KR20240073050A - PARG inhibitory compounds - Google Patents

Abstract

The present invention relates to compounds of formula (I) or their enantiomers, diastereomers, tautomers, pharmaceutically acceptable solvates, pharmaceutically acceptable crystal forms, pharmaceutically acceptable salts or prodrugs. The invention further relates to compounds of formula (I) of the invention for use in therapy. The present compounds are particularly useful as PARC inhibitors and can be used in methods of treating proliferative disorders, preferably cancer.

Description

PARG inhibitory compounds

The present invention relates to compounds of formula (I):

[Formula (I)]

or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystal form, pharmaceutically acceptable salt or prodrug thereof. The invention further relates to compounds of formula (I) of the invention for use in therapy. The present compounds are particularly useful as PARG inhibitors and can be used in methods of treating proliferative disorders, preferably cancer.

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

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

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

Human PARG encodes a 111 kDa protein of 976 amino acids. It contains an N-terminal regulatory domain, a catalytic domain and an ADP-ribose binding macrodomain. Five human PARG transcripts were identified. Full-length PARGs are mostly nuclear; The smaller isoform is localized primarily to the cytoplasm. PARG primarily functions as an exo-hydrolase, which hydrolyzes the α-O-glycosidic ribose-ribose bond of PAR, releasing primarily mono(ADP-ribose). PARG can also act as an endo-hydrolase. PARG preferentially degrades long, linear PAR chains, while its activity is greatly reduced by small, branched PAR chains (O'Sullivan et al., Nat. Commun. 2019,10,1182).

PARG is the predominant cellular PAR-degrading enzyme, but is unable to act on terminal protein-ribose bonds. 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 the protein-binding mono(ADP-ribose) moiety (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 mainly found in the cytoplasm, but can also be found in mitochondria and nuclei (Rack et al., Genes Dev. 2020,34, 263).

Genomic abnormalities targeting tumor suppressor genes or oncogenes often render cancer cells dependent on specific DNA repair pathways. For example, it is well known that PARP inhibitors are particularly effective against tumors with 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 such as those between PARP and BRCA is an attractive new therapeutic approach for cancer treatment.

PARG participates in DNA replication and various DNA repair mechanisms, including single-strand break (SSB) repair and replication fork restart. PARG inhibitors exhibited a synthetic lethal phenotype in cells with high levels of DRS due to 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 DNA damaging agents such as irradiation and 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).

Considering the therapeutic potential of PARG inhibitors in cancer treatment, there is an increasing need for the development of highly potent and selective PARG inhibitors beyond those already described (a) James et al., ACS Chem. Biol. 2016,11,3179; b) Waszkowycz et al., J. Med. Chem. 2018,61,10767).

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

Document US 2019/233411 discloses certain Gcn2 inhibitors and uses thereof.

Document WO 2009/050183 discloses certain imidazo[1,2-a]pyridine derivatives useful for treating diseases mediated by ALK-5 and/or ALK-4 receptors.

Providing a compound that is a cell permeability inhibitor of PARG was the technical objective of the present invention. The technical problem of the present invention is solved by the embodiments described herein and as characterized by the claims.

Accordingly, in a first embodiment, the present invention provides a compound of formula (I):

[Formula (I)]

Or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystal form, pharmaceutically acceptable salt or prodrug thereof is provided. As used herein, the term “compound of formula (I)” is understood to preferably also include compounds of formula (Ia) to (Ibo), unless otherwise specified.

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

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

Compounds of formula (I) are useful for treating diseases or disorders in which PARG activity is implicated.

Compounds of formula (I) are useful in methods of treating proliferative disorders. In a preferred embodiment of the invention, the proliferative disorder is cancer, preferably human cancer.

Justice

Unless specifically indicated otherwise, the following definitions apply throughout this specification and claims.

The term “hydrogen” is used herein to refer to protium, deuterium and/or tritium, preferably protium. Accordingly, the term “non-hydrogen atom” refers to any atom that is not hydrogen, i.e., any atom that is not protium, deuterium, or tritium.

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

The term “cycloaliphatic” is used in reference to a cyclic group and indicates that the cyclic group is non-aromatic.

As used herein, the term “alkyl” refers to a monovalent saturated acyclic (i.e., acyclic) hydrocarbon group, which may be linear or branched. Accordingly, an “alkyl” group does not include any carbon-carbon double bond or any carbon-carbon triple bond. “C _1-5 alkyl” refers to an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (eg n-propyl or isopropyl) or butyl (eg n-butyl, isobutyl, sec-butyl or tert-butyl). Unless otherwise defined, the term “alkyl” preferably refers to C _1-4 alkyl, more preferably methyl or ethyl, and even more preferably methyl.

As used herein, the term “alkenyl” may be linear or branched and contains one or more (e.g., 1 or 2) carbon-carbon double bonds, but may contain any carbon-carbon triple bonds. refers to a monovalent unsaturated acyclic hydrocarbon group that does not contain The term “C _2-5 alkenyl” refers to an alkenyl group having 2 to 5 carbon atoms. Preferred exemplary alkenyl groups include 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) )am. Unless otherwise defined, the term “alkenyl” preferably refers to C _2-4 alkenyl.

As used herein, the term “alkynyl” can be linear or branched and has one or more (e.g., 1 or 2) carbon-carbon triple bonds and optionally one or more (e.g., 1 or refers to a monovalent unsaturated acyclic hydrocarbon group containing 2) carbon-carbon double bonds. The term “C _2-5 alkynyl” refers to an alkynyl group having 2 to 5 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (eg, propargyl), or butynyl. Unless otherwise defined, the term “alkynyl” preferably refers to C _2-4 alkynyl.

As used herein, the term “alkylene” refers to an alkanediyl group, that is, a divalent saturated acyclic hydrocarbon group that may be linear or branched. “C _1-5 alkylene” refers to an alkylene group having 1 to 5 carbon atoms, and the term “C _0-3 alkylene” refers to a covalent bond (corresponding to the option “C ₀ alkylene”) or a C _1-3 Indicates the presence of alkylene. Preferred exemplary alkylene groups include methylene (-CH ₂ -), ethylene (eg -CH ₂ -CH ₂ - or -CH(-CH ₃ )-), propylene (eg -CH ₂ -CH ₂ -CH ₂ -, -CH(-CH ₂ -CH ₃ )-, -CH ₂ -CH(-CH ₃ ) or -CH(-CH ₃ )-CH ₂ -) or butylene (e.g. -CH ₂ -CH ₂ -CH ₂ -CH ₂ -). Unless otherwise defined, the term “alkylene” preferably refers to C _1-4 alkylene (including especially linear C _1-4 alkylene), more preferably methylene or ethylene, even more preferably methylene. refers to

As used herein, the term “alkenylene” refers to an alkenediyl group, which may be linear or branched and contains one or more (e.g., 1 or 2) carbon-carbon double bonds, but may contain any Refers to a divalent unsaturated acyclic hydrocarbon group that does not contain a carbon-carbon triple bond. “C _2-5 alkenylene” refers to an alkenylene group having 2 to 5 carbon atoms. Unless otherwise defined, the term “alkenylene” preferably refers to C _2-4 alkenylene (including especially linear C _2-4 alkenylene).

As used herein, the term “alkynylene” refers to an alkynediyl group, which may be linear or branched and has one or more (e.g., 1 or 2) carbon-carbon triple bonds and optionally one or more (e.g., refers to a divalent unsaturated acyclic hydrocarbon group containing (e.g., 1 or 2) carbon-carbon double bonds. “C _2-5 alkynylene” refers to an alkynylene group having 2 to 5 carbon atoms. Unless otherwise defined, the term “alkynylene” preferably refers to C _2-4 alkynylene (including especially linear C _2-4 alkynylene).

As used herein, the term “carbocyclyl” refers to monocyclic rings as well as bridged rings, spiro rings, and/or fused ring systems (which may, for example, consist of two or three rings). refers to a hydrocarbon ring group, wherein the ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic), or aromatic. Unless otherwise defined, “carbocyclyl” preferably refers to aryl, cycloalkyl or cycloalkenyl.

As used herein, the term “heterocyclyl” includes monocyclic rings as well as bridged rings, spiro rings, and/or fused ring systems (which may, for example, consist of two or three rings). Refers to a ring group, wherein the ring group comprises one or more (e.g., 1, 2, 3 or 4) ring heteroatoms independently selected from O, S, N, P and Si, 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 be optionally oxidized. may be, wherein one or more carbon ring atoms may be selectively oxidized (i.e., to form an oxo group), and further wherein the ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic), or aromatic. For example, each heteroatom containing ring included in the ring group may have 1 or 2 O atoms and/or 1 or 2 S atoms (which may be optionally oxidized) and/or 1, 2, may contain 3 or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that the corresponding heteroatom-containing ring contains at least one Carbon ring atoms (which may be optionally oxidized) are present. Unless otherwise defined, “heterocyclyl” preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl.

Preferably, the term "heterocyclyl" refers to a ring group comprising monocyclic rings as well as bridged rings, spiro rings and/or fused ring systems (which may for example consist of two or three rings). wherein the ring group comprises one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, 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 be selectively oxidized, and wherein one or more carbon ring atoms may be selectively oxidized (i.e., oxo forming a group), further wherein the ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. For example, each heteroatom containing ring included in the ring group may have 1 or 2 O atoms and/or 1 or 2 S atoms (which may be optionally oxidized) and/or 1, 2, may contain 3 or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that the corresponding heteroatom-containing ring contains at least one Carbon ring atoms (which may be optionally oxidized) are present. Unless otherwise defined, “heterocyclyl” preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl.

As used herein, the term “aryl” refers to monocyclic aromatic rings as well as bridged rings and/or fused ring systems containing at least one aromatic ring (e.g., consisting of two or three fused rings). refers to aromatic hydrocarbon ring groups, including ring systems (where at least one of these fused rings is aromatic); bridged ring systems consisting of two or three rings (where at least one of these bridged rings is aromatic). “Aryl” means, for example, phenyl, naphthyl, diallinyl (i.e., 1,2-dihydronaphthyl), tetralinyl (i.e., 1,2,3,4-tetrahydronaphthyl), indanyl. , indenyl (e.g., 1H-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl. Unless otherwise defined, “aryl” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably Refers to phenyl.

As used herein, the term "arylene" refers to an aryl group as defined hereinabove but having two points of attachment, i.e., a monocyclic aromatic ring as well as a bridged ring containing at least one aromatic ring and /or fused ring systems (e.g. ring systems consisting of 2 or 3 fused rings, at least one of which is aromatic); bridged ring systems consisting of 2 or 3 rings (these bridged rings refers to a divalent aromatic hydrocarbon ring group, including (at least one of which is aromatic)). “Arylene” means, for example, phenylene (e.g., phen-1,2-diyl, phen-1,3-diyl, or phen-1,4-diyl), naphthylene (e.g., naphthalene-1 ,2-diyl), naphthalene-1,3-diyl, naphthalene-1,4-diyl, naphthalene-1,5-diyl, naphthalene-1,6-diyl, naphthalene-1,7-diyl, naphthalene-2, 3-diyl, naphthalene-2,5-diyl, naphthalene-2,6-diyl, naphthalene-2,7-diyl or naphthalene-2,8-diyl), 1,2-dihydronaphthylene, 1,2, It may refer to 3,4-tetrahydronaphthylene, indanylene, indenylene, anthracenylene, phenanthrenylene, 9H-fluorenylene, or azulenylene. Unless otherwise defined, “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 Specifically, it refers to phenylene (particularly phen-1,4-diyl).

