Novel PARG inhibitors

Abstract

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

Description

[0001] Novel PARG inhibitors

[0002] Field of the invention

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

[0004] Background of the invention

[0005] Cancer is a leading cause of death worldwide. Although progression-free survival and overall survival of cancer patients has improved over the past two decades, millions of cancer patients still have few therapeutic options and poor survival outcomes (Jemal et al., J. Natl. Cancer Inst. 2017, 109, 1975).

[0006] DNA replication stress (DRS) is a hallmark of cancer cells and a major source of genomic instability (a) Halazonetis et al., Science 2008, 319, 1352; b) Negrini et al., Nat. Rev. Mol. Cell Biol. 2010, 11 , 220). In broad terms, DRS refers to the deregulation of DNA replication and cell cycle progression. DRS can be induced from endogenous or exogenous causes such as oncogene activation and chemotherapeutics, respectively (Zeman and Cimprich, Nat. Cell Biol. 2013, 16, 2). At the level of the replication fork, DRS leads to replication fork stalling, disengagement of the replisome and eventually collapse. Several DNA repair proteins are involved in replication fork stability, protection, and restart under DRS conditions (a) Costantino et al., Science 2014, 343, 88; b) Scully et al., Curr. Opin. Genet. Dev. 2021 71 , 154).

[0007] Poly(ADP)ribosylation (PARylation) is a transient and reversible post-translational modification that occurs at DNA damaged sites and is catalyzed by the poly (ADP-ribose) polymerase (PARP) family of proteins (Cohen and Chang, Nat. Chem. Biol. 2018, 14, 236). PARylation of various DNA repair proteins leads to their activation. Degradation of the poly(ADP) ribose chains is mediated primarily by the poly(ADP-ribose) glycohydrolase (PARG) protein. DNA damage dependent PARylation / dePARylation is a rapid and dynamic process which needs to be well regulated since imbalances between the two processes can lead to DNA damage.

[0008] Human PARG encodes a 111 kDa protein of 976 amino acids. It contains a N-terminal regulatory domain, a catalytic domain and an ADP-ribose binding macrodomain. Five human PARG transcripts have been identified. Full length PARG is mostly nuclear; the smaller isoforms localize primarily to the cytoplasm. PARG functions primarily as an exo-hydrolase and it releases mainly mono(ADP-ribose) by hydrolyzing the a-O-glycosidic ribose-ribose bond in PAR. PARG can also act as an endo-hydrolase. PARG preferentially degrades long and linear PAR chains whereas its activity with small and branched PAR chains is significantly reduced (O’Sullivan et al., Nat. Commun. 2019, 10, 1182).

[0009] Although PARG is the dominant cellular PAR degrading enzyme, it cannot act on the terminal protein-ribose bond. Additional hydrolases such as terminal ADP-ribose protein glycohydrolase (TARG1) and ADP-ribosylhydrolase 3 (ARH3) are also known to catalyze PAR-degradation. TARG1 and ARH3 complete the reversal of PARylation by removing protein-bound mono(ADP-ribose) moieties (a) Fontana et al., Elife 2017, doi: 10.7554 / eLife.28533; b) Rack et al., Genes Dev. 2020, 34, 263). TARG1 is located in the nucleus and cytoplasm. ARH3 is found primarily in the cytoplasm but it can also be found in the mitochondria and in the nucleus (Rack et al., Genes Dev. 2020, 34, 263).

[0010] Genomic aberrations targeting tumor suppressor genes or oncogenes, often make cancer cells dependent on specific DNA repair pathways. For instance, it is well known that PARP inhibitors are particularly effective against tumors carrying mutations in the BRCA1 and BRCA2 genes (a) Bryant et al., Nature 2005, 434, 913; b) Farmer et al., Nature 2005, 434, 917). Targeting synthetic lethal interactions like the one between PARP and BRCA is an attractive novel therapeutic approach for cancer treatment.

[0011] PARG participates in DNA replication and in various DNA repair mechanisms including singlestrand break (SSB) repair and replication fork restart. PARG inhibitors have shown synthetic lethal phenotype in cells with high levels of DRS caused by low expression of genes involved in DNA replication and / or replication fork stability (Pillay et al., Cancer Cell. 2019, 35, 519). Moreover, PARG inactivation, depletion or inhibition sensitizes cells to irradiation and to DNA damaging agents such as alkylating agents (e.g. temozolomide and methyl methanesulfonate) (a) Fujihara et al., Curr. Cancer Drug Targets 2009, 9, 953; b) Gogola et al., Cancer Cell 2018, 33, 1078; c) Houl et al., Nat Commun. 2019, 10, 5654).

[0012] Given the therapeutic potential of PARG inhibitors in cancer treatment, there is an increased need for the development of highly potent and selective PARG inhibitors beyond the ones that have already been described (a) James et al., ACS Chem. Biol. 2016, 11 , 3179; b) Waszkowycz et al., J. Med. Chem. 2018, 61 , 10767).

[0013] Certain compounds that are useful as PARG inhibitors are further disclosed in documents WO 2016 / 092326, WO 2016 / 097749 and WO 2021 / 055744. Further compounds particularly useful as PARG inhibitors are disclosed in documents WO 2024 / 074497 and WO 2023 / 183850.

[0014] Summary of the invention

[0015] 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.

[0016] In a first embodiment, the present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof. It is to be understood that through the present description the term “compound of formula (I)” preferably encompasses also a compound of formula (II), (III) and (IV), unless explicitly indicated to the contrary.

[0017] 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.

[0018] In a further embodiment, the present invention relates to the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, for use in therapy.

[0019] The compounds of formula (I) are useful for treating a disease or disorder in which PARG activity is implicated.

[0020] 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.

[0021] Definitions

[0022] The following definitions apply throughout the present specification and the claims, unless specifically indicated otherwise.

[0023] 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.

[0024] The term “hydrocarbon group” refers to a group consisting of carbon atoms and hydrogen atoms.

[0025] The term “alicyclic” is used in connection with cyclic groups and denotes that the corresponding cyclic group is non-aromatic.

[0026] As used herein, the term “alkyl” refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group which may be linear or branched. Accordingly, an “alkyl” group does not comprise any carbon-to-carbon double bond or any carbon-to-carbon triple bond. A “C1-5 alkyl” denotes an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless defined otherwise, the term “alkyl” preferably refers to C1-4 alkyl, more preferably to methyl or ethyl, and even more preferably to methyl. As used herein, the term “alkenyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. The term “C2-5 alkenyl” denotes an alkenyl group having 2 to 5 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1 -en-1-yl, prop-1 -en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., buta-1 ,3-dien-1-yl or buta-1 ,3- dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless defined otherwise, the term "alkenyl" preferably refers to C2 alkenyl.

[0027] 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 alkynyl.

[0028] 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 C alkylene (including, in particular, linear CM alkylene), more preferably to methylene or ethylene, and even more preferably to methylene.

[0029] 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 alkenylene (including, in particular, linear C2-4 alkenylene).

[0030] 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 alkynylene (including, in particular, linear C2 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 modified with =NH or =N(CI-3 alkyl), preferably 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.

[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 modified with =NH or =N(CI-3 alkyl), preferably 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, -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- thiad iazol-2 ,5-d iyl), phenoxazinylene, pyrazolo[1 ,5-a]pyrimidi nylene, 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-di hyd rofu ro[3,4-c]pyrid inylene) , imidazopyridinylene (e.g., imidazo[1 ,2-a]pyridi nylene or imidazo[3,2-a]pyridinylene), quinazolinylene, thienopyridinylene, tetrahydrothienopyridinylene (e.g., 4,5,6,7-tetrahydrothieno[3 ,2-c]pyrid inylene) , 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, further wherein one or more S ring atoms (if present) may be modified with =NH or =N(CI-3 alkyl) and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said saturated ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “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, further wherein one or more S ring atoms (if present) may be modified with =NH or =N(CI-3 alkyl) and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said saturated ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heterocycloalkylene” may, e.g., refer to aziridinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, piperazinylene, azepanylene, diazepanylene (e.g., 1 ,4-diazepanylene), oxazolidinylene, isoxazolidinylene, thiazolidinylene, isothiazolidinylene, morpholinylene, thiomorpholinylene, oxazepanylene, oxiranylene, oxetanylene, tetrahydrofuranylene, 1 ,3-dioxolanylene, tetrahydropyranylene, 1 ,4-dioxanylene, oxepanylene, thiiranylene, thietanylene, tetrahydrothiophenylene (i.e., thiolanylene), 1 ,3-dithiolanylene, thianylene, 1 ,1-dioxothianylene, thiepanylene, decahydroquinolinylene, decahydroisoquinolinylene, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylene. Unless defined otherwise, “heterocycloalkylene” preferably refers to a divalent 3 to 11 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, “heterocycloalkylene” refers to a divalent 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.

[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 S ring atoms (if present) may be modified with =NH or =N(CI-3 alkyl), wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring comprised in said unsaturated alicyclic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heterocycloalkenyl” may, e.g., refer to imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1 H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), tetrahydropyridinyl (e.g., 1 ,2,3,6-tetrahydropyridinyl), dihydropyridinyl (e.g., 1 ,2-dihydropyridinyl or 2,3-dihydropyridinyl), pyranyl (e.g., 2H-pyranyl or 4H-pyranyl), thiopyranyl (e.g., 2H-thiopyranyl or 4H-thiopyranyl), dihydropyranyl, 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 S ring atoms (if present) may be modified with =NH or =N(CI-3 alkyl), wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring comprised in said unsaturated alicyclic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatomcontaining ring.

[0050] Preferably, the term “heterocycloalkenylene” refers to a heterocycloalkenyl group, as defined hereinabove, as defined hereinabove, but having two points of attachment, i.e. a divalent unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring comprised in said unsaturated alicyclic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring.

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

[0052] As used herein, the term “haloalkyl” refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms which are selected independently from fluoro, chloro, bromo and iodo, and are preferably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group. “Haloalkyl” may, e.g., refer to -CF3, -CHF2I-CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3, or -CH(CF3)2. A particularly preferred “haloalkyl” group is -CF3.

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

[0054] As used herein, the terms “optional”, “optionally" and “may” denote that the indicated feature may be present but can also be absent. Whenever the term “optional”, “optionally” or “may" is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, the expression “X is optionally substituted with Y” (or “X may be substituted with Y”) means that X is either substituted with Y or is unsubstituted. Likewise, if a component of a composition is indicated to be “optional”, the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.

[0055] Various groups are referred to as being “optionally substituted” in this specification. Generally, these groups may carry one or more substituents, such as, e.g., one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety. Unless defined otherwise, the “optionally substituted” groups referred to in this specification carry preferably not more than two substituents and may, in particular, carry only one substituent. Moreover, unless defined otherwise, it is preferred that the optional substituents are absent, i.e. that the corresponding groups are unsubstituted.

[0056] A skilled person will appreciate that the substituent groups comprised in the compounds of the present invention may be attached to the remainder of the respective compound via a number of different positions of the corresponding specific substituent group. Unless defined otherwise, the preferred attachment positions for the various specific substituent groups are as illustrated in the examples.

[0057] As used herein, unless explicitly indicated otherwise or contradicted by context, the terms “a”, “an” and “the” are used interchangeably with “one or more” and “at least one”. Thus, for example, a composition comprising “a" compound of formula (I) can be interpreted as referring to a composition comprising “one or more” compounds of formula (I).

[0058] It is to be understood that wherever numerical ranges are provided / disclosed herein, all values and subranges encompassed by the respective numerical range are meant to be encompassed within the scope of the invention. Accordingly, the present invention specifically and individually relates to each value that falls within a numerical range disclosed herein, as well as each subrange encompassed by a numerical range disclosed herein.

[0059] As used herein, the term “about” preferably refers to ±10% of the indicated numerical value, more preferably to +5% of the indicated numerical value, and in particular to the exact numerical value indicated. If the term “about” is used in connection with the endpoints of a range, it preferably refers to the range from the lower endpoint -10% of its indicated numerical value to the upper endpoint +10% of its indicated numerical value, more preferably to the range from of the lower endpoint -5% to the upper endpoint +5%, and even more preferably to the range defined by the exact numerical values of the lower endpoint and the upper endpoint.

[0060] As used herein, the term “comprising” (or “comprise”, “comprises", “contain”, “contains”, or “containing”), unless explicitly indicated otherwise or contradicted by context, has the meaning of “containing, inter alia”, i.e., “containing, among further optional elements, ...’’. In addition thereto, this term also includes the narrower meanings of “consisting essentially of’ and “consisting of’. For example, the term "A comprising B and C” has the meaning of "A containing, inter alia, B and C”, wherein A may contain further optional elements (e.g., “A containing B, C and D” would also be encompassed), but this term also includes the meaning of “A consisting essentially of B and C” and the meaning of "A consisting of B and C” (i.e., no other components than B and C are comprised in A).

[0061] Detailed description of the invention

[0062] The invention is described in detail in the following. It is to be understood that the present invention specifically relates to each and every combination of features and embodiments described herein, including any combination of general and / or preferred features / embodiments.

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

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

[0065] R1 is preferably -CN, methyl, fluoromethyl, difluoromethyl, -(C1-2 alkylene)-OH or C2 alkenyl, more preferably R1is methyl or -CN. In an embodiment, wherein R1 is methyl, particularly preferred R1 is CD3. In an alternative embodiment, R1 is -CN.

[0066] R2 and R3 are each independently C1-2 alkyl or C1-2 haloalkyl, or R2 and R3 together with the carbon atom to which they are attached form C3-5 cycloalkyl or 4-5 membered heterocycloalkyl, wherein said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups selected from C1-2 alkyl (such as methyl), C1-2 haloalkyl (such as fluoromethyl) and -F.

[0067] Preferably, R2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more methyl or -F, or oxetanyl optionally substituted with one or more methyl or -F.

[0068] More preferably, R2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more -F.

[0069] Even more preferably, R2 and R3 together with the carbon atom to which they are attached form cyclopropyl.

[0070] In formula (I), W is selected from -NHS(O)y-, wherein y is 1 or 2. Preferably, y is 2. Thus, W is preferably -NHS(O)2-. Preferably as understood herein, the left side of W, as defined herein, is attached to the carbon atom that carries R1, R2 and R3, and the right side of W, as defined herein, is attached to the ring system shown in formula (I). In formula (I), Xi and X3 are independently selected from the group consisting of N, CH, C(Ci-2 alkyl), C-CI and CF, preferably independently selected from the group consisting of N, CH, CF and CCI, more preferably independently selected from the group consisting of N, CH and CF. Preferably, Xi is CF or CH and X3 is CH, more preferably Xi and Xsare each CH.

[0071] In formula (I), X2 is C-Yc2-Rc2.

[0072] YC2is selected from a covalent bond, C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, cycloalkylene and heterocycloalkylene wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more groups independently selected from RS1, and further wherein one or more - CH2- units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from -O-, -NH-, -N(CI-5 alkyl)-, -CO-, -S-, -SO-, and -SO2-, and wherein said cycloalkylene and heterocycloalkylene are each optionally substituted with one or more groups independently selected RS2.

[0073] Rc2is selected from hydrogen, halogen, -OH, -NH2, -SH, -CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; wherein said alkyl, alkenyl, and alkynyl in X2 are each optionally substituted with one or more groups independently selected from RS1, and wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl in X2are each optionally substituted with one or more groups independently selected from RS2.

[0074] Preferably, Yc2 is selected from a covalent bond, -(C1-3 alkylene)-, -CO-(Ci-3 alkylene)-, (C1-3 alkylene)-CO-, -CONH-(CI-3 alkylene)-, -(C1-3 alkylene)-CONH-, -NHCO-(CI-3alkylene)-, -(C1.3 alkylene)- NHCO-, -NH-(CI-3alkylene)-, -(C1-3 alkylene)-NH-, -N(CI-5alkyl)-, -O-(Ci-3alkylene)-, -(C1-3 alkylene)-O- , -SO2-(Ci-3 alkylene)-, -(C1-3 alkylene)-SO2-, -CONH-, -NHCO-, -NH-, -O-, -CO- and -SO2-, wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more groups independently selected from RS1. C1-3 alkylene is herein preferably a -CH2- group.

[0075] Preferably, Rc2 is selected from hydrogen, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2. More preferably, Rc2 is selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2. Even more preferably, Rc2 is selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl are each optionally substituted with one or more groups independently selected from RS2. Even more preferably, Rc2 is selected from heterocycloalkyl, and heterocycloalkenyl wherein said heterocycloalkyl, and heterocycloalkenyl are each optionally substituted with one or more groups independently selected from RS2. Even more preferably, Rc2 is heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more groups independently selected from RS2.

[0076] Thus preferably, if X2 is C-Yc2-Rc2, -Yc2-Rc2 is is selected from -O-C1-12 alkyl, -NH-C1-12 alkyl, -N(Ci. 5 alkyl)-Ci-i2 alkyl, -O-C2-12 alkenyl, -NH-C2-12 alkenyl, -N(CI-5 alkyl)-C2-i2 alkenyl, -O-C2-12 alkynyl, -NH- C2-12 alkynyl, -N(CI-5 alkyl)-C2-i2 alkynyl, -(C0-3 alkylene)-cycloalkyl, -CO-(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-CO-cycloalkyl, -CONH-(Co-3 alkylene)-cycloalkyl, (C0-3 alkylene)-CONH-cycloalkyl, -NHCO-(Co- 3 alkylene)-cycloalkyl, -(C0-3 alkylene)-NHCO-cycloalkyl, -NH-(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)- NH-cycloalkyl, -0-(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-O-cycloalkyl, -S02-(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-SO2-cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO- cycloalkyl, -SO2-cycloalkyl, -(C0-3 alkylene)-cycloalkenyl, -CO-(Co-3 alkylene)-cycloalkenyl, -(C0-3 alkylene)-CO-cycloalkenyl, -CONH-(Co-3 alkylene)-cycloalkenyl, (C0-3 alkylene)-CONH-cycloalkenyl, - NHCO-(CO-3 alkylene)-cycloalkenyl, -(C0-3 alkylene)-NHCO-cycloalkenyl, -NH-(Co-3 alkylene)- cycloalkenyl, -(C0-3 alkylene)-NH-cycloalkenyl, -0-(Co-3 alkylene)-cycloalkenyl, -(C0-3 alkylene)-O- cycloalkenyl, -S02-(Co-3 alkylene)-cycloalkenyl, -(C0-3 alkylene)-SO2-cycloalkenyl, -CONH-cycloalkenyl, - NHCO-cycloalkenyl, -NH-cycloalkenyl, -O-cycloalkenyl, -CO-cycloalkenyl, -SO2-cycloalkenyl, -(C0-3 alkylene)-heterocycloalkyl, -CO-(Co-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-CO-heterocycloalkyl, - CONH-(CO-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(Co-3 alkylene)- heterocycloalkyl, -(C0-3 alkylene)-NHCO-heterocycloalkyl, -NH-(Co-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-NH-heterocycloalkyl, -0-(Co-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-O- heterocycloalkyl, -S02-(Co-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-SO2-heterocycloalkyl, -CONH- heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO- heterocycloalkyl, -SO2-heterocycloalkyl, -(C0-3 alkylene)-heterocycloalkenyl, -CO-(Co-3 alkylene)- heterocycloalkenyl, -(C0-3 alkylene)-CO-heterocycloalkenyl, -CONH-(Co-3 alkylene)-heterocycloalkenyl, - (C0-3 alkylene)-CONH-heterocycloalkenyl, -NHCO-(Co-3 alkylene)-heterocycloalkenyl, -(C0-3 alkylene)- NHCO-heterocycloalkenyl, -NH-(Co-3 alkylene)-heterocycloalkenyl, -(C0-3 alkylene)-NH- heterocycloalkenyl, -0-(Co-3 alkylene)-heterocycloalkenyl, -(C0-3 alkylene)-O-heterocycloalkenyl, -SO2- (C0-3 alkylene)-heterocycloalkenyl, -(C0-3 alkylene)-SO2-heterocycloalkenyl, -CONH-heterocycloalkenyl, - NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO- heterocycloalkenyl, -SO2-heterocycloalkenyl, -(C0-3 alkylene)-aryl, -CO-(Co-3 alkylene)-aryl, -(C0-3 alkylene)-CO-aryl, -CONH-(Co-3 alkylene)-aryl, -(C0-3 alkylene)-CONH-aryl, -NHCO-(Co-3 alkylene)-aryl, - (C0-3 alkylene)-NHCO-aryl, -NH-(Co-3 alkylene)-aryl, -(C0-3 alkylene)-NH-aryl, -0-(Co-3 alkylene)-aryl, -(Co- 3 alkylene)-O-aryl, -S02-(Co-3 alkylene)-aryl, -(C0-3 alkylene)-SO2-aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -S02-aryl, -(C0-3 alkylene)-heteroaryl, -CO-(Co-3 alkylene)-heteroaryl, -(C0-3 alkylene)- CO-heteroaryl, -CONH-(Co-3 alkylene)-heteroaryl, -(C0-3 alkylene)-CONH-heteroaryl, -NHCO-(Co-3 alkylene)-heteroaryl, -(C0-3 alkylene)-NHCO-heteroaryl, -NH-(Co-3 alkylene)-heteroaryl, -(C0-3 alkylene)- NH-heteroaryl, -0-(Co-3 alkylene)-heteroaryl, -(C0-3 alkylene)-O-heteroaryl, -S02-(Co-3 alkylene)- heteroaryl, -(C0-3 alkylene)-SO2-heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -0- heteroaryl, -CO-heteroaryl and -SO2-heteroaryl, wherein said alkylene is optionally substituted with one or more groups independently selected from RS1, and wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2.

[0077] More preferably, -Yc2-Rc2 is selected from -(C0-3 alkylene)-heterocycloalkyl, -CO-(Co-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)-CO-heterocycloalkyl, -CONH-(Co-3 alkylene)heterocycloalkyl, -

[0078] (C0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(Co-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)-NHCO- heterocycloalkyl, -NH-(Co-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)-NH-heterocycloalkyl, -0-(Co-3 alkylene) heterocycloalkyl, (C0-3 alkylene)-O-heterocycloalkyl, -S02-(Co-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)-SO2-heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl,

[0079] -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO2-heterocycloalkyl, -(C0-3 alkylene)-heterocycloalkenyl, -

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

[0081] Even more preferably, -Yc2-Rc2 is selected from -(C0-3 alkylene)-heterocycloalkyl, -CONH- heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO- heterocycloalkyl, -SO2-heterocycloalkyl, -(C0-3 alkylene)-heterocycloalkenyl, -CONH-heterocycloalkenyl, - NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO- heterocycloalkenyl, -SO2-heterocycloalkenyl, -(C0-3 alkylene)aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -0- aryl, -CO-aryl, -S02-aryl, -(C0-3 alkylene)heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH- heteroaryl, -O-heteroaryl, -CO-heteroaryl and -SO2-heteroaryl, still more preferably -(C0-3 alkylene)- heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -0- heterocycloalkyl, -CO-heterocycloalkyl, -SO2-heterocycloalkyl, -(C0-3 alkylene)-heterocycloalkenyl, - CONH-heterocycloalkenyl, -NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, - CO-heterocycloalkenyl, and -SO2-heterocycloalkenyl, wherein said alkylene is optionally substituted with one or more groups independently selected from RS1, and wherein said heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2.

[0082] Even more preferably, -Yc2-Rc2 is selected from -(C0-3 alkylene)heterocycloalkyl, -(C0-3 alkylene)heterocycloalkenyl, -(C0-3 alkylene)aryl, and -(C0-3 alkylene)heteroaryl, wherein said heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2-.

[0083] Even more preferably, -Yc2-Rc2 is selected from heterocycloalkyl, and heterocycloalkenyl, wherein said heterocycloalkyl, and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from RS2.

[0084] Even more preferably, -Yc2-Rc2 is heterocycloalkyl wherein said heterocycloalkyl is optionally substituted with one or more groups independently selected from RS2.

[0085] In formula (I), X4, X5and X6are each independently selected from N and C-Rx, wherein Rxis selected from -H, C1-5 alkyl, C1-5 alkenyl, C1-5 alkynyl, -0(Ci-5 alkyl), -CN and Hal, wherein said alkyl, alkenyl and alkynyl group is optionally substituted with one or more groups independently selected from RS1.

[0086] Preferably, Rxis selected from -H, C1-2 alkyl, -0(Ci-2 alkyl), and Hal, wherein said alkyl group is optionally substituted with one or more groups independently selected from RS1.

[0087] More preferably, Rxis selected from -H, C1-2 alkyl, and -0(Ci-2 alkyl), wherein said alkyl group is optionally substituted with one or more groups independently selected from RS1.

[0088] Even more preferably, Rxis selected from -H, and C1-2 alkyl, wherein said alkyl group is optionally substituted with one or more groups independently selected from RS1.

[0089] Even more preferably, Rxis selected from -H, and C1-2 alkyl. Particularly preferred C1.2 alkyl is methyl. However, in an alternative preferred embodiment, Rxis -H.

[0090] Preferably, not more than two of X4, X5and X6are N. More preferably, not more than one of X4, X5and X6is N. If two of X4, X5and X6are N, it is preferred that X4, and X5are each N, or that X4and X6are each N. If one of X4, X5and X6is N, it is preferred that X4or X5is N. If one of X4, X5and X6is N, it is particularly preferred that X4is N.

[0091] In formula (I), Y is -N(RN1)-WCOVI.RCOVI.

[0092] RCOVI jSselected from , C2 alkenyl, and C2 alkynyl, wherein said alkenyl is optionally substituted with one or more optional substituents selected from CM alkyl, -COO-(Ci-4 alkyl), -CONH-(Ci- 4 alkyl), -(CM alkylene)N(Ci-4 alkyl)(CM alkyl), -(CM alkylene)-(W-heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, and said alkynyl is optionally substituted with an optional substituent selected from CM alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0093] Suitable cycloalkyl group is for example a cyclopropyl group. Suitable aryl group is for example a phenyl group.

[0094] Preferably, RC0V1is selected from and C2 alkenyl, wherein said alkenyl is optionally substituted with one or more optional substituents selected from CM alkyl, -COO-(CM alkyl), -CONH-(Ci. 4 alkyl), -(CM alkylene)N(Ci-4 alkyl)(CM alkyl), -(CM alkylene)-(A / -heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3.

[0095] More preferably,

[0096] -Wc°vi- is selected from -CO-, -SO- and -SO2-. Preferably, -WCOV1- is selected from -CO-, and - SO2-. More preferably, -WCOV1- is -CO-.

[0097] RN1is selected from hydrogen and CM alkyl. Suitable CM alkyl is for example methyl or ethyl. Preferably, RN1is hydrogen.

[0098] In formula (I), RS1is selected from halogen, -CN, -OH, -O(Ci-5 alkyl), -O(Ci-5 haloalkyl), C1-5 haloalkyl, -SH, -S(Ci-5alkyl), -SO2(Ci.5alkyl), -S(O)(NH)(CI-5alkyl), -S(O)(N-CI-3alkyl)(Ci-5alkyl), -N=S(O)(CI-5alkyl)(Ci^ alkyl), -S(Ci-5haloalkyl), -P(O)(Ci-5alkyl)(Ci-5alkyl), -P(O)(O-Ci-5alkyl) (O-Ci-5 alkyl), -P(O)(O-Ci-5alkyl)(Ci-5alkyl), -NH2, -NH(CI-5alkyl), -NH(CI-5haloalkyl), -N(CI-5alkyl)(Ci^ alkyl), -N(CI-5haloalkyl)(Ci-5 alkyl), -( / V-heterocycloalkyl), -CO(Ci-5alkyl), -CONH2, -CONH(CI-5alkyl), -CON(CI-5alkyl)(Ci-5alkyl), -CO-( / V-heterocycloalkyl), -NHCO-(CI-5alkyl), -N(CI-5alkyl)-CO-(Ci-5 alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci-5alkyl), -N(CI-5alkyl)CONH2, -N(CI-5alkyl)CONH-(Ci-5alkyl), and -N(CI-5alkyl)CON(Ci-5alkyl)(Ci-5alkyl).

[0099] Preferably, RS1is selected from halogen, -CN, -OH, -O(Ci-5 alkyl), -O(Ci-5 haloalkyl), C1-5 haloalkyl, -SH, -S(Ci-5alkyl), -S(Ci-5haloalkyl), -NH2, -NH(CI-5alkyl), -NH(Ci-s haloalkyl), -N(CI-5alkyl)(Ci- 5 alkyl), -N(CI-5 haloalkyl)(Ci-5 alkyl), -( / V-heterocycloalkyl), -CO(Ci-5 alkyl), -CONH2, -CONH(CI-5 alkyl), -CON(CI-5 alkyl)(Ci-5 alkyl), -CO-( / V-heterocycloalkyl), -NHCO-(CI-5 alkyl), -N(CI-5 alkyl)-CO-(Ci-5 alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci-5alkyl), -N(CI-5alkyl)CONH2, -N(CI-5alkyl)CONH-(Ci-5alkyl), and -N(CI-5alkyl)CON(Ci-5alkyl)(Ci-5alkyl).

[0100] More preferably, RS1is selected from halogen, -CN, -OH, -O(Ci-5 alkyl), -O(Ci-5 haloalkyl), C1-5 haloalkyl, -SH, -S(Ci-5alkyl), -S(Ci-5haloalkyl), -NH2, -NH(CI-5alkyl), -NH(CI-5haloalkyl), -N(CI-5alkyl)(Ci- 5 alkyl), -N(CI-5 haloalkyl)(Ci-5alkyl), -( / V-heterocycloalkyl), -CONH2, -CONH(CI-5alkyl), -CON(CI-5alkyl)(Ci-5 alkyl), -CO-( / V-heterocycloalkyl), -NHCO-(CI-5alkyl), -N(CI-5alkyl)-CO-(Ci-5alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci-5alkyl), -N(CI-5alkyl)CONH2, -N(CI-5alkyl)CONH-(Ci-5alkyl), and -N(CI-5alkyl)CON(Ci-s alkyl)(Ci-5alkyl).

[0101] Even more preferably, RS1is selected from halogen, -CN, -OH, -O(Ci-5 alkyl), -O(Ci-5 haloalkyl), C1-5 haloalkyl, -SH, -S(Ci-s alkyl), -S(Ci-5haloalkyl), -NH2, -NH(CI-5alkyl), -NH(CI-5haloalkyl), -N(CI-5alkyl)(Ci-5 alkyl), -N(CI-5 haloalkyl)(Ci-5 alkyl), and -( / V-heterocycloalkyl).

[0102] Even more preferably, RS1is selected from halogen, -CN, -OH, -SH, and -NH2.

[0103] In formula (I), RS2is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(Ci-5 alkyl), - O(Ci-5haloalkyl), -SH, -S(Ci-5alkyl), -S(O)(Ci-5alkyl), -SO2(Ci-5 alkyl), -S(O)(NH)(CI-5alkyl), -S(O)(N-Ci- 3 alkyl)(Ci-5 alkyl), -S(O)(NH)-( / V-heterocycloalkyl), -S(O)(N-CI-3 alkyl)-( / V-heterocycloalkyl), -S(O)(NH)- (C1-5 alkylene)-( / V-heterocycloalkyl), -S(O)(N-CI-3 alkyl)-(Ci-s alkylene)-( / V-heterocycloalkyl), -S(O)(NH)- (C1-5 alkylene)-heterocycloalkyl, -S(O)(N-CI-3 alkyl)-(Ci-s alkylene)-heterocycloalkyl, -S(O)(NH)-(CI-5 alkylene)-N(Ci-5 alkyl)(Ci-s alkyl), -S(O)(N-CI-3alkyl)-(Ci-5alkylene)-N(Ci-5alkyl)(Ci-5alkyl), -N=S(O)(CI-5alkyl)(Ci-5 alkyl), -S(Ci-5 haloalkyl), -S(O)(Ci-5 haloalkyl), -SO2(Ci-5 haloalkyl), -P(O)(Ci-5 alkyl)(Ci-s alkyl), -P(O)(O-Ci-5 alkyl)(O-Ci-5 alkyl), -P(O)(O-Ci-5alkyl)(Ci-5alkyl), -NH2, -NH(CI-5alkyl), -NH(CI-5 haloalkyl), -N(CI-5 alkyl)(Ci-s alkyl), -N(CI-5 haloalkyl)(Ci-5 alkyl), -( / V-heterocycloalkyl), -CO(Ci-5 alkyl), - COOH, -COO(Ci-5alkyl), -CONH2, -CONH(CI-5alkyl), -CON(CI-5alkyl)(Ci-5alkyl), -CO-( / V- heterocycloalkyl), -CONH-( / V-heterocycloalkyl), -CON(CI-5 alkyl)-( / V-heterocycloalkyl), -CONH-(CI-5 alkylene)-( / V-heterocycloalkyl), -CON(CI-5 alkyl)-(Ci-s alkylene)-( / V-heterocycloalkyl), -CONH-(CI-5 alkylene)-heterocycloalkyl, -CON(CI-5 alkyl)-(Ci-5 alkylene)-heterocycloalkyl, -CONH-(Ci-s alkylene)-N(Ci. 5 alkyl)(Ci-5alkyl), -CON(CI-5alkyl)-(Ci-5alkylene)-N(Ci-5alkyl)(Ci-5alkyl), -NHCO-(CI-5alkyl), -N(Ci-s alkyl)-CO-(Ci-5alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci-5alkyl), -N(CI-5alkyl)CONH2, -N(CI-5alkyl)CONH-(Ci-5alkyl), and -N(CI-5alkyl)CON(Ci-5alkyl)(Ci-5alkyl), -(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(O)(Ci-s alkyl), -(C1.5 alkylene)-SO2(Ci-5 alkyl), -(C1-5 alkylene)-S(O)(NH)(Ci-5 alkyl), -(C1-5 alkylene)-S(O)(N-Ci-3 alkyl)(Ci-s alkyl), -(C1-5 alkylene)-N=S(O)(Ci-5 alkyl)(Ci-s alkyl), -(C1-5 alkylene)-S(Ci-s haloalkyl), -(C1-5 alkylene)-S(O)(Ci-s haloalkyl), -(C1-5 alkylene)-S(O)2(Ci-5 haloalkyl), -(C1-5 alkylene)-P(O)(Ci-5 alkyl)(Ci-s alkyl), -(C1-5 alkylene)-P(O)(O-Ci-5 alkyl)(O-Ci-s alkyl), -(C1-5 alkylene)-P(O)(O-Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-NH2, -(C1-5 alkylene)-NH(Ci-5 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)-(A / -heterocycloalkyl), -(C1-5 alkylene)-N(Ci-5 haloalkyl)(Ci-5 alkyl), -(C1-5 alkylene)-CO(Ci-5 alkyl), -(C1-5 alkylene)-COO(Ci-5 alkyl), - (C1.5 alkylene)-COOH, -(C1-5 alkylene)-CONH2, -(C1-5 alkylene)-CONH(Ci-5alkyl), -(C1-5 alkylene)-CON(Ci-5 alkyl)(Ci-s alkyl), -(C1-5 alkylene)-CO-(W-heterocycloalkyl), -(C1-5 alkylene)-NHCO-(Ci- 5 alkyl), -(C1-5 alkylene)-N(Ci-5alkyl)-CO-(Ci-5alkyl), -(C1.5 alkylene)-NHCONH2, -(C1.5 alkylene)-NHCONH-(Ci-5 alkyl), -(C1-5 alkylene)-NHCON(Ci-5alkyl)(Ci-5alkyl), -(C1-5 alkylene)-N(Ci-5alkyl)CONH2, -(C1.5 alkylene)-N(Ci-5alkyl)CONH-(Ci-s alkyl), and -(C1-5 alkylene)-N(Ci-5alkyl)CON(Ci-5alkyl)(Ci-5 alkyl), wherein said heterocycloalkyl is optionally substituted with one or more groups selected from C1-5 alkyl. -O-(Ci-5 alkyl), CN and -OH.

