PARG inhibitory compounds

Abstract

The present invention relates to a compound of formula (I), (I): or a pharmaceutically acceptable salt thereof. The present invention further relates to the compound of formula (I), (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] PARG inhibitory compounds

[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] Further compounds particularly useful as PARG inhibitors are disclosed in documents WO 2024 / 074497 and WO 2023 / 183850.

[0015] Further PARG inhibitors are disclosed in document WO 2024 / 002284.

[0016] Summary of the invention It was an objective technical problem of the present invention to provide compounds that are cell- permeable inhibitors of PARG. The technical problem of the present invention is solved by the embodiments described herein and as characterized by the claims.

[0017] Accordingly, in a first embodiment, the present invention provides a compound of formula (I): or a pharmaceutically acceptable salt thereof.

[0018] 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. It is to be understood that whenever reference is made to a compound of formula (I), a direct reference to a compound of formula (II) is also meant.

[0019] In a further embodiment, the present invention relates to the compound of formula (I) of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of the present invention, for use in therapy.

[0020] The compounds of formula (I) are useful for treating a disease or disorder in which PARG activity is implicated.

[0021] 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.

[0022] Definitions

[0023] The following definitions apply throughout the present specification and the claims, unless specifically indicated otherwise.

[0024] 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.

[0025] The term “hydrocarbon group” refers to a group consisting of carbon atoms and hydrogen atoms.

[0026] The term “alicyclic” is used in connection with cyclic groups and denotes that the corresponding cyclic group is non-aromatic. As used herein, the term “alkyl” refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group which may be linear or branched. Accordingly, an “alkyl” group does not comprise any carbon-to-carbon double bond or any carbon-to-carbon triple bond. A “C1-5 alkyl” denotes an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless defined otherwise, the term “alkyl” preferably refers to C1-4 alkyl, more preferably to methyl or ethyl, and even more preferably to methyl.

[0027] As used herein, the term “alkenyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. The term “C2-5 alkenyl” denotes an alkenyl group having 2 to 5 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1 -en-1-yl, prop-1 -en-2-yl, or prop-2-en-1 -yl), butenyl, butadienyl (e.g., buta-1 ,3-dien-1-yl or buta-1 ,3- dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless defined otherwise, the term “alkenyl” preferably refers to C2-4 alkenyl.

[0028] 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.

[0029] 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.

[0030] As used herein, the term “alkenylene” refers to an alkenediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. A “C2- 5 alkenylene” denotes an alkenylene group having 2 to 5 carbon atoms. Unless defined otherwise, the term “alkenylene” preferably refers to C2-4 alkenylene (including, in particular, linear C2-4 alkenylene). As used herein, the term “alkynylene” refers to an alkynediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds. A “C2-5 alkynylene” denotes an alkynylene group having 2 to 5 carbon atoms. Unless defined otherwise, the term “alkynylene” preferably refers to C2-4 alkynylene (including, in particular, linear C2-4 alkynylene).

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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).

[0036] As used herein, the term “heteroaryl” refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said aromatic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heteroaryl” may, e.g., refer to thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1- benzopyranyl or 4H-1 -benzopyranyl), isochromenyl (e.g., 1 H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 1 H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3- pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, p-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1 , 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.

[0037] As used herein, the term “heteroarylene” refers to a heteroaryl group, as defined herein above, but having two points of attachment, i.e. a divalent aromatic ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said aromatic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heteroarylene” may, e.g., refer to thienylene (i.e., thiophenylene; e.g., thien-2,3-diyl, thien-2,4-diyl, or thien-2,5-diyl), benzo[b]thienylene, naphtho[2,3-b]thienylene, thianthrenylene, furylene (i.e., furanylene; e.g., furan-2,3-diyl, furan-2,4-diyl, or furan-2,5-diyl), benzofuranylene, isobenzofuranylene, chromanylene, chromenylene, isochromenylene, chromonylene, xanthenylene, phenoxathiinylene, pyrrolylene, imidazolylene, pyrazolylene, pyridylene (i.e., pyridinylene), pyrazinylene, pyrimidinylene, pyridazinylene, indolylene, isoindolylene, indazolylene, indolizinylene, purinylene, quinolylene, isoquinolylene, phthalazinylene, naphthyridinylene, quinoxalinylene, cinnolinylene, pteridinylene, carbazolylene, p-carbolinylene, phenanthridinylene, acridinylene, perimidinylene, phenanthrolinylene, phenazinylene, thiazolylene (e.g., thiazol-2,4-diyl, thiazol-2,5-diyl, or thiazol-4,5-diyl), isothiazolylene (e.g., isothiazol-3,4-diyl, isothiazol-3,5-diyl, or isothiazol-4,5-diyl), phenothiazinylene, oxazolylene (e.g., oxazol-2,4-diyl, oxazol-2,5-diyl, or oxazol-4,5-diyl), isoxazolylene (e.g., isoxazol-3,4-diyl, isoxazol-3,5-diyl, or isoxazol-4,5-diyl), oxadiazolylene (e.g., 1 ,2,4-oxadiazol-3,5-diyl, 1 ,2,5-oxadiazol-3,4-diyl, or 1 ,3,4- oxadiazol-2,5-diyl), thiadiazolylene (e.g., 1 ,2,4-thiadiazol-3,5-diyl, 1 ,2,5-thiadiazol-3,4-diyl, or 1 ,3,4- thiadiazol-2,5-diyl), phenoxazinylene, pyrazolo[1 ,5-a]pyrimidinylene, 1 ,2-benzoisoxazolylene, benzothiazolylene, benzothiadiazolylene, benzoxazolylene, benzisoxazolylene, benzimidazolylene, benzo[b]thiophenylene (i.e., benzothienylene), triazolylene (e.g., 1 H-1 ,2,3-triazolylene, 2H-1 ,2,3- triazolylene, 1 H-1 ,2,4-triazolylene, or 4H-1 ,2,4-triazolylene), benzotriazolylene, 1 H-tetrazolylene, 2H-tetrazolylene, triazinylene (e.g., 1 ,2,3-triazinylene, 1,2,4-triazinylene, or 1 ,3,5-triazinylene), furo[2,3- c]pyridinylene, dihydrofuropyridinylene (e.g., 2,3-dihydrofuro[2,3-c]pyridinylene or 1 ,3-dihydrofuro[3,4-c]pyridinylene), imidazopyridinylene (e.g., imidazo[1 ,2-a]pyridinylene or imidazo[3,2-a]pyridinylene), quinazolinylene, thienopyridinylene, tetrahydrothienopyridinylene (e.g., 4, 5, 6, 7-tetrahyd rothieno[3, 2-c]pyridi nylene), dibenzofuranylene, 1 ,3-benzodioxolylene, benzodioxanylene (e.g., 1 ,3-benzodioxanylene or 1 ,4-benzodioxanylene), or coumarinylene. Unless defined otherwise, the term “heteroarylene” preferably refers to a divalent 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a “heteroarylene” refers to a divalent 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from 0, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. A “heteroarylene”, including any of the specific heteroarylene groups described herein, may be attached through two carbon ring atoms, particularly through those two carbon ring atoms that have the greatest distance from one another (in terms of the number of ring atoms separating them by the shortest possible connection) within one single ring or within the entire ring system of the corresponding heteroarylene.

[0038] 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).

[0039] 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).

[0040] 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, 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.

[0041] 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.

[0042] 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, 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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 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.

[0048] 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 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.

[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 “haloalky I” refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms which are selected independently from fluoro, chloro, bromo and iodo, and are preferably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group. “Haloalkyl” may, e.g., refer to -CF3, -CHF2, -CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3, or -CH(CF3)2. A particularly preferred “haloalkyl” group is -CF3.

[0053] The terms “bond” and “covalent bond” are used herein synonymously, unless explicitly indicated otherwise or contradicted by context. As used herein, the terms “optional”, “optionally” and “may” denote that the indicated feature may be present but can also be absent. Whenever the term “optional”, “optionally” or “may” is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, the expression “X is optionally substituted with Y” (or “X may be substituted with Y”) means that X is either substituted with Y or is unsubstituted. Likewise, if a component of a composition is indicated to be “optional”, the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.

[0054] 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.

[0055] 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.

[0056] 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).

[0057] 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.

[0058] 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.

[0059] 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).

[0060] Detailed description of the invention

[0061] 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.

[0062] In a first embodiment, the present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof.

[0063] In formula (I), Z is selected from: optionally substituted by one or more group independently selected from Rs1.

[0064] Preferably, Z is selected from:

[0065]

[0066] More preferably, Z is selected from:

[0067] Again more preferably, Z is selected from: Alternatively, if Z moiety may have the following configuration:

[0068] Alternatively, if Z moiety i may have the following configuration

[0069] Preferably,

[0070] In formula (I), R1, R2 and R3 in Z are as defined in the following.

[0071] R1 is -H, -CN, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-0-(Ci-2 alkyl);

[0072] R2 is -H, C1-2 alkyl or -F, and

[0073] R3 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, or

[0074] 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.

[0075] Accordingly, 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)-0-(Ci-2 alkyl).

[0076] Preferably, R1 is -CN, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-0-(Ci-2 alkyl).

[0077] R1 is more 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 Ri is CD3. In an alternative embodiment, Ri is fluoromethyl. In again an alternative embodiment, Ri is -CN.

[0078] R2 is -H, C1-2 alkyl (such as methyl) or -F. Preferably, R2 is -H or F. More preferably, R2 is -H.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] It is preferred that in R3 said alkyl, said alkenyl, and said alkynyl are not substituted.

[0084] 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).

[0085] 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 R3 are as defined hereinabove. In a particularly preferred embodiment, Ri is methyl, R2 is H and R3 is methyl.

[0086] In one embodiment, Ri, R2 and R3 may each be H. In one embodiment, Ri is as defined herein, including any preferred definition of Ri, and R2 and R3 may each be H. In one embodiment, Ri is methyl, R2 is -CN and R3 is H. In a particularly preferred embodiment, Ri is methyl, R2 is H and R3 is H.

[0087] Further a proviso applies that preferably , then Ri is not H and / or at least one of R2 and R3 is not -H. In other words, preferably then at least one of Ri , R2, and

[0088] Ra is not -H. In formula (I), R4 is a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, optionally substituted with one or more groups independently selected from Rs2.

[0089] Preferably, R4 is a heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, optionally substituted with one or more groups independently selected from Rs2.

[0090] More preferably, R4 is aryl or heteroaryl, optionally substituted with one or more groups independently selected from Rs2.

[0091] Even more preferably R4 is heteroaryl, optionally substituted with one or more groups independently selected from Rs2.

[0092] Still more preferably, more preferably R4 is five membered heteroaryl, optionally substituted with one or more groups independently selected from Rs2.

[0093] Again more preferably, R4 is five membered heteroaryl, substituted at position 3 with respect to its empty valence with -CHF2 or -CF3, preferably with CHF2. / S\ ^CHF2

[0094] \\ / /

[0095] It is particularly preferred that R4 is N-N

[0096] In formula (I), Rs is selected from -H, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, cyclopropyl, cyclobutyl, oxetanyl, and halogen.

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

[0098] More preferably, Rs is selected from -H, C1-2 alkyl, and halogen.

[0099] Even more preferably, Rs is selected from -H and halogen.

[0100] Still more preferably, Rs is H. However, in one embodiment, Rs is Hal, such as Cl. In one embodiment, Rs is F.

[0101] In formula (I), -A-L1-L2-L3 is defined as outlined in the following.

[0102] In formula (I), A is selected from:

[0103] - 1 ,4-phenylene, optionally substituted with one or more groups independently selected from RS2,

[0104] - heteroarylene (such as 1 ,4-(six-membered heteroarylene)), optionally substituted with one or more groups independently selected from Rs2, and

[0105] - heterocycloalkylene or heterocycloalkenylene (such as 1 ,4-piperazinylene), optionally substituted with one or more groups independently selected from Rs2.

[0106] Particularly preferred 1 ,4-phenylene that is optionally substituted as disclosed herein, is selected from:

[0107] herein, in these formulas the bottom empty valence of A is connected to Li.

[0108] Particularly preferred heteroarylene is a 1,4-(six-membered heteroarylene), optionally substituted with one or more groups independently selected from Rs2. Particularly preferred six-membered heteroarylene is pyridinylene, i.e. 2, 5-pyridinylene, which is optionally substituted with one or more groups independently selected from Rs2. For example, A being heteroarylene is selected from: . Preferably, A is selected from understood herein, in these formulas the bottom empty valence of A is connected to Li.

[0109] A further suitable example of heteroarylene as A is five-membered heteroarylene, such as 1 ,3- (five-membered-heteroarylene), for example a thienylene (such as 1 ,3-thienylene).

[0110] Heterocycloalkylene or heterocycloalkenylene in A, as defined herein, is preferably, a sixmembered heterocycloalkylene or a six-membered heterocycloalkenylene, respectively. If A is heterocycloalkylene or heterocycloalkenylene, optionally substituted with one or more groups independently selected from Rs2, preferably A is heterocycloalkylene, optionally substituted with one or more groups independently selected from Rs2. More preferably, A is 1 ,4-piperazinylene, optionally substituted with one or more groups independently selected from Rs2. Thus, preferably, A is selected from , , valence of A, as depicted in provided formulae, is connected to Li.

[0111] In formula (I), Li is selected from -SO(NRH)-, -S(NRH)(NRH)-, -SO(NRH)-NRH-, -SO2-O-, -SO2-NRH- , -CO-NRH-, -C(=NCN)-NRH-, -SO(=N-SO2-(CI-5 alkyl), -CH2-CO-, -CO-, -CO-O-, and -CO-(A / - heterocycloalkylene)-, wherein the left empty valence connected to A and the right empty valence is connected to L2, wherein RH is H or C1-5 alkyl, wherein said alkyl is optionally substituted with one or more groups selected from -OH and Hal.

[0112] It is preferred that Li is selected from -SO(NRH)-, -S(NRH)(NRH)-, -SO(NRH)-NRH-, -SO2-O-, -SO2- NRH-, -CO-NRH-, and -C(=NCN)-NRH-, wherein the left empty valence connected to A and the right empty valence is connected to L2, wherein RH is H or C1-5 alkyl, wherein said alkyl is optionally substituted with one or more groups selected from -OH and Hal.

[0113] Preferably, Li is selected from -SO(NRH)-, -S(NRH)(NRH)-, -SO2-NRH-, and -CO-NRH-, wherein the left empty valence connected to A and the right empty valence is connected to L2, wherein RH is H or C1- 5 alkyl, wherein said alkyl is optionally substituted with one or more groups selected from -OH and Hal.

[0114] More preferably, Li is selected from -SO(NRH)-, -SO2-NRH-, and -CO-NRH-, wherein the left empty valence connected to A and the right empty valence is connected to L2, wherein RH is H or C1-5 alkyl, wherein said alkyl is optionally substituted with one or more groups selected from -OH and Hal.

[0115] Suitable -SO(NRH)- include -SO(NH)- and -SO(NCH3)-. Suitable -SO2-NRH- include -SO2-NH- and -SO2-N(CH3)-. Suitable -CO-NRH- include -CONH- and -CON(CH3)-.

[0116] Accordingly, it is particularly preferred that Li is selected from -SO(NH)-, -SO(NCH3)-, -SO2-NH-, -SO2-N(CH3)-, -CONH- and -CON(CH3)-.

[0117] Again more preferably, Li is -SO(NH)- or -SO(NCH3)-.

[0118] Still more preferably, Li is -SO(NH)-.

[0119] However, Li may also be, in one preferred embodiment, -CONH- or -CON(CH3)-.

[0120] Alternatively, -A-L1- may be according to formula: wherein the six-membered ring is optionally substituted with one or more groups independently selected from Rs2, wherein the bottom empty valence is connected to L2.

[0121] However, it is preferred that -A-L1- is not according to formula: as described herein.

[0122] In formula (I), -L2- is a bond, C1-4 alkylene, or C3-6 cycloalkylene, preferably -L2- is a bond or C1-4 alkylene, more preferably -L2- is C1-4 alkylene. Preferably, said C1-4 alkylene is a linear alkylene. More preferably, said C1-4 alkylene is a linear C2-3 alkylene. Even more preferably, L2 is -CH2CH2-. However, in one embodiment, -L2- is a bond, or in other words. It is absent.

[0123] In formula (I), L3 is selected from -OH, -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci 5 alkyl), -N(CI-5 alkyl)(cycloalkyl) , -N(CI-5 alkyl)(heterocycloalkyl), -NH(cycloalkyl), -NH(heterocycloalkyl), heterocycloalkyl, / V-heterocycloalkyl, and -N=S(O)(CI-5 alkyl)(Ci 5 alkyl), wherein said alkyl is optionally substituted with one or more groups selected from -OH and Hal, and wherein said heterocycloalkyl, said cycloalkyl and said / V-heterocycloalkyl are each optionally substituted with one or more groups independently selected from Rs2. Particularly preferred cycloalkyl, heterocycloalkyl and N- heterocycloalkyl moieties are 4-7 membered cycloalkyl, heterocycloalkyl and N-heterocycloalkyl, respectively.

[0124] It is preferred that L3 is selected from -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -N(CI-5 alkyl)(cycloalkyl) , -N(CI-5 alkyl)(heterocycloalkyl), -NH(cycloalkyl), -NH(heterocycloalkyl), heterocycloalkyl, / V-heterocycloalkyl, and -N=S(O)(CI-5 alkyl)(Ci 5 alkyl), wherein said alkyl is optionally substituted with one or more groups selected from -OH and Hal, and wherein said heterocycloalkyl, said cycloalkyl and said / V-heterocycloalkyl are each optionally substituted with one or more groups independently selected from Rs2. Particularly preferred cycloalkyl, heterocycloalkyl and N- heterocycloalkyl moieties are 4-7 membered cycloalkyl, heterocycloalkyl and N-heterocycloalkyl, respectively. Preferably, L3 is selected from -NH(Ci-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -N(CI-5 alkyl)(cycloalkyl) , -N(CI-5 alkyl)(heterocycloalkyl), -NH(cycloalkyl), -NH(heterocycloalkyl), heterocycloalkyl and N- heterocycloalkyl, wherein said alkyl is optionally substituted with one or more groups selected from -OH and Hal, and wherein said heterocycloalkyl, said cycloalkyl and said / V-heterocycloalkyl are each optionally substituted with one or more groups independently selected from Rs2. Particularly preferred cycloalkyl, heterocycloalkyl and N-heterocycloalkyl moieties are 4-7 membered cycloalkyl, heterocycloalkyl and N-heterocycloalkyl, respectively.

[0125] More preferably, L3 is selected from -NH(Ci-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), heterocycloalkyl and / V-heterocycloalkyl, wherein said alkyl is optionally substituted with one or more groups selected from - OH and Hal, and wherein said heterocycloalkyl and said / V-heterocycloalkyl is optionally substituted with one or more groups independently selected from Rs2.

[0126] Even more preferably, L3 is selected from -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci 5 alkyl), and N- heterocycloalkyl, wherein said alkyl is optionally substituted with one or more groups selected from -OH and Hal, and wherein said / V-heterocycloalkyl is optionally substituted with one or more groups independently selected from Rs2.

[0127] Even more preferably, L3 is selected from -NH(CI-5 alkyl), and -N(CI-5 alkyl)(Ci 5 alkyl) wherein said alkyl is optionally substituted with one or more groups selected from -OH and Hal. It is however preferred that the alkyl is not substituted. Particularly preferred C1-5 alkyl group is methyl.

[0128] Thus, even more preferably, L3 is -NH(CH3) or -N(CH3)2. Accordingly, L3 may be -NH(CH3). Alternatively L3 may be -N(CH3)2.

[0129] Alternatively, in one embodiment, L3 is heterocycloalkyl or N-heterocycloalkyl, wherein said heterocycloalkyl and said / V-heterocycloalkyl is optionally substituted with one or more groups independently selected from Rs2. Said N-heterocycloalkyl may be N-morpholinyl or N-azetidinyl. More preferably, said N-heterocycloalkyl is N-azetidinyl. Said heterocycloalkyl may preferably be azetidinyl, preferably 3-azetidinyl.

[0130] In one embodiment, L3 is -OH or -NH2. Accordingly, L3 may be -OH. Alternatively, L3 may be -NH2.

[0131] Preferably, the following provision applies to -A-L1-L2-L3: -A-L1-L2-L3 is not: In formula (I), RS1is selected from halogen, -CN, -OH, -0(Ci-5 alkyl), -0(Ci-5 haloalkyl), C1-5 haloalkyl, -SH, -S(Ci-5 alkyl), -SO2(Ci-5 alkyl), -S(O)(NH)(Ci-s alkyl), -S(0)(N-CI-3 alkyl)(Ci-5 alkyl), -N=S(O)(CI-5alkyl)(Ci-5 alkyl), -S(Ci-5 haloalkyl), -P(O)(Ci-5alkyl)(Ci-5 alkyl), -P(O)(O-Ci-5alkyl) (O-C1-5 alkyl), -P(O)(O-Ci-5alkyl)(Ci-5 alkyl), -NH2, -NH(Ci-s alkyl), -NH(Ci-s haloalkyl), -N(Ci-s alkyl)(Ci-5 alkyl), -N(CI-5haloalkyl)(Ci-5 alkyl), -( / V-heterocycloalkyl), -CO(Ci-5alkyl), -CONH2, -CONH(CI-5alkyl), -CON(CI-5alkyl)(Ci-5 alkyl), -CO-( / V-heterocycloalkyl), -NHCO-(CI-5alkyl), -N(Ci-s alkyl)-C0-(Ci-5 alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci-5 alkyl), -N(Ci-5alkyl)CONH2, -N(Ci-5alkyl)CONH-(Ci-5alkyl), and -N(Ci-s alkyl)CON(Ci-5alkyl)(Ci-5 alkyl).

[0132] Preferably, RS1is selected from halogen, -CN, -OH, -0(Ci-5 alkyl), -0(Ci-5 haloalkyl), C1-5 haloalkyl, -SH, -S(Ci-5 alkyl), -S(Ci-5 haloalkyl), -NH2, -NH(CI-5 alkyl), -NH(Ci-5haloalkyl), -N(Ci-5alkyl)(Ci- 5 alkyl), -N(CI-5haloalkyl)(Ci-5 alkyl), -( / V-heterocycloalkyl), -CO(Ci-5alkyl), -CONH2, -CONH(CI-5alkyl), -CON(CI-5 alkyl)(Ci-5 alkyl), -CO-( / V-heterocycloalkyl), -NHCO-(CI-5alkyl), -N(CI-5alkyl)-C0-(Ci-5 alkyl), -NHCONH2, -NHCONH-(CI-5 alkyl), -NHCON(CI-5alkyl)(Ci-5 alkyl), -N(Ci-5alkyl)CONH2, -N(Ci-5alkyl)CONH-(Ci 5 alkyl), and -N(CI-5alkyl)CON(Ci-5alkyl)(Ci-5 alkyl).

[0133] More preferably, RS1is selected from halogen, -CN, -OH, -0(Ci-5 alkyl), -0(Ci-5 haloalkyl), C1-5 haloalkyl, -SH, -S(Ci-5 alkyl), -S(Ci-5 haloalkyl), -NH2, -NH(CI-5 alkyl), -NH(Ci-5haloalkyl), -N(Ci-5alkyl)(Ci- 5 alkyl), -N(CI-5haloalkyl)(Ci-5 alkyl), -( / V-heterocycloalkyl), -CONH2, -CONH(CI-5alkyl), -CON(Ci-s alkyl)(Ci-5alkyl), -CO-( / V-heterocycloalkyl), -NHCO-(Ci-s alkyl), -N(CI-5alkyl)-C0-(Ci-5 alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci-5 alkyl), -N(Ci-5alkyl)CONH2, -N(Ci-5alkyl)CONH-(Ci 5 alkyl), and -N(CI-5alkyl)CON(Ci-5alkyl)(Ci-5 alkyl).

[0134] Even more preferably, RS1is selected from halogen, -CN, -OH, -0(Ci-5 alkyl), -0(Ci-5 haloalkyl), C1-5 haloalkyl, -SH, -S(Ci-5 alkyl), -S(Ci-5 haloalkyl), -NH2, -NH(CI-5 alkyl), -NH(Ci-5haloalkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -N(CI-5 haloalkyl)(Ci-5 alkyl), and -( / V-heterocycloalkyl).

[0135] Even more preferably, RS1is selected from halogen, -CN, -OH, -SH, and -NH2.

[0136] In formula (I), Rs2is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -0(Ci-5 alkyl), - O(Ci-5haloalkyl), -SH, -S(Ci-5alkyl), -S(0)(Ci-5 alkyl), -SO2(Ci-5 alkyl), -S(O)(NH)(Ci-s alkyl), -S(O)(N-Ci- 3 alkyl)(Ci-5alkyl), -N=S(O)(Ci-s alkyl)(Ci-5 alkyl), -S(Ci-5haloalkyl), -S(O)(Ci-5haloalkyl), -SO2(Ci-5 haloalkyl), -P(0)(Ci-5 alkyl)(Ci-5 alkyl), -P(O)(O-Ci-5alkyl)(O-Ci-5alkyl), -P(O)(O-Ci-5alkyl)(Ci-5alkyl), -NH2, -NH(CI-5 alkyl), -NH(CI-5 haloalkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -N(Ci-5haloalkyl)(Ci-5 alkyl), - ( / V-heterocycloalkyl), -CO(Ci-5 alkyl), -COOH, -COO(Ci-5alkyl), -CONH2, -CONH(CI-5alkyl), -CON(Ci-s alkyl)(Ci-5alkyl), -CO-( / V-heterocycloalkyl), -NHCO-(Ci-s alkyl), -N(CI-5alkyl)-C0-(Ci-5 alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci-5 alkyl), -N(Ci-5alkyl)CONH2, -N(Ci-5alkyl)CONH-(Ci 5 alkyl), and -N(Ci-s alkyl)CON(Ci-5alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-0(Ci-5 alkyl), -(C1-5 alkylene)-0(Ci-5 haloalkyl), -(C1-5 alkylene)-SH, -(C1-5 alkylene)-S(Ci-5 alkyl), -(C1-5 alkylene)-S(0)(Ci-5 alkyl), -(C1-5 alkylene)-SO2(Ci-5 alkyl), -(C1-5 alkylene)-S(0)(NH)(Ci-5 alkyl), -(C1-5 alkylene)-S(O)(N-Ci-3alkyl)(Ci-5alkyl), -(C1-5 alkylene)-N=S(O)(Ci-5alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-S(Ci-5 haloalkyl), -(C1-5 alkylene)-S(0)(Ci-5 haloalkyl), -(C1-5 alkylene)- S(O)2(Ci-5 haloalkyl), -(C1-5 alkylene)-P(O)(Ci-5alkyl)(Ci-5alkyl), -(C1-5 alkylene)-P(O)(O-Ci-5alkyl)(O- C1-5 alkyl), -(C1-5 alkylene)-P(0)(0-Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-NH2, -(C1-5 alkylene)-NH(Ci-s alkyl), -(C1-5 alkylene)-NH(Ci-5 haloalkyl), -(C1-5 alkylene)-N(Ci-s alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci-s alkyl)(Ci-5 haloalkyl), -(C1-5 alkylene)-(W-heterocycloalkyl), -(C1-5 alkylene)-N(Ci-s haloalkyl)(Ci-5 alkyl), - C00-(Ci-5 alkylene)-NH2, -C00-(Ci-5 alkylene)-NH(Ci-s alkyl), -C00-(Ci-5 alkylene)-NH(Ci-5haloalkyl), - C00-(Ci-5 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -C00-(Ci-5 alkylene)-N(Ci-s alkyl)(Ci-5 haloalkyl), -C00-(Ci- 5 alkylene)-(W-heterocycloalkyl), -C00-(Ci-5 alkylene)-N(Ci-s haloalkyl)(Ci-5 alkyl), -(C1-5 alkylene)-CO(Ci- 5 alkyl), -(C1-5 alkylene)-C00(Ci-5 alkyl), -(C1-5 alkylene)-COOH, -(C1-5 alkylene)-C0NH2, -(C1-5 alkylene)-C0NH(Ci-5 alkyl), -(C1-5 alkylene)-CON(Ci-5alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-CO-( / V- heterocycloalkyl), -(C1-5 alkylene)-NHCO-(Ci-s alkyl), -(C1-5 alkylene)-N(Ci-s alkyl)-C0-(Ci-5 alkyl), -(C1-5 alkylene)-NHCONH2, -(C1-5 alkylene)-NHCONH-(Ci-5alkyl), -(C1-5 alkylene)-NHCON(Ci-5alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci-5alkyl)CONH2, -(C1-5 alkylene)-N(Ci-s alkyl)CONH-(Ci-5alkyl), and -(C1-5 alkylene)-N(Ci-5alkyl)CON(Ci-5alkyl)(Ci-5 alkyl).

