CDCI3): 9.87 (s, 1 H), 7.73 (s, 1 H), 7.08 (t, J = 53.6 Hz, 1 H), 6.63 (s, 1 H), 5.63-5.18 (m, 1 H), 4.92-4.73 (m, 2H), 4.50-4.35 (m, 2H), 3.60-3.46 (m, 2H), 3.44-3.33 (m, 1 H), 2.65-2.53 (m, 1 H), 2.50-2.35 (m, 1 H), 1.75 (s, 3H), 1.47 (s, 3H), 1.21 (s, 3H), 1.15 (d, J = 6.4 Hz, 3H)

[0300] Preparation of Intermediate 4.1

[0301] (2S,2'S)-3,3'-(benzylazanediyl)bis(1-methoxypropan-2-ol)

[0302] To a mixture of phenylmethanamine (20.00 g, 187 mmol) in methanol (200 mL) was added (S)-2- (methoxymethyl)oxirane (49.34 g, 560 mmol). Then, the reaction mixture was stirred at 80 °C for 16 h. The resulting mixture was concentrated under vacuum to give the crude product (2S,2'S)-3,3'- (benzylazanediyl)bis(1-methoxypropan-2-ol) (52 g, 184 mmol, 98.32 % yield) as brown oil which was used without further purification in the next step.

[0303] RT 0.324 min (LCMS method 6); m / z 284.1 (M+H)+(ESP);1H NMR (DMSO-d6, 400 MHz): 7.31 - 7.22 (m, 5 H), 4.58 (d, J = 4.0 Hz, 2 H), 3.69-3.63 (m, 2 H), 3.60-3.55(m, 2H), 3.28-3.25 (m, 2 H), 3.19 (s, 6 H), 3.17-3.16 (m, 2 H), 2.47-2.40 (m, 2 H), 2.39-2.30 (m, 2 H)

[0304] Preparation of Intermediate 4.2

[0305] (2S,2'S)-(benzylazanediyl)bis(3-methoxypropane-1 ,2-diyl) diethanesulfonate

[0306] To a mixture of (2S,2'S)-3,3'-(benzylazanediyl)bis(1-methoxypropan-2-ol) (5.00 g, 17.6 mmol) and

[0307] TEA (13 mL, 52.9 mmol) in DCM (50 mL) was added ethanesulfonyl chloride (5.0 mL, 52.9 mmol) dropwise at 0°C. The mixture was stirred at 0 °C for 2 h, then poured into ice-water (50 mL), extracted with DCM (50 mL; 3x), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product (2S,2'S)-(benzylazanediyl)bis(3-methoxypropane-1 ,2-diyl) diethanesulfonate (8.00 g, crude) as a yellow oil which was used directly in the next step without further purification.

[0308] RT 0.547min (LCMS method 6); m / z 468.2 (M+H)+(ESI+).

[0309] Preparation of Intermediate 4.3

[0310] (2R, 6R)-1 ,4-dibenzyl-2,6-bis(methoxymethyl)piperazine and (2S,5R)-1 ,4-dibenzyl-2,5- bis(methoxymethyl)piperazine

[0311] To a mixture of (2S,2'S)-(benzylazanediyl)bis(3-methoxypropane-1 ,2-diyl) diethanesulfonate (8.00 g, crude) in ethanol (80 mL) was added TEA (9.4 mL, 68.4 mmol) and benzylamine (2.8 mL, 25.7 mmol). Then, the mixture heated to 80 °C, stirred for 2 h and concentrated under vacuum. The residue was purified by column chromatography (ISCO; 80g SepaFlash Silica Flash Column, Eluent of 20% to 30% Ethylacetate / Petroleum ether @ 40 mL / min) to give the mixture of products (2R,6R)-1 ,4-dibenzyl-2,6- bis(methoxymethyl)piperazine and (2S,5R)-1 ,4-dibenzyl-2,5-bis(methoxymethyl)piperazine (1.00 g, crude) as a yellow oil.

[0312] RT 0.455 min (LCMS method 6); m / z 355.2 (M+H)+(ESI+).

[0313] Preparation of Intermediate 4.4

[0314] (2R,6R)-2,6-bis(methoxymethyl)piperazine and (2S,5R)-2,5-bis(methoxymethyl)piperazine

[0315] To a mixture of Pd(OH)2 (300 mg, 0.427 mmol), Pd / C (300 mg, 0.282 mmol) in HFIP (12 mL) was added the mixture of compounds (2R,6R)-1 ,4-dibenzyl-2,6-bis(methoxymethyl)piperazine and (2S.5R)- 1 ,4-dibenzyl-2,5-bis(methoxymethyl)piperazine (1000 mg, 1.38 mmol) under Ar2. The mixture was degassed with H2 (3x), stirred at 80 °C for 16 h, filtered and concentrated under reduced pressure to give the crude mixture of products (2R,6R)-2,6-bis(methoxymethyl)piperazine and (2S,5R)-2,5- bis(methoxymethyl)piperazine (1 .00 g, crude) as a brown oil.