As used herein, the term “heteroaryl” refers to monocyclic aromatic rings as well as bridged rings and/or fused ring systems containing at least one aromatic ring (e.g., with two or three fused rings). refers to aromatic ring groups, including ring systems made up of two or three rings, at least one of which is aromatic; The aromatic ring group includes one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, 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 be selectively oxidized, further wherein one or more carbon ring atoms may be selectively oxidized (i.e., forming a group). For example, each heteroatom-containing ring included in the aromatic ring group may have 1 or 2 O atoms and/or 1 or 2 S atoms (which may be optionally oxidized) and/or 1, 2 , may contain 3 or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and at least one in the corresponding heteroatom-containing ring. of carbon ring atoms (which may be optionally oxidized) are present. “Heteroaryl” means, for example, thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuryl. Nyl, isobenzofuranyl, chromanyl, chromenyl (e.g. 2H-1-benzopyranyl or 4H-1-benzopyranyl), isochromenyl (e.g. 1H-2-benzopyranyl) , chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g. 1H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (e.g. 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, β-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 (e.g. furazanyl) or 1,3,4-oxazolyl diazolyl), 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, benzothiadia Zolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e. benzothienyl), triazolyl (e.g. 1H-1,2,3-triazolyl), 2H- 1,2,3-triazolyl, 1H-1,2,4-triazolyl, or 4H-1,2,4-triazolyl), benzotriazolyl, 1H-tetrazolyl, 2H-tetrazolyl, triazinyl ( For example, 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydropuropyridinyl (e.g. For example, 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 otherwise defined, the term “heteroaryl” refers to a 5-membered group containing one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N. refers to a monocyclic ring or fused ring system of from 5 to 14 members (more preferably from 5 to 10 members), wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are selectively oxidized, wherein one or more carbon ring atoms are selectively oxidized; Even more preferably, “heteroaryl” is a 5- or 6-membered group containing one or more (e.g. 1, 2 or 3) ring heteroatoms independently selected from O, S, and N. Refers to a cyclic ring, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.

As used herein, the term "heteroarylene" refers to a heteroaryl group as defined hereinabove but having two points of attachment, i.e., a monocyclic aromatic ring as well as a bridged group containing at least one aromatic ring. Rings and/or fused ring systems (e.g., ring systems consisting of two or three fused rings, at least one of which is aromatic); bridged ring systems consisting of two or three rings (e.g., ring systems consisting of two or three fused rings) refers to a divalent aromatic ring group, including at least one of the rings is aromatic), wherein the aromatic ring group is one or more independently selected from O, S, and N (e.g., 1, 2, 3 or 4) ring heteroatoms, the remaining ring atoms being carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may be optionally oxidized. may be, and further wherein one or more carbon ring atoms may be selectively oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring included in the aromatic ring group may have 1 or 2 O atoms and/or 1 or 2 S atoms (which may be optionally oxidized) and/or 1, 2 , may contain 3 or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and at least one in the corresponding heteroatom-containing ring. of carbon ring atoms (which may be optionally oxidized) are present. “Heteroarylene” refers to, for example, 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, phenoxathionylene, pyrrolylene, imidazolylene, pyranyl Zolene, pyridinylene (i.e. pyridinylene), pyrazinylene, pyrimidinylene, pyridazinylene, indolilene, isoindolylene, indazolylene, indolizinylene, purinylene, quinolylene, Isoquinolylene, phthalazinylene, naphthyridinylene, quinoxalinylene, cinnolinylene, pteridinylene, carbazolilene, β-carbolinylene, phenanthridinylene, acridinylene, perimidinylene , phenanthrolinylene, phenazynylene, thiazolilene (e.g., thiazole-2,4-diyl, thiazole-2,5-diyl or thiazole-4,5-diyl), isothiazolylene ( For example, isothiazole-3,4-diyl, isothiazole-3,5-diyl or isothiazole-4,5-diyl), phenothiazinylene, oxazonylene (e.g., oxazole -2,4-diyl, oxazole-2,5-diyl or oxazole-4,5-diyl), isoxazole (e.g. isoxazole)-3,4-diyl, isoxazole-3,5 -diyl, or isoxazole-4,5-diyl), oxadiazolylene (e.g. 1,2,4-oxadiazole-3,5-diyl, 1,2,5-oxadiazole-3 ,4-diyl or 1,3,4-oxadiazole-2,5-diyl), thiadiazolylene (e.g. 1,2,4-thiadiazole-3,5-diyl, 1,2 , 5-thiadiazole-3,4-diyl or 1,3,4-thiadiazole-2,5-diyl), phenoxazinylene, pyrazolo [1,5-a] pyrimidinylene, 1, 2-benzoisoxazolylene, benzothiazolylene, benzothiadiazolylene, benzooxazolylene, benzisoxazolylene, benzimidazolylene, benzo[b]thiophenylene (i.e. benzothienylene), Triazolilene (e.g., 1H-1,2,3-triazolilene, 2H-1,2,3-triazolilene, 1H-1,2,4-triazolilene or 4H-1,2, 4-triazonylene), benzotriazonylene, 1H-tetrazolylene, 2H-tetrazolylene, triazinylene (e.g. 1,2,3-triazinylene, 1,2,4-triazinyl lene or 1,3,5-triazinylene), furo[2,3-c]pyridinylene, dihydropuropyridinylene (e.g. 2,3-dihydrofuro[2,3-c] pyridinylene or 1,3-dihydrofuro[3,4-c]pyridinylene), imidazopyridinylene (e.g. imidazo[1,2-a]pyridinylene or imidazo[3 ,2-a]pyridinylene), quinazolinylene, thienopyridinylene, tetrahydrothienopyridinylene (e.g., 4,5,6,7-tetrahydrothieno[3,2-c ]pyridinylene), dibenzofuranilene, 1,3-benzodioxanilene, benzodioxanilene (e.g., 1,3-benzodioxanilene or 1,4-benzodioxanilene) or coumarinylene can refer to. Unless otherwise defined, the term “heteroarylene” refers to a heteroarylene group containing one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N. Refers to a divalent 5- to 14-membered (more preferably 5- to 10-membered) monocyclic ring or fused ring system, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) case) is selectively oxidized, wherein one or more carbon ring atoms are selectively oxidized; Even more preferably, “heteroarylene” is a divalent 5-membered or Refers to a 6-membered monocyclic ring, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. . “Heteroarylene,” including any specific heteroarylene group described herein, refers to a group having two carbon ring atoms, especially within one single ring or within an entire ring system of the corresponding heteroarylene (the shortest possible linkage). can be attached via the two carbon ring atoms that have the greatest distance from each other (in terms of the number of ring atoms separating them by ).

As used herein, the term "cycloalkyl" refers to monocyclic rings as well as bridged rings, spiro rings and/or fused ring systems (which may consist of two or three rings; e.g. , refers to a saturated hydrocarbon ring group containing a fused ring system consisting of two or three fused rings. “Cycloalkyl” may refer to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl. Unless otherwise defined, “cycloalkyl” preferably refers to C _3-11 cycloalkyl, more preferably C _3-7 cycloalkyl. Particularly preferred “cycloalkyl” is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g. cyclopropyl or cyclohexyl).

As used herein, the term “cycloalkylene” refers to a cycloalkyl group as defined hereinabove but having two points of attachment, i.e. monocyclic rings as well as bridged rings, spiro rings and/or fused rings. refers to a divalent, saturated hydrocarbon ring group containing a system (which may, for example, consist of two or three rings; for example, a fused ring system consisting of two or three fused rings). “Cycloalkylene” means, for example, cyclopropylene (e.g., cyclopropane-1,1-diyl or cyclopropane-1,2-diyl), cyclobutylene (e.g., cyclobutane-1,1-diyl), diyl, cyclobutane-1,2-diyl, or cyclobutane-1,3-diyl), cyclopentylene (e.g., cyclopentane-1,1-diyl, cyclopentane-1,2-diyl, or cyclopentane-1,2-diyl, or cyclopentane-1,3-diyl) pentane-1,3-diyl), cyclohexylene (e.g. cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl or cyclohexane-1,4 -diyl), cycloheptylene, decalinylene (i.e., decahydronaphthylene), or adamantylene. Unless otherwise defined, “cycloalkylene” preferably refers to C _3-11 cycloalkylene, more preferably C _3-7 cycloalkylene. Particularly preferred “cycloalkylenes” are divalent, monocyclic, saturated hydrocarbon rings having 3 to 7 ring members (e.g., cyclopropylene or cyclohexylene).

As used herein, the term "heterocycloalkyl" refers to monocyclic rings as well as bridged rings, spiro rings and/or fused ring systems (which may consist of two or three rings; e.g. refers to a saturated ring group comprising a fused ring system (e.g., consisting of two or three fused rings), wherein the ring group is one or more independently selected from O, S, N, P, and Si (e.g., one , 2, 3 or 4) ring heteroatoms, the remaining ring atoms being 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 be selectively oxidized, and further one or more carbon ring atoms may be selectively oxidized (i.e., to form an oxo group). For example, each heteroatom containing ring included in the saturated ring group may have 1 or 2 O atoms and/or 1 or 2 S atoms (which may be optionally oxidized) and/or 1, 2 , may contain 3 or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and at least one in the corresponding heteroatom-containing ring. of carbon ring atoms (which may be optionally oxidized) are present. “Heterocycloalkyl” refers to, for example, 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), oxazepanil, oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxephanil , thiranyl, thiethanyl, tetrahydrothiophenyl (i.e. thiolanyl), 1,3-dithiolanyl, thianyl, 1,1-dioxothianyl, thiephanyl, decahydroquinolinyl, deca may refer to hydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless otherwise defined, “heterocycloalkyl” refers to a 3- to 11-membered saturated ring group, preferably a monocyclic ring or a fused ring system (e.g., a fused ring system consisting of two fused rings), wherein the ring group comprises one or more (e.g., 1, 2, 3 or 4) ring heteroatoms independently selected from O, 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; More preferably, “heterocycloalkyl” is a 5- to 7-membered saturated group containing one or more (e.g. 1, 2 or 3) ring heteroatoms independently selected from O, S and N. Refers to a cyclic ring group, 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.

Preferably, as used herein, the term "heterocycloalkyl" refers to monocyclic rings as well as bridged rings, spiro rings and/or fused ring systems (which may for example consist of two or three rings). refers to a saturated ring group comprising a fused ring system, e.g., consisting of two or three fused rings, wherein the ring group is independently selected from O, S, and N, e.g. , 2, 3 or 4) ring heteroatoms, the remaining ring atoms being carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) can be selectively oxidized, and in addition one or more carbon ring atoms can be selectively oxidized (i.e., to form an oxo group). For example, each heteroatom containing ring included in the saturated ring group may have 1 or 2 O atoms and/or 1 or 2 S atoms (which may be optionally oxidized) and/or 1, 2 , may contain 3 or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and at least one in the corresponding heteroatom-containing ring. of carbon ring atoms (which may be optionally oxidized) are present. “Heterocycloalkyl” refers to, for example, 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), oxazepanil, oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxephanil , thiranyl, thiethanyl, tetrahydrothiophenyl (i.e. thiolanyl), 1,3-dithiolanyl, thianyl, 1,1-dioxothianyl, thiephanyl, decahydroquinolinyl, deca may refer to hydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless otherwise defined, “heterocycloalkyl” refers to a 3- to 11-membered saturated ring group, preferably a monocyclic ring or a fused ring system (e.g., a fused ring system consisting of two fused rings), wherein the ring group comprises one or more (e.g., 1, 2, 3 or 4) ring heteroatoms independently selected from O, 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; More preferably, “heterocycloalkyl” is a 5- to 7-membered saturated group containing one or more (e.g. 1, 2 or 3) ring heteroatoms independently selected from O, S and N. Refers to a cyclic ring group, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.

As used herein, the term “heterocycloalkylene” refers to a heterocycloalkyl group as defined hereinabove but having two points of attachment, i.e. monocyclic rings as well as bridged rings, spiro rings and/or refers to a divalent, saturated ring group comprising a fused ring system (which may, for example, consist of two or three rings; for example, a fused ring system consisting of two or three fused rings), wherein said ring The group comprises one or more (e.g., 1, 2, 3 or 4) ring heteroatoms independently selected from O, 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 be optionally oxidized, and further one or more carbon ring atoms. Atoms can be selectively oxidized (i.e., form oxo groups). For example, each heteroatom containing ring included in the saturated ring group may have 1 or 2 O atoms and/or 1 or 2 S atoms (which may be optionally oxidized) and/or 1, 2 , may contain 3 or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and at least one in the corresponding heteroatom-containing ring. of carbon ring atoms (which may be optionally oxidized) are present. “Heterocycloalkylene” means, for example, aziridinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, piperazinylene, azepanylene, diazepanylene. (e.g. 1,4-diazephanylene), oxazolidinylene, isoxazolidinylene, thiazolidinylene, isothiazolidinylene, morpholinylene, thiomorpholynylene, oxazepanylene, oxira Nylene, oxetanylene, tetrahydrofuranylene, 1,3-dioxolanylene, tetrahydropyranylene, 1,4-dioxanilene, oxepanylene, thiranilene, thiethanylene, tetrahydrothiophenylene ( i.e., thiolanylene), 1,3-dithiolanilene, tianilene, 1,1-dioxothianilene, thiephanylene, decahydroquinolinylene, decahydroisoquinolinylene, or 2-oxa -5-aza-bicyclo[2.2.1]hept-5-ylene. Unless otherwise defined, “heterocycloalkylene” refers to a divalent, 3- to 11-membered saturated ring group, preferably a monocyclic ring or a fused ring system (e.g., a fused ring system consisting of two fused rings). refers to wherein the ring group comprises one or more (e.g., 1, 2, 3 or 4) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms ( where present) and/or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized; More preferably, “heterocycloalkylene” is a divalent 5- to 7-membered alkylene group containing one or more (e.g. 1, 2 or 3) ring heteroatoms independently selected from O, S and N. Refers to a circularly saturated monocyclic ring group, 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.