[0137] Preferably, Rs2is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -0(Ci-5 alkyl), -O(Ci- 5 haloalkyl), -SH, -S(Ci-5 alkyl), -S(O)(Ci-5alkyl), -SO2(Ci-5alkyl), -S(O)(NH)(CI-5alkyl), -S(O)(N-CI-3alkyl)(Ci-5alkyl), -N=S(O)(Ci-s alkyl)(Ci-5 alkyl), -S(Ci-5 haloalkyl), -S(O)(Ci-5haloalkyl), -SO2(Ci-5haloalkyl), -P(O)(Ci-5alkyl)(Ci-5 alkyl), -P(O)(O-Ci-5alkyl)(O-Ci-5alkyl), -P(O)(O-Ci-5alkyl)(Ci-5alkyl), -NH2, -NH(CI-5alkyl), -NH(CI-5 haloalkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -N(CI-5haloalkyl)(Ci-5 alkyl), - ( / V-heterocycloalkyl), -C0(Ci-5 alkyl), -C00H, -C00(Ci-5 alkyl), -CONH2, -CONH(CI-5alkyl), -CON(CI-5alkyl)(Ci-5alkyl), -CO-( / V-heterocycloalkyl), -NHCO-(CI-5alkyl), -N(Ci-s alkyl)-C0-(Ci-5 alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci-5 alkyl), -N(CI-5alkyl)CONH2, -N(CI-5alkyl)CONH-(Ci-5alkyl), and -N(Ci-s alkyl)CON(Ci-5alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-0(Ci-5 alkyl), -(C1-5 alkylene)-0(Ci-5 haloalkyl), -(C1-5 alkylene)-SH, -(C1-5 alkylene)-S(Ci-5 alkyl), -(C1-5 alkylene)-S(0)(Ci-5 alkyl), -(C1-5 alkylene)-SO2(Ci-5 alkyl), -(C1-5 alkylene)-S(O)(NH)(Ci-5alkyl), -(C1-5 alkylene)-S(O)(N-Ci-3alkyl)(Ci-5alkyl), -(C1-5 alkylene)-N=S(O)(Ci-5alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-S(Ci-5 haloalkyl), -(C1-5 alkylene)-S(0)(Ci-5 haloalkyl), -(C1-5 alkylene)- S(O)2(Ci-5 haloalkyl), -(C1-5 alkylene)-P(O)(Ci-5alkyl)(Ci-5alkyl), -(C1-5 alkylene)-P(O)(O-Ci-5alkyl)(O- C1-5 alkyl), -(C1-5 alkylene)-P(0)(0-Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-NH2, -(C1-5 alkylene)-NH(Ci-s alkyl), -(C1-5 alkylene)-NH(Ci-5 haloalkyl), -(C1-5 alkylene)-N(Ci-s alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci-s alkyl)(Ci-5 haloalkyl), -(C1-5 alkylene)-( / V-heterocycloalkyl), -(C1-5 alkylene)-N(Ci-s haloalkyl)(Ci-5 alkyl), - (C1-5 alkylene)-C0(Ci-5 alkyl), -(C1-5 alkylene)-C00(Ci-5 alkyl), -(C1-5 alkylene)-COOH, -(C1-5 alkylene)-C0NH2, -(C1-5 alkylene)-CONH(Ci-5alkyl), -(C1-5 alkylene)-CON(Ci-5alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-CO-(W-heterocycloalkyl), -(C1-5 alkylene)-NHCO-(Ci-s alkyl), -(C1-5 alkylene)-N(Ci-s alkyl)-CO- (C1-5 alkyl), -(C1-5 alkylene)-NHCONH2, -(C1-5 alkylene)-NHCONH-(Ci-5alkyl), -(C1-5 alkylene)-NHCON(Ci- 5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci-5alkyl)CONH2, -(C1-5 alkylene)-N(Ci-5alkyl)CONH-(Ci-5alkyl), and — (C1-5 alkylene)-N(Ci-5 alkyl)CON(Ci-s alkyl)(Ci-5 alkyl).

[0138] More preferably, Rs2is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -0(Ci-5 alkyl), -0(Ci-5 haloalkyl), -SH, -S(Ci-5 alkyl), -SO2(Ci-5 alkyl), -S(O)(NH)(Ci-s alkyl), -S(O)(N-CI-3alkyl)(Ci-5 alkyl), -N=S(O)(CI-5alkyl)(Ci-5 alkyl), -S(Ci-5 haloalkyl), -P(O)(Ci-5alkyl)(Ci-5 alkyl), -P(O)(O-Ci-5alkyl)(O- C1-5 alkyl), -P(O)(O-Ci-5alkyl)(Ci-5 alkyl), -NH2, -NH(Ci-s alkyl), -NH(Ci-s haloalkyl), -N(Ci-s alkyl)(Ci-5 alkyl), -N(CI-5haloalkyl)(Ci-5 alkyl), -( / V-heterocycloalkyl), -CO(Ci-5alkyl), -CONH2, -CONH(CI-5alkyl), -CON(CI-5alkyl)(Ci-5 alkyl), -CO-( / V-heterocycloalkyl), -NHCO-(CI-5alkyl), -N(Ci-s alkyl)-C0-(Ci-5 alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci-5 alkyl), -N(CI-5alkyl)CONH2, -N(CI-5alkyl)CONH-(Ci-5alkyl), and -N(Ci-s alkyl)CON(Ci-5alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-0(Ci-5 alkyl), -(C1-5 alkylene)-0(Ci-5 haloalkyl), -(C1-5 alkylene)-SH, -(C1-5 alkylene)-S(Ci 5 alkyl), -(C1-5 alkylene)-SO2(Ci-5alkyl), -(C1-5 alkylene)-S(O)(NH)(Ci-5alkyl), -(C1-5 alkylene)-S(O)(N-Ci-3alkyl)(Ci-s alkyl), -(C1-5 alkylene)-N=S(O)(Ci-5alkyl)(Ci-s alkyl), -(C1-5 alkylene)- S(Ci-5haloalkyl), -(C1-5 alkylene)-P(O)(Ci-5alkyl)(Ci-5alkyl), -(C1-5 alkylene)-P(O)(O-Ci-5alkyl)(O-Ci-5alkyl), -(C1-5 alkylene)-P(O)(O-Ci-5alkyl)(Ci-5alkyl), -(C1-5 alkylene)-NH2, -(C1-5 alkylene)-NH(Ci-5alkyl), - (C1-5 alkylene)-N H(Ci -5 haloalkyl), -(C1-5 alkylene)-N(Ci -5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci -5 alkyl)(Ci- 5 haloalkyl), -(C1-5 alkylene)-( / V-heterocycloalkyl), -(C1-5 alkylene)-N(Ci-s haloalkyl)(Ci-5 alkyl), -(C1-5 alkylene)-C0(Ci-5 alkyl), -(C1-5 alkylene)-CONH2, -(C1-5 alkylene)-C0NH(Ci-5 alkyl), -(C1-5 alkylene)-C0N(Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-CO-( / V-heterocycloalkyl), -(C1-5 alkylene)-NHCO-(Ci- 5 alkyl), -(C1-5 alkylene)-N(Ci-5alkyl)-C0-(Ci-5 alkyl), -(C1-5 alkylene)-NHCONH2, -(C1-5 alkylene)-NHC0NH-(Ci-5 alkyl), -(C1-5 alkylene)-NHCON(Ci-5alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci-5alkyl)CONH2, -(C1-5 alkylene)-N(Ci-5alkyl)CONH-(Ci-5alkyl), and -(C1-5 alkylene)-N(Ci-5alkyl)CON(Ci-5alkyl)(Ci-5alkyl).

[0139] Still more preferably, Rs2is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -0(Ci-5 alkyl), -0(Ci-5 haloalkyl), -SH, -S(Ci-5 alkyl), -S(Ci-5 haloalkyl), -NH2, -NH(CI-5 alkyl), -NH(CI-5 haloalkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -N(CI-5 haloalkyl)(Ci-5 alkyl), -( / V-heterocycloalkyl), -CO(Ci-5 alkyl), -CONH2, -CONH(CI-5alkyl), -CON(CI-5 alkyl)(Ci-5 alkyl), -CO-( / V-heterocycloalkyl), -NHCO-(CI-5alkyl), -N(CI-5 alkyl)-CO-(Ci-5alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci-5 alkyl), -N(CI-5alkyl)CONH2, -N(CI-5alkyl)CONH-(Ci-5alkyl), -N(Ci-s alkyl)CON(Ci-5alkyl)(Ci-5 alkyl), -(C1- 5 alkylene)-CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-0(Ci-5 alkyl), -(C1-5 alkylene)-0(Ci-5 haloalkyl), -(C1- 5 alkylene)-SH, -(C1-5 alkylene)-S(Ci-5 alkyl), -(C1-5 alkylene)-S(Ci-5 haloalkyl), -(C1-5 alkylene)-NH2, -(C1-5 alkylene)-NH(Ci-5 alkyl), -(C1-5 alkylene)-NH(Ci-s haloalkyl), -(C1-5 alkylene)-N(Ci-s alkyl)(Ci-5 alkyl), -(C1- 5 alkylene)-N(Ci-5 alkyl)(Ci-5 haloalkyl), -(C1-5 alkylene)-( / V-heterocycloalkyl), -(C1-5 alkylene)-N(Ci-s haloalkyl)(Ci-5 alkyl), -(C1-5 alkylene)-C0(Ci-5 alkyl), -(C1-5 alkylene)-C0NH2, -(C1-5 alkylene)-CONH(Ci-s alkyl), -(C1-5 alkylene)-C0N(Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-CO-(W-heterocycloalkyl), -(C1-5 alkylene)-NHC0-(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci-s alkyl)-C0-(Ci-5 alkyl), -(C1-5 alkylene)-NHCONH2, - (C1-5 alkylene)-NHC0NH-(Ci-5 alkyl), -(C1-5 alkylene)-NHCON(Ci-5alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci- 5 alkyl)CONH2, -(C1-5 alkylene)-N(Ci-s alkyl)CONH-(Ci-5alkyl), and -(C1-5 alkylene)-N(Ci-s alkyl)CON(Ci- 5 alkyl)(Ci-5 alkyl).

[0140] Again more preferably, Rs2is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -0(Ci-5 alkyl), -0(Ci-5 haloalkyl), -SH, -S(Ci-5 alkyl), -S(Ci-5 haloalkyl), -NH2, -NH(CI-5 alkyl), -NH(CI-5 haloalkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -N(Ci-5haloalkyl)(Ci-5 alkyl), -( / V- heterocycloalkyl), -CONH2, -CONH(CI-5alkyl), -CON(CI-5 alkyl)(Ci-5 alkyl), -CO-(A / - heterocycloalkyl), -NHCO-(CI-5 alkyl), -N(Ci-5alkyl)-C0-(Ci-5 alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5 alkyl)(Ci-5 alkyl), -N(Ci-5alkyl)CONH2, -N(Ci-5alkyl)CONH-(Ci-5alkyl), -N(Ci-5alkyl)C0N(Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-0(Ci-5 alkyl), - (C1-5 alkylene)-0(Ci-5 haloalkyl), -(C1-5 alkylene)-SH, -(C1-5 alkylene)-S(Ci-5 alkyl), -(C1-5 alkylene)-S(Ci-5 haloalkyl), -(C1-5 alkylene)-NH2, -(C1-5 alkylene)-NH(Ci-s alkyl), -(C1-5 alkylene)-NH(Ci-s haloalkyl), -(C1-5 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci-s alkyl)(Ci-5 haloalkyl), -(C1-5 alkylene)-( / V- heterocycloalkyl), -(C1-5 alkylene)-N(Ci-s haloalkyl)(Ci-5 alkyl), -(C1-5 alkylene)-C0NH2, -(C1-5 alkylene)-C0NH(Ci-5 alkyl), -(C1-5 alkylene)-CON(Ci-5alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-CO-( / V- heterocycloalkyl), -(C1-5 alkylene)-NHC0-(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci-s alkyl)-C0-(Ci-5 alkyl), -(C1-5 alkylene)-NHCONH2, -(C1-5 alkylene)-NHCONH-(Ci-5alkyl), -(C1-5 alkylene)-NHCON(Ci-5alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci-5alkyl)CONH2, -(C1-5 alkylene)-N(Ci-5alkyl)CONH-(Ci-5alkyl), and -(C1-5 alkylene)-N(Ci-5alkyl)CON(Ci-5alkyl)(Ci-5 alkyl).

[0141] Again more preferably, Rs2is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -0(Ci-5 alkyl), -0(Ci-5 haloalkyl), -SH, -S(Ci-5 alkyl), -S(Ci-5 haloalkyl), -NH2, -NH(CI-5 alkyl), -NH(CI-5 haloalkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -N(CI-5 haloalkyl)(Ci-5 alkyl), -( / V-heterocycloalkyl), -(C1-5 alkylene)- CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-0(Ci-5 alkyl), -(C1-5 alkylene)-0(Ci-5 haloalkyl), -(C1-5 alkylene)-SH, -(C1-5 alkylene)-S(Ci-5 alkyl), -(C1-5 alkylene)-S(Ci-5 haloalkyl), -(C1-5 alkylene)-NH2, -(C1-5 alkylene)-NH(Ci-5 alkyl), -(C1-5 alkylene)-NH(Ci-s haloalkyl), -(C1-5 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -(C1- 5 alkylene)-N(Ci-5 alkyl)(Ci-5 haloalkyl), -(C1-5 alkylene)-( / V-heterocycloalkyl), -(C1-5 alkylene)-N(Ci-5 haloalkyl)(Ci-5alkyl), -(C1-5 alkylene)-CONH2, -(C1-5 alkylene)-CONH(Ci-5alkyl), -(C1-5 alkylene)-CON(Ci- 5 alkyl)(Ci-5 alkyl), and — (C1-5 alkylene)-CO-( / V-heterocycloalkyl).

[0142] 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.

[0143] Most preferably, Rs2is selected from halogen, -CN, -OH, -SH, and -NH2.

[0144] The compounds of the present invention will be described in the following preferred embodiments. It is to be understood that only some of the features Z, R1, R2, R3, R4, Rs, A, Li , L2 and L3 are recited when defining said particular embodiment. For any feature that is absent in the definition it is to be understood that said feature is as defined for formula (I) or any specific embodiment defined herein. In particular, if only one or more of R1, R2, R3 are recited, the recitation is applicable to any one of possible Z group, including each of them individually, as well as including any specific stereoconfiguration thereof.

[0145] In a first specific embodiment, of the compound of formula (I), R1 is methyl. One possible methyl group is CD3. However, if not specifically indicated otherwise, R1 in this specific embodiment is methyl.

[0146] In a second specific embodiment of the compound of formula (I), R1 is -CN.

[0147] In a third specific embodiment of the compound of formula (I), R2 and R3 are both -H.

[0148] In a fourth specific embodiment of the compound of formula (I), R2 is H, and R3 is methyl (which may also specifically refer to -CD3).

[0149] In a fifth specific embodiment of the compound of formula (I), R1 is methyl, R2 is H, and R3 is methyl.

[0150] In a sixth specific embodiment of the compound of formula

[0151] In this sixth specific embodiment, Ri, R2, and R3 are as defined in formula (I) or in any one of specific embodiments referred to herein. Preferably, in this sixth specific embodiment, R1 is methyl, R2 is H, and R3 is H.

[0152] In this sixth embodiment, further specific combinations of R1, R2, and R3 are considered particularly suitable:

[0153] Accordingly, the present invention provides, within this specific sixth embodiment, each individua combination of Ri, R2, and Rs as provided herein.

[0154] In this sixth specific embodiment, the Z moiety may have the following configuration: However, in this sixth specific embodiment, the Z moiety may also have the following configuration: . Alternatively, in this sixth specific embodiment, the Z moiety may have the following configuration: . Further alternatively, the Z moiety may have the following configuration: . Accordingly, the present invention specifically relates to each of the recited individual configurations of the compound of formula (I), according to this sixth embodiment.

[0155] In a seventh specific embodiment of the compound of formula

[0156] In this seventh specific embodiment, R1, R2, and R3 are as defined in formula (I) or in any one of specific embodiments referred to herein. Preferably, in this seventh specific embodiment, R1 is methyl, R2 is H, and R3 is methyl. In this seventh specific embodiment, the Z moiety may have the following configuration: . However, in this seventh specific embodiment, the Z moiety may also have the following configuration: .

[0157] In an eighth specific embodiment of the compound of formula

[0158] In this eighth specific embodiment, Ri, R2, and R3 are as defined in formula (I) or in any one of specific embodiments referred to herein. Preferably, in this eighth specific embodiment, Ri is methyl, R2 is H, and R3 is methyl.

[0159] In this eighth specific embodiment, the Z moiety may have the following configuration: . However, in this eighth specific embodiment, the Z moiety may also have the following configuration: .

[0160] In a ninth specific embodiment of the compound of formula

[0161] In this ninth specific embodiment, Ri, R2, and R3 are as defined in formula (I) or in any one of specific embodiments referred to herein. Preferably, in this ninth specific embodiment, Ri is methyl, R2is H, and R3 is methyl.

[0162] In this ninth embodiment, further specific combinations of Ri, R2, and R3 are considered particularly suitable:

[0163] Ri R3

[0164] Accordingly, the present invention provides, within this specific ninth embodiment, each individua combination of Ri, R2, and Rs as provided herein.

[0165] In this ninth specific embodiment, the Z moiety may have the following configuration:

[0166] However, in this ninth specific embodiment, the Z moiety may also have the following configuration: . Alternatively, in this ninth specific embodiment, the Z moiety may have the following configuration: Further alternatively, the Z moiety may have the following configuration: . Accordingly, the present invention specifically relates to each of the recited individual configurations of the compound of formula (I), according to this ninth embodiment.

[0167] In a tenth specific embodiment of the compound of formula In this tenth specific embodiment, R1, R2, and R3 are as defined in formula (I) or in any one of specific embodiments referred to herein. Preferably, in this tenth specific embodiment, R1 is methyl, R2 is H, and R3 is methyl.

[0168] In this tenth embodiment, further specific combinations of R1, R2, and R3 are considered particularly suitable:

[0169] Accordingly, the present invention provides, within this specific tenth embodiment, each individua combination of Ri, R2, and Rs as provided herein.

[0170] In this tenth specific embodiment, the Z moiety may have the following configuration:

[0171] However, in this tenth specific embodiment, the Z moiety may also have the following configuration: . Alternatively, in this tenth specific embodiment, the Z moiety may have the following configuration: Further alternatively, the Z moiety may have the following configuration: Accordingly, the present invention specifically relates to each of the recited individual configurations of the compound of formula (I), according to this tenth embodiment.

[0172] In an eleventh specific embodiment of the compound of formula

[0173] In this eleventh specific embodiment, R1, R2, and R3 are as defined in formula (I) or in any one of specific embodiments referred to herein. Preferably, in this eleventh specific embodiment, R1 is methyl, R2 is H, and R3 is methyl.

[0174] In this eleventh embodiment, further specific combinations of R1, R2, and R3 are considered particularly suitable:

[0175] Accordingly, the present invention provides, within this specific eleventh embodiment, each individual combination of Ri, R2, and Rs as provided herein.

[0176] In this eleventh specific embodiment, the Z moiety may have the following configuration:

[0177] However, in this eleventh specific embodiment, the Z moiety may also have the following configuration: . Alternatively, in this eleventh specific embodiment, the Z moiety may have the following configuration: Further alternatively, the Z moiety may have the following configuration: . Accordingly, the present invention specifically relates to each of the recited individual configurations of the compound of formula (I), according to this eleventh embodiment.

[0178] In a twelfth specific embodiment of the compound of formula

[0179] In this twelfth specific embodiment, R1, R2, and R3 are as defined in formula (I) or in any one of specific embodiments referred to herein. Preferably, in this twelfth specific embodiment, R1 is methyl, R2 is H, and R3 is methyl.

[0180] In this twelfth specific embodiment, the Z moiety may have the following configuration:

[0181] . However, in this twelfth specific embodiment, the Z moiety may also have the following configuration: . Alternatively, in this twelfth specific embodiment, the Z moiety may have the following configuration: . Further alternatively, the Z moiety may have the following configuration: . Accordingly, the present invention specifically relates to each of the recited individual configurations of the compound of formula (I), according to this twelfth embodiment.

[0182] In a thirteenth specific embodiment of the compound of formula

[0183] In this thirteenth specific embodiment, Ri, R2, and R3 are as defined in formula (I) or in any one of specific embodiments referred to herein. Preferably, in this thirteenth specific embodiment, R1 is methyl,

[0184] R2 is H, and R3 is methyl.

[0185] In this thirteenth specific embodiment, the Z moiety may have the following configuration:

[0186] However, in this thirteenth specific embodiment, the Z moiety may also have the following configuration: . Alternatively, in this thirteenth specific embodiment, the Z moiety may have the following configuration: Further alternatively, the Z moiety may have the following configuration: . Accordingly, the present invention specifically relates to each of the recited individual configurations of the compound of formula (I), according to this thirteenth embodiment.

[0187] In a fourteenth specific embodiment of the compound of formula

[0188] In a fifteenth specific embodiment, A is 1 ,4-phenylene, optionally substituted with one or more groups independently selected from Rs2.

[0189] In a sixteenth specific embodiment, A is heteroarylene, optionally substituted with one or more groups independently selected from Rs2. Preferably, A is 1 ,4-(six-membered heteroarylene), optionally substituted with one or more groups independently selected from Rs2.

[0190] In a seventeenth specific embodiment, A is heterocycloalkylene or heterocycloalkenylene, optionally substituted with one or more groups independently selected from Rs2. Preferably, A is heterocycloalkylene, optionally substituted with one or more groups independently selected from Rs2. Preferably, said heterocycloalkylene is 1 ,4-piperazinylene, optionally substituted with one or more groups independently selected from Rs2. Alternatively, in this seventeenth specific embodiment, A is heterocycloalkenylene, optionally substituted with one or more groups independently selected from Rs2, such as tetrahydropyridinylene, preferably 1 ,2,3,6-tetrahydropyridinylene.

[0191] In an eighteenth specific embodiment, A is 1 ,4-piperazinylene, optionally substituted with one or two methyl groups, Li is -CON(CH3)-, wherein the left empty valence is connected to A and the right empty valence is connected to L2, L2 is C1-4 alkylene, preferably -CH2CH2-, and L3 is selected from -N(CI-5 alkyl)(cycloalkyl), -N(CI-5 alkyl)(heterocycloalkyl), -NH(cycloalkyl), -NH(heterocycloalkyl), and N- heterocycloalkyl, wherein said heterocycloalkyl and said / V-heterocycloalkyl is optionally substituted with one or more groups independently selected from Rs2.

[0192] In a nineteenth specific embodiment, A is 1 ,4-phenylene or 2,5-pyridinylene, optionally substituted with one or more groups selected from Rs2, preferably from methyl, Hal, -OH and -ON, Li is -SO(NH)-, wherein the left empty valence connected to A and the right empty valence is connected to L2, L2 is C1-4 alkylene, preferably -CH2CH2-, and L3 is selected from -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), and N- heterocycloalkyl, wherein said alkyl is optionally substituted with one or more groups selected from -OH and Hal, and wherein said / V-heterocycloalkyl is optionally substituted with one or more groups independently selected from Rs2.

[0193] In a twentieth specific embodiment, R4 is N-N In a twenty-first specific embodiment, R4 is a 5- to 6-membered heteroaryl group which is optionally substituted by one or more groups selected from Rs2; wherein the heteroatom of the 5- to 6-membered heteroaryl group is N and / or S, and the number of heteroatoms is 1 , 2 or 3, preferably 3.

[0194] In a twenty-second specific embodiment, Rs is H. In a twenty-third specific embodiment, Rs is Cl.

[0195] In one embodiment, present invention relates to a compound of formula (II): or a pharmaceutically acceptable salt thereof.

[0196] Z’ is selected from:

[0197] R3

[0198] R2—

[0199] Alternatively, if Z' moiety is Ri^V , it may have the following configuration .

[0200] In formula (II), Ri, R2and R3in Z are as defined for formula (I), including any preferred definition and any specific embodiment of the compound of formula (I), as well as any (optional or not) provision applying thereto. It is particularly preferred that Ri is methyl, and R2and R3 are each -H.

[0201] In formula (II), R4 is as defined for formula (I), including any preferred embodiment and any preferred definition of the compound of formula (I). In formula (II), it is particularly preferred that R4 is

[0202] In formula (II), Rs is as defined for formula (I), including any preferred embodiment and any preferred definition of the compound of formula (I). Preferably, Rs is selected from -H and halogen. More preferably, Rs is H. However, in one embodiment, Rs is Hal, such as Cl. In one embodiment, Rs is F.

[0203] In formula (II), -A-LI-I_2-I_3 is defined as outlined in the following.

[0204] In formula (II):

[0205] A is 1 ,4-phenylene, optionally substituted with one or more groups independently selected from Rs2, preferably from methyl, Hal, -OH and -CN, or 1 ,4-(six-membered heteroarylene), optionally substituted with one or more groups independently selected from Rs2, preferably from methyl, Hal, -OH and -CN;

[0206] Li is -SO(NH)- or -SO(NCH3)-, preferably -SO(NCH3)-, wherein the left empty valence connected to A and the right empty valence is connected to L2;

[0207] L2is as defined for formula (I), including any preferred definitions and any preferred embodiments of the compound of formula (I), in particular it is preferred that L2is a linear C2-3 alkylene, even more preferably, L2is -CH2CH2-; La is as defined for formula (I), including any preferred definitions and any particular embodiments of the compound of formula (I), it is particularly preferred that L3 is selected from -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci -5 alkyl), and / V-heterocycloalkyl, wherein said alkyl is optionally substituted with one or more groups selected from -OH and Hal, and wherein said / V-heterocycloalkyl is optionally substituted with one or more groups independently selected from Rs2.

[0208] Particularly preferred 1 ,4-phenylene that is optionally substituted as disclosed herein, is selected from: herein, in these formulas the bottom empty valence of A is connected to Li.

[0209] Particularly preferred heteroarylene is a 1,4-(six-membered heteroarylene), optionally substituted with one or more groups independently selected from Rs2. Particularly preferred six-membered heteroarylene is pyridinylene, i.e. 2, 5-pyridinylene, which is optionally substituted with one or more groups independently selected from Rs2. For example, A being heteroarylene is selected from: . Preferably, A is selected from understood herein, in these formulas the bottom empty valence of A is connected to Li.

[0210] A further suitable example of heteroarylene as A is five-membered heteroarylene, such as 1 ,3- (five-membered-heteroarylene), for example a thienylene (such as 1 ,3-thienylene). Alternatively, in formula (II):

[0211] A is heterocycloalkylene or heterocycloalkenylene (such as 1 ,4-piperazinylene), optionally substituted with one or more groups independently selected from Rs2, preferably A is 1 ,4-piperazinylene, optionally substituted with one or two methyl groups;

[0212] Li is -CONH- or -CON(CH3)-, preferably -CON(CH3)-, wherein the left empty valence is connected to A and the right empty valence is connected to L2;

[0213] L2 is as defined for formula (I), including any preferred definition and any particular embodiment of the compound of formula (I), preferably L2 is C1-4 alkylene, more preferably L2 is -CH2CH2-;

[0214] L3 is selected from -N(CI-5 alkyl)(cycloalkyl), -N(CI-5 alkyl)(heterocycloalkyl), -NH(cycloalkyl), - NH(heterocycloalkyl), and / V-heterocycloalkyl, wherein said cycloalkyl, said heterocycloalkyl and said N- heterocycloalkyl is optionally substituted with one or more groups independently selected from Rs2. Preferably, L3 is selected from -N(CI-5 alkyl)(heterocycloalkyl), -NH(heterocycloalkyl), and N- heterocycloalkyl, wherein said heterocycloalkyl and said / V-heterocycloalkyl is optionally substituted with one or more groups independently selected from Rs2.

[0215] Heterocycloalkylene or heterocycloalkenylene in A, as defined herein, is preferably, a sixmembered heterocycloalkylene or a six-membered heterocycloalkenylene, respectively. If A is heterocycloalkylene or heterocycloalkenylene, optionally substituted with one or more groups independently selected from Rs2, preferably A is heterocycloalkylene, optionally substituted with one or more groups independently selected from Rs2. More preferably, A is 1 ,4-piperazinylene, optionally substituted with one or more groups independently selected from Rs2. Thus, preferably, A is selected from , , valence of A, as depicted in provided formulae, is connected to Li.