[0316] RT 0.357 min (LCMS method 1), m / z 175.1 (M+H)+(ESF)

[0317] Preparation of example 4 and 4a

[0318] 8-((3R,5R)-3,5-bis(methoxymethyl)piperazin-1 -yl)-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(3- methyloxetan-3-yl)imidazo[1 ,5-a] pyridine-6-sulfonam ide and 8-((2S ,5R)-2 , 5- bis(methoxymethyl)piperazin-1 -yl)-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3- yl)imidazo[1 , 5-a] pyridi ne-6-sulfonamide formate

[0319] To a mixture of 8-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3- yl)imidazo[1 ,5-a]pyridine-6-sulfonamide (100 mg, 0.229 mmol) in 1 ,4-dioxane (3 mL) was added CS2CO3 (187 mg, 0.574 mmol), Pd-PEPPSI-IPent Cl o-picoline (79 mg, 0.0918 mmol) and the mixture of compounds (2R,5S)-2,5-bis(methoxymethyl)piperazine and (2R,6R)-2,6-bis(methoxymethyl)piperazine (400 mg, 1.15 mmol). The reaction mixture was degassed, purged with N2 (3 x), stirred at 80 °C for 1 h, filtered and concentrated under vacuum. The residue was purified by reverse-phase flash chromatography (ISCO®; 25 g Flash Column Welch Ultimate XB_C18 20-45 pm; 100 A, mobile phase: A: 0.1 % formic acid in water, B: MeCN; B%: 20% to 30% @ 60mL / min) and lyophilized directly. The resulting mixture of isomer products 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%: 22%-52%, 25 min) to give after lyophilization the product 8-((2S,5R)-2,5-bis(methoxymethyl)piperazin-1-yl)-3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)imidazo[1 ,5-a]pyridine-6-sulfonamide formate (17 mg, 0.0276 mmol, 12.03 % yield) as a brown solid and impure compound 4 (20 mg). This impure fraction was further purified by preparative HPLC (column: Waters Xbridge 150*25 mm* 5 pm; mobile phase: A: 10 mM aqueous solution of NH4HCO3, B: MeCN; B%: 15%-52%, 10 min) and lyophilized directly to give the product 8-((3R,5R)-3,5-bis(methoxymethyl)piperazin-1-yl)-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N- (3-methyloxetan-3-yl)imidazo[1 ,5-a]pyridine-6-sulfonamide formate (10 mg, 0.017 mmol, yield: 7.4%) as a yellow solid.

[0320] Example 4a: RT 0.432 min (LCMS method 6); m / z 574.2 (M+H)+(ESI+); RT 2.287 min (SFC Method 45); ee: 82.91 %;1H NMR (400 MHz, CD3CN): 9.64 (s, 1 H), 8.17 (br s, 1 H), 7.85 (s, 1 H), 7.23 (t, J =53.6 Hz, 1 H), 6.61 (s, 1 H), 4.70-4.67 (m, 2 H), 4.27-4.20 (m, 3 H), 3.66-3.64 (m, 2 H), 3.45 - 3.40 (m, 2 H), 3.35(s, 3 H), 3.20-3.12 (m, 5 H), 2.70(s, 3H),1 .59 (s, 3 H)

[0321] Example 4: RT 0.430 min (LCMS method 1 ); m / z 574.2 (M+H)+(ESI+); RT 1 .682 min (SFC Method 13); ee: 92.78%;1H NMR (400 MHz, CD3CN): 9.67 (s, 1 H), 7.87 (s, 1 H) 7.24 (t, J =53.6 Hz, 1 H), 6.63 (s, 1 H), 6.53 (br s, 1 H), 4.71 -4.68 (m, 2 H), 4.23-4.22 (m, 2 H), 3.64-3.51 (m, 2 H), 3.50 - 3.47 (m, 2 H), 3.38 (s, 6 H), 3.37 - 3.35 (m, 2 H), 3.28-3.26 (m, 4 H),1 .59 (s, 3 H).

[0322] Preparation of Intermediate 5.1

[0323] Methyl 2-hydroxy-3-methoxypropanoate

[0324] To a solution of methyl oxirane-2-carboxylate (10 g, 98.0 mmol) in methanol (30 mL) was added Mg(OTf)2 (63.17 g, 196 mmol). The mixture was stirred at 60 °C for 48 h, then diluted with ethyl acetate(100 mL), washed with brine (100 mL, 2x), dried over anhydrous NazSCX filtered and concentrated under reduced pressure to give the product methyl 2-hydroxy-3-methoxypropanoate (10.00 g, 59.644 mmol, 60.89 % yield, 80% purity) as a brown oil which was used directly in the next step without further purification.

[0325] 1H NMR (400 MHz, CDCh): 4.34-4.31 (m, 1H), 3.82 (s, 3H), 3.73-3.67 (m, 2H), 3.40 (s, 3H)

[0326] Preparation of Intermediate 5.2

[0327] Methyl 3-methoxy-2-(((trifluoromethyl)sulfonyl)oxy)propanoate To a solution of methyl 2-hydroxy-3-methoxypropanoate (0.20 g, 1.49 mmol, 80% purity) in DCM (2 mL) was added DIEA (0.53 mL, 2.98 mmol) and trifluoromethanesulfonic anhydride (0.20 mL, 1.19 mmol) at 0 °C. The reaction mixture was then warmed to 20 °C and stirred for 0.5 h. In parallel, twenty- nine reactions were conducted with the same protocol. All the reactions were purified respectively by flash silica gel chromatography (ISCO; 4 g SepaFlash Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 50 mL / min). The desired fractions were combined and the resulting solution was concentrated under vacuum to give the product methyl 3-methoxy-2- (((trifluoromethyl)sulfonyl)oxy)propanoate (3.00 g, 11.3 mmol, 31.49% yield) as brown oil.