[0104] Preferably, RS2is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(Ci-5 alkyl), -O(Ci- 5 haloalkyl), -SH, -S(Ci-5alkyl), -S(O)(Ci-5alkyl), -SO2(Ci-5alkyl), -S(O)(NH)(Ci-s alkyl), -S(O)(N-CI-3alkyl)(Ci-5 alkyl), -N=S(O)(CI-5 alkyl)(Ci-s alkyl), -S(Ci-5 haloalkyl), -S(O)(Ci-s haloalkyl), -SO2(Ci-5 haloalkyl), -P(O)(Ci-5alkyl)(Ci-5alkyl), -P(O)(O-Ci-5alkyl)(O-Ci-5alkyl), -P(O)(O-Ci-5alkyl)(Ci-s alkyl), -NH2, -NH(CI-5alkyl), -NH(CI-5haloalkyl), -N(CI-5alkyl)(Ci-5alkyl), -N(CI-5haloalkyl)(Ci-5alkyl), - (W-heterocycloalkyl), -CO(Ci-5alkyl), -COOH, -COO(Ci-5alkyl), -CONH2, -CONH(CI-5alkyl), -CON(CI-5 alkyl)(Ci-5 alkyl), -CO-(W-heterocycloalkyl), -NHCO-(CI-5 alkyl), -N(CI-5 alkyl)-CO-(Ci-5 alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci.5alkyl), -N(CI-5alkyl)CONH2, -N(CI-5alkyl)CONH-(Ci-5alkyl), and -N(CI-5alkyl)CON(Ci-5alkyl)(Ci-5alkyl), -(C1.5 alkylene)-CN, -(C1.5 alkylene)-OH, -(C1-5 alkylene)-O(Ci-5 alkyl), -(C1-5 alkylene)-O(Ci-5 haloalkyl), -(C1.5 alkylene)-SH, -(C1-5 alkylene)-S(Ci-5 alkyl), -(C1-5 alkylene)-S(O)(Ci-5 alkyl), -(C1.5 alkylene)-SO2(Ci-5 alkyl), -(C1-5 alkylene)-S(O)(NH)(Ci-5 alkyl), -(C1-5 alkylene)-S(O)(N-Ci-3 alkyl)(Ci-s alkyl), -(C1.5 alkylene)-N=S(O)(Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-S(Ci-5 haloalkyl), -(C1-5 alkylene)-S(O)(Ci-5 haloalkyl), -(C1-5 alkylene)- S(O)2(Ci-5 haloalkyl), -(C1-5 alkylene)-P(O)(Ci-5 alkyl)(Ci-5 alkyl), -(C1.5 alkylene)-P(O)(O-Ci-5 alkyl)(O- C1-5 alkyl), -(C1-5 alkylene)-P(O)(O-Ci-5 alkyl)(Ci-5 alkyl), -(C1.5 alkylene)-NH2, -(C1-5 alkylene)-NH(Ci-5 alkyl), -(C1-5 alkylene)-NH(Ci-5 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-5 haloalkyl)(Ci-s alkyl), - (C1-5 alkylene)-CO(Ci-5 alkyl), -(C1-5 alkylene)-COO(Ci-5 alkyl), -(C1.5 alkylene)-COOH, -(C1-5 alkylene)-CONH2, -(C1-5 alkylene)-CONH(Ci-5 alkyl), -(C1-5 alkylene)-CON(Ci-5 alkyl)(Ci-s alkyl), -(C1-5 alkylene)-CO-(W-heterocycloalkyl), -(C1-5 alkylene)-NHCO-(Ci-5 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-s alkyl)CONH2, -(C1-5 alkylene)-N(Ci-s alkyl)CONH-(Ci-5 alkyl), and -(C1-5 alkylene)-N(Ci-5 alkyl)CON(Ci-5 alkyl)(Ci-5 alkyl).

[0105] More preferably, RS2is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(Ci-5 alkyl), - O(Ci-5haloalkyl), -SH, -S(Ci-5alkyl), -SO2(Ci-5alkyl), -S(O)(NH)(CI-5alkyl), -S(O)(N-CI-3alkyl)(Ci-5alkyl), -N=S(O)(CI-5alkyl)(Ci-5alkyl), -S(Ci-5haloalkyl), -P(O)(Ci-5alkyl)(Ci-5alkyl), -P(O)(O-Ci-5alkyl)(O- C1-5 alkyl), -P(O)(O-Ci-5alkyl)(Ci-5alkyl), -NH2, -NH(CI-5alkyl), -NH(CI-5haloalkyl), -N(CI-5alkyl)(Ci-5alkyl), -N(CI-5haloalkyl)(Ci-5 alkyl), -( / V-heterocycloalkyl), -CO(Ci-5alkyl), -CONH2, -CONH(CI-5alkyl), -CON(CI-5 alkyl)(Ci-5alkyl), -CO-( / V-heterocycloalkyl), -NHCO-(CI-5alkyl), -N(CI-5alkyl)-CO-(Ci-5 alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci-5alkyl), -N(CI-5alkyl)CONH2, -N(CI-5alkyl)CONH-(Ci-5alkyl), and -N(CI-5alkyl)CON(Ci-5alkyl)(Ci-5alkyl), -(C1.5 alkylene)-CN, -(C1.5 alkylene)-OH, -(C1-5 alkylene)-O(Ci-5 alkyl), -(C1-5 alkylene)-O(Ci-s 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-3 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-N=S(O)(Ci-5 alkyl)(Ci-s alkyl), -(C1-5 alkylene)- S(Ci-5 haloalkyl), -(C1-5 alkylene)-P(O)(Ci-5 alkyl)(Ci-s alkyl), -(C1-5 alkylene)-P(O)(O-Ci-5 alkyl)(O-Ci-s alkyl), -(C1-5 alkylene)-P(O)(O-Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-NH2, -(C1-5 alkylene)-NH(Ci-5 alkyl), - (C1-5 alkylene)-NH(Ci-5 haloalkyl), -(C1-5 alkylene)-N(Ci-5 alkyl)(Ci-s alkyl), -(C1-5 alkylene)-N(Ci-s alkyl)(Ci . 5 haloalkyl), -(C1-5 alkylene)-(W-heterocycloalkyl), -(C1-5 alkylene)-N(Ci-5 haloalkyl)(Ci-s alkyl), -(C1-5 alkylene)-CO(Ci-5 alkyl), -(C1-5 alkylene)-CONH2, -(C1-5 alkylene)-CONH(Ci-5 alkyl), -(C1-5 alkylene)-CON(Ci-5 alkyl)(Ci-s alkyl), -(C1-5 alkylene)-CO-( / V-heterocycloalkyl), -(C1-5 alkylene)-NHCO-(Ci- 5 alkyl), -(C1-5 alkylene)-N(Ci-5 alkyl)-CO-(Ci-5 alkyl), -(C1-5 alkylene)-NHCONH2, -(C1-5 alkylene)-NHCONH-(Ci-5 alkyl), -(C1.5 alkylene)-NHCON(Ci-5alkyl)(Ci-5alkyl), -(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).

[0106] Even more preferably, RS2is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(Ci-5 alkyl), -O(Ci-5 haloalkyl), -SH, -S(Ci-5alkyl), -S(Ci-5haloalkyl), -NH2, -NH(CI-5alkyl), -NH(Ci^ haloalkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -N(CI-5 haloalkyl)(Ci-5 alkyl), -( / V-heterocycloalkyl), -CO(Ci-5 alkyl), -CONH2, -CONH(CI-5alkyl), -CON(Ci-s alkyl)(Ci-5alkyl), -CO-( / V-heterocycloalkyl), -NHCO-(Ci^ alkyl), -N(CI-5alkyl)-CO-(Ci-5alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci-5 alkyl), -N(CI-5 alkyl)CONH2, -N(CI-5alkyl)CONH-(Ci-5alkyl), -N(CI-5alkyl)CON(Ci-5alkyl)(Ci-5alkyl), -(Ci- 5 alkylene)-CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-0(Ci-5 alkyl), -(C1.5 alkylene)-0(Ci-5 haloalkyl), -(Ci- 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-5 haloalkyl), -(C1.5 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -(Ci- 5 alkylene)-N(Ci-5 alkyl)(Ci-5 haloalkyl), -(C1-5 alkylene)-(W-heterocycloalkyl), -(C1.5 alkylene)-N(Ci-5 haloalkyl)(Ci-5 alkyl), -(C1-5 alkylene)-CO(Ci-5 alkyl), -(C1-5 alkylene)-CONH2, -(C1-5 alkylene)-CONH(Ci-5 alkyl), -(C1-5 alkylene)-CON(Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-CO-(A / -heterocycloalkyl), -(C1-5 alkylene)-NHCO-(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci-5 alkyl)-CO-(Ci-5 alkyl), -(C1-5 alkylene)-NHCONH2, - (C1-5 alkylene)-NHCONH-(Ci-5 alkyl), -(C1-5 alkylene)-NHCON(Ci-5 alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci- 5 alkyl)CONH2, -(C1-5 alkylene)-N(Ci-5alkyl)CONH-(Ci-5alkyl), and -(C1.5 alkylene)-N(Ci-5alkyl)CON(Ci-5alkyl)(Ci-5 alkyl).

[0107] Even more preferably, RS2is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(Ci-5 alkyl), -O(Ci-5 haloalkyl), -SH, -S(Ci-5alkyl), -S(Ci-5haloalkyl), -NH2, -NH(CI-5alkyl), -NH(CI-5 haloalkyl), -N(CI-5alkyl)(Ci-5alkyl), -N(CI-5haloalkyl)(Ci-5alkyl), -(N- heterocycloalkyl), -CONH2, -CONH(CI-5alkyl), -CON(CI-5alkyl)(Ci-5alkyl), -CO-(N- heterocycloalkyl), -NHCO-(CI-5alkyl), -N(CI-5alkyl)-CO-(Ci-5alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci-5alkyl), -N(CI-5alkyl)CONH2, -N(Ci-s alkyl)CONH-(Ci-s alkyl), -N(CI-5alkyl)CON(Ci-5 alkyl)(Ci-5alkyl), -(C1-5 alkylene)-CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-O(Ci-5alkyl), - (C1-5 alkylene)-O(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-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)-( / - heterocycloalkyl), -(C1-5 alkylene)-N(Ci-5 haloalkyl)(Ci-5 alkyl), -(C1-5 alkylene)-CONH2, -(C1-5 alkylene)-CONH(Ci-5 alkyl), -(C1-5 alkylene)-CON(Ci-5 alkyl)(Ci-s alkyl), -(C1-5 alkylene)-CO-( / - heterocycloalkyl), -(C1-5 alkylene)-NHCO-(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci-5 alkyl)-CO-(Ci-5 alkyl), -(C1-5 alkylene)-NHCONH2, -(C1.5 alkylene)-NHCONH-(Ci-5alkyl), -(C1-5 alkylene)-NHCON(Ci-5alkyl)(Ci-5alkyl), -(C1-5 alkylene)-N(Ci-5 alkyl)CONH2, -(C1-5 alkylene)-N(Ci-s alkyl)CONH-(Ci-5 alkyl), and -(C1-5 alkylene)-N(Ci-5 alkyl)CON(Ci-s alkyl)(Ci-5alkyl).

[0108] Even more preferably, RS2is selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(Ci-5 alkyl), -O(Ci-5 haloalkyl), -SH, -S(Ci-5alkyl), -S(Ci-5haloalkyl), -NH2, -NH(CI-5alkyl), -NH(Ci^ haloalkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -N(CI-5 haloalkyl)(Ci-5 alkyl), -( / V-heterocycloalkyl), -(C1.5 alkylene)- CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-O(Ci-5 alkyl), -(C1.5 alkylene)-O(Ci-5 haloalkyl), -(C1-5 alkylene)-SH, -(C1-5 alkylene)-S(Ci-s alkyl), -(C1.5 alkylene)-S(Ci-5 haloalkyl), -(C1.5 alkylene)-NH2, -(C1-5 alkylene)-NH(Ci-5 alkyl), -(C1-5 alkylene)-NH(Ci-5 haloalkyl), -(C1.5 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -(Ci- 5 alkylene)-N(Ci-5 alkyl)(Ci-5 haloalkyl), -(C1-5 alkylene)-(A / -heterocycloalkyl), -(C1.5 alkylene)-N(Ci-5 haloalkyl)(Ci-5 alkyl), -(C1-5 alkylene)-C0NH2, -(C1-5 alkylene)-C0NH(Ci-5 alkyl), -(C1-5 alkylene)-CON(Ci- 5 alkyl)(Ci-5 alkyl), and -(C1-5 alkylene)-CO-(W-heterocycloalkyl).

[0109] 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.

[0110] Even more preferably, RS2is selected from halogen, -CN, -OH, -SH, and -NH2.

[0111] In a first specific embodiment, of the compound of formula (I), R1 is methyl. One possible methyl group is CD3.

[0112] In a second specific embodiment of the compound of formula (I), R1 is -CN.

[0113] In a third Xi is CH and X3 is CH.

[0114] In a fourth specific embodiment of the compound of formula (I), -Yc2-Rc2 is not H.

[0115] In a fifth specific embodiment of the compound of formula (I), -Yc2-Rc2 is aryl, preferably -Yc2-Rc2 is phenyl, wherein said aryl (said phenyl) is optionally substituted with one or more groups independently selected from halogen, CN, OH, C1-5 alkyl, C1-5 haloalkyl, O(Ci-5 alkyl), -O(Ci-s haloalkyl), SH, S(Cis alkyl), S(Ci5 haloalkyl), NH2, NH(CI-5 alkyl), NH(CI-5haloalkyl), N(CI-5alkyl)(Ci-5alkyl), -N(CI-5haloalkyl)(Ci-5alkyl), -CO(Ci-5 alkyl), CONH2, CONH(CI-5alkyl), and CON(CI-5alkyl)(Ci-5alkyl).

[0116] In a sixth specific embodiment of the compound of formula (I), -Yc2-Rc2 is heteroaryl, preferably selected from imidazolyl, pyridazinyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and indazolyl, wherein said heteroaryl is optionally substituted with one or more groups independently selected from halogen, CN, OH, C1.5 alkyl, C1.5 haloalkyl, O(Ci-5alkyl), -O(Ci-5haloalkyl), SH, S(Ci5alkyl), S(Ci5haloalkyl), NH2, NH(CI-5alkyl), NH(CI-5haloalkyl), N(CI-5alkyl)(Ci-5alkyl), -N(CI-5haloalkyl)(Ci-5alkyl), -CO(Ci-5alkyl), CONH2, CONH(CI-5alkyl), and CON(CI-5alkyl)(Ci-5alkyl).

[0117] In a seventh specific embodiment of the compound of formula (I), -Yc2-Rc2 is heterocycloalkyl, preferably selected from morpholinyl, 1 ,1-dioxothiomorpholinyl, azetinyl, pyrrolidinyl, piperidinyl, 6-oxo- 1 ,6- dihydropyridinyl, or piperazinyl, wherein said heterocycloalkyl is optionally substituted with one or more groups independently selected from RS2. More preferably, -Yc2-Rc2 is piperazinyl, optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(Ci-5 alkyl), -O(Ci-5haloalkyl), -SH, -S(Ci-5alkyl), -S(Ci-5 haloalkyl), -NH2, -NH(CI-5alkyl), -NH(CI-5 haloalkyl), -N(CI-5alkyl)(Ci-5alkyl), -N(CI-5haloalkyl)(Ci-5alkyl), -CO(Ci-5alkyl), -CONH2, -CONH(CI-5 alkyl), and -CON(CI-5 alkyl)(Ci-5 alkyl). Even more preferably, -Yc2-Rc2 is piperazinyl (preferably N-piperazinyl) optionally substituted (preferably N-substituted) with -CO(Ci-5 alkyl), -CONH2, -CONH(CI-5 alkyl), and -CON(CI-5 alkyl)(Ci-s alkyl). Most preferably, -Yc2-Rc2 is piperazinyl (preferably N-piperazinyl) substituted (preferably N-substituted, preferably at a different N- atom than that attached to the ring system as shown in formula (I)), with -CON(CI-5 alkyl)(Ci-s alkyl), preferably with -CON(CH3)2. In an eighth specific embodiment of the compound of formula (I), -Yc2-Rc2 is heterocycloalkyl, wherein said heterocycle comprises a spiro ring system, optionally selected from 2-oxaspiro[3.5]non-6- en-7-yl, 2-oxaspiro[3.5]non-7-yl, 2-oxa-8-azaspiro[4.5]dec-8-yl, 9-oxa-3-azaspiro[5.5]undec-3-yl, 2-oxa-6- azaspiro[3.4]oct-6-yl, 1-oxa-7-azaspiro[3.5]non-7-yl, 1 -oxa-8-azaspiro[4.5]dec-8-yl, 6-oxa-2- azaspiro[3.3]hept-2-yl, 2,8-diazaspiro[4.5]dec-8-yl, 7-oxa-3-azabicyclo[3.3.0]oct-3-yl, 8-oxa-3- azabicyclo[4.3.0]non-3-yl, 2-oxa-6-azaspiro[3.5]non-6-yl, 7-oxo-3,6,8-triazabicyclo[4.3.0]non-3-yl, 3- pyrrolino[3,4-c]pyrazol-2-yl, 3,6- diazabicyclo[3.1.1]hept-3-yl, and 2,7-diazaspiro[3.5]non-7-yl.

[0118] In a ninth specific embodiment of the compound of formula (I), -Yc2-Rc2 is heterocycloalkenyl, wherein said heterocycloalkenyl is optionally substituted with one or more groups independently selected from RS2. Preferably, in this eighth specific embodiment, -Yc2-Rc2 is oxacyclohexenyl or azacyclohexenyl, optionally substituted with one or more groups independently selected from RS2. More preferably, -Yc2- RC2 is azacyclohexenyl substituted (preferably N-substituted) with -CON(CI-5 alkyl)(Ci-5 alkyl), preferably with -CON(CH3)2.

[0119] In a tenth specific embodiment of the compound of formula (I), -Yc2-Rc2 is selected from: yl)

[0120] In an eleventh specific embodiment of the compound of formula (I), -Yc2-Rc2 is selected from

[0121]

[0122] In a thirteenth specific embodiment, X4is N and X5and X6are each independently C-Rx. Further preferably, in this specific embodiment, X5and X6are each CH, X5and X6are CH and CCH3, respectively, X5and X6are CCH3 and CH, respectively, or X5and X6are each CCH3.

[0123] In a fourteenth specific embodiment, X4and X5are each N, and X6is C-Rx. Further preferably, in this specific embodiment, X6is CH or CCH3.

[0124] In a fifteenth specific embodiment, X4and X6are each N, and X5is C-Rx. Further preferably, in this specific embodiment, X5is CH or CCH3.

[0125] In a sixteenth specific embodiment, X4, X5and X6are each independently C-Rx, wherein Rxis selected from -H, C1-5 alkyl, C1-5 alkenyl, C1-5 alkynyl, -O(Ci-5 alkyl), -CN and Hal, wherein said alkyl, alkenyl and alkynyl group is optionally substituted with one or more groups independently selected from RS1. Preferably, Rxis selected from -H, and C1-5 alkyl wherein said alkyl group is optionally substituted with one or more groups independently selected from RS1. More preferably, Rxis selected from -H, and C1-5 alkyl. Even more preferably, Rxis -H. Accordingly, in this sixteenth specific embodiment, it is preferred that X4, X5and X6are each independently C-H.

[0126] In a seventeenth specific embodiment, RCOV1is

[0127] In an eighteenth specific embodiment, Y is selected from o o ,

[0128] In a nineteenth specific embodiment, R2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more methyl or -F. Preferably, in this herein, preferably R1 is selected from methyl and -CN, more preferably R1 is methyl. Alternatively, R1 is -CN.

[0129] In a twentieth specific embodiment, R2 and R3 together with the carbon atom to which they are attached form oxetanyl optionally substituted with one or more methyl or -F. Preferably, in this twentieth °^\ / R specific embodiment, the compound comprises a moiety of formula1, preferably selected from defined herein, preferably R1 is selected from methyl and -CN, more preferably R1 is methyl. Alternatively, R1 is -CN.

[0130] In one embodiment, the present invention relates to a compound of formula (II):

[0131] (ID or a pharmaceutically acceptable salt thereof. It is to be understood that the definitions of any of R1, R2, R3, W, Xi, X2, X3, and Y are as in formula (I) hereinabove, including any of the specific embodiments of the compound of formula (I) recited hereinabove. This is particularly preferred embodiment of the compound of formula (I).

[0132] In one embodiment, the present invention relates to a compound of formula (III): or a pharmaceutically acceptable salt thereof. It is to be understood that the definitions of any of R1, R2, R3, W, Xi, X2, X3, and Y are as in formula (I) hereinabove, including any of the specific embodiments of the compound of formula (I) recited hereinabove.

[0133] In one embodiment, the present invention relates to a compound of formula (IV): or a pharmaceutically acceptable salt thereof. It is to be understood that the definitions of any of Ri, R2, R3, W, Xi, X2, X3, and Y are as in formula (I) hereinabove, including any of the specific embodiments of the compound of formula (I) recited hereinabove.

[0134] Exemplary preferred compounds of formula (I) are selected from the following compounds or their pharmaceutically acceptable salts:

[0135]

[0136] Further preferred compounds of formula (I) are selected from the following compounds or their pharmaceutically acceptable salts:

[0137] Further preferred compounds of formula (I) are selected from the following compounds or their pharmaceutically acceptable salts:

[0138]

[0139] Further preferred compounds of formula (I) are selected from the following compounds or their pharmaceutically acceptable salts:

[0140]

[0141] Further preferred compounds of formula (I) are selected from the following compounds or their pharmaceutically acceptable salts:

[0142]

[0143] According to the present invention, a compound of formula (I) can preferably be selected from the compounds described in Table 2, or their pharmaceutically acceptable salts. Accordingly, a compound of formula (I) is preferably a compound selected from:

[0144] 4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)- N,N-dimethylpiperazine-1-carboxamide;

[0145] A / -(7-(N-(1-methylcyclopropyl)sulfamoyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0146] N-(6-(N-(1-methylcyclopropyl)sulfamoyl)isoquinolin-3-yl)bicyclo[1.1.0]butane-1 -carboxamide

[0147] 4-(6-(bicyclo[1 .1 .0]butane-1 -carboxamido)-3-(N-(1 -methylcyclopropyl)sulfamoyl)naphthalen-1 -yl)- N,N-dimethylpiperazine-1-carboxamide;

[0148] 4-(3-(bicyclo[1 .1 .0]butane-1-carboxamido)-6-(N-(1-methylcyclopropyl)sulfamoyl)isoquinolin-8-yl)- N,N-dimethylpiperazine-1-carboxamide;

[0149] N-(6-(N-(1-methylcyclopropyl)sulfamoyl)-8-(2-oxa-7-azaspiro[3.5]nonan-7-yl)isoquinolin-3- yl)bicyclo[1 .1 .0]butane-1 -carboxamide ;

[0150] N-(7-(N-( 1 -methylcyclopropyl)sulfamoyl)naphthalen-2-yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0151] N-(7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1 .1 .0]butane-1 -carboxamide ;

[0152] N-(7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)acrylamide;

[0153] (2S,6S)4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin- 5-yl)-N,N,2,6-tetramethylpiperazine-1-carboxamide;

[0154] (S)4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)- N,N,2-trimethylpiperazine-1-carboxamide; (S)-N-(5-(4-isobutyryl-3-methylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0155] N-(5-(4-isobutyrylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0156] 4-(2-acrylamido-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N-dimethylpiperazine-1- carboxamide;

[0157] 4-(2-(2-fluoroacrylamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N- dimethylpiperazine-1-carboxamide;

[0158] N-(5-(4-(isopropylthio)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0159] N-(5-(4-(isopropylsulfonyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0160] N-(5-(4-methyl-4-(methylthio)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0161] N-(5-(4-methyl-4-(methylsulfonyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0162] 4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-3-methyl-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin- 5-yl)-N,N-dimethylpiperazine-1-carboxamide;

[0163] 4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-4-methyl-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin- 5-yl)-N,N-dimethylpiperazine-1-carboxamide;

[0164] N-(6-(N-(1-methylcyclopropyl)sulfamoyl)isoquinolin-3-yl)acrylamide;

[0165] N-methyl-N-(7-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-2-yl)acrylamide;

[0166] N-(7-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-2-yl)acrylamide;

[0167] 4-(6-acrylamido-3-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)naphthalen-1-yl)-N,N- dimethylpiperazine-1-carboxamide;

[0168] N-(6-(N-(1 -methylcyclopropyl)su lfamoyl)q u i noli n-3-yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0169] N-(7-(N-(1-methylcyclopropyl)sulfamoyl)quinoxalin-2-yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0170] N-(7-(N-(1-methylcyclopropyl)sulfamoyl)quinoxalin-2-yl)acrylamide;

[0171] 2-fluoro-N-(7-(N-(1-methylcyclopropyl)sulfamoyl)quinoxalin-2-yl)acrylamide;

[0172] N-(7-(N-(1-methylcyclopropyl)sulfamoyl)quinazolin-2-yl)acrylamide;

[0173] N-(5-(4-hydroxypiperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0174] N-(5-(4-(hydroxymethyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide; Tert-butyl 4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate; N-(5-((3S,5S)-3,5-dimethylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide; N-(5-(4-methyl-4-(methylthio)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0175] N-(5-(4-methyl-4-(S-methylsulfonimidoyl)piperidin-1-yl)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1.1.0]butane-1 -carboxamide;

[0176] N-(5-((3S,4S)-4-hydroxy-3-methylpiperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0177] N-(5-((cis)-4-hydroxy-3-methylpiperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0178] N-(5-(2,2-dioxido-2-thia-7-azaspiro[4.4]nonan-7-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin- 2-yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0179] N-(7-(N-(1-methylcyclopropyl)sulfamoyl)-5-(2-thia-7-azaspiro[3.5]nonan-7-yl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0180] N-(5-((1 R or S,2R or S)-2-methyl-1-(methylimino)-1-oxido-1 l6-thiomorpholino)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1.1.0]butane-1 -carboxamide;

[0181] N-(5-((1S or R,2S or R)-2-methyl-1-(methylimino)-1-oxido-1l6-thiomorpholino)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1.1.0]butane-1 -carboxamide;

[0182] N-(5-((1S or R,2R or S)-2-methyl-1-(methylimino)-1-oxido-1 l6-thiomorpholino)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1.1.0]butane-1 -carboxamide;

[0183] N-(5-((1 R or S,2S or R)-2-methyl-1-(39uinoline39o)-1-oxido-1 l6-thiomorpholino)-7-(N-(1- methylcyclopropyl)sulfamoyl)39uinoline-2-yl)bicyclo[1.1.0]butane-1 -carboxamide;

[0184] (R)-N-(5-(4-isobutyryl-3-methylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0185] N-(5-(4-(N,S-dimethylsulfonimidoyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0186] N-(5-(2-methyl- 1 -(methyl i mi no)-1 -oxido-1 l6-thiomorpholino)-7-(N-( 1 - methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1.1.0]butane-1 -carboxamide;

[0187] N-(5-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)39uinoline-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0188] 4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)- N,N-dimethyl-3,6-dihydropyridine-1 (2H)-carboxamide; N-(5-(4-acetylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0189] N-(5-((2S,6S)-2,6-dimethylmorpholino)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0190] N-(7-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)naphthalen-2- yl)acrylamide;

[0191] N-(5-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-2- yl)acrylamide;

[0192] N-(5-(4-(hydroxymethyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-2- yl)acrylamide;

[0193] N-(5-(4-(methoxymethyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-2- yl)acrylamide;

[0194] N-(7-(N-(1-methylcyclopropyl)sulfamoyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)naphthalen-2- yl)acrylamide; and 4-(6-acrylamido-3-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-1-yl)-N,N-dimethylpiperazine-1- carboxamide; or a pharmaceutically acceptable salt thereof.

[0195] More preferably, a compound of formula (I) is a compound selected from:

[0196] 4-(2-(bicyclo[1 .1 .0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)- N,N-dimethylpiperazine-1-carboxamide;

[0197] (R)-N-(5-(4-isobutyryl-3-methylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0198] 4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-4-methyl-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin- 5-yl)-N,N-dimethylpiperazine-1-carboxamide;

[0199] (2S,6S)-4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin- 5-yl)-N,N,2,6-tetramethylpiperazine-1-carboxamide;

[0200] (S)-4-(2-(bicyclo[1 .1 .0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)- N,N,2-trimethylpiperazine-1-carboxamide;

[0201] N-(5-(4-isobutyrylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0202] N-(5-(4-(isopropylsulfonyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0203] A / -(7-(N-(1-methylcyclopropyl)sulfamoyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide; N-(5-(4-methyl-4-(methylsulfonyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0204] (S)-N-(5-(4-isobutyryl-3-methylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;

[0205] Tert-butyl 4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate;

[0206] 4-(2-(bicyclo[1 .1 .0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)- N,N-dimethyl-3,6-dihydropyridine-1 (2H)-carboxamide; and

[0207] 4-(2-acrylamido-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N-dimethylpiperazine-1- carboxamide, or a pharmaceutically acceptable salt thereof.

[0208] 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).

[0209] The scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds of formula (I) which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N- dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. Preferred pharmaceutically acceptable salts of the compounds of formula (I) include a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, and a phosphate salt. A particularly preferred pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride salt. Accordingly, it is preferred that the compound of formula (I), including any one of the specific compounds of formula (I) described herein, is in the form of a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, or a phosphate salt, and it is particularly preferred that the compound of formula (I) is in the form of a hydrochloride salt.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] 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, (ill) 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. The present invention further embraces the prodrugs of the compounds of formula (I). As preferably understood herein, the term “prodrug” of the compound of formula (I) refers to a derivative of the compounds of formula (I) that upon administration to a subject becomes metabolized to the said compound of formula (I). Said prodrugs of the compound of formula (I) may include modifications of -OH, -NH2, or -COOH group if present in the compound of formula (I), which preferably can be hydrolyzed to - OH, -NH2, or -COOH groups, respectively, e.g. upon administration to the subject. For example, as known to the skilled person, such prodrugs may preferably include for the compounds of formula (I) which comprise -OH moiety derivatives wherein said -OH moiety is turned into an -ORXmoiety, wherein Rx preferably comprises a moiety selected from -CO-, -CH2-O-CO, -CH2-O-CO-O-, and -CH(CH3)-O-COO-, more preferably wherein Rx is selected from -CO-Ry, -CH2-O-CO-Ry, -CH2-O-CO-O-Ry, and -CH(CH3)-O- 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, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(Ci-5alkyl), -O(Ci-5haloalkyl), -SH, -S(Ci-5alkyl), -S(Ci-5haloalkyl), -NH2, -NH(CI-5 alkyl), -NH(CI-5 haloalkyl), -N(CI-5alkyl)(Ci-5alkyl), -N(CI-5haloalkyl)(Ci-5alkyl), -CONH2, -CONH(CI-5 alkyl), and -CON(CI-5 alkyl)(Ci-s alkyl), and wherein the said carbocyclyl and heterocyclyl are each optionally substituted with a group selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -O(Ci-s alkyl), -O(Ci-5 haloalkyl), -SH, -S(Ci-5alkyl), -S(Ci-5haloalkyl), -NH2, -NH(CI-5alkyl), -NH(CI-5 haloalkyl), -N(CI-5alkyl)(Ci-s alkyl), -N(CI-5haloalkyl)(Ci-5alkyl), -CONH2, -CONH(CI-5 alkyl), 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 -COORymoiety, wherein Ryis as defined hereinabove. Further examples of groups that can be derivatized to yield prodrugs are known to the skilled person.