[0216] In formula (II), RS1and Rs2are as defined for formula (I), including any preferred definitions and any particular embodiments of the compound of formula (I).

[0217] It further preferably applies to the compound of formula (II) that then Ri is not H and / or at least one of R2 and R3 is not -H.

[0218] It is preferred that the compound of formula (I) is a compound selected from:

[0219] or a pharmaceutically acceptable salt thereof.

[0220] Preferably, the compound of formula (I) is any one of the following compounds:

[0221] or a pharmaceutically acceptable salt thereof.

[0222] 5 Alternatively, preferred compound of formula (I) is any one of the following compounds or a pharmaceutically acceptable salt thereof. Particularly preferred compound is: or its pharmacetucally acceptable salt. A further particularly preferred compound is: pharmaceutically acceptable salt of any one of these compounds.

[0223] A further particularly preferred compound is: having the structure pharmaceutically acceptable salt of any one of these compounds.

[0224] Preferably, the compound of formula (I) is a compound selected from the following compounds:

[0225] (25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2,6- trimethylpiperazine-1-carboxamide;

[0226] (25.65)-N-(2-(azetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 -carboxamide;

[0227] 8-(4-(2-(azetidin-1 -yl)ethylsulfonimidoyl)-2-methylphenyl)-1-chloro-3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0228] 1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0229] (25.65)-N-(2-((3-cyanocyclobutyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6- (N-(1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 -carboxamide;

[0230] (25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N-(2-(3-fluoroazetidin-1 -yl)ethyl)-N,2,6- trimethylpiperazine-1-carboxamide;

[0231] (25.65)-N-(2-(cyclopropyl(methyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6- (N-(1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 -carboxamide;

[0232] (25.65)-N-(2-(3-cyanoazetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 -carboxamide;

[0233] 3-[5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl]-8-[(3S,5S)-4-[3-(dimethylamino)azetidine-1-carbonyl]- 3,5-dimethyl-piperazin-1-yl]-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0234] (25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(4-methylpiperazin-1- yl)ethyl)piperazine-1-carboxamide; (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(pyrrolidin-1 - yl)ethyl)piperazine-1-carboxamide;

[0235] (25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(methyl(oxetan-3- yl)amino)ethyl)piperazine-1-carboxamide;

[0236] 4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5- a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N-methyl-3,6-dihydropyridine-1 (2H)-carboxamide;

[0237] 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(dimethylalanyl)piperazin-1-yl)-N-(1- methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0238] (25.65)-N-(2-(azetidin-1-yl)ethyl)-4-(6-(N-(1-cyanocyclopropyl)sulfamoyl)-3-(5-(difluoromethyl)- 1 , 3, 4-thiadiazol-2-yl)imidazo[1 ,5-a]pyridin-8-yl)-N, 2, 6-trimethylpiperazine-1 -carboxamide;

[0239] (25.65)-N-(2-(azetidin-1-yl)ethyl)-N,2,6-trimethyl-4-(6-(N-(1 -methylcyclopropyl)sulfamoyl)-3-(5- (trifluoromethyl)-l ,3,4-thiadiazol-2-yl)imidazo[1 ,5-a]pyridin-8-yl)piperazine-1-carboxamide;

[0240] (25.65)-N-(2-(azetidin-1 -yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(cis-2- fluoro-1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1- carboxamide;

[0241] (25.65)-N-(2-(azetidin-1 -yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- (fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;

[0242] (25.65)-N-(2-(azetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-((1 R,2S)-

[0243] 1 ,2-dimethylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 -carboxamide;

[0244] 8-(4-(2-(azetidin-1 -yl)-N-(methylsulfonyl)ethylsulfonimidoyl)-2-methylphenyl)-1-chloro-3-(5- (difluoromethyl)-l ,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0245] (25.65)-N-(azetidin-3-yl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 -carboxamide;

[0246] 1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-hydroxyethylsulfonimidoyl)-2- methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0247] (25.65)-N-(2-(((trans)-3-cyanocyclobutyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol- 2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;

[0248] (25.65)-N-(2-(((cis)-3-cyanocyclobutyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2- yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1- carboxamide; (25.65)-N-(2-(((trans)-3-cyanocyclobutyl)(methyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6- trimethylpiperazine-1-carboxamide;

[0249] (25.65)-N-(2-(((cis)-3-cyanocyclobutyl)(methyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6- trimethylpiperazine-1-carboxamide;

[0250] (25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(1 -methylazetidin-3- yl)piperazine-1 -carboxamide;

[0251] 1 -chloro- 3-(5-(difluoromethyl)-1 , 3, 4-thiadiazol-2-yl)-8-(4-(3-(dimethylamino)azetidine-1 - carbonyl)piperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide;

[0252] 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(5-(2-(dimethylamino)ethylsulfonimidoyl)-3- methylpyridin-2-yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0253] 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(6-(2-(dimethylamino)ethylsulfonimidoyl)-2- methoxypyridin-3-yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0254] 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- hydroxyphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0255] 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- methoxyphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0256] 2-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5- a]pyridin-8-yl)-5-(2-(dimethylamino)ethylsulfonimidoyl)pyridine 1-oxide;

[0257] (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N-(2-((dimethyl(oxo)-X6- sulfaneylidene)amino)ethyl)-N,2,6-trimethylpiperazine-1 -carboxamide;

[0258] 1 -chloro- 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(2-methyl-4-(2-(4-methylpiperazin-1- yl)ethylsulfonimidoyl)phenyl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide;

[0259] 1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)- 2-hydroxyphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0260] 1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)- 2-methoxyphenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0261] 1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(6-(2-(dimethylamino)ethylsulfonimidoyl)- 2-methoxypyridin-3-yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0262] 8-(2-cyano-4-(2-(dimethylamino)ethylsulfonimidoyl)phenyl)-3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide; 1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(5-(2-(dimethylamino)ethylsulfonimidoyl)- 3-methylpyridin-2-yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0263] 1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(6-(2-(dimethylamino)ethylsulfonimidoyl)-

[0264] 2-hydroxypyridin-3-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide;

[0265] 1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(6-(2-(dimethylamino)ethylsulfonimidoyl)-

[0266] 2-methylpyridin-3-yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0267] (2S,6S,E)-N'-cyano-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2,6- trimethylpiperazine-1-carboximidamide;

[0268] 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-((3S,5S)-4-(N-(2-(dimethylamino)ethyl)-N- methylsulfamoyl)-3,5-dimethylpiperazin-1 -yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;

[0269] (2S , 6S)-4- (3-(5-(difl uoromethy I)- 1 , 3, 4-th i ad iazol-2-yl)- 1 -fl uoro-6- (N- (1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2,6- trimethylpiperazine-1-carboxamide;

[0270] (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2- morpholinoethyl)piperazine-1-carboxamide;

[0271] 1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-

[0272] 2-fluorophenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0273] 1-chloro-8-(2-cyano-4-(2-(dimethylamino)ethylsulfonimidoyl)phenyl)-3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0274] 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- methylphenyl)-1-fluoro-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0275] 2-((2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2,6-dimethylpiperazin-1 -yl)-N,N- dimethylacetamide;

[0276] 2-(4-( 1 -chloro- 3- (5- (d ifl uoromethyl)- 1 ,3, 4-thi adi azol-2-yl)-6-(N-( 1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)piperazin-1-yl)-N,N-dimethylacetamide;

[0277] 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-4-(dimethylglycyl)-3,5-dimethylpiperazin- 1 -yl)-N-(1 -methylcyclopropyl )i mid azo[ 1 , 5-a]pyrid i ne-6-su Ifo namide ;

[0278] 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-((3S,5S)-4-(dimethyl-D-alanyl)-3,5- dimethylpiperazin-1 -yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0279] (R)-4-(3-(5-(difl uoromethy I)- 1 , 3, 4-thi ad iazol- 2-y l)-6- (N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2- dimethylpiperazine-1-carboxamide;

[0280] (S)-4-(3-(5- (difl uoro methy l)-1 , 3, 4-th i ad iazol- 2-y l)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2- dimethylpiperazine-1-carboxamide;

[0281] 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((1s,2S,6R)-1-((2-(dimethylamino)ethyl)imino)-2,6- dimethyl-1 -oxido-1 l6-thiomorpholino)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0282] 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-((1 r,2S,6R)-1-((2-(dimethylamino)ethyl)imino)-2,6- dimethyl-1 -oxido-1 l6-thiomorpholino)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0283] 8-(4-(2-aminoethylsulfonimidoyl)-3-methylphenyl)-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N- (1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0284] 8-(4-(2-aminoethylsulfonimidoyl)-3-methylphenyl)-1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol- 2-yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0285] 8-(4-(2-aminoethylsulfonimidoyl)-2-methylphenyl)-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N- (1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0286] 8-(4-(2-aminoethylsulfonimidoyl)-2-methylphenyl)-1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-

[0287] 2-yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0288] 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-((R)-4-(dimethyl-D-alanyl)-3-methylpiperazin-1-yl)- N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0289] 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-((S)-4-(dimethyl-D-alanyl)-3-methylpiperazin-1-yl)- N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0290] 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-3- methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0291] 1 -chloro- 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-

[0292] 3-methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0293] 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0294] 1 -chloro- 3-(5-(difluoromethyl)-1 , 3, 4-thiadiazol-2-yl)-8-(6-(2- (dimethylamino)ethylsulfonimidoyl)pyridin-3-yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;

[0295] 1 -chloro- 3-(5-(difluoromethyl)-1 , 3, 4-thiadiazol-2-yl)-8-(5-(2- (dimethylamino)ethylsulfonimidoyl)pyridin-2-yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;

[0296] (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)- [1 .2.4]triazolo[4,3-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2,6-trimethylpiperazine-1-carboxamide;

[0297] 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-

[0298] [1 .2.4]triazolo[4,3-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2-dimethylpiperazine-1 -carboxamide;

[0299] 2-(di methy lam i no)ethyl (2S, 6S)-4-(3-(5- (d ifl uoromethyl)- 1 , 3, 4-th i ad i azol-2-yl )-6-(N-( 1 - methylcyclopropyl)sulfamoyl)-[1 ,2,4]triazolo[4,3-a]pyridin-8-yl)-2,6-dimethylpiperazine-1-carboxylate;

[0300] 2-(di methy lam i no)ethyl 4-(3-(5- (d ifl uoromethyl)- 1 , 3, 4-th i ad i azol-2-yl )-6-(N-( 1 - methylcyclopropyl)sulfamoyl)-[1 ,2,4]triazolo[4,3-a]pyridin-8-yl)-2-methylpiperazine-1-carboxylate;

[0301] 2-(di methy lam I no)ethyl 4-(1 -ch loro-3-(5-(d ifl uoro methyl )- 1 , 3, 4-th i ad i azol-2-yl )-6-(N-(3- methyloxetan-3-yl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)piperazine-1-carboxylate;

[0302] 1 -chloro- 3-(5-(difluoromethyl)-1 , 3, 4-thiadiazol-2-yl)-8-(4-(2- (dimethylamino)ethylsulfonimidoyl)phenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;

[0303] 8-(4-(2-aminoethylsulfonimidoyl)phenyl)-1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N- (1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0304] 2-(di methy lam I no)ethyl 4-(1 -chloro-6-(N-( 1 -cyanocyclop ropyl)sulfamoyl)-3-(5-(d ifl uoromethyl)-

[0305] 1 ,3,4-thiadiazol-2-yl)imidazo[1 ,5-a]pyridin-8-yl)piperazine-1-carboxylate;

[0306] 2-(dimethylamino)ethyl 4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-1-fluoro-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)piperazine-1-carboxylate;

[0307] 2-(di methy lam i no)ethyl 4-(3-(5- (d ifl uoromethyl)- 1 , 3, 4-th i ad i azol-2-yl )-6-(N-( 1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-methylpiperazine-1-carboxylate;

[0308] 2-(di methy lam i no)ethyl 4-(3-(5- (d ifl uoromethyl)- 1 , 3, 4-th i ad i azol-2-yl )-6-(N-( 1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)piperazine-1-carboxylate;

[0309] 1 -chloro- 3-(5-(difluoromethyl)-1 , 3, 4-thiadiazol-2-yl)-8-(4-(dimethyl-D-alanyl)piperazin-1-yl)-N-(1 - methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0310] 2-(di methy lam i no)ethyl 4-(3-(5- (d ifl uoromethyl)- 1 , 3, 4-th i ad i azol-2-yl )-6-(N-( 1 - methylcyclopropyl)sulfamoyl)-[1 , 2, 4]triazolo[4,3-a]pyridin-8-yl)piperazine-1 -carboxylate;

[0311] 1 -chloro- 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-((2- (dimethylamino)ethyl)sulfonyl)piperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;

[0312] 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(dimethyl-L-alanyl)piperazin-1-yl)-N-(1 - methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0313] 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(dimethyl-D-alanyl)piperazin-1 -yl)-N-(1- methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0314] 2-(di methy lam i no)ethyl (2S, 6S)-4-(3-(5- (d ifl uoromethyl)- 1 , 3, 4-th i ad i azol-2-yl )-6-(N-( 1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2,6-dimethylpiperazine-1 -carboxylate; and

[0315] 2-(di methy lam i no)ethyl 4-(1 -ch loro-3-(5-(d ifl uoro methyl )- 1 , 3, 4-th i ad i azol-2-yl )-6-(N-( 1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)piperazine-1-carboxylate; or a pharmaceutically acceptable salt thereof.

[0316] Suitable compound of formula (I) may preferably be a compound selected from the following compounds:

[0317] (25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2,6- trimethylpiperazine-1-carboxamide;

[0318] (25.65)-N-(2-(azetidin-1 -yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 -carboxamide;

[0319] 8-(4-(2-(azetidin-1 -yl)ethylsulfonimidoyl)-2-methylphenyl)-1-chloro-3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0320] 1 -chloro- 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)- 2-methylphenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0321] (25.65)-N-(2-((3-cyanocyclobutyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6- (N-(1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 -carboxamide;

[0322] (25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N-(2-(3-fluoroazetidin-1 -yl)ethyl)-N,2,6- trimethylpiperazine-1-carboxamide;

[0323] (25.65)-N-(2-(cyclopropyl(methyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6- (N-(1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 -carboxamide;

[0324] (25.65)-N-(2-(3-cyanoazetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 -carboxamide;

[0325] 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-8-[(3S,5S)-4-[3-(dimethylamino)azetidine-1-carbonyl]- 3,5-dimethyl-piperazin-1-yl]-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0326] (25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(4-methylpiperazin-1- yl)ethyl)piperazine-1-carboxamide;

[0327] (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(pyrrolidin-1 - yl)ethyl)piperazine-1-carboxamide;

[0328] (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(methyl(oxetan-3- yl)amino)ethyl)piperazine-1-carboxamide;

[0329] 4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5- a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N-methyl-3,6-dihydropyridine-1 (2H)-carboxamide;

[0330] (25.65)-N-(2-(azetidin-1-yl)ethyl)-N,2,6-trimethyl-4-(6-(N-(1 -methylcyclopropyl)sulfamoyl)-3-(5- (trifluoromethyl)-l ,3,4-thiadiazol-2-yl)imidazo[1 ,5-a]pyridin-8-yl)piperazine-1-carboxamide

[0331] (25.65)-N-(2-(azetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(cis-2- fluoro-1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1- carboxamide;

[0332] (25.65)-N-(2-(azetidin-1 -yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- (fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;

[0333] (25.65)-N-(2-(azetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-((1 R,2S)-

[0334] 1 ,2-dimethylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 -carboxamide;

[0335] (25.65)-N-(2-(azetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-((1 S,2R)-

[0336] 1 ,2-dimethylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 -carboxamide;

[0337] 8-(4-(2-(azetidin-1 -yl)-N-(methylsulfonyl)ethylsulfonimidoyl)-2-methylphenyl)-1-chloro-3-(5- (difluoromethyl)-l ,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0338] 1 -chloro- 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-hydroxyethylsulfonimidoyl)-2- methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0339] (25.65)-N-(2-(((trans)-3-cyanocyclobutyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol- 2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;

[0340] (25.65)-N-(2-(((cis)-3-cyanocyclobutyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2- yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1- carboxamide;

[0341] (25.65)-N-(2-(((trans)-3-cyanocyclobutyl)(methyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6- trimethylpiperazine-1-carboxamide;

[0342] (25.65)-N-(2-(((cis)-3-cyanocyclobutyl)(methyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6- trimethylpiperazine-1-carboxamide;

[0343] 1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(2-methyl-4-(2-(4-methylpiperazin-1- yl)ethylsulfonimidoyl)phenyl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide;

[0344] 1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)- 2-methoxyphenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0345] 1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(6-(2-(dimethylamino)ethylsulfonimidoyl)-

[0346] 2-methoxypyridin-3-yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0347] 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-4-(N-(2-(dimethylamino)ethyl)-N- methylsulfamoyl)-3,5-dimethylpiperazin-1 -yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;

[0348] (2S , 6S)-4- (3-(5-(difl uoromethy I)- 1 , 3, 4-th i ad iazol-2-yl)- 1 -fl uoro-6- (N- (1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2,6- trimethylpiperazine-1-carboxamide;

[0349] (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2- morpholinoethyl)piperazine-1-carboxamide;

[0350] 1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-

[0351] 2-fluorophenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0352] (S)-1 -chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2- (dimethylamino)ethylsulfonimidoyl)-2-fluorophenyl)-N-(1 -methylcyclopropyl)imidazo[1,5-a]pyridine-6- sulfonamide

[0353] (R)-1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2- (dimethylamino)ethylsulfonimidoyl)-2-fluorophenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;

[0354] 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- methylphenyl)-1-fluoro-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0355] (R)-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- methylphenyl)-1-fluoro-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0356] (S)-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- methylphenyl)-1-fluoro-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0357] 2-((2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2,6-dimethylpiperazin-1 -yl)-N,N- dimethylacetamide;

[0358] (S)-4-(3-(5- (difl uoro methy l)-1 , 3, 4-th i ad iazol- 2-y l)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2- dimethylpiperazine-1-carboxamide;

[0359] 1 -chloro- 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-

[0360] 3-methylphenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide; (S)-1 -chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2-

[0361] (dimethylamino)ethylsulfonimidoyl)-3-methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;

[0362] (R)-1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-

[0363] (dimethylamino)ethylsulfonimidoyl)-3-methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;

[0364] 1 -chloro- 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)- 3-methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0365] 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;

[0366] (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)-

[0367] [1 ,2,4]triazolo[4,3-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2,6-trimethylpiperazine-1-carboxamide;

[0368] 1 -chloro- 3-(5-(difluoromethyl)-1 , 3, 4-thiadiazol-2-yl)-8-(4-(2-

[0369] (dimethylamino)ethylsulfonimidoyl)phenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;

[0370] (S)-1 -chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2-

[0371] (dimethylamino)ethylsulfonimidoyl)phenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;

[0372] (R)-1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-

[0373] (dimethylamino)ethylsulfonimidoyl)phenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;

[0374] 1 -chloro- 3-(5-(difluoromethyl)-1 , 3, 4-thiadiazol-2-yl)-8-(4-(dimethyl-D-alanyl)piperazin-1-yl)-N-(1 - methylcyclopropyl)imi dazo[1 , 5-a] pyridi ne-6-sulfonamide; and

[0375] 2-(di methy lam I no)ethyl 4-(1 -ch loro-3-(5-(d ifl uoro methyl )- 1 , 3, 4-th i ad i azol-2-yl )-6-(N-( 1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)piperazine-1-carboxylate; or a pharmaceutically acceptable salt thereof.

[0376] Suitable compound of formula (I) may more preferably be a compound selected from the following compounds:

[0377] (2S,6S)-N-(2-(azetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide; and

[0378] 8-(4-(2-(azetidin-1 -yl)ethylsulfonimidoyl)-2-methylphenyl)-1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol- 2-yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (such as (R)-8-(4-(2- (azetidin-1-yl)ethylsulfonimidoyl)-2-methylphenyl)-1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol- 2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide or (S)-8-(4-(2-(azetidin-1 - yl)ethylsulfonimidoyl)-2-methylphenyl)-1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(1- methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide); or a pharmaceutically acceptable salt thereof.

[0379] 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).

[0380] 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-p henylsulfonate, 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.

[0381] 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.

[0382] 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.

[0383] 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.

[0384] 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.

[0385] 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 by76Br 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.

[0386] The present invention further embraces the prodrugs of the compounds of formula (I). As preferably understood herein, the term “prodrug” of the compound of formula (I) refers to a derivative of the compounds of formula (I) that upon administration to a subject becomes metabolized to the said compound of formula (I). Said prodrugs of the compound of formula (I) may include modifications of -OH, -NH2, or -COOH group if present in the compound of formula (I), which preferably can be hydrolyzed to - OH, -NH2, or -COOH groups, respectively, e.g. upon administration to the subject. For example, as known to the skilled person, such prodrugs may preferably include for the compounds of formula (I) which comprise -OH moiety derivatives wherein said -OH moiety is turned into an -ORx moiety, wherein Rxpreferably comprises a moiety selected from -CO-, -CH2-O-CO, -CH2-O-CO-O-, and -CH(CH3)-0-C00-, more preferably wherein Rxis selected from -CO-Ry, -CH2-0-C0-Ry, -CH2-0-C0-0-Ry, and -CH(CH3)-0- COO-Ry, wherein Ryis preferably carbocyclyl, heterocyclyl, C1-5 alkyl, -NH-(CI-5 alkyl) or -S-(Ci-5 alkyl), wherein the said alkyl is optionally substituted with a group selected from halogen, -ON, -OH, C1-5 alkyl, C1-5 haloalkyl, -0(Ci-5 alkyl), -0(Ci-5 haloalkyl), -SH, -S(Ci-5 alkyl), -S(Ci-5 haloalkyl), -NH2, -NH(Ci-s alkyl), -NH(CI-5 haloalkyl), -N(CI-5alkyl)(Ci-5 alkyl), -N(CI-5haloalkyl)(Ci-5 alkyl), -CONH2, -CONH(CI-5alkyl), and -CON(Ci-s alkyl)(Ci 5 alkyl), and wherein the said carbocyclyl and heterocyclyl are each optionally substituted with a group selected from halogen, -ON, -OH, C1-5 alkyl, C1-5 haloalkyl, -0(Ci-5 alkyl), -0(Ci-5 haloalkyl), -SH, -S(Ci-5 alkyl), -S(Ci-5 haloalkyl), -NH2, -NH(CI-5 alkyl), -NH(CI-5 haloalkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -N(CI-5haloalkyl)(Ci-5 alkyl), -CONH2, -CONH(CI-5alkyl), and -CON(CI-5 alkyl) (CI 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 -C00Rymoiety, wherein Ryis as defined hereinabove. Further examples of groups that can be derivatized to yield prodrugs are known to the skilled person.

[0387] Pharmaceutical compositions

[0388] 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.

[0389] The pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., poly (ethylene glycol), including polyethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, a non-ionic surfactant, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate (e.g., Kolliphor® HS 15, CAS 70142-34-6), a phospholipid, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, a cyclodextrin, a-cyclodextrin, p-cyclodextrin, y- cyclodextrin, hydroxyethyl-p-cyclodextrin, 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.

[0390] 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.

[0391] 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.

[0392] The compounds of formula (I) or the above described pharmaceutical compositions comprising a compound of formula (I) may be administered to a subject by any convenient route of administration, whether systemically / peripherally or at the site of desired action, including but not limited to one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection techniques or infusion techniques, and including, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for example, subcutaneously or intramuscularly), pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or intracameral), rectal, or vaginal administration.

[0393] 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.

[0394] 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.

[0395] 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.

[0396] 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.

[0397] 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.

[0398] 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 liposomal ly entrapped compounds. The present invention thus also relates to liposomes containing a compound of the invention.

[0399] 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.

[0400] 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.

[0401] 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.

[0402] 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).

[0403] 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.

[0404] A proposed, yet non-limiting dose of the compounds according to the invention for oral administration to a human (of approximately 70 kg body weight) may be 0.05 to 2000 mg, preferably 0.1 mg to 1000 mg, of the active ingredient per unit dose. The unit dose may be administered, e.g., 1 to 3 times per day. The unit dose may also be administered 1 to 7 times per week, e.g., with not more than one administration per day. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient / subject as well as the severity of the condition to be treated. The precise dose and also the route of administration will ultimately be at the discretion of the attendant physician or veterinarian.

[0405] Therapeutic use

[0406] 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.

[0407] The present invention provides compounds that function as inhibitors of PARG. Thus, the present invention provides a method of inhibiting PARG enzyme activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0408] 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.

[0409] 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.

[0410] 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.

[0411] 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.

[0412] 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.

[0413] 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.

[0414] 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.

[0415] 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.

[0416] 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).

[0417] 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, Merkel-cell 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, squamous-cell 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.

[0418] Preferably, the cancer to be treated is selected from lung, colon, breast, ovarian, prostate, liver, pancreas, brain, gastric and skin cancer.

[0419] 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:

[0420] (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);

[0421] (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;

[0422] (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];

[0423] (iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB 1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, pp1 1 -29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro- 4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (for example Ras / Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (R1 15777) and lonafarnib (SCH66336)), inhibitors of cell signalling through MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1 152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors;

[0424] (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 av[33 function and angiostatin)];

[0425] (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;

[0426] (viii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;

[0427] (ix) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multidrug resistance gene therapy; and (x) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

[0428] 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.

[0429] 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.

[0430] 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.

[0431] Examples

[0432] 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.

[0433] Synthesis of the compounds of formula (I) and (II)

[0434] The syntheses of different embodiments of the compounds of formula (I) or (II) according to the present invention are preferably carried out according to the general synthetic sequences as shown in Schemes 1 -2. It is to be understood that the compounds provided herein, but not falling under the scope of formula (I), can also be prepared as described herein.

[0435] In addition to said routes described below, also other routes may be used to synthesize the target compounds, in accordance with common general knowledge of a person skilled in the art of organic synthesis. The order of transformations exemplified in the following Schemes is therefore not intended to be limiting, and suitable synthesis steps from various schemes can be combined to form additional synthesis sequences. In addition, modification of any of the substituents can be achieved before and / or after the exemplified transformations. These modifications can be such as the introduction of protective groups, cleavage of protective groups, reduction or oxidation of functional groups, halogenation, 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. In certain cases, synthesis may require a further step to be introduced, a step apparent to the skilled person and compatible with the routes described herein.

[0436] Accordingly, the compounds of the present invention may also be prepared in analogy to the specific procedures shown in the Examples section.

[0437] Scheme 1

[0438]

[0439] Scheme 1 illustrates a preferred synthetic approach to compounds of the general formula (la) or the general formula (Ila) in which Rs is defined as being hydrogen. It is to be understood that in formula (Ila), Z is Z’.

[0440] 1 2 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, BH3.Me2S, PtO2 / H2, sodium tetrahydroborate etc., (see for example: Long et al, WO2018 / 71535). The reaction is performed at temperatures ranging from 20-40°C. The reaction is preferably completed after 0.5-24 hours.

[0441] In the second step, a compound of formula 2 is reacted with ethyl 2-chloro-2-oxoacetate 3 under basic condition to give a compound of formula 4. The acylation is preferably carried out in a 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, WO2015 / 25025). The reaction is performed at temperatures ranging from -5°C to room temperature. The reaction is preferably completed after 1-24 hours.

[0442] 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 neat conditions. The reaction is performed at temperatures ranging from 70-140°C. The reaction is preferably completed after 1-24 hours.

[0443] In the fourth step, a compound of formula 5 is converted to a compound of formula 6 in which R4 is as defined for the compound of formula (I) or (II) 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 at 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-(d ifl uoromethyl)-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.

[0444] In the fifth step, a compound of formula 6 in which R4 is as defined for the compound of formula (I) or (II) 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.

[0445] In the sixth step, a compound of formula 8 in which R4 is as defined for the compound of formula (I) is reacted with chlorination reagent to give a sulfonyl chloride of formula 9. This sulfonyl chloride formation can be carried out by treatment with NCS, sulfonyl chloride, DCDMH, CI2 etc., in MeCN with equivalent acetic acid and water (see for example: Sutton et al, WO 2021 / 055744). Preferred is the herein described use of DCDMH in MeCN with equivalent acetic acid and water. The reactions are preferably run under an atmosphere of argon for 0.5-5 hours at 0°C to room temperature.

[0446] In the seventh step, a compound of formula 8 in which R4 is as defined for the compound of formula

[0447] (I) or (II) is reacted with an amine of formula 9 in which Z is as defined for the compound of formula (I) or

[0448] (II) 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, 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.