[0328] 1H NMR (400 MHz, CDCI3): 5.30-5.27 (m, 1 H), 3.94-3.85 (m, 5H), 3.44 (s, 3H)

[0329] Preparation of Intermediate 5.4

[0330] Methyl O-methyl-N-(2-methyl-1 -(tritylamino)propan-2-yl)serinate

[0331] To a solution of methyl 3-methoxy-2-(((trifluoromethyl)sulfonyl)oxy)propanoate (3.00 g, 11.3 mmol) in MeCN (30 mL) was added K2CO3 (2.83 g, 20.5 mmol) and 2-methyl-N1 -tritylpropane-1 ,2-diamine (4.10 g, 12.4 mmol). The reaction mixture was stirred at 80 °C for 16 h, then filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO; 40 g SepaFlash Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give the product methyl O-methyl-N-(2-methyl-1 -(tritylamino)propan-2-yl)serinate (2.00 g, 4.48 mmol, 39.74 % yield) as an off- white solid.

[0332] 1H NMR (400 MHz, CDCI3); 7.55 - 7.53 (m, 6H), 7.32 - 7.29 (m, 6H), 7.23 - 7.21 (m, 3H), 3.67(s, 3H), 3.36-3.30(m, 2H), 3.28(s, 3H), 3.25-3.15(m,1 H), 2.01 (s, 2H), 1.24(s, 3H), 1.03(s, 3H)

[0333] Preparation of Intermediate 5.5

[0334] 3-(methoxymethyl)-5,5-dimethylpiperazin-2-one

[0335] To a solution of methyl O-methyl-N-(2-methyl-1-(tritylamino)propan-2-yl)serinate (2.00 g, 4.48 mmol) in DCM (20 mL) was added TFA ( 10 mL). The mixture was stirred at 25 °C for 16 h and then mixture concentrated under vacuum. The residue was dissolved in H2O (10 mL), then filtered and the filtrate was concentrated under vacuum. The resulting residue was dissolved in MeOH (10 mL), neutralized by cation exchange resin (500 mg) at 20°C for 16 h. After filtration, the filtrate was concentrated under vacuum to give the product 3-(methoxymethyl)-5,5-dimethylpiperazin-2-one (700 mg, 4.06 mmol, 90.76 % yield) as a brown oil.

[0336] 1H NMR (400 MHz, CDCI3) 5.76(s, 1 H), 3.92-3.89(m, 1 H), 3.68-3.61 (m, 2H), 3.38(s, 3H), 3.31 -

[0337] 3.28(m, 1 H), 3.14-3.04(m, 1 H), 1.30(s, 3H), 1 .21 (s, 3H).

[0338] Preparation of Intermediate 5.6

[0339] 6-(methoxymethyl)-2,2-dimethylpiperazine

[0340] To a solution of 3-(methoxymethyl)-5,5-dimethylpiperazin-2-one (700 mg, 4.06 mmol) in THF (0.5 mL) was added BH3 / THF ( 4.0 mL, 4.00 mmol, 1 mol / L in THF) at 0 °C. The reaction mixture was stirred at 60 °C for 2 h, then cooled, quenched with MeOH (10 mL) at 0 °C and further stirred at 60 °C for 2 h. The resulting mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified directly by reversed-phase flash chromatography (ISCO; 20 g Flash Column Welch Ultimate XB_C18 20-40 pm; 120 A, mobile phase: A: 0.1 % formic acid in water, B: MeCN; B%: 10%-30% @ 20mL / min) and lyophilized to give the product 6-(methoxymethyl)-2,2-dimethylpiperazine (500 mg, 3.16 mmol, 77.74 % yield) as a brown oil.

[0341] 1H NMR (400 MHz, CD3OD) 3.45-3.41 (m, 3H), 3.40-3.36 (s, 3H), 2.97-2.87 (m, 1 H), 2.67-2.64 (m, 1 H), 2.69-2.53 (m, 2H), 1 .36 (s, 3H), 1 ,26(s, 3H)

[0342] Preparation of Example 5

[0343] 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(5-(methoxymethyl)-3,3-dimethylpiperazin-1 -yl)-N-(3- methyloxetan-3-yl)imidazo[1 ,5-a]pyridine-6-sulfonamide

[0344] To a solution of 8-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3- yl)imidazo[1 ,5-a]pyridine-6-sulfonamide (20 mg, 0.0459 mmol) in DMF (0.5 mL) were added CS2CO3 (45 mg, 0.138 mmol), Pd-PEPPSI-IPentCI o-picoline (3.9 mg, 0.00459 mmol) and 6-(methoxymethyl)-2,2- dimethylpiperazine (15 mg, 0.0918 mmol). The mixture was degassed with N2 (3x) and stirred at 90 °C for 0.5 h. The resulting mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL, 3x). The combined organic layer was washed with brine (10 mL, 2x), dried over anhydrous NajSCU, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 urn; mobile phase: A: 10 mmol / L NH4HCO3 in water, B: MeCN; B%: 32%-62%, 9 min) and lyophilized to give the product 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(5- (methoxymethyl)-3,3-dimethylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)imidazo[1 ,5-a]pyridine-6- sulfonamide (11 mg, 0.0189 mmol, 41.11 % yield) as a yellow solid.