[0215] Pharmaceutical compositions

[0216] 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.

[0217] The pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., polyethylene glycol), including polyethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, a non-ionic surfactant, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate (e.g., Kolliphor® HS 15, CAS 70142-34-6), a phospholipid, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, a cyclodextrin, a-cyclodextrin, p-cyclodextrin, y- cyclodextrin, hydroxyethyl-p-cyclodextrin, 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] Said compounds or pharmaceutical compositions may also be administered by sustained release systems. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained-release matrices include, e.g., polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D-(— )-3-hydroxybutyric acid. Sustained-release pharmaceutical compositions also include liposomally entrapped compounds. The present invention thus also relates to liposomes containing a compound of the invention.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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).

[0231] 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.

[0232] 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.

[0233] Therapeutic use

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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).

[0246] 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:

[0247] (I) other antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5oc-reductase such as finasteride;

[0248] (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];

[0249] (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;

[0250] (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 avp3 function and angiostatin)];

[0251] (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;

[0252] (viii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;

[0253] (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

[0254] (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.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] Examples

[0259] 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.

[0260] Synthesis of the compounds of formula (I)

[0261] The syntheses of preferred embodiments of the compounds of formula (I) according to the present invention are preferably carried out according to the general synthetic sequences as shown hereinbelow.

[0262] Scheme 1

[0263] Scheme 1 illustrates a preferred synthetic approach to compounds of the general Formula (la) in which X2 is defined as being C-Yc2-Rc2, Y is defined as being -N(RN1)-WCOV1-RCOV1, W is defined as being -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R1, R2and R3, and the right side of W, as defined herein, attached to the ring system shown in formula (la), and all the other variables are defined according to compound of Formula

[0264] (I)

[0265] In the first step, a compound of formula 1 in which X1, X3, X4, X5and X6are as defined for the compound of formula (I) and in which PG1 and PG2 are protecting groups such as an acetyl group reacted with an amine of formula 2 in which R1, R2and R3are as defined for the compound of Formula (I) to give a compound of formula 3 in which W is -NHS(O)2- with the left side of W being attached to the carbon atom that carries R1, R2and R3, and the right side of W being attached to the ring system shown in Formula (I). 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.

[0266] In the second step, the removal of the protecting group PG1 in formula 3 X1, X3, X4, X5and X6are as defined for the compound of Formula (I), PG1 and PG2 are protecting groups such as an acetyl group and W is -NHS(O)2- as defined in step 1 is performed under basic conditions to afford a compound of formula 4 (see for example: Muto Susumu et al, US2005 / 215645, 2005, A1). Preferred is the herein described use of NaOH, KOH etc., in a mixture solvent of water and MeOH. The reactions are preferably run under an atmosphere of argon for 0.5-24 hours at 0°C to room temperature.

[0267] In the third step, the hydroxyl moiety of a compound of formula 4 in which X1, X3, X4, X5, X6, R1, R2and R3are as defined for the compound of Formula (I), PG2 is a protecting groups such as an acetyl group and W is -NHS(O)2- as defined in step 1 is converted into a triflate (OTf) group which will be used for the following coupling reaction (other halogene groups also can be considered). This reaction can be carried out by treating with Tf2O or N,N-bis(trifluoromethylsulfonyl)aniline under basic conditions, (see for example: Fuchibe, Kohei et al, Organic Letters, 2015, vol. 17, # 5, p. 1126 - 1129). Preferred is the herein described use of Tf2O in DCM with addition of triethylamine, pyridine, di-iso-propylethylamine etc. The reactions are preferably run under an atmosphere of argon for 0.5-24 hours at 0°C to room temperature.

[0268] In the fourth step, a compound of formula 5 in which X1, X3, X4, X5, X6, R1, R2and R3are as defined for the compound of formula (I), PG2 is a protecting groups such as an acetyl group and is -NHS(O)2- as defined in step 1 is coupled with various chemical moieties such as non-aromatic hetorocycles, hetaryl... to give a compound of formula 6 in which X2is defined as for the compound of Formula (I). This coupling reaction can be carried out by a palladium-catalyzed cross-coupling reaction (see for example: a) Jiang, Buchwald in ‘Metal-Catalyzed CrossCoupling Reactions’, 2nd edition.: de Meijere, Diederich, Eds.: Wiley- VCH: Weinheim, Germany, 2004; b) Sutton et al, WO 2021 / 055744). In case of a carbon -nitrogen coupling, preferred is the herein described use of cesium carbonate and Pd-PEPPSI-IPentCI o-picoline in dioxane. The reactions are preferably run under an atmosphere of argon for 1-48 hours at 80-120°C in a microwave oven or in an oil bath. 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.

[0269] In the fifth step, the protecting group PG2 in a compound of formula 6 in which X1, X3, X4, X5, X6, R1, R2and R3are as defined for the compound of Formula (I), PG2 is a protecting groups such as an acetyl group and W is -NHS(O)2- as defined in step 1 is cleaved to give amino (NH2) group by hydrolysis. This deprotection can be carried out under acidic conditions (see for example: Yamazaki, Yukari et al, Chemistry Letters, 2020, vol. 49, # 2, p. 133 - 136). Preferred is the herein described use of HCI / H2O in a mixture of water and EtOH. The reactions are preferably run under an atmosphere of argon for 0.5-24 hours at room temperature to the boiling point of the solvent.

[0270] In the final step, The NH2 group in a compound of formula 7 in which X1, X3, X4, X5, X6, R1, R2and R3are as defined for the compound of formula (I), and W is -NHS(O)2- as defined in step 1 , is converted to group Y being -N(RN1)-WC0V1-RC0V1to give a compound of Formula (la).

[0271] The synthetic strategy is described as followed:

[0272] 7 9

[0273] In the optional first step, a compound of formula 7 in which X1, X3, X4, X5, X6, R1, R2and R3are as defined for the compound of formula (I) and W is -NHS(O)2- as defined in step 1 is reacted with formula 8 in which RN1is CM alkyl and LG1 is a leaving group such as CI-, Br-, I-, MsO- or aldehyde to give a compound of formula 9. When LG1 is leaving group such as CI-, Br-, I-, MsO-, the alkylation is preferably carried out in basic conditions using preferentially deprotonating agents or bases such as NaH, K2CO3 or CS2CO3 etc.in suitable solvents such as for example DCM, DMF or THF (see for example: Sankaranarayananv et al, US2004106802), under an atmosphere of argon for 3-24 hours at a temperature ranged betweenO °C to 80 °C. When LG1 is an aldehyde group, this reaction is preferably carried out in the presence of a suitable reducing agent such as for example sodium cyanoborohydride or sodium triacetoxyborohydride, in the presence of acetic acid (cat.), molecular sieve, in a suitable solvent such as MeOH, DCE, / -PrOH ect, preferably under an atmosphere of argon for 12-24 hours at room temperature to 80 °C(see for example: Ong et al, US2013203686).

[0274] In the final step, a compound of formula 9 in which X1, X3, X4, X5, X6, R1, R2and R3are as defined for the compound of formula (I), W is -NHS(O)2- as defined in step 1 , is reacted with a compound of formula 10 in which Rcovi.wcovi jSdefined for the compound of formula (I) and LG2 is leaving group such as HO-, CI-, -0- W^-R00 1, MeO-, to give a compound of Formula (la). When LG2 is HO-, this amidation reaction is preferably carried in the presence of a suitable base such as for example triethylamine, pyridine, di-iso-propylethylamine etc, in the presence of a suitable condensating agent such as HATU, EDCI / HOBt, T3P, CDI etc. in a suitable solvent such as for example DCM or DMF, preferably under an atmosphere of argon for 2 - 24 hours at room temperature (see for example: Blake et WO2020 / 131674). When LG2 is Cl- or -O-Wcov1-Rcov1, this reaction is carried out in of the presence of a suitable base such as triethylamine, pyridine, di-iso-propylethylamine etc in a suitable solvent such as for example DCM or THF under an atmosphere of argon for 2-24 hours at a temperature ranged between 0 °C and 50 °C (see for example: Lyeret al, Chem. Communications, 2018, 54, 11021 - 11024). When LG is MeO-, the reaction can be performed in the presence of a deprotonating agent such as LiHMDS in a suitable solvent such as THF under an atmosphere of argon for 0.5-24 hours at a temperature ranged between 0 °C and 50 °C (see for example: Bosch, Liu is et al, Tetrahedron Letters, 2011 , vol. 52, # 7, p. 753 - 756).

[0275] Scheme 2

[0276] Formula (lb)

[0277] Scheme 2 illustrates a preferred synthetic approach to compounds of the general Formula (lb) in which X2is defined as CH, Y is defined as being -N(RN1)-WC0V1-RC0V1, W is defined as being -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R1, R2and R3, and the right side of W, as defined herein, attached to the ring system shown in Formula (lb), and all the other variables are defined according to compound of Formula (I)

[0278] In the first step, a compound of formula 11 in which X1, X3, X4, X5and X6are as defined for the compound of formula (I) is reacted with benzyl mercaptan to give a compound of formula 12. This coupling reaction can be carried out by a palladium-catalyzed C-S cross-coupling reaction (see for example: Jiang, Buchwald in ‘Metal-Catalyzed Cross-Coupling Reactions’, 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.

[0279] In the second step, a compound of formula 12 in which X1, X3, X4, X5and X6are as defined for the compound of formula (I) is reacted with a chlorinating reagent to give a sulfonyl chloride of formula 13. This sulfonyl chloride formation can be carried out by treatment with W-chlorosuccinimide (NCS), sulfonyl chloride, 1 ,3-dichloro-5,5-dimethylhydantoin (DCDMH), Ch etc., in MeCN with equivalent acetic acid and water, (see for example: Sutton et al, WO 2021 / 055744). Preferred is the herein described use of DCDMH as chlorinating reagent. The reactions are preferably run under an atmosphere of argon for 0.5 - 5 hours from 0 °C to room temperature.

[0280] In the third step, a compound of formula 13 in which X1, X3, X4, X5and X6are as defined for the compound of Formula (I) is reacted with an amine of formula 2 in which R1, R2, R3are defined as for compound of Formula (I) to give a compound of formula 14 in which W is -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R1, R2and R3, and the right side of W, as defined herein, attached to the ring system shown in compound of formula 14. This reaction can be carried out under basic conditions (see for example: Guo et al, WO2013 / 006394). Preferred is the herein described use of trimethylamine, pyridine etc., in DCM, THF or DMF. The reactions are preferably run under an atmosphere of argon for 0.5 - 24 hours from 0 °C to room temperature.

[0281] In the fourth step, the bromide group in compound of formula 14 in which X1, X3, X4, X5, X6, R1, R2and R3are as defined for the compound of Formula (I), W is -NHS(O)2- as defined in step 3, is converted to an amino group to give a compound of formula 15. This reaction can be carried out by Buchwald coupling with Tert-Butylcarbamate (NH2B0C) or benzophenone imine (HNCPI12), followed by cleavage of the protecting groups (see for example: Xiang, Zheng et al, Journal of Organic Chemistry, 2011 , vol. 76, # 15, p. 6367 - 6371). Preferred Buchwald coupling condition is the herein described use of NH2B0C, Xantphos, Pd2(dba)3 in dioxane. The reactions are preferably run under an atmosphere of argon for 0.5 - 24 hours from 80 °C to 120 °C in a microwave oven or in an oil bath. Preferred protecting group cleavage conditions are the herein described use of HCI / dioxane, TFA / DCM, ect. The reactions are preferably run under an atmosphere of argon for 0.5 - 24 hours at 0 °C to room temperature.

[0282] In the final step, The NH2 group in a compound of formula 15 in which X1, X3, X4, X5, X6, R1, R2and R3are as defined for the compound of formula (I), and W is -NHS(O)2- as defined in step 3, is converted to group Y being -N(RN1)-WC0V1-RC0V1to give a compound of Formula (lb).

[0283] The synthetic strategy is described as followed :

[0284] In this optional step, a compound of formula 15 in which X1, X3, X4, X5, X6, R1, R2and R3are as defined for the compound of formula (I) and W is -NHS(O)2- as defined in step 3, is reacted with a compound of formula 8 in which RN1is C1-4 alkyl and LG1 is a leaving group such as CI-, Br-, I-, MsO- or aldehyde to give a compound of formula 16. When LG1 is leaving group such as CI-, Br-, I-, MsO-, the alkylation is preferably carried out in basic conditions using preferentially deprotonating agents or bases such as NaH, K2CO3 or CS2CO3 etc.in suitable solvents such as for example DCM, DMF or THF (see for example: Sankaranarayananv et al, US2004106802), under an atmosphere of argon for 3-24 hours at a temperature ranged between 0 °C to 80 °C. When LG1 is an aldehyde group, this reaction is preferably carried out in the presence of a suitable reducing agent such as for example sodium cyanoborohydride or sodium triacetoxyborohydride, in the presence of acetic acid (cat.), molecular sieve, in a suitable solvent such as MeOH, DCE, / -PrOH ect, preferably under an atmosphere of argon for 12-24 hours at room temperature to 80 °C (see for example: Ong et al, US2013203686). Formula I

[0285] In the final step, a compound of formula 16 in which X1, X3, X4, X5, X6, R1, R2and R3are as defined for the compound of Formula (I), W is -NHS(O)2- as defined in step 3, is reacted with formula 10 in which RCOV wcovaredefined for the compound of Formula (I) and LG2 is a leaving group such as HO-, CI-, -0- Wcov.Rcov MeO-, to give a compound of Formula (lb). When LG2 is HO-, this amidation reaction is preferably carried in the presence of a suitable base such as for example triethylamine, pyridine, di-iso- propylethylamine etc, in the presence of a suitable condensating agent such as HATU, EDCI / HOBt, T3P, CDI etc. in a suitable solvent such as for example DCM or DMF, preferably under an atmosphere of argon for 2 - 24 hours at room temperature (see for example: Blake et WO2020 / 131674). When LG2 is Cl- or - 0-Wcovi.Rcov^ this reaction is carried out in of the presence of a suitable base such as triethylamine, pyridine, di-iso-propylethylamine etc in a suitable solvent such as for example DCM or THF under an atmosphere of argon for 2-24 hours at a temperature ranged between 0 °C and 50 °C (see for example: Lyer et al, Chem. Communications, 2018, 54, 11021 - 11024). When LG is MeO-, the reaction can be performed in the presence of a deprotonating agent such as LiHMDS in a suitable solvent such as THF under an atmosphere of argon for 0.5-24 hours at a temperature ranged between 0 °C and 50 °C (see for example: Bosch, Lluis et al, Tetrahedron Letters, 2011 , vol. 52, # 7, p. 753 - 756).

[0286] Scheme 3

[0287]

[0288] Scheme 3 illustrates a preferred synthetic approach to compounds of the general Formula (le) in which X2 is defined as being C-Yc2-Rc2, X4as being N, X6as being C-Rx, wherein Rxis selected from C1- 5 alkyl, X5as being CH, Y is defined as being -N(RN1)-WC0V1-RC0V1, W is defined as being -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R1, R2and R3, and the right side of W, as defined herein, attached to the ring system shown in Formula (le), and all the other variables are defined according to compound of Formula (I)

[0289] In the first step, the methyl group in a compound of formula 22 in which X1, X3are defined as for the compound of Formula (I) is converted to aldehyde moiety. This reaction can be carried out in the presence of DMF-DMA, followed by treatment with sodium periodate (NalO4) (see for example: Vetelino, Michael G. et al, Tetrahedron Letters, 1994, vol. 35, # 2, p. 219 - 222), or in the presence of azobisisobutyronitrile (AIBN), N-bromosuccinimide (NBS), followed by treatment with N- methylmorpholine-N-oxide (NMO) (see for example: Wallace, Debra J. et al, Organic Process Research and Development, 2011 , vol. 15, # 4, p. 831 - 840). Preferred is the herein described use of AIBN, NBS in carbon tetrachloride (CCI4) at 50 °C to 100 °C for 0.5-24 hours followed by treatment with NMO and 4 A molecular sieve in MeCN at 0 °C to 50 °C for 0.5-24 hours.

[0290] In the second step, the nitro (NO2) moiety in a compound of formula 23 in which X1, X3are defined as for the compound of Formula (I) is converted to an amino (NH2) group. This reduction can be carried out in the presence of Fe and NH4CI in EtOH - (see for example: Altevogt, Luca et al, Synlett, 2020, vol. 31 , # 12, p. 1177 - 1181), Preferred is the herein described use of Fe powder and NH4CI in EtOH. The reactions are preferably run under an atmosphere of nitrogen for 0.5 - 24 hours at 50 °C to 100 °C.

[0291] In the third step, a compound of formula 24 in which X1, X3are defined as for the compound of Formula (I) is reacted with an alkyl cyanide R-CN to give a compound of formula 25 in which X6is defined as being C-Rx, wherein Rxis selected from C1.5 alkyl and X5is defined as being CH. The reaction are carried out in the presence of a suitable alkyl cyanide, in the presence of a suitable base such as potassium tert-butylate, f-BuOK in a suitable solvent such as DMSO preferably under an atmosphere of nitrogen for 0.5 - 24 hours at 0 °C to 50 °C. (see for example: Beesu, Mallesh et al, Journal of Medicinal Chemistry, 2015, vol. 58, # 19, p. 7833 - 7849).

[0292] In the fourth step, a compound of formula 25 in which X1, X3, X5and X6are defined as in the third step is reacted with benzyl mercaptan to give a compound of formula 26. This nucleophilic aromatic substitution reaction is carried out in the presence benzyl mercaptan, optionally in the presence of a suitable base such as for example cesium carbonate in a suitable solvent such as for example DMF. The reaction is preferably run under an atmosphere of argon for 1 - 48 hours at 50 - 100°C in a microwave oven or in an oil bath (see for example: Diane Harris Boschelli et al, US2003 / 212276, 2003, A1).

[0293] In the fifth step, amino (NH2) group in a compound of formula 26 in which X1, X3, X5and X6are defined are defined as in the fourth step is protected by a suitable protecting group PG2 such as for example Boc, Cbz ... This protection can be carried out for example in the presence of di-tert-butyl- dicarbonate (BOC2O), in presence of 4-dimethylaminopyridine (DMAP), in the presence of a suitable base such as diisopropylamine (DIPEA), in a suitable solvent such as dichloromethane (DCM). The reaction is preferably run under an atmosphere of argon for 1 - 48 hours at 0 - 50°C (see for example: Abengozar, Alberto et al, European Journal of Organic Chemistry, 2015, vol. 2015, # 19, p. 4214 - 4223).

[0294] In the sixth step, a compound of formula 27 in which X1, X3, X5,X6and PG2are defined are defined as in the fifth step reacts with a chlorinating reagent to give a sulfonyl chloride of formula 28. This sulfonyl chloride formation can be carried out by treatment with NCS, sulfonyl chloride, DCDMH, CI2 etc., in MeCN with 1 to 5 equivalent (s) of acetic acid and water, (see for example: Sutton et al, WO 2021 / 055744). Preferred is the herein described use of DCDMH as chlorinating reagent. The reactions are preferably run under an atmosphere of argon for 0.5 - 5 hours from 0 °C to room temperature. In the seventh step, a compound of formula 28 in which X1, X3, X5,X6and PG2 are defined are defined as in the sixth step reacts with an amine of formula 2 in which R1, R2and R3are as defined for the compound of Formula (I) to give a compound of formula 9 in which W is defined as being -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R1, R2and R3, and the right side of W, as defined herein, attached to the ring system shown in compound of formula 29. The reaction can be carried out under basic conditions (see for example: Sutton et al, WO 2021 / 055744). Preferred is the herein described use of trimethylamine, pyridine etc., in DCM, THF or DMF. The reactions are preferably run under an atmosphere of argon for 0.5-24 hours at 0°C to room temperature.

[0295] In the eighth step, a compound of formula 29 in which X1, X3, X5,X6, W and PG2 are defined are defined as in the seventh step, R1, R2and R3are as defined for the compound of Formula (I) is coupled with various chemical moieties such as non-aromatic hetorocycles, hetaryl... to give a compound of formula 30 in which X2is restricted C-Yc2-Rc2 defined as for the compound of Formula (I). This coupling reaction can be carried out by a palladium-catalyzed cross-coupling reaction (see for example: a) Jiang, Buchwald in ‘Metal-Catalyzed CrossCoupling Reactions’, 2nd edition.: de Meijere, Diederich, Eds.: Wiley- VCH: Weinheim, Germany, 2004; b) Sutton et al, WO 2021 / 055744). In case of a carbon -nitrogen coupling, preferred is the herein described use of cesium carbonate and Pd-PEPPSI-IPentCI o-picoline in dioxane. The reactions are preferably run under an atmosphere of argon for 1-48 hours at 80-120°C in a microwave oven or in an oil bath. 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.

[0296] In the ninth step, the protecting group PG2 in a compound of formula 30 in which X1, X3, X5,X6, W and PG2 are defined are defined as in the eighth step, R1, R2and R3are as defined for the compound of Formula (I) is cleaved to give an amino (NH2) group. This deprotection can be carried out under acidic conditions (see for example: Yamazaki, Yukari et al, Chemistry Letters, 2020, vol. 49, # 2, p. 133 - 136). Preferred is the herein described use of HCI / H2O in a mixture of water and EtOH. The reactions are preferably run under an atmosphere of argon for 0.5-24 hours at room temperature to the boiling point of the solvent.

[0297] In the final step, the strategy used for converting a compound of formula 31 to a compound Formula (le) is performed similarly as in the final step of Scheme 1 or Scheme 2.

[0298] Scheme 4

[0299] Formula (Ig)

[0300] Scheme 4 illustrates a preferred synthetic approach to compounds of the general Formula (Ig) in which X2is defined as being CH, X4is defined as being N, Y is defined as being N(RN1)-WCOV1-RCOV1 , W is defined as being -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R1, R2and R3, and the right side of W, as defined herein, attached to the ring system shown in Formula (Ig), and all the other variables are defined according to compound of Formula (I).

[0301] 35 36 In the first step, the chloride group in compound of formula 35 in which X1, X3, X5, X6, R1, R2and R3are defined as for the compound of formula (I), W is defined as being -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R1, R2and R3, and the right side of W, as defined herein, attached to the ring system shown in a compound of formula 36 is converted to an amino moiety. This reaction can be carried out by Buchwald coupling with Tert-Butylcarbamate (NH2B0C) or benzophenone imine (HNCPh2), followed by cleavage of the protecting groups (see for example: Xiang, Zheng et al, Journal of Organic Chemistry, 2011 , vol. 76, # 15, p. 6367 - 6371). Preferred Buchwald coupling condition is the herein described use of NH2B0C, Xantphos, Pd2(dba)s in dioxane. The reactions are preferably run under an atmosphere of argon for 0.5 - 24 hours from 80 °C to 120 °C in a microwave oven or in an oil bath. Preferred protecting group cleavage conditions are the herein described use of HCI / dioxane, TFA / DCM, ect. The reactions are preferably run under an atmosphere of argon for 0.5 - 24 hours at 0 °C to room temperature.

[0302] In the final step, the strategy for converting a compound of formula 36 to a compound of Formula (Ig) is similar as the final step of Scheme 1 or Scheme 2.

[0303] Scheme 5

[0304]

[0305] Formula (Ih)

[0306] Scheme 5 illustrates a preferred synthetic approach to compounds of the general Formula (Ih) in which X2 is defined as being C-Yc2-Rc2, X5is defined as being N, Y is defined as being -N(RN1)-WCOV1- Rcov^ w is defined as being -NHS(O)2- with preferably as understood herein, the leftside of W, as defined herein, attached to the carbon atom that carries R1, R2and R3, and the right side of W, as defined herein, attached to the ring system shown in Formula (Ih), and all the other variables are defined according to compound of Formula (I)

[0307] In the first step, an amino (NH2) group in a compound of formula 37 in which X1, X3, X4and X6are defined as for the compound of Formula (I) is protected by a protecting group PG2 such as Boc, Cbz ... This protection can be carried out for example in the presence of di-tert-butyl-dicarbonate (BOC2O), in presence of 4-dimethylaminopyridine (DMAP), in the presence of a suitable base such as diisopropylamine (DIPEA), in a suitable solvent such as dichloromethane (DCM). The reaction is preferably run under an atmosphere of argon for 1 - 48 hours at 0 - 50°C (see for example: Abengbzar, Alberto et al, European Journal of Organic Chemistry, 2015, vol. 2015, # 19, p. 4214 - 4223).

[0308] In the second step, a compound of formula 38 in which X1, X3, X4and X6are defined as for the compound of Formula (I) and in which PG2 is defined in step 1 is reacted with benzyl mercaptan to give a compound of formula 39. This coupling reaction can be carried out by a palladium-catalyzed C-S crosscoupling reaction (see for example: Jiang, Buchwald in ‘Metal-Catalyzed Cross-Coupling Reactions’, 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.

[0309] In the third step, a compound of formula 39 in which X1, X3, X4and X6are as defined for the compound of formula (I), and in which PG2 is defined in step 1 is reacted with q chlorinating reagent to give a sulfonyl chloride compound of formula 40. This sulfonyl chloride formation can be carried out by treatment with W-chlorosuccinimide (NCS), sulfonyl chloride, 1 ,3-dichloro-5,5-dimethylhydantoin (DCDMH), CI2 etc., in MeCN with equivalent acetic acid and water, (see for example: Sutton et al, WO 2021 / 055744). Preferred is the herein described use of DCDMH as chlorinating reagent. The reactions are preferably run under an atmosphere of argon for 0.5 - 5 hours from 0 °C to room temperature. In the fourth step, a compound of formula 40 in which X1, X3, X4and X6are as defined for the compound of formula (I) and PG2 is defined as in step 1 is reacted with an amine of formula 2 in which R1, R2and R3are as defined for the compound of Formula (I) to give a compound of formula 41 in which W is defined as being -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R1, R2and R3, and the right side of W, as defined herein, attached to the ring system shown in compound of formula 41. 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.

[0310] In the fifth step, a compound of formula 41 in which X1, X3, X4, X6, R1, R2and R3are as defined for the compound of formula (I), W is being defined as in step fourth and PG2 is defined as in step 1 is coupled with various chemical moieties such as non-aromatic hetorocycles, hetaryl... to give a compound of formula 42 in which X2is defined is defined as being C-Yc2-Rc2as for the compound of Formula (I). This coupling reaction can be carried out by a palladium-catalyzed cross-coupling reaction (see for example: a) Jiang, Buchwald in ‘Metal-Catalyzed CrossCoupling Reactions’, 2nd edition.: de Meijere, Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004; b) Sutton et al, WO 2021 / 055744). In case of a carbon - nitrogen coupling, preferred is the herein described use of cesium carbonate and Pd-PEPPSI-IPentCI 0- 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.

[0311] 42 43

[0312] In the sixth step, the protecting group PG2 in a compound of formula 42 in which X1, X2, X3, X4, X6, R1, R2and R3are as defined for the compound of Formula (I), W is being defined as in step fourth and PG2 is defined as in step 1 is cleaved to give an amino (NH2) moiety. This deprotection can be carried out under acidic conditions (see for example: Yamazaki, Yukari et al, Chemistry Letters, 2020, vol. 49, # 2, p. 133 - 136). Preferred is the herein described use of HCI / H2O in a mixture of water and EtOH. The reactions are preferably run under an atmosphere of argon for 0.5-24 hours at room temperature to the boiling point of the solvent.

[0313] In the final step, the strategy for converting a compound of formula 43 to Formula (Ih) is similar as the final step described in Scheme 1 or Scheme 2.

[0314] Scheme 6

[0315] Scheme 6 illustrates a preferred synthetic approach to compounds of the general Formula (li) in which X2is defined as being CH, X5is defined as being N, Y is defined as being -N(RN1)-WC0V1-RC0V1„ W is defined as being -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R1, R2and R3, and the right side of W, as defined herein, attached to the ring system shown in Formula (li), and all the other variables are defined according to compound of Formula (I).

[0316] 44 45

[0317] In the first step, a compound of formula 44 in which X1, X3, X4and X6are defined as for the compound of Formula (I) and X5is defined as being N, is reacted with benzyl mercaptan to give a compound of formula 45. This coupling reaction can be carried out by a palladium-catalyzed C-S crosscoupling reaction (see for example: Jiang, Buchwald in ‘Metal-Catalyzed Cross-Coupling Reactions’, 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.

[0318] In the second step, a compound of formula 45 in which X1, X3, X4and X6are defined as for the compound of Formula (I) and X5is defined as being N, is reacted with chlorinating reagent to give a sulfonyl chloride of formula 46. This sulfonyl chloride formation can be carried out by treatment with NCS, sulfonyl chloride, DCDMH, CI2 etc., in MeCN with 1 to 5 equivalent (s) of acetic acid and water (see for example: Sutton et al, WO 2021 / 055744). Preferred chlorinating reagent is the herein described use of DCDMH. The reactions are preferably run under an atmosphere of argon for 0.5 - 5 hours at 0 °C to room temperature.

[0319] 46 47

[0320] In the third step, a compound of formula 46 in which in which X1, X3, X4and X6are defined as for the compound of Formula (I) and X5is defined as being as N, is reacted with an amine of formula 2 in which R1, R2and R3are as defined for the compound of formula (I) to give a compound of formula 47 in which W is defined as being -NHS(O)2- with preferably as understood herein, the left side of W, as defined herein, attached to the carbon atom that carries R1, R2and R3, and the right side of W, as defined herein, attached to the ring system shown in compound of formula 47. 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.

[0321] 47 48

[0322] In the fourth step, the chloride group in compound of formula 47 in which X1, X3, X4, X6, R1, R2and R3are as defined for the compound of Formula (I), X5is defined as being as N and W is is being defined as in step third is converted to an amino (NH2) group.

[0323] This reaction can be carried out by Buchwald coupling with Tert-Butylcarbamate (NH2B0C) or benzophenone imine (HNCPI12), followed by cleavage of the protecting groups (see for example: Xiang, Zheng et al, Journal of Organic Chemistry, 2011 , vol. 76, # 15, p. 6367 - 6371). Preferred Buchwald coupling condition is the herein described use of NH2B0C, Xantphos, Pd2(dba)s in dioxane. The reactions are preferably run under an atmosphere of argon for 0.5 - 24 hours from 80 °C to 120 °C in a microwave oven or in an oil bath. Preferred protecting group cleavage conditions are the herein described use of HCI / dioxane, TFA / DCM, ect. The reactions are preferably run under an atmosphere of argon for 0.5 - 24 hours at 0 °C to room temperature. RN11

[0324] 48 Formula (li)

[0325] In the final step, the strategy for converting a compound of formula 48 to a compound of Formula (li) is similar as the final step of Scheme 1 or Scheme 2.

[0326] Preparative examples

[0327] 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.

[0328] General considerations

[0329] Abbreviations used in the descriptions that follow are: AcOH (acetic acid); AIBN (Azobisisobutyronitrile); aq. (aqueous); br. (broad,1H NMR signal); B0CNH2 (tert-butylcarbamate); BOC2O (di-tert-butyldicarbonate); BOP (Benzotriazole-1 -yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate); CCk (carbone tetrachloride); CDCh (deuterated chlorofor mL); cHex (cyclohexane); CS2CO3 (cesium carbonate); DBU (2,3,4,6,7,8,9,10-octahydropyrimido[1 ,2-a]azepine); DCE (dichloroethane); d (doublet,1H NMR signal); DCH or DCDMH (1 ,3-dichloro-5,5-dimethyl- imidazolidine-2, 4-dione); DCM (dichloromethane); DIPEA (di-zso-propylethylamine); DMA

[0330] (Dimethylacetamide); DMAP (4- W-W-dimethylaminopyridine), DME (1 ,2-dimethoxyethane), DMF (N-N- dimethylformamide); DMSO (dimethyl sulfoxide); ES (electrospray); EtOAc (ethyl acetate); EtOH (ethanol); FA (formic acid); Fe (iron); h or hr (hour(s)); H2SO4 (Sulfuric acid);1H NMR (proton nuclear magnetic resonance spectroscopy); HCI (hydrogen chloride); HPLC (High Performance Liquid Chromatography), iPrOH ( / so-propanol); K2CO3 (Potassium carbonate); UAIH4 (Lithium aluminium hydride); LiHMDS (Lithium bis(trimethylsilyl)amide); m (multiplet,1H NMR signal); mCPBA (metachloroperoxybenzoic acid); Mel (Methyl iodide); MeCN (acetonitrile), MeOH (methanol); min (minute(s)); MS (mass spectrometry); MTBE (methyl tert-butyl ether); NaH (Sodium hydride); NaOH (sodium hydroxide); NBS (N-bromosuccinimide); NCS (N-chlorosuccinimide); NH4CI (ammonium chloride); NMO (4-methyl morpholine N-oxide); NMR (nuclear magnetic resonance); Pd2dbas (tris(dibenzylideneacetone)dipalladium ); 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)palladipm) POCI3 (Phosphorus oxychloride); q (quartet, 1 H NMR signal); quin (quintet, 1 H NMR signal); rac (racemic); RT (retention time); s (singlet,1H NMR signal); sat. (saturated); SO2 (sulfur dioxide); SO2CI2 (sulfuryl chloride); t (triplet,1H NMR signal); tBuOK (potassium tert-butylate); tBuONa (sodium tertbutylate); tBuXphos (2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl-di-tert-butyl(2',4',6'-triisopropyl- [1 ,1'-biphenyl]-2-yl)phosphine); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride), Tf2<D (trifluoromethanesulfonic anhydride); THF (tetrahydrofuran); TLC (Thin Layer Chromatography); TMSI (Trimethylsilyl iodide); UPLC (Ultra-High Performance Liquid Chromatography), UV (ultraviolet), wt-% (percent by weight); Xantphos (4 , 5-Bis(d iphenyl phosphino)-9 , 9-d imethylxanthene) .