[0449] In the final step, a compound of formula 10 in which R4 is as defined for the compound of formula (I) or (II) is coupled with amine type compounds of formula 11 or boronic ester type or boronic acid type compounds of formula 12 or 13 in which A, L1, L2 and L3 are as defined for the compound of formula (I) or (II) to give a compound of general formula (la) or (Ila) in which Rs is defined as being hydrogen. In case of amine type compounds 11, the 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-IHept Cl or Pd-PEPPSI-I PentCi o-picoline in dioxane. The reactions are preferably run under an atmosphere of argon for 1-48 hours at 80-120°C in a microwave oven or in an oil bath. 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. In case of boronic ester type or boronic acid type compounds of formula 12 or 13, the coupling can be carried out by a palladium-catalyzed cross-coupling reaction using a suitable palladium catalyst such as for example Pd(dppf)Cl2.CH2Cl2 or Pd(dppf)Cl2 in presence of a suitable base such as potassium carbonate or cesium carbonate, in a suitable solvent such as a mixture of dioxane and water. 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.

[0450] Scheme 2 illustrates a preferred synthetic approach to compounds of the general formula (I) or the general formula (II). It is noted that in the compound of formula (II), Z is Z’.

[0451] In the first step, a compound of formula 7 in which R4 is as defined for the compound of formula (I) or (II) is reacted with an iodide reagent to give a compound of formula 14. This iodization can be carried out by treatment with NIS, I2 etc., in MeCN, THF, dioxane, DMF etc. (see for example: Bentley et al; WO2011 / 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.

[0452] In the second step, a compound of formula 8 in which R4 is as defined for the compound of formula (I) or (II) is reacted with chlorination reagent to give a sulfonyl chloride of formula 9 in which Rsb is restricted to iodine and chlorine (-I or Cl). This sulfonyl chloride formation can be carried out by treatment with NCS, sulfonyl chloride, DCDMH, CI2 etc., in MeCN with equivalent acetic acid and water (see for example: Sutton et al, WO 2021 / 055744). Preferred is the herein described use of DCDMH in MeCN with equivalent acetic acid and water. The reactions are preferably run under an atmosphere of argon for 0.5-5 hours at 0°C to room temperature.

[0453] In the third step, a compound of formula 15 in which R4 is as defined for the compound of formula (I) or (II) and Rsb is -I of -Cl is reacted with an amine of formula 9 in which Z is as defined for the compound of formula (I) or (II) to give a compound of formula 16. This reaction can be carried out under basic conditions (see for example: Sutton et al, WO 2021 / 055744). Preferred is the herein described use of trimethylamine, pyridine etc., in DCM, THF or DMF. The reactions are preferably run under an atmosphere of argon for 0.5-24 hours at 0°C to room temperature.

[0454] In the fourth step, a compound of formula 16 in which R4 is as defined for the compound of formula (I) or (II) and Rsb is -I or -Cl is converted into a compound of formula 17 in which Rs is as defined for the compound of formula (I) or (II). For the transformation of Rsb into Rs different palladium-cross coupling can be performed using an appropriate coupling partner such as for example, but not limited to, a boronic acid, a boronic ester or an organotin compound in presence of a suitable palladium catalyst such as for example, but not limited to, Pd(Phs)4, in the presence of a suitable base such as for example, but not limited to, potassium carbonate, cesium carbonate at a suitable temperature for an appropriate time. In case Rs is defined as being a hydrogen in a compound of formula 17, the iodide of a compound of formula 16 can be removed by hydrogenation to give a compound of formula 17. The reaction is preferably carried out in THF, MeOH, EtOH, dioxane or DMF in the presence of a hydrogenation catalyst like Pd / C, Pd(0H)2, Raney Ni, PtC etc. under an atmosphere of hydrogen (see for example: Aissaoui et al, US2011 / 105514). The reaction is performed at temperatures ranging from 20-80°. The reaction is preferably completed after 0.5-24 hours.

[0455] In the final step, a compound of formula 17 in which R4 and Rs are as defined for the compound of formula (I) or (II) is coupled with amine type compounds of formula 11 or boronic ester type or boronic acid type compounds of formula 12 or 13 in which A, L1 , L2 and L3 are as defined for the compound of formula (I) or (II) to give a compound of general formula (I) or (II). In case of amine type compounds 11, the 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-IHept Cl or Pd-PEPPSI-I PentCi o-picoline in dioxane. The reactions are preferably run under an atmosphere of argon for 1 -48 hours at 80-120°C in a microwave oven or in an oil bath. 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.

[0456] In case of boronic ester type or boronic acid type compounds of formula 12 or 13, the coupling can be carried out by a palladium-catalyzed cross-coupling reaction using a suitable palladium catalyst such as for example Pd(dppf)Cl2.CH2Cl2 or Pd(dppf)Cl2 in presence of a suitable base such as potassium carbonate or cesium carbonate, in a suitable solvent such as a mixture of dioxane and water. 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.

[0457] Preparative examples

[0458] The compounds described in this section are defined by their chemical formulae and their corresponding chemical names. In case of conflict between any chemical formula and the corresponding chemical name indicated herein, the present invention relates to both the compound defined by the chemical formula and the compound defined by the chemical name, and particularly relates to the compound defined by the chemical formula.

[0459] General considerations

[0460] 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); BOC2O (di-tert- butyldicarbonate); BuOH (Butanol); (Cataxium APdGs (Mesylate[(di(1-adamantyl)-n-butylphosphine)-2- (2'-amino-1 ,1 '-biphenyl)]palladium(ll)); (CDCh (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- / so-propylethylamine); DMAP (4- / V-W-dimethylaminopyridine), DME (1 ,2-dimethoxyethane), DMEDA (dimethylethylenediamine ); DMF ( / V-W-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]-1H-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 (metachloroperoxybenzoic acid), MeCN (acetonitrile), MeOH (methanol); min (minute(s)); Mn02 (Manganese (IV) oxide); MS (mass spectrometry); MS2O (methanesulfonic anhydride); MTBE (methyl ferf-butyl ether); NaBH4 (sodium borohydride); NaHCOs (sodium hydrogenocarbonate); Na2S20s (sodium thiosulfate); Na2SO4 (sodium sulfate); NCS (N-chlorosuccinimide); NH3 (ammonia); NH4CI (ammonium fluoride); NiCb (nickel dichloride); NIS (N-lodosuccinimide); NMP (N-methylpyrrolidone); NMR (nuclear magnetic resonance); Pd / C (palladium on charcoal); Pd2dbas (tris(dibenzylideneacetone)dipalladium ); Pd(dppf)Cl2 (1 ,1 -Bis(diphenylphosphino)ferrocene dichloropalladium ); Pd(dppf)Cl2.CH2Cl2 (1,1 Bis(diphenylphosphino)ferrocene dichloropalladium.dichloromethane); Pd(Ph3)2Cl2 (Bis(triphenylphosphine)palladium(ll) 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(0H)2 (palladium hydroxide); Pd(Phs)4 (Palladium-tetrakis(triphenylphosphine)); Phl(0Ac)2 ((Diacetoxyiodo)benzene)); PMB (paramethoxybenzyl); P(tBu)3 (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); ferf-BuBrettPhos-Pd-G3 ([(2-Di-ferf-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1 ,1 '-biphenyl)-2- (2'-amino-1 ,1 '-biphenyl)]palladium(ll) methanesulfonate); tBuXPhos Pd G3 (Methanesulfonato(2-di-t- butylphosphino-2',4',6'-tri-i-propyl-1 ,1 '-biphenyl)(2'-amino-1 ,1 '-biphenyl-2-yl)palladium(ll))TBDMSCI 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 ,1'-biphenyl-2-yl)palladium(ll)).

[0461] General Procedure: All starting materials and solvents were obtained either from commercial sources or prepared according to literature references. Commercially available reagents and anhydrous solvents were used as supplied, without further purification. Unless otherwise stated all reactions were stirred. All air- and moisture-sensitive reactions were carried out in oven-dried (at 120°C) glassware under an inert atmosphere of nitrogen or argon. Compound names were generated using ChemDraw professional (Perkin Elmer). In some cases generally accepted names of commercially available reagents were used in place of ChemDraw generated names.

[0462] Reversed Phase HPLC conditions for LCMS Analysis: Method 1 : SHIMADZU LCMS-2020 Kinetex EVO C18 2.1X30 mm, 5 urn at 50°C; Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 1 .5 mL / min; eluted with the mobile phase over 0.80 min employing UV detection at 220 nm and 254 nm. Gradient information: 0- 0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-1 .20 min, held at 5% A-95% B; 1 .20-1 .21 min, returned to 95% A-5% B, 1.21-1 .55 min, held at 95% A-5% B.

[0463] Method 2: SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X30 mm, 5 pm at 50°C; Mobile Phase:

[0464] 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.

[0465] Method 3: SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X30 mm, 5 pm at 40°CMobile Phase:

[0466] 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.

[0467] Method 4: SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X20 mm 2.6 pm at 50°C; Mobile Phase:

[0468] A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 2.0 mL / min; eluted with the mobile phase over 1.00 min employing UV detection at 220 nm and 254 nm. Gradient information: 0.01-0.60 min, ramped from 95% A-5% B to 5% A-95% B; 0.61-0.78 min, held at 5% A-95% B; 0.78-0.79 min, returned to 95% A-5% B, 0.79-0.80 min, held at 95% A-5% B.

[0469] Method 5: SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X30 mm 5 pm at 50°C Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 1 .5 mL / min; eluted with the mobile phase over 1.00 min employing UV detection at 220 nm and 254 nm. Gradient information: 0.01-0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-0.95 min, held at 5% A-95% B; 0.95-0.96 min, returned to 95% A-5% B, 0.96-1 .00 min, held at 95% A-5% B.

[0470] Method 6: SHIMADZU LCMS-2020 HALO C18 3.0X30 mm, 5 pm at 50°C; Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in Acetonitrile (v / v); flow rate held at 1.5 mL / min; eluted with the mobile phase over 1 .05 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-0.50 min, ramped from 95% A-5% B to 5% A-95% B; 0.50-0.80 min, held at 5% A-95% B; 0.80-0.81 min, returned to 95% A-5% B, 0.81-1 .05 min, held at 95% A-5% B.

[0471] Method 7: SHIMADZU LCMS-2020 HALO C18 3.0X30mm,5um at 50°C; Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in Acetonitrile (v / v); flow rate held at 1.2 mL / min; eluted with the mobile phase over 3.0 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-2.10 min, ramped from 95% A-5% B to 5% A-95% B; 2.10-2.80 min, held at 5% A-95% B; 2.81-3.00 min, returned to 95% A-5% B, 2.81-3.00 min, held at 95% A-5% B.

[0472] Method 8: SHIMADZU LCMS-2020 HALO C18 3.0X30mm,5um at 50 °C; Mobile Phase: A:

[0473] 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 1 .5 mL / min; eluted with the mobile phase over 0.80 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-0.45 min, ramped from 95% A-5% B to 5% A-95% B; 0.45-0.70 min, held at 5% A-95% B; 0.70-0.71 min, returned to 95% A-5% B, 0.71-0.80 min, held at 95% A-5% B

[0474] Method 9: SHIMADZU LCMS-2020 HALO C18 3.0X30 mm, 5 pm at 50 °C, Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in Acetonitrile (v / v); flow rate held at 1 .5 mL / min; eluted with the mobile phase over 1 .05 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-0.50 min, ramped from 95% A-5% B to 5% A-95% B; 0.50-0.80 min, held at 5% A-95% B; 0.80-0.81 min, returned to 95% A-5% B, 0.81-1.05 min, held at 95% A-5% B.

[0475] Method 10: SHIMADZU LCMS-2020 HALO C18 3.0X30 mm, 5 pm at 50 °C, Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in Acetonitrile (v / v); flow rate held at 2 mL / min; eluted with the mobile phase over 1 .05 min employing UV detection at 220 nm and 254 nm. Gradient information: 0- 0.40 min, ramped from 95% A-5% B to 5% A-95% B; 0.40-0.75 min, held at 5% A-95% B; 0.75-0.76 min, returned to 95% A-5% B, 0.76-1 .05 min, held at 95% A-5% B.

[0476] Method 11 : SHIMADZU LCMS-2020 XBridge C18, 2.1X50mm, 5 pm at 50 °C, Mobile Phase: A: 10mmol / L NH4HCO3 in water (v / v); B: Acetonitrile (v / v); flow rate held at 1 .5 mL / min; eluted with the mobile phase over 2.20 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-1.5 min, ramped from 95% A-5% B to 5% A-95% B; 1 .50-1 .90 min, held at 5% A-95% B; 1 .90-1 .91 min, returned to 95% A-5% B, 1 .91-2.20 min, held at 95% A-5% B.

[0477] Method 12: Shimadzu LCMS 2020 Wepure XPtC-C18 2.1X30 mm, 5 pm at 40 °C, Mobile Phase: A: 0.025% NH3'H2O in water (v / v, B: MeCN; flow rate held at 1 .5 mL / min; eluted with the mobile phase over 1 .55 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-1 .20 min, held at 5% A-95% B; 1 .20-1 .21 min, returned to 95% A-5% B, 1 .21-1 .55 min, held at 95% A-5% B.

[0478] SFC Analytical Methods SFC Method 1 : Column:Chiralpak I C-3 50*4.6 mm I.D., 3 urn; Mobile phase: Phase A for CO2, and Phase B for MeOH+ACN(0.05% DEA); Gradient elution: 40% MeOH+ACN(0.05% DEA) in CO2 , Flow rate: 3mL / min; Detector: PDA; Column Temp: 35C; Back; Pressure: 100 Bar)

[0479] SFC Method 2: Column: Chiralpak I C-3 50x4.6mm I.D., 3um; Mobile phase: Phase A for CO2, and Phase B for and Phase B for IPA+ACN(0.05%DEA); Gradient elution: IPA+ACN (0.05% DEA) in CO2 from 30% to 60%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

[0480] SFC Method 3: Column: Chiralcel OD-3 50*4.6mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for IPA+ACN(0.05%DEA); Gradient elution: IPA+ACN (0.05 %DEA) in CO2 from 20% to 60%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

[0481] SFC Method 4: Column: Chiralcel OJ-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and 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.

[0482] SFC Method 5: Column: Chiralcel OJ-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) in CO2 from 5% to 40%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

[0483] SFC Method 6: Column: Chiralpak IC-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for IPA+ACN (ACN (0.05% DEA); Gradient elution: IPA+ACN (ACN (0.05% DEA) in CO2 from 20% to 60%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

[0484] SFC Method 7: Column: Chiralpak IC-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05 %DEA) in CO2 from 20% to 60%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

[0485] SFC Method 8: Column: Chiralpak AD-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) in CO2 from 20% to 60%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

[0486] SFC Method 9: Column: Chiralcel OD-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for IPA+ACN (0.05% DEA); Gradient elution: B in CO2 from 20% to 60% , Flow rate: 4 mL / min; Detector: PDA; Colum Temp: 35°C; Back Pressure:! 00 Bar

[0487] SFC Method 10: Column: Chiralpak IC-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for IPA+ACN (0.05% DEA); Gradient elution: B in CO2 from 30% to 60%, Flow rate:4 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure:! 00 Bar SFC Method 11 : Column: Chiralpak AS-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: 40% B in CO2, Flow rate: 3 mL / min; Detector: PDA;

[0488] Column Temp: 35°C; Back Pressure:! 00 Bar

[0489] SFC Method 12: Column: Chiralpak AY-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for IPA+ACN (0.05% DEA); Gradient elution: 40% B in CO2, Flow rate: 3 mL / min; Detector: PDA Column Temp: 35°C; Back Pressure:! 00 Bar

[0490] SFC Method 13: Column: Chiralcel AD-3 50*4.6 mm I.D.,3 pm; Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution:30% EtOH (0.05% DEA) in CO2, Flow rate: 3mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar

[0491] SFC Method 14: Column: Chiralpak IC-3 50*4.6 mm I.D.,3 pm; Mobile phase: Phase A for CO2 and Phase B for IPA+ACN (0.05% DEA); Gradient elution: 60% IPA+ACN (0.05% DEA) in CO2, Flow rate: 3mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure:! 00 Bar"

[0492] SFC Method 15: Column: Chiralpak AS-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: B in CO2 from 5% to 40%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar

[0493] SFC Method 16: Column: Lux 3um Cellulose-4 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for MeOH (0.05% DEA); Gradient elution: 30% to 60% MeOH (0.05% DEA) in CO2, Flow rate: 3mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar

[0494] SFC Method 17: Column: Chiralpak AS-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for MeOH (0.05% DEA); Gradient elution: B in CO2 from 5% to 40%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure:! 00 Bar

[0495] SFC Method 18: Column: Chiralpak AD-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for IPA+ACN (0.05% DEA); Gradient elution: B in CO2 from 20% to 60%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar

[0496] SFC Method 19: Column:(S,S) Whelk-01 50*4.6 mm I.D., 3.5um Mobile phase: Phase A for CO2, and Phase B for IPA+ACN (0.05% DEA); Gradient elution: B in CO2 from 20% to 60%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar SFC Method 20: Column: Column: Chiralpak I H-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) in CO2 from 5% to 40%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

[0497] SFC Method 21 : Column: Chiralcel OD-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and 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.

[0498] SFC Method 22: Column: Chiralpak IK-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for MeOH (0.05% DEA); Gradient elution: 40% MeOH (0.05% DEA) in CO2, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0499] SFC Method 23: Column: Chiralpak IK-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: 50% EtOH (0.05% DEA) in CO2, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0500] SFC Method 24: Column: Chiralpak IK-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for IPA+ACN (0.05% DEA); Gradient elution: IPA+ACN (0.05% DEA) in CO2 from 20% to 60%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0501] SFC Method 25: Column: Chiralpak IC-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for IPA+ACN (0.05% DEA); Gradient elution: IPA+ACN (0.05% DEA) from 20% to 60% in CO2, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0502] SFC Method 26: Column: Chiralpak IK-3 50*4.6 mm I.D.,3 pm; Mobile phase: Phase A for CO2, and Phase B for EtOH+ACN (0.05% DEA); Gradient elution: EtOH+ACN (0.05% DEA) in CO2 from 20% to 60%; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0503] SFC Method 27: Column: Chiralpak IK-3 50*4.6 mm I.D.,3 pm; Mobile phase: Phase A for CO2, and Phase B for IPA+ACN (0.05% DEA); Gradient elution: 50% IPA+ACN (0.05% DEA) in CO2, Flow rate: 3mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar

[0504] SFC Method 28: Column: Chiralcel OX-3 50*4.6 mm I.D.,3 pm; Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) in CO2 from 10% to 60% , Flow rate: 3mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar

[0505] SFC Method 29: Column: Chiralpak IC-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2 and Phase B for IPA+ACN (0.05% DEA); Gradient elution: 30% IPA+ACN (0.05% DEA) in CO2, Flow rate: 3mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure:! 00 Bar

[0506] SFC Method 30: Column: Chiralcel OD-3 50*4.6 mm I.D.,3 pm; Mobile phase: Phase A for CO2, and Phase B for IPA+ACN (0.05% DEA); Gradient elution:30% IPA+ACN (0.05% DEA) in CO2, Flow rate: 3mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar

[0507] 1H NMR Spectroscopy:

[0508] 1H NMR spectra were acquired on a Bruker Avance III spectrometer at 400 MHz using residual undeuterated solvent as reference.1H NMR signals are specified with their multiplicity / combined multiplicities as apparent from the spectrum; possible higher-order effects are not considered. Chemical shifts of the signals (5) are specified as ppm (parts per million).

[0509] Salt stoichiometry:

[0510] In the present text, in particular in the experimental section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and / or purification process, is, in most cases, unknown. Unless specified otherwise, suffixes to chemical names or structural formulae such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HO", "x CF3COOH", "x Na+", for example, are to be understood as not a stoichiometric specification, but solely as a salt form. This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and / or purification processes described, as solvates, such as hydrates with (if defined) unknown stoichiometric composition.

[0511] Preparation of Intermediate 1.1

[0512] Benzyl(3S,5S)-4-((2-(dimethylamino)ethyl)(methyl)carbamoyl)-3,5-dimethylpiperazine-1- carboxylate

[0513] To a solution of benzyl (3S,5S)-3,5-dimethylpiperazine-1 -carboxylate (6.00 g, 24.2 mmol), TEA (10 mL, 72.5 mmol) in DCM (60 mL) was dropwise added a solution of triphosgene (4.30 g, 14.5 mmol) in DCM (40 mL) over 30 mins at 0 °C and the mixture was stirred at 20 °C for 2 h under N2. After 2 h, triethylamine (4.94 g, 48.3 mmol) was added dropwise. The reaction mixture was stirred at 20 °C for 1 h, then, diluted with water (100 mL) and extracted with DCM (100 mL, 2x). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash (ISCO; 330 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, mobile phase: A: 0.1 % formic acid in water, B: MeCN; B%: 0%-15% @ 200 mL / min) to give the product solution. The pH of the solution was adjusted to « 7~8 by adding NaHCOs (aq., sat.) and the product was extracted with ethyl acetate (100 mL, 2x). The combined organic layer was washed with brine (200 mL), dried over anhydrous NazSC , filtered and concentrated under vacuum to give the product benzyl (3S,5S)- 4-((2-(dimethylamino)ethyl)(methyl)carbamoyl)-3,5-dimethylpiperazine-1 -carboxylate (4.00 g, 10.6 mmol, 43.97 % yield) as yellow oil.

[0514] RT 0.421 min (Method 1); m / z 377.1 (M+H)+(ESP);1HNMR (CDCh, 400 MHz): 7.40-7.30 (m, 5H), 5.20-5.11 (m, 2H), 3.71-3.62 (m, 1 H), 3.62-3.54 (m, 2H), 3.48-3.34 (m, 2H), 3.31-3.25(m, 2H), 3.17-3.13 (m, 1 H), 2.97 (s, 3H), 2.46-2.42 (m, 2H), 2.26 (s, 6H), 1.18-0.98 (m, 6H)

[0515] Preparation of Intermediate 1 .2 (2S,6S)-N-(2-(dimethylamino)ethyl)-N,2,6-trimethylpiperazine-1-carboxamide dihydrochloride

[0516] A solution of benzyl (3S, 5S)-4- ((2-(d imethylami no)ethyl) (methyl)carbamoyl)-3, 5-dimethy Ipiperazi ne- 1 -carboxylate (4.00 g, 10.6 mmol) in HCI (aq., 6 M, 40 mL, 240 mmol) was stirred at 100 °C for 2 h. The resulting mixture was cooled to room temperature, washed with EtOAc (50 mL , 2x). The aqueous phase was further diluted with water (100 mL) and, then lyophilized directly to give the crude product (2S,6S)-N- (2-(dimethylamino)ethyl)-N,2,6-trimethylpiperazine-1-carboxamide dihydrochloride (4.30 g, 2HCI salt) as a yellow waxy solid.

[0517] RT 0.553 min (Method 1); m / z 243.2 (M+H)+(ESP);1HNMR (DMSO-de, 400 MHz): 10.89 (s, 1 H), 9.48 (s, 2H), 3.70-3.64 (m, 1 H), 3.60-3.51 (m, 3H), 3.22-3.08 (m, 4H), 2.95 (s, 3H), 2.94-2.86 (m, 2H), 2.64 (s, 6H), 1.12 (d, J = 6.4 Hz, 6H) (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2,6- trimethylpiperazine-1-carboxamide

[0518] Synthesis of 8-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(1 - methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide has been performed according to previously reported procedure, i.e. the compound has been made as reported in example 18c of WO2023 / 057389, which is herewith incorporated herein by reference in its entirety. To a mixture of 8-chloro-3-(5- (difluoromethyl)-l ,3,4-thiadiazol-2-yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (1.00 g, 2.38 mmol) in DMF (15 mL) was added (2S,6S)-N-(2-(dimethylamino)ethyl)-N,2,6-trimethylpiperazine- 1 -carboxamide dihydrochloride (1.05 g, 3.33 mmol, 2 HCI salt) , Pd-PEPPSI-IPentCI o-picoline (300 mg, 0.357 mmol) and CS2CO3 (2.33 g, 7.15 mmol). The mixture was degassed with N2 (3x) and then stirred at 110 °C for 4 h. Meanwhile, three additional reactions were conducted in parallel on the same scale. The resulting reaction mixtures were combined, diluted with water (200 mL) and extracted with EtOAc (200 mL, 2x). The combined organic layer was washed with brine (200 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (ISCO; 330 g Flash Column Welch Ultimate XB_C18 20-40 pm; 120 A, mobile phase: A: 0.1 % formic acid in water, B: MeCN; B%: 0%-40% @ 100mL / min) to give a product solution. Then, the pH of the solution was adjusted to « 7~8 by adding NaHCOs (aq., sat.) and the product was extracted with ethyl acetate (500 mL, 2x). The combined organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and under vacuum to give an impure product which was further purified by preparative HPLC (column: Kromasil Eternity XT 250*80 mm*10 pm; mobile phase: A: 10 mM aqueous solution of NH4HCO3, B: MeCN; B%: 25%-55%, 20 min) and lyophilized directly to give the product (2S,6S)-4-(3-(5- (difluoromethyl)-l ,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N- (2-(dimethylamino)ethyl)-N,2,6-trimethylpiperazine-1-carboxamide (1.70 g, 2.72 mmol, 28.52%) as a yellow solid.

[0519] RT 0.496 min (Method 1); m / z 626.3 (M+H)+(ESI*);1HNMR (CDCb, 400 MHz): 9.86 (s, 1 H), 7.73 (s, 1 H), 7.08 (t, J = 53.2, 1 H), 6.66 (s, 1 H), 5.21 (s, 1 H), 3.78-3.65 (m, 3H), 3.34-3.30 (m, 2H), 3.24-3.14 (m, 3H), 3.03 (s, 3H), 2.50-2.47 (m, 2H), 2.29 (s, 6H), 1.39 (s, 3H), 1.32 (d, J= 6.4 Hz, 6H), 0.99-0.90 (m, 2H), 0.65-0.57 (m, 2H)

[0520] Preparation of Intermediate 2.1 benzyl (3S,5S)-4-((2-(azetidin-1-yl)ethyl)(methyl)carbamoyl)-3,5-dimethylpiperazine-1- carboxylate

[0521] To a solution of benzyl (3S,5S)-3,5-dimethylpiperazine-1 -carboxylate (150 mg, 0.604 mmol) and TEA (0.25 mL, 1.81 mmol) in DCM (1 mL) was added triphosgene (108 mg, 0.362 mmol) in DCM (1 mL) dropwise at 0°C. The reaction mixture was stirred for 2hours at 20 °C under N2 and 2-(azetidin-1-yl)-N- methylethan-1 -amine hydrochloride (146 mg, 0.966 mmol) was added. The reaction mixture was further stirred at 20 °C for 12 h, then diluted with water (10 mL) and extracted with DCM (10 mL; 2x). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (ISCO; 40 g Flash Column Welch Ultimate XB_C18 20-40 pm; 120 A, mobile phase: A: 0.1 % formic acid in water, B: MeCN; B%: 0%-15% @ 80 mL / min). The pH of the resulting solution was adjusted to 8 with NaHCOs (aq., sat.) and the product was extracted with ethyl acetate (20 mL, 2x). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the product benzyl (3S,5S)-4-((2-(azetidin-1 -yl)ethyl)(methyl)carbamoyl)-3,5-dimethylpiperazine-1 -carboxylate (40 mg, crude) as yellow oil.

[0522] RT 0. 422 min (method 6); m / z 389.2 (M+H)+(ESI*);

[0523] Preparation of Intermediate 2.2

[0524] (2S,6S)-N-(2-(azetidin-1-yl)ethyl)-N,2,6-trimethylpiperazine-1-carboxamide

[0525]

[0526] To a solution of benzyl (3S,5S)-4-((2-(azetidin-1-yl)ethyl)(methyl)carbamoyl)-3,5- dimethylpiperazine-1-carboxylate (40 mg, 0.103 mmol) in n-BuOH (5.0 mL) was added Pd / C (25 mg, 0.103 mmol, 10% purity) at room temperature. The reaction mixture was stirred at 30 °C for 12 h under H2 (45 Psi), then filtered and concentrated under reduced pressure to give the product (2S,6S)-N-(2- (azetidin-1 -yl)ethyl)-N, 2, 6-trimethylpiperazine-1 -carboxamide (25 mg, crude) as yellow oil.