[0345] RT 0.435 min (LCMS method 6); m / z 558.2 (M+H)+(ESI+); RT 1.227 min, 1.421 min (SFC Method 41);1H NMR (400 MHz, CDCI3): 9.87 (s, 1 H), 7.73 (s, 1 H), 7.08 (t, J = 53.6 Hz, 1 H), 6.63 (s, 1 H), 5.66 (br s, 1 H), 4.95-4.75 (m, 2H), 4.50-4.30 (m, 2H), 3.65-3.41 (m, 5H), 3.40 (s, 3H), 2.80-2.60 (m, 2H), 1.74 (s, 3H), 1.50 (s, 3H), 1.26 (s, 3H)

[0346] Preparation of Example 5a & 5b

[0347] (R or S)-3-(5-(difl uoromethy I)- 1 , 3, 4-th iadiazol-2-y l)-8-(5-(methoxy methy l)-3,3-d i methy I pi perazi n - 1 - yl)-N-(3-methyloxetan-3-yl)imidazo[1 ,5-a]pyridine-6-sulfonamide and (S or R)-3-(5-(difluoromethyl)- 1 ,3,4-thiadiazol-2-yl)-8-(5-(methoxymethyl)-3,3-dimethylpiperazin-1-yl)-N-(3-methyloxetan-3- yl)imidazo[1 ,5-a]pyridine-6-sulfonamide

[0348] 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(5-(methoxymethyl)-3,3-dimethylpiperazin-1 -yl)-N-(3- methyloxetan-3-yl)imidazo[1 ,5-a]pyridine-6-sulfonamide (80 mg, 0.148 mmol) was purified by preparative SFC (column: Chiralpak AS (250mm*30mm,10pm); mobile phase: A: CO2, B: MeOH(0.1 % NH3H2O); Gradient elution:0% to 20% B, 10 mins) to give two product solutions. The solution containing peak 1 was concentrated under reduced pressure and further lyophilized to give the product (R or S)-3-(5- (difluoromethyl)-l ,3,4-thiadiazol-2-yl)-8-(5-(methoxymethyl)-3,3-dimethylpiperazin-1 -yl)-N-(3- methyloxetan-3-yl)imidazo[1 ,5-a]pyridine-6-sulfonamide (34 mg, 0.0603 mmol, 40.86% yield) as a light yellow solid.

[0349] RT 0.558 min (LCMS method 4); m / z 558.2 (M+H)+(ESI+); RT 1 .223 min, (SFC Method 41); ee: 99.51 %,1H NMR (400 MHz, CDCI3) 9.87 (s, 1 H), 7.73 (s, 1 H), 7.08 (t, J = 53.6 Hz, 1 H), 6.63 (s, 1 H), 5.46 (br s, 1 H), 4.95-4.75 (m, 2H), 4.50-4.30 (m, 2H), 3.65-3.41 (m, 5H), 3.40 (s, 3H), 2.80-2.60 (m, 2H), 1.74 (s, 3H), 1.50 (s, 3H), 1.26 (s, 3H) The solution containing peak 2 was concentrated under reduced pressure and further lyophilized to give the product (S or R)-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(5-(methoxymethyl)-3,3- dimethylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)imidazo[1 ,5-a]pyridine-6-sulfonamide (29 mg, 0.0526 mmol, 35.62 % yield) as a light yellow solid.

[0350] RT 0.560 min (LCMS method 4); m / z 558.2 (M+H)+(ESP); RT 1.421 min, (SFC Method 41); ee: 98.19%;1H NMR (400 MHz, CDCh) 9.87 (s, 1 H), 7.73 (s, 1 H), 7.08 (t, J = 53.6 Hz, 1 H), 6.63 (s, 1 H), 5.47(br s, 1 H), 4.95-4.75 (m, 2H), 4.50-4.30 (m, 2H), 3.65-3.41 (m, 5H), 3.40 (s, 3H), 2.80-2.60 (m, 2H), 1.74 (s, 3H), 1.50 (s, 3H), 1.26 (s, 3H)

[0351] The following Table 1 provides an overview on the compounds described in the Example section.

[0352] Table 1. Summary of the structures of the prepared compounds.

[0353] It is to be understood that indicator “R or S” or conversely “S or R” refer to arbitrarily assigned configurations, in particular to the situation where it is known that both compounds are enantiomers of each other, but their absolute configurations remain unknown.

[0354] The example listed in the table below were produced using similar experimental procedures as reported for the example 1 Biological evaluation of the exemplary compounds

[0355] The compound of formula (I) was 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.

[0356] PARG protein expression and purification

[0357] A codon optimized gene encoding human PARG (448-976 [H446G, L447S, L473S, N479S, S802A, R811 K, M8411, S858P, I916T, 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.

[0358] 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.

[0359] PARG enzymatic IC50 assay

[0360] PARG enzyme as incubated with compound or vehicle (DMSO) for 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.

[0361] Materials: hPARG: Peak Protein, 30 nM

[0362] Substrate: ADP-pNP, 800 pM, Jena Bioscience catalog # NU-955

[0363] Reaction time: 60 minutes

[0364] Assay buffer: 50 mM Tris-HCI pH 8.0, 100 mM NaCI, 2 mM DTT

[0365] Temperature: 30 °C

[0366] Total volume: 30 pL

[0367] Controls:

[0368] • 0% inhibition control: DMSO

[0369] • 100% inhibition control: No enzyme

[0370] The protocol that was used for enzyme reaction and detection is as follows:

[0371] 1. Transfer 100 nL of the final concentration of test compounds or vehicle (DMSO) to the appropriate wells of a microtiter plate.

[0372] 2. Centrifuge the plate at 1000 rpm for 1 minute.

[0373] 3. Transfer 14.6 pL of 2x final concentration of enzyme in assay buffer or assay buffer alone to the appropriate wells.

[0374] 4. Centrifuge the plate at 1000 rpm for 1 minute.

[0375] 5. Incubate the plate at room temperature for 2 hours.

[0376] 6. Transfer 15.4 pL of 2x substrate in assay buffer to all the test wells.

[0377] 7. Centrifuge the plate at 1000 rpm for 1 minute.

[0378] 8. Read the plate on a plate reader (e.g. , Spark Tecan).

[0379] The Absorbance I C50 value of compounds of Formula (I) in Example 1 is provided in Table 2 below.