Preferably, the term "heterocycloalkylene" refers to heterocycloalkyl groups as defined hereinabove but having two points of attachment, i.e. monocyclic rings as well as bridged rings, spiro rings and/or fused ring systems ( refers to a divalent saturated ring group comprising a fused ring system, which may for example consist of two or three rings; for example, a fused ring system consisting of two or three fused rings, wherein the ring group is and one or more (e.g., 1, 2, 3 or 4) ring heteroatoms independently selected from N, wherein the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (where present ) and/or one or more N ring atoms (if present) may be selectively oxidized, and further one or more carbon ring atoms may be selectively oxidized (i.e., to form an oxo group). For example, each heteroatom containing ring included in the saturated ring group may have 1 or 2 O atoms and/or 1 or 2 S atoms (which may be optionally oxidized) and/or 1, 2 , may contain 3 or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and at least one in the corresponding heteroatom-containing ring. of carbon ring atoms (which may be optionally oxidized) are present. “Heterocycloalkylene” means, for example, aziridinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, piperazinylene, azepanylene, diazepanylene. (e.g. 1,4-diazephanylene), oxazolidinylene, isoxazolidinylene, thiazolidinylene, isothiazolidinylene, morpholinylene, thiomorpholynylene, oxazepanylene, oxira Nylene, oxetanylene, tetrahydrofuranylene, 1,3-dioxolanylene, tetrahydropyranylene, 1,4-dioxanilene, oxepanylene, thiranilene, thiethanylene, tetrahydrothiophenylene ( i.e. thiolanylene), 1,3-dithiolanilene, tianilene, 1,1-dioxothianilene, thiephanylene, decahydroquinolinylene, decahydroisoquinolinylene, or 2-oxa -5-aza-bicyclo[2.2.1]hept-5-ylene. Unless otherwise defined, “heterocycloalkylene” refers to a divalent, 3- to 11-membered saturated ring group, preferably a monocyclic ring or a fused ring system (e.g., a fused ring system consisting of two fused rings). refers to wherein the ring group comprises one or more (e.g., 1, 2, 3 or 4) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms ( where present) and/or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized; More preferably, “heterocycloalkylene” is a divalent 5- to 7-membered alkylene group containing one or more (e.g. 1, 2 or 3) ring heteroatoms independently selected from O, S and N. Refers to a circularly saturated monocyclic ring group, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.

As used herein, the term " N -heterocycloalkyl" refers to a heterocycloalkyl group as defined above, wherein said heterocycloalkyl has at least one nitrogen atom serving as the point of attachment for said heterocycloalkyl. Includes.

As used herein, the term “cycloalkenyl” refers to monocyclic rings as well as bridged rings, spiro rings and/or fused ring systems (which may consist of two or three rings; e.g. refers to an unsaturated alicyclic (non-aromatic) hydrocarbon ring group comprising an unsaturated cycloaliphatic (non-aromatic) hydrocarbon ring group (e.g., a fused ring system consisting of 2 or 3 fused rings), wherein the hydrocarbon ring group is one or more (e.g., 1 or 2) Contains carbon-carbon double bonds and does not contain any carbon-carbon triple bonds. “Cycloalkenyl” may refer to, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. Unless otherwise defined, “cycloalkenyl” preferably refers to C _3-11 cycloalkenyl, more preferably C _3-7 cycloalkenyl. Particularly preferred "cycloalkenyl" is a monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and containing at least one (e.g. 1 or 2, preferably 1) carbon-carbon double bond. am.

As used herein, the term “cycloalkenylene” refers to a cycloalkenyl group as defined hereinabove but having two points of attachment, i.e. monocyclic rings as well as bridged rings, spiro rings and/or fused rings. A divalent unsaturated alicyclic (non-aromatic) hydrocarbon ring comprising a ring system (which may for example consist of two or three rings; for example a fused ring system consisting of two or three fused rings) refers to a group, wherein the hydrocarbon ring group includes one or more (e.g., 1 or 2) carbon-carbon double bonds and does not include any carbon-carbon triple bonds.

As used herein, the term “heterocycloalkenyl” refers to monocyclic rings as well as bridged rings, spiro rings, and/or fused ring systems (e.g., which may consist of two or three rings; e.g. refers to an unsaturated alicyclic (non-aromatic) ring group comprising an unsaturated cycloaliphatic (non-aromatic) ring system (e.g., a fused ring system consisting of two or three fused rings), wherein the ring group is one independently selected from O, S, N, P and Si. comprising at least one (e.g. 1, 2, 3 or 4) ring heteroatoms, the remaining ring atoms being carbon atoms, wherein one or more S ring atoms (if present) and/or one or more The N ring atom (if present) and/or one or more P ring atoms (if present) may be selectively oxidized, wherein one or more carbon ring atoms may be selectively oxidized (i.e., form an oxo group). , further wherein the ring group contains at least one double bond between adjacent ring atoms and does not contain any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring included in the unsaturated alicyclic ring group may have 1 or 2 O atoms and/or 1 or 2 S atoms (which may be optionally oxidized) and/or 1 atom, may contain 2, 3 or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and At least one carbon ring atom (which may be optionally oxidized) is present. “Heterocycloalkenyl” refers to, for example, imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl -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), dihydropyra Nyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindolyl, octahydroquinolinyl (e.g. 1,2,3,4,4a,5,6,7-octahydro quinolinyl) or octahydroisoquinolinyl (e.g., 1,2,3,4,5,6,7,8-octahydroisoquinolinyl). Unless otherwise defined, “heterocycloalkenyl” refers to a 3- to 11-membered unsaturated alicyclic ring group that is preferably a monocyclic ring or a fused ring system (e.g., a fused ring system consisting of two fused rings). refers to wherein the ring group comprises one or more (e.g., 1, 2, 3 or 4) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms ( where present) and/or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, wherein said ring group has at least one double bond between adjacent ring atoms. and does not contain any triple bonds between adjacent ring atoms; More preferably, “heterocycloalkenyl” is a 5- to 7-membered group containing one or more (e.g. 1, 2 or 3) ring heteroatoms independently selected from O, S and N. Refers to a cyclically unsaturated non-aromatic ring group, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are selectively oxidized, and wherein one or more carbon ring atoms are optionally oxidized and , wherein the ring group contains at least one double bond between adjacent ring atoms and does not contain any triple bond between adjacent ring atoms.

Preferably, the term "heterocycloalkenyl" refers to monocyclic rings as well as bridged rings, spiro rings and/or fused ring systems (which may for example consist of two or three rings; e.g. 2 refers to an unsaturated alicyclic (non-aromatic) ring group comprising a fused ring system consisting of 2 or 3 fused rings, wherein the ring group is one or more independently selected from O, S, and N (e.g., one , 2, 3 or 4) ring heteroatoms, the remaining ring atoms being carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may be selectively oxidized, wherein one or more carbon ring atoms may be selectively oxidized (i.e., form an oxo group), further wherein the ring group comprises at least one double bond between adjacent ring atoms and adjacent It does not contain any triple bonds between ring atoms. For example, each heteroatom-containing ring included in the unsaturated alicyclic ring group may have 1 or 2 O atoms and/or 1 or 2 S atoms (which may be optionally oxidized) and/or 1 atom, may contain 2, 3 or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and At least one carbon ring atom (which may be optionally oxidized) is present. “Heterocycloalkenyl” refers to, for example, imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl -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), dihydropyra Nyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindolyl, octahydroquinolinyl (e.g. 1,2,3,4,4a,5,6,7-octahydro quinolinyl) or octahydroisoquinolinyl (e.g., 1,2,3,4,5,6,7,8-octahydroisoquinolinyl). Unless otherwise defined, “heterocycloalkenyl” refers to a 3- to 11-membered unsaturated alicyclic ring group that is preferably a monocyclic ring or a fused ring system (e.g., a fused ring system consisting of two fused rings). refers to wherein the ring group comprises one or more (e.g., 1, 2, 3 or 4) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms ( where present) and/or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, wherein said ring group has at least one double bond between adjacent ring atoms. and does not contain any triple bonds between adjacent ring atoms. More preferably, “heterocycloalkenyl” is a 5- to 7-membered group containing one or more (e.g. 1, 2 or 3) ring heteroatoms independently selected from O, S and N. Refers to a cyclically unsaturated non-aromatic ring group, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are selectively oxidized, and wherein one or more carbon ring atoms are optionally oxidized and , wherein the ring group contains at least one double bond between adjacent ring atoms and does not contain any triple bond between adjacent ring atoms.

As used herein, the term “heterocycloalkenylene” refers to a heterocycloalkenyl group as defined hereinabove but having two points of attachment, i.e. monocyclic rings as well as bridged rings, spiro rings and/or or a divalent unsaturated alicyclic (non-aromatic) comprising a fused ring system (which may for example consist of two or three rings; for example a fused ring system consisting of two or three fused rings). Refers to a ring group, wherein the ring group comprises one or more (e.g., 1, 2, 3 or 4) ring heteroatoms independently selected from O, S, N, P and Si, and the remainder The ring atom is a carbon atom, 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 be optionally oxidized. and wherein one or more carbon ring atoms can be selectively oxidized (i.e., to form an oxo group), and further wherein the ring group comprises at least one double bond between adjacent ring atoms and an optional bond between adjacent ring atoms. Contains no triple bonds. For example, each heteroatom-containing ring included in the unsaturated alicyclic ring group may have 1 or 2 O atoms and/or 1 or 2 S atoms (which may be optionally oxidized) and/or 1 atom, may contain 2, 3 or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and At least one carbon ring atom (which may be optionally oxidized) is present.

Preferably, the term "heterocycloalkenylene" refers to heterocycloalkenyl groups as defined hereinabove but having two points of attachment, i.e. monocyclic rings as well as bridged rings, spiro rings and/or fused ring systems. refers to a divalent unsaturated alicyclic (non-aromatic) ring group comprising (e.g., may consist of two or three rings; e.g., a fused ring system consisting of two or three fused rings) , wherein the ring group comprises one or more (e.g., 1, 2, 3 or 4) ring heteroatoms independently selected from O, 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 be selectively oxidized, wherein one or more carbon ring atoms may be selectively oxidized (i.e., to form an oxo group) ), further wherein the ring group includes at least one double bond between adjacent ring atoms and does not include any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring included in the unsaturated alicyclic ring group may have 1 or 2 O atoms and/or 1 or 2 S atoms (which may be optionally oxidized) and/or 1 atom, may contain 2, 3 or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and At least one carbon ring atom (which may be optionally oxidized) is present.

As used herein, the term “halogen” refers to fluoro (-F), chloro (-Cl), bromo (-Br), or iodo (-I). As will be understood by those skilled in the art, the terms “halogen” and “halo” may be used interchangeably.

As used herein, the term "haloalkyl" means one or more (preferably 1 to 6, more preferably all fluoro) atoms independently selected from fluoro, chloro, bromo and iodo. It refers to an alkyl group substituted with (preferably 1 to 3) halogen atoms. It will be appreciated that the maximum number of halogen atoms is limited by the number of attachment sites available and therefore depends on the number of carbon atoms included in the alkyl moiety of the haloalkyl group. “Haloalkyl” refers to, for example, -CF ₃ , -CHF ₂ , -CH ₂ F, -CF ₂ -CH ₃ , -CH ₂ -CF ₃ , -CH ₂ -CHF ₂ , -CH ₂ -CF ₂ -CH ₃ , -CH ₂ -CF ₂ -CF ₃ or -CH(CF ₃ ) ₂ may be referred to. A particularly preferred “haloalkyl” group is -CF ₃ .