[0331] 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.

[0332] Reversed Phase HPLC methods for LCMS Analysis:

[0333] Method 1 : SHIMADZU LCMS-2020 Kinetex EVO C182.1X30 mm, 5 pm at 50°C; Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 1.5 mL / min; eluted with the mobile phase over 0.80 min employing UV detection at 220 nm and 254 nm. Gradient information: 0- 0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-1 .20 min, held at 5% A-95% B; 1 .20-1 .21 min, returned to 95% A-5% B, 1.21-1.55 min, held at 95% A-5% B.

[0334] Method 2 : SHIMADZU LCMS-2020 Kinetex EVO C182.1X30 mm, 5 pm at 40°C : Mobile Phase : A: 0.025% NHs^O 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.

[0335] Method 3: Agilent 1200\G6110A Kinetex EVO C18 2.1X30 mm, 5 m at 50°C; Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 1.5.0 mL / min; eluted with the mobile phase over 0.80 min employing UV detection at 220 nm and 254 nm. Gradient information: 0.01 -0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-1 .20 min, held at 5% A-95% B; 1.20-1 .21 min, returned to 95% A-5% B, 1.21-1.50 min, held at 95% A-5% B.

[0336] Method 4: 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.

[0337] Method 5: SHIMADZU LCMS-2020 Kinetex® EVO C182.1X20 mm 2.6 pm at 50°C; Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 2.0 mL / min; eluted with the mobile phase over 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.

[0338] Method 6: SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X30 mm 5 pm at 50°C; Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 1 .5 mL / min; eluted with the mobile phase over 1.00 min employing UV detection at 220 nm and 254 nm. Gradient information: 0.01-0.60 min, ramped from 95% A-5% B to 5% A-95% B; 0.60-0.78 min, held at 5% A-95% B; 0.78-0.79 min, returned to 95% A-5% B, 0.79-0.80 min, held at 95% A-5% B.

[0339] Method 7: 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 .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.

[0340] Method 8: SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X30mm,5 pm at 50°C; Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 2.0 mL / min; eluted with the mobile phase over 0.80 min employing UV detection at 220 nm and 254 nm. Gradient information: 0- 0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-1 .20 min, held at 5% A-95% B; 1 .20-1 .21 min, returned to 95% A-5% B, 1.21-1.55 min, held at 95% A-5% B.

[0341] 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.

[0342] Method 10: 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 Acetonitrile (v / v); flow rate held at 2.0 mL / min; eluted with the mobile phase over 0.80 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-0.60 min, ramped from 95% A-5% B to 5% A-95% B; 0.60-0.78 min, held at 5% A-95% B; 0.78-0.79 min, returned to 95% A-5% B, 0.79-0.80 min, held at 95% A-5% B.

[0343] Method 11 : SHIMADZU LCMS-2020 Shim-pack Scepter C18-1202.1 x33 mm, 5 pm at40°C; Mobile Phase: A: 10 mM NH^HCOa in water; B: Acetonitrile; flow rate held at 1.7 mL / min; eluted with the mobile phase over 1.00 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-0.70 min, ramped from 95% A-5% B to 5% A-95% B; 0.70-0.90 min, held at 5% A-95% B; 0.90-0.91 min, returned to 95% A-5% B, 0.91-1.00 min, held at 95% A-5% B.

[0344] Method 12: SHIMADZU LCMS-2020 Kinetex® EVO C183.0x50mm, 2.6 pm at 50°C; Mobile Phase: A: 0.04% TFA in water (v / v); B: 0.02% TFA in Acetonitrile (v / v); flow rate held at 0.9 mL / min; eluted with the mobile phase over 4.00 min employing UV detection at 220 nm and 254 nm. Gradient information: 0- 3.40 min, ramped from 95% A-5% B to 5% A-95% B; 3.40-3.70 min, held at 5% A-95% B; 3.70-3.71 min, returned to 95% A-5% B, 3.71-4.00 min, held at 95% A-5% B.

[0345] The methods described hereinabove may also be referred to as LCMS methods. It is to be noted that in the following, unless indicated explicitly to the contrary, if the purity is reported, the reported purity value of the compound originates from LCMS measurements.

[0346] SFC Analytical Methods:

[0347] 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 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.

[0348] SFC Method 5: 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: EtGH(0.05 %DEA) in CO2 from 20% to 60%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

[0349] SFC Method 6: 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: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

[0350] SFC Method 8: Column: Chiralcel OD-3 50*4.6 mm I.D.,3um 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: 3mL / min; Detector: PDA; Column Temp: 35C; Back Pressure: 100 Bar.

[0351] SFC Method 9: Colum Chiralpak IC-3 50*4.6 mm LD.,3um 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: 100Bar.

[0352] 1H NMR Spectroscopy:

[0353] 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).

[0354] Salt stoichiometry:

[0355] 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.

[0356] Preparation of Intermediate 1.1

[0357] 1-bromo-2-(bromomethyl)-5-fluoro-3-nitrobenzene

[0358] To a solution of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (10.00 g, 42.7 mmol) in carbon tetrachloride (100 mL) was added NBS (16.73 g, 94.0 mmol) and AIBN (0.35 g, 2.14 mmol). Then the mixture was heated to 75 °C and stirred for 5 h. The reaction mixture was poured into water (100 mL), extracted with EtOAc (40 mL, 2x). The combined organic layer was washed with brine (40 mL, 2x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to afford the product 1-bromo-2-(bromomethyl)-5-fluoro-3-nitrobenzene (4.00 g, 12.8 mmol, 29.91 % yield) as yellow oil.

[0359] 1HNMR (DMSO-cfe, 400 MHz): 8.18 (dd, J = 8.40, 2.40 Hz, 1 H), 8.09 (dd, J = 8.40, 2.40 Hz, 1 H), 4.76 (s, 2H).

[0360] Preparation of Intermediate 1 .2

[0361] 2-bromo-4-fluoro-6-nitrobenzaldehyde

[0362] To a solution of 1-bromo-2-(bromomethyl)-5-fluoro-3-nitrobenzene (4.00 g, 12.8 mmol) in MeCN (40 mL) was added 4 A molecular sieve (4.00 g) and 4-methylmorpholine N-oxide (2.99 g, 25.6 mmol) at 25 °C.The mixture was stirred at this temperature for 2 h, diluted with EtOAc (30 mL, 2x), filtered, poured into water (100 mL) andextracted with EtOAc (50 mL, 2x). The combined organic layer was washed with brine (30 mL, 2x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford the product 2-bromo-4-fluoro-6-nitrobenzaldehyde (2.90 g, 11 .7 mmol, 91 .47 % yield) as yellow oil.

[0363] 1HNMR (DMSO-de, 400 MHz):10.16 (s, 1 H), 8.24 (dd, J = 8.00, 2.40 Hz, 1 H,) 8.20 (dd, J = 8.00, 2.40 Hz, 1H).

[0364] Preparation of Intermediate 1 .3

[0365] 2-amino-6-bromo-4-fluorobenzaldehyde

[0366] To a solution of 2-bromo-4-fluoro-6-nitrobenzaldehyde (4.00 g, 16.1 mmol) in EtOH (40 mL) and water (10 mL) was added NH4CI (4.31 g, 80.6 mmol) and Fe (3.80 g, 64.5 mmol) at 20 °C. The mixture was stirred at 90 °C for 0.5 h, then filtered and washed with EtOAc (15 mL*2).Then, the filtrate was poured into water (100 mL) and extracted with EtOAc (40 mL, 2x). The combined organic layer was washed with brine (25 mL, 2x), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the product2-amino-6-bromo-4-fluorobenzaldehyde (2.50 g, 11 .5 mmol, 71 .10 % yield) as a yellow solid.

[0367] RT 0.400 min (LCMS Method 5); m / z 218.1 (M+H)+(ESI+).1HNMR (DMSO-d6, 400 MHz): 10.14 (s, 1H), 7.87 (s, 2H), 6.79 (dd, J = 8.00, 2.40 Hz, 1 H), 6.57 (dd, J = 8.00, 2.40 Hz, 1H).

[0368] Preparation of Intermediate 1 .4

[0369] 5-bromo-7-fluoroquinolin-2-amine

[0370] To a solution of 2-amino-6-bromo-4-fluorobenzaldehyde (3.00 g, 13.8 mmol) and MeCN (1.69 g, 41.3 mmol, 2.15 mL) in DMF (30 mL) was added f-BuOK in THF (41 mL, 41.3 mmol, 1 M) at 0 °C.The mixture was stirred at 20 °C for 0.5 h, then poured into NH4CI (aq., sat., 100 mL) at 0 °C. The precipitatewas filtered. Then, the solid was washed with H2O (50 mL), collected and dried under reduced pressure to give the product 5-bromo-7-fluoroquinolin-2-amine (2.40 g, 9.46 mmol, 68.74 % yield) as a yellow solid.

[0371] RT 0.255min (LCMS Method 5); m / z 243.2 (M+H)+(ESI+);1HNMR (DMSO-d6, 400 MHz): 8.03 (d, J = 9.2 Hz, 1 H), 7.45 (dd, J = 2.4, 9.2 Hz, 1 H), 7.17 (dd, J = 2.4, 9.2 Hz, 1 H), 6.87 (s, 2H), 6.83 (d, J = 9.2 Hz, 1 H).

[0372] Preparation of Intermediate 1 .5 7-(benzylthio)-5-bromoquinolin-2-amine

[0373] To a solution of 5-bromo-7-fluoroquinolin-2-amine (800 mg, 3.32 mmol) and phenylmethanethiol (0.39 mL, 3.32 mmol) in DMF (8 mL) was added CS2CO3 (3244 mg, 9.96 mmol) at 25 °C. The mixture was degassed, purged with N2 (3x). and phenylmethanethiol (0.39 mL, 3.32 mmol) was added at 25 °C. The mixture was stirred at 80 °C for 2 h, then poured into NH4CI (aq., sat., 100 mL) at 0 °C and extracted with EtOAc (50 mL, 2x). The combined organic layer was washed with brine (30 mL, 2x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the product 7-(benzylthio)-5-bromoquinolin-2-amine (450 mg, 5.91 mmol, 47.36 % yield) as a yellow solid.

[0374] RT 0.391 min (LCMS Method 5); m / z 347.1 (M+H)+(ESI+).

[0375] Preparation of Intermediate 1 .6 tert-butyl (7-(benzylthio)-5-bromoquinolin-2-yl)carbamate

[0376] To a solution of 7-(benzylthio)-5-bromoquinolin-2-amine (1.40 g, 4.05 mmol) in DCM (5 ml_) was added (Boc)2O (1062 mg, 4.87 mmol), DIPEA (1 .4 mL, 8.11 mmol) and DMAP (50 mg, 0.405 mmol) at 20 °C and the mixture was stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiC>2, petroleum ether: ethyl acetate = 1 :0 to 3:1) to give the product tert-butyl (7-(benzylthio)-5-bromoquinolin-2-yl) carbamate (1.50 g, 3.37 mmol, 83.06 % yield) as a white solid.

[0377] RT 0.596 min (LCMS Method 5); m / z 389.1 (M+H-t-Bu)+(ESI+);1HNMR (DMSO-cfe, 400 MHz): 10.29 (s, 1 H), 8.33 (d, J = 7.6 Hz, 1 H), 8.08 (d, J = 7.6 Hz, 1H), 7.73 (s, 1 H), 7.53 (s, 1 H), 7.43 (d, J = 7.6 Hz, 2H), 7.32 (t, J = 7.2 Hz, 2H), 7.27-7.23 (m, 1 H), 4.46-4.40 (m, 2H), 1.49 (s, 9H).

[0378] Preparation of Intermediate 1 .7 fert-butyl (5-bromo-7-(chlorosulfonyl)quinolin-2-yl)carbamate

[0379] To a solution of fert-butyl (7-(benzylthio)-5-bromoquinolin-2-yl)carbamate (1.00 g, 2.25 mmol) in MeCN (25 mL) was added AcOH (0.26 mL, 4.49 mmol), H2O (40 mg, 2.25 mmol, 0.04 mL) at 25°C, and then DCDMH (885 mg, 4.49 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 15 min, then poured into ice-water (30 mL)and extracted with DCM (30 mL, 2x). The combined organic layer was washed with brine (20 mL, 2x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the product fert-butyl (5-bromo-7-(chlorosulfonyl)quinolin-2-yl)carbamate (800 mg,1 .90 mmol, 84.49 % yield) as yellow oil.

[0380] RT 0.575min (LCMS Method 5); m / z 365.0 (M-t-Bu+H)+(ESI+).

[0381] Preparation of Intermediate 1 .8 fert-butyl (5-bromo-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate

[0382] To a solution of 1-methylcyclopropan-1 -amine (306 mg, 2.85 mmol) and DIPEA (1.3 mL, 7.59 mmol) in DCM (3 mL) was added fert-butyl N-(5-bromo-7-chlorosulfonyl-2-quinolyl)carbamate (800 mg, 1.90 mmol) in DCM (5mL) at 0 °C and the mixture was stirred for 0.5 h. The mixture was concentrated under vacuum to give a residue which was further purified by reversed-phase HPLC (ISCO®; 80g Flash Conlmn; 120A, mobile phase: A: 0.1% TFA in water, B: MeCN; B%: 85%-88%, @ 60 mL / min) to give the product tert-butyl (5-bromo-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate (550 mg, 1.17 mmol, 61 .62 % yield) as a white solid.

[0383] RT 0.519 min (LCMS Method 5); m / z 402.1 (M- t-Bu +H)+(ESI+);1HNMR (DMSO-d6, 400 MHz): 10.54 (s, 1 H), 8.51 (d, J = 9.2 Hz, 1 H), 8.39 (s, 1 H), 8.31 (d, J = 9.2 Hz, 1 H), 8.11 (d, J = 1 .6 Hz, 1 H), 8.01 (d, J = 1.6 Hz, 1H), 1.51 (s, 9H), 1.07 (s, 3H), 0.64-0.60 (m, 2H), 0.42-0.41 (m, 2H).

[0384] Preparation of Intermediate 1.9 fert-butyl (5-(4-(dimethylcarbamoyl)piperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)carbamate To a solution of tert-butyl (5-bromo-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate (50 mg, 0.110 mmol), CS2CO3 (89 mg, 0.274 mmol), N,N-dimethylpiperazine-1-carboxamide 34 mg, 0.219 mmol) in dioxane (1 mL) was added Pd-PEPPSI-IPentCI o-picoline (9.4 mg, 0.0110 mmol) at 25 °C and the mixture was degassed and purged with N2 (3x). The mixture was stirred at 80 °C under N2 for 1 h, then poured into water (60 mL) and extracted with EtOAc (30 mL, 2x). The combined organic layer was washed with brine (20 mL, 2x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reversed-phase HPLC (ISCO®; 25g Flash Conlmn; 120A, mobile phase: A: 0.1% TFA in water, B: MeCN; B%: 50%-55% @ 30 mL / min) to give the product tert-butyl (5-(4-(dimethylcarbamoyl)pi perazin- 1 -yl)-7-(N-(1 -methylcyclopropyl)su lfamoyl)q u i nolin- 2-yl)carbamate (20 mg, 0.103 mmol, 31.56 % yield) as a yellow solid.

[0385] RT 0.460 min (LCMS Method 5); m / z 533.4 (M+H)+ (ESI+);1HNMR (DMSO-d6, 400 MHz): 10.29 (s, 1H), 8.50 (d, J = 9.2 Hz, 1 H), 8.18 (s, 1 H), 8.13 (d, J = 9.2 Hz, 1 H), 7.82 (s, 1 H), 7.32 (s, 1 H), 3.41- 3.36 (m, 4H), 3.04-3.01 (m, 4H), 2.80 (s, 6H), 1 .50 (s, 9H), 1 .03 (s, 3H), 0.62-0.55 (m, 2H), 0.37- 0.34 (m, 2H).

[0386] Preparation of Intermediate 1.10

[0387] 4-(2-amino-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N-dimethylpiperazine-1- carboxamide

[0388] Tert-butyl (5-(4-(dimethylcarbamoyl)piperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin- 2-yl)carbamate (60 mg, 0.113 mmol) was added into formic acid (1.0 mL, 0.113 mmol) at 25 °C and the mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give the product 4-(2-amino-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N-dimethylpiperazine-1- carboxamide (70 mg, 0.123 mmol, crude,) as a yellow oil.

[0389] RT 0.308 min (LCMS Method 5); m / z 433.2 (M+H)+ (ESI+);

[0390] Preparation of Intermediate 1.11 methyl bicyclo[1 .1 .0]butane-1 -carboxylate To a mixture of methyl 3-chlorocyclobutane-1 -carboxylate (100 mg, 0.673 mmol) in THF (1 mL) was added LiHMDS in THF (0.807 mL, 0.807 mmol, 1M) at 0°C under N2 atmosphere. The mixture was stirred at 0°C for 1h. The resulting yellow solution of methyl bicyclo[1.1.0]butane-1 -carboxylate (Theoretical quantity: 75 mg, 0.372 mmol / mL, 1 .807 mL) was used into the next step without further purification.

[0391] Preparation of Example 1

[0392] 4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)- N,N-dimethylpiperazine-1-carboxamide

[0393] To a solution of 4-(2-amino-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N- dimethylpiperazine-1 -carboxamide (30 mg, 0.0694 mmol) in THF (1 mL) was added methyl bicyclo[1 .1 .0]butane-1 -carboxylate (0.56 mL 0.208 mmol, 0.372 mmol / mL) at 0 °C, and followed by adding LiHMDS in THF (0.243 mL, 0.243 mmol, 1 M) at 0 °C. The temperature was raised slowly to 25°C. Then, the mixture was stirred at 25 °C under N2 for 1 h, poured into water (60 mL) and extracted with EtOAc (50 mL, 2x). The combined organic layer was washed with brine (30 mL, 2x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 28%-58%, 10 min) and lyophilized to give an impure product which was further purified by preparative HPLC (column: Waters Xbridge 150*25 mm 10pm; mobile phase: A: 10 mmol / L NH4HCO3 in water, B: MeCN; B%: 26%-56%, 18 min) and lyophilized to give the product 4-(2- (bicyclo[1 .1 .0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N- dimethylpiperazine-1 -carboxamide (2.4 mg, 0.00456 mmol, 6.57 % yield) as a white solid.

[0394] RT 0.416 min (LCMS Method 5); m / z 513.3 (M+H)+(ESI+);1HNMR (DMSO-ofe, 400 MHz): 10.65 (br, 1 H), 8.53 (d, J = 9.2 Hz, 1 H), 8.37 (d, J = 9.2 Hz, 1 H), 8.20 (br, 1 H), 7.87 (s, 1 H), 7.34 (s, 1 H), 3.46- 3.40 (m, 4H), 3.16-3.02 (m, 4H), 2.80 (s, 6H), 2.57 (d, J = 2.4 Hz, 2H), 2.44-2.41 (m, 1 H), 1.12 (br, 2H), 1.03 (s, 3H), 0.65-0.60 (m, 2H), 0.40-0.35 (m, 2H).

[0395] Preparation of Intermediate 2.1 tert-butyl (7-(N-(1-methylcyclopropyl)sulfamoyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinolin-2- yl)carbamate

[0396] To a solution of fert-butyl (5-bromo-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate (50 mg, 0.110 mmol) in dioxane (1 mL) was added 2-oxa-7-azaspiro[3.5]nonane (28 mg, 0.219 mmol), CS2CO3 (89 mg, 0.274 mmol) and Pd-PEPPSI-IPentCI o-picoline (11 mg, 0.0110 mmol) at 20 °C. The mixture was degassed with N2 (3x) and stirred at 80 °C under N2 for 1h. The resulting mixture was poured into water (60 mL) and extracted with EtOAc (30 mL, 2x). The combined organic layer was washed with brine (20 mL, 2x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 55%-85%, 10 min) to afford fert-butyl (7-(N-(1-methylcyclopropyl)sulfamoyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinolin-2- yl)carbamate (70 mg, 0.144 mmol, crude) as a white solid.

[0397] RT 0.480 min (LCMS Method 5); m / z 447.2 (M+H-tBu)+(ESI+);1HNMR (DMSO-cfe, 400 MHz): 10.26 (s, 1 H), 8.40 (d, J = 9.2 Hz, 1 H), 8.15 (s, 1 H), 8.12 (d, J = 9.2 Hz, 1H), 7.78 (s, 1 H), 7.27 (s, 1 H), 4.41 (s, 4H), 2.94-2.85 (m, 4H), 2.10-2.05 (m, 4H), 1.50 (s, 9H), 1.02 (s, 3H), 0.64-0.58 (m, 2H), 0.39- 0.33 (m, 2H).

[0398] Preparation of Intermediate 2.2

[0399] 2-amino-N-(1-methylcyclopropyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinoline-7-sulfonamide

[0400] A mixture of tert-butyl (7-(N-(1-methylcyclopropyl)sulfamoyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7- yl)quinolin-2-yl)carbamate (70 mg, 0.139 mmol) in formic acid (1 .0 mL, 0.139 mmol) was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to give the product 2-amino-N-(1- methylcyclopropyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinoline-7-sulfonamide (50 mg, 0.124 mmol,

[0401] 89.20 % yield) as yellow solid.

[0402] RT 0.300 min (LCMS Method 5); m / z 403.2 (M+H)+(ESI+)

[0403] Preparation of Example 2

[0404] / V-(7-(N-(1-methylcyclopropyl)sulfamoyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide

[0405] At 20°C, to a solution of 2-amino-N-(1-methylcyclopropyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7- yl)quinoline-7-sulfonamide (20 mg, 0.0497 mmol) in THF (2 mL) was added methyl bicyclo[1.1.0]butane- 1-carboxylate (0.40 mL, 0.149 mmol, 0.372 mmol / mL, the preparation of methyl bicyclo[1.1.0]butane-1- carboxylate is similar as intermediate 1.11) followed by addition of LiHMDS in THF (0.174 mL, 0.174 mmol, 1 M). The mixture was heated to 40 °C, stirred for 1 h under N2, then poured into water (40 mL) and extracted with EtOAc (30 mL, 2x). The combined organic layer was washed with brine (20 mL, 2x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters xbridge 150*25mm 10pm; mobile phase: A: 10 mmol / L NH4HCO3 in water, B: MeCN; B%: 30%-60%, 10 min) and lyophilized to afford the product / -(7-(N-(1-methylcyclopropyl)sulfamoyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinolin-2- yl)bicyclo[1.1.0]butane-1 -carboxamide (5.0 mg, 0.01 mmol, 20.14 % yield) as a white solid.

[0406] RT 0.423 min (LCMS Method 5); m / z 483.3 (M+H)+(ESI+);1H NMR (DMSO-d6, 400 MHz): 10.63 (s, 1H), 8.44 (d, J = 8.8 Hz, 1 H), 8.36 (br, 1H), 8.18 (s, 1 H), 7.84 (s, 1 H), 7.29 (d, J = 8.8 Hz, 1H), 4.41 (s, 4H), 2.98-2.93 (m, 4H), 2.56 (d, J = 2.8 Hz, 2H), 2.41-2.39 (m, 1H), 2.10-2.05 (m, 4H), 1.12 (d, J = 2.8 Hz, 2H), 1.02 (s, 3H), 0.63-0.58 (m, 2H), 0.39-0.34 (m, 2H).

[0407] Preparation of intermediate 3.1

[0408] 6-(benzylthio)-3-chloroisoquinoline To a solution of 6-bromo-3-chloroisoquinoline (1 g, 4.12 mmol) in dioxane (10 mL) was added phenylmethanethiol (563.40 mg, 4.54 mmol), Xantphos (477.21 mg, 824.74 pmol), Pd2(dba)s (377.62 mg, 412.37 mol) and DIPEA (1 .07 g, 8.25 mmol). The mixture was degassed, purged with N2 (3x) andstirred at 90°C for 2 h under N2. The resulting mixture was filtered and the filtrate was concentrated under vacuum. The resulting residue was triturated with MeOH (20 mL) at 20°C for 10 min. After filtration, the cake was collected and dried under vacuum to give the product 6-(benzylthio)-3-chloroisoquinoline (1 g, 3.50 mmol, 84.85% yield) as a yellow solid.

[0409] RT 0.571 min (LCMS method 5); m / z 285.8 (M+H)+(ESP);1H NMR (DMSO-cfe, 400 MHz): 9.09 (s, 1H), 8.05 (d, J = 8.8 Hz, 1 H), 7.87 (d, J = 7.6 Hz, 2H), 7.61 (d, J = 8.8 Hz, 1 H), 7.47 (d, J = 7.6 Hz, 2H), 7.35-7.30 (m, 2H), 7.29-7.22 (m, 1H), 4.44 (s, 2H)

[0410] Preparation of intermediate 3.2

[0411] 3-chloroisoquinoline-6-sulfonyl chloride

[0412] To a solution of 6-(benzylthio)-3-chloroisoquinoline (900 mg, 3.15 mmol) in AcOH (8 mL) and H2O (4 mL) was added NCS (1 .68 g, 12.60 mmol) at 0°C. The mixture was stirred at 20°C for 2 h and poured into water (90 mL).The aqueous layer was extracted with EtOAc (30 mL, 2x). The combined organic layer was washed with brine (60 mL, 5x), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give the product 3-chloroisoquinoline-6-sulfonyl chloride (825 mg, 3.15 mmol, 99.95% yield) as a yellow solid. The product was used in the next step directly.

[0413] Alternative preparation of intermediate 3.2

[0414] 3-chloroisoquinoline-6-sulfonyl chloride

[0415] To a mixture of 6-benzylsulfanyl-3-chloro-isoquinoline (500 mg, 1.75 mmol) in MeCN (10 mL) at 0°C were added AcOH (420 mg, 7.00 mmol), water (126 mg, 7.00 mmol) and sulfuryl chloride (708 mg, 5.25 mmol). The reaction mixture was warmed to 25 °C, stirred for 1 .5 h and, then diluted with DCM (20 mL). The organic layer was washed with water (20 mL, 2 x) and brine (10 mL), then dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the product 3-chloroisoquinoline-6-sulfonyl chloride (450 mg, crude) as a light brown oil which was used directly in the next step without further purification.

[0416] Preparation of intermediate 3.3

[0417] 3-chloro-N-(1-methylcyclopropyl)isoquinoline-6-sulfonamide

[0418] To a solution of 1-methylcyclopropan-1 -amine hydrochloride (677.23 mg, 6.30 mmol, HCI salt) in TEA (3.18 g, 31.48 mmol, 4.38 mL) was added a solution of 3-chloroisoquinoline-6-sulfonyl chloride (825 mg, 3.15 mmol) in DCM (1 mL) drop-wise at 0°C. The mixture was stirred at 0°C for 1 h and then concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, mobile phase: A:, Ethyl acetate B: Petroleum ether; A%: 0% to 30%, @ 12 mL / min) to give the product 3-chloro-N-(1-methylcyclopropyl)isoquinoline-6- sulfonamide (450 mg, 1.52 mmol, 48.18% yield) as a yellow solid.

[0419] RT 0.412 min (LCMS method 5); m / z 296.8 (M+H)+(ESI+);1H NMR (DMSO, 400 MHz): 9.34 (s, 1 H), 8.51 (s, 1 H), 8.41 (s, 1 H), 8.39 (d, J = 8.8 Hz, 1 H), 8.34 (s, 1 H), 7.96 (dd, J = 1 .6, 8.4 Hz, 1 H), 1 .06 (s, 3H), 0.62-0.58 (m, 2H), 0.42-0.37 (m, 2H)

[0420] Alternative preparation of intermediate 3.3

[0421] 3 hloro-N-(1-methylcyclopropyl)isoquinoline-6-sulfonamide

[0422] To a solution of 1-methylcyclopropan-1 -amine hydrochloride (554 mg, 5.15 mmol, HCI salt) in pyridine (10 mL) at 0 °C was added a solution of 3-chloroisoquinoline-6-sulfonyl chloride (450 mg, 1.72 mmol) in THF (5 mL) dropwise over 5 min. The reaction mixture was stirred at 0 °C for 1 h, then quenched with water (20 mL) and extracted with EtOAc (10 mL, 3x). The combined organic layer was washed with brine (10 mL), 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, mobile phase: A: ethyl acetate, B: petroleum ether; A%:0 to 50%, @ 40 mL / min) to give the product 3-chloro-N-(1- methylcyclopropyl)isoquinoline-6-sulfonamide (130 mg, 394 mol, 7.65% yield, 90% purity) as a white solid. RT 0.388 min (LCMS Method 10); m / z 297.0 (M+H)+(ESI+);1H NMR (CDCI3, 400 MHz): 9.19 (s, 1 H), 8.40 (s, 1 H), 8.13 (d, J = 8.8 Hz, 1 H), 7.96 (dd, J = 1.6, 8.8 Hz, 1H), 7.87 (d, J = 1.6 Hz, 1 H), 5.10 (s, 1 H), 1 .25 (s, 3H), 0.78 (t, J = 6.4 Hz, 2H), 0.53 (t, J = 6.4 Hz, 2H).

[0423] Preparation of intermediate 3.4 tert-butyl (6-(N-(1-methylcyclopropyl)sulfamoyl)isoquinolin-3-yl)carbamate

[0424] A mixture of 3-chloro-N-(1 -methylcyclopropyl)isoquinoline-6-sulfonamide (150 mg, 505.44 pmol), tert-butyl carbamate (118.42 mg, 1.01 mmol), CS2CO3 (329.36 mg, 1.01 mmol), Xantphos (58.49 mg, 101.09 pmol) and Pd3(dba)3(46.28 mg, 50.54 pmol) in dioxane (0.5 mL) was degassed with N2 (3x) and stirred at 90°C for 16 h under N2. The resulting mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether : ethyl acetate = 3 : 1) to give the product tert-butyl (6-(N-(1-methylcyclopropyl)sulfamoyl)isoquinolin-3-yl)carbamate (60 mg, 158.96 pmol, 31 .45% yield) as a yellow solid.

[0425] RT 0.470 min (method 6); m / z 378.0 (M+H)+(ESI+)

[0426] Preparation of intermediate 3.5

[0427] 3-amino-N-(1-methylcyclopropyl)isoquinoline-6-sulfonamide

[0428] A solution of tert-butyl (6-(N-(1-methylcyclopropyl)sulfamoyl)isoquinolin-3-yl)carbamate (50 mg, 132.47 pmol) in HCI / dioxane (1 mL) was stirred at 20°C for 1 h, then poured into NaHCO3(aq., sat., 15 mL) and extracted with EtOAc (5 mL; 2x). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give the product 3- amino-N-(1-methylcyclopropyl)isoquinoline-6-sulfonamide (60 mg, crude) as a yellow solid.

[0429] RT 0.276 min (LCMS method 6); m / z 277.7 (M+H)+(ESI+)

[0430] Preparation of Example 3

[0431] N-(6-(N-(1-methylcyclopropyl)sulfamoyl)isoquinolin-3-yl)bicyclo[1.1.0]butane-1 -carboxamide To a solution of methyl bicyclo[1 .1.0]butane-1 -carboxylate (0.9 mL, 362 pmol, 0.40 mmol / mL similar preparation as for intermediate 1 .11) and 3-amino-N-(1-methylcyclopropyl)isoquinoline-6-sulfonamide (50 mg, 180.28 pmol) in THF (0.1 mL) was added LiHMDS in THF (1 M, 721.13 pL) drop-wise at 0°C. The mixture was stirred at 40°C for 1 h under N2, then poured into water (10 mL) and extracted with EtOAc (3 mL, 2x). The combined organic layer was washed with brine (6 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 mm*10 pm; mobile phase: A: 0.079% NH4HCO3 in water, B: MeCN; B%: 25%- 55%, 10 min) and lyophilized directly to give the product N-(6-(N-(1- methylcyclopropyl)sulfamoyl)isoquinolin-3-yl)bicyclo[1.1.0]butane-1 -carboxamide (3.07 mg, 8.59 pmol, 4.76% yield, 100% purity) as a white solid.

[0432] RT 0.422 min (LCMS method 6); m / z 358.1 (M+H)+(ESI+);1H NMR (400 MHz, DMSO-cfe) 10.47 (s, 1H), 9.27 (s, 1 H), 8.59 (s, 1 H), 8.31 (s, 2H), 8.25 (d, J = 8.8 Hz, 1 H), 7.77 (d, 8.4 Hz, 1 H), 2.55 (d, J = 3.2 Hz, 2H), 2.36-2.31 (m, 1 H), 1.10 (d, J = 1.6 Hz, 2H), 1.05 (s, 3H), 0.63-0.57 (m, 2H), 0.41-0.35 (m, 2H).