[0380] Cellular PAR chain assay

[0381] 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) (250pM). 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 EC50 values:

[0382] The PAR chain EC50 value for compounds of Formula (I) in Example 1 is provided in Table 2 below. Cellular Viability Assay

[0383] NCI-H460 and MDA-MB-436 as PARG-inhibition sensitive cell lines, and U2OS as PARG-inhibition insensitive cell line, were plated at 1000 cells / well, 5000 cells / well and 2000 cells / well, respectively, in 96- well white plates with clear flat bottom. The outer wells of the plate were excluded and filled with PBS to compensate for evaporation-mediated effects in the plate periphery. After 24 hours, the compounds were added with the Tecan digital dispenser (D300e), in duplicates. After 96 hours of incubation of NCI-H460 and U2OS cells and after 120 hours of incubation of MDA-MB-436 cells, 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) for NCI-H460 and U2OS cell lines, and a 2104 EnVision plate reader for MDA-MB-436. 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:

[0384] The PARGi (NCI-H460, MDA-MB-436 and U2OS) cellular viability EC50 values for compounds of Formula (I) are provided in Table 2 below. hERG assay

[0385] Compounds were solubilised to 33mM in DMSO before dilution in HBPS to 100mM. 8-Point concentration-response curves were generated using serial dilutions from the top test concentration.

[0386] Electrophysiological recordings were made from a Chinese Hamster Ovary cell lines stably expressing the full-length hERG ion channel (human Kv11 .1 ). Single cell ionic currents were measured in whole-cell configuration at room temperature (25°C) using a QPatch II automated electrophysiology platform (Sophion Bioscience). The internal solution for hERG contained (mM): 120 KCI, 5.374 CaCh, 1.75 MgChJOEGTA, 10 HEPES and was buffered to pH 7.3 with KOH. The external solution (HEPES- buffered saline, HBPS) contained (mM): 138 NaCI, 4.5 KCI, 1 .8 CaCI2, 1 .0 MgCI2, 10 HEPES, 10 glucose, buffered to pH7.4 with NaOH. Cells were clamped at a holding potential of -80mV. After a depolarising step to +40mV for 1500ms, cells were repolarised to -40mV for 1500ms. Currents were measured from the second step and referenced to the holding current. Compounds were incubated for 120 seconds. Concentration-response curves were generated by cumulative addition of compound with concentrations low to high. In all cases, steady-state inhibition was achieved before the next concentration of compound was added.

[0387] Table 2: Inhibition of PARG and cellular activity of compounds according to the present invention.

[0388] The IC50 (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.

[0389] (T) Example number

[0390] (D IC50 in pM determined in PARG enzymatic assay (PARG protein and 2 hours incubation) described under PARG enzymatic I C50 assay

[0391] (3) EC50 in pM determined in cellular assay as described under Cellular PAR chain assay (conditions with treatment of TMZ).

[0392] (4) EC50 in pM determined in cellular assay as described under Cellular PAR chain assay (conditions without treatment of TMZ).

[0393] (5). EC50 in pM determined in NCIH-460 cells as described under Cellular viability assay.

[0394] (6) EC50 in pM determined in U2OS cells as described under Cellular viability assay.

[0395] (7) EC50 in pM determined in MDA-MB-436 cells as described under Cellular viability assay

[0396] (§) Human CLint (liver) [mL / min / kg]

[0397] ® hERG IC50 (pM)

[0398] Table 2.

[0399] Further assays

[0400] Kinetic solubility assay

[0401] 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:

[0402] 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.

[0403] 2. Test compounds and controls (10 mM in DMSO, 10 pL / tube) were added into the buffer (490 pL / well) which were placed in a Mini-UniPrep filter. The buffer was prepared as the customer’s requirement.

[0404] 3. The kinetic solubility samples were vortexed for 2 minutes.

[0405] 4. The solubility solutions were shaked in an orbital shaker for 24 hr at room temperature.

[0406] 5. 200 pL of each solubility solution were transferd into a 96-deep well for analysis when the samples were directly filtered by the syringeless filter device.

[0407] 6. The test compound concentration of the filtrate were determined using HPLC-UV.

[0408] 7. Three UV standard solutions were injected into HPLC from low to high concentrations, followed by testing of the K.S. supernatant. Testing samples were injected in duplicate.

[0409] Bidirectional permeability in Caco2

[0410] The bidirectional permeability in Caco-2 cells assay was performed for the exemplary compounds of formula (I) according to the following protocol:

[0411] 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 21stto 28thday for confluent cell monolayer formation.

[0412] 2. The integrity of the monolayer was verified by performing Lucifer yellow rejection assay.

[0413] 3. The quality of the monolayer was verified by measuring the unidirectional (A—B) permeability of fenoterol / nadolol (low permeability marker), propranolol / metopronolol (high permeability marker) and bi-directional permeability of digoxin (a P-glycoprotein substrate marker) in duplicate wells. 4. Standard assay conditions for test compounds:

[0414] -test concentration: 2 pM (DMS0<1 %);

[0415] -replicates: n=2;

[0416] -directions: bi-directional transport including A^B and B-*A;

[0417] -incubation time: single time point, 2 hours;

[0418] -transport buffer: HBSS containing 10 mM HEPES, pH7.40 ± 0.05;

[0419] -incubation condition: 37±1 °C, 5% CO2, relatively saturated humidity.

[0420] 5. Dosing solution were spiked and mixed with transport buffer and stop solution (containing an appropriate internal standard (IS)) as TO sample.

[0421] 6. At the end of incubation, sample solutions from both donor and receiver wells were mixed with stop solution immediately.