The terms “bond” and “covalent bond” are used synonymously herein unless explicitly indicated otherwise or contradictory from context.

As used herein, the terms “optional,” “optionally,” and “may” mean that the indicated feature may or may not be present. Whenever the terms “optional,” “optionally,” or “may” are used, the invention specifically refers to both possibilities, i.e., the possibility that the corresponding feature is present or, alternatively, the corresponding feature is absent. It will. For example, the expression “X is optionally substituted with Y” (or “X may be substituted with Y”) means that X may or may not be substituted with Y. Likewise, when a component of a composition is indicated as “optional,” the invention specifically relates to both possibilities: either the corresponding component is present (contained in the composition) or the corresponding component is absent from the composition.

Various groups are referred to herein as “optionally substituted.” In general, these groups may have one or more substituents, for example 1, 2, 3 or 4 substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available for the substituted moiety. Unless otherwise defined, “optionally substituted” groups referred to herein preferably have no more than two substituents and in particular may have only one substituent. Moreover, unless otherwise defined, it is preferred that there are no optional substituents, ie the corresponding groups are unsubstituted.

Those skilled in the art will understand that substituents contained in the compounds of the present invention may be attached to the remainder of each compound through a number of different positions for the corresponding specific substituent. Unless otherwise defined, preferred attachment positions for various specific substituents are as illustrated in the Examples.

As used herein, unless explicitly indicated otherwise or contradictory from 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) may be interpreted as referring to a composition comprising “one or more” compounds of formula (I).

It should be understood that where numerical ranges are provided or disclosed herein, all values and subranges included in each numerical range are intended to be included within the scope of the invention. Accordingly, the present invention relates specifically and individually to each value falling within the numerical range disclosed herein as well as to each subrange within the numerical range disclosed herein.

As used herein, the term “about” preferably means ±10% of the indicated value, more preferably ±5% of the indicated value, especially the exact value indicated. When the term "about" is used in connection with an endpoint of a range, it preferably refers to a range from -10% of the lower endpoint of the indicated numerical value to +10% of the upper endpoint of the numerical value indicated, more preferably the lower endpoint. It refers to a range from -5% to the upper endpoint +5%, more preferably a range defined by the exact values of the lower endpoint and the upper endpoint.

As used herein, the term "comprising" (or "includes," "includes," "includes," "includes," or "contains") does not mean otherwise explicitly indicated or contradictory to the context. Unless otherwise specified, it has the meaning of “containing, among other things,” that is, “containing, among additional optional elements.” In addition, the term also includes the narrower meanings of “consisting essentially of” and “consisting of.” For example, the term “A comprising B and C” means “A comprising B and C,” where A may contain additional optional elements (e.g., “B, "A containing C and D"), the term also includes "A consists essentially of B and C" and "A consists essentially of B and C" (i.e. A contains elements other than B and C) It also includes the meaning that “no other ingredients are included.”

The present invention is explained in detail below. It should be understood that the invention relates to each and every combination of the features and embodiments described herein, including in particular any combination of general and/or preferred features/embodiments.

In a first embodiment, the invention provides a compound of formula (I):

[Formula (I)]

or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystal form, pharmaceutically acceptable salt or prodrug thereof.

R ₁ is hydrogen, chloro, fluoro, cyano, formyl, (C _1-2 )alkyl, (C ₂ )alkenyl, (C ₂ )alkynyl, (C _1-2 )haloalkyl, -(C _1-2 alkylene)-OH and -(C _1-2 alkylene)-O-(C _1-2 alkyl), preferably chloro, fluoro, cyano, formyl, (C _{1 -2} )alkyl, (C ₂ )alkenyl, (C ₂ )alkynyl, (C _1-2 )haloalkyl, -(C _1-2 alkylene)-OH and -(C _1-2 alkylene)- is selected from the group consisting of O-(C _1-2 alkyl). Preferably, R ₁ is hydrogen, chloro, fluoro, cyano, formyl, (C _1-2 )alkyl, (C ₂ )alkenyl, (C ₂ )alkynyl and (C _1-2 )haloalkyl. from the group consisting of, preferably chloro, fluoro, cyano, formyl, (C _1-2 )alkyl, (C ₂ )alkenyl, (C ₂ )alkynyl and (C _1-2 )haloalkyl. is selected from the group consisting of More preferably, R ₁ is selected from the group consisting of cyano, (C _1-2 )alkyl, and (C _1-2 )haloalkyl. Preferably, (C _1-2 )alkyl as discussed herein is methyl. Preferably, the (C _1-2 )haloalkyl as discussed herein is fluoromethyl. Therefore, preferably R ₁ is selected from the group consisting of cyano, methyl and fluoromethyl. More preferably, R ₁ is cyano. However, in an alternative preferred embodiment R ₁ is methyl and in a particularly preferred alternative embodiment where R ₁ is methyl R ₁ is CD ₃ . In another preferred embodiment, R ₁ is fluoromethyl.

R ₂ and R ₃ are independently each (C _1-2 )alkyl or (C _1-2 )haloalkyl, preferably methyl, or R ₂ and R ₃ together with the carbon atom to which they are attached form cyclopropyl. do. Preferably, R ₂ and R ₃ together with the carbon atom to which they are attached form cyclopropyl.

W is -NHS(O) _y -, -S(O) _y NH-, -NHS(O)(NH)-, -NHS(O)(NCH ₃ )-, -S(O)(NH)-NH -, -S(O)(NCH ₃ )-NH-, where y is 1 or 2. Preferably, y is 2. Accordingly, in a preferred embodiment, W is selected from -NHS(O) ₂ -, -S(O) ₂ NH-, -NHS(O)(NH)-, and -S(O)(NH)-NH- do. More preferably, W is selected from -NHS(O) ₂ -, and -S(O) ₂ NH-, and even more preferably W is -NHS(O) ₂ -. Preferably, as understood herein, the left side of W as defined herein is attached to the carbon atom carrying R ₁ , R ₂ and R 3 and the right side of W as defined herein is attached to the carbon atom carrying R 1 , R 2 and R ₃ and the right side of W as defined herein is It is attached to the ring system shown in . In one preferred embodiment, W is -NHS(O) ₂ - or -NHS(O)(NCH ₃ )-. In one preferred embodiment, W is -NHS(O)(NCH ₃ )-.

X ₁ and X ₃ are independently selected from the group consisting of N, CH, C(C _1-2 alkyl), CCI and CF, and preferably are independently selected from the group consisting of N, CH and CF. Preferably, X ₁ is CF or CH and X ₃ is CH, more preferably X ₁ and X ₃ are each CH. However, in an alternative preferred embodiment, X ₁ is CF and X ₃ is CH.

X ₂ is N or CY _C2 -R _C2 , preferably X ₂ is CY _C2 -R _C2 .

Y _C2 is selected from covalent bond, C _1-5 alkylene, C _2-5 alkenylene, C _2-5 alkynylene, cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene, wherein Alkylene, the alkenylene and the alkynylene are each halogen, CN, OH, O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, SH, S(C _1-5 alkyl), -S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), CONH ₂ , CONH(C _{1- 5} alkyl), CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), NHCO-(C _1-5 alkyl), N(C _1-5 alkyl)- CO-(C _1-5 alkyl), NHCONH ₂ , NHCONH-(C _1-5 alkyl), NHCON(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 alkyl)CONH ₂ , independently selected from N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl). Halogen, CN, OH, O(C _1-5 alkyl), SH, S(C ₁₅ alkyl), NH ₂ , NH(C _1-5 alkyl), and N(C _1-5 alkyl)(C _1-5 alkyl), and further wherein one or more -CH ₂ - units included in the alkylene, alkenylene or alkynylene are -O-, NH-, N(C _{1- 5} alkyl)-, CO-, S-, -SO-, and SO ₂ -, and further wherein said cycloalkylene, said cycloalkenylene, said heterocycloalkylene and said Heterocycloalkenylene is halogen, CN, OH, C _1-5 alkyl, C _1-5 haloalkyl, O(C _1-5 alkyl), -O(C _1-5 haloalkyl), SH, S(C), respectively. ₁₅ alkyl), -S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _{1- 5} alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl) ), CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), NHCO-(C _1-5 alkyl), N(C _1-5 alkyl)-CO- (C _1-5 alkyl), NHCONH ₂ , NHCONH-(C _1-5 alkyl), NHCON(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 alkyl)CONH ₂ , N( C _1-5 alkyl)CONH-(C _1-5 alkyl), and N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene) - CN, -(C _1-5 alkylene)OH, -(C _1-5 alkylene)O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl ), -(C _1-5 alkylene)SH, -(C _1-5 alkylene)S(C ₁₅ alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), - (C _1-5 alkylene)NH ₂ , -(C _1-5 alkylene)NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), - (C _1-5 alkylene)N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)( N -heterocycloalkyl), -(C _1-5 alkylene)N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkyl lene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)CONH ₂ , -(C _1-5 alkylene)CONH(C _1-5 alkyl), -(C _1-5 alkylene )CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)CO-( N -heterocycloalkyl), -(C _1-5 alkylene)NHCO-(C _{1 -5} alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)NHCONH ₂ , -(C _{1- 5} alkylene)NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)N( C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)N(C _{1 -5} alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, CN, OH, C _1-5 alkyl, O(C _1-5 alkyl), SH, is optionally substituted with one or more groups selected from S(C ₁₅ alkyl), NH ₂ , NH(C _1-5 alkyl), and N(C _1-5 alkyl)(C _1-5 alkyl). Preferably, Y _C2 is selected from a covalent bond, C _1-5 alkylene, C _2-5 alkenylene, C _2-5 alkynylene, cycloalkylene and heterocycloalkylene, wherein the alkylene, the alkene Nylene and the alkynylene are each halogen, CN, OH, O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, SH, S(C ₁₅ alkyl), - S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N (C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), NHCO-(C _1-5 alkyl), N(C _1-5 alkyl)-CO-(C _1-5 alkyl), NHCONH ₂ , NHCONH-(C _1-5 alkyl), NHCON(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 alkyl)CONH ₂ , N(C _1-5 alkyl) )CONH-(C _1-5 alkyl), and N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, CN, OH, O With one or more groups selected from (C _1-5 alkyl), SH, S(C ₁₅ alkyl), NH ₂ , NH(C _1-5 alkyl), and N(C _1-5 alkyl)(C _1-5 alkyl) optionally substituted, and further wherein said alkylene, said alkenylene or one or more -CH ₂ - units contained in said alkynylene are each -O-, NH-, N(C _1-5 alkyl)-, CO- , S-, -SO-, and SO ₂ -, and further wherein said cycloalkylene and said heterocycloalkylene are each halogen, CN, OH, C _1-5 alkyl, C _1-5 haloalkyl, O(C _1-5 alkyl), -O(C _1-5 haloalkyl), SH, S(C ₁₅ alkyl), -S(C _1-5 haloalkyl), NH ₂ , NH (C _1-5 alkyl), -NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl ), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), CON(C _1-5 alkyl)(C _1-5 alkyl), - CO-( N -heterocycloalkyl), NHCO-(C _1-5 alkyl), N(C _1-5 alkyl)-CO-(C _1-5 alkyl), NHCONH ₂ , NHCONH-(C _1-5 alkyl ), NHCON(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 alkyl)CONH ₂ , N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and N( C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)OH, -(C _{1- 5} alkylene)O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)SH, -(C _1-5 Alkylene)S(Cis alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)NH ₂ , -(C _1-5 alkylene) NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)(C _{1- 5} alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)( N -heterocycloalkyl), -(C _1-5 alkylene)N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene )CONH ₂ , -(C _1-5 alkylene)CONH(C _1-5 alkyl), -(C _1-5 alkylene)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)CO-( N -heterocycloalkyl), -(C _1-5 alkylene)NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 Alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)NHCONH ₂ , -(C _1-5 alkylene)NHCONH-(C _1-5 alkyl), -(C _1-5 Alkylene)NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)N( From C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl) independently selected, preferably halogen, CN, OH, C _1-5 alkyl, O(C _1-5 alkyl), SH, S(C ₁₅ alkyl), NH ₂ , NH(C _1-5 alkyl), and is optionally substituted with one or more groups selected from N(C _1-5 alkyl)(C _1-5 alkyl). More preferably, Y _C2 is selected from a covalent bond, C _1-5 alkylene, C _2-5 alkenylene, and C _2-5 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each Halogen, CN, OH, O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, SH, S(C ₁₅ alkyl), -S(C _1-5 halo alkyl), NH ₂ , NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl) )(C _1-5 alkyl),-( N -heterocycloalkyl), -CO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), NHCO-(C _1-5 alkyl), N(C _1-5 alkyl)-CO-(C _1-5 alkyl), NHCONH ₂ , NHCONH -(C _1-5 alkyl), NHCON(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 alkyl)CONH ₂ , N(C _1-5 alkyl)CONH-(C _{1- 5} alkyl), and N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, CN, OH, O(C _1-5 alkyl) , SH, S(C ₁₅ alkyl), NH ₂ , NH(C _1-5 alkyl), and N(C _1-5 alkyl)(C _1-5 alkyl), and further Here, the alkylene, the alkenylene, or one or more -CH ₂ - units included in the alkynylene are -O-, NH-, N(C _1-5 alkyl)-, CO-, S-, -SO-, respectively. , and SO ₂ -. More preferably, Y _C2 is a covalent bond, -(C _1-3 alkylene)-, -CO-(C _1-3 alkylene)-, (C _1-3 alkylene)-CO-, -CONH- (C _1-3 alkylene)-, -(C _1-3 alkylene)-CONH-, -NHCO-(C _1-3 alkylene)-, -(C _1-3 alkylene)-NHCO-, - NH-(C _1-3 alkylene)-, -(C _1-3 alkylene)-NH-, -N(C _1-5 alkyl)-, -O-(C _1-3 alkylene)-, - (C _1-3 alkylene)-O-, SO ₂ -(C _1-3 alkylene)-, -(C _1-3 alkylene)SO ₂ -, -CONH-, -NHCO-, -NH-, is selected from -O-, -CO- and SO ₂ -. C _1-3 alkylene is preferably the -CH ₂ - group herein.