[0433] Preparation of Intermediate 4.1

[0434] 6-acetamido-3-(N-(1 -methylcyclopropyl)sulfamoyl)naphthalen-1 -yl acetate

[0435] To a solution of 1-methylcyclopropan-1 -amine hydrochloride (7.08 g, 65.83 mmol, HCI salt) and NaHCOs (11.06 g, 131.67 mmol) in water (30 mL) was added a solution of 6-acetamido-3- (chlorosulfonyl)naphthalen-l-yl acetate (which is a compound obtained according to the literature procedure: Journal of Medicinal Chemistry (2008), 51 (19), 6173-6187 & W02000071506 A2) (15 g, 43.89 mmol) in THF (50 mL) dropwise at 0 °C. The mixture was warmed to 20 °C and stirred for 2 h. The resulting mixture was concentrated under vacuum. The resulting residue was triturated with water (200 mL) at 20°C for 10 min and filtered. The solid was filtered and dried under vacuum to give the product 6- acetamido-3-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-1-yl acetate (10 g, 26.57 mmol, 60.53% yield) as a brown solid.

[0436] RT 0.361 min (LCMS method 1); m / z 377.0 (M+H)+(ESI+);1H NMR (DMSO-cfe, 400 MHz,): 10.39 (s, 1H), 8.49 (s, 1 H), 8.19 (s, 1 H), 8.17 (s, 1 H), 7.98 (d, J = 9.2 Hz, 1 H), 7.79 (dd, J = 8.8, 1.6 Hz, 1H), 7.48 (d, J = 1.6 Hz, 1 H), 2.48 (s, 3H), 2.13 (s, 3H), 1.06 (s, 3H), 0.63-0.60 (m, 2H), 0.39-0.36 (m, 2H)

[0437] Preparation of Intermediate 4.2 N-(5-hydroxy-7-(N-(1 -methylcyclopropyl)sulfamoyl)naphthalen-2-yl)acetamide

[0438] To a solution of 6-acetamido-3-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-1-yl acetate (10 g, 26.57 mmol) in MeOH (50 mL) was added a solution of NaOH (3.19 g, 79.70 mmol) in water (60 mL) dropwise at 0 °C. The mixture was stirred at 20 °C for 2 h, then concentrated to remove MeOH and diluted with EtOAc (500 mL). The organic layer was washed with brine (200 mL, 3x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum to give the product N-(5-hydroxy-7-(N- (1-methylcyclopropyl)sulfamoyl)naphthalen-2-yl)acetamide (6 g, 14.35 mmol, 54.03% yield, 80% purity) as a brown solid.

[0439] RT 0.317 min (method 1); m / z 334.9 (M+H)+(ESI+);1H NMR (DMSO-cfe, 400 MHz,): 10.74 (s, 1 H), 10.25 (s, 1 H), 8.30 (d, J = 1.6 Hz, 1 H), 8.11 (d, J = 9.2 Hz, 1 H), 8.04 (s, 1H), 7.69(s, 1 H), 7.68 (dd, J = 9.2, 2.0 Hz, 1H), 7.06 (d, J = 1.6 Hz, 1 H), 2.12 (s, 3H), 1.08 (s, 3H), 0.64-0.62 (m, 2H), 0.38-0.35 (m, 2H) Preparation of Intermediate 4.3

[0440] 6-acetamido-3-(N-(1 -methylcyclopropyl)sulfamoyl)naphthalen-1 -yl trifluoromethanesulfonate

[0441] To a solution of N-(5-hydroxy-7-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-2-yl)acetamide (350 mg, 1 .05 mmol) and TEA (211 .83 mg, 2.09 mmol, 291 .37 pL) in DCM (5 mL) was dropwise added trifluoromethylsulfonyl anhydride (354.37 mg, 1.26 mmol, 207.24 pL) at 0°C. The mixture was stirred at 20 °C for 2 h, then diluted with water (10 mL) and extracted with DCM (5 mL, 3x). The organic layer was washed with water (10 mL, 3x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash Column, mobile phase: A:, Ethyl acetate; B: Petroleum ether; A%: 0% to 50%, @ 30 mL / min) to give the product 6-acetamido-3-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-1-yl trifluoromethanesulfonate (320 mg, 617.43 pmol, 59.00% yield, 90% purity) as a brown solid.

[0442] RT 0.561 min (LCMS method 1); m / z 467.0 (M+H)+(ESI+);1H NMR (CDCI3, 400 MHz,): 8.50 (s, 1 H), 8.43 (s, 1 H), 8.07 (d, J = 8.8 Hz, 1 H), 7.74 (s, 1 H), 7.72 (dd, J = 8.8, 2.0 Hz, 1 H), 7.55 (s, 1 H), 5.07 (s, 1H), 2.29 (s, 3H), 1.23 (s, 3H), 0.82-0.79 (m, 2H), 0.53-0.50 (m, 2H).

[0443] Preparation of Intermediate 4.4 4-(6-acetamido-3-(N-(1 -methylcyclopropyl)sulfamoyl)naphthalen-1-yl)-N,N-dimethylpiperazine-1- carboxamide

[0444] To a solution of 6-acetamido-3-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-1-yl trifluoromethanesulfonate (40 mg, 85.75 pmol) and N,N-dimethylpiperazine-1 -carboxamide (20.22 mg, 128.63 pmol) in dioxane (1.5 mL) was added K2CO3 (23.70 mg, 171.51 pmol) and Pd-PEPPSI-IPentCI 0- picoline (5.84 mg, 6.00 pmol). The mixture was degassed with N2 (3x) andwas stirred at 90 °C for 4 h. The resulting mixture was cooled down to 20 °C, filtered and the filtrate was concentrated under vacuum. The resulting crude product was purified by preparative TLC (EtOAc : MeOH= 10:1) to give the product 4-(6-acetamido-3-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-1-yl)-N,N-dimethylpiperazine-1- carboxamide (65 mg, 123.53 pmol, 72.00% yield, 90% purity) as an off-white solid.

[0445] RT 0.405 min (LCMS method 1); m / z 474.4 (M+H)+(ESI+);1H NMR (DMSO-ofe, 400 MHz,): 10.30 (s, 1H), 8.36 (d, J = 1.6 Hz, 1 H), 8.14 (d, J = 9.2 Hz, 1H), 8.06 (s, 1 H), 7.94 (s, 1 H), 7.76 (dd, J = 9.2, 2.0 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1 H), 3.52 ( s, 4H), 3.03 ( s, 4H), 2.80 (s, 6H), 2.12 (s, 3H), 1.01 (s, 3H), 0.63- 0.60 (m, 2H), 0.37-0.34 (m, 2H).

[0446] Preparation of Intermediate 4.5

[0447] 4-(6-amino-3-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-1-yl)-N,N-dimethylpiperazine-1- carboxamide

[0448] To a solution of 4-(6-acetamido-3-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-1-yl)-N,N- dimethylpiperazine-1-carboxamide (55 mg, 0.116 mmol) in EtOH (2 mL) was added HCI (aq., 2.0 mL, 12 N). The mixture was stirred at 50 °C for 1 h. The resulting mixture was cooled to 20 °C, concentrated under reduce pressure to give the product 4-(6-amino-3-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen- 1-yl)-N,N-dimethylpiperazine-1-carboxamide(55 mg, 0.116 mmol) as a brown solid.

[0449] RT 0.378 min (method 1); m / z 432.5 (M+H)+(ESI+);

[0450] Preparation of Example 4 4-(6-(bicyclo[1 .1 .0]butane-1 -carboxamido)-3-(N-(1 -methylcyclopropyl)sulfamoyl)naphthalen-1 -yl)- N,N-dimethylpiperazine-1-carboxamide

[0451] At 0°C, to a solution of 4-(6-amino-3-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-1-yl)-N,N- dimethylpiperazine-1 -carboxamide (40 mg, 0.0927 mmol) in THF (0.5 mL) was added methyl bicyclo[1.1.0]butane-1 -carboxylate (2.9 mL, 0.371 mmol, 0.128 mmol / mL, similar preparation as for intermediate 1.11) followed by addition of LiHMDS in THF (0.278 mmol, 0.278 mL, 1 M) at 0 °C. The mixture was stirred at 20 °C for 1 h under N2, then quenched with NH4CI (sat, aq., 5 mL) and extracted with EtOAc (5 mL; 2x). The combined organic layer was washed with brine (5 mL; 2x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether : ethyl acetate= 0:1 ) to give a crude product, which was further purified by trituration with EtOAc (0.5 mL) at 20 °C for 10 min. The precipitate was filtered, collected, and dried under vacuum to give the product 4-(6-(bicyclo[1.1.0]butane-1-carboxamido)-3-(N-(1- methylcyclopropyl)sulfamoyl)naphthalen-1-yl)-N,N-dimethylpiperazine-1 -carboxamide (3.6 mg, 0.007 mmol, 7.6% yield, >99% purity) as an off-white solid.

[0452] RT 0.450 min (LCMS method 1); m / z 512.5 (M+H)+(ESP);1H NMR (DMSO-ofe, 400 MHz,): 9.98 (s, 1H), 8.39 (s, 1 H), 8.12 (d, J = 9.2 Hz, 1 H), 8.06 (s, 1 H), 7.91 (s, 1 H), 7.20 (d, J = 9.2 Hz, 1 H), 7.29 (s, 1 H), 3.45-3.37 (m, 4H), 3.09-3.00 (m, 4H), 2.80 (s, 6H), 2.50 (s, 2H), 2.36-2.31 (m, 1 H), 1.12 (s, 2H), 1.00 (s, 3H), 0.61 (s, 2H), 0.36-0.35 (m, 2H).

[0453] Preparation of Intermediate 5.1 tert-butyl (6-bromo-8-chloroisoquinolin-3-yl)carbamate

[0454] A mixture of 6-bromo-8-chloroisoquinolin-3-amine (2.00 g, 4.66 mmol) and BOC2O (1016 mg, 4.66 mmol) was stirred at 100 °C for 16 h. The resulting mixture was cooled to 20°C triturated with EtOAc (2 mL) at 20 °C for 10 min and filtered. The solid was filtered and dried under vacuum to give the product tert-butyl (6-bromo-8-chloroisoquinolin-3-yl)carbamate (800 mg, 1 .90 mmol, 40.80 % yield) as a brown solid. RT 0.722 min (LCMS method 1), m / z 303.0(M-t-Bu+H)+(ESI+),1H NMR (DMSO-cfe, 400 MHz) :

[0455] 10.19 (s, 1 H), 9.25 (s, 1 H), 8.24 (s, 1 H), 8.21 (s, 1 H), 7.82 (d, J = 1.2 Hz, 1 H), 1.52 (s, 9H)

[0456] Preparation of Intermediate 5.2 tert-butyl (6-(benzylthio)-8-chloroisoquinolin-3-yl)carbamate

[0457] To a solution of tert-butyl (6-bromo-8-chloroisoquinolin-3-yl)carbamate (620 mg, 1.73 mmol) and phenylmethanethiol (0.24 mL, 1.91 mmol) in DMF (12 mL) was added DIEA (0.60 mL, 3.47 mmol), Pd2(dba)3 (159 mg, 0.173 mmol) and Xantphos (150 mg, 0.260 mmol). The mixture was degassed with N2 (3x) and stirred at 100 °C for 2 h. The resulting mixture was cooled to 20 °C and filtered. The solid was collected, triturated in MeOH (5 mL) at 20°C for 16 h and the mixture was filtered. The filter cake was collected and dried under vacuum to give the product tert-butyl (6-(benzylthio)-8-chloroisoquinolin-3- yl)carbamate (300 mg, 0.449 mmol, 25.90 % yield) as a green solid.

[0458] RT 0.700 min (LCMS method 1), m / z 345.0(M-t-Bu+H)+(ESI+),1H NMR (DMSO-ofe, 400 MHz,) : 10.03 (s, 1 H), 9.12 (s, 1 H), 8.11 (s, 1 H), 7.78 (s, 1 H), 7.52 (s, 1 H), 7.46 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.27-7.24 (m, 1 H), 4.46 (s, 2H), 1.51 (s, 9H)

[0459] Preparation of Intermediate 5.3 tert-butyl (8-chloro-6-(chlorosulfonyl)isoquinolin-3-yl)carbamate

[0460] To a solution of tert-butyl (6-(benzylthio)-8-chloroisoquinolin-3-yl)carbamate (280 mg, 0.419 mmol) in MeCN (3 mL) was added H2O (23 mg, 1.26 mmol), AcOH (75 mg, 1.26 mmol) and SO2CI2 (168 mg, 1 .26 mmol) at 0 °C. The mixture was stirred at 0°C for 1 h, then diluted with EtOAc (10 mL) and washed with brine(10 mL; 3x). The organic layer was collected, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum to give the product tert-butyl (8-chloro-6- (chlorosulfonyl)isoquinolin-3-yl)carbamate (30 mg, 0.0636 mmol, 15.2% yield) as a brown solid. The product was used for next step directly without any further purification.

[0461] Preparation of Intermediate 5.4 tert-butyl (8-chloro-6-(N-(1-methylcyclopropyl)sulfamoyl)isoquinolin-3-yl)carbamate

[0462] To a solution of 1-methylcyclopropan-1 -amine hydrochloride (17 mg, 0.159 mmol, HCI salt) and NaHCCh (0.046 mL, 0.398 mmol) in water (1 mL) was added a solution of tert-butyl (8-chloro-6- (chlorosulfonyl)isoquinolin-3-yl)carbamate (30 mg, 0.0795 mmol) in THF (1 mL) at 0°C. The mixture was stirred at 0°C for 1 h and then, diluted with EtOAc (5 mL). The organic layer was washed with brine (5 mL; 3x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The crude product was triturated with petroleum ether (1 mL) at 20°C for 10 min and filtered. The filter cake was collected and dried under vacuum to give the product tert-butyl (8-chloro-6-(N-(1- methylcyclopropyl)sulfamoyl)isoquinolin-3-yl)carbamate (10 mg, 0.0218 mmol, 27.5% yield) as a yellow solid.

[0463] RT 0.616 min (LCMS method 2); m / z 356.0 (M-tBu+H)+(ESP);1H NMR (MeOD, 400 MHz): 9.39 (s, 1 H), 8.37 (s, 1 H), 8.26 (s, 1 H), 7.81 (d, J = 1.6 Hz, 1 H), 1.58 (s, 9H), 1.17 (s, 3H), 0.77-0.69 (m, 2H), 0.52-0.42 (m, 2H)

[0464] Preparation of Intermediate 5.5 tert-butyl (8-(4-(dimethylcarbamoyl)piperazin-1 -yl)-6-(N-( 1 - methylcyclopropyl)sulfamoyl)isoquinolin-3-yl)carbamate

[0465] To a solution of N,N-dimethylpiperazine-1-carboxamide (6.1 mg, 0.0388 mmol) and tert-butyl (8- chloro-6-(N-(1-methylcyclopropyl)sulfamoyl)isoquinolin-3-yl)carbamate (8.0 mg, 0.0194 mmol) in dioxane (1 mL) was added CS2CO3 (13 mg, 0.0388 mmol) and Pd-PEPPSI-IPentCI o-picoline (1.9 mg, 0.00194 mmol). The mixture was degassed with N2 (3x) and stirred at 90 °C for 1 h. The resulting mixture was cooled down to 20 °C, filtered and the filtrate was concentrated under vacuum. The crude product was purified by preparative TLC (petroleum ether : ethyl acetate=0:1) to give the product tert-butyl (8-(4- (dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)isoquinolin-3-yl)carbamate (5.0 mg, 0.00845 mmol, 43.50 % yield) as a brown solid. RT 0.563 min (LCMS method 1); m / z 533.3 (M+H)+(ESI+);

[0466] Preparation of Intermediate 5.6

[0467] 4-(3-amino-6-(N-(1-methylcyclopropyl)sulfamoyl)isoquinolin-8-yl)-N,N-dimethylpiperazine-1- carboxamide

[0468] To a solution of tert-butyl (8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)isoquinolin-3-yl)carbamate (5.0 mg, 9.39 mol) in dioxane (1 mL) was added HCI / dioxane (0.0023 mL, 4 N).The mixture was stirred at 20 °C for 16 h and, then concentrated to dryness under vacuum. The resulting residue was basified by NaHCOa (aq., sat.) until pH=8 andthe solution was extracted with EtOAc (5 mL,2x). The combined organic layer was washed with brine (5 mL, 2x), separated, dried over anhydrous NaaSC , filtered and the filtrate was concentrated under vacuum to give the product 4-(3-amino-6-(N-(1-methylcyclopropyl)sulfamoyl)isoquinolin-8-yl)-N,N-dimethylpiperazine-1- carboxamide (3.0 mg, 0.00624 mmol, 66.50 % yield) as brown oil.

[0469] RT 0.406 min (LCMS method 1); m / z 433.3 (M+H)+(ESI+)

[0470] Preparation of Example 5

[0471] 4-(3-(bicyclo[1.1.0]butane-1-carboxamido)-6-(N-(1-methylcyclopropyl)sulfamoyl)isoquinolin-8-yl)- N,N-dimethylpiperazine-1-carboxamide

[0472] To a solution of methyl bicyclo[1 .1 .0]butane-1 -carboxylate (0.24 mL, 0.0694 mmol, 0.285 mmol / mL similar preparation as for intermediate 1.11) and 4-(3-amino-6-(N-(1- methylcyclopropyl)sulfamoyl)isoquinolin-8-yl)-N,N-dimethylpiperazine-1 -carboxamide (3.0 mg, 0.00694 mmol) in THF (0.1 mL) was added LIHMDS in THF (0.035 mL, 0.0347 mmol, 1 M) at 0 °C. The reaction mixture was warmed slowly to 20°C then, stirred at 20 °C for 1 h under N2, quenched with NH4CI (aq., sat., 5 mL) and extracted with EtOAc (5 mL, 2x). The combined organic layer was washed with water (3 mL; 3x), dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting residue was purified by preparative TLC (petroleum etherethyl acetate=0:1) to give the product 4-(3- (bicyclo[1.1.0]butane-1-carboxamido)-6-(N-(1-methylcyclopropyl)sulfamoyl)isoquinolin-8-yl)-N,N- dimethylpiperazine-1 -carboxamide (2.0 mg, 0.00384 mmol, 55.30 % yield) as a brown solid.

[0473] RT 0.484 (LCMS method 1); m / z 513.3 (M+H)+(ESI+);1H NMR (CDCI3,400 MHz) : 9.29 (s, 1 H), 8.63 (s, 1 H), 8.32 (br s, 1 H), 8.05 (s, 1 H), 7.32 (d, J = 1.6 Hz, 1 H), 5.17 (s, 1 H), 3.55-3.50 (m, 4H), 3.22- 3.17 (m, 4H), 2.91 (s, 6H), 2.51 (d, J = 3.6 Hz, 2H), 2.29 -2.26 (m, 1 H), 1.27 (d, J = 3.6 Hz, 2H), 1.24 (s, 3H), 0.83-0.79 (m, 2H), 0.54-0.49 (m, 2H)

[0474] Preparation of Intermediate 6.1 tert-butyl (6-(N-(1-methylcyclopropyl)sulfamoyl)-8-(2-oxa-7-azaspiro[3.5]nonan-7-yl)isoquinolin-3- yl)carbamate

[0475] To a solution of 2-oxa-7-azaspiro[3.5]nonane (12 mg, 0.0971 mmol) and tert-butyl (8-chloro-6-(N- (1-methylcyclopropyl)sulfamoyl)isoquinolin-3-yl)carbamate (20 mg, 0.0486 mmol) in dioxane (1 mL) was added CS2CO3 (32 mg, 0.0971 mmol) and Pd-PEPPSI-IPentCI o-picoline (4.7 mg, 0.00486 mmol). The mixture was degassed with N2 (3x) and stirred at 100 °C for 1 h. The resulting mixture was cooled down to 20 °C, filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether : ethyl acetate=2:1) to give the product tert-butyl (6-(N-(1- methylcyclopropyl)sulfamoyl)-8-(2-oxa-7-azaspiro[3.5]nonan-7-yl)isoquinolin-3-yl)carbamate (13 mg, 0.0196 mmol, 40.43 % yield) as an off-white solid.

[0476] RT 0.577 min (LCMS method 1); m / z 503.2 (M+H)+(ESI+);

[0477] Preparation of Intermediate 6.2

[0478] 3-amino-N-(1-methylcyclopropyl)-8-(2-oxa-7-azaspiro[3.5]nonan-7-yl)isoquinoline-6-sulfonamide

[0479] To a solution of tert-butyl (6-(N-(1-methylcyclopropyl)sulfamoyl)-8-(2-oxa-7-azaspiro[3.5]nonan-7- yl)isoquinolin-3-yl)carbamate (13 mg, 0.0259 mmol) in DCM (1 mL) was added TFA (0.20 mL, 0.0259 mmol). The mixture was stirred at 20 °C for 2 h and then, concentrated. The resultingresidue was diluted with MeOH (2 mL), basified with alkaline resin to pH=7, filtered and the filtrate was concentrated under vacuum to give the product 3-amino-N-(1-methylcyclopropyl)-8-(2-oxa-7-azaspiro[3.5]nonan-7- yl)isoquinoline-6-sulfonamide (10 mg, 0.0224 mmol, 86.45 % yield) as a brown solid.

[0480] RT 0.406 min (LCMS method 1); m / z 403.2 (M+H)+(ESI+)

[0481] Preparation of Example 6

[0482] N-(6-(N-(1-methylcyclopropyl)sulfamoyl)-8-(2-oxa-7-azaspiro[3.5]nonan-7-yl)isoquinolin-3- yl)bicyclo[1 .1 .0]butane-1 -carboxamide

[0483] At 0°C, to a solution of methyl bicyclo[1.1.0]butane-1 -carboxylate (0.69 mL, 0.196 mmol, 0.285 mmol / mL similar preparation as for intermediate 1 .11) was added 3-amino-N-(1-methylcyclopropyl)-8-(2- oxa-7-azaspiro[3.5]nonan-7-yl)isoquinoline-6-sulfonamide (10 mg, 0.0248 mmol), followed by addition of LiHMDS in THF (0.30 mL, 0.300 mmol, 1 M). The reaction mixture was warmed slowly to 20°C then, stirred at 20 °C for 1 h under N2;, quenched with NH4CI (aq., sat., 5 mL) and extracted with EtOAc (5 mL, 2x). The combined organic layer was washed with water (3 mL; 3x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether : ethyl acetate=0:1) to give the product N-(6-(N-(1-methylcyclopropyl)sulfamoyl)-8-(2-oxa-7- azaspiro[3.5]nonan-7-yl)isoquinolin-3-yl)bicyclo[1.1.0]butane-1 -carboxamide (8.8 mg, 0.0180 mmol, 72.39 % yield) as a yellow solid. RT 0.513 (LCMS method 1); m / z 483.1 (M+H)+(ESI+);1H NMR (CDCI3 ,400 MHz): 9.23 (s, 1 H), 8.60 (s, 1 H), 8.28 (s, 1 H), 8.01 (s, 1 H), 7.28 (s, 1 H), 5.18 (s, 1 H), 4.53-4.51 (m, 4H), 3.07-3.05 (m, 4H), 2.50 (d, J = 3.6 Hz, 2H), 2.28-2.25 (m, 1 H), 2.18-2.16 (m, 4H), 1.26 (s, 2H), 1.23 (s, 3H), 0.82-0.79 (m, 2H), 0.52-0.49 (m, 2H)

[0484] Preparation of Intermediate 9.1

[0485] Benzyl(7-bromonaphthalen-2-yl)sulfane

[0486] To a solution of 2,7-dibromonaphthalene (2 g, 6.99 mmol) and phenylmethanethiol (851.29 mg, 6.85 mmol) in dioxane (25 mL) was added DIPEA (1.81 g, 13.99 mmol), Pd2(dba)3 (640.45 mg, 699.39 pmol) and Xantphos (809.36 mg, 1 .40 mmol) at 20 °C. The mixture was stirred at 100 °C for 12 h under N2 and, then concentrated under vacuum at 45 °C. The resulting residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate= 1 :0 to 50:1) to give an impure product, which was further purified by reversed-phase flash chromatography (ISCO®; 330 g Flash Column: Spherical C1820- 45 pm; 100 A; mobile phase: A: 0.1% FA in water, B: MeCN; B%: 5%-95%, @ 80 mL / min) to give the product benzyl(7-bromonaphthalen-2-yl)sulfane (1.94 g, crude) as a yellow solid which was used in the next step without any further purification.

[0487] Preparation of Intermediate 9.2

[0488] 7-bromonaphthalene-2-sulfonyl chloride

[0489] To the mixture of 2-benzylsulfanyl-7-bromo-naphthalene (1 g, 3.04 mmol) in MeCN (10 mL), H2O (54.78 mg, 3.04 mmol) and AcOH (273.58 mg, 4.56 mmol) was added a solution of 1 ,3-dichloro-5,5- dimethyl-imidazolidine-2, 4-dione (1.08 g, 5.47 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then poured into water (30 mL) and extracted with EtOAc (30 mL, 2x).The combined organic layer was washed with brine (30 mL, 5x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the product 7-bromonaphthalene-2-sulfonyl chloride (1.13 g, crude) as a yellow gum which was used in the next step without any further purification.

[0490] Preparation of Intermediate 9.3

[0491] 7-bromo-N-(1-methylcyclopropyl)naphthalene-2-sulfonamide

[0492] To a solution of 7-bromonaphthalene-2-sulfonyl chloride (1.13 g, 3.68 mmol) in DCM (15 mL) were added DIPEA (1.90 g, 14.74 mmol) and 1-methylcyclopropan-1 -amine hydrochloride (455.89 mg, 4.24 mmol, HCI salt) at -10 °C .The mixture was stirred at -10 °C for 1 h under N2, then warmed to room temperature, quenched with H2O (30 mL) and extracted with EtOAc (30 m, 3x). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate: 1 / 0 to 5 / 1) to give the product 7-bromo-N-(1-methylcyclopropyl)naphthalene-2-sulfonamide (255 mg, 668.61 pmol, 18.14% yield, 89.21% purity) as a yellow solid.

[0493] RT 0.509 min (LCMS method 10); m / z 339.8 (M+H)+(ESI+);1H NMR (CDCI3, 400 MHz) 8.39 (s, 1 H), 8.144 (s, 1 H), 7.94 (d, J = 8.8 Hz, 1 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.80 (d, J = 8.8 Hz, 1 H), 7.72 (d, J = 8.8 Hz, 1 H), 4.95 (s, 1H), 1.22 (s, 3H), 0.78-0.76 (m, 2H), 0.49-0.47 (m, 2H).

[0494] Preparation of Intermediate 9.4

[0495] Tert-butyl (7-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-2-yl)carbamate BocNH2, t-Bu Xphos,

[0496] Pd2(dba)3, t-BuONa dioxane

[0497] To a solution of 7-bromo-N-(1-methylcyclopropyl)naphthalene-2-sulfonamide (150 mg, 393.30 pmol, 89.21% purity) in dioxane (4 mL) were added tert-butyl carbamate (77.47 mg, 661.31 pmol), t- BuXphos (37.44 mg, 88.17 pmol), t-BuONa (84.74 mg, 881.74 pmol) followed by Pd2(dba)3 (40.37 mg, 44.09 pmol) at 20 °C. The reaction mixture was degassed, purged with N2 (3x) and stirred at 20 °C for 12 h. Then, the mixture was diluted with EtOAc (5 mL), filtered and the filter cake was washed with EtOAc (5 mL, 3x). The combined filtrate was concentrated under vacuum to give a residue, which was purified by preparative TLC (Petroleum ether / Ethyl acetate = 3 / 1) to give the product tert-butyl (7-(N-(1- methylcyclopropyl)sulfamoyl)naphthalen-2-yl)carbamate (57 mg, 151.41 pmol, 34.34% yield) as a yellow gum.

[0498] RT 0.553 min (LCMS method 10); m / z 377.0 (M+H)+(ESI+);

[0499] Preparation of Intermediate 9.5

[0500] 7-amino-N-(1-methylcyclopropyl)naphthalene-2-sulfonamide

[0501] To a solution of tert-butyl (7-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-2-yl)carbamate (57 mg, 151.41 pmol) in DCM (3 mL) was added TFA (924.00 mg, 8.10 mmol) at 20 °C. The mixture was stirred at 20 °C for 2 hours and then, concentrated under vacuum at 20 °C. The resulting residue was basified to a pH value of 8 with aq. NaHCOs (sat.) and the product was extracted with EtOAc (20 mL, 2x). The combined organic layer was washed with brine (15 mL, 3x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the product 7-amino-N-(1-methylcyclopropyl)naphthalene-2- sulfonamide (50 mg, crude) as a yellow gum used in the next step without further purification.

[0502] 1H NMR (CD3OD, 400 MHz) 8.09 (d, J = 2.0 Hz, 1 H), 7.79 (d, J = 8.8 Hz, 1 H), 7.70 (d, J = 8.8 Hz, 1 H), 7.47 (dd, J = 8.8, 2.0 Hz, 1 H), 7.15 (dd, J = 8.8, 2.0 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 1.115 (s, 3H), 0.74-0.70 (m, 2H), 0.41-0.37 (m, 2H).

[0503] Preparation of Example 9

[0504] N-(7-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-2-yl)bicyclo[1.1.0]butane-1 -carboxamide

[0505] At 0°C, to a solution of 7-amino-N-(1-methylcyclopropyl)naphthalene-2-sulfonamide (49 mg, 177.31 pmol) in THF (2 mL) was added methyl bicyclo[1.1.0]butane-1 -carboxylate (1.58 mL, 177.31 pmol, 0.112 mmol / mL similar preparation as for intermediate 1.11) followed by addition of LiHMDS in THF (620.58 uL, 1 M) was added. The temperature was raised slowly to 20°C. The reaction mixture was stirred at 20 °C for 1 h under N2 atmosphere then, quenched with NH4CI (aq., sat., 20 mL) and extracted with EtOAc (15 mL, 3x). The combined organic layer was washed with brine (15 mL), dried over Na2SO4, filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10pm; mobile phase: A: 10 mmol / L NH4HCO3 in water, B: MeCN; B%: 28%-58%, 9 min) to give the product N-(7-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide (8 mg, 22.37 pmol, 12.62% yield, >99% purity) as a white solid.

[0506] RT 0.553 min (LCMS method 2); m / z 357.0 (M+H)+(ESI+);1H NMR (400 MHz, DMSO-cfe) 9.97 (s, 1H), 8.43 (s, 1H), 8.22 (s, 1 H), 8.12 (s, 1 H), 8.02 (d, J = 8.8 Hz, 1 H), 7.97 (d, J = 8.8 Hz, 1H), 7.87 (dd, J = 8.8, 2.0 Hz, 1 H), 7.67 (dd, J = 8.8, 2.0 Hz, 1 H), 2.53-2.51 (m, 2H), 2.34-2.29 (m, 1H), 1.22-1.06 (m, 2H), 1.03 (s, 3H), 0.61-0.57 (m, 2H), 0.37-0.34 (m, 2H).

[0507] Preparation of intermediate 12.1

[0508] 7-(benzylthio)-2-chloroquinoline

[0509] To a solution of 7-bromo-2-chloro-quinoline (4 g, 16.49 mmol) in dioxane (50 mL) was added Xantphos (1.91 g, 3.30 mmol), DIPEA (4.26 g, 32.98 mmol, 5.75 mL),Pd2(dba)3 (1.51 g, 1.65 mmol) and phenylmethanethiol (1 .84 g, 14.84 mmol, 1 .74 mL) at 20 °C. The mixture was degassed, purged with N2 (3x), then heated to 100°C and stirred for 12 h under N2. Then, the reaction mixture was cooled down to room temperature, quenched by H2O (60 mL) and extracted with EtOAc (60 mL; 3x). The combined organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (ISCO®; 330 g Flash Coulmn: Spherical C18 20-45 pm; 100 A, mobile phase: A: 0.1% TFA in water, B: MeCN; B%: 5%- 95%, @ 80 mL / min). The product solution was neutralized with NaHCOa (aq., sat., 30 mL) at 0°C and extracted with EtOAc (20 mL; 3x). The combined organic layer was washed with brine (30 mL; 3x), dried over anhydrous NaaSO-i, filtered and the filtrate was concentrated under reduced pressure to afford the product 7-(benzylthio)-2-chloroquinoline (850 mg, 1 .96 mmol, 7.0% yield, 66% purity) as a yellow solid.

[0510] RT 0.531 min (LCMS method 6); m / z 286.0 (M+H)+(ESI+)

[0511] Preparation of intermediate 12.2

[0512] 2-chloroquinoline-7-sulfonyl chloride

[0513] To a mixture of 7-benzylsulfanyl-2-chloro-quinoline (420 mg, 1 .47 mmol) in AcOH (8 mL) and H2O (4 mL) was added NCS (784.96 mg, 5.88 mmol) at 0°C. The mixture was warmed to 20°C, stirred for 1 h, then diluted with H2O (25 mL) at 20°C and extracted with EtOAc (20 mL; 3x). The combined organic layer was washed with brine (30 mL; 3x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford the product 2-chloroquinoline-7-sulfonyl chloride (700 mg, crude) as a yellow solid. The crude product was used for the next step directly.