[0422] 7. All samples including TO samples, donor samples and receiver samples were analyzed using LC / MS / MS. Concentrations of test compound were expressed as peak area ratio of analytes versus IS without a standard curve.

[0423] Liver Microsomes Stability Assay

[0424] 1 . Materials

[0425] 1.1 Liver microsomes

[0426] Animal or human liver microsomes were purchased from Xenotech or Corning and stored in a freezer (lower than -60°C) before use.

[0427] 1 .2 p-nicotinamide adenine dinucleotide phosphate reduced form, tetrasodium salt, Vendor: Chem-lmpex International, Cat.No. 00616

[0428] 1 .3 Control compounds: Testosterone, diclofenac and propafenone.

[0429] 2. Preparation of Working Solution

[0430] Stock Solution: 10 mM test compound in DMSO.

[0431] Working solution: 100 pM test or control compounds in 100% acetonitrile (concentration of organic solvent: 1 % (v / v) DMSO and 99% (v / v) acetonitrile)

[0432] 3. Assay Procedure

[0433] A total of two sample plates with 96-well format were prepared for incubation, labelled as 'Incubation' T60 and 'Incubation' NCF60. Empty 'Incubation' T60 and NCF60 plates were pre-warmed for 10 min minutes. Liver microsomes were diluted to 0.56 mg / mL in 100 mM phosphate buffer. Microsome working solutions (0.56 mg / mL) were transferred (445 pL) into pre-warmed 'Incubation' T60 and NCF60 plates, followed by incubation for 10 min at 37°C with constant shaking.

[0434] Liver microsomes (54 pL) were transferred to a Blank60 plate, followed by the addition of 6 pL NAPDH cofactor and 180 pL stop solution (acetonitrile containing internal standards) into each well.

[0435] An aliquot (5 pL) of compound working solution (100 pM) was added into the 'incubation' plates (T60 and NCF60) containing microsomes and mixed 3 times thoroughly.

[0436] For the 'Incubation' NCF60 plate, 50 pL of buffer was added and mixed 3 times thoroughly. The plates were incubated at 37°C for 60 min while shaking, samples were mixed once and 60 pL was transferred from the NCF60 incubation plate to the stop plate containing stop solution after the 60-min incubation.

[0437] Stop solution (180 pL) and NAPDH cofactor (6 pL) were added to 'Quenching' plate TO. Plates were chilled to prevent evaporation.

[0438] For the 'Incubation' T60 plate: mixed 3 times thoroughly, and immediately removed 54 pL mixture for the 0-min time point to stop plate ('Quenching' plate TO). NAPDH cofactor (44 pL) was added to the 'Incubation' T60 plate. The plate was incubated at 37°C for 60 min while shaking. At 5, 15, 30, 45, and 60 min, 180 pL stop solution was added to the 'Quenching' plates, samples were mixed once, and 60 pL was serially transferred from 'Incubation' T60 plate per time point.

[0439] Consequently, for the wells containing the test or control compounds, the final concentration was 1 pM for test compounds, testosterone, diclofenac and propafenone, 0.5 mg / mL for animal or human liver microsomes, 0.01 % (v / v) for DMSO and 0.99% (v / v) for acetonitrile.

[0440] All sampling plates were shaken for 10 min, then centrifuged at 3220 xg for 20 minutes at 4°C. Supernatant (80 pL) was transferred into 240 pL HPLC water, and mixed by plate shaker for 10 min. Each bioanalysis plate was sealed and shaken for 10 minutes prior to LC-MS / MS analysis.

[0441] 4. Bioanalytical Analysis

[0442] Concentrations of test conpounds and positive controls, testosterone, diclofenac and propafenone in the samples were determined by using a liquid chromatography-tandem mass spectrometry (LC- MS / MS) method.

[0443] 5. Data Calculation

[0444] In the determination of the in vitro elimination constant, ke, of test compound and control compounds, the peak area ratios (PAR) of analyte / internal standard were used to calculate the percentage of remaining (%Remaining) with the following equation:

[0445] ° / Remaining - °fanaiytct° internal standard at each timepointxgg

[0446] PAR of analyte to internal standard at T = 0

[0447] CLint(mic) = 0.693 1 T1 / 2 / mg microsome protein per mL

[0448] CLint(liver) = CLint(mic) x mg microsomal protein / g liver weight x g liver weight / kg body weight

[0449] According to the well-stirred model, hepatic intrinsic clearance and hepatic clearance can be calculated by the following formula.

[0450] CL(liver) = (CLint(liver) x fu x Qh) / (CLint(liver) x fu + Qh)

[0451] The default value of fu(the fraction unbound in blood) is assumed as 1 .

[0452] The parameters in equations are listed in following table.

[0453] When the %Remaining value at the maximal incubation time, which was 60 min in this study, was higher than 75%, it is considered to be within the acceptable experimental variation, i.e., CV =25%. Therefore, a corresponding T1 / 2 value of >145 min is reported. Consequently, the corresponding CLint(mic)value is reported as <9.6 pL / min / mg protein.

[0454] 6. References

[0455] [1] Brian Davies and Tim Morris, Physiological Parameters in Laboratory Animals and Human. Pharmaceutical Research, Vol. 10 No.7, 1993

[0456] [2] Journal of Pharmacology and Experimental Therapeutics, 1997, 283(1): 46-58 Hepatocyte Metabolic Stability

[0457] 1 . Materials

[0458] 1.1 Hepatocyte

[0459] Animal or human hepatocytes were purchased from Bioreclamation I VT or RILD.

[0460] 1 .2 Control compounds: 7-Ethoxycoumarin and 7-Hydroxycoumarin

[0461] 2. Preparation of Working Solution

[0462] Stock Solution: 10 mM test compound and 30 mM control compound in DMSO.