[0527] 1H NMR (CDCh, 400 MHz): 3.52 - 3.41 (m, 1 H), 3.30 - 3.34 (m, 2H), 3.20 - 3.24 (m, 4H), 2.95 (s, 3H), 2.95 - 2.91 (m, 3H), 2.64 - 2.47 (m, 4H), 2.04-2.11 (m, 2H), 1.13 - 1.08 (m, 6H)

[0528] Preparation of example 2

[0529] (2S,6S)-N-(2-(azetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1- carboxamide formate

[0530] To a solution of 8-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(1- methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (20 mg, 0.0476 mmol) in 1 ,4-Dioxane (0.5 mL) was added (2S,6S)-N-(2-(azetidin-1 -yl)ethyl)-N, 2, 6-trimethylpiperazine-1 -carboxamide (18 mg, 0.0715 mmol), Pd-PEPPSI-IPentCI o-picoline (4.0 mg, 0.00476 mmol) and CS2CO3 (47 mg, 0.143 mmol). The reaction mixture was degassed with N2 (3x), stirred at 100 °C for 3 h, then diluted with H2O (10 mL) and extracted with EtOAc (10 mL, 2x). The combined organic layer was washed with brine (10 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*7 m; mobile phase: A: 0.1 % FA in water, B: MeCN; B%: 20%-50%, 15 min) and lyophilized directly to give the product (2S,6S)-N-(2- (azetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 -carboxamide formate (6.6 mg, 0.00925 mmol, 19.41 % yield, 96.40% purity based on LCMS method 6, FA salt) as a yellow solid.

[0531] RT 0.495 min (LCMS: method 6); m / z 638.3 (M +H)+(ESI+). RT 1 .678 min: (SFC Method 3); 95.5% ee;1H NMR (CDCh, 400 MHz): 9.85 (s, 1 H), 8.59 (s, 1 H), 7.72 (s, 1 H), 7.22 (t, J = 54.0 Hz, 1 H), 6.69 (s, 1 H), 5.48 (br, 1 H), 3.83 - 3.67 (m, 6H), 3.59-3.52 (m, 1 H), 3.40 - 3.31 (m, 3H), 3.20 (m, 2H), 3.07 (s, 3H), 3.01-2.95- (m, 2H), 2.41-2.33 (m, 2H), 1.38 (s, 3H), 1.32 (d, J = 6.4 Hz, 6H), 0.98 - 0.91 (m, 2H), 0.63 - 0.56 (m, 2H).

[0532] Preparation of example 2a

[0533] Preparation of Intermediate 2a.1

[0534] (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N-(2,2-dimethoxyethyl)-N,2,6- trimethylpiperazine-1-carboxamide

[0535] A solution of triphosgene (2087 mg, 7.03 mmol) in DCM (10 mL) was added drop wise to a solution of 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(1- methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (7.00 g, 14.1 mmol) in DCM (50 mL) followed by TEA (5.8 mL, 42.2 mmol) at 0 °C and the reaction was stirred at 25 °C for 0.5 h. Then, a solution of 2,2- dimethoxy-N-methylethan-1 -amine (5029 mg, 42.2 mmol) in DCM (10 mL) was added and the reaction was stirred at 25 °C for 16 h. The reaction mixture was quenched with a solution of water ( 100 mL) and extracted with DCM (50 mL, 2x).The organic layer was washed with brine (100 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: 50mm*H400mm Welch Ultimate XB_C18 20-40 pm; 120 A; mobile phase: A: 0.1 % formic acid in water, B: MeCN; B%: 65%-85%, 30 min) and lyophilized to give the product (2S,6S)- 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin- 8-yl)-N-(2,2-dimethoxyethyl)-N,2,6-trimethylpiperazine-1-carboxamide (6.00 g, 9.34 mmol, 66.36 % yield) as a yellow solid.

[0536] RT 0.584 min (LCMS: method 6); m / z 611.2 (M-MeOH+1)+(ESI+);1H NMR (CDCh, 400 MHz): 9.82 (s, 1 H), 7.70 (s, 1 H), 7.06 (t, J = 54.0 Hz, 1 H), 6.68 (s, 1 H), 5.70 (s, 1 H), 4.55 (t, J =5.2 Hz, 1 H), 3.79-3.73 (m, 1 H), 3.72-3.65 (m, 2 H), 3.42 (s, 3 H), 3.42 (s, 3 H), 3.35-3.28 (m, 2 H), 3.23-3.09 (m, 3 H), 3.07 (s, 3 H), 1.36 (s, 3 H), 1.30 (s, 3 H), 1.29 (s, 3 H), 0.87-0.97 (m, 2 H), 0.53-0.62 (m, 2 H).

[0537] Preparation of Intermediate 2a.2

[0538] (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2- oxoethyl)piperazine-1-carboxamide

[0539] To a mixture of (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N-(2,2-dimethoxyethyl)-N,2,6- trimethylpiperazine-1 -carboxamide ( 6.00 g, 9.34 mmol) in formic acid (60 mL) was added H2O (6.0 mL) at 25°C. The mixture was stirred at 25 °C for 2 h, then poured into H2O (300 mL), filtered and the filter cake was dried under reduced pressure to afford the product (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2- oxoethyl)piperazine-1 -carboxamide (5.40 g, 9.05 mmol, 96.95 % yield) as a yellow solid.

[0540] RT 0.555 min (LCMS: method 6); m / z 597.3 (M +H)+(ESI+).1H NMR (CDCh, 400 MHz): 9.88 (s, 1 H), 9.67 (s, 1 H), 7.74 (s, 1 H), 7.09 (t, J = 54.0 Hz, 1 H), 6.67 (s, 1 H), 5.16 (s, 1 H), 4.32 (d, J = 18.8 Hz, 1 H), 4.07 (d, J= 18.8 Hz, 1 H), 3.82-3.72 (m, 2H), 3.41-3.31 (m, 2H), 3.27-3.17 (m, 2H), 3.12 (s, 3H), 1.40 (s, 3H), 1.36 (s, 3H), 1.35 (s, 3H), 1.01-0.90 (m, 2H), 0.68-0.58 (m, 2H)

[0541] Preparation of example 2a

[0542] (2S, 6S)-N-(2- (azeti di n- 1 -y l)ethy l)-4-(3-(5-(dif I uoromethy I )- 1 , 3,4-thi adi azol -2-y l)-6-(N -(1 ■ methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1- carboxamide

[0543] To a solution of (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-oxoethyl)piperazine-1 - carboxamide (5.40 g, 9.05 mmol), azetidine hydrochloride (1693 mg, 18.1 mmol) in DCE (70 mL) was added NaBH(OAc)3 (3.836 g, 18.1 mmol) at 0 °C under N2.The reaction mixture was stirred at 20 °C for 2 h, then poured into NaHCOs (aq., sat., 200 mL) and extracted with DCM (200 mL, 2x). The combined organic layer was washed with brine (200 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by purified by column chromatography (ISCO; 80 g SepaFlash Silica Flash Column, Eluent of MeOH (0.5% NH4OH additive) @ 100 mL / min) and lyophilized directly to afford the product (2S,6S)-N-(2-(azetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N- (1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 -carboxamide (1955 mg, 3.07 mmol, 33.87 % yield) as a yellow solid.

[0544] RT 0.495 min (LCMS: method 6); m / z 638.3 (M +H)+(ESI+). RT 1.678 min: (SFC Method 3), ee > 99.9%;1H NMR (CDCh, 400 MHz): 9.85 (s, 1 H), 7.72 (s, 1 H), 7.08 (t, J = 54.0 Hz, 1 H), 6.67 (s, 1 H), 5.53 (br, 1 H), 3.76-.63 (m, 2H), 3.58-3.43 (m, 1 H), 3.36-3.21 (m, 6H), 3.20-3.13 (m, 2H), 3.12-3.04 (m, 1 H), 3.00 (s, 3H), 2.66-2.49 (m, 2H), 2.14-2.00 (m, 2H), 1.39 (s, 3H), 1.31 (d, J = 6.4 Hz, 6H), 0.98-0.91 (m, 2H), 0.65-0.56 (m, 2H)

[0545] Preparation of Intermediate 3.1

[0546] 8-bromo-1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(4-methoxybenzyl)-N-(1- methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (1 g, 2.01 mmol) in DMF (10 mL) was added K2CO3 (831 mg, 6.02 mmol) and 1-(chloromethyl)-4-methoxybenzene (0.471 g, 3.01 mmol). The mixture was stirred at 45 °C for 2 h under N2, then diluted with water (50 mL) and extracted with ethyl acetate (20 mL, 3x). The combined organic layer was washed with brine (20 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the product 8-bromo-1 -chloro-3- (5- (d ifl uoromethyl)-1 ,3,4- thiadiazol-2-yl)-N-(4-methoxybenzyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (600 mg, crude) as a yellow solid.

[0547] RT 0.698 min (method 5); m / z 620.0 (M+H+2)+(ESP)

[0548] Preparation of Intermediate 3.2

[0549] 2-((3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thio)ethan-1-ol

[0550] To a solution of 2-(4-fluoro-2-methylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (2 g, 8.47 mmol) in DMF (12 mL) was added K2CO3 (2.34 g, 16.9 mmol) and 2-mercaptoethan-1-ol (2.32 g, 29.7 mmol). The mixture was stirred at 100 °C for 16 h, then diluted with water (100 mL) and extracted with ethyl acetate (50 mL, 3x). The combined organic layer was washed with brine (30 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 15-55% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give the product 2-((3-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl)thio)ethan-1 -ol (300 mg, 1.02 mmol, 94.17% purity, 11.34% yield) as a white oil.

[0551] 1H NMR (CDCh, 400 MHz): 7.68 (d, J = 7.6 Hz, 1 H), 7.27 (s, 1 H), 7.11 (d, J = 7.6 Hz, 1 H), 3.76 (t, J= 5.6 Hz, 1 H), 3.15 (t, J = 5.6 Hz, 2H), 2.76 (t, J= 5.4 Hz, 2H), 2.51 (s, 3H), 1.34 (s, 12H)

[0552] Preparation of Intermediate 3.3

[0553] 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-((2-hydroxyethyl)thio)-2- methylphenyl)-N-(4-methoxybenzyl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6- sulfonamide

[0554] To a solution of 8-bromo-1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(4-methoxybenzyl)- N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (300 mg, 0.485 mmol) in dioxane (3 mL) was were added water (0.6 mL), K2CO3 (201 mg, 1.45 mmol), 2-((3-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)thio)ethan-1-ol (214 mg, 0.727 mmol) and Pd(dppf)Cl2.CH2Cl2 (53 mg, 0.0727 mmol). The mixture was stirred at 80 °C for 2 h, then diluted with water (30 mL) and extracted with ethyl acetate (10 mL, 3x). The combined organic layer was washed with brine (10 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash Silica Flash Column, Eluent of 10-60% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give the product 1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4- ((2-hydroxyethyl)thio)-2-methylphenyl)-N-(4-methoxybenzyl)-N-(1-methylcyclopropyl)imidazo[1 ,5- a]pyridine-6-sulfonamide (245 mg, 0.347 mmol, 93.74% purity, 67.09% yield) as a yellow solid.

[0555] RT 0.944 min (method 1); m / z 706.1 (M+H)+(ESI+);1H NMR (DMSO-de, 400 MHz): 9.65 (d, J= 1 .6 Hz, 1 H), 7.70 (t, J = 53.2 Hz, 1 H), 7.32 (s, 1 H), 7.28 (d, J= 8.0 Hz, 1 H), 7.18 (d, J= 8.0 Hz, 1 H), 7.17 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 1.6 Hz, 1 H), 6.64 (d, J = 8.8 Hz, 2H), 5.01 (t, J = 5.6 Hz, 1 H), 4.56-4.45 (m, 2H), 3.62 (t, J = 6.8 Hz, 2H), 3.54 (s, 3H), 3.12 (t, J = 6.8 Hz, 2H), 2.08 (s, 3H), 1.22 (s, 3H), 1.01-0.91 (m, 2H), 0.69-0.61 (m, 2H)

[0556] Preparation of Intermediate 3.4

[0557] 1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-hydroxyethylsulfonimidoyl)-2- methylphenyl)-N-(4-methoxybenzyl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6- sulfonamide

[0558] To a solution of 1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-((2-hydroxyethyl)thio)-2- methylphenyl)-N-(4-methoxybenzyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (245 mg, 0.347 mmol) and ammonium carbamate (271 mg, 3.47 mmol) in methanol (5 mL) was added Phl(OAc)2 (479 mg, 2.78 mmol). The resulting mixture was stirred at 50 °C for 2 h, then diluted with water (30 mL) and extracted with ethyl acetate (10 mL, 3x). The combined organic layer was washed with brine (10 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash Silica Flash Column, Eluent of 25-75% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give the product 1-chloro-3-(5- (difluoromethyl)-l ,3,4-thiadiazol-2-yl)-8-(4-(2-hydroxyethylsulfonimidoyl)-2-methylphenyl)-N-(4- methoxybenzyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (200 mg, 0.271 mmol, 85.96% purity, 67.22% yield) as a yellow solid.

[0559] RT 0.543 min (method 5); m / z 737.1 (M+H)+ (ESI+);1H NMR (DMSO-de, 400 MHz): 9.69 (s, 1 H), 7.92 (s, 1 H), 7.86 (d, J = 7.6 Hz, 1 H), 7.71 (t, J = 53.2 Hz, 1 H), 7.49 (d, J = 7.6 Hz, 1 H), 7.18 (d, J = 8.4 Hz, 2H), 7.04 (s, 1 H), 6.66 (d, J = 8.4 Hz, 2H), 4.89 (t, J = 5.6 Hz, 1 H), 4.5-4.46 (m, 2H), 3.70-3.65 (m, 2H), 3.56 (s, 3H), 3.36-3.35 (m, 2H), 2.20 (s, 3H), 1.22 (s, 3H), 1.04-0.93 (m, 2H), 0.69-0.61 (m, 2H).

[0560] Preparation of Intermediate 3.5

[0561] 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(4-methoxybenzyl)-8-(2-methyl-4-

[0562] (vinylsulfonimidoyl)phenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide

[0563]

[0564] To a solution of 1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2- hydroxyethylsulfonimidoyl)-2-methylphenyl)-N-(4-methoxybenzyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5- a]pyridi ne-6-sulfonamide (100 mg, 0.136 mmol) in DCM (1.5 mL) was added TEA (41 .17 mg, 0.407 mmol). followed by a solution of MS2O (50 mg, 0.285 mmol) in DCM (0.5 mL) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h, diluted with water (20 mL) and extracted with DCM (10 mL, 3x). The combined organic layer was washed with brine (10 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the product 1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(4- methoxybenzyl)-8-(2-methyl-4-(vinylsulfonimidoyl)phenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5- a]pyridine-6-sulfonamide (40 mg, crude) as a yellow oil.

[0565] RT 0.888 min (method 1; m / z 719.1 (M+H)+(ESP)

[0566] Preparation of Intermediate 3.6

[0567] 1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(2-methyl-4-

[0568] (vinylsulfonimidoyl)phenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide To a solution of 1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(4-methoxybenzyl)-8-(2- methyl-4-(vinylsulfonimidoyl)phenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (40 mg, 0.0556 mmol) in DCM (0.5 mL) was added TFA (0.50 mL, 0.0556 mmol). The mixture was stirred at 50 °C for 0.5 h and then, concentrated under vacuum to give the product 1 -chloro-3-(5-(difluoromethyl)- 1 ,3,4-thiadiazol-2-yl)-8-(2-methyl-4-(vinylsulfonimidoyl)phenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5- a]pyridine-6-sulfonamide (30 mg, crude) as a brown oil.

[0569] RT 0.823 min (method 1); m / z 599.1 (M+H)+(ESI+)

[0570] Preparation of Example 3

[0571] 8-(4-(2-(azetidin-1-yl)ethylsulfonimidoyl)-2-methylphenyl)-1 -chloro-3-(5-(difluoromethyl)-

[0572] 1 ,3,4-thiadiazol-2-yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide

[0573] To a solution of 1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(2-methyl-4-

[0574] (vi nyls u Ifo n imi doyl) p henyl)- N-( 1 -methylcyc lopropyl) i midazo[1 , 5-a] pyrid i ne-6-s u Ifo n ami de (30 mg, 0.0501 mmol) in dioxane (0.5 mL) was added azetidine (8.6 mg, 0.150 mmol) and DIEA (32 mg, 0.250 mmol). The mixture was stirred at 25 °C for 20 min, then diluted with water (10 mL) and extracted with ethyl acetate (5 mL, 3x). The combined organic layer was washed with brine (5 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: A: 10 mmol / L NH4HCO3 in water, B: MeCN; B%: 35%-65%, 10 min) and lyophilized to give the product 8-(4-(2-(azetidin-1 -yl)ethylsulfonimidoyl)-2- methylphenyl)-1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5- a]pyridine-6-sulfonamide (14 mg, 0.0209 mmol, 97.36% purity based on method 4, 41.81 % yield) as a yellow solid.

[0575] RT 0.445 min (method 4); m / z 656.0 (M+H)+(ESI+);1H NMR (CDCh, 400 MHz): 10.24 (d, J = 1.2 Hz, 1 H), 7.97 (s, 1 H), 7.93 (d, J = 8.0, Hz, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.19 (d, J = 1.2 Hz, 1 H), 7.10 (t, J= 53.6 Hz, 1 H), 5.42 (s, 1 H), 3.25-3.17 (m, 6H), 2.94-2.87 (m, 1 H), 2.83-2.75 (m, 1 H), 2.24 (s, 3H), 2.10-

[0576] 2.03 (m, 2H), 1.41 (s, 3H), 0.97-0.90 (m, 2H), 0.68-0.61 (m, 2H)

[0577] Preparation of Example 3a

[0578] (R or S)-8-(4-(2-(azetidin-1 -yl)ethylsulfonimidoyl)-2-methylphenyl)-1-chloro-3-(5-(difluoromethyl)- 1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide and Preparation of Example 3b

[0579] (S or R)-8-(4-(2-(azetidin-1-yl)ethylsulfonimidoyl)-2-methylphenyl)-1-chloro-3-(5-(difluoromethyl)-

[0580] 1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide

[0581] The 8-(4-(2- (azetid i n- 1 -yl)ethylsulfoni midoyl)-2-methy Ip he nyl)- 1 -chloro-3- (5- (d ifl uoromethyl)-1 ,3,4- thiadiazol-2-yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (13 mg, 0.0198 mmol) was purified by preparative SFC (Column: Chiralpak IC-3 50x4.6mm I.D., 3um Mobile phase: Phase A for CO2, and Phase B for IPA+ACN (0.05% DEA); Gradient elution: IPA+ACN (0.05% DEA) in CO2 from 30% to 60% Flow rate: 3mL / min; Detector: PDA Column Temp: 35°C;Back Pressure: 100 Bar) and concentrated under vacuum to give the Fraction 1 and the Fraction 2:

[0582] Fraction 1 which was concentrated under vacuum to give the product (R or S)-8-(4-(2-(azetidin-1 - yl)ethylsulfonimidoyl)-2-methylphenyl)-1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(1- methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (3.5 mg, 0.00515 mmol, 97.68% purity, 26.00 % yield) as a light yellow solid.

[0583] RT 0.476 min (method 5); m / z 656.1 (M+H)+(ESI*). RT 1.595 min (SFC Method 2); ee > 99.9%.1H NMR (400 MHz, CDCh): 10.25 (d, J = 1 .2 Hz, 1 H), 7.97 (s, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 7.20 (d, J = 1 .2 Hz, 1 H), 7.11 (t, J = 53.4 Hz, 1 H), 5.32 (s, 1 H), 3.24-3.21 (m, 6H), 2.97-2.90 (m, 1 H), 2.84-2.80 (m, 1 H), 2.25 (s, 3H), 2.11-2.04 (m, 2H), 1.41 (s, 3H), 0.98-0.91 (m, 2H), 0.68-0.62 (m, 2H)

[0584] Fraction 2 which was concentrated under vacuum to give the product (S or R)-8-(4-(2-(azetidin-1 - yl)ethylsulfonimidoyl)-2-methylphenyl)-1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(1- methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (3.8 mg, 0.00585 mmol, 100% purity, 29.54 % yield) as a light yellow solid.

[0585] RT 0.470 min (method 5); m / z 656.1 (M+H)+(ESI*). RT 2.422 min (SFC Method 2); ee > 99.9%.1H NMR (400 MHz, CDCh): 10.25 (d, J = 1 .2 Hz, 1 H), 7.97 (s, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 7.20 (d, J = 1 .2 Hz, 1 H), 7.11 (t, J = 53.4 Hz, 1 H), 5.28 (s, 1 H), 3.23-3.17 (m, 6H), 2.94-2.88 (m, 1 H), 2.82-2.76 (m, 1 H), 2.25 (s, 3H), 2.10-2.03 (m, 2H), 1.42 (s, 3H), 0.97-0.91 (m, 2H), 0.67-0.63 (m, 2H)

[0586] Preparation of Intermediate 4.1 tert-butyl (2-((3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)thio)ethyl)carbamate

[0587] To a solution of 2-(4-fl uoro-2-methylp henyl)-4,4, 5, 5-tetramethyl- 1 ,3,2-dioxaborolane (11 .99 g, 50.8 mmol) in DMF (60mL) were added tert-butyl (2-mercaptoethyl)carbamate (6.00 g, 33.8 mmol) and K2CO3 (10.29 g, 74.5 mmol). The mixture was stirred at 120 °C for 16 h, then diluted with water (80 mL) and extracted with EtOAc (80 mL, 3x). The combined organic layers was washed with brine (120mL, 3x), dried over anhydrous Na2SC , filtered and concentrated under reduced pressure. The residue was purified by preparative Normal Phase HPLC (column: Welch Ultimate XB-CN 250*70*10 urn; mobile phase: A: Hexane-EtOH, B: MeCN; B%: 1 %-15%, 25 min) and concentrated under vacuum to give the product tertbutyl (2-((3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thio)ethyl)carbamate (4.8 g, 12.24 mmol , 36% yield) as a white solid.

[0588] RT 1.755 min (method 7); m / z 294.1 (M-Boc+H)+(ESI*). 1 H NMR (DMSO-cfe, 400 MHz): 7.68 (d, J = 8.4 Hz, 1 H), 7.14-7.12 (m, 2H), 4.90 (s, 1 H), 3.38-3.29 (m, 2H), 3.09-3.05 (m, 2H), 2.51 (s, 3H), 1.43 (s, 9H), 1.34 (s, 12H). Preparation of Intermediate 4.2 tert-butyl (2- ((4-(1-chloro-3-(5-(di fluoro methyl) -1,3,4-thiadi azol-2-y l)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-3-methylphenyl)thio)ethyl)carbamate

[0589] Preparation of 1 ,8-dichloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(1- methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide has been reported in WO2023 / 057389 as example 18d. Accordingly, 1 ,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1- methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide was prepared as reported in example 18d of WO2023 / 057389, which is incorporated herein by reference in its entirety. To a solution of 1 ,8-dichloro- 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (1 g, 2.2 mmol), tert-butyl (2-((3-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)thio)ethyl)carbamate (1.04 g, 2.64 mmol)in 1 ,4-dioxane (40 mL) and water (4 mL) was added Pd(dppf)Cl2 (483 mg, 0.66 mmol) and CS2CO3 (2.87 g, 8.81 mmol) at room temperature. The reaction mixture was degassed with N2 (3x), stirred at 90 °C for 4 h and filtered. The filtrate was diluted with water (80 mL) and extracted with EtOAc (80 mL, 3x). The combined organic layers was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. In parallel, three other reactions were conducted on the same scale. The resulting residues were combined ..purified by column chromatography (ISCO; 40 g SepaFlash Silica Flash Column, Eluent of 8%~15% Ethylacetate / Petroleum ether @ 60 mL / min) and concentrated under vacuum.to afford a crude product which was further purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25 mm*4 m; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 60%-75%, 15 min). The fractions containing the product were gathered and the pH was adjusted to 7~8 by adding aqueous NaHCOs (sat.) and the compound was extracted with DCM (30 mL, 3x). The combined organic layers was washed with brine (80 mL), dried over anhydrous Na2SC , filtered and concentrated to give the product tert-butyl (2- ((4-(1 -ch loro-3-(5-(d ifl uoromethyl)- 1 , 3, 4-th iad iazol -2-yl)-6-(N- (1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-3-methylphenyl)thio)ethyl)carbamate (380 mg, 0.555 mmol, 6% yield) as a yellow solid.

[0590] RT 0.64 min (method 6); m / z 629.2 (M -56+H)+(ESI+) . 1 H NMR (CDCh, ,400 MHz): 10.21 (s, 1 H), 7.35 (s, 1 H), 7.31 (d, J= 8.0 Hz, 1 H), 7.23 (s, 1 H), 7.18(d, J= 8.0 Hz, 1 H), 7.16 (t, J = 53.6 Hz, 1 H), 5.19 (s, 1 H), 4.94 (s, 1 H), 3.40 (t, J = 6.4 Hz, 2H), 3.14 (t, J = 6.4 Hz, 2H), 2.13 (s, 3H), 1.47 (s, 9H), 1.40 (s, 3H), 0.97-0.92 (m, 2H), 0.68-0.58 (m, 2H)

[0591] Preparation of Intermediate 4.3 tert-butyl (2- (4-(1-chloro-3-(5-(di fluoromethyl) -1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-3- methylphenylsulfonimidoyl)ethyl)carbamate

[0592] To a solution of tert-butyl (2-((4-(1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-3-methylphenyl)thio)ethyl)carbamate (380 mg, 0.555 mmol) and ammonium carbamate (129.2 mg, 1 .665 mmol) in methanol (5 mL) was added Phl(OAc)2 (285 mg, 1.664 mmol). The mixture was stirred at 25°C for 2 h, then diluted with water (5 mL) and extracted with DCM (5 mL; 3x). The combined organic layers was washed with brine (10 mL, 2x), dried over anhydrous NazSC , filtered and concentrated under reduced pressure. The residue was purified by preparativeTLC (DCM: MeOH=10:1) to give the product tert-butyl (2-(4-(1-chloro-3-(5-(difluoromethyl)- 1 , 3,4-thi ad iazol-2-yl)-6-(N- (1 -methylcycl op ropy l)sulfamoy l)i mid azo [1 , 5-a] pyrid i n-8-yl)-3- methylphenylsulfonimidoyl)ethyl)carbamate (200 mg, 0.279 mmol, 50.35% yield) as a yellow solid.

[0593] RT 0.55 min (method 6); m / z 716.2 (M+H)+(ESI*). 1 H NMR (CDCh, 400 MHz): 10.25 (s, 1 H), 7.95(s, 1 H), 7.91 (d, J= 8.4 Hz, 1 H), 7.45 (d, J = 8.4 Hz, 1 H), 7.18(s, 1 H), 7.10 (t, J = 53.6 Hz, 1 H), 5.64 (s, 1 H), 5.26 (s, 1 H), 3.68-3.55 (m, 2H), 3.47-3.32 (m, 2H), 2.26 (s, 3H), 1.45 (s, 9H), 1.42 (s, 3H), 1.02- 0.87 (m, 2H), 0.74-0.59 (m, 2H) Preparation of Intermediate 4.4

[0594] 8-(4-(2-aminoethylsulfonimidoyl)-2-methylphenyl)-1-chloro-3-(5-(difluoromethyl)-1,3,4- thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide

[0595] To a solution of tert-butyl (2-(4-(1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-3-methylphenylsulfonimidoyl)ethyl)carbamate (1.00 eq, 290 mg, 0.383 mmol) in DCM (4mL) was added TFA (37.4 eq, 1 mL, 14.3 mmol). The mixture was stirred at 20 °C for 2 h, then poured into NaHCOs (5 mL) and extracted with DCM (5 mL, 3x). The combined organic layers was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated to give crude product 8-(4-(2-aminoethylsulfonimidoyl)-2-methylphenyl)-1-chloro-3-(5- (difl uoromethyl)- 1 , 3, 4-thi ad iazol- 2-yl)- N-(1 -methylcyclopropyl)i mid azo[ 1 , 5-a] py ri di ne-6-s ulfo n ami de (290 mg, 0.442 mmol) as a yellow solid which was directly used the next step without any further purification.