[0514] RT 0.490 min (LCMS method 6); m / z 262.1 (M+H)+(ESI+)

[0515] Preparation of intermediate 12.3

[0516] 2-chloro-N-(1-methylcyclopropyl)quinoline-7-sulfonamide

[0517] To a mixture of 1-methylcyclopropan-1 -amine hydrochloride (122.10 mg, 1.13 mmol, HCI salt) and DIPEA (665.66 mg, 5.15 mmol, 897.12 pL) was added a solution of 2-chloroquinoline-7-sulfonyl chloride (450 mg, 1.72 mmol) in DCM (10 mL) drop-wise at 0°C. The mixture was warmed to 20 °C, stirred for 16 h and then, concentrated under reduced pressure. The resulting residue was poured into H2O (20 mL) and extracted with EtOAc (20 mL; 3x). The combined organic layer was washed with brine (30 mL; 3x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, mobile phase: A:, Ethyl acetate; B: Petroleum ether; A%: 0% to 50%, @ 35 mL / min) to afford the product 2-chloro-N-(1-methylcyclopropyl)quinoline-7-sulfonamide (110 mg, 303.23 pmol, 17.66% yield, 81.8% purity) as a white solid.

[0518] RT 0.437 min (LCMS method 6); m / z 297.2 (M+H)+(ESI+)

[0519] Preparation of intermediate 12.4 tert-butyl (7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate

[0520] To a mixture of 2-chloro-N-(1-methylcyclopropyl)quinoline-7-sulfonamide (40 mg, 134.78 pmol) and tert-butyl carbamate (18.95 mg, 161.74 pmol) in dioxane (3 mL) was added CS2CO3 (87.83 mg, 269.57 pmol), Xantphos (15.60 mg, 26.96 pmol) and Pd2(dba)3 (12.34 mg, 13.48 pmol). The mixture was degassed, purged with N2 (3x) heated to 95°C for 3 h, and concentrated under reduced pressure. The resulting residue was diluted with MeOH (1 mL) and purified by preparative TLC (petroleum ether : ethyl acetate = 1 : 1) to give the product tert-butyl (7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate (20 mg, 49.66 pmol, 36.84% yield, 93.7% purity) as a yellow solid.

[0521] RT 0.471 min (LCMS method 6); m / z 322.3 (M-t-Bu+H)+(ESI+);1H NMR (DMSO-cfe, 400 MHz):10.32 (s, 1 H), 8.40 (d, J = 9.2 Hz, 1 H), 8.25 (s, 1 H), 8.16 (d, J = 9.2 Hz, 1 H), 8.13 (d, J = 1.6 Hz, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.74 (dd, J = 8.4, 1 .6 Hz, 1 H), 1 .51 (s, 9 H), 1 .05 (s, 3 H), 0.56-0.66 (m, 2 H), 0.31-0.43 (m, 2 H).

[0522] Preparation of intermediate 12.5

[0523] 2-amino-N-(1-methylcyclopropyl)quinoline-7-sulfonamide A solution of tert-butyl (7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate (90 mg, 0.238 mmol) in HCI / dioxane (2.0 mL, 8.00 mmol) was stirred at 25 °C for 24 h. The reaction mixture was then concentrated under vacuum, diluted with EtOAc (20 mL) and washed with aq. NaHCOs (sat., 20mL). The organic layer was separated, washed with brine (30mL) and concentrated under vacuum to give the product 2-amino-N-(1-methylcyclopropyl)quinoline-7-sulfonamide (61 mg, 0.196 mmol, 89% purity, 82.10 % yield) as a yellow solid.

[0524] RT 0.248 min (LCMS method 7); m / z 277.9 (M+H)+(ESI+);1H NMR (CDCI3, 400 MHz): 8.25 (s, 1 H), 7.94 (d, J = 8.8 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 1 H), 7.69 (dd, J = 8.4 Hz, J = 2.0 Hz, 1 H), 6.88 (d, J = 8.8 Hz, 1 H), 5.20 (br, 2H), 5.04 (s, 1H), 1.22 (s, 3H), 0.83-0.80 (m, 2H), 0.51-0.46 (m, 2H).

[0525] Preparation of Example 12

[0526] N-(7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1.1.0]butane-1 -carboxamide

[0527] To a solution of [1.1.0]butane-1 -carboxylate (0.38 mL, 141 pmol, 0.372 mmol / mL, similar preparation as for intermediate 1.11) was added 2-amino-N-(1-methylcyclopropyl)quinoline-7- sulfonamide (30 mg, 0.108 mmol) in THF (0.5 mL). The mixture was degassed, purged with N2 (3x), and then LiHMDS in THF (1 M, 378.60 pL) was added dropwise via syringe over 1 min at 0°C . The mixture was warmed to 25°C, stirred for 1 h and then, poured into water (20 mL). The aqueous layer was extracted with ethyl acetate (10 mL, 2x). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 mm*10 pm; mobile phase: A: 0.079% NH4HCO3 in water, B: MeCN; B%: 25%-55%, 8 min) and lyophilized directly to afford the product N-(7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1 .1 .0]butane-1 -carboxamide (3.50 mg, 9.8 pmol, 9.05% yield, 97.5% purity) as a white solid.

[0528] RT 0.399 min (LCMS method 6); m / z 358.3 (M+H)+(ESP);1H NMR (400 MHz, DMSO-cfe) 10.67 (s, 1 H), 8.48-8.36 (m, 2H), 8.27 (s, 1 H), 8.18 (d, J = 1.6 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1 H), 7.77 (dd, J = 8.4, 1.6 Hz, 1 H), 2.57 (d, J = 3.6 Hz, 2H), 2.46-2.39 (m, 1 H), 1.13 (d, J = 2.4 Hz, 2H), 1.05 (s, 3H), 0.62- 0.58 (m, 2H), 0.40-0.35 (m, 2H).

[0529] Preparation of Example 13

[0530] N-(7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)acrylamide formate

[0531] To the mixture of 2-chloro-N-(1-methylcyclopropyl)quinoline-7-sulfonamide (50 mg, 168.48 pmol), acrylamide (11.98 mg, 168.48 pmol, 11.63 pL), CS2CO3 (109.79 mg, 336.96 pmol) in dioxane (0.5 mL) was added Pd-PEPPSI-IPentCI o-picoline (2-methylpyridine) (16.39 mg, 16.85 pmol) in a glove box. The mixture was stirred at 80 °C for 2 h under N2. In parallel, six reactions were conducted with the same protocol on the same scale of 2-chloro-N-(1-methylcyclopropyl)quinoline-7-sulfonamide. The combined resulting mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL, 2x). The combined organic layer was washed with brine (30 mL, 2x), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ethenethyl acetate = 2:1). The impure residue was further purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 pm; mobile phase: A: 0.225% formic acid in water,, B: MeCN; B%: 23%- 53%, 10 min) and lyophilized directly to give the product N-(7-(N-(1 -methylcyclopropyl)sulfamoyl)quinolin- 2-yl)acrylamide formate (4.46 mg, 11.70 pmol, 1.16% yield, 99% purity, FA salt) as a white solid.

[0532] RT 0.626 min (LCMS: Method 8); m / z 331.8 (M +H)+(ESI+).1H NMR (DMSO-cfe, 400 MHz):11.22 (s, 1 H), 8.56 (d, J = 9.2 Hz, 1 H), 8.50 (d, J = 9.2 Hz, 1 H), 8.32 (s, 1 H), 8.19 (d, J = 1 .6 Hz, 1 H), 8.15 (d, J = 8.4 Hz, 1 H), 7.80 (dd, J = 8.4, 1.6 Hz, 1 H), 6.70 (dd, J = 17.2, 10.0 Hz, 1 H), 6.40 (dd, J = 17.2, 1.6 Hz, 1H), 5.87 (dd, J = 10.0, 1.6 Hz, 1 H), 1.06 (s, 3H), 0.66-0.56 (m, 2H), 0.44-0.34 (m, 2H).

[0533] Preparation of Intermediate 14.1

[0534] Tert-butyl (3S,5S)-4-(dimethylcarbamoyl)-3,5-dimethylpiperazine-1-carboxylat

[0535] To a solution of tert-butyl (3S,5S)-3,5-dimethylpiperazine-1-carboxylate (330 mg, 1.54 mmol) and TEA (0.82 mL, 4.62 mmol) in DCM (3 mL) at 0 °C was added dimethylcarbamic chloride (232 mg, 2.16 mmol). The mixture was stirred at 25 °C for 1 hr, then poured into aq. NaHCOs (sat., 20 mL) and extracted with EtOAc (10 mL, 3x). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the product tert-butyl (3S,5S)-4-(dimethylcarbamoyl)-3,5- dimethylpiperazine-1 -carboxylate (360 mg, 1.26 mmol, 81.92 % yield) as yellow oil.

[0536] 1H NMR (DMSO-C / 6, 400 MHz): 3.29-2.22 (m, 1 H), 3.14-3.11 (m, 1H), 3.09 (s, 6H), 2.99-2.97 (m, 2H), 2.85-2.83 (m, 2H), 1.39 (s, 9H), 1.01 (d, J = 6.4 Hz, 6H). Preparation of Intermediate 14.2

[0537] (2S,6S)-N, N, 2, 6-tetramethylpiperazine-1-carboxamide hydrochloride

[0538] To a solution of tert-butyl (3S,5S)-4-(dimethylcarbamoyl)-3,5-dimethylpiperazine-1 -carboxylate (360 mg, 1 .26 mmol) in DCM (0.5 mL) was added HCI / dioxane (0.5 mL, 4 M). The mixture was stirred at 25 °C for 2 hrs and concentrated under vacuum. The resulting residue was triturated with methyl tert-butyl ether (3 mL, 3x), then filtered and the filter cake was dried under vacuum to give product (2S ,6S)-N , N ,2,6- tetramethylpiperazine-1 -carboxamide hydrochloride (270 mg, 1.22 mmol, 96.53 % yield, HCI salt) as a white solid.

[0539] 1H NMR (DMSO-cfe, 400 MHz): 9.25 (br s, 1 H), 3.48-3.44 (m, 2 H), 3.35-3.30 (m, 4 H), 2.85 (s, 6 H), 1.41 (d, J = 6.4 Hz, 6 H).

[0540] Preparation of Intermediate 14.3

[0541] Tert-butyl (7 -(benzylthio) -5-bromoqui noli n-2-y I) (tert-butoxy carbonyl) carbarn ate

[0542] To a solution of 7-(benzylthio)-5-bromoquinolin-2-amine (20.00 g, 57.9 mmol), DIPEA (21 mL, 116 mmol) and DMAP (1.42 g, 11.6 mmol) in DCM (200 mL) was added (Boc)2O (37.93 g, 174 mmol). The mixture was stirred at 20 °C for 16 h, then poured into water (500 mL) and extracted with ethyl acetate (300 mL; 3x). The combined organic layer was washed with brine (200 mL; 3x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO; 220 g SepaFlash Silica Flash Column, Eluent of 10~50% Ethyl acetate / Petroleum ethergradient @ 100 mL / min) and concentrated under reduced pressure to give the product tert-butyl (7- (benzylthio)-5-bromoquinolin-2-yl)(tert-butoxycarbonyl)carbamate (21.30 g, 33.6 mmol, 58.03 % yield, 86% purity) was obtained as a yellow oil.

[0543] RT 0.746 min (LCMS Method 9); m / z 547.0 (M+H)+(ESI+)

[0544] Preparation of Intermediate 14.4

[0545] Tert-butyl (5-bromo-7-(chlorosulfonyl)quinolin-2-yl)(tert-butoxycarbonyl)carbamate

[0546] To a solution of tert-butyl (7-(benzylthio)-5-bromoquinolin-2-yl)(tert-butoxycarbonyl)carbamate (20.00 g, 36.7 mmol), AcOH (4.2 mL, 73.3 mmol) and H2O (0.66 mL, 36.7 mmol) in MeCN (200 mL) at 0°C was added 1 ,3-dichloro-5,5-dimethylimidazolidine-2, 4-dione (14.45 g, 73.3 mmol) in batches over 30 min. The reaction was stirred at 0 °C for 15 min, then poured into ice-water (200 mL) and extracted with DCM (200 mL; 3x). The combined organic layer was washed with brine (100 mL; 3x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the product tert-butyl (5-bromo-7- (chlorosulfonyl)quinolin-2-yl)(tert-butoxycarbonyl)carbamate (19.00 g, crude) as a yellow oil which was directly used in the next step without any further purification.

[0547] RT 0.862 min (LCMS Method 2); m / z 366.9 (M-Boc-tBu+H)+(ESI+)

[0548] Preparation of Intermediate 14.5

[0549] Tert-butyl (5-bromo-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)(tert- butoxycarbonyljcarbamate

[0550] To a solution of tert-butyl (5-bromo-7-(chlorosulfonyl)quinolin-2-yl)(tert-butoxycarbonyl)carbamate (19.00 g, crude) in DCM (190 mL) at 0 °C was added 1-methylcyclopropan-1 -amine hydrochloride (5.88 g, 54.6 mmol) and DIPEA (25 mL, 146 mmol). Then, the mixture was stirred at 0 °C for 0.5 h and concentrated under vacuum. The residue was purified by reversed-phase flash (ISCO®; 80 g Flash Column Welch Ultimate XB_C18 20-40 pm; 120 A, mobile phase: A: 0.1% FA in water, B: MeCN; B%: 10%-30% @ 60 mL / min) to give the product tert-butyl (5-bromo-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)(tert-butoxycarbonyl)carbamate (12.70 g, 18.0 mmol, 40.02 % yield, 79% purity) as a white solid.

[0551] RT 0.670 min (LCMS Method 9); m / z 556.2 (M+H)+(ESI+)

[0552] Preparation of Intermediate 14.6

[0553] Tert-butyl (tert-butoxycarbonyl)(5-((3S,5S)-4-(dimethylcarbamoyl)-3,5-dimethylpiperazin-1- yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate

[0554]

[0555] To a solution of tert-butyl (5-bromo-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)(tert- butoxycarbonyl)carbamate (240 mg, 0.431 mmol) in 1 ,4-dioxane (4 mL) was added (2S,6S)-N,N,2,6- tetramethylpiperazine-1 -carboxamide hydrochloride (191 mg, 0.863 mmol, HCI salt), CS2CO3 (562 mg, 1.73 mmol), Pd-PEPPSI-IPentCI o-picoline (2-methylpyridine) (42 mg, 0.0431 mmol). The mixture was degassed with Nz (3x) and stirred at 100 °C for 1 h under N2. The resulting mixture was cooled to room temperature, diluted with H2O (20 mL) and extracted with EtOAc (20 mL, 2x). The combined organic layer was washed with brine (20 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, mobile phase: A: Ethyl acetate, B: Petroleum ether; A%:0 to 50%, @ 30 mL / min) to give the product tert-butyl (tert-butoxycarbonyl)(5-((3S,5S)-4-(dimethylcarbamoyl)-3,5-dimethylpiperazin-1 -yl)- 7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate (80 mg, 0.121 mmol, 28.07 % yield) as a yellow solid

[0556] RT 0.554 min (LCMS Method 9); m / z 561 . (M+H-Boc)+(ESI+);

[0557] Preparation of Intermediate 147

[0558] (2S,6S)-4-(2-amino-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N,2,6- tetramethylpiperazine-1-carboxamide

[0559] To a mixture of tert-butyl (tert-butoxycarbonyl)(5-((3S,5S)-4-(dimethylcarbamoyl)-3,5- dimethylpiperazin-1 -yl)-7-(N-(1 -methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate (80 mg, 0.121 mmol) in DCM (0.2 mL) was added TFA (0.1 mL, 0.2 mmol). Then, the reaction mixture was stirred at 20 °C for 1 h, adjusted to pH 9 with aq. NaHCOs (sat.) and extracted with ethyl acetate (10 mL, 2x). The combined organic layer was washed with brine (20 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give product (2S,6S)-4-(2-amino-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N, N, 2, 6-tetramethylpiperazine-1 -carboxamide (35 mg, 0.076 mmol, 62.77 % yield) as a yellow solid.

[0560] RT 0.434 min (LCMS Method 9); m / z 461.2 (M+H)+ (ESI+);

[0561] Preparation of Example 14

[0562] (2S,6S)-4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N,2,6-tetramethylpiperazine-1-carboxamide

[0563] To a solution of (2S,6S)-4-(2-amino-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N,2,6- tetramethylpiperazine-1 -carboxamide (20 mg, 0.0434 mmol) in THF (0.3 mL) was added methyl bicyclo[1.1.0]butane-1 -carboxylate (0.29 mL, 0.109 mmol, 0.372 mmol / mL, similar preparation as for intermediate 1.11), followed by addition of LiHMDS in THF (0.22 mL, 0.217 mmol, 1 M) at 0°C. The mixture was stirred for 25 °C under N2 for 1 h, then quenched with aq. NH4CI (sat.) and extracted with ethyl acetate (30 mL, 3x). The combined organic layer was washed with brine (30 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*25 mm*10 pm; mobile phase: A: 10 mM aqueous solution of NH4HCO3, B: MeCN; B%: 38%-68%, 9 min) and lyophilized directly to give the product (2S,6S)- 4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N,2,6- tetramethylpiperazine-1 -carboxamide (7.0 mg, 0.0128 mmol, 29.59 % yield, 99.37% purity) as a white solid.

[0564] RT 0.517 min (LCMS Method 9); m / z 541.3 (M+H)+(ESI+); RT 1.442 min, (SFC method 4); ee% 100%;1HNMR (DMSO-cfe, 400 MHz): 10.65 (s, 1 H), 8.54 (d, J = 9.2 Hz, 1H), 8.37 (d, J = 9.2 Hz, 1 H), 8.22 (s, 1H), 7.88 (d, J= 1.6 Hz, 1 H), 7.34 (d, J = 1.6 Hz, 1H), 3.62-3.72 (m, 2H), 3.11-3.21 (m, 2H), 2.90 (s, 6 H), 2.79-2.88 (m, 2H), 2.57 (d, J= 2.8 Hz, 2H), 2.38-2.43 (m, 1 H), 1.19 (d, J = 6.4 Hz, 6 H), 1.12 (d, J = 2.8 Hz, 2H), 1 .03 (s, 3H), 0.58-0.67 (m, 2H), 0.35-0.42 (m, 2 H)

[0565] Preparation of Intermediate 16.1 tert-butyl (S)-(tert-butoxycarbonyl)(5-(4-(dimethylcarbamoyl)-3-methylpiperazin-1-yl)-7-(N- (1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate

[0566] To a solution of tert-butyl (5-bromo-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)(tert- butoxycarbonyl)carbamate (200 mg, 0.359 mmol) in 1 ,4-Dioxane (3 mL) were added (S)-N,N,2- trimethylpiperazine-1-carboxamide hydrochloride (149 mg, 0.719 mmol, HCI salt), CS2CO3 (4.00 eq, 468 mg, 1.44 mmol) and Pd-PEPPSI-IPentCI o-picoline (2-methylpyridine) (35 mg, 0.0359 mmol). The mixture was degassed with N2 (3x), stirred at 100 °C for 1 h under N2, then cooled to room temperature, diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL, 2x). The combined organic layer was washed with brine (20 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, mobile phase: A: ethyl acetate, B: petroleum ether; A%:0 to 50%, @ 30 mL / min) to give the product tert-butyl (S)-(tert-butoxycarbonyl)(5-(4-(dimethylcarbamoyl)-3-methylpiperazin-1 -yl)-7-(N-( 1 - methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate (35 mg, 0.0541 mmol, 15.06 % yield) as a yellow solid.

[0567] RT 0.608 min (LCMS Method 9); m / z 647.4 (M+H)+(ESI+);

[0568] Preparation of Intermediate 16.2 (S)-4-(2-amino-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N,2- trimethylpiperazine-1-carboxamide To the mixture of tert-butyl (S)-(tert-butoxycarbonyl)(5-(4-(dimethylcarbamoyl)-3-methylpiperazin- 1-yl)-7-(N-(1 -methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate (35 mg, 0.0541 mmol) in DCM (1 mL) was added TFA (0.5 mL, 1 .00 mmol). The resulting mixture was stirred at 20°C for 1 h. Then, the pH was adjusted to 9 with aq. NaHCOa (sat.,) and the reaction mixture was extracted with ethyl acetate (10 mL, 2x). The combined organic layer was washed with brine (20 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give product (S)-4-(2-amino-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N,2-trimethylpiperazine-1 -carboxamide (24 mg, 0.0537 mmol, 99.32 % yield) as a yellow solid.

[0569] RT 0.411 min (LCMS Method 9); m / z 447.1 (M+H)+ (ESI+);

[0570] Preparation of Example 16

[0571] (S)-4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N,2-trimethylpiperazine-1-carboxamide

[0572] At 0°C, to a solution of (S)-4-(2-amino-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N,2- trimethylpiperazine-1 -carboxamide (24 mg, 0.0537 mmol) in THF (0.3 mL) was added methyl bicyclo[1.1.0]butane-1 -carboxylate (0.36 mL, 0.134 mmol, 0.372 mmol / mL, similar preparation as for intermediate 1.11) followed by addition of LiHMDS in THF (0.27 mL, 0.269 mmol, 1 M). The mixture was warmed to 25 °C, stirred under N2 for 1 h, then quenched with slow addition of aq. NH4CI (sat., 20 mL) and extracted with ethyl acetate (30 mL, 3x). The combined organic layer was washed with brine (30 mL, 2x), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*10 pm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B%: 39%-64%, 9 min) and lyophilized directly to give the product (S)-4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N,2-trimethylpiperazine-1 -carboxamide (4.5 mg, 0.00827 mmol, 15.38 % yield, 97.84% purity) as a white solid.

[0573] RT 0.505 min (LCMS Method 9); m / z 527.2 (M+H)+(ESI+); RT 2.253 min (SFC method 8); ee% 100%;1HNMR (DMSO-cfe, 400 MHz): 11.12 (s, 1 H), 9.01 (d, J = 9.2 Hz, 1H), 8.85 (d, J = 9.2 Hz, 1 H), 8.67 (s, 1 H), 8.35 (s, 1 H), 7.81 (s, 1 H), 4.34-4.44 (m, 1 H), 3.86-3.99 (m, 2H), 3.62-3.71 (m, 1 H), 3.50- 3.58 (m, 1 H), 3.42-3.48 (m, 1 H), 3.28-3.36 (m, 1 H), 3.26 (s, 6 H), 3.03 (d, J = 2.8 Hz, 2H), 2.85-2.90 (m, 1 H), 1 .90 (d, J = 6.80 Hz, 3H), 1 .59 (d, J = 2.8 Hz, 2H), 1 .50 (s, 3H), 1 .03-1 .14 (m, 2H), 0.79-0.88 (m, 2 H)

[0574] Preparation of Intermediate 17.1 tert-butyl (S)-(tert-butoxycarbonyl)(5-(4-isobutyryl-3-methylpiperazin-1-yl)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate

[0575] To a solution of tert-butyl (5-bromo-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)(tert- butoxycarbonyl)carbamate (100 mg, 0.180 mmol) in 1 ,4-dioxane (0.4 mL) were added (S)-2-methyl-1-(2- methylpiperazin-1-yl)propan-1-one hydrochloride (74 mg, 0.359 mmol, HCI salt), CS2CO3 (234 mg, 0.719 mmol) and Pd-PEPPSI-IPentCI o-picoline (2-methylpyridine) (17 mg, 0.0180 mmol). The mixture was degassed with N2 (3x), stirred at 100 °C for 1 h, then poured into H2O (20 mL) and extracted with EtOAc (20 mL, 2x). The combined organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash Silica Flash Column, mobile phase: A: ethyl acetate, B: petroleum ether; A%:20% to 55%, @ 35 mL / min) to give the product tert-butyl (S)-(tert-butoxycarbonyl)(5-(4- isobuty ryl-3-methyl pi perazi n- 1 -yl)-7-(N -( 1 -methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate (45 mg, 0.0467 mmol, 25.98 % yield, 67% purity) as a yellow oil.

[0576] RT 0.619 min (LCMS Method 9); m / z 646.3(M+H)+(ESI+)

[0577] Preparation of Intermediate 17.5

[0578] (S)-2-amino-5-(4-isobutyryl-3-methylpiperazin-1-yl)-N-(1-methylcyclopropyl)quinoline-7- sulfonamide

[0579]

[0580] To a solution of tert-butyl (S)-(tert-butoxycarbonyl)(5-(4-isobutyryl-3-methylpiperazin-1-yl)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate (45 mg, 0.0460 mmol) in DCM (1 mL) was added TFA (2.0 ml, 0.230 mmol) and stirred at 20 °C for 30 min. The resulting mixture was poured into NaHCCh (20 mL) and extracted with EA (20 mL, 3x). The combined organic layers were washed with brine (20 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the product (S)-2-amino-5-(4-isobutyryl-3-methylpiperazin-1-yl)-N-(1-methylcyclopropyl)quinoline-7-sulfonamide (20 mg, 0.0364 mmol, 79.06 % yield, 81% purity) as a brown solid.

[0581] RT 0.431 min (LCMS Method 9); m / z 446.2 (M+H)+(ESI+)

[0582] Preparation of Example 17

[0583] (S)-N-(5-(4-isobutyryl-3-methylpiperazin-1-yl)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1.1.0]butane-1 -carboxamide

[0584] At 0°C, to a solution of (S)-2-amino-5-(4-isobutyryl-3-methylpiperazin-1-yl)-N-(1- methylcyclopropyl)quinoline-7-sulfonamide (20 mg, 0.0364 mmol) in THF (0.2 mL) was added methyl bicyclo[1.1.0]butane-1 -carboxylate (0.0727 mmol, similar preparation as for intermediate 1.11 ) in THF (0.3 mL), followed by addition of LiHMDS (0.073 mL, 0.0727 mmol, 1 M in THF) . The reaction mixture was stirred at 0°C for 1 h, then poured into aq. NH4CI (sat., 30 mL) and extracted with EtOAc (20 mL, 3x). The combined organic layer was washed with brine (20 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm* 5 pm; mobile phase: A: 10 mmol NH4HCO3 in water, B: MeCN; B%: 32%-68%, 10 min) and lyophilized to give the product (S)-N-(5-(4-isobutyryl-3-methylpiperazin-1-yl)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1.1.0]butane-1 -carboxamide (1.7 mg, 0.00312 mmol, 8.58 % yield, 96.5% purity) as a white solid.

[0585] RT 0.519 min (LCMS Method 9); m / z 526.3 (M+H)+(ESI+); RT 1.530 min (SFC: Method 4); ee: 100%;1H NMR (DMSO-d6, 400 MHz): 10.69(s, 1 H), 8.58 (d, J = 9.6 Hz, 1 H), 8.39 (d, J = 9.6 Hz, 1 H), 8.20 (br s, 1 H), 7.89 (s, 1 H), 7.33 (s, 1 H), 4.78-4.36 (m, 1H), 3.98-3.69 (m, 1 H), 3.26-3.10 (m, 2H), 2.92 - 2.87 (m, 3H), 2.70-2.65 (m, 1 H), 2.57-2.50 (m, 2H), 2.41-2.40 (m, 1 H), 1.55-1.36 (m, 3H), 1.20-1.15 (m, 2H), 1.10 (s, 3H), 1.08-1.00 (m, 6H), 0.65-0.57 (m, 2H), 0.42-0.34 (m, 2H).

[0586] Preparation of Intermediate 18.1 tert-butyl (tert-butoxycarbonyl)(5-(4-isobutyrylpiperazin-1-yl)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate

[0587] To a solution of tert-butyl (5-bromo-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)(tert- butoxycarbonyl)carbamate (100 mg, 0.180 mmol) in 1 ,4-dioxane (1 mL) were added 2-methyl-1- (piperazin-1 -yl)propan-1 -one (56 mg, 0.359 mmol), CS2CO3 (234 mg, 0.719 mmol) and Pd-PEPPSI-IPent Cl o-picoline (2-methylpyridine) (17 mg, 0.0180 mmol). The reaction mixture was degassed under vacuum, purged with N2 (3x) and stirred at 100 °C for 1 h under N2. The mixture was then cooled to room temperature, diluted with H2O (10 mL) and extracted with EtOAc (10 mL, 2x). The combined organic layer was washed with brine (2 mL, 3x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, mobile phase: A: ethyl acetate, B: petroleum ether; A%:0 to 50%, @ 30 mL / min) to give the product tertbutyl (tert-butoxycarbonyl)(5-(4-isobutyrylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)carbamate (60 mg, 0.0682 mmol, 37.94 % yield, 71 .79% purity) as a yellow solid.

[0588] RT 0.600 min (LCMS Method 4); m / z 632.3 (M+H)+(ESI+).

[0589] Preparation of Intermediate 18.2

[0590] 2-amino-5-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclopropyl)quinoline-7-sulfonamide

[0591] 2,2,2-trifluoroacetate

[0592]

[0593] To a solution of tert-butyl (tert-butoxycarbonyl)(5-(4-isobutyrylpiperazin-1-yl)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate (60 mg, 0.0682 mmol) in DCM (1 mL) was added TFA ( 0.20 mL, 2.87 mmol). The reaction mixture was stirred at 25 °C for 2 h, then diluted with H2O (20 mL) and extracted with DCM (20 mL; 2x). The combined organic layer was washed with brine (2 mL; 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the product 2-amino-5-(4- isobutyryl pi perazi n-1 -yl)-N-( 1 -methylcyclopropyl)q u i noline-7-su Ifonamide 2,2,2-trifluoroacetate (50 mg, crude) as a yellow solid which was used directly in the next step without further purification.

[0594] RT 0.415 min (LCMS Method 4); m / z 432.1 (M+H)+(ESI+).

[0595] Preparation of Example 18

[0596] N-(5-(4-isobutyrylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- y I) bicyclo[1.1.0] butane-1 -carboxamide

[0597] At 0 °C, to a solution of 2-amino-5-(4-isobutyrylpiperazin-1 -yl)-N-(1 -methylcyclopropyl)quinoline-7- sulfonamide 2,2,2-trifluoroacetate (50 mg, crude) in THF (0.2 mL) was added methyl bicyclo[1 .1 .0]butane- 1-carboxylate (0.232 mmol, similar preparation as for intermediate 1.11 ) in THF (0.3 mL), followed by addition of LiHMDS (0.23 mL, 0.232 mmol, 1 M in THF) . The reaction mixture was stirred at 0 °C for 1 h, then quenched with aqeous NH4CI (sat., 5 mL) and extracted with ethyl acetate (10 mL; 3x). The combined organic layer was washed with brine (2 mL; 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 mm* 5 m; mobile phase: A: 10 mM aqueous solution of NH4HCO3, B: MeCN; B%: 25%-55%, 10 min) and lyophilized directly to give the product N-(5-(4-isobutyrylpiperazin-1-yl)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1.1.0]butane-1 -carboxamide (11.67 mg, 0.0228 mmol, 19.69 % yield) as a white solid.

[0598] RT 0.491 min (LCMS Method 4); m / z 512.2 (M+H)+ (ESI+); 1 HNMR (DMSO-d6, 400 MHz): 8.54 (d, J=9.2 Hz, 1 H), 8.49 (d, J=9.2 Hz, 1 H), 8.32 (s, 1 H), 8.10 (s, 1 H) 7.35 (s, 1 H), 5.01 (s, 1 H), 3.70- 4.12 (m, 4 H), 3.11-3.05 (m, 4 H), 2.90-2.84 (m, 1 H), 2.53 (d, J=3.6 Hz, 2 H), 2.34-2.30 (m, 1 H), 1 .30 (d, J=3.6 Hz, 2 H), 1.25 (s, 3 H), 1.20 (d, J=6.8 Hz, 6 H), 0.79-0.87 (m, 2 H), 0.47-0.55 (m, 2 H)

[0599] Preparation of Example 19

[0600] 4-(2-acrylamido-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N- dimethylpiperazine-1-carboxamide

[0601] To a solution of 4-(2-amino-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N- dimethylpiperazine-1 -carboxamide (20 mg, 0.0462 mmol) in DCM (0.5 mL) was added TEA (0.038 mL,

[0602] 0.277 mmol) and acrylic anhydride (5.8 mg, 0.0462 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hour and then concentrated under vacuum directly at 30 °C. The resulting residue was dissolved in MeCN (2 mL) and water (0.5 mL), then purified by preparative HPLC (column: Welch Ultimate C18 150*25 mm*5 pm; mobile phase: A: 10 mmol N^HCOa in water, B: MeCN; B%: 25%-55%, 10 min) and lyophilized to give the product 4-(2-acrylamido-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N- di methylpiperazine- 1 -carboxamide (1 .4 mg, 0.00269 mmol, 97.55% purity, 5.82 % yield) as a yellow solid.