[0463] Working solution: 100 pM test compound or 300 pM control compounds in 100% acetonitrile (Concentration of organic solvent: 1 % (v / v) DMSO and 99% (v / v) acetonitrile)

[0464] 3. Assay Procedure

[0465] Cryopreserved hepatocytes were thawed, isolated, and suspended in Williams’ Medium E, then diluted with pre-incubated Williams’ Medium E to a final concentration of 0.510x106 cells / mL.

[0466] One hundred and ninety-eight (198) pL of cells suspension (0.510x106 cells / mL) were added into appropriate wells. The incubation plate was pre-incubated in a 37.0°C incubator for about 10 minutes. Then 2 pL of test compound and positive controls were added into plate except for the blank plate. Incubate all plates at 37.0°C in a 95.0% humidified incubator at 5.0% CO2 to start the reactions with constant shaking.

[0467] For the TO plate, a corresponding quenching plate was prepared by adding 125 pL / well of acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (stop solution), and 25 pL / well of the incubation sample were transferred to this plate after shaking for 1 minute to ensure homogeneity.

[0468] At each time-point, the corresponding plate was removed from the incubator, and 25 pL / well of the corresponding sample was transferred to its corresponding quenching plate containing 125 pL / well of stop solution. Medium control (MC) plates (T0-MC and T90-MC) were prepared by adding everything except for Williams’ Medium E at the corresponding time-points.

[0469] The plates were then sealed and shaken for 10 minutes prior to centrifugation at 4000 rpm and 4°C for 20 minutes. 80 pL / well of the resulting supernatant were diluted with 240 pL / well of pure water and sealed and shaken for 10 minutes prior to LC-MS / MS analysis. 4. Bioanalytical Analysis

[0470] Concentrations of test compounds and positive controls, 7-Ethoxycoumarin and 7- Hydroxycoumarin in the samples were determined by using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[0471] 5. Data Calculation

[0472] In the determination of the in vitro elimination constant, ke, of test compound and control compounds, the peak area ratios (PAR) of analyte / internal standard were used to calculate the percentage of remaining (%Remaining) with the following equation: e e

[0473] CLint (hep) = k I million cells per mL

[0474] CLint (liver)=CLint (hep) x liver weight (g / kg body weight) x hepatocellularity

[0475] According to the well-stirred model, hepatic intrinsic clearance and hepatic clearance can be calculated by the following formula.

[0476] CL(liver) - (CLint(liver) X fuX Qh) / (CLint(liver) X fu+ Qh)

[0477] The default value of fu (the fraction unbound in blood) is assumed as 1 .

[0478] The parameters in equations are listed in following table.

[0479]

[0480] When the %Remaining value at the maximal incubation time, which was 90 min in this study, was higher than 75%, it is considered to be within the acceptable experimental variation, i.e., CV =25%. Therefore, a corresponding T1 / 2 value of >216.8 min is reported. Consequently, the corresponding CLint(hep) (pL / min / 106 cells) is reported as <7.5.

[0481] 6. References

[0482] [1] Anna-Karin Sohlenius-Sternbeck. Determination of the hepatocellularity number for human, dog, rabbit, rat and mouse livers from protein concentration measurements. Toxicology in Vitro, Vol. 20 No.8, 2006

[0483] [2] Brian Davies and Tim Morris, Physiological Parameters in Laboratory Animals and Human. Pharmaceutical Research, Vol. 10 No.7, 1993

[0484] [3] Obach R S, Baxter J G, Liston T E, et al. The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data [J], Journal of Pharmacology and Experimental Therapeutics, 1997, 283(1): 46

Claims

New PCT-Patent Application based on US 63 / 595,060 FoRx Therapeutics AG Vossius Ref.: AF3731 PCT BSClaims1. A compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1 is -H, -CN, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-O-(C1-2 alkyl);R2 is -H or -F, andR3 is selected from -H, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and -CN, wherein said alkyl, said alkenyl, and said alkynyl are each optionally substituted with one or more groups independently selected from RS1, orR2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more groups independently selected from RS2;X2 is C-YC2-RC2;YC2is 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-s alkyl)- , -CO-, -S-, -SO-, and -SO2-, and wherein said cycloalkylene and heterocycloalkylene are each optionally substituted with one or more groups independently selected RS2;RC2 is selected from hydrogen, halogen, -OH, -NH2, -SH, -CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl;wherein said alkyl, alkenyl, and alkynyl in X2 are each optionally substituted with one or more groups independently selected from RS1, and wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl in Xj are each optionally substituted with one or more groups independently selected from RS2;R4 is a five membered heteroaryl, optionally substituted with one or more groups independently selected from RS2;R5 is selected from -H, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, cyclopropyl, cyclobutyl, oxetanyl, and halogen;RS1is selected from halogen, -CN, -OH, -0(C1-5 alkyl), -0(C1-5 haloalkyl), C1-5 haloalkyl, -SH, -S(C1-5 alkyl), -SO2(C1-5 alkyl), -S(O)(NH)(C1-5 alkyl), -S(O)(N-CI-3alkyl)(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(CI-5haloalkyl), -N(C1-5 alkyl)(C1-5 alkyl), -N(C1-5 haloalkyl)(C1-5 alkyl), -(A / -heterocycloalkyl), -CO(C1-s alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -C0-(N- heterocycloalkyl), -NHCO-(C1-5 alkyl), -N(C1-5 alkyl)-CO-(C1-5 alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -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); andRS2is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -0(C1-5 alkyl), -O(C1-s haloalkyl), -SH, -S(C1-5 alkyl), -S(O)(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), -S(O)(C1-5 haloalkyl), -SO2(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), -( / V-heterocycloalkyl), -CO(C1-5 alkyl), -COOH, -COO(C1-5 alkyl), -CONH2I-CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -C0-(N- heterocycloalkyl), -NHCO-(C1-5 alkyl), -N(C1-5 alkyl)-CO-(C1-5 alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -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)-S(0)(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(0)(C1-5 alkyl)(C1-5 alkyl), -(C1-5 alkylene)-S(C1-5 haloalkyl), -(C1-5 alkylene)- S(O)(C1-5 haloalkyl), -(C1-5 alkylene)-S(O)2(C1-5 haloalkyl), -(C1-5 alkylene)-P(O)(C1-s 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-s 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), -COO-(C1-5 alkylene)-NH2, -COO-(C1-5 alkylene)-NH(C1-5 alkyl), -COO-(C1-5 alkylene)-NH(C1-s haloalkyl), - COO-(C1-5 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), -COO-(C1-5 alkylene)-N(C1-5 alkyl)(C1-5 haloalkyl), - COO-(C1-5 alkylene)-(N-heterocycloalkyl), -COO-(C1-5 alkylene)-N(C1-5 haloalkyl)(C1-5 alkyl), -(C1- 5 alkylene)-CO(C1-5 alkyl), -(C1-5 alkylene)-COO(C1-5 alkyl), -(C1-5 alkylene)-COOH, -(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-(A / -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).