[0596] RT 0.47 min (method 6); m / z 616.0 (M+H)+(ESI+). 1 H NMR (CDCh, 400 MHz): 10.20 (s, 1 H), 7.99(s, 1 H), 7.97 (d, J= 8.0 Hz, 1 H), 7.45 (d, J= 8.0 Hz, 1 H), 7.25(s, 1 H), 7.10 (t, J = 53.6 Hz, 1 H), 5.64 (s, 1 H), 3.65-3.46 (m, 2H), 3.46-3.25 (m, 2H), 2.24 (s, 3H), 1.37 (s, 3H), 0.93-0.89 (m, 2H), 0.65-0.60 (m, 2H)

[0597] Preparation of Example 4

[0598] 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- methylphenyl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide

[0599] To a solution of 8-(4-(2-aminoethylsulfonimidoyl)-2-methylphenyl)-1-chloro-3-(5-(difluoromethyl)- 1 , 3,4-thiadiazol-2-yl)-N-(1 -methylcyclopropyl)imidazo[1 , 5-a]pyridi ne-6-s ulfonamide (290 mg, 0.442 mmol) and (CH2O)n (70.67 mg, 2.35 mmol) in methanol (5 mL) was added NaBHsCN (110.2 mg, 1.41 mmol). The mixture was stirred at 20 °C for 2 h, then poured into water (10 mL) and filtered. The filter cake was collected, triturated in MeOH (0.5 mL) at room temperature for 30 mins, filtered and dried under vacuum to give the 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2- (dimethylamino)ethylsulfonimidoyl)-2-methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide (145 mg, 0.225 mmol, 55.47% yield) as a light yellow solid.

[0600] RT 0.644 min (method 3); m / z 644.1 (M+H)+(ESI*).1H NMR (CDC , 400 MHz,): 10.24 (s, 1 H), 7.98 (s, 1 H), 7.95 (d, J = 8.0 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 7.11 (m, 2H), 5.26 (s, 1 H), 3.42-3.34 (m, 2H), 2.92-2.81 (m, 2H), 2.30 (s, 6H), 2.25 (s, 3H), 1.41 (s, 3H), 0.95-0.94 (m, 2H), 0.65-0.64 (m, 2H)

[0601] Preparation of Example 4a

[0602] S or R-1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2-

[0603] (dimethylamino)ethylsulfonimidoyl)-2-methylphenyl)-N-(1-methylcyclopropyl)imidazo[1,5- a]pyridine-6-sulfonamide and Preparation Example 4b

[0604] R or S-1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2-

[0605] (dimethylamino)ethylsulfonimidoyl)-2-methylphenyl)-N-(1-methylcyclopropyl)imidazo[1,5- a]pyridine-6-sulfonamide

[0606] The mixture of crude 1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2- (dimethylamino)ethylsulfonimidoyl)-2-methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide (96 mg, 0.148 mmol) was purified by preparative SFC (column: DAICEL CHIRALPAK IC (250mm*30mm,10um); Mobile Phase: A: CO2-ACN, B: / -PrOH (0.1 % NH3 H2O): 60% / -PrOH (0.1 % NH3 H2O additive) in Supercritical CO2, Gradient information: 4 min, Flow Rate: 120 mL / min) concentrated under reduced pressure and lyophilized to give the product peak 1 (S or R)-1 -c h loro-3- (5-(d ifl uoromethyl)- 1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2-methylphenyl)-N-(1- methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (38.48 mg, 0.057 mmol, 38.39% yield) as a yellow solid, and the product peak 2 (R or S)-1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2- (dimethylamino)ethylsulfonimidoyl)-2-methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide (38.42 mg, 0.059 mmol, 40.02% yield) as a yellow solid.

[0607] Product peak 1 :

[0608] RT 0.643 min (method 3); m / z 644.1 (M+H)+(ESI+). RT 1.07 min (SFC method 1); 99.55% ee;1H NMR (CDCI3, 400 MHz,): 10.25 (s, 1 H), 7.96 (s, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 1 H),

[0609] 7.24 (s, 1 H), 7.10 (t, J = 53.6 Hz, 1 H), 5.26 (s, 1 H), 3.45-3.30 (m, 2H), 2.90-2.75 (m, 2H), 2.28 (s, 6H),

[0610] 2.25 (s, 3H), 1.42 (s, 3H), 0.95-0.85 (m, 2H), 0.75-0.60 (m, 2H)

[0611] Product peak 2:

[0612] RT 0.638 min (method 3); m / z 644.1 (M+H)+(ESI+). RT 1.808 min (SFC method 1); 99.28% ee;1H NMR (CDCh, 400 MHz,): 10.25 (s, 1 H), 7.98 (s, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 7.24 (s, 1 H), 7.11 (t, J = 53.6 Hz, 1 H), 5.25 (s, 1 H), 3.40-3.38 (m, 2H), 2.90-2.80 (m, 1 H), 2.80-2.70 (m, 1 H), 2.28 (s, 6H), 2.25 (s, 3H), 1.42 (s, 3H), 0.95-0.85 (m, 2H), 0.65-0.55 (m, 2H)

[0613] It is noted that while two enantiomers 4a and 4b of compound 4 were separated, their absolute configurations have not been elucidated / assigned.

[0614] 5 (2S,6S)-N-(2-((3-cyanocyclobutyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-

[0615] (1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1- carboxamide

[0616] To a solution of (2S,6S)-N-(2-((3-cyanocyclobutyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6- trimethylpiperazine-1-carboxamide (15 mg, 0.0251 mmol) in methanol (1 mL) was added 3- aminocyclobutanecarbonitrile (12 mg, 0.126 mmol) ) and NaBHsCN (7.9 mg, 0.126 mmol) at 0 °C under N2.The mixture was stirred at 20 °C for 0.5 h. In parallel, another reaction was conducted using the same protocol but on different scale of (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-oxoethyl)piperazine-1 - carboxamide (5 mg). The reaction mixtures were combined, diluted with water (4 mL) and extracted with ethyl acetate (4 mL; 3x). The combined organic layer was washed with brine (4 mL; 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC (DCM: MeOH=10:1) and lyophilized to give a mixture of the trans and cis mixture product of (2S,6S)-N- (2-((3-cyanocyclobutyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N, 2, 6-trimethylpiperazine-1 -carboxamide (11 mg, 0.0169 mmol, 48.95 % yield) as a yellow solid.

[0617] RT 0.480 min (LCMS: method 6); m / z 677.2 (M +H)+(ESI*).;1H NMR (CDCh, 400 MHz): 9.79 (s, 1 H), 7.65 (s, 1 H), 7.02 (t, J = 53.6 Hz, 1 H), 6.66 (s, 1 H), 5.28-5.23 (m, 1 H), 3.65 - 3.59 (m, 2H), 3.59- 3.45 (m, 1 H), 3.28 - 3.24 (m, 3H), 3.16-3.05 (m, 3H), 2.98 (s, 3H), 2.73-2.57 (m, 4H), 2.58-3.50 (m, 1 H), 2.14-1.98 (m, 2H), 1.31 (s, 3H), 1.26-1.22 (m, 6H), 0.90-0.83 (m, 2H), 0.57-0.49 (m, 2H).

[0618] Preparation of Example 6 (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N-(2-(3-fluoroazetidin-1-yl)ethyl)-N,2,6- trimethylpiperazine-1-carboxamide

[0619] To a solution of (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-oxoethyl)piperazine-1 - carboxamide (15 mg, 0.0251 mmol) in methanol (1 mL) was added 3-fluoroazetidine hydrochloride (14 mg, 0.126 mmol) and NaBHsCN (7.9 mg, 0.126 mmol) at O °C under N2.The mixture was stirred at 20 °C for 0.5 h. In parallel, another reaction was conducted with the same protocol but on a different scale of (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5- a]pyridin-8-yl)-N, 2, 6-trimethyl-N-(2-oxoethyl)piperazine-1 -carboxamide (5 mg). The reaction mixtures were combined, diluted with water (4 mL) and extracted with ethyl acetate (4 mL; 3x). The combined organic layer was washed with brine (4 mL; 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC (DCM: MeOH=10:1) and lyophilized to give the product (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N-(2-(3-fluoroazetidin-1 -yl)ethyl)-N,2,6- trimethylpiperazine-1 -carboxamide (12.76 mg, 0.0195 mmol, 58.20 % yield) as a yellow solid.

[0620] RT 0.474 min (LCMS: method 6); m / z 656.2 (M +H)+(ESI*). RT 1.852 min: (SFC: Method 7, ee%: 100 %);1H NMR (CDCh, 400 MHz): 9.86 (s, 1 H), 7.73 (s, 1 H), 7.08 (t, J = 54.0 Hz, 1 H), 6.66 (s, 1 H), 5.23 - 5.02 (m, 2H), 3.80 - 3.65 (m, 4H), 3.60-3.50 (m, 1 H), 3.35-3.30 (m, 2H), 3.28-3.25 (m, 1 H), 3.24 - 3.09 (m, 4H), 3.03 (s, 3H), 2.80 - 2.66 (m, 2H), 1 .39 (s, 3H), 1 .32 (d, J = 6.0 Hz, 6H), 0.99 - 0.92 (m, 2H), 0.64 - 0.58 (m, 2H). Preparation of Example 7

[0621] (2S,6S)-N-(2-(cyclopropyl(methyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-

[0622] (1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1- carboxamide

[0623] To a solution of (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-oxoethyl)piperazine-1 - carboxamide (15 mg, 0.0251 mmol) in methanol (1 mL) was added N-methylcyclopropanamine (8.9 mg, 0.126 mmol) and NaBHsCN (7.9 mg, 0.126 mmol) at O °C under N2. The mixture was stirred at 20 °C for 0.5 h. In parallel, another reaction was conducted using the same protocol but on a different scale of (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5- a]pyridin-8-yl)-N, 2, 6-trimethyl-N-(2-oxoethyl)piperazine-1 -carboxamide (5 mg). The 2 reaction mixtures were combined. The resulting mixture was diluted with water (4 mL) and extracted with ethyl acetate (4 mL; 3x). The combined organic layer was washed with brine (4 mL; 2x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (DCM: MeOH=10:1) and lyophilized to give the product (2S,6S)-N-(2-(cyclopropyl(methyl)amino)ethyl)-4- (3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8- yl)-N,2,6-trimethylpiperazine-1 -carboxamide (4.88 mg, 0.00749 mmol, purity:100%, 22.38 % yield) as a yellow solid.

[0624] RT 0.488 min (LCMS: method 6); m / z 652.2 (M +H)+(ESI*). RT 1.458 min: (SFC: Method 5, ee%: 100 %);1H NMR (CDCh, 400 MHz): 9.86 (s, 1 H), 7.73 (s, 1 H), 7.08 (t, J = 53.6 Hz, 1 H), 6.65 (s, 1 H), 5.14 (s, 1 H), 3.85 - 3.74 (m, 1 H), 3.72-3.63 (m, 2H), 3.35-3.30 (m, 2H), 3.27-3.10 (m, 3H), 3.02 (s, 3H), 2.89- 2.62 (m, 2H), 2.43 (s, 3H), 1.84 - 1.70 (m, 1 H), 1.39 (s, 3H), 1.31 (d, J = 6.4 Hz, 6H), 1.01-0.89 (m, 2H), 0.66-0.59 (m, 2H), 0.59-0.19 (m, 4H). Ill

[0625] Preparation of Example 8

[0626] (2S,6S)-N-(2-(3-cyanoazetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1- carboxamide

[0627] To a solution of (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-oxoethyl)piperazine-1- carboxamide (15 mg, 0.0251 mmol) in methanol (1 mL) was added azetidine-3-carbonitrile hydrochloride (15 mg, 0.126 mmol) and NaBHsCN (7.9 mg, 0.126 mmol) at O °C under N2. The mixture was stirred at 20 °C for 0.5 h. In parallel, another reaction was conducted using the same protocol but on a different scale of (2S , 6S)-4- (3-(5- (difl uoromethyl)- 1 , 3, 4-th i ad i azo l-2-y l)-6-(N-( 1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-oxoethyl)piperazine-1 - carboxamide (5 mg). The reaction mixtures were combined, diluted with water (4 mL) and extracted with ethyl acetate (4 mL; 3x). The combined organic layer was washed with brine (4 mL; 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC (DCM: MeOH=10:1) and lyophilized to give the product (2S,6S)-N-(2-(3-cyanoazetidi n- 1 -yl)ethyl)-4-(3-(5- (difluoromethyl)-l ,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)- N,2,6-trimethylpiperazine-1 -carboxamide (9.1 mg, 0.0137 mmol, purity: 100%, 40.89 % yield) as a yellow solid.

[0628] RT 0.476 min (LCMS: method 6); m / z 663.2 (M +H)+(ESP). RT 1.828 min: (SFC: Method 5, ee%: 100 %);1H NMR (CDCh, 400 MHz): 9.86 (s, 1 H), 7.73 (s, 1 H), 7.09 (t, J = 54.0 Hz, 1 H), 6.67 (s, 1 H), 5.21 (s, 1 H), 3.77-3.67 (m, 2H), 3.65-3.60 (m, 2H), 3.54-3.46 (m, 1 H), 3.42 ( t, J= 6.4 Hz, 2H), 3.40-3.30 (m, 2H), 3.27 - 3.12 (m, 4H), 3.03 (s, 3H), 2.670-2.60 (m, 2H), 1.38 (s, 3H), 1.33 (d, J= 6.4 Hz, 6H), 0.97 - 0.89 (m, 2H), 0.64 - 0.57 (m, 2H).

[0629] Preparation of Intermediate 9.1 benzyl (3S,5S)-4-(3-(dimethylamino)azetidine-1-carbonyl)-3,5-dimethylpiperazine-1-carboxylate

[0630] Cbz

[0631] To a solution of benzyl (3S,5S)-3,5-dimethylpiperazine-1-carboxylate (200 mg, 0.805 mmol) in DCM (1 mL) was added TEA (0.33 mL, 2.42 mmol). The reaction mixture was degassed and purged with N2 (3x), and then a solution of triphosgene (110 mg, 0.371 mmol) in DCM (1 mL) was added dropwise at 0 °C and stirred at 25 °C for 2 h under N2. After 2 h, N,N-dimethylazetidin-3-amine hydrochloride (218 mg, 1.61 mmol, HCI salt) was added and stirred at 25 °C for 2 h. The resulting mixture was quenched with water (10 mL), and extracted with DCM (10 mL, 2x). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250*70 mm, 10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 5%-35%, 9 min) and lyophilized directly to give the product benzyl (3S,5S)-4-(3-(dimethylamino)azetidine-1 -carbonyl)-3,5-dimethylpiperazine-1 - carboxylate; formic acid (200 mg, 0.476 mmol, 59.00 % yield, formic acid salt) as colorless gum.

[0632] LCMS: RT 0.407 min (method 6); m / z 375.2 (M+H)+(ESI+);1H NMR (DMSO-de, 400 MHz): 8.13 (s, 8.13), 7.39-7.31 (m, 5H), 5.14-5.06 (m, 2H), 4.05-3.95 (m, 1 H), 3.90-3.80 (m, 2H), 3.71-3.69 (m, 3H), 3.53-3.46 (m, 5H), 2.21 (s, 6H), 1.08 (6, J= 6.4 Hz, 6H).

[0633] Preparation of Intermediate 9.2

[0634] (3-(dimethylamino)azetidin-1-yl)((2S,6S)-2,6-dimethylpiperazin-1-yl)methanone

[0635] To a solution of benzyl (3S,5S)-4-(3-(dimethylamino)azetidine-1 -carbonyl)-3,5-dimethylpiperazine-1 - carboxylate formic acid (100 mg, 0.238 mmol, formic acid salt) in methanol (5 mL) under N2 was added Pd / C (10 mg, wt%: 10%). The resulting mixture was degassed and purged with H2 (3x), stirred at 25 °C for 2 h under H2 balloon. The resulting mixture was diluted with MeOH (15 mL), filtered and the filtrate was concentrated under reduced pressure to give the crude product (3-(dimethylamino)azetidin-1- yl)((2S,6S)-2,6-dimethylpiperazin-1-yl)methanone (70 mg, crude) as colorless gum, which was used for next step directly without further purification.

[0636] LCMS: RT 0.525 min (method 6); m / z 241.3 (M+H)+(ESP);1H NMR (DMSO-de, 400 MHz): 3.97- 3.95 (m, 1 H), 3.74-3.73 (m, 2H), 3.57-3.54 (m, 1 H), 3.35-3.30(m, 2 H), 3.17-3.10 (m, 1 H), 2.95-2.92 (m, 1 H), 2.85-2.80 (m, 2H), 2.73-2.66 (m, 1 H), 2.04 (s, 6H), 1.06 (6, J= 6.4 Hz, 6H).

[0637] Preparation of Example 9

[0638] 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-4-(3-(dimethylamino)azetidine-1-carbonyl)-

[0639] 3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide

[0640] To a solution of (3-(dimethylamino)azetidin-1 -yl)((2S,6S)-2,6-dimethylpiperazin-1 -yl)methanone (60 mg, 0.250 mmol) in 1 ,4-dioxane (1 mL) was added CS2CO3 (217 mg, 0.667 mmol), 8-chloro-3-(5- (difl uoromethyl)- 1 , 3, 4-thi ad iazol- 2-yl)- N-(1 -methylcyclopropyl)i mid azo[ 1 , 5-a] py ri di ne-6-s ulfo n ami de (35 mg, 0.0834 mmol) and Pd-PEPPSI-I Pent Cl o-picoline (2-methylpyridine) (7.0 mg, 0.00834 mmol). The suspension was degassed under vacuum and purged with N2 (3x), stirred at 100 °C for 2 h under N2 atmosphere. The resulting mixture was quenched with water (10 mL), and extracted with EtOAc (10 mL, 3x). The combined organic layers were washed with brine (10 mL, 2x), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 15%-45%, 9 min) and lyophilized to give the product 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol- 2-yl)-8-((3S,5S)-4-(3-(dimethylamino)azetidine-1-carbonyl)-3,5-dimethylpiperazin-1-yl)-N-(1- methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (6.0 mg, 0.00965 mmol, 11.58 % yield) as a yellow solid.

[0641] LCMS: RT 0.460 min (method 6); m / z 624.3 (M+H)+(ESP); SFC: (Method 8) RT 1.249 min, 100.0% ee;1H NMR (CDCb, 400 MHz): 9.81 (s, 1 H), 7.76 (s, 1 H), 7.08 (t, J = 53.6 Hz, 1 H), 6.53 (s, 1 H), 5.19 (br.s, 1 H), 4.13 (t, J= 8.0 Hz, 1 H), 4.01-3.97 (m, 2H), 3.95(d, J= 6.0 Hz, 1 H), 3.88-3.84 (m, 1 H), 3.64 (dd, J = 12.0, 1 H), 3.35 (dd, J = 12.0, 6.0 Hz, 1 H), 3.11-3.08 (m, 1 H), 2.23 (s, 6H), 1.39 (s, 3H), 1.38 (d, J= 6.0 Hz, 6H) , 0.96-0.94 (m, 2H), 0.62-0.59 (m, 2H).

[0642] Preparation of Intermediate 11.1

[0643] Benzyl (3S,5S)-4-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)(methyl)carbamoyl)-3, 5- dimethylpiperazine-1-carboxylate formate

[0644] To a solution of tert-butyl 4-(2-(methylamino)ethyl)piperazine-1 -carboxylate (228 mg, 0.937 mmol), TEA (0.39 mL, 2.81 mmol) in DCM (2 mL) was dropwise added a solution of triphosgene (167 mg, 0.562 mmol) in DCM (2 mL) at 0 °C. The mixture was stirred at 20 °C for 2 h under N2 and, benzyl (3S,5S)-3,5- dimethylpiperazine-1 -carboxylate (233 mg, 0.937 mmol) was added. The reaction mixture was further stirred at 20 °C for 16 h, then diluted with water (10 mL) and extracted with DCM (10 mL, 2x). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reversed-phase flash (ISCO; 40 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, mobile phase: A: 0.1 % formic acid in water, B: MeCN; B%: 0%-15% @ 80 mL / min) and lyophilized directly to give the product benzyl (3S,5S)-4-((2-(4-(tert- butoxycarbonyl)piperazin-1-yl)ethyl)(methyl)carbamoyl)-3,5-dimethylpiperazine-1-carboxylate formate (135 mg, 0.261 mmol, 27.83 % yield, FA salt) as yellow oil.

[0645] RT 0. 480 min (LCMS: method 6; m / z 518.3 (M+H)+(ESI*);1H NMR (CDCh, 400 MHz): 8.23(s, 1 H), 7.28-7.43 (m, 5 H), 5.01-5.26 (m, 2 H), 3.81-3.64 (m, 4 H), 3.60-3.50 (m, 2 H), 3.49-3.42 (m, 4 H), 3.42-3.36 (m, 2 H), 2.98 (s, 3 H), 2.65-2.60 (m, 2 H), 2.60-2.50 (m, 4 H), 1.45 (s, 9 H) 1.10-1.01 (m, 6 H).

[0646] Preparation of Intermediate 11 .2 tert-butyl 4-(2-((2S,6S)-N, 2, 6-trimethylpiperazine-1-carboxamido)ethyl)piperazine-1-carboxylate

[0647] To a solution of benzyl (3S,5S)-4-((2-(4-(tert-butoxycarbonyl)piperazin-1- yl)ethyl)(methyl)carbamoyl)-3,5-dimethylpiperazine-1-carboxylate formate (135 mg, 0.261 mmol, FA salt) in methanol (2 mL) was added Pd / C (116 mg, 0.391 mmol). The mixture was stirred at 25 °C for 12 h under H2 (15 psi), then filtered and concentrated under vacuum (35 °C) to give product tert-butyl 4-(2- ((2S,6S)-N,2,6-trimethylpiperazine-1-carboxamido)ethyl)piperazine-1-carboxylate (90 mg, 0.235 mmol, 89.98 % yield) as colorless oil.

[0648] 1H NMR (MeOH-ok, 400 MHz): 4.14-4.34 (m, 2 H), 3.70-3.85 (m, 4 H), 3.61-3.70 (m, 2 H), 3.34- 3.52 (m, 4 H), 3.31 (s, 3 H), 3.04-3.16 (m, 6 H), 1.48 (s, 9 H), 1.26-1.34 (m, 6 H).

[0649] Preparation of Intermediate 11 .3 tert-butyl 4-(2-((2S, 6 S) -4-(3-(5-(di fl uoromethy I) -1,3, 4-thiadi azol-2-y l)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1-

[0650] carboxamido)ethyl)piperazine-1-carboxylate formate

[0651] To a solution of 8-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(1- methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (101 mg, 0.241 mmol), tert-butyl 4-(2-((2S,6S)- N,2,6-trimethylpiperazine-1-carboxamido)ethyl)piperazine-1 -carboxylate (77 mg, 0.201 mmol), CS2CO3 (131 mg, 0.402 mmol) in DMF (2 mL) was added Pd-PEPPSI-IPent Cl o-picoline (17 mg, 0.0201 mmol). The mixture was degassed with N2 (3x) and stirred at 100 °C for 16 h. The resulting mixture was filtered and the filtrate was purified by reversed-phase flash (ISCO; 40 g Flash Column Welch Ultimate XB_C18 20-40 pm; 120 A, mobile phase: A: 0.1 % formic acid in water, B: MeCN; B%: 5%-55% @ 60 mL / min) to give, after lyopilization, the product tert-butyl 4-(2-((2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)- 6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamido)ethyl)piperazine-1 -carboxylate formate (62 mg, 0.0763 mmol, 31.66 % yield, FA salt) as a light yellow solid.

[0652] RT 0. 532 min (LCMS: method 6); m / z 767.4 (M+H)+(ESI+)

[0653] Preparation of Example 11a

[0654] (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(piperazin-1- yl)ethyl)piperazine-1-carboxamide 2, 2, 2-trifluoroacetate

[0655] To a solution of tert-butyl 4-(2-((2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1- carboxamido)ethyl)piperazine-1 -carboxylate formate (52 mg, 0.0678 mmol, FA salt) in DCM (1 mL) was added TFA (583 mg, 0.678 mmol) and the mixture was stirred at 25 °C for 2 h. The resulting mixture was filtered and concentrated under vacuum to afford the crude product (2S, 6S)-4-(3-(5-(difl uoromethy I)- 1 ,3,4- thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2- (piperazin-1 -yl)ethyl)piperazine-1 -carboxamide 2,2,2-trifluoroacetate (52 mg, crude, TFA salt) which was used without any further purification. LCMS: RT 0. 834 min (LCMS: method 2); m / z 667.2 (M+H)+(ESI+).

[0656] Preparation of example 11

[0657] (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(4-methylpiperazin- 1-yl)ethyl)piperazine-1 -carboxamide formate To a solution of (2S,6S)-4-[3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-[(1- methylcyclopropyl)sulfamoyl]imidazo[1 ,5-a]pyridin-8-yl]-N,2,6-trimethyl-N-(2-piperazin-1 - ylethyl)piperazine-1-carboxamide 2,2,2-trifluoroacetate (52 mg, 0.0666 mmol, TFA salt) in methanol (1 mL) was added NaBH3CN (3.00 eq, 16 mg, 0.200 mmol) and (HCOH)n (6.0 mg, 0.200 mmol). The reaction mixture was stirred at 20 °C for 2 h, then filtered and the filtrate was purified by preparative-HPLC (YMC-Actus Triart C18 150*30mm*7um; mobile phase: A: 0.1 % FA in water, B: MeCN; B%: 20%-50%, 15 min ).The product solution was lyopilizated to afford the product (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(4- methylpiperazin-1 -yl)ethyl)piperazine-1-carboxamide formate (29 mg, 0.0398 mmol, 59.76% yield, FA salt) as a yellow solid.

[0658] RT 0.855 min (LCMS: method 2); m / z 681 .3 (M +H)+(ESI+). RT 1 .249 min (SFC: Method 6 ), > 99%ee;1H NMR (CH3CN-d3, 400 MHz): 9.68 (s, 1 H), 8.31 (s, 1 H), 7.80 (s, 1 H), 7.24 (t, J = 54.0 Hz, 1 H), 6.62 (s, 1 H), 6.48 (s, 1 H), 3.77-3.59 (m, 3 H), 3.43-3.31 (m, 2 H), 3.21-3.10 (m, 3 H), 2.97 (s, 3 H), 2.95-2.85 (m, 4 H), 2.56-2.52 (m, 4 H), 2.52-2.44 (m, 2 H), 2.31 (s, 3 H), 1.29(s, 3 H), 1.29-1.18 (m, 6 H) 0.91-0.72 (m, 2 H), 0.56-0.39 (m, 2 H).

[0659] Preparation of Intermediate 12.1

[0660] Benzyl (3S,5S)-3,5-dimethyl-4-(methyl(2-(pyrrolidin-1-yl)ethyl)carbamoyl)piperazine-1- carboxylate formate

[0661] Cbz

[0662] To a solution of benzyl (3S, 5S)-3,5-dimethylpiperazine-1 -carboxylate (500 mg, 2.01 mmol) in DCM (10 mL) was added TEA (611.2 mg, 6.04 mmol). The reaction mixture was degassed and purged with N2 for three times and then a solution of triphosgene (359 mg, 1.21 mmol) in DCM (3 mL) was added dropwise at 0 °C. The reaction mixture was further stirred at 25 °C for 2 h under N2. After 2 h, N-methyl- 2-pyrrolidin-1 -yl-ethanamine dihydrochloride (648 mg, 3.22 mmol, 2 HCI salt) was added and stirred at 25 °C for 2 h. The resulting mixture was poured into ice-water (20 mL) and stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with DCM (10 mL, 2x). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250*70 mm, 10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 18%-48%, 18 min) and lyophilized to give the product benzyl (3S, 5S)-3, 5-dimethy I-4- (methyl (2-(pyrrolidi n- 1-yl)ethyl)carbamoyl)piperazine-1 -carboxylate formate (675 mg, 1.50 mmol, 74.26 % yield, FA salt) as colorless gum.

[0663] RT 0. 430 min (LCMS: method 6); m / z 403.2 (M+H)+(ESI+);1H NMR (CDCh, 400 MHz): 8.51 (s, 1 H), 7.39-7.31 (m, 5H), 5.15 (m, 2H), 3.74-3.68 (m, 1 H), 3.63-3.56 (m, 2H), 3.54-3.49 (m, 1 H), 3.41-3.36 (m, 2H), 3.30-3.25 (m, 2H), 3.15-3.07 (m, 6H), 3.03 (s, 3H), 2.05-1.95 (m, 4H), 1.10-1.05 (m, 6H)

[0664] Preparation of Intermediate 12.2 (2S,6S)-N,2,6-trimethyl-N-(2-(pyrrolidin-1-yl)ethyl)piperazine-1-carboxamide dihydrochloride

[0665] A solution of benzyl (3S,5S)-3,5-dimethyl-4-(methyl(2-(pyrrolidin-1 -yl)ethyl)carbamoyl)piperazine-1 - carboxylate;formic acid (670 mg, 1 .49 mmol, FA salt) in HCI (aq., 6 N, 12 mL) was stirred at 100 °C for 2 h. The resulting mixture was diluted with H2O (5 mL) and extracted with EtOAc (10 mL, 3x). The aqueous phase was lyophilized to give the product (2S, 6S)-N,2,6-trimethyl-N-(2-pyrrolidin-1 -ylethyl)piperazine-1 - carboxamide dihydrochloride (600 mg, 1.72 mmol, crude, 2 HCI salt) as colorless gum.