[0603] RT 0.385 min (LCMS Method 5); m / z 487.3 (M+H)+(ESI+);1H NMR (DMSO-cfe,400 MHz): 11.18 (s, 1H), 8.59 (d, J = 8 Hz, 1 H), 8.51 (d, J = 8 Hz, 1 H), 8.22 (s, 1H), 7.87 (s, 1H), 7.37 (s, 1 H), 6.68 (dd, J = 16.8, 9.6 Hz, 1 H), 6.41 (d, J = 16.8 Hz, 1 H), 5.86 (d, J = 9.6 Hz, 1 H), 3.45-3.40 (m, 4H), 3.15-3.05 (m, 4H), 2.80 (s, 6H), 1.04 (s, 3H), 0.66-0.61 (m, 2H), 0.43-0.35 (m, 2H). Preparation of Example 20

[0604] 4-(2-(2-fluoroacrylamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N- d imethy I pi perazine-1 carboxamide

[0605] To a solution of 4-(2-amino-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N- dimethylpiperazine-1 -carboxamide (30 mg, 0.0694 mmol) in THF (1 mL) was added LiHMDS in THF (0.35 mL, 0.347 mmol, 1 M) at 0 °C and the mixture was stirred at 20 °C for 0.5 h. Then, methyl 2-fluoroacrylate (22 mg, 0.208 mmol) was added. The reaction mixture was heated to 40 °C, stirred for 1 h, then poured into aq. NH4CI (sat., 60 mL) at 0 °C and extracted with ethyl acetate (30 mL, 2x). The combined organic layer was washed with brine (20 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: Welch Ultimate C18 150*25 mm*5 pm; mobile phase: A: 10 mmol NFUHCOain water, B: MeCN; B%: 29%-59%, 10 min) and lyophilized to give the product 4-(2-(2-fluoroacrylamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N- dimethylpiperazine-1 -carboxamide (1 .3 mg, 0.00237 mmol, 95% purity, 3.42% yield) as a white solid.

[0606] RT 0.432 min (LCMS Method 5); m / z 505.3 (M+H)+(ESI+);1H NMR (DMSO-d6,400 MHz): 11 .11 (s, 1H), 8.62 (d, J = 8 Hz, 1 H), 8.31 (d, J = 8 Hz, 1 H), 8.23 (s, 1H), 7.93 (s, 1H), 7.39 (s, 1 H), 5.94 (dd, J = 47.6, 3.2 Hz, 1 H), 556 (dd, J = 15.2, 3.2 Hz, 1 H), 3.45-3.40 (m, 4H), 3.10-3.03 (m, 4H), 2.81 (s, 6H), 1.03 (s, 3H), 0.66-0.60 (m, 2H), 0.42-0.32 (m, 2H)

[0607] Preparation of Intermediate 21 .1 tert-butyl (5-(4-(isopropylthio)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin- 2-yl)carbamate

[0608] To a suspension of tert-butyl (5-bromo-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)carbamate (250 mg, 0.548 mmol), 4-isopropylsulfanylpiperidine (349 mg, 2.19 mmol) and CS2CO3 (446 mg, 1.37 mmol) in 1 ,4-dioxane (2.5 mL) was added Pd-PEPPSI-IPentCI o-picoline (2-methylpyridine) (47 mg, 0.0548 mmol). The mixture was degassed with N2 (3x), stirred at 80 °C for 2 h under N2, then diluted with H2O (15 mL) and extracted with EtOAc (10 mL, 3x). The combined organic layer was washed with brine (10 mL, 3x), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give the product tert-butyl (5-(4-(isopropylthio)piperidi n-1 -yl)-7-(N-( 1 -methylcyclopropyl)sulfamoyl)q ui nolin-2- yl)carbamate (290 mg, 0.542 mmol, crude) as yellow oil which was used in the next without any further purification.

[0609] RT 0.649 min (LCMS Method 9); m / z 535.3 (M+H)+(ESI+).

[0610] Preparation of Intermediate 21.2

[0611] 2-amino-5-(4-isopropylsulfanyl-1-piperidyl)-N-(1-methylcyclopropyl)quinoHne-7- sulfonamide

[0612] To a solution of tert-butyl (5-(4-(isopropylthio)piperidin-1-yl)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate (290 mg, 0.542 mmol) in DCM (3 mL) was added TFA (1 .0 mL). The reaction mixture was stirred at 20 °C for 2 h and, then concentrated under vacuum. The residue was purified by reversed-phase flash chromatography (ISCO®; 80 g Flash Column Welch Ultimate XB_C18 20-40 pm; 120 A, mobile phase: A: 0.1% TFA in water, B: MeCN; B%: 10%-20% @ 60 mL / min). The fractions containing the product were combined and extracted with EtOAc (10 mL, 3x). The combined organic layer was washed with brine (10 mL, 2x), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the product 2-amino-5-(4-isopropylsulfanyl-1 -piperidyl)-N- (1 -methylcyclopropyl)quinoline-7-sulfonamide (135 mg, 0.311 mmol, 57.27 % yield) as a yellow solid.

[0613] 1H NMR (CDCh, 400 MHz ): 8.20 (d, J = 8.8 Hz, 1 H), 7.91 (d, J = 1 .6 Hz, 1 H), 7.26 (d, J = 1 .6 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 4.99 (s, 3H), 3.35-3.32 (m, 2H), 3.11-3.08 (m, 1 H), 2.91-2.88 (m, 3H), 2.18- 2.14 (m, 2H), 1 .92-1 .88 (m, 2H), 1 .33 (d, J = 6.8 Hz, 6H), 1 .22 (s, 3H), 0.84 (t, J = 6.4 Hz, 2H), 0.48 (t, J = 6.4 Hz, 2H).

[0614] Preparation of Example 21

[0615] N-(5-(4-(isopropylthio)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- y I) bicyclo[1.1.0] butane-1 -carboxamide

[0616] To a mixture of 2-amino-5-(4-isopropylsulfanyl-1-piperidyl)-N-(1-methylcyclopropyl)quinoline-7- sulfonamide (135 mg, 0.311 mmol) and methyl bicyclo[1.1.0]butane-1 -carboxylate (0.373 mmol, similar preparation as for intermediate 1.11) in THF (1.5 mL) was added drop-wise a LiHMDS solution (1.1 mL,

[0617] 1.1 mmol, 1 M in THF) at 0°C. The reaction mixture was stirred at 0°C for 1 h, then poured into water (30 mL) and extracted with EtOAc (10 mL, 3x). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative-HPLC (column: Waters Xbridge 150*25 mm*5 pm; mobile phase: A: 10 mM aqueous solution of NH4HCO3; B%: 52%-82%, 9 min) and lyophilized directly to give product N-(5-(4- (isopropylthio)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1.1.0]butane-1- carboxamide (41 mg, 0.118 mmol, 37.9 % yield) as a white solid.

[0618] RT 0.594 min (LCMS Method 9); m / z 515.3 (M+H)+(ESI+);1H NMR (CDCI3, 400 MHz ): 8.49 (d, J =

[0619] 9.2 Hz, 1 H), 8.43 (d, J = 9.2 Hz, 1 H), 8.37 (s, 1 H), 8.04 (d, J = 1.2 Hz, 1 H), 7.35 (d, J = 1.2 Hz, 1 H), 5.13 (s, 1H), 3.40-3.37 (m, 2H), 3.10-3.08 (m, 1 H), 2.94-2.91 (m, 3H), 2.53-2.52 (m, 2H), 2.32-2.31 (m, 1 H), 2.21-2.16 (m, 2H), 1.94-1.91 (m, 2H), 1.32 (d, J = 6.8 Hz, 6H), 1.29-1.28 (m, 2H), 1.22 (s, 3H), 0.81 (t, J = 6.4 Hz, 2H), 0.48 (t, J = 6.4 Hz, 2H).

[0620] Preparation of Example 22

[0621] N-(5-(4-(isopropylsulfonyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- y I) bicyclo[1.1.0]butane-1 -carboxamide

[0622] To a solution of N-(5-(4-(isopropylthio)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin- 2-yl)bicyclo[1 .1 .0]butane-1 -carboxamide (44 mg, 0.0855 mmol) in DCM (0.2 mL) was added m-CPBA (52 mg, 0.256 mmol, 85% purity). The reaction mixture was stirred at 20°C for 2 h and concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5pm; mobile phase: mobile phase: A: 10 mM aqueous solution of NH4HCO3; B%: 25%-55%, 15 min) and lyophilized to give product N-(5-(4-(isopropylsulfonyl)piperidin-1-yl)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1.1.0]butane-1 -carboxamide (3.0 mg, 0.00552 mmol, 6.46 % yield) as white solid.

[0623] RT 0.499 min (LCMS Method 9); m / z 547.3 (M+H)+(ESI+);1H NMR (CDCb, 400 MHz): 8.51 (d, J = 9.2 Hz, 1 H), 8.43 (d, J = 9.2 Hz, 1 H), 8.31 (s, 1 H), 8.08 (d, J = 1 .2 Hz, 1 H), 7.36 (d, J = 1 .2 Hz, 1 H), 5.00 (s, 1H), 3.56-3.53 (m, 2H), 3.31-3.22 (m, 2H), 2.89-2.88 (m, 2H), 2.53-2.52 (m, 2H), 2.34-2.25 (m, 5H), 1.45 (d, J = 6.8 Hz, 6H), 1.31-1.28 (m, 2H), 1.24 (s, 3H), 0.51 (t, J = 6.4 Hz, 2H), 0.49 (t, J = 6.4 Hz, 2H).

[0624] Preparation of Intermediate 23.1

[0625] Benzyl 1-thia-6-azaspiro[2.5]octane-6-carboxylate

[0626] Cbz Cbz

[0627] I I

[0628] To a solution of benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (3.00 g, 12.1 mmol) in methanol (75 mL) was added thiourea (2.77 g, 36.4 mmol). The reaction mixture was stirred at 60 °C for 3 h and then, concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, mobile phase: A: ethyl acetate, B: petroleum ether; A%: 0 to 20%, @ 30 mL / min) to give the product benzyl 1-thia-6-azaspiro[2.5]octane-6-carboxylate (3.50 g, crude) as colorless oil.

[0629] RT 0.470 min (LCMS method 7); m / z 264.1 (M+H)+(ESI+);1H NMR (DMSO-cfe, 400 MHz): 7.43- 7.25 (m, 5 H), 5.09 (s, 2 H), 4.95-4.80 (m, 2 H), 3.28-3.13 (m, 2 H), 2.58 (s, 2 H), 2.05-1.97 (m, 2 H), 1.58- 1.40 (m, 2 H)

[0630] Preparation of Intermediate 23.2

[0631] Benzyl 4-merca pto-4-methylpi peridi ne-1 -carboxylate

[0632] Cbz Cbz i i

[0633] To a solution of benzyl 1-thia-6-azaspiro[2.5]octane-6-carboxylate (3.10 g, crude) in THF (50 mL) was added I AIH4 (7.1 mL, 17.7 mmol, 2.5 M in THF) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 1 h, then slowly poured into aq. HCI (60 mL, 0.1 M in water) at 0 °C, stirred at 0 °C for 5 min and extracted with ethyl acetate (250 mL, 3x). The combined organic layer was washed with brine (250 mL, 2x), dried over anhydrous NazSO-i, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, mobile phase: A: ethyl acetate, B: petroleum ether; A%: 0 to 20%, @ 30 mL / min) to give the product benzyl 4-mercapto-4- methylpiperidine-1 -carboxylate (1.50 g, 5.65 mmol, 48.02 % yield) as a white oil.

[0634] RT 0.485 min (LCMS method 7); m / z 266.1 (M+H)+(ESI+);1H NMR (CDCI3, 400 MHz): 7.42-7.31 (m, 5 H), 5.31 (s, 2 H), 3.94-3.79 (m, 2 H), 3.48-3.22 (m, 2 H), 1.72-1.62 (m, 4 H), 1.48 (s, 3 H)

[0635] Preparation of Intermediate 23.3

[0636] Benzyl 1-thia-6-azaspiro[2.5]octane-6-carboxylate

[0637] Cbz Cbz i

[0638] To a solution of benzyl 4-mercapto-4-methylpiperidine-1-carboxylate (1460 mg, 5.50 mmol) in DMF (20 mL) were added K2CO3 (2281 mg, 16.5 mmol) and methyl iodide (1171 mg, 8.25 mmol) at 0 °C. Then, the mixture was warmed to 20 °C, stirred for 16 h under N2, poured into water (200 mL) and extracted with ethyl acetate (500 mL, 3x). The combined organic layer was washed with brine (250 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated to give benzyl 1-thia-6-azaspiro[2.5]octane-6-carboxylate (1 .50 g, crude) as a colorless oil.

[0639] RT 0.491 min (LCMS method 10); m / z 280.1 (M+H)+(ESI+);1H NMR (CDCI3, 400 MHz): 7.38-7.31 (m, 5 H), 5.12 (s, 2 H), 3.82-3.65 (m, 2 H), 3.48-3.35 (m, 2 H), 1.97 (s, 3 H), 1.76-1 .64 (m, 2 H), 1.60-1.45 (m, 2 H), 1.33 (s, 3 H)

[0640] Preparation of Intermediate 23.4

[0641] 4-methyl-4-(methylthio)piperidine

[0642] To a solution of benzyl 4-methyl-4-(methylthio)piperidine-1 -carboxylate (330 mg, 1 .18 mmol) in DCM (6 mL) was added TMSI (945 mg, 4.72 mmol). The reaction mixture was stirred at 20 °C for 2 h and, then concentrated under reduced pressure. The resulting residue was poured into HCI / dioxane (4N, 3 mL) and stirred at 20 °C for 1 h. The precipitate was filtered, collected and triturated with methyl tert-butylether (50 mL) at room temperature for 15 min. Then, the suspension was filtered and the solid was dried under vacuum to give the product 4-methyl-4-(methylthio)piperidine hydrochloride (200 mg, 1.10 mmol, 93.18 % yield, HCI salt) as a yellow solid.

[0643] 1H NMR (D20, 400 MHz): 7.85 (s, 1 H), 3.34-3.22 (m, 2H), 3.21-3.12 (m, 2H), 1.95 (s, 3H), 1.93-1.86 (m, 2H), 1.82-1.71 (m, 2H), 1.33 (s, 3 H).

[0644] Preparation of Intermediate 23.5

[0645] Tert-butyl (5-(4-methyl-4-(methylthio)piperidin-1-yl)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate

[0646] To a suspension of 4-methyl-4-(methylthio)piperidine hydrochloride (199 mg, 1.10 mmol, HCI salt), tert-butyl (5-bromo-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate (250 mg, 0.548 mmol), CS2CO3 (535 mg, 1.64 mmol) in 1 ,4-dioxane (8 mL) was added Pd-PEPPSI-IPentCI o-picoline (94 mg, 0.110 mmol). The reaction mixture was degassed with N2 (3x), stirred at 80 °C for 1 h, then poured into water (30 mL) and extracted with ethyl acetate (50 mL; 2x). The combined organic layer was washed with brine (50 mL; 2x), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, mobile phase: A: ethyl acetate, B: petroleum ether; A%: 0 to 20%, @ 30 mL / min) to give the product tert-butyl (5-(4-methyl4- (methylth io)pi perid in- 1 -yl)-7-(N-( 1 -methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate (200 mg, 0.384 mmol, 70.11 % yield) as a white solid.

[0647] RT 0.649 min (LCMS Method 9); m / z 521 .1 (M +H)+(ESI+).

[0648] Preparation of Intermediate 23.6

[0649] 2-amino-5-(4-methyl-4-(methylthio)piperidin-1-yl)-N-(1-methylcyclopropyl)quinoline-7- sulfonamide

[0650] A solution of tert-butyl (5-(4-methyl-4-(methylthio)piperidin-1-yl)-7-(N-(1 - methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate (100 mg, 0.192 mmol) in formic acid (1.0 mL) was stirred at 40 °C for 0.5 h. The resulting mixture was concentrated under reduced pressure. The residue was poured into aq.Na2COs (sat. 50 mL) and extracted with DCM (50 mL; 2x). The combined organic layer was washed with brine (20 mL; 2x), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the product 2-amino-5-(4-methyl-4-(methylthio)piperidin-1-yl)-N-(1- methylcyclopropyl)quinoline-7-sulfonamide (60 mg, 0.143 mmol, 74.47 % yield) as a yellow solid.

[0651] RT 0. 0.475 min (LCMS Method 9; m / z 421.3 (M+H)+(ESI+);

[0652] Preparation of Example 23

[0653] N-(5-(4-methyl-4-(methylthio)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-

[0654] 2-y I) bicyclo[1.1.0]butane-1 -carboxamide

[0655] To a solution of 2-am i no-5-(4-methyl-4-(methylth io)piperidin-1 -yl)-N-(1 -methylcyclopropyl)q u i noli ne- 7-sulfonamide (20 mg, 0.0476 mmol) and methyl bicyclo[1.1.0]butane-1 -carboxylate (0.143 mmol, similar preparation as for intermediate 1.11) in THF (0.5 mL) was added LiHMDS (0.14 mL, 1 M in THF) at 0 °C and, the reaction mixture was stirred at 20 °C for 0.5 h under N2. Then, the mixture was poured into ice-cooled aq. NH4CI (sat., 30 mL) and extracted with ethyl acetate (30 mL; 2x). The combined organic layer was washed with brine (20 mL; 2x), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10 pm; mobile phase: A: 10 mmol / L NH4HCO3 in water, B: MeCN; B%: 25%-55%, 10 min) and lyophilized directly to afford the product N-(5-(4-methyl-4-(methylthio)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1.1.0]butane-1 -carboxamide (2.1 mg, 0.00376 mmol, 7.90 % yield) as an off-white solid.

[0656] RT 0.575 min (LCMS Method 9); m / z 501.3 (M +H)+(ESI+).1H NMR (DMSO-d6, 400 MHz): 10.67 (s, 1 H), 8.46 (d, J=9.2 Hz, 1H), 8.35 (d, J=9.2 Hz, 1 H), 8.23 (s, 1 H), 7.85 (s, 1 H), 7.37 (s, 1 H), 3.23-3.14 (m, 2H), 3.12-3.03 (m, 2H), 2.57-2.47 (m, 2H), 2.42-2.35 (m, 1 H), 2.02 (s, 3H), 1.98-1.90 (m, 4 H), 1.42 (s, 3H), 1.20-1.10 (m, 2H), 1.03 (s, 3H), 0.70-0.60 (br, 2H), 0.45-0.38 (br, 2 H)

[0657] Preparation of Example 24

[0658] N-(5-(4-methyl-4-(methylsulfonyl)piperidin-1-yl)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1.1.0]butane-1 -carboxamide

[0659] To a solution of N-(5-(4-methyl4-(methylthio)piperidin-1-yl)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1 .1 .0]butane-1 -carboxamide (4.0 mg, 0.00799 mmol) in DCM (0.5 mL) was added 3-chloro-benzenecarboperoxoic acid (5.5 mg, 0.0320 mmol). The reaction mixture was stirred at 20 °C for 2 h and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10pm; mobile phase: A: 10 mmol / L NH4HCO3 in water, B: MeCN; B%: 32%-62%, 10 min) and lyophilized directly to afford the product N-(5-(4-methyl- 4-(methylsulfonyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1.1.0]butane- 1 -carboxamide (0.57 mg, 0.00107 mmol, 13.39 % yield) as a white solid.

[0660] RT 0.563 min (LCMS Method 2); m / z 533.1 (M +H)+(ESI+).1H NMR (CDCI3, 400 MHz): 8.54 (d, J = 9.2 Hz, 1 H), 8.46 (d, J= 9.2 Hz, 1 H), 8.34 (s, 1 H), 8.11 (s, 1 H), 7.44 (s, 1 H), 5.00 (s, 1 H), 3.46-3.35 (d, J = 12.6 Hz, 2H), 3.12-3.02 (m, 2H), 2.93 (s, 3H), 2.69-2.60(m, 2H), 2.60-2.51 (m, 2H), 2.40-2.32 (m, 1 H), 1.93 (d, J = 12.6 Hz, 2H), 1.64 (s, 3H), 1.35-1.30 (m, 2H), 1.28 (s, 3H), 0.90-0.82 (m, 2H), 0.58-0.50 (m, 2 H)

[0661] Preparation of Intermediate 25.1

[0662] 5-bromo-7-fluoro-3-methylquinolin-2-amine

[0663] To a solution of 2-amino-6-bromo-4-fluorobenzaldehyde (2 g, 9.17 mmol) in DMF (25 mL) was added propiononitrile (1 .51 g, 27.5 mmol) at 0 °C. The mixture was degassed with N2 (3x) and then, t- BuOK in THF (28 mL, 27.5 mmol, 1 M) was added at 0°C. The reaction mixture was stirred for 20 min at 0 °C, then poured into aq. NH4CI (sat., 60 mL), further diluted with water (60 mL) and extracted with EtOAc (100 mL, 3x). The combined organic layer was washed with brine (200 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The resulting residue was triturated in a mixture of EtOAc (2 mL) and MeCN (10 mL) at 20 °C for 2 min, then, filtered and washed with DCM (2 mL). The precipitate was collected and dried under vacuum to give the product 5-bromo-7-fluoro-3-methylquinolin- 2-amine (1 .7 g, 6.51 mmol, purity: 97.22%, 70.07% yield).

[0664] RT 0.267 min (LCMS Method 10); m / z 255.1 (M+H)+(ESI+).1HNMR (DMSO-d6, 400 MHz): 7.85 (s, 1H), 7.43 (dd, J = 8.8, 2.4 Hz, 1 H), 7.19 (dd, J = 11.2, 2.4 Hz, 1 H), 6.72 (s, 2H), 2.25 (s, 3H).

[0665] Preparation of Intermediate 25.2

[0666] 7-(benzylthio)-5-bromo-3-methylquinolin-2-amine To a solution of 5-bromo-7-fluoro-3-methylquinolin-2-amine (1.6 g, 6.27 mmol) in DMF (16 mL) was added CS2CO3 (6.131 g, 18.8 mmol) at 25 °C. The mixture was degassed with N2 (3x) and phenylmethanethiol (0.66 mL, 5.65 mmol) was added at 20 °C. The mixture was stirred at 80 °C for 2 h, then poured into aq. NH4CI (sat., 100 mL) at 0 °C and extracted with EtOAc (100 mL, 2x). The combined organic layer was washed with brine (150 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the product 7-(benzylthio)-5-bromo-3-methylquinolin-2-amine (2.45 g, crude) as a brown oil.

[0667] RT 0.390 min (LCMS Method 10); m / z 359.1 (M+H)+(ESI+).

[0668] Preparation of Intermediate 25.3 tert-butyl (7-(benzylthio)-5-bromo-3-methylquinolin-2-yl)carbamate

[0669] Bn Bn Boc i i i

[0670] To a solution of 7-(benzylthio)-5-bromo-3-methylquinolin-2-amine (2.10 g, crude, theoretical molar quantity: 5.85 mmol) in DCM (50 mL) were added (Boc)2O (1.53 g, 7.01 mmol), DIPEA (2.0 mL, 11.7 mmol) and DMAP (0.071 g, 0.585 mmol) at 20 °C. The mixture was stirred at 30 °C for 12 h and concentrated under vacuum. The residue was dissolved in MeOH (15 mL). K2CO3 (1300 mg) was added. The reaction mixture was stirred for 12 h at 30 °C; then further diluted with MeOH (50 mL), filtered and the filter cake was washed with MeOH (10 mL, 2x). The combined filtrate was concentrated under vacuum to give a residue which was purified by column chromatography (SiO2, mobile phase: A: ethyl acetate, B: petroleum ether; A%:0 to 33%) to give the product tert-butyl (7-(benzylthio)-5-bromo-3-methylquinolin-2- yl)carbamate (1 .20 g, 1 .93 mmol, purity:74.17%, 33.14% yield) as a yellow gum.

[0671] RT 0.489 min (LCMS Method 10); m / z 403.0 (M -t-Bu+H)+(ESI+);

[0672] Preparation of Intermediate 25.4 tert-butyl (5-bromo-7-(chlorosulfonyl)-3-methylquinolin-2-yl)carbamate To a solution of tert-butyl (7-(benzylthio)-5-bromo-3-methylquinolin-2-yl)carbamate (1131 mg, 1.82 mmol, purity:74.17%) in MeCN (12 mL) were added AcOH (0.28 mL, 4.92 mmol), H2O (44 mg, 2.46 mmol) at 25 °C. The mixture was cooled down to 0°C, and 1 ,3-d ichloro-5,5-d imethyl imidazol id ine-2, 4-dione (970 mg, 4.92 mmol) was added at 0 °C. Then, the reaction mixture was stirred at 0 °C for 15 min. In parallel, another reaction was conducted using the same protocol but on a different scale of tert-butyl (7- (benzylthio)-5-bromo-3-methylquinolin-2-yl)carbamate (30 mg). The reaction mixtures were combined resulting mixture, poured into ice-water (60 mL) and extracted with DCM (80 mL, 2x). The combined organic layer was washed with brine (120 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the product tert-butyl (5-bromo-7-(chlorosulfonyl)-3- methylquinolin-2-yl)carbamate (0.91 g, crude) as yellow oil.

[0673] RT 0.515 min (LCMS Method 10); m / z 378.9 (M+H-t-Bu)+(ESI+);

[0674] Preparation of Intermediate 25.5

[0675] To a solution of 1-methylcyclopropan-1 -amine hydrochloride (518 mg, 4.82 mmol) and DIPEA (2.2 mL, 12.9 mmol) in DCM (15 mL) was added tert-butyl (5-bromo-7-(chlorosulfonyl)-3-methylquinolin-2- yl)carbamate (1 .4 g, crude, theoretical molar quantity: 3.21 mmol) at 0 °C and the mixture was stirred for 0.5 h. In parallel, another reaction was conducted using the same protocol but on a different scale of tertbutyl (5-bromo-7-(chlorosulfonyl)-3-methylquinolin-2-yl)carbamate (200 mg). The reaction mixtures were combined, poured into aq. Na2SOa (sat., 60 mL) and extracted with DCM (50 mL, 3x). The combined organic layer was washed with brine (90 mL, 2x), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, mobile phase: A: ethyl acetate, B: petroleum ether; A%: 0 to 30%, @ 100 mL / min) to give an impure compound which was further purified by reversed-phase HPLC (ISCO; 40 g Flash column; 120 A, mobile phase: A: 0.1 % FA in water, B: MeCN; B%: 85%-88%, @ 60 mL / min) to give the product tert-butyl (5-bromo-3-methyl-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)carbamate (520 mg, 1.08 mmol, purity:97.83% 22.31% yield) as a white solid.

[0676] RT 0.471 min (LCMS Method 10); m / z 414.0 (M- t-Bu +H)+(ESI+).1HNMR (DMSO-cfe, 400 MHz): 9.67 (s, 1H), 8.35 (s, 1 H), 8.33 (s, 1 H), 8.20 (s, 1 H), 8.07 (s, 1 H), 2.48 (s, 3H), 1.50 (s, 9H), 1.06 (s, 3H), 0.65-0.60 (m, 2H), 0.44-0.39 (m, 2H). Preparation of Intermediate 25.6

[0677] 2-amino-5-bromo-3-methyl-N-(1-methylcyclopropyl)quinoline-7-sulfonamide

[0678] A solution of tert-butyl (5-bromo-3-methyl-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)carbamate (300 mg, 0.638 mmol) in formic acid (3 mL) was stirred at 40 °C for 1 h. The resulting mixture was concentrated under vacuum to give the product 2-amino-5-bromo-3-methyl-N-(1- methylcyclopropyl)quinoline-7-sulfonamide (260 mg, crude) as a white solid.

[0679] RT 0.299 min (LCMS Method 10); m / z 370.0 (M+H)+(ESI+);

[0680] Preparation of Intermediate 257

[0681] 4-(2-amino-3-methyl-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N- d i methyl pi perazine-1 carboxamide

[0682] To a solution of 2-amino-5-bromo-3-methyl-N-(1-methylcyclopropyl)quinoline-7-sulfonamide (55 mg, 0.149 mmol) in dioxane (1.5 mL) were added N,N-dimethylpiperazine-1-carboxamide (140 mg, 0.891 mmol), Pd-PEPPSI-IPent Cl o-picoline (2-methylpyridine) (3.8 mg, 0.0297 mmol) and CS2CO3 (242 mg, 0.743 mmol). The reaction mixture was degassed with N2 (3x), stirred at 80 °C for 3 h, then cooled to room temperature, diluted with H2O (10 mL) and extracted with EtOAc (10 mL, 2x). The combined organic layer was washed with brine (10 mL, 2x), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM: MeOH=10:1) to give the product 4-(2-amino-3-methyl-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N-dimethylpiperazine-1- carboxamide (20 mg, 0.0407 mmol, purity: 90.94%, 27.08% yield) as a yellow solid. RT 0.565 min (LCMS Method 11); m / z 447.3 (M +H)+(ESI+).1HNMR (DMSO-d6, 400 MHz): 7.98 (s, 1 H), 7.94 (s, 1 H), 7.59 (s, 1 H), 7.10 (s, 1H), 6.54 (s, 2H), 3.45-3.35 (m, 4H), 3.01-2.91 (m, 4H), 2.80 (s, 6H), 2.27 (s, 3H), 1.01 (s, 3H), 0.66-0.57 (m, 2H), 0.38-0.31 (m, 2H).

[0683] Preparation of Example 25

[0684] 4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-3-methyl-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N-dimethylpiperazine-1-carboxamide

[0685] To a solution of 4-(2-amino-3-methyl-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N- dimethylpiperazine-1 -carboxamide (10 mg, 0.0204 mmol, 90.94% purity) in THF (1 mL) was added LIHMDS in THF (0.067 mL, 0.0672 mmol, 1 M) at 0 °C and the mixture was stirred at 0°C for 0.5 h under N2. Then, methyl bicyclo[1 .1 .0]butane-1 -carboxylate (0.0727 mmol, similar preparation as for intermediate 1 .11 ) in THF (0.3 mL) was added to the mixture at 0°C. The reaction mixture was heated to 40 °C, stirred for 1 h, then cooled to 20 °C, poured into ice water (1 mL), diluted with water (1 mL) and extracted with EtOAc (3 mL, 3x). The combined organic layers were washed with brine (3 mL, 2x), dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: Waters xbridge C18 150*25mm*10pm; mobile phase: A: 10 mM aqueous solution of NH4HCO3 in water, B: MeCN; B%: 27%-57%, 10min) and lyophilized directly to give the product 4-(2-(bicyclo[1 .1 .0]butane-1 - carboxamido)-3-methyl-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N-dimethylpiperazine-1- carboxamide (1 .6 mg, 0.00300 mmol, purity 96.77%, 14.71% yield) as a white solid.

[0686] RT 0.584 min (LCMS Method 11); m / z 527.3 (M +H)+(ESI+).1HNMR (DMSO-cfe, 400 MHz): 10.29 (s, 1 H), 8.34 (s, 1 H), 8.17 (s, 1 H), 7.94 (s, 1 H), 7.40 (s, 1H), 3.51-3.41 (m, 4H), 3.11-3.01 (m, 4H), 2.81 (s, 6H), 2.47 (d, J = 3.20 Hz, 2H), 2.37 (s, 3H), 2.35-2.32 (m, 1 H), 1.11 (d, J = 2.40 Hz, 2H), 1.01 (s, 3H), 0.63-0.60 (m, 2H), 0.38-0.35 (m, 2H).

[0687] Preparation of Intermediate 26.1

[0688] N-(3-(benzylthio)-5-bromophenyl)-3-oxobutanamide

[0689] To a solution of N-(3,5-dibromophenyl)-3-oxobutanamide (9.00 g, 26.9 mmol) in 1 ,4-dioxane (90 mL) was added DIEA (19 mL, 107 mmol), Pd2(dba)3 (2.46 g, 2.69 mmol) and Xantphos (1.55 g, 2.69 mmol). Then, the mixture was degassed, purged with N2 (3x) and phenylmethanethiol (2.8 mL, 24.2 mmol) was added. The reaction mixture was stirred at 80 °C for 1.5 h, then poured into water (500 mL) and extracted with ethyl acetate (300 mL, 3x). The combined organic layer was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by Flash silica gel chromatography (ISCO; 12 g Sepa Flash Silica Flash Column, mobile phase: A: ethyl acetate, B: petroleum ether; A%: 50% to 65%, @ 100 mL / min) to afford an impure product which was further purified by reversed-phase flash chromatography (ISCO; 100 g Flash Column Welch Ultimate XB_C18 2040 pm; 120 A, mobile phase: A: 0.1 % formic acid in water, B: MeCN; B%: 55%-65% @ 50mL / min) and lyophilized directly to give the product N-(3-(benzylthio)-5-bromophenyl)-3-oxobutanamide (2.10 g, 5.55 mmol, 20.66 % yield) as an off-white solid.

[0690] RT 0.468 min (LCMS Method 10); m / z 377.9 (M +H)+(ESI+).1H NMR (DMSO-cfe, 400 MHz): 10.22 (s, 1 H), 7.66 (s, 1 H), 7.47 (s, 1 H), 7.39-7.36 (m, 2H), 7.33-7.29 (m, 2H), 7.27-7.20 (m, 2H), 4.27 (s, 2H), 3.54 (s, 2H), 2.20 (s, 3H)

[0691] Preparation of Intermediate 26.2

[0692] 7-(benzylthio)-5-bromo-4-methylquinolin-2-ol

[0693] A solution of N-(3-(benzylthio)-5-bromophenyl)-3-oxobutanamide (2100 mg, 5.55 mmol) in EtOH (13 mL, 225 mmol) and H2SO4 (7.4 mL, 135 mmol) was stirred at 50 °C for 16 h. The reaction mixture was then poured into 200 mL of ice water. The precipitate was filtered and triturated with MeOH (30 mL) at 25 °C for 2 min after filtration, collected and dried under vacuum to give the product 7-(benzylthio)-5-bromo- 4-methylquinolin-2-ol (1760 mg, crude) as a yellow solid which was used in the next step without any further purification.