R _C2 is hydrogen, halo, -OH, -NH ₂ , -SH, -CN, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl , heterocycloalkenyl, aryl, and heteroaryl. Preferably, R _C2 is hydrogen, halo, -OH, -NH ₂ , -SH, -CN, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, cycloalkyl, heterocycloalkyl , aryl, and heteroaryl. More preferably, R _C2 is selected from hydrogen, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. Even more preferably, R _C2 is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. Even more preferably, R _C2 is selected from heterocycloalkyl, aryl, and heteroaryl. The alkyl, alkenyl, or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, -SH, - S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _{1 -5} alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), - CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl ), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _{1- 5} alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -P (O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), and -P(O) independently selected from (O(C _1-5 alkyl))(C _1-5 alkyl), preferably halogen, -CN, -OH, -O(C _1-5 alkyl)-, -O(C _{1- 5} haloalkyl)-, C _1-5 haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl) , -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO( C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _{1- 5} alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O) (C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl) , -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), - CO(C _{1 -5} alkyl), -CO(C _1-5 haloalkyl), -CO-cycloalkyl, -COO(C _1-5 alkyl), -COO(C _1-5 haloalkyl), -COO-cycloalkyl, - CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-C _1-5 alkyl) , -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl) )(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl) , -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _{1 -5} alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN , -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl ), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 halo alkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -( C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _{1 -5} alkyl), -(C _1-5 alkylene)-P(O _{)(C 1-5 alkyl)(C 1-5 alkyl), -(C 1-5 alkylene )} -P(O)(O (C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl) , -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 halo alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _{1 -5} haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl) , -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 haloalkyl), -(C _1-5 alkylene)- CO-cycloalkyl, -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _{1- 5} alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene) -N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene)- N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH-( C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _1-5 alkyl ), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), preferably halogen, CN, OH, C _1-5 alkyl, C _1-5 haloalkyl, O(C _1-5 alkyl), -O(C _1-5 haloalkyl), SH, S(C _1-5 alkyl), S(O)(C _1-5 alkyl), S(O) ₂ (Cis alkyl), S(O)(NH)(C ₁₅ alkyl), S(O)(N(C ₁₅ alkyl))(C ₁₅ alkyl), -N=S(O)(C ₁₅ alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), N(C _{1- 5} alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), COO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), NHCO-(C _{1 -5} alkyl), N(C _1-5 alkyl)-CO-(C _1-5 alkyl), NHCONH ₂ , NHCONH-(C _1-5 alkyl), NHCON(C _1-5 alkyl)(C _1-5 Alkyl), N(C _1-5 alkyl)CONH ₂ , N(C _1-5 alkyl)CONH-(C _1-5 alkyl), N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), NHCOO(C _1-5 alkyl), N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C ₁₅ alkyl), -P(O)(O(C _1-5 alkyl))(O (C ₁₅ alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene )OH, -(C _1-5 alkylene)O(C _1-5 alkyl), -(C _1-5 alkylene)- O(C _1-5 haloalkyl), -(C _1-5 alkylene) SH, -(C _1-5 alkylene)S(C ₁₅ alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)S(O )(C _1-5 alkyl), -(C _1-5 alkylene)S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)S(O)(NH)(C _{1 -5} alkyl), -(C _1-5 alkylene)S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O) (C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C ₁₅ alkyl)), -( C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)NH ₂ , -(C _1-5 alkylene )NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)(C _{1 -5} alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)( N -heterocycloalkyl), -( C _1-5 alkylene)N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkyl Len)CONH ₂ , -(C _1-5 alkylene)CONH(C _1-5 alkyl), -(C _1-5 alkylene)CON(C _1-5 alkyl)(C _1-5 alkyl), -( C _1-5 alkylene)CO-( N -heterocycloalkyl), -(C _1-5 alkylene)NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)N(C _{1- 5} alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)NHCONH ₂ , -(C _1-5 alkylene)NHCONH-(C _1-5 alkyl), -(C _{1- 5} alkylene)NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)N (C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl )(C _1-5 alkyl), -(C _1-5 alkylene)NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)N(C _1-5 alkyl)COO-(C _{1 -5} alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 halo alkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH )(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _{1- 5} alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)( C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH (C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N( C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), - N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _{1 -5} alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)) , -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -( C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, - (C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S( O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH) (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)- P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , - (C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N( C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene) -( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _{1 -5} alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _{1- 5} alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene) -N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene) -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 halo Alkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _{1- 5} alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -( C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), - NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl) )(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene) -NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 halo alkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl).