2. The compound of claim 1 , wherein R1 is methyl or fluoromethyl.

3. The compound of claim 1 , wherein R1 is -CN.

4. The compound of any one of claims 1 to 3, whereinR2is -H or -F, andR3 is selected from -H, halogen, C1-6 alkyl, C2-e alkenyl, C2-e alkynyl, C1-6 haloalkyl, and -CN, wherein said alkyl, said alkenyl, and said alkynyl are each optionally substituted with one or more groups independently selected from RS1.

5. The compound of claim 4, wherein R2is -H.

6. The compound of claim 4 or 5, wherein R3 is selected from -H, and C1-2alkyl.

7. The compound of any one of claims 1 to 6, wherein -Yc2-Rc2 is selected from heterocycloalkyl, and heterocycloalkenyl, wherein said heterocycloalkyl, and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from RS2.

8. The compound of claim 7, wherein9. The compound of any one of claims 1 to 8, wherein10. The compound of any one of claims 1 to 9, wherein R5 is H.

11. The compound of claim 1 , wherein the compound is selected from the following compounds or their pharmaceutically acceptable salts:

12. A pharmaceutical composition comprising the compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.

13. The compound of any one of claims 1 to 11 , or the pharmaceutical composition of claim 12, for use in therapy.

14. The compound of any one of claims 1 to 11 , or the pharmaceutical composition of claim 12, for treating a disease or disorder in which PARG activity is implicated.

15. The compound for use or the pharmaceutical composition for use of claim 14, for treating a proliferative disorder, preferably wherein the proliferative disorder is cancer, preferably a human cancer.

16. The compound for use or the pharmaceutical composition for use of claim 15, wherein the proliferative disorder is cancer, selected from breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, colorectal cancer, gastric cancer, skin cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, esophageal cancer, kidney cancer, colorectal cancer, stomach cancer, thyroid cancer, lymphoma, leukemia, melanoma, uterine cancer, mantlecell lymphoma, renal cell carcinoma, appendicle cancer, hematologic cancer, MYH-related polyposis, gallbladder cancer, bile duct cancer, testicular cancer, bone cancer, and head and neck cancer.

17. The compound for use or the pharmaceutical composition for use of claim 15, wherein the proliferative disorder is cancer, selected from lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin cancer.

18. Use of the compound of any one of claims 1 to 1 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a proliferative condition.

19. The use of claim 18, wherein the proliferative condition is cancer, preferably a human cancer.

20. The use of claim 19, wherein the proliferative disorder is cancer, selected from breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, colorectal cancer, gastric cancer, skin cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, esophageal cancer, kidney cancer, colorectal cancer, stomach cancer, thyroid cancer, lymphoma, leukemia, melanoma, uterine cancer, mantle cell lymphoma, renal cell carcinoma, appendicle cancer, hematologic cancer, MYH-related polyposis, gallbladder cancer, bile duct cancer, testicular cancer, bone cancer, and head and neck cancer.21 . The use of claim 19, wherein the proliferative disorder is cancer, selected from lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin cancer.

22. Use of the compound of any one of claims 1 to 11 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of disease or disorder in which PARG activity is implicated.

23. A method of treating a disease or disorder in which PARG activity is implicated, the method comprising the step of administering a therapeutically effective amount of the compound of claim 1 to a subject in need thereof.

24. A method of treating a proliferative disease, the method comprising the step of administering atherapeutically effective amount of the compound of claim 1 to a subject in need thereof.

25. The method according to claim 24, where the proliferative disorder is cancer, preferably a human cancer.

26. The method according to claim 25, wherein the proliferative disorder is cancer, selected from breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, colorectal cancer, gastric cancer, skin cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, esophageal cancer, kidney cancer, colorectal cancer, stomach cancer, thyroid cancer, lymphoma, leukemia, melanoma, uterine cancer, mantle cell lymphoma, renal cell carcinoma, appendicle cancer, hematologic cancer, MYH-related polyposis, gallbladder cancer, bile duct cancer, testicular cancer, bone cancer, and head and neck cancer.

27. The method according to claim 25, wherein the proliferative disorder is cancer, selected from lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin cancer.

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