[0694] Preparation of Intermediate 26.3

[0695] 5-bromo-2-hydroxy-4-methylquinoline-7-sulfonyl chloride

[0696] To a solution of 7-(benzylthio)-5-bromo-4-methylquinolin-2-ol (1.76 g, 4.89 mmol) in MeCN (18 mL) were added AcOH (880 mg, 14.7 mmol) and H2O (264 mg, 14.7 mmol). Then, the mixture was cooled down to 0°C and sulfuryl chloride (2.0 mL, 24.4 mmol) was added. The reaction mixture was stirred at 0°C until some white solid was formed. Then, the precipitate was filtered, triturated with H2O (2 mL) at 25 °C for 2 min, collected and dried under vacuum to give the product 5-bromo-2-hydroxy-4-methylquinoline- 7-sulfonyl chloride (620 mg, crude) as a white solid.

[0697] RT 0.409 min (LCMS Method 10); m / z 335.9, 337.9 (M +H)+(ESI+).

[0698] Preparation of Intermediate 26.4 tert-butyl((5-bromo-2-hydroxy-4-methylquinolin-7-yl)sulfonyl)(1- methylcyclopropyljcarbamate

[0699] A solution of 5-bromo-2-hydroxy-4-methylquinoline-7-sulfonyl chloride (1.02 g, 3.03 mmol) in THF (10 mL) was added to a solution of 1-methylcyclopropan-1 -amine hydrochloride (652 mg, 6.06 mmol) in aq. NaHCOs (sat, 4.0 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and poured into water (30 mL). The precipitate was filtered, collected and dried under vacuum to give the product 5-bromo-2- hydroxy-4-methyl-N-(1-methylcyclopropyl)quinoline-7-sulfonamide (800 mg, 2.15 mmol, 71 .11% yield) as a white solid.

[0700] RT 1 .731 min (LCMS Method 12); m / z 371 .0, 372.9 (M +H)+(ESI+).1H NMR (DMSO-d6, 400 MHz): 12.14 (br, 1 H), 8.38 (s, 1 H), 7.81 (d, J = 2.0 Hz, 1 H), 7.75 (d, J = 2.0 Hz, 1 H), 6.64 (s, 1H), 2.79 (s, 3H), 1.11 (s, 3H), 0.71-0.58 (m, 2H), 0.48-0.40 (m, 2H)

[0701] Preparation of Intermediate 26.5 tert-butyl ((5-bromo-2-hydroxy-4-methylquinolin-7-yl)sulfonyl)(1- methylcyclopropyljcarbamate

[0702] To a solution of 5-bromo-2-hydroxy-4-methyl-N-(1-methylcyclopropyl)quinoline-7-sulfonamide (1300 mg, 1 .86 mmol) in THF (12 mL) was added tert-butoxycarbonyl tert-butyl carbonate (810 mg, 3.71 mmol) and DMAP (45 mg, 0.371 mmol) at 20 °C. The mixture was stirred at 20 °C for 2 h and concentrated under reduced pressure. The resulting residue was triturated with a mixture of petroleum ether / ethyl acetate (5 / 1 , 8 mL) at 20 °C for 5 min. The precipitate was filtered, collected and dried under vacuum to give the product tert-butyl ((5-bromo-2-hydroxy-4-methylquinolin-7-yl)sulfonyl)(1- methylcyclopropyl)carbamate (870 mg, 1.85 mmol, 99.45% yield) as a white solid.

[0703] RT 0.467 min (LCMS Method 10); m / z 470.9 (M +H)+(ESI+).1H NMR (DMSO-d6, 400 MHz): 12.17 (s, 1H), 7.83 (s, 1 H), 7.73(s, 1 H) 6.69 (s, 1 H), 2.79 (s, 3H), 1.50 (s, 3H), 1.31 (s, 9H), 1.11-0.84 (m, 4H)

[0704] Preparation of Intermediate 26.6 tert-butyl ((5-(4-(dimethylcarbamoyl)piperazin-1-yl)-2-hydroxy-4-methylquinolin-7- yl)sulfonyl)(1-methylcyclopropyl)carbamate

[0705] To a solution of tert-butyl ((5-bromo-2-hydroxy-4-methylquinolin-7-yl)sulfonyl)(1- methylcyclopropyl)carbamate (720 mg, 1.53 mmol) in DMF (8 mL) were added N,N-dimethylpiperazine- 1-carboxamide (1441 mg, 9.16 mmol), Pd-PEPPSI-IPent Cl o-picoline (2-methylpyridine) (223 mg, 0.229 mmol), CS2CO3 (995 mg, 3.05 mmol). The reaction mixture was degassed with N2 (3x), stirred at 100 °C for 1.5 h, then filtered and concentrated under reduced pressure. The resulting residue was purified by reversed-phase flash chromatography (ISCO; 100 g Flash Column Welch Ultimate XB_C18 20-40 pm; 120 A, mobile phase: A: 0.1% formic acid in water, B: MeCN; B%: 45%-50% @ 50mL / min) and lyophilized directly to give the product tert-butyl ((5-(4-(dimethylcarbamoyl)piperazin-1-yl)-2-hydroxy-4- methylquinolin-7-yl)sulfonyl)(1 -methylcyclopropyl)carbamate (200 mg, crude) as a yellow solid.

[0706] RT 0.446 min (LCMS Method 10); m / z 548.0 (M +H)+(ESI+). Preparation of Intermediate 267 tert-butyl ((5-(4-(dimethylcarbamoyl)piperazin-1-yl)-2-(4-methoxybenzyl)-4-methylquinolin-

[0707] 7-yl)sulfonyl)(1-methylcyclopropyl)carbamate

[0708] To a solution of tert-butyl ((5-(4-(dimethylcarbamoyl)piperazin-1-yl)-2-hydroxy-4-methylquinolin-7- yl)sulfonyl)(1-methylcyclopropyl)carbamate (180 mg, 0.329 mmol) in DMA (2.5 mL) were added BOP (174 mg, 0.394 mmol) and DBU (0.074 mL, 0.493 mmol). The mixture was stirred at 20 °C for 15 min and (4- methoxyphenyl)methanamine (90 mg, 0.657 mmol) was added. The reaction mixture was stirred at 80 °C for 8 h, then diluted with water (3 mL) and filtered. The precipitate was dried under reduced pressure to give the product tert-butyl ((5-(4-(dimethylcarbamoyl)piperazin-1-yl)-2-(4-methoxybenzyl)-4- methylquinolin-7-yl)sulfonyl)(1-methylcyclopropyl)carbamate (140 mg, 0.210 mmol, 63.88% yield) as a white solid.

[0709] RT 0.421 min (LCMS Method 10); m / z 667.1 (M +H)+(ESI+).1H NMR (DMSO-d6, 400 MHz): 7.70 (s, 1 H), 7.65 (t, J = 5.6 Hz, 1 H), 7.33-7.21 (m, 2H), 7.12 (s, 1 H), 6.91-6.84 (m, 2H), 6.69 (s, 1 H), 4.52 (d, J = 5.6 Hz, 2H), 3.71 (s, 2H), 3.60-3.50 (m, 2H), 3.29 (s, 3H), 3.14-2.97 (m, 4H), 2.87-2.70 (m, 9H), 2.68- 2.62 (m, 2H), 1.52 (s, 3H), 1.22 (s, 9H), 1.05-0.81 (m, 4H)

[0710] Preparation of Intermediate 26.8

[0711] 4-(2-amino-4-methyl-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N- dimethylpiperazine-1-carboxamide A solution of tert-butyl ((5-(4-(dimethylcarbamoyl)piperazin-1-yl)-2-((4-methoxybenzyl)amino)-4- methylquinolin-7-yl)sulfonyl)(1-methylcyclopropyl)carbamate (120 mg, 0.212 mmol) in TFA (3.0 mL) was stirred at 50 °C for 2 h. The mixture was concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 250*50 mm*15 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 12%-42%, 11 min) and lyophilized directly to give the product 4-(2- amino4-methyl-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N-dimethylpiperazine-1- carboxamide (40 mg, 0.0896 mmol, 42.30% yield) as a yellow solid.

[0712] RT 0.295 min (LCMS Method 10); m / z 447.2 (M +H)+(ESI+).1H NMR (DMSO-d6, 400 MHz): 8.37 (s, 1H), 7.84 (s, 1 H), 7.57 (s, 1 H), 6.88 (s, 1H), 3.360-3.58 (m, 2H), 3.15-3.04 (m, 4H), 2.92 (s, 3H), 2.79 (s, 6H), 2.79-2.72 (m, 2H), 1.07 (s, 3H), 0.70-0.58 (m, 2H), 0.48-0.37 (m, 2H)

[0713] Preparation of Example 26

[0714] 4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-4-methyl-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N-dimethylpiperazine-1-carboxamide

[0715] A solution of 4-(2-amino-4-methyl-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N- dimethylpiperazine-1 -carboxamide (30 mg, 0.0672 mmol) in THF (0.5 mL) was degassed with N2 (3x). Then, methyl bicyclo[1.1.0]butane-1 -carboxylate (0.0727 mmol, similar preparation as for intermediate 1 .11 ) in THF (0.3 mL) was added at 0 °C, fol...

Claims

CLAIMS1 . A compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein:Ri is hydrogen, -CN, formyl, C1-2 alkyl, C2 alkenyl, C2 alkynyl, C1-2 haloalkyl, -(C1-2 alkylene)-OH or -(C1-2 alkylene)-O-(Ci-2 alkyl);R2 and R3 are each independently C1-2 alkyl or C1-2 haloalkyl, or R2 and R3 together with the carbon atom to which they are attached form C3-5 cycloalkyl or 4-5 membered heterocycloalkyl, wherein said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups selected from C1-2 alkyl, C1-2 haloalkyl and -F;W is selected from -NHS(O)y-, wherein y is 1 or 2, wherein the N atom of W is attached to the carbon atom that carries R1, R2and R3, and the S atom of W is attached to the ring system shown in formula (I);Xi is CF or CH and Xs is CH;X2 is C-Yc2-Rc2, whereinYC2is selected from a covalent bond, C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, cycloalkylene and heterocycloalkylene wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more groups independently selected from RS1, and further wherein one or more -CH2- units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from -O-, -NH-, -N(CI-5 alkyl)-, -CO-, -S-, - SO-, and -SO2-, and wherein said cycloalkylene and heterocycloalkylene are each optionally substituted with one or more groups independently selected RS2, andRc2is selected from hydrogen, halogen, -OH, -NH2, -SH, -CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; wherein saidalkyl, alkenyl, and alkynyl in X2 are each optionally substituted with one or more groups independently selected from RS1, and wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl in X2are each optionally substituted with one or more groups independently selected from RS2;X4, X5and X6are each independently selected from N and C-Rx, wherein Rxis selected from -H, C1-5 alkyl, C1-5 alkenyl, C1-5 alkynyl, -O(Ci-5 alkyl), -CN and Hal, wherein said alkyl, alkenyl and alkynyl group is optionally substituted with one or more groups independently selected from RS1;Y is -N(RN1)-WCOVI.RCOVI(whereinRCOVI jsselected from, C2 alkenyl, and C2 alkynyl, wherein said alkenyl is optionally substituted with one or more optional substituents selected from CM alkyl, -COO-(C alkyl), - CONH-(CI-4 alkyl), -(C alkylene)N(CM alkyl)(CM alkyl), -(CM alkylene)-(W-heterocycloalkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Hal, -CN and -CF3, and said alkynyl is optionally substituted with an optional substituent selected from CM alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl,Wcov1- is selected from -CO-, -SO- and -SO2-,RN1is selected from hydrogen and CM alkyl;RS1is selected from halogen, -CN, -OH, -O(Ci-5 alkyl), -O(Ci-5 haloalkyl), C1-5 haloalkyl, -SH, -S(Ci-5 alkyl), -SO2(Ci-5alkyl), -S(O)(NH)(CI-5alkyl), -S(O)(N-CI-3alkyl)(Ci-5alkyl), -N=S(O)(CI-5alkyl)(Ci-5alkyl), -S(Ci-5haloalkyl), -P(O)(Ci-5alkyl)(Ci-5alkyl), -P(O)(O-Ci-5alkyl) (O-C1-5 alkyl), -P(O)(O-Ci- 5 alkyl)(Ci-5alkyl), -NH2, -NH(CI-5alkyl), -NH(Ci-s haloalkyl), -N(Ci-s alkyl)(Ci-5alkyl), -N(CM haloalkyl)(Ci-5alkyl), -( / V-heterocycloalkyl), -CO(Ci-5alkyl), -CONH2, -CONH(CI-5alkyl), -CON(CM alkyl)(Ci-5 alkyl), -CO-(W-heterocycloalkyl), -NHCO-(CI-5 alkyl), -N(CI-5 alkyl)-CO-(Ci-5 alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci-5alkyl), -N(CI-5alkyl)CONH2, -N(CM alkyl)CONH-(Ci-5alkyl), and -N(CI-5alkyl)CON(Ci-5alkyl)(Ci-5alkyl); and RS2is selected from halogen, -CN, -OH, C1-5 alkyl, C1.5 haloalkyl, -O(Ci-5 alkyl), -O(Ci-5 haloalkyl), -SH, -S(CM alkyl), -S(O)(Ci-5alkyl), -SO2(CM alkyl), -S(O)(NH)(CI-5alkyl), -S(O)(N-CI-3alkyl)(Ci-5 alkyl), -S(O)(NH)-( / V-heterocycloalkyl), -S(O)(N-CI-3alkyl)-( / V- heterocycloalkyl), -S(O)(NH)-(CI-5 alkylene)-( / V-heterocycloalkyl), -S(O)(N-CI-3alkyl)-(Ci-s alkylene)-(W-heterocycloalkyl), -S(O)(NH)-(CI-5 alkylene)-heterocycloalkyl, -S(O)(N-CI-3alkyl)-(Ci-s alkylene)-heterocycloalkyl, -S(O)(NH)-(CI-5 alkylene)-N(Ci-s alkyl)(Ci-s alkyl), -S(O)(N-CI-3alkyl)- (C1-5 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -N=S(O)(CI-5 alkyl)(Ci-5 alkyl), -S(Ci-5 haloalkyl), -S(O)(Ci-5 haloalkyl), -SO2(Ci.5haloalkyl), -P(O)(Ci-5alkyl)(Ci-5alkyl), -P(O)(O-Ci-5alkyl)(O-Ci-5alkyl), - P(O)(O-Ci-5alkyl)(Ci-5alkyl), -NH2, -NH(CI-5alkyl), -NH(CI-5haloalkyl), -N(CI-5alkyl)(Ci^alkyl), -N(CI-5 haloalkyl)(Ci-5 alkyl), -( / V-heterocycloalkyl), -C0(Ci-5 alkyl), -COOH, -COO(Ci-5 alkyl), -CONH2, -CONH(CI-5alkyl), -CON(CI-5alkyl)(Ci-5alkyl), -CO-(A / -heterocycloalkyl), -CONH- (N-heterocycloalkyl), -CON(CI-5 alkyl)-( / V-heterocycloalkyl), -CONH-(CI-5 alkylene)-(A / - heterocycloalkyl), -CON(CI-5 alkyl)-(Ci-s alkylene)-( / V-heterocycloalkyl), -CONH-(CI-5 alkylene)- heterocycloalkyl, -CON(CI-5 alkyl)-(Ci-5 alkylene)-heterocycloalkyl, -CONH-(CI-5 alkylene)-N(Ci-5 alkyl)(Ci-5alkyl), -CON(CI-5alkyl)-(Ci-5alkylene)-N(Ci-5alkyl)(Ci-5alkyl), -NHCO-(Ci-s alkyl), -N(Ci- 5 alkyl)-CO-(Ci-5alkyl), -NHCONH2, -NHCONH-(CI-5alkyl), -NHCON(CI-5alkyl)(Ci-5alkyl), -N(Ci^ alkyl)CONH2, -N(Ci-s alkyl)CONH-(Ci-5alkyl), and -N(CI-5alkyl)CON(Ci-5alkyl)(Ci-5alkyl), -(C1-5 alkylene)-CN, -(C1-5 alkylene)-OH, -(C1-5 alkylene)-O(Ci-5 alkyl), -(C1-5 alkylene)-O(Ci-5 haloalkyl), -(C1-5 alkylene)-SH, -(C1-5 alkylene)-S(Ci-5 alkyl), -(C1.5 alkylene)-S(O)(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-3 alkyl)(Ci-5alkyl), -(C1-5 alkylene)-N=S(O)(Ci-5alkyl)(Ci-5alkyl), -(C1.5 alkylene)-S(Ci-5haloalkyl), - (C1-5 alkylene)-S(O)(Ci-5 haloalkyl), -(C1-5 alkylene)-S(O)2(Ci-5 haloalkyl), -(C1-5 alkylene)-P(O)(Ci-5 alkyl)(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)-NH(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)-(N-heterocycloalkyl), -(C1-5 alkylene)-N(Ci-s haloalkyl)(Ci-5 alkyl), -(C1-5 alkylene)- CO(Ci-5 alkyl), -(C1-5 alkylene)-COO(Ci-5 alkyl), -(C1-5 alkylene)-COOH, -(C1-5 alkylene)-CONH2, - (C1-5 alkylene)-CONH(Ci-5 alkyl), -(C1-5 alkylene)-CON(Ci-s alkyl)(Ci-5 alkyl), -(C1-5 alkylene)-CO- (N-heterocycloalkyl), -(C1-5 alkylene)-NHCO-(Ci-5 alkyl), -(C1-5 alkylene)-N(Ci-s alkyl)-CO-(Ci-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-5 alkyl)CONH2, -(C1-5 alkylene)-N(Ci- 5 alkyl)CONH-(Ci-5 alkyl), and -(C1-5 alkylene)-N(Ci-5 alkyl)CON(Ci-s alkyl)(Ci-s alkyl), wherein said heterocycloalkyl is optionally substituted with one or more groups selected from C1-5 alkyl. -O-(Ci-5 alkyl), CN and -OH.

2. The compound of claim 1 , wherein R1 is -CN, methyl, fluoromethyl, difluoromethyl, -(C1-2 alkylene)- OH or C2 alkenyl.

3. The compound of claim 1 or 2, wherein R1is methyl or -CN.

4. The compound of any one of claims 1 to 3, wherein R1 is methyl, particularly CD3.

5. The compound of any one of claims 1 to 3, wherein R1 is -CN.

6. The compound of any one of claims 1 to 5, wherein R2 and R3 together with the carbon atom to which they are attached form cyclopropyl optionally substituted with one or more -F.

7. The compound of any one of claims 1 to 6, wherein R2 and R3 together with the carbon atom to which they are attached form cyclopropyl.

8. The compound of any one of claims 1 to 7, wherein Xi and X3 are each CH.

9. The compound of any one of claims 1 to 8, wherein -Yc2-Rc2 is is selected from -O-C1-12 alkyl, -NH- C1-12 alkyl, -N(CI-5 alkyl)-Ci-i2 alkyl, -O-C2-12 alkenyl, -NH-C2-12 alkenyl, -N(CI-5 alkyl)-C2-i2 alkenyl, -O-C2-12 alkynyl, -NH-C2-12 alkynyl, -N(CI-5 alkyl)-C2-i2 alkynyl, -(C0-3 alkylene)-cycloalkyl, -CO-(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-CO-cycloalkyl, -CONH-(Co-3 alkylene)-cycloalkyl, (C0-3 alkylene)-CONH-cycloalkyl, -NHCO-(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-NHCO-cycloalkyl, - NH-(CO-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-NH-cycloalkyl, -0-(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-O-cycloalkyl, -S02-(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-SO2-cycloalkyl, -CONH- cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, -SO2-cycloalkyl, -(C0-3 alkylene)-cycloalkenyl, -CO-(Co-3 alkylene)-cycloalkenyl, -(C0-3 alkylene)-CO-cycloalkenyl, -CONH- (C0-3 alkylene)-cycloalkenyl, (C0-3 alkylene)-CONH-cycloalkenyl, -NHCO-(Co-3 alkylene)- cycloalkenyl, -(C0-3 alkylene)-NHCO-cycloalkenyl, -NH-(Co-3 alkylene)-cycloalkenyl, -(C0-3 alkylene)-NH-cycloalkenyl, -0-(Co-3 alkylene)-cycloalkenyl, -(C0-3 alkylene)-O-cycloalkenyl, -SO2- (C0-3 alkylene)-cycloalkenyl, -(C0-3 alkylene)-SO2-cycloalkenyl, -CONH-cycloalkenyl, -NHCO- cycloalkenyl, -NH-cycloalkenyl, -O-cycloalkenyl, -CO-cycloalkenyl, -SO2-cycloalkenyl, -(C0-3 alkylene)-heterocycloalkyl, -CO-(Co-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-CO- heterocycloalkyl, -CONH-(Co-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(CO-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-NHCO-heterocycloalkyl, -NH-(Co-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-NH-heterocycloalkyl, -0-(Co-3 alkylene)- heterocycloalkyl, -(C0-3 alkylene)-O-heterocycloalkyl, -S02-(Co-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-SO2-heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH- heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO2-heterocycloalkyl, -(C0-3 alkylene)-heterocycloalkenyl, -CO-(Co-3 alkylene)-heterocycloalkenyl, -(C0-3 alkylene)-CO- heterocycloalkenyl, -CONH-(Co-3 alkylene)-heterocycloalkenyl, -(C0-3 alkylene)-CONH- heterocycloalkenyl, -NHCO-(Co-3 alkylene)-heterocycloalkenyl, -(C0-3 alkylene)-NHCO- heterocycloalkenyl, -NH-(Co-3 alkylene)-heterocycloalkenyl, -(C0-3 alkylene)-NH-heterocycloalkenyl,-0-(Co-3 alkylene)-heterocycloalkenyl, -(C0-3 alkylene)-O-heterocycloalkenyl, -S02-(Co-3 alkylene)- heterocycloalkenyl, -(C0-3 alkylene)-SO2-heterocycloalkenyl, -CONH-heterocycloalkenyl, -NHCO- heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO-heterocycloalkenyl, -SO2- heterocycloalkenyl, -(C0-3 alkylene)-aryl, -CO-(Co-3 alkylene)-aryl, -(C0-3 alkylene)-CO-aryl, -CONH- (C0-3 alkylene)-aryl, -(C0-3 alkylene)-CONH-aryl, -NHCO-(Co-3 alkylene)-aryl, -(C0-3 alkylene)- NHCO-aryl, -NH-(Co-3 alkylene)-aryl, -(C0-3 alkylene)-NH-aryl, -0-(Co-3 alkylene)-aryl, -(C0-3 alkylene)-O-aryl, -S02-(Co-3 alkylene)-aryl, -(C0-3 alkylene)-SO2-aryl, -CONH-aryl, -NHCO-aryl, -NH- aryl, -O-aryl, -CO-aryl, -SO2-aryl, -(C0-3 alkylene)-heteroaryl, -CO-(Co-3 alkylene)-heteroaryl, -(C0-3 alkylene)-CO-heteroaryl, -CONH-(Co-3 alkylene)-heteroaryl, -(C0-3 alkylene)-CONH-heteroaryl, - NHCO-(CO-3 alkylene)-heteroaryl , -(C0-3 alkylene)-NHCO-heteroaryl, -NH-(Co-3 alkylene)-heteroaryl, -(C0-3 alkylene)-NH-heteroaryl, -0-(Co-3 alkylene)-heteroaryl, -(C0-3 alkylene)-O-heteroaryl, -SO2- (C0-3 alkylene)-heteroaryl, -(C0-3 alkylene)-SO2-heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, - NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and -SO2-heteroaryl, wherein said alkylene is optionally substituted with one or more groups independently selected from RS1, and wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2.

10. The compound of any one of claims 1 to 9, wherein -Yc2-Rc2 is is selected from -(C0-3 alkylene)- heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -0- heterocycloalkyl, -CO-heterocycloalkyl, -SO2-heterocycloalkyl, -(C0-3 alkylene)-heterocycloalkenyl, -CONH-heterocycloalkenyl, -NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -0- heterocycloalkenyl, -CO-heterocycloalkenyl, -SO2-heterocycloalkenyl, -(C0-3 alkylene)aryl, -CONH- aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -S02-aryl, -(C0-3 alkylene)heteroaryl, -CONH- heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and -SO2-heteroaryl, still more preferably -(C0-3 alkylene)-heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO- heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO2- heterocycloalkyl, -(C0-3 alkylene)-heterocycloalkenyl, -CONH-heterocycloalkenyl, -NHCO- heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO-heterocycloalkenyl, and -SO2-heterocycloalkenyl, wherein said alkylene is optionally substituted with one or more groups independently selected from RS1, and wherein said heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from RS2.

11. The compound of any one of claims 1 to 10, wherein -Yc2-Rc2 is heterocycloalkyl wherein said heterocycloalkyl is optionally substituted with one or more groups independently selected from RS2.

12. The compound of any one of claims 1 to 11 , wherein Rxis selected from -H, and C1.2 alkyl, wherein said alkyl group is optionally substituted with one or more groups independently selected from RS1.

13. The compound of any one of claims 1 to 12, wherein RCOV1is14. The compound of any one of claims 1 to 13, -WCOV1- is -CO-.

15. The compound of any one of claims 1 to 14, wherein RN1is hydrogen.

16. The compound of any one of claims 1 to 15, wherein X4is N.

17. The compound of claim 16, wherein the compound is a compound of formula (II):or a pharmaceutically acceptable salt thereof, wherein of R1, R2, R3, W, Xi, X2, X3, and Y are as in any one of claims 1 to 16.

18. The compound of claim 1 , wherein the compound is a compound selected from the following compounds or a pharmaceutically acceptable salt thereof:

9. The compound of claim 1 , wherein the compound is a compound selected from 4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)- N,N-dimethylpiperazine-1-carboxamide;A / -(7-(N-(1-methylcyclopropyl)sulfamoyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;N-(6-(N-(1-methylcyclopropyl)sulfamoyl)isoquinolin-3-yl)bicyclo[1.1.0]butane-1 -carboxamide 4-(6-(bicyclo[1 .1 .0]butane-1 -carboxamido)-3-(N-(1 -methylcyclopropyl)sulfamoyl)naphthalen-1 -yl)- N,N-dimethylpiperazine-1-carboxamide;4-(3-(bicyclo[1 .1 .0]butane-1-carboxamido)-6-(N-(1-methylcyclopropyl)sulfamoyl)isoquinolin-8-yl)- N,N-dimethylpiperazine-1-carboxamide;N-(6-(N-(1-methylcyclopropyl)sulfamoyl)-8-(2-oxa-7-azaspiro[3.5]nonan-7-yl)isoquinolin-3- yl)bicyclo[1 .1 .0]butane-1 -carboxamide ;N-(7-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-2-yl)bicyclo[1.1.0]butane-1 -carboxamide;N-(7-(N-(1 -methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1 .1 .0]butane-1 -carboxamide ;N-(7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2-yl)acrylamide;(2S,6S)-4-(2-(bicyclo[1 .1 .0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin- 5-yl)-N,N,2,6-tetramethylpiperazine-1-carboxamide;(S)-4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N,2-trimethylpiperazine-1-carboxamide;(S)-N-(5-(4-isobutyryl-3-methylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;N-(5-(4-isobutyrylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;4-(2-acrylamido-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N-dimethylpiperazine-1- carboxamide;4-(2-(2-fluoroacrylamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N- dimethylpiperazine-1-carboxamide;N-(5-(4-(isopropylthio)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;N-(5-(4-(isopropylsulfonyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;N-(5-(4-methyl-4-(methylthio)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;N-(5-(4-methyl-4-(methylsulfonyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;4-(2-(bicyclo[1 .1 .0]butane-1-carboxamido)-3-methyl-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N-dimethylpiperazine-1-carboxamide;4-(2-(bicyclo[1 .1 .0]butane-1-carboxamido)-4-methyl-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N-dimethylpiperazine-1-carboxamide;N-(6-(N-(1-methylcyclopropyl)sulfamoyl)isoquinolin-3-yl)acrylamide;N-methyl-N-(7-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-2-yl)acrylamide;N-(7-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-2-yl)acrylamide;4-(6-acrylamido-3-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)naphthalen-1-yl)-N,N- dimethylpiperazine-1-carboxamide;N-(6-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-3-yl)bicyclo[1.1.0]butane-1 -carboxamide;N-(7-(N-(1-methylcyclopropyl)sulfamoyl)quinoxalin-2-yl)bicyclo[1.1.0]butane-1 -carboxamide;N-(7-(N-(1-methylcyclopropyl)sulfamoyl)quinoxalin-2-yl)acrylamide;2-fluoro-N-(7-(N-(1-methylcyclopropyl)sulfamoyl)quinoxalin-2-yl)acrylamide;N-(7-(N-(1-methylcyclopropyl)sulfamoyl)quinazolin-2-yl)acrylamide;N-(5-(4-hydroxypiperidin-1 -yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide; N-(5-(4-(hydroxymethyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;Tert-butyl 4-(2-(bicyclo[1 .1 .0]butane-1-carboxamido)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate; N-(5-((3S,5S)-3,5-dimethylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide; N-(5-(4-methyl-4-(methylthio)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide; N-(5-(4-methyl-4-(S-methylsulfonimidoyl)piperidin-1-yl)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1.1.0]butane-1 -carboxamide; N-(5-((3S,4S)-4-hydroxy-3-methylpiperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide; N-(5-((cis)-4-hydroxy-3-methylpiperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide; N-(5-(2,2-dioxido-2-thia-7-azaspiro[4.4]nonan-7-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin- 2-yl)bicyclo[1 .1 .0]butane-1 -carboxamide; N-(7-(N-(1-methylcyclopropyl)sulfamoyl)-5-(2-thia-7-azaspiro[3.5]nonan-7-yl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide; N-(5-((1 R or S,2R or S)-2-methyl-1-(methylimino)-1-oxido-1 l6-thiomorpholino)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1.1.0]butane-1 -carboxamide; N-(5-((1S or R,2S or R)-2-methyl-1-(methylimino)-1-oxido-1l6-thiomorpholino)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1.1.0]butane-1 -carboxamide; N-(5-((1S or R,2R or S)-2-methyl-1-(methylimino)-1-oxido-1 l6-thiomorpholino)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1.1.0]butane-1 -carboxamide; N-(5-((1 R or S,2S or R)-2-methyl-1-(189uinoline189o)-1-oxido-1l6-thiomorpholino)-7-(N-(1- methylcyclopropyl)sulfamoyl)189uinoline-2-yl)bicyclo[1.1.0]butane-1 -carboxamide; (R)-N-(5-(4-isobutyryl-3-methylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide; N-(5-(4-(N,S-dimethylsulfonimidoyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide; N-(5-(2-methyl-1 -(methylimi no)- 1 -oxido-116-th iomorphol ino)-7-(N-(1 - methylcyclopropyl)sulfamoyl)quinolin-2-yl)bicyclo[1 .1 .0]butane-1 -carboxamide;N-(5-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)190uinoline-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;4-(2-(bicyclo[1 .1 .0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)- N,N-dimethyl-3,6-dihydropyridine-1(2H)-carboxamide;N-(5-(4-acetylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;N-(5-((2S,6S)-2,6-dimethylmorpholino)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;N-(7-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)naphthalen-2- yl)acrylamide;N-(5-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-2- yl)acrylamide;N-(5-(4-(hydroxymethyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-2- yl)acrylamide;N-(5-(4-(methoxymethyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-2- yl)acrylamide;N-(7-(N-(1-methylcyclopropyl)sulfamoyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)naphthalen-2- yl)acrylamide; and 4-(6-acrylamido-3-(N-(1-methylcyclopropyl)sulfamoyl)naphthalen-1-yl)-N,N-dimethylpiperazine-1- carboxamide; or a pharmaceutically acceptable salt thereof, preferably selected from4-(2-(bicyclo[1 .1 .0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)- N,N-dimethylpiperazine-1-carboxamide;(R)-N-(5-(4-isobutyryl-3-methylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-4-methyl-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N-dimethylpiperazine-1-carboxamide;(2S,6S)4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin- 5-yl)-N,N,2,6-tetramethylpiperazine-1-carboxamide;(S)4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N,2-trimethylpiperazine-1-carboxamide;N-(5-(4-isobutyrylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;N-(5-(4-(isopropylsulfonyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;N-(7-(N-(1-methylcyclopropyl)sulfamoyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;N-(5-(4-methyl-4-(methylsulfonyl)piperidin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;(S)-N-(5-(4-isobutyryl-3-methylpiperazin-1-yl)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-2- yl)bicyclo[1 .1 .0]butane-1 -carboxamide;Tert-butyl 4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1- methylcyclopropyl)sulfamoyl)quinolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate;4-(2-(bicyclo[1.1.0]butane-1-carboxamido)-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N , N-dimethyl-3 ,6-d i hyd ropy ridine-1 (2H)-carboxamide; and4-(2-acrylamido-7-(N-(1-methylcyclopropyl)sulfamoyl)quinolin-5-yl)-N,N-dimethylpiperazine-1- carboxamide, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising the compound of any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. The compound of any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 20, for use in therapy.

22. The compound for use or the pharmaceutical composition for use of claim 21 , for use in a method of treating a disease or disorder in which PARG activity is implicated,23. The compound for use of the pharmaceutical composition for use of claim 21 , for use in a method of treating a proliferative disorder, preferably wherein the proliferative disorder is cancer, preferably a human cancer.

24. Use of the compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a proliferative condition.

25. The use of claim 24, wherein the proliferative condition is cancer, preferably a human cancer.

26. Use of the compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of disease or disorder in which PARG activity is implicated.

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

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

29. The method of claim 28, where the proliferative disorder is cancer, preferably a human cancer.

Images