Therefore, preferably -Y _C2 -R _C2 is -OC _1-12 alkyl, -NH-C _1-12 alkyl, -N(C _1-5 alkyl)-C _1-12 alkyl, -OC _2-12 Alkenyl, -NH-C _2-12 alkenyl, -N(C _1-5 alkyl)-C _2-12 alkenyl, -OC _2-12 alkynyl, -NH-C _2-12 alkynyl, -N (C _1-5 alkyl)-C _2-12 alkynyl, (C _0-3 alkylene)-cycloalkyl, -CO-(C _0-3 alkylene)cycloalkyl, (C _0-3 alkylene)- CO-cycloalkyl, -CONH-(C _0-3 alkylene)cycloalkyl, -(C _0-3 alkylene)-CONH-cycloalkyl, -NHCO-(C _0-3 alkylene)cycloalkyl, (C _0-3 alkylene)-NHCO-cycloalkyl, -NH-(C _0-3 alkylene)cycloalkyl, -(C _0-3 alkylene)-NH-cycloalkyl, -O-(C _0-3 alkyl lene)cycloalkyl, -(C _0-3 alkylene)-O-cycloalkyl, -SO ₂ -(C _0-3 alkylene)cycloalkyl, -(C _0-3 alkylene)-SO ₂ -cycloalkyl , -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, -SO ₂ -cycloalkyl, (C _0-3 alkylene)-cycloalkenyl , -CO-(C _0-3 alkylene)cycloalkenyl, (C _0-3 alkylene)-CO-cycloalkenyl, -CONH-(C _0-3 alkylene)cycloalkenyl, -(C _{0 -3} alkylene)-CONH-cycloalkenyl, -NHCO-(C _0-3 alkylene)cycloalkenyl, (C _0-3 alkylene)-NHCO-cycloalkenyl, -NH-(C _0-3 Alkylene) cycloalkenyl, -(C _0-3 alkylene)-NH-cycloalkenyl, -O-(C _0-3 alkylene) cycloalkenyl, -(C _0-3 alkylene)-O- Cycloalkenyl, -SO ₂ -(C _0-3 alkylene)cycloalkenyl, -(C _0-3 alkylene)-SO ₂ -cycloalkenyl, -CONH-cycloalkenyl, -NHCO-cycloalkenyl , -NH-cycloalkenyl, -O-cycloalkenyl, -CO-cycloalkenyl, -SO ₂ -cycloalkenyl, -(C _0-3 alkylene)-heterocycloalkyl, -CO-(C _{0 -3} alkylene)heterocycloalkyl, -(C _0-3 alkylene)-CO-heterocycloalkyl, -CONH-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)- CONH-heterocycloalkyl, -NHCO-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-NHCO-heterocycloalkyl, -NH-(C _0-3 alkylene)heterocyclo Alkyl, -(C _0-3 alkylene)-NH-heterocycloalkyl, -O-(C _0-3 alkylene) heterocycloalkyl, -(C _0-3 alkylene)-O- heterocycloalkyl, - SO ₂ -(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-SO ₂ -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-hetero Cycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, -(C _0-3 alkylene)-heterocycloalkenyl, -CO-(C _0-3 alkylene ) Heterocycloalkenyl, -(C _0-3 alkylene)-CO-heterocycloalkenyl, -CONH-(C _0-3 -(C _0-3 alkylene)-CONH-heterocycloalkenyl, -NHCO -(C _0-3 -(C _0-3 alkylene)-NHCO-heterocycloalkenyl, -NH-(C _0-3 -(C _0-3 alkylene)-NH-heterocycloalkenyl, -O -(C _0-3 alkylene) heterocycloalkenyl, -(C _0-3 alkylene)-O-heterocycloalkenyl, -SO ₂ -(C _0-3 alkylene)heterocycloalkenyl, -( C _0-3 alkylene) -SO ₂ -heterocycloalkenyl, -CONH-heterocycloalkenyl, -NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO -heterocycloalkenyl, -SO ₂ -heterocycloalkenyl, (C _0-3 alkylene)aryl, -CO-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-CO- Aryl, -CONH-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-CONH-aryl, -NHCO-(C _0-3 alkylene)aryl, -(C _0-3 alkylene) )-NHCO-aryl, -NH-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-NH-aryl, -O-(C _0-3 alkylene)aryl, -(C _{0 -3} alkylene)-O-aryl, -SO ₂ -(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, - NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-3 alkylene)heteroaryl, -CO-(C _0-3 alkylene)heteroaryl, -(C _{0 -3} alkylene)-CO-heteroaryl, -CONH-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-CONH-heteroaryl, -NHCO-(C _0-3 alkylene )Heteroaryl, -(C _0-3 alkylene)-NHCO-heteroaryl, -NH-(C _0-3 alkylene)heteroaryl, (C _0-3 alkylene)-NH-heteroaryl, -O- (C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-O-heteroaryl, -SO ₂ -(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene) -SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and -SO ₂ -heteroaryl, preferably -Y _C2 -R _C2 is -OC _1-12 alkyl, -NH-C _1-12 alkyl, -N(C _1-5 alkyl)-C _1-12 alkyl, -OC _2-12 alkenyl, -NH- C _2-12 alkenyl, -N(C _1-5 alkyl)-C _2-12 alkenyl, -OC _2-12 alkynyl, -NH-C _2-12 alkynyl, -N(C _1-5 alkyl )-C _2-12 alkynyl, (C _0-3 alkylene)-cycloalkyl, -CO-(C _0-3 alkylene)cycloalkyl, (C _0-3 alkylene)-CO-cycloalkyl, - CONH-(C _0-3 alkylene)cycloalkyl, -(C _0-3 alkylene)-CONH-cycloalkyl, -NHCO-(C _0-3 alkylene)cycloalkyl, (C _0-3 alkylene) -NHCO-cycloalkyl, -NH-(C _0-3 alkylene)cycloalkyl, -(C _0-3 alkylene)-NH-cycloalkyl, -O-(C _0-3 alkylene)cycloalkyl, - (C _0-3 alkylene)-O-cycloalkyl, -SO ₂ -(C _0-3 alkylene)cycloalkyl, -(C _0-3 alkylene)-SO ₂ -cycloalkyl, -CONH-cycloalkyl , -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, -SO ₂ -cycloalkyl, -(C _0-3 alkylene)-heterocycloalkyl, -CO-( C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-CO-heterocycloalkyl, -CONH-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene )-CONH-heterocycloalkyl, -NHCO-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-NHCO-heterocycloalkyl, -NH-(C _0-3 alkylene) Heterocycloalkyl, -(C _0-3 alkylene)-NH-heterocycloalkyl, -O-(C _0-3 alkylene) heterocycloalkyl, -(C _0-3 alkylene)-O-cycloalkyl, -SO ₂ -(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-SO ₂ -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH- Heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, (C _0-3 alkylene)aryl, -CO-(C _0-3 alkylene)aryl, - (C _0-3 alkylene)-CO-aryl, -CONH-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-CONH-aryl, -NHCO-(C _0-3 alkylene )aryl, -(C _0-3 alkylene)-NHCO-aryl, -NH-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-NH-aryl, -O-(C _{0 -3} alkylene)aryl, -(C _0-3 alkylene)-O-aryl, -SO ₂ -(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO- aryl, -SO ₂ -aryl, -(C _0-3 alkylene)heteroaryl, -CO-(C _{0- 3} alkylene)heteroaryl, -(C _0-3 alkylene)-CO-heteroaryl, -CONH-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-CONH-heteroaryl , -NHCO-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-NHCO-heteroaryl, -NH-(C _0-3 alkylene)heteroaryl, (C _0-3 alkyl len)-NH-heteroaryl, -O-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-O-heteroaryl, -SO ₂ -(C _0-3 alkylene)hetero Aryl, -(C _0-3 alkylene)-SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and -SO ₂ -heteroaryl, wherein the alkyl, alkenyl, or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _{1 -5} haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO (C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _{1- 5} alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O )(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)( C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl) )), and -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), preferably halogen, -CN, -OH, -O(C _1-5 alkyl) ), -O(C _1-5 haloalkyl), -C _1-5 haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , - NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _{1 -5} alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). optionally substituted with a group, wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S( O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH( C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl ), -CO(C _1-5 alkyl), -CO(C _1-5 haloalkyl), -CO-cycloalkyl, -COO(C _1-5 alkyl), -COO(C _1-5 haloalkyl), -COO-cycloalkyl, -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO -(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _{1- 5} alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl) )CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), - NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P (O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)- O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene) -S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _{1 -5} alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene )-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl) )(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene) -NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl )(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 haloalkyl), -( C _1-5 alkylene)-CO-cycloalkyl, -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _{1- 5} alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene) -NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)- NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), - (C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -( C _1-5 alkylene)-N(C _1-5 alkyl)CON(C 1-5 alkyl _{)(C 1-5 alkyl), -(C 1-5 alkylene )} -OCONH ₂ , -(C _{1- 5} alkylene)-OCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene) -NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), preferably halogen, -CN , -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl) , -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)( N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 halo Alkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -COO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl) )-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _{1- 5} alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl) )COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene )-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkyl lene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S (O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _{1 -5} alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))( O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene )-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 Alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene )-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkyl lene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-(W-heterocycloalkyl), -(C _1-5 alkylene)-NHCO -(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _{1-5 alkyl), -(C 1-5 alkylene} )-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _{1 -5} alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkyl len)-OCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO (C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), more preferably halogen, -CN, -OH , C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S (O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)( C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)( C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), - NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 Alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(C _1-5 alkyl)( C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), - (C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene )-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)- S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl) , -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O) (O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _{1 -5} alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene) -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _{1- 5} alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _{1- 5} alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)( C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _{1- 5} haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene) -S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _{1- 5} haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)- NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene )-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _{1 -5} alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH , C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S (C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl) , -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _{1- 5} alkyl)(C _1-5 alkyl). More preferably, -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -CO-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene) -CO-heterocycloalkyl, -CONH-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(C _0-3 alkylene)hetero Cycloalkyl, -(C _0-3 alkylene)-NHCO- heterocycloalkyl, -NH-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-NH-heterocycloalkyl, -O-(C _0-3 alkylene) heterocycloalkyl, (C _0-3 alkylene)-O-cycloalkyl, (C _0-3 alkylene)-O-heterocycloalkyl, -SO ₂ -(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-SO ₂ -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO- heterocycloalkyl, -NH-heterocycloalkyl, -O -Heterocycloalkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, -(C _0-3 alkylene)-heterocycloalkenyl, -CO-(C _0-3 alkylene)heterocycloalkenyl , -(C _0-3 alkylene)-CO-heterocycloalkenyl, -CONH-(C _0-3 alkylene)heterocycloalkenyl, -(C _0-3 alkylene)-CONH-heterocycloalkenyl , -NHCO-(C _0-3 alkylene)heterocycloalkenyl, -(C _0-3 alkylene)-NHCO-heterocycloalkenyl, -NH-(C _0-3 alkylene)heterocycloalkenyl, -(C _0-3 alkylene)-NH-heterocycloalkenyl, -O-(C _0-3 alkylene) heterocycloalkenyl, (C _0-3 alkylene)-O-heterocycloalkenyl, - SO ₂ -(C _0-3 alkylene)heterocycloalkenyl, -(C _0-3 alkylene)-SO ₂ -heterocycloalkenyl, -CONH-heterocycloalkenyl, -NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO-heterocycloalkenyl, -SO ₂ -heterocycloalkenyl, -(C _0-3 alkylene)aryl, -CO-(C _{0 -3} alkylene)aryl, -(C _0-3 alkylene)-CO-aryl, -CONH-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-CONH-aryl, -NHCO -(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-NHCO-aryl, -NH-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-NH- Aryl, -O-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-O-aryl, -SO ₂ -(C _0-3 alkylene)aryl, -(C _0-3 alkyl lene)-SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-3 alkylene)heteroaryl , -CO-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-CO-heteroaryl, -CONH-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-CONH-heteroaryl, -NHCO-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-NHCO-heteroaryl, -NH-(C _0-3 alkylene)hetero Aryl, -(C _0-3 alkylene)-NH-heteroaryl, -O-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-O-heteroaryl, -SO ₂ - (C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl , -CO-heteroaryl and -SO ₂ -heteroaryl, preferably -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -CO-(C _0-3 alkyl len)heterocycloalkyl, -(C _0-3 alkylene)-CO-heterocycloalkyl, -CONH-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-CONH-hetero Cycloalkyl, -NHCO-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-NHCO- heterocycloalkyl, -NH-(C _0-3 alkylene)heterocycloalkyl, - (C _0-3 alkylene)-NH-heterocycloalkyl, -O-(C _0-3 alkylene) heterocycloalkyl, (C _0-3 alkylene)-O-cycloalkyl, -SO ₂ -(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-SO ₂ -heterocycloalkyl,-CONH-heterocycloalkyl, -NHCO-heterocycloalkyl,-NH-heterocycloalkyl, -O -Heterocycloalkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, -(C _0-3 alkylene)aryl, -CO-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-CO-aryl, -CONH-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-CONH-aryl, -NHCO-(C _0-3 alkylene)aryl, -( C _0-3 alkylene)-NHCO-aryl, -NH-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-NH-aryl, -O-(C _0-3 alkylene) Aryl, -(C _0-3 alkylene)-O-aryl, -SO ₂ -(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-3 alkylene)heteroaryl, -CO-(C _0-3 alkylene)hetero Aryl, -(C _0-3 alkylene)-CO-heteroaryl, -CONH-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-CONH-heteroaryl, -NHCO-( C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-NHCO-heteroaryl, -NH-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-NH -Heteroaryl, -O-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-O- heteroaryl, -SO ₂ -(C _0-3 alkylene)heteroaryl, -( C _0-3 alkylene)-SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO- heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and -SO ₂ -heteroaryl selected from, wherein the heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl) , -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl) ), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), - N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), - CO(C _1-5 haloalkyl), -CO-cycloalkyl, -COO(C _1-5 alkyl), -COO(C _1-5 haloalkyl), -COO-cycloalkyl, -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl ), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl) (C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _{1- 5} alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl) , -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl ), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _{1- 5} alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O( C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl ), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _{1- 5} haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 haloalkyl), -(C _1-5 alkylene)-CO -Cycloalkyl, -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _{1 -5} alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl ), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)- N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene)-N (C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _1-5 alkyl) , and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl , C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _{1 -5} alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl)) (C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _{1 -5} alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl) , -( N -heterocycloalkyl), CO(C _1-5 alkyl), -COO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 Alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl ), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _{1 -5} alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl)COO-(C _1-5 alkyl) , -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P( O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _{1- 5} alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _{1- 5} alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O) (C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _{1- 5} alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 Alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-(W- Heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl) , -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl )(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), - (C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene) -NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _{1 -5} alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _1-5 alkyl), and - (C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _{1- 5} haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl) , -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _{1- 5} alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl) , -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO- ( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _{1- 5} alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl ), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P( O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _{1 -5} alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O (C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)- S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _{1 -5} alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _{1- 5} alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene) -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl)) (C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)- NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _{1 -5} alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl) (C _1-5 alkyl), -(C _1-5 alkylene)-CO(C 1-5 alkyl _{), -(C 1-5 alkylene)-CONH 2 , -(C 1-5 alkylene ) -} CONH(C _1-5 alkyl), -(C _1-5 alkylene _{)-CON(C 1-5 alkyl)(C 1-5 alkyl), -(C 1-5 alkylene )} -CO-( N - Heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _{1- 5} alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C 1-5 alkylene ₎ -N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), further Preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -(C _{1- 5} alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -SH, - S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl) , -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl )(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _{1 -5} haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), - is optionally substituted with one or more groups selected from CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl).

More preferably, -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O- Heterocycloalkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, -(C _0-3 alkylene)-heterocycloalkenyl, -CONH-heterocycloalkenyl, -NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO-heterocycloalkenyl, -SO ₂ -heterocycloalkenyl, -(C _0-3 alkylene)aryl, -CONH-aryl, - NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-3 alkylene)heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, - is selected from NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and -SO ₂ -heteroaryl, preferably -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl , -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O- heterocycloalkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, -(C _0-3 Alkylene)aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-3 alkylene)heteroaryl, -CONH -heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and -SO ₂ -heteroaryl, wherein the heterocycloalkyl, heterocycloalkenyl, aryl Or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, - S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl) ), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S( C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), - CO(C _1-5 haloalkyl), -CO -Cycloalkyl, -COO(C _1-5 alkyl), -COO(C _1-5 haloalkyl), -COO-cycloalkyl, -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _{1 -5} alkyl)(C _1-5 alkyl), -CO-(W-heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _{1- 5} alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N (C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-( C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), - P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _{1 -5} alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O) (C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P( O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl) ), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _{1 -5} alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 haloalkyl), -(C _1-5 alkylene)-CO-cycloalkyl, -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _{1 -5} alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _{1 -5} alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -( C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _{1- 5} alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)( C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH-(C _1-5 alkyl), -(C _1-5 alkylene)- OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _{1 -5} alkyl)COO-(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl) ), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)( C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), - CO(C _{1- 5} alkyl), -COO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl ), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)( C _1-5 alkyl), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _{1 -5} alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -( C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), - (C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene) -S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S (O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)( O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), - (C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _{1- 5} alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)- N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , - (C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 Alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _{1 -5} alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkyl len)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), - (C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _{1 -5} alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-OCON( C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), - O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _{1- 5} alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N( C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl) , -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _{1- 5} alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _{1 -5} alkyl)(C _1-5 alkyl), -P(O)(C _{1-5 alkyl)(C 1-5 alkyl} ), -P(O)(O(C _1-5 alkyl))(O( C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkyl lene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _{1- 5} alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)- S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl)) (O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkyl lene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _{1- 5} alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -( C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkyl lene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)- NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -( C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -( C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 Alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -(C _1-5 alkylene)-OH, -(C _1-5 alkylene )-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _{1- 5} haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _{1 -5} haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N (C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -( C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -NH ₂ , -NH(C _1-5 alkyl), -N(C _1-5 alkyl)(C _{1 -5} alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON (C _1-5 alkyl)(C _1-5 alkyl).