[0666] RT 0. 0.130 min (LCMS: method 10; m / z 269.2 (M+H)+(ESI*));1H NMR (DMSO-de, 400 MHz): 11.17 (br, s, 1 H), 9.42 (br, s, 2H), 3.72 - 3.58 (m, 2H), 3.56 - 3.46 (m, 4H), 3.34 - 3.20 (m, 2H), 3.18 - 3.09 (m, 2H), 3.03 - 2.95 (m, 2H), 2.93 (s, 3H), 2.90-2.89 (m, 2H), 2.06 - 1.94 (m, 2H), 1.90 - 1.80 (m, 2H), 1.13 (d, J = 6.4 Hz, 6H). 1.11 (s, 3H).

[0667] Preparation of Example 12

[0668] (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(pyrrolidin-1- yl)ethyl)piperazine-1-carboxamide formate

[0669] To a solution of (2S,6S)-N,2,6-trimethyl-N-(2-pyrrolidin-1-ylethyl)piperazine-1 -carboxamide dihydrochloride (244 mg, 0.715 mmol, 2 HCI salt) in 1 ,4-dioxane (5 mL) and DMF (2.5 mL) was added CS2CO3 (621 mg, 1.91 mmol), 8-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(1- methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (100 mg, 0.238 mmol) and Pd-PEPPSI-IPent Cl o-picoline (20 mg, 0.0238 mmol). The suspension was degassed under vacuum and purged with N2 (3x). The mixture was stirred at 100 °C for 2 h under N2 atmosphere. The mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL, 3x). The combined layers were washed with brine (10 mL, 2x), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 23%-53%, 11 min) and lyophilized to give the product (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(pyrrolidin-1 - yl)ethyl)piperazine-1 -carboxamide formate (57 mg, 0.0802 mmol, 33.66 % yield, FA salt) as a yellow solid.

[0670] RT 0. 487 min (LCMS: method 6; m / z 652.3 (M+H)+(ESP); RT 0. 487 min (SFC: Method 6, 96.47% ee);1H NMR (CDCb, 400 MHz): 9.85 (s, 1 H), 8.582 (s, 1 H), 7.72 (s, 1 H), 7.08 (t, J = 54.0 Hz, 1 H), 6.66 (s, 1 H), 5.32 (br s, 1 H), 3.78-3.75 (m, 1 H), 3.72 - 3.65 (m, 2H), 3.40 - 3.27 (m, 3H), 3.23-3.16 (m, 2H), 3.04 (s, 3H), 2.82 - 2.75 (m, 2H), 2.72-2.71 (m, 4H), 1.84-1.83 (m, 4H), 1.39 (s, 3H), 1.31 (s, 3H), 1.30 (s, 3H), 1.00 - 0.88 (m, 2H), 0.65 - 0.56 (m, 2H).

[0671] Preparation of Intermediate 13.1 (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[ 1, 5-a]pyridin-8-yl)-N-(2, 2-dimethoxyethyl)-N, 2, 6- t methylpiperazine-1-carboxamide

[0672] To a solution of 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1 -yl)-N- (1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (300 mg, 0.603 mmol) and TEA (0.25 mL, 1.81 mmol) in DCM (7 mL) was added triphosgene (200 mg, 0.674 mmol) in DCM (2 mL) dropwise at 0°C. The mixture was then stirred at 25 °C for 0.5 h and, 2,2-dimethoxy-N-methyl-ethanamine (216 mg, 1.81 mmol) in DCM (1 mL) was added. The reaction mixture was further stirred at 25 °C for 16 h, then diluted with water (10 mL) and extracted with DCM (10 mL; 3x). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated. The residue was purified by reversed-phase flash (ISCO; 40 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, mobile phase: A: 0.1 % formic acid in water, B: MeCN; B%: 0%-60% @ 100 mL / min). The resulting solution was lyophilized directly to give the product (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)- 6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N-(2,2-dimethoxyethyl)-N,2,6- trimethylpiperazine-1-carboxamide (200 mg, 0.258 mmol, purity: 82.85%, 42.73 % yield) as a yellow solid.

[0673] RT 0. 551 min (LCMS: method 6; m / z 665.2 (M+Na)+(ESI+);1H NMR (CDCh, 400 MHz): 9.88 (s, 1 H), 7.75 (s, 1 H), 7.10 (t, J = 54.0 Hz, 1 H), 6.67 (s, 1 H), 5.12 (s, 1 H), 4.58 (t, J= 5.4 Hz, 1 H), 3.82 - 3.75 (m, 2H), 3.74-3.69 (m, 2H), 3.45- 3.43 (m, 6H), 3.36 - 3.30 (m, 2H), 3.24 - 3.17 (m, 2H), 3.11 (s, 3H), 1 .41 (s, 3H), 1 .37 - 1 .30 (m, 6H), 1 .01 - 0.91 (m, 2H), 0.63-0.55 (m, 2H).

[0674] Preparation of Intermediate 13.2

[0675] (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[ 1, 5-a]pyridin-8-yl)-N, 2, 6-trimethyl-N-(2- oxoethyl)piperazine-1-carboxamide

[0676] To a solution of (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N-(2,2-dimethoxyethyl)-N,2,6- trimethylpiperazine-1-carboxamide (600 mg, 0.722 mmol) in formic acid (5.0 mL) was added dropwise water ( 0.20 mL) at 25°C. The reaction mixture was stirred at 25°C for 2 h, then diluted with water (50 mL) and, lyophilized directly to give the product (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6- (N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-oxoethyl)piperazine- 1-carboxamide (400 mg, 0.670 mmol, purity: 100%, 92.79% yield) as a yellow solid.

[0677] RT 0. 529 min (LCMS: method 6; m / z 597.1 (M+H)+(ESP);1H NMR (CDCb, 400 MHz): 9.86 (s, 1 H), 9.65 (s, 1 H), 7.72 (s, 1 H), 7.11 (t, J= 54.0 Hz, 1 H), 6.67 (s, 1 H), 5.29 (s, 1 H), 4.30 (d, J = 18.4 Hz, 1 H), 4.05 (d, J = 18.4 Hz, 1 H), 3.80-3.70 (m, 2H), 3.35-3.32 (m, 2H), 3.25-3.10 (m, 2H), 3.10 (s, 3H), 1 .39 (s, 3H), 1 .34 (d, J = 6.4 Hz, 6H), 0.98-0.89 (m, 2H), 0.63 - 0.57 (m, 2H). Preparation of Example 13

[0678] (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(methyl(oxetan-3- yl)amino)ethyl)piperazine-1-carboxamide

[0679] To a solution of (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-oxoethyl)piperazine-1 - carboxamide (15 mg, 0.0251 mmol) in methanol (1 mL) was added N-methyloxetan-3-amine (22 mg, 0.251 mmol) and NaBHsCN (7.9 mg, 0.126 mmol) at 0 °C under N2. The mixture was stirred at 20 °C for 2 h, then diluted with water (4 mL) and extracted with EtOAc (4 mL, 2x). The combined organic layer was washed with brine (4 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 urn; mobile phase: A: 0.225% FA in water, B: MeCN; B%: 42%-72%, 10 min) and lyophilized directly to give the product (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5- a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(methyl(oxetan-3-yl)amino)ethyl)piperazine-1 -carboxamide (3.5 mg, 0.00527 mmol, 20.97 % yield) as a yellow solid.

[0680] RT 0. 494 min (LCMS: method 6); m / z 668.3 (M+H)+(ESI+); RT 1.797 min: (SFC: Method 6, ee%: 100.00%);1H NMR (CDCh, 400 MHz): 9.86 (s, 1 H), 7.73 (s, 1 H), 7.11 (t, J = 54.0 Hz, 1 H), 6.66 (s, 1 H), 5.17 (s, 1 H), 4.68 (t, J= 6.4 Hz, 2H), 4.60-4.53 (m, 2H), 3.79 - 3.61 (m, 4H), 3.40-3.35 (m, 2H), 3.24-3.15 (m, 3H), 3.08 (s, 3H), 2.53 - 2.32 (m, 2H), 2.21 (s, 3H), 1 .39 (s, 3H), 1 .33 (d, J = 6.4 Hz, 6H), 0.98 - 0.91 (m, 2H), 0.65 - 0.57 (m, 2H).

[0681] Exemplified compounds are summarized in Table 1.

[0682] Table 1

[0683] The examples reported in Table 2 below were prepared according to (i.e., per analogy to) Examples 1 to 4b reported in the Table 1 or using methodologies known by someone skilled in the art. Table 2

[0684]

[0685] Example 56

[0686] 3-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-(l-((2-(dimethylamino)ethyl)imino)-2,6- dimethyl-l-oxido-l6-thiomorpholino)-N-(l-methylcyclopropyl)imidazo[l,5-a]pyridine-6- sulfonamide

[0687] Example 56 was not isolated but separated, using standard procedures, into 4 pure single stereoisomers 56a, 56b, 56c, 56d for which the configuration of the respective stereocenters is has not been assigned.

[0688] Biological evaluation of the exemplary compounds

[0689] 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.

[0690] PARG protein expression and purification

[0691] Acodon optimized gene encoding human PARG (448-976 [H446G, L447S, L473S, N479S, S802A, R811 K, M841 I, 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.

[0692] 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.

[0693] PARG enzymatic ICso assay

[0694] 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.

[0695] Materials: hPARG: Peak Protein, 30 nM

[0696] Substrate: ADP-pNP, 800 pM, Jena Bioscience catalog # NU-955

[0697] Reaction time: 60 minutes

[0698] Assay buffer: 50 mM Tris-HCI pH 8.0, 100 mM NaCI, 2 mM DTT

[0699] Temperature: 30 °C

[0700] Total volume: 30 pL

[0701] Controls:

[0702] • 0% inhibition control: DMSO

[0703] • 100% inhibition control: No enzyme

[0704] The protocol that was used for enzyme reaction and detection is as follows:

[0705] 1. Transfer 100 nL of the final concentration of test compounds or vehicle (DMSO) to the appropriate wells of a microtiter plate. 2. Centrifuge the plate at 1000 rpm for 1 minute.

[0706] 3. Transfer 14.6 pL of 2x final concentration of enzyme in assay buffer or assay buffer alone to the appropriate wells.

[0707] 4. Centrifuge the plate at 1000 rpm for 1 minute.

[0708] 5. Incubate the plate at room temperature for 15 minutes or 2 hours.

[0709] 6. Transfer 15.4 L of 2x substrate in assay buffer to all the test wells.

[0710] 7. Centrifuge the plate at 1000 rpm for 1 minute.

[0711] 8. Read the plate on a plate reader (e.g., Spark Tecan).

[0712] The Absorbance ICso value of compounds of Formula (I) are provided in Table 3 below.

[0713] Cellular Viability Assay

[0714] NCI-H460 as PARG-inhibition sensitive cell lines, and U2OS as PARG-inhibition insensitive cell line, were plated at 1000 cells / well, 5000 cells / wel I and 2000 cells / well, respectively, in 96-well white plates with clear flat bottom. After 24 hours, the compounds were added with the Tecan digital dispenser (D300e), in duplicates. The outer wells of the plate were excluded. After 96 hours of incubation, 150 pl of the growth medium were removed and 50 pl of Cell Titer-Gio (Promega) were added per well. Following an incubation of 10 minutes, luminescence was read using a plate reader (Tecan) 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:

[0715] The cellular viability (NCI-H460 and U2OS) ECso values for compounds of Formula (I) are provided in Table 3 below. hERG assay

[0716] 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.

[0717] 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 CaCb, 1.75 MgCb. EGTA, 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.

[0718] Table 3: Inhibition of PARG and cellular activity of compounds according to the present invention.

[0719] The ICso (inhibitory concentration at 50% of maximal effect) or EC50 (half maximal effective concentration) values are indicated in M, empty space means that the corresponding compounds have not been tested in the respective assay.

[0720] (T) Example number

[0721] (D IC50 in pM determined in PARG enzymatic assay (PARG protein and 2 hours incubation) described under PARG enzymatic I C50 assay

[0722] EC50 in pM determined in NCIH-460 cells as described under Cellular viability assay. (4) EC50 in pM determined in U2OS cells as described under Cellular viability assay.

[0723] Table 3.

[0724] Further assays

[0725] Kinetic solubility assay

[0726] 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:

[0727] 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.

[0728] 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.

[0729] 3. The kinetic solubility samples were vortexed for 2 minutes.

[0730] 4. The solubility solutions were shaked in an orbital shaker for 24 hr at room temperature.

[0731] 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.

[0732] 6. The test compound concentration of the filtrate were determined using HPLC-UV.

[0733] 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.

[0734] Bidirectional permeability in Caco2

[0735] The bidirectional permeability in Caco-2 cells assay was performed for the exemplary compounds of formula (I) according to the following protocol: 1. Caco-2 cells purchased from ATCC were seeded onto polyethylene membranes (PET) in 96- well BD insert plates at 1 x 105 cells / cm2, and refreshed medium every 4~5 days until to the 21stto 28thday for confluent cell monolayer formation.

[0736] 2. The integrity of the monolayer was verified by performing Lucifer yellow rejection assay.

[0737] 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.

[0738] 4. Standard assay conditions for test compounds:

[0739] -test concentration: 2 pM (DMSO<1 %);

[0740] -replicates: n=2;

[0741] -directions: bi-directional transport including A— B and B^A;

[0742] -incubation time: single time point, 2 hours;

[0743] -transport buffer: HBSS containing 10 mM HEPES, pH7.40 ± 0.05;

[0744] -incubation condition: 37±1 °C, 5% CO2, relatively saturated humidity.

[0745] 5. Dosing solution were spiked and mixed with transport buffer and stop solution (containing an appropriate internal standard (IS)) as TO sample.

[0746] 6. At the end of incubation, sample solutions from both donor and receiver wells were mixed with stop solution immediately.

[0747] 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.

[0748] Liver Microsomes Stability Assay

[0749] 1 . Materials

[0750] 1.1 Liver microsomes

[0751] Animal or human liver microsomes were purchased from Xenotech or Corning and stored in a freezer (lower than -60°C) before use.

[0752] 1.2 p-nicotinamide adenine dinucleotide phosphate reduced form, tetrasodium salt, Vendor: Chem-lmpex International, Cat.No. 00616

[0753] 1 .3 Control compounds: Testosterone, diclofenac and propafenone.

[0754] 2. Preparation of Working Solution

[0755] Stock Solution: 10 mM test compound in DMSO.

[0756] Working solution: 100 M test or control compounds in 100% acetonitrile (concentration of organic solvent: 1 % (v / v) DMSO and 99% (v / v) acetonitrile) 3. Assay Procedure

[0757] 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.

[0758] 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.

[0759] 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.

[0760] 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.

[0761] Stop solution (180 pL) and NAPDH cofactor (6 pL) were added to 'Quenching' plate TO. Plates were chilled to prevent evaporation.

[0762] 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.

[0763] 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.

[0764] 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.

[0765] 4. Bioanalytical Analysis

[0766] 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.

[0767] 5. Data Calculation

[0768] 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:

[0769] „ . PAR of analyte to internal standard at each time point , „ >

[0770] %Remainmg = - - - - - x 100

[0771] PAR of analyte to internal standard at T = 0

[0772] CLmt(mic) = 0.693 / T1 / 2 / mg microsome protein per mL

[0773] CLmt(liver) = CLmt(rnic) x mg microsomal protein / g liver weight x g liver weight / kg body weight

[0774] According to the well-stirred model, hepatic intrinsic clearance and hepatic clearance can be calculated by the following formula.

[0775] CL(liver) = (CLint(liver) x fu x Qh) / (CLint(liver) x fu + Qh)

[0776] The default value of fu (the fraction unbound in blood) is assumed as 1.

[0777] The parameters in equations are listed in following table.

[0778] Liver WeightHepatic B,ood HowMicrosomal Protein

[0779] Species

[0780] (g / kg Body Weight) H-2! <Qh) (mL / min / kg) I1 2i(mg / g|iver weight)

[0781] Mouse 88 90.0

[0782] Rat 40 55.2

[0783] Dog 32 30.9 45

[0784] Monkey 30 43.6

[0785] Human 20 20.7

[0786] 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. 6. References

[0787] [1] Brian Davies and Tim Morris, Physiological Parameters in Laboratory Animals and Human. Pharmaceutical Research, Vol. 10 No.7, 1993

[0788] [2] Journal of Pharmacology and Experimental Therapeutics, 1997, 283(1): 46-58

[0789] Hepatocyte Metabolic Stability

[0790] 1 . Materials

[0791] 1.1 Hepatocyte

[0792] Animal or human hepatocytes were purchased from BioreclamationIVT or RILD.

[0793] 1 .2 Control compounds: 7-Ethoxycoumarin and 7-Hydroxycoumarin

[0794] 2. Preparation of Working Solution

[0795] Stock Solution: 10 mM test compound and 30 mM control compound in DMSO.

[0796] 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)

[0797] 3. Assay Procedure

[0798] 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.

[0799] 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.

[0800] 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.

[0801] 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.

[0802] 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

[0803] 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.

[0804] 5. Data Calculation

[0805] 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:

[0806] PAR of analyte to internal standard at each time point ,

[0807] %Remaining = - - - - - x 1n0n0

[0808] PAR of analyte to internal standard at T = 0

[0809] CLmt (hep) = k / million cells per mL

[0810] CLmt (liver) = CLmt (hep)xliver weight (g / kg body weight)xhepatocellularity

[0811] According to the well-stirred model, hepatic intrinsic clearance and hepatic clearance can be calculated by the following formula.

[0812] CL(liver) - (CLint(liver)xfuxQh) / (CLint(liver)xfu+Qh)

[0813] The default value of fu (the fraction unbound in blood) is assumed as 1.

[0814] The parameters in equations are listed in following table.

[0815] Liver Weight (g / kg Liver Blood Hepatocellularity

[0816] Species Flow (Qh)

[0817] Body Weight) P 3] (of cells / g liver) m

[0818] (mL / min / kg) I2 31 ' '

[0819] Mouse 88 90.0 135x106

[0820] Rat 40 55.2 117x106 Dog 32 30.9 215x106

[0821] Monkey 30 43.6 120x106

[0822] Human 20 20.7 139x106

[0823] 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) ( L / min / 106 cells) is reported as <7.5.

[0824] 6. References

[0825] [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 [2] Brian Davies and Tim Morris, Physiological Parameters in Laboratory Animals and Human.

[0826] Pharmaceutical Research, Vol. 10 No.7, 1993

[0827] [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

1. CLAIMSor a pharmaceutically acceptable salt thereof, wherein:Z is selected from:is optionally substituted with one or more groups independently selected from RS1;Ri is -CN, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)- O-(Ci-2alkyl);R2 is -H, C1-2 alkyl 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;R4 is a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, optionally substituted with one or more groups independently selected from Rs2;Rs is selected from -H, C1-2 alkyl, C2 alkenyl, C2 alky nyl, C1-2 haloalkyl, cyclopropyl, cyclobutyl, oxetanyl, and halogen;-A-L1-L2-L3 is defined as follows:A is selected from:- 1 ,4-phenylene, optionally substituted with one or more groups independently selected from Rs2,- heteroarylene, optionally substituted with one or more groups independently selected from Rs2, and- heterocycloalkylene or heterocycloalkenylene, optionally substituted with one or more groups independently selected from Rs2,Li is selected from -SO(NRH)-, -S(NRH)(NRH)-, -SO(NRH)-NRH-, -SO2-O-, -SO2-NRH-, -CO-NRH-, -C(=NCN)-NRH-, -SO(=N-SO2-(CI-5 alkyl), -CH2-CO-, -CO-, -C0-0-, and -CO-(A / - heterocycloalkylene)-, wherein the left empty valence connected to A and the right empty valence is connected to L2, wherein RH is H or C1-5 alkyl, wherein said alkyl is optionally substituted with one or more groups selected from -OH and Hal, or-A-L1- is according to formula:wherein the six-membered ring is optionally substituted with one or more groups independently selected from Rs2, wherein the bottom empty valence is connected to L2;-L2- is a bond, C1-4 alkylene or C3-6 cycloalkylene; and-L3 is selected from -OH, -NH2, -NH(Ci-s alkyl), -N(Ci-s alkyl)(Ci-5 alkyl), -N(Ci-s alkyl)(cycloalkyl) , -N(CI-5 alkyl)(heterocycloalkyl), -NH(cycloalkyl), -NH(heterocycloalkyl), heterocycloalkyl, N- heterocycloalkyl, and -N=S(O)(CI-5 alkyl)(Ci-5 alkyl), wherein said alkyl is optionally substituted with one or more groups selected from -OH and Hal, and wherein said heterocycloalkyl, said cycloalkyl and said / V-heterocycloalkyl are each optionally substituted with one or more groups independently selected from Rs2;RS1is selected from halogen, -ON, -OH, -O(Ci-5 alkyl), -O(Ci-5 haloalkyl), C1-5 haloalkyl, -SH, -S(Ci-5 alkyl), -SO2(Ci-5 alkyl), -S(O)(NH)(Ci-s alkyl), -S(O)(N-Ci-3alkyl)(Ci-5alkyl), -N=S(0)(CI-5 alkyl)(Ci-5 alkyl), -S(Ci-5 haloalkyl), -P(O)(Ci-5 alkyl)(Ci-5 alkyl), -P(O)(O-Ci- 5 alkyl) (O-C1-5 alkyl), -P(O)(O-Ci-5 alkyl)(Ci-5 alkyl), -NH2, -NH(Ci-s alkyl), -NH(Ci-s haloalkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -N(CI-5 haloalkyl)(Ci-5 alkyl), -( / V-heterocycloalkyl), -C0(Ci-5 alkyl), -CONH2, -C0NH(CI-5alkyl), -C0N(CI-5 alkyl)(Ci-5 alkyl), -CO-(A / - heterocycloalkyl), -NHC0-(CI-5 alkyl), -N(CI-5 alkyl)-C0-(Ci-5 alkyl), -NHCONH2, -NHC0NH-(CI-5alkyl), -NHC0N(CI-5alkyl)(Ci-5 alkyl), -N(CI-5alkyl)CONH2, -N(CI-5alkyl)CONH-(Ci-5alkyl), and -N(CI-5 alkyl)CON(Ci-s alkyl)(Ci-5 alkyl); andRs2is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -0(Ci-5 alkyl), -0(Ci-5 haloalkyl), -SH, -S(Ci-5 alkyl), -S(0)(Ci-5 alkyl), -SO2(Ci-5 alkyl), -S(O)(NH)(Ci-s alkyl), -S(O)(N- C1-3 alkyl)(Ci-5alkyl), -N=S(O)(Ci-s alkyl)(Ci-5 alkyl), -S(Ci-5 haloalkyl), -S(0)(Ci-5 haloalkyl), -SO2(Ci-5haloalkyl), -P(O)(Ci-5 alkyl)(Ci-5alkyl), -P(O)(O-Ci-5 alkyl)(0-Ci-5 alkyl), - P(O)(O-Ci-5 alkyl)(Ci-5 alkyl), -NH2, -NH(CI-5alkyl), -NH(CI-5 haloalkyl), -N(Ci-s alkyl)(Ci-5 alkyl), -N(CI-5haloalkyl)(Ci-5 alkyl), -( / V-heterocycloalkyl), -C0(Ci-5 alkyl), -C00H, -C00(Ci-5 alkyl), -CONH2, -CONH(CI-5alkyl), -CON(CI-5 alkyl)(Ci-5 alkyl), -C0-(N- heterocycloalkyl), -NHCO-(CI-5 alkyl), -N(CI-5 alkyl)-C0-(Ci-5 alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci-5 alkyl), -N(CI-5alkyl)CONH2, -N(CI-5alkyl)CONH-(Ci-5alkyl), and -N(CI-5 alkyl)CON(Ci-s alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-0(Ci-5 alkyl), -(C1-5 alkylene)-0(Ci-5 haloalkyl), -(C1-5 alkylene)-SH, -(C1-5 alkylene)-S(Ci-5 alkyl), -(C1-5 alkylene)-S(0)(Ci-5 alkyl), -(C1-5 alkylene)-SO2(Ci-5 alkyl), -(C1-5 alkylene)-S(O)(NH)(Ci-5alkyl), -(C1-5 alkylene)-S(O)(N-Ci-3alkyl)(Ci-s alkyl), -(C1-5 alkylene)-N=S(0)(Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-S(Ci-5 haloalkyl), -(C1-5 alkylene)- S(0)(Ci-5 haloalkyl), -(C1-5 alkylene)-S(O)2(Ci-5 haloalkyl), -(C1-5 alkylene)-P(0)(Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-P(O)(O-Ci-5alkyl)(0-Ci-5 alkyl), -(C1-5 alkylene)-P(0)(0-Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-NH2, -(C1-5 alkylene)-NH(Ci-5alkyl), -(C1-5 alkylene)-NH(Ci-5haloalkyl), - (C1-5 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci-s alkyl)(Ci-5 haloalkyl), -(C1-5 alkylene)-( / V-heterocycloalkyl), -(C1-5 alkylene)-N(Ci-s haloalkyl)(Ci-5 alkyl), -C00-(Ci-5 alkylene)-NH2, -C00-(Ci-5 alkylene)-NH(Ci-5alkyl), -C00-(Ci-5 alkylene)-NH(Ci-5haloalkyl), - C00-(Ci-5 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -C00-(Ci-5 alkylene)-N(Ci-s alkyl)(Ci-5 haloalkyl), - C00-(Ci-5 alkylene)-( / V-heterocycloalkyl), -C00-(Ci-5 alkylene)-N(Ci-s haloalkyl)(Ci-5 alkyl), -(C1- 5 alkylene)-C0(Ci-5 alkyl), -(C1-5 alkylene)-C00(Ci-5 alkyl), -(C1-5 alkylene)-COOH, -(C1-5 alkylene)-CONH2, -(C1-5 alkylene)-CONH(Ci-5alkyl), -(C1-5 alkylene)-CON(Ci-5alkyl)(Ci-5 alkyl), - (C1-5 alkylene)-CO-(A / -heterocycloalkyl), -(C1-5 alkylene)-NHC0-(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci- 5 alkyl)-C0-(Ci-5 alkyl), -(C1-5 alkylene)-NHCONH2, -(C1-5 alkylene)-NHCONH-(Ci-5alkyl), -(C1-5 alkylene)-NHC0N(Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci-5alkyl)CONH2, -(C1-5alkylene)-N(Ci-5alkyl)CONH-(Ci-s alkyl), and -(C1-5 alkylene)-N(Ci-s alkyl)CON(Ci-s alkyl)(Ci-s alkyl), with the provision that -A-L1-L2-L3 is not:and thatthen Ri is not H and / or at least one of R2 and R3 is not -H.

2. The compound ot claim 1, wherein3. The compound of claim 2, wherein R1 is methyl, R2 is H and R3 is H.

4. The compound of claim 2, wherein R1 and R2 are each methyl and R3 is H.

5. The compound of any one of claims 1 to 4, wherein R4 is five membered heteroaryl, substituted at position 3 with respect to its empty valence with -CHF2, preferably wherein6. The compound of any one of claims 1 to 5, wherein Rs is H.

7. The compound of any one of claims 1 to 5, wherein Rs is Cl.

8. The compound of any one of claims 1 to 7, wherein A is 1 ,4-p henylene, optionally substituted with one or more groups independently selected from Rs2, preferably optionally substituted with a group selected from methyl, -F and -CN.

9. The compound of claim 8, wherein Li is -SO(NH)-.

10. The compound of claim 9, wherein L2 is -CH2CH2- and L3 is -NH(CH3) or -N(CH3)2.

11. The compound of any one of claims 1 to 7, wherein A is 1 ,4-(six-membered heteroarylene), optionally substituted with one or more groups independently selected from Rs2.

12. The compound of claim 11 , wherein A is pyridinylene, preferably 2,5-pyridinylene, optionally substituted with one or more groups independently selected from Rs2, preferably optionally substituted with a group selected from methyl, -F and -CN.

13. The compound of claim 12, wherein the nitrogen atom in pyridinylene moiety is oxidized.

14. The compound of any one of claims 11 to 13, wherein Li is -SO(NH)-.

15. The compound of claim 14, wherein L2 is -CH2CH2- and L3 is -NH(CH3) or -N(CH3)2.

16. The compound of any one of claims 1 to 7, wherein A is 1 ,4-pi perazi nylene, optionally substituted with one or more groups independently selected from Rs2.

17. The compound of claim 16, wherein A is selected from(such18. The compound of claim 17, wherein Li is -CO-NRH-, preferably wherein Li is -C0-N(CH3)-.