Even more preferably, -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-heterocycloalkenyl, -(C _0-3 alkylene )aryl, and -(C _0-3 alkylene)heteroaryl, preferably -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkyl len)aryl, and -(C _0-3 alkylene)heteroaryl, wherein the heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _{1- 5} alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))( C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _{1- 5} alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), - CO(C _1-5 haloalkyl), -CO-cycloalkyl, -COO(C _1-5 alkyl), -COO(C _1-5 haloalkyl), -COO-cycloalkyl, -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N - Heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl) , -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), - N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _{1 -5} alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _{1- 5} alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -( C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)- S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S( O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), - (C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O (C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -( C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N (C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _{1- 5} haloalkyl), -(C _1-5 alkylene)-CO-cycloalkyl, -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl ), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -( C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _{1 -5} alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -( independently selected from C _1-5 alkylene)-NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), Preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S (C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl) , -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), - N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), - CO(C _1-5 alkyl), -COO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N (C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _{1- 5} alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _{1-5 alkyl)(C 1-5 alkyl} ), -P(O)(O(C _1-5 alkyl)) (O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _{1 -5} alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -( C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkyl lene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 Alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _{1 -5} alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -( C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl) , -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _{1 -5} alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkyl lene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO- (C _1-5 alkyl), -(C _1-5 alkylene )-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl) , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkyl len)-NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), more preferably halogen, - CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl ), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O) (N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl) , -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 Haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _{1- 5} alkyl)(C _1-5 alkyl), -CO-(N-heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N( C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(C _{1- 5} alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl) ))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _{1- 5} alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _{1 -5} alkylene)-S(O)2(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _{1 -5} alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)- P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _{1- 5} alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _{1- 5} alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene) -CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), - (C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N (C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl) , -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -( C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _{1- 5} alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O (C _1-5 haloalkyl), -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)- O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _{1 -5} alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), - NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _{1- 5} alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and - is optionally substituted with one or more groups selected from CON(C _1-5 alkyl)(C _1-5 alkyl).

Even more preferably, -Y _C2 -R _C2 is heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl, more preferably heterocycloalkyl, aryl, and heteroaryl, more preferably heterocycloalkyl and is selected from heteroaryl, and even more preferably from heterocycloalkyl, wherein said heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), - ( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CO(C _1-5 haloalkyl), -CO-cycloalkyl, -COO(C _1-5 alkyl), -COO(C _{1 -5} haloalkyl), -COO-cycloalkyl, -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -hetero Cycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N (C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _{1 -5} alkyl), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _{1- 5} alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _{1 -5} alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S (O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O )(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -( C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O( C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkyl lene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N( C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 haloalkyl), -(C _1-5 alkylene)-CO-cycloalkyl, -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl) , -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl _{), -(C 1-5 alkylene)-N(C 1-5 alkyl)-CO-(C 1-5 alkyl )} , -(C _{1 -5} alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _{1 -5} alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _{1- 5} alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH-(C _{1-5 alkyl), -(C 1-5 alkylene} )-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), preferably independently selected from Examples include halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S( C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _{1 -5} haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N (C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -COO(C _1-5 alkyl), -CONH ₂ , - CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N (C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl), -N (C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl) ))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -( C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), - (C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _{1- 5} alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl ), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _{1 -5} alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -( C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 halo alkyl), -(C _1-5 alkylene)-(W-heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -( C _1-5 alkylene)-CO(C _{1-5 alkyl), -(C 1-5 alkylene} )-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), - (C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _{1- 5} alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 Alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl ), -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , - (C _1-5 alkylene)-OCONH-(C _{1-5 alkyl), -(C 1-5 alkylene} )-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _{1- 5} alkylene)-NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), more preferably halogen. , -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _{1- 5} alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S( O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 halo alkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _{1 -5} haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), - CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _{1 -5} alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , - N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _{1- 5} alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _{1 -5} alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -( C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _{1 -5} alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)( C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene )-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl ), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkyl len)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl) , -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene) -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), - O(C _1-5 haloalkyl), -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene) -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _{1 -5} alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -( C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl) , -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen. , -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _{1- 5} haloalkyl), -S(C _1-5 alkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)( C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl).

In one embodiment, -Y _C2 -R _C2 is heterocycloalkenyl, wherein heterocycloalkenyl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ ( C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S (O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO (C _1-5 alkyl), -CO(C _1-5 haloalkyl), -CO-cycloalkyl, -COO(C _1-5 alkyl), -COO(C _1-5 haloalkyl), -COO-cyclo Alkyl, -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _{1 -5} alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)( C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _{1 -5} alkyl), -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)( O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkyl lene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _{1 -5} haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl) ), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl) )(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P( O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _{1 -5} alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl )(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _{1 -5} alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 haloalkyl), -(C _1-5 alkylene)-CO-cycloalkyl, -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene) -CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-( C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , - (C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _{1- 5} alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene) -OCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S( O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _{1 -5} alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -COO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), - CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO- (C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl)COO-( C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl) )), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH , -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)- S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)( NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene )-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _{1 -5} alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)- N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkyl lene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO( C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ ,-(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON (C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _{1 -5} alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl),-(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkyl lene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene )-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH -(C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _{1- 5} alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 Alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl) )(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl ), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl ), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH -(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-( C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _{1-5 alkyl)(C 1-5 alkyl} ), -P(O)(C _1-5 alkyl)(C _1-5 alkyl ), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl) , -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _{1- 5} alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O )2(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)( N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _{1 -5} alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _{1 -5} alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _{1- 5} alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene) -N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _{1 -5} haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _{1- 5} alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)- CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO -(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene )-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N (C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl ), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl) , -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl) , -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , - (C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N( C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl) , -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _{1- 5} alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _{1- 5} haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N( C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)( C _1-5 alkyl).

Preferably, when -Y _C2 -R _C2 is aryl, -Y _C2 -R _C2 is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _{1- 5} alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O) (C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl) , -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _{1 -5} alkyl), - CO(C _1-5 haloalkyl), -CO-cycloalkyl, -COO(C _1-5 alkyl), -COO(C _1-5 haloalkyl), -COO-cycloalkyl, - CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl ), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _{1- 5} alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl) ), -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)- CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 halo alkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), - (C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O _{)(C 1-5 alkyl)(C 1-5 alkyl), -(C 1-5 alkylene )} -P(O)( O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl ), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl ), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 haloalkyl), -(C _1-5 alkylene) -CO-cycloalkyl, -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON( C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _{1- 5} alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _{1 -5} alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene )-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene) -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH- (C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), preferably halogen, -CN, -OH, C _{1- 5} alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)( C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl) ))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH( C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -COO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _{1 -5} alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , - N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH- (C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl)COO-(C _{1- 5} alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -( C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O )(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)( C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P (O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl) )), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -( C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)- ( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _{1- 5} alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _{1 -5} alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl ), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)- N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene)-N (C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _1-5 alkyl) , and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), - ( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), - CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _{1- 5} alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), - P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -( C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene) -O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene )-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ ( C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkyl) lene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl) ))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene )-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N( C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 halo Alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene )-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON (C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _{1 -5} alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl) , more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -SH , -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), - NH(C _1-5 haloalkyl), -N (C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _{1 -5} alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _{1- 5} alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl ), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _{1- 5} haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _{1- 5} alkyl) and is optionally substituted with one or more groups selected from alkyl).

Preferably, when -Y _C2 -R _C2 is heteroaryl, then -Y _C2 -R _C2 is imidazolyl, pyridazinyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or indazolyl, wherein heteroaryl Aryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S( C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _{1 -5} haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N (C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), - CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO- (C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -P(O )(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O( C _1-5 alkyl))(C _1-5 alkyl), -(C 1-5 alkylene _{)-CN, -(C 1-5 alkylene)-OH, -(C 1-5 alkylene )} -O (C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)- S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl) , -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), - (C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 Alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)),-(C _{1- 5} alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)- NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _{1 -5} alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-(W-heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _{1 -5} alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _{1- 5} alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl) CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl) CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _{1- 5} alkyl), -O(C _1-5 haloalkyl), -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _{1 -5} alkylene)-O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -(C _1-5 alkylene)- SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -NH ₂ , -NH(C _{1 -5} alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl) , -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 halo alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), More preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, - S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _{1 -5} alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _{1- 5} alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl).

Preferably, when -Y _C2 -R _C2 is heterocycloalkyl, -Y _C2 -R _C2 is morpholinyl, 1,1-dioxothiomorpholinyl, azetinyl, pyrrolidinyl, piperidinyl, 6-oxo-1,6-dihydropyridinyl or piperazinyl, where heterocycloalkyl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _{1- 5} alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _{1 -5} alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O )(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl) ), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CO(C _1-5 haloalkyl), -CO-cycloalkyl, -COO(C _1-5 alkyl), -COO(C _1-5 haloalkyl), -COO-cycloalkyl, -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _{1 -5} alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _{1- 5} alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O( C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene) -CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _{1- 5} haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))( C _1-5 alkyl), -(C _1-5 alkylene _{)-P(O)(C 1-5 alkyl)(C 1-5 alkyl), -(C 1-5 alkylene )} -P(O) (O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _{1- 5} haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)( C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 haloalkyl), -(C _1-5 alkylene )-CO-cycloalkyl, -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON (C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _{1 -5} alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkyl lene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene )-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH -(C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _{1- 5} alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), preferably halogen, -CN, -OH, C _{1 -5} alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O) (C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 Alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH (C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _{1- 5} alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -COO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON( C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH -(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl)COO-(C _{1 -5} alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)) , -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -( C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, - (C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S( O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH) (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)- P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , - (C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N( C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene) -( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _{1 -5} alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _{1- 5} alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene) -N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene)- N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH-( C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _1-5 alkyl ), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl , C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _{1 -5} alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl)) (C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _{1 -5} alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl) , -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl) , -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH- (C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl) , -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkyl lene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N (C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _{1- 5} alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _{1- 5} alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)- N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _{1- 5} haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO -( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO- (C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene) -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N( C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl) selected from, more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), - (C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _{1 -5} alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), - NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -( C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 Alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). More preferably, -Y _C2 -R _C2 is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)( NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _{1 -5} alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl) (C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), - CO(C _1-5 alkyl), -CO(C _{1 -5} haloalkyl), -CO-cycloalkyl, -COO(C _1-5 alkyl), -COO(C _1-5 haloalkyl), -COO-cycloalkyl, -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-(W-heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl) )-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _{1- 5} alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl) )COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene )-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkyl lene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S (O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _{1 -5} alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))( O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene )-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 Alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene )-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 haloalkyl), -(C _1-5 alkylene)-CO-cycloalkyl, -(C _{1 -5} alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _{1- 5} alkyl), -(C _1-5 alkylene)-CO-(N-heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl) CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CON (C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH-(C _1-5 alkyl), -( C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S( O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH( C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl ), -CO(C _1-5 alkyl), -COO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , - NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH- (C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _{1-5 alkyl)(C 1-5 alkyl} ), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON (C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)( C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _{1 -5} alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S( C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), - (C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl) (C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkyl lene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH( C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -( C _1-5 alkylene)-N(C _1-5 haloalkyl)(C 1-5 alkyl _{), -(C 1-5 alkylene)-CO(C 1-5 alkyl )} , -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl ), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene )-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _{1- 5} alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C 1-5 alkylene ₎ -OCONH ₂ , -(C _1-5 alkylene)-OCONH-(C _1-5 alkyl), -(C _{1 -5} alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene )-N(C _1-5 alkyl)COO-(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O( C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N= S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _{1- 5} haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), - CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl) , -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON( C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _{1 -5} alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _{1 -5} alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN , -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl ), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 halo alkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -( C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _{1 -5} alkyl), -(C _1-5 alkylene)-P(O _{)(C 1-5 alkyl)(C 1-5 alkyl), -(C 1-5 alkylene )} -P(O)(O (C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl) , -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 halo alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _{1 -5} haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl) , -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl ), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -( C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _{1 -5} alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN , -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl) ), -S(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), - NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl ), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O (C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH( C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). It is piperazinyl substituted with . Even more preferably, -Y _C2 -R _C2 is -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _{1 -5} alkyl) (preferably N-substituted) piperazinyl (preferably N-peperazinyl). Most preferably, -Y _C2 -R _C2 is -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably substituted with -CON(CH ₃ ) ₂ (preferably substituted with formula (I ), preferably N-substituted, at an N atom different from the N atom attached to the ring system shown in ) (preferably N-piperazinyl).