19. The compound of claim 18, wherein L2 is -CH2CH2- and L3 is -NH(CH3) or -N(CH3)2.

20. The compound of claim 17, wherein Li is -SO(NH)-.21 . The compound of claim 20, wherein L2 is -CH2CH2- and L3 is -NH(CH3) or -N(CH3)2.

22. The compound of claim 18 or the compound of claim 20, wherein L2 is -CH2CH2- and L3 is 3- azetidinyl.

23. The compound of claim 1 , wherein the compound is a compound selected from,or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 , wherein the compound is a compound selected from:or a pharmaceutically acceptable salt thereof.25.or a pharmaceutically acceptable salt thereof, wherein:Z’ is selected fromRi is -H, -CN, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-0-(Ci-2 alkyl);R2 is -H, C1-2 alkyl 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;R4 is a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, (preferably five membered heteroaryl), optionally substituted with one or more groups independently selected from Rs2;Rs is selected from -H, C1-2 alkyl, C2 alkenyl, C2 alky nyl, C1-2 haloalkyl, cyclopropyl, cyclobutyl, oxetanyl, and halogen;-A-L1-L2-L3 is defined as follows:(a) A is 1 ,4-phenylene, optionally substituted with one or more groups independently selected from Rs2, preferably from methyl, Hal, -OH and -ON, or 1 ,4-(six-membered heteroarylene, optionally substituted with one or more groups independently selected from Rs2, preferably from methyl, Hal, -OH and -ON;Li is -SO(NH)- or -S0(NCH3)-, preferably -S0(NCH3)-, wherein the left empty valence connected to A and the right empty valence is connected to L2;-L2- is a bond, C1-4 alkylene or C3-6 cycloalkylene, preferably L2 is a linear C2-3 alkylene, more preferably, L2 is -CH2CH2-; andL3 is selected from -NH(Ci-s alkyl), -N(Ci-s alkyl)(Ci-s alkyl), -N(Ci-s alkyl)(cycloalkyl) , - N(CI-5 alkyl)(heterocycloalkyl), -NH(cycloalkyl), -NH(heterocycloalkyl), heterocycloalkyl and / V-heterocycloalkyl, wherein said alkyl is optionally substituted with one or more groups selected from -OH and Hal, and wherein said heterocycloalkyl, said cycloalkyl and said / V-heterocycloalkyl are each optionally substituted with one or more groups independently selected from Rs2, preferably L3 is selected from -NH(Ci-s alkyl), -N(CI-5 alkyl)(Ci -5 alkyl), and / V-heterocycloalkyl, wherein said alkyl is optionally substituted with one or more groups selected from -OH and Hal, and wherein said / V-heterocycloalkyl is optionally substituted with one or more groups independently selected from Rs2, or(b) A is heterocycloalkylene or heterocycloalkenylene (such as 1 ,4-piperazinylene), optionally substituted with one or more groups independently selected from Rs2, preferably A is 1 ,4-piperazinylene, optionally substituted with one or two methyl groups; Li is -CONH- or -CON(CH3)-, preferably -CON(CH3)-, wherein the left empty valence is connected to A and the right empty valence is connected to L2;-L2- is a bond, C1-4 alkylene or C3-6 cycloalkylene, preferably L2 is a linear C2-3 alkylene, more preferably, L2 is -CH2CH2-; andL3 is selected from -N(CI-5 alkyl)(cycloalkyl), -N(CI-5 alkyl)(heterocycloalkyl), - NH(cycloalkyl), -NH(heterocycloalkyl), and / V-heterocycloalkyl, wherein said cycloalkyl, said heterocycloalkyl and said / V-heterocycloalkyl is optionally substituted with one or more groups independently selected from Rs2;RS1is selected from halogen, -CN, -OH, -0(Ci-5 alkyl), -0(Ci-5 haloalkyl), C1-5 haloalkyl, -SH, -S(Ci-5 alkyl), -SO2(Ci-5 alkyl), -S(O)(NH)(Ci-s alkyl), -S(0)(N-CI-3 alkyl)(Ci-5 alkyl), -N=S(0)(CI-5 alkyl)(Ci-5 alkyl), -S(Ci-5 haloalkyl), -P(0)(Ci-5 alkyl)(Ci-5 alkyl), -P(O)(O-Ci-in5 alkyl) (O-C1-5 alkyl), -P(0)(0-Ci-5 alkyl)(Ci-5 alkyl), -NH2, -NH(Ci-s alkyl), -NH(Ci-s haloalkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -N(CI-5 haloalkyl)(Ci-5 alkyl), -( / V-heterocycloalkyl), -C0(Ci-5 alkyl), -CONH2, -C0NH(CI-5alkyl), -C0N(CI-5 alkyl)(Ci-5 alkyl), -CO-(A / - heterocycloalkyl), -NHC0-(CI-5 alkyl), -N(CI-5 alkyl)-CO-(Ci-5 alkyl), -NHCONH2, -NHC0NH-(CI-5alkyl), -NHC0N(CI-5alkyl)(Ci-5 alkyl), -N(CI-5alkyl)CONH2, -N(CI-5alkyl)CONH-(Ci-5alkyl), and -N(CI-5 alkyl)CON(Ci-s alkyl)(Ci-5 alkyl); andRs2is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -0(Ci-5 alkyl), -0(Ci-5 haloalkyl), -SH, -S(Ci-5 alkyl), -S(0)(Ci-5 alkyl), -SO2(Ci-5 alkyl), -S(O)(NH)(Ci-s alkyl), -S(O)(N- C1-3 alkyl)(Ci-5alkyl), -N=S(O)(Ci-s alkyl)(Ci-5 alkyl), -S(Ci-5 haloalkyl), -S(O)(Ci-5 haloalkyl), -SO2(Ci-5haloalkyl), -P(O)(Ci-5 alkyl)(Ci-5alkyl), -P(O)(O-Ci-5 alkyl)(0-Ci-5 alkyl), - P(O)(O-Ci-5 alkyl)(Ci-5 alkyl), -NH2, -NH(CI-5alkyl), -NH(CI-5 haloalkyl), -N(Ci-s alkyl)(Ci-5 alkyl), -N(CI-5haloalkyl)(Ci-5 alkyl), -( / V-heterocycloalkyl), -C0(Ci-5 alkyl), -C00H, -C00(Ci-5 alkyl), -CONH2, -CONH(CI-5alkyl), -CON(CI-5 alkyl)(Ci-5 alkyl), -CO-( / V- heterocycloalkyl), -NHC0-(CI-5alkyl), -N(CI-5 alkyl)-CO-(Ci-5alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci-5 alkyl), -N(CI-5alkyl)CONH2, -N(CI-5alkyl)CONH-(Ci-5alkyl), and -N(CI-5 alkyl)CON(Ci-s alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-0(Ci-5 alkyl), -(C1-5 alkylene)-0(Ci-5 haloalkyl), -(C1-5 alkylene)-SH, -(C1-5 alkylene)-S(Ci-5 alkyl), -(C1-5 alkylene)-S(0)(Ci-5 alkyl), -(C1-5 alkylene)-SO2(Ci-5 alkyl), -(C1-5 alkylene)-S(O)(NH)(Ci-5alkyl), -(C1-5 alkylene)-S(O)(N-Ci-3alkyl)(Ci-s alkyl), -(C1-5 alkylene)-N=S(0)(Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-S(Ci-5 haloalkyl), -(C1-5 alkylene)- S(0)(Ci-5 haloalkyl), -(C1-5 alkylene)-S(O)2(Ci-5 haloalkyl), -(C1-5 alkylene)-P(0)(Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-P(O)(O-Ci-5alkyl)(0-Ci-5 alkyl), -(C1-5 alkylene)-P(O)(O-Ci-5alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-NH2, -(C1-5 alkylene)-NH(Ci-5alkyl), -(C1-5 alkylene)-NH(Ci-5haloalkyl), - (C1-5 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci-s alkyl)(Ci-5 haloalkyl), -(C1-5 alkylene)-( / V-heterocycloalkyl), -(C1-5 alkylene)-N(Ci-s haloalkyl)(Ci-5 alkyl), -C00-(Ci-5 alkylene)-NH2, -C00-(Ci-5alkylene)-NH(Ci-5alkyl), -C00-(Ci-5alkylene)-NH(Ci-5haloalkyl), - C00-(Ci-5 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -C00-(Ci-5 alkylene)-N(Ci-s alkyl)(Ci-5 haloalkyl), - C00-(Ci-5 alkylene)-( / V-heterocycloalkyl), -C00-(Ci-5 alkylene)-N(Ci-s haloalkyl)(Ci-5 alkyl), -(C1- 5 alkylene)-C0(Ci-5 alkyl), -(C1-5 alkylene)-C00(Ci-5 alkyl), -(C1-5 alkylene)-COOH, -(C1-5 alkylene)-CONH2, -(C1-5 alkylene)-CONH(Ci-5alkyl), -(C1-5 alkylene)-CON(Ci-5alkyl)(Ci-5 alkyl), - (C1-5 alkylene)-CO-( / V-heterocycloalkyl), -(C1-5 alkylene)-NHC0-(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci- 5 alkyl)-CO-(Ci-5alkyl), -(C1-5 alkylene)-NHCONH2, -(C1-5 alkylene)-NHCONH-(Ci-5alkyl), -(C1-5 alkylene)-NHCON(Ci-5alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci-5alkyl)CONH2, -(C1-5 alkylene)-N(Ci 5 alkyl)CONH-(Ci-5alkyl), and -(C1-5 alkylene)-N(Ci-5alkyl)CON(Ci-5alkyl)(Ci-5alkyl), with the proviso thatthen Ri is not H and / or at least one of R2 and R3 is not-H.

26. The compound of claim 1 , wherein the compound is a compound selected from the following compounds:(25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2,6- trimethylpiperazine-1-carboxamide;(25.65)-N-(2-(azetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;8-(4-(2-(azetidin-1 -yl)ethylsulfonimidoyl)-2-methylphenyl)-1-chloro-3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide;1 -chloro- 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2-methylphenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;(25.65)-N-(2-((3-cyanocyclobutyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6- (N-(1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;(25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N-(2-(3-fluoroazetidin-1-yl)ethyl)-N,2,6- trimethylpiperazine-1-carboxamide;(25.65)-N-(2-(cyclopropyl(methyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6- (N-(1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;(25.65)-N-(2-(3-cyanoazetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;3-[5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl]-8-[(3S,5S)-4-[3-(dimethylamino)azetidine-1-carbonyl]- 3,5-dimethyl-piperazin-1-yl]-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;(25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(4-methylpiperazin- 1-yl)ethyl)piperazine-1 -carboxamide;(2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(pyrrolidin-1- yl)ethyl)piperazine-1-carboxamide;(25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(methyl(oxetan-3- yl)amino)ethyl)piperazine-1-carboxamide;4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5- a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N-methyl-3,6-dihydropyridine-1 (2H)-carboxamide;3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(dimethylalanyl)piperazin-1-yl)-N-(1- methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;(25.65)-N-(2-(azetidin-1-yl)ethyl)-4-(6-(N-(1-cyanocyclopropyl)sulfamoyl)-3-(5-(difluoromethyl)- 1 , 3, 4-thiadiazol-2-yl)imidazo[1 ,5-a]pyridin-8-yl)-N, 2, 6-trimethylpiperazine-1 -carboxamide;(25.65)-N-(2-(azetidin-1-yl)ethyl)-N,2,6-trimethyl-4-(6-(N-(1 -methylcyclopropyl)sulfamoyl)-3-(5- (trifluoromethyl)-l, 3, 4-thiadiazol-2-yl)imidazo[1,5-a]pyridin-8-yl)piperazine-1 -carboxamide;(25.65)-N-(2-(azetidin-1 -yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(cis-2- fluoro-1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1- carboxamide;(25.65)-N-(2-(azetidin-1 -yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;(25.65)-N-(2-(azetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-((1 R,2S)- 1 ,2-dimethylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;8-(4-(2-(azetidin-1 -yl)-N-(methylsulfonyl)ethylsulfonimidoyl)-2-methylphenyl)-1-chloro-3-(5-(difl uoromethyl)- 1 , 3, 4-th i ad i azol-2-yl )-N- ( 1 -methylcycl opropyl) imi d azo [1 , 5-a] py ri d i ne-6- sulfonamide;(25.65)-N-(azetidin-3-yl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;1 -chloro- 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-hydroxyethylsulfonimidoyl)-2- methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;(25.65)-N-(2-(((trans)-3-cyanocyclobutyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 -carboxamide;(25.65)-N-(2-(((cis)-3-cyanocyclobutyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2- yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1- carboxamide;(25.65)-N-(2-(((trans)-3-cyanocyclobutyl)(methyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6- trimethylpiperazine-1-carboxamide;(25.65)-N-(2-(((cis)-3-cyanocyclobutyl)(methyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6- trimethylpiperazine-1-carboxamide;(25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(1 -methylazetidin-3- yl)piperazine-1 -carboxamide;1 -chloro- 3-(5-(difluoromethyl)-1 , 3, 4-thiadiazol-2-yl)-8-(4-(3-(dimethylamino)azetidine-1 - carbonyl)piperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide;3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(5-(2-(dimethylamino)ethylsulfonimidoyl)-3- methylpyridin-2-yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(6-(2-(dimethylamino)ethylsulfonimidoyl)-2- methoxypyridin-3-yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- hydroxyphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- methoxyphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;2-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5- a]pyridin-8-yl)-5-(2-(dimethylamino)ethylsulfonimidoyl)pyridine 1-oxide;(2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N-(2-((dimethyl(oxo)-X6- sulfaneylidene)amino)ethyl)-N,2,6-trimethylpiperazine-1 -carboxamide;1 -chloro- 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(2-methyl-4-(2-(4-methylpiperazin-1- yl)ethylsulfonimidoyl)phenyl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide;1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2-hydroxyphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2-methoxyphenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(6-(2-(dimethylamino)ethylsulfonimidoyl)-2-methoxypyridin-3-yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;8-(2-cyano-4-(2-(dimethylamino)ethylsulfonimidoyl)phenyl)-3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide;1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(5-(2-(dimethylamino)ethylsulfonimidoyl)-3-methylpyridin-2-yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(6-(2-(dimethylamino)ethylsulfonimidoyl)-2-hydroxypyridin-3-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide;1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(6-(2-(dimethylamino)ethylsulfonimidoyl)-2-methylpyridin-3-yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;(2S,6S,E)-N'-cyano-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2,6- trimethylpiperazine-1-carboximidamide;3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-4-(N-(2-(dimethylamino)ethyl)-N- methylsulfamoyl)-3,5-dimethylpiperazin-1 -yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;(2S , 6S)-4- (3-(5-(difl uoromethy I)- 1 , 3, 4-thi ad iazol-2-yl)- 1 -fl uoro-6- (N- (1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2,6- trimethylpiperazine-1-carboxamide;(2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2- morpholinoethyl)piperazine-1-carboxamide;1 -chloro- 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2-fluorophenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;1-chloro-8-(2-cyano-4-(2-(dimethylamino)ethylsulfonimidoyl)phenyl)-3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide;3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- methylphenyl)-1-fluoro-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;2-((2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-2,6-dimethylpiperazin-1 -yl)-N,N- dimethylacetamide;2-(4-( 1 -chloro- 3- (5- (d ifl uoromethyl)- 1 ,3, 4-thi adi azol-2-yl)-6-(N-( 1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)piperazin-1 -yl)-N,N-dimethylacetamide;3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-4-(dimethylglycyl)-3,5-dimethylpiperazin-1 -yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-4-(dimethyl-D-alanyl)-3,5- dimethylpiperazin-1 -yl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;(R)-4-(3-(5-(difl uoromethy I)- 1 , 3,4-thi ad iazol- 2-y l)-6- (N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2- dimethylpiperazine-1-carboxamide;(S)-4-(3-(5- (difl uoro methy l)-1 , 3, 4-th i ad iazol- 2-y l)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2- dimethylpiperazine-1-carboxamide;3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((1s,2S,6R)-1-((2-(dimethylamino)ethyl)imino)-2,6- dimethyl-1 -oxido-1 l6-thiomorpholino)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((1 r,2S,6R)-1-((2-(dimethylamino)ethyl)imino)-2,6- dimethyl-1 -oxido-1 l6-thiomorpholino)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;8-(4-(2-aminoethylsulfonimidoyl)-3-methylphenyl)-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N- (1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;8-(4-(2-aminoethylsulfonimidoyl)-3-methylphenyl)-1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol- 2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide;8-(4-(2-aminoethylsulfonimidoyl)-2-methylphenyl)-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N- (1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;8-(4-(2-aminoethylsulfonimidoyl)-2-methylphenyl)-1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide;3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-((R)-4-(dimethyl-D-alanyl)-3-methylpiperazin-1-yl)- N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-((S)-4-(dimethyl-D-alanyl)-3-methylpiperazin-1-yl)- N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-3- methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;1 -chloro- 3-(5-(difluoromethyl)-1 , 3, 4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)- 3-methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- methylphenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;1 -chloro- 3-(5-(difluoromethyl)-1 , 3, 4-thiadiazol-2-yl)-8-(6-(2- (dimethylamino)ethylsulfonimidoyl)pyridin-3-yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;1 -chloro- 3-(5-(difluoromethyl)-1 , 3, 4-thiadiazol-2-yl)-8-(5-(2-(dimethylamino)ethylsulfonimidoyl)pyridin-2-yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;(2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)-[1 .2.4]triazolo[4,3-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2,6-trimethylpiperazine-1- carboxamide;4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-[1 .2.4]triazolo[4,3-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2-dimethylpiperazine-1 - carboxamide;2-(di methy lam i no)ethyl (2S, 6S)-4-(3-(5- (d ifl uoromethyl)- 1 , 3, 4-th i ad i azol-2-yl )-6-(N-( 1 - methylcyclopropyl)sulfamoyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-2,6-dimethylpiperazine-1 - carboxylate;2-(di methy lam i no)ethyl 4-(3-(5- (d ifl uoromethyl)- 1 , 3, 4-th i ad i azol-2-yl )-6-(N-( 1 - methylcyclopropyl)sulfamoyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-2-methylpiperazine-1- carboxylate;2-(di methy lam i no)ethyl 4-(1 -ch loro-3-(5-(d ifl uoro methyl )- 1 , 3, 4-th i ad i azol-2-yl )-6-(N-(3- methyloxetan-3-yl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)piperazine-1-carboxylate;1 -chloro- 3-(5-(difluoromethyl)-1 , 3, 4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)phenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;8-(4-(2-aminoethylsulfonimidoyl)phenyl)-1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-N- (1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;2-(di methy lam i no)ethyl 4-(1 -chloro-6-(N-( 1 -cyanocyclop ropyl)sulfamoyl)-3-(5-(d ifl uoromethyl)-1 ,3,4-thiadiazol-2-yl)imidazo[1 ,5-a]pyridin-8-yl)piperazine-1-carboxylate;2-(dimethylamino)ethyl 4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-1-fluoro-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)piperazine-1-carboxylate;2-(di methy lam i no)ethyl 4-(3-(5- (d ifl uoromethyl)- 1 , 3, 4-th i ad i azol-2-yl )-6-(N-( 1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-2-methylpiperazine-1-carboxylate;2-(di methy lam i no)ethyl 4-(3-(5- (d ifl uoromethyl)- 1 , 3, 4-th i ad i azol-2-yl )-6-(N-( 1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)piperazine-1-carboxylate;1 -chloro- 3-(5-(difluoromethyl)-1 , 3, 4-thiadiazol-2-yl)-8-(4-(dimethyl-D-alanyl)piperazin-1-yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;2-(di methy lam i no)ethyl 4-(3-(5- (d ifl uoromethyl)- 1 , 3, 4-th i ad i azol-2-yl )-6-(N-( 1 - methylcyclopropyl)sulfamoyl)-[1, 2, 4]triazolo[4,3-a]pyridin-8-yl)piperazine-1 -carboxylate;1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-((2-(dimethylamino)ethyl)sulfonyl)piperazin-1 -yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(dimethyl-L-alanyl)piperazin-1-yl)-N-(1- methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(dimethyl-D-alanyl)piperazin-1 -yl)-N-(1- methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;2-(dimethylamino)ethyl (2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-2,6-dimethylpiperazine-1-carboxylate; and2-(di methy lam I no)ethyl 4-(1 -ch loro-3-(5-(d ifl uoro methyl )- 1 , 3, 4-th i ad i azol-2-yl )-6-(N-( 1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)piperazine-1-carboxylate; or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1 , wherein the compound is a compound selected from the following compounds:(25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2,6- trimethylpiperazine-1-carboxamide;(25.65)-N-(2-(azetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;8-(4-(2-(azetidin-1 -yl)ethylsulfonimidoyl)-2-methylphenyl)-1-chloro-3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide;1 -chloro- 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2-methylphenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;(25.65)-N-(2-((3-cyanocyclobutyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6- (N-(1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;(25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N-(2-(3-fluoroazetidin-1-yl)ethyl)-N,2,6-trimethylpiperazine-1-carboxamide;(25.65)-N-(2-(cyclopropyl(methyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6- (N-(1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;(25.65)-N-(2-(3-cyanoazetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;3-[5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl]-8-[(3S,5S)-4-[3-(dimethylamino)azetidine-1-carbonyl]- 3,5-dimethyl-piperazin-1-yl]-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;(25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(4-methylpiperazin- 1-yl)ethyl)piperazine-1 -carboxamide;(2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(pyrrolidin-1- yl)ethyl)piperazine-1-carboxamide;(25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2-(methyl(oxetan-3- yl)amino)ethyl)piperazine-1-carboxamide;4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5- a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N-methyl-3,6-dihydropyridine-1 (2H)-carboxamide;(25.65)-N-(2-(azetidin-1-yl)ethyl)-N,2,6-trimethyl-4-(6-(N-(1 -methylcyclopropyl)sulfamoyl)-3-(5- (trifluoromethyl)-l, 3, 4-thiadiazol-2-yl)imidazo[1,5-a]pyridin-8-yl)piperazine-1 -carboxamide(25.65)-N-(2-(azetidin-1 -yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(cis-2- fluoro-1 -methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1- carboxamide;(25.65)-N-(2-(azetidin-1 -yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- (fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;(25.65)-N-(2-(azetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-((1 R,2S)- 1 ,2-dimethylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;(25.65)-N-(2-(azetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-((1 S,2R)- 1 ,2-dimethylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;8-(4-(2-(azetidin-1 -yl)-N-(methylsulfonyl)ethylsulfonimidoyl)-2-methylphenyl)-1-chloro-3-(5- (difl uoromethyl)- 1 , 3, 4-th i ad i azol-2-yl )-N- ( 1 -methylcycl opropyl) imi d azo [1 , 5-a] py ri d i ne-6- sulfonamide;1 -chloro- 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-hydroxyethylsulfonimidoyl)-2- methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;(25.65)-N-(2-(((trans)-3-cyanocyclobutyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine- 1 -carboxamide;(25.65)-N-(2-(((cis)-3-cyanocyclobutyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2- yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide;(25.65)-N-(2-(((trans)-3-cyanocyclobutyl)(methyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6- trimethylpiperazine-1-carboxamide;(25.65)-N-(2-(((cis)-3-cyanocyclobutyl)(methyl)amino)ethyl)-4-(3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6- trimethylpiperazine-1-carboxamide;1 -chloro- 3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(2-methyl-4-(2-(4-methylpiperazin-1- yl)ethylsulfonimidoyl)phenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2-methoxyphenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(6-(2-(dimethylamino)ethylsulfonimidoyl)-2-methoxypyridin-3-yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-((3S,5S)-4-(N-(2-(dimethylamino)ethyl)-N- methylsulfamoyl)-3,5-dimethylpiperazin-1 -yl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;(2S , 6S)-4- (3-(5-(difl uoromethyl)- 1 , 3, 4-thi ad iazol-2-yl)- 1 -fl uoro-6- (N- (1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2,6- trimethylpiperazine-1-carboxamide;(25.65)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethyl-N-(2- morpholinoethyl)piperazine-1-carboxamide;1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2-fluorophenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;(S)-1 -chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2-fluorophenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5- a]pyridine-6-sulfonamide(R)-1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2-fluorophenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5- a]pyridine-6-sulfonamide;3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- methylphenyl)-1-fluoro-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;(R)-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- methylphenyl)-1-fluoro-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;(S)-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- methylphenyl)-1-fluoro-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;2-((2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-2,6-dimethylpiperazin-1 -yl)-N,N- dimethylacetamide;(S)-4-(3-(5- (difl uoro methy l)-1 , 3, 4-th i ad iazol- 2-y l)-6-(N-(1 - methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2- dimethylpiperazine-1-carboxamide;1 -chloro- 3-(5-(difluoromethyl)-1 , 3, 4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-3-methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;(S)-1 -chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-3-methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5- a]pyridine-6-sulfonamide;(R)-1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-3-methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5- a]pyridine-6-sulfonamide;1 -chloro- 3-(5-(difluoromethyl)-1 , 3, 4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)- 3-methylphenyl)-N-(1-methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)-2- methylphenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide;(2S,6S)-4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1 -methylcyclopropyl)sulfamoyl)-[1 ,2,4]triazolo[4,3-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N,2,6-trimethylpiperazine-1- carboxamide;1 -chloro- 3-(5-(difluoromethyl)-1 , 3, 4-thiadiazol-2-yl)-8-(4-(2-(dimethylamino)ethylsulfonimidoyl)phenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;(S)-1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2- (dimethylamino)ethylsulfonimidoyl)phenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;(R)-1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-8-(4-(2- (dimethylamino)ethylsulfonimidoyl)phenyl)-N-(1 -methylcyclopropyl)imidazo[1 ,5-a]pyridine-6- sulfonamide;1 -chloro- 3-(5-(difluoromethyl)-1 , 3, 4-thiadiazol-2-yl)-8-(4-(dimethyl-D-alanyl)piperazin-1-yl)-N-(1 - methylcyclopropyl)imidazo[1 , 5-a] pyridi ne-6-sulfonamide; and2-(dimethylamino)ethyl 4-(1-chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)piperazine-1-carboxylate; or a pharmaceutically acceptable salt thereof.

28. The compound of claim 1 , wherein the compound is a compound selected from the following compounds: (2S,6S)-N-(2-(azetidin-1-yl)ethyl)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,2,6-trimethylpiperazine-1 - carboxamide; and8-(4-(2-(azetidin-1 -yl)ethylsulfonimidoyl)-2-methylphenyl)-1-chloro-3-(5-(difluoromethyl)-1 ,3,4- thi ad iazo l-2-y l)-N-(1 -methylcyc lopropyl) i mid azo [1 , 5-a] py ri di ne-6-sulfonami de (such as (R)-8-(4- (2-(azetidin-1-yl)ethylsulfonimidoyl)-2-methylphenyl)-1 -chloro- 3-(5-(difluoromethyl)-1 ,3,4- thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide or (S)-8-(4-(2- (azetidin-1-yl)ethylsulfonimidoyl)-2-methylphenyl)-1 -chloro-3-(5-(difluoromethyl)-1 ,3,4-thiadiazol- 2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide); or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising the compound of any one of claims 1 to 28 and a pharmaceutically acceptable carrier.

30. The compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of claim 29, for use in therapy.

31. The compound for use or the pharmaceutical composition for use of claim 30, wherein the compound or the pharmaceutical composition is for use in a method of treating a disease or disorder in which PARG activity is implicated.

32. The compound for use or the pharmaceutical composition for use of claim 31 , for use in a method of treating a proliferative disorder.

33. The compound for use or the pharmaceutical composition for use of claim 32, wherein the proliferative disorder is cancer, preferably a human cancer.

34. The compound for use or the pharmaceutical composition for use of claim 33, wherein the cancer to be treated is selected from lung, colon, breast, ovarian, prostate, liver, pancreas, brain, gastric and skin cancer.

35. Use of the compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of claim 29, in a manufacture of a medicament for use in a method of treating a disease or disorder in which PARG activity is implicated.

36. Use of the compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of claim 29, in a manufacture of a medicament for use in a method of treating a proliferative disorder.

37. The use of claim 36, wherein the proliferative disorder is cancer, preferably a human cancer.

38. The use of claim 37, wherein the cancer to be treated is selected from lung, colon, breast, ovarian, prostate, liver, pancreas, brain, gastric and skin cancer.

39. A method of treating a proliferative disorder, the method comprising the step of administering the compound of claim 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, to a subject in need thereof.

40. The method of claim 39, wherein the proliferative disorder is cancer.

41. The method of claim 40, wherein the cancer to be treated is selected from lung, colon, breast, ovarian, prostate, liver, pancreas, brain, gastric and skin cancer.

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