Preferably, when -Y _C2 -R _C2 is heterocycloalkenyl, -Y _C2 -R _C2 is oxacyclohexenyl or azacyclohexenyl, where heterocycloalkenyl is halogen, CN, OH, C _{1 -5} alkyl, C _1-5 haloalkyl, O(C _1-5 alkyl), -O(C _1-5 haloalkyl), SH, S(C ₁₅ alkyl), S(O)(C ₁₅ alkyl), S(O) ₂ (C ₁₅ alkyl), S(O)(NH)(C ₁₅ alkyl), S(O)(N(C ₁₅ alkyl))(C ₁₅ alkyl), -N=S(O)( C ₁₅ alkyl)(C ₁₅ alkyl), -S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), N(C _1-5 Alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CO(C _1-5 haloalkyl), -CO-cycloalkyl, COO(C _1-5 alkyl), - COO(C _1-5 haloalkyl), -COO-cycloalkyl, CONH ₂ , CONH(C _1-5 alkyl) , CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N - heterocycloalkyl), NHCO-(C _1-5 alkyl), N(C _1-5 alkyl)-CO-( C _1-5 alkyl), NHCONH ₂ , NHCONH-(C _1-5 alkyl), NHCON(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 alkyl)CONH ₂ , N(C _1-5 alkyl)CONH-(C _1-5 alkyl), N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _{1- 5} alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), NHCOO(C _1-5 alkyl), N( _{C 1-5} alkyl)COO-(C _1-5 alkyl), -P( O)(C _1-5 alkyl)(C ₁₅ alkyl), -P(O)(O(C _1-5 alkyl))(O(C ₁₅ alkyl)), -P(O)(O(C _{1- 5} alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)OH, -(C _1-5 alkylene)O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)SH, -(C _1-5 alkylene)S(C ₁₅ alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)S(O)(C ₁₅ alkyl), -(C _1-5 alkylene)S( O) ₂ (C ₁₅ alkyl), -(C _1-5 alkylene)S(O)(NH)(C ₁₅ alkyl), -(C _1-5 alkylene)S(O)(N(C ₁₅ alkyl) ))(C ₁₅ alkyl), -(C _1-5 alkylene _{)-P(O)(C 1-5 alkyl)(C 15 alkyl), -(C 1-5 alkylene )} -P(O)( O(C _1-5 alkyl))(O(C ₁₅ alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)NH ₂ , -(C _1-5 alkylene)NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)(C _1-5 haloalkyl) , -(C _1-5 alkylene)( N -heterocycloalkyl), -(C _1-5 alkylene)N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 haloalkyl), -(C _1-5 alkylene)-CO-cycloalkyl, -( C _1-5 alkylene)CONH ₂ , -(C _1-5 alkylene)CONH(C _1-5 alkyl), -(C _1-5 alkylene)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)CO-( N -heterocycloalkyl), -(C _1-5 alkylene)NHCO-(C _1-5 alkyl), -(C _1-5 alkylene) N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)NHCONH ₂ , -(C _1-5 alkylene)NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)CONH ₂ , -(C _{1- 5} alkylene)N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _{1 -5} alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-OCON( C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)N(C _1-5 alkyl) independently selected from COO-(C _1-5 alkyl), preferably halogen, CN, OH, C _1-5 alkyl, C _1-5 haloalkyl, O(C _1-5 alkyl), -O(C _{1 -5} haloalkyl), SH, S(C ₁₅ alkyl), S(O)(C ₁₅ alkyl), S(O) ₂ (C ₁₅ alkyl), S(O)(NH)(C ₁₅ alkyl), S (O)(N(C ₁₅ alkyl))(C ₁₅ alkyl), -N=S(O)(C ₁₅ alkyl)(C ₁₅ alkyl), -S(C _1-5 haloalkyl), NH ₂ , NH (C _1-5 alkyl), -NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl ), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), COO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), CON(C _1-5 alkyl) (C _1-5 alkyl), -CO-( N -heterocycloalkyl), NHCO-(C _1-5 alkyl), N(C _1-5 alkyl)-CO-(C _1-5 alkyl), NHCONH ₂ , NHCONH-(C _1-5 alkyl), NHCON(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 alkyl)CONH ₂ , N(C _1-5 alkyl)CONH-(C _1-5 alkyl), N(C _1-5 alkyl)CON(C _{1-5 alkyl)(C 1-5 alkyl} ), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _{1 -5} alkyl)(C _1-5 alkyl), NHCOO(C _1-5 alkyl), N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl) )(C ₁₅ alkyl), -P(O)(O(C _1-5 alkyl))(O(C ₁₅ alkyl)), -P(O)(O(C _1-5 alkyl))(C _{1- 5} alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)OH, -(C _1-5 alkylene)O(C _1-5 alkyl), -(C _{1- 5} alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)SH, -(C _1-5 alkylene)S(C ₁₅ alkyl), -(C _1-5 alkylene )-S(C _1-5 haloalkyl), -(C _1-5 alkylene)S(O)(C ₁₅ alkyl), -(C _1-5 alkylene)S(O) ₂ (C ₁₅ alkyl) , -(C _1-5 alkylene)S(O)(NH)(C ₁₅ alkyl), -(C _1-5 alkylene)S(O)(N(C ₁₅ alkyl))(C ₁₅ alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C ₁₅ alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl) )(O(C ₁₅ alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene )NH ₂ , -(C _1-5 alkylene)NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene )N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkyl lene)(W- heterocycloalkyl), -(C _1-5 alkylene)N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _{1 -5} alkyl), -(C _1-5 alkylene)CONH ₂ , -(C _1-5 alkylene)CONH(C _1-5 alkyl), -(C _1-5 alkylene)CON(C _1-5 Alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)CO-( N -heterocycloalkyl), -(C _1-5 alkylene)NHCO-(C _1-5 alkyl), -( C _1-5 alkylene)N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)NHCONH ₂ , -(C _1-5 alkylene)NHCONH-( C _1-5 alkyl), -(C _1-5 alkylene)NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)CON(C _{1 -5} alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH-(C _1-5 alkyl), -(C _{1- 5} alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)N (C _1-5 alkyl)COO-(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _{1- 5} alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _{1 -5} alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O )(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl) ), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-(N-heterocycloalkyl), -NHCO -(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _{1- 5} alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl) )CON(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl) ))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -( C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), - (C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _{1- 5} alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl ), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _{1 -5} alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -( C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 halo alkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -( C _1-5 alkylene)-CO(C _{1-5 alkyl), -(C 1-5 alkylene} )-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), - (C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _{1- 5} alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 Alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl ), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -(C _1-5 alkylene)-OH, -(C _{1 -5} alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S (C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)- S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl ), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl ), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -( C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _{1- 5} alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), - is optionally substituted with one or more groups selected from CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). More preferably, -Y _C2 -R _C2 is halogen, CN, OH, C _1-5 alkyl, C _1-5 haloalkyl, O(C _1-5 alkyl), -O(C _1-5 haloalkyl) , SH, S(C ₁₅ alkyl), S(O)(C ₁₅ alkyl), S(O) ₂ (C ₁₅ alkyl), S(O)(NH)(C ₁₅ alkyl), S(O)(N (C ₁₅ alkyl))(C ₁₅ alkyl), -N=S(O)(C ₁₅ alkyl)(C ₁₅ alkyl), -S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CO(C _1-5 haloalkyl), -CO-cycloalkyl, COO(C _1-5 alkyl), -COO(C _1-5 halo alkyl), -COO-cycloalkyl, CONH ₂ , CONH(C _1-5 alkyl), CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), NHCO- (C _1-5 alkyl), N(C _1-5 alkyl)-CO-(C _1-5 alkyl), NHCONH ₂ , NHCONH-(C _1-5 alkyl), NHCON(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 alkyl)CONH ₂ , N(C _1-5 alkyl)CONH-(C _1-5 alkyl), N(C _1-5 alkyl)CON(C _1-5 alkyl) )(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), NHCOO(C _1-5 alkyl), N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C ₁₅ alkyl), -P(O)(O(C _1-5 alkyl) )(O(C ₁₅ alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _{1- 5} alkylene)OH, -(C _1-5 alkylene)O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 Alkylene)SH, -(C _1-5 alkylene)S(C ₁₅ alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene) S(O)(C ₁₅ alkyl), -(C _1-5 alkylene)S(O) ₂ (C ₁₅ alkyl), -(C _1-5 alkylene)S(O)(NH)(C ₁₅ alkyl ), -(C _1-5 alkylene)S(O)(N(C ₁₅ alkyl))(C ₁₅ alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl) (C ₁₅ alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C ₁₅ alkyl)), -(C _1-5 alkylene)-P (O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)NH ₂ , -(C _1-5 alkylene)NH(C _1-5 alkyl) , -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)(C _1-5 alkyl), -(C _{1 -5} alkylene)N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)( N - heterocycloalkyl), -(C _1-5 alkylene)N( C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 haloalkyl), -(C _1-5 alkylene)-CO-cycloalkyl, -(C _1-5 alkylene)CONH ₂ , -(C _1-5 alkylene)CONH(C _1-5 alkyl), - (C _1-5 alkylene)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)CO-( N - heterocycloalkyl), -(C _1-5 alkyl len)NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)NHCONH ₂ , -(C _1-5 alkylene)NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _{1 -5} alkylene)N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkyl Len)N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH -(C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)N(C _1-5 alkyl)COO-(C _1-5 alkyl), preferably halogen, CN, OH, C _1-5 alkyl, C _1-5 haloalkyl, O(C _1-5 alkyl), -O(C _1-5 haloalkyl), SH, S(C ₁₅ alkyl), S(O)(C ₁₅ alkyl), S(O) ₂ (C ₁₅ alkyl), S(O)(NH)(C ₁₅ alkyl), S(O)(N(C ₁₅ alkyl))(C ₁₅ alkyl), -N=S(O)(C ₁₅ alkyl) (C ₁₅ alkyl), -S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), COO(C _1-5 alkyl) , CONH ₂ , CONH(C _1-5 alkyl), CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), NHCO-(C _1-5 alkyl), N(C _1-5 alkyl)-CO-(C _1-5 alkyl), NHCONH ₂ , NHCONH-(C _1-5 alkyl), NHCON(C _1-5 alkyl)(C _1-5 alkyl), N( C _1-5 alkyl)CONH ₂ , N(C _1-5 alkyl)CONH-(C _1-5 alkyl), N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl) , -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), NHCOO(C _1-5 alkyl), N(C _1-5 alkyl) COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C ₁₅ alkyl), -P(O)(O(C _1-5 alkyl))(O(C ₁₅ alkyl) ), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)OH, -( C _1-5 alkylene)O(C _1-5 alkyl), -(C 1-5 alkylene _{)-O(C 1-5 haloalkyl), -(C 1-5 alkylene )} SH, -(C _1-5 alkylene)S(C ₁₅ alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)S(O)(C ₁₅ alkyl ), -(C _1-5 alkylene)S(O) ₂ (C ₁₅ alkyl), -(C _1-5 alkylene)S(O)(NH)(C ₁₅ alkyl), -(C _1-5 Alkylene)S(O)(N(C ₁₅ alkyl))(C ₁₅ alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C ₁₅ alkyl), -( C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C ₁₅ alkyl)), -(C _1-5 alkylene)-P(O)(O(C _{1 -5} alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)NH ₂ , -(C _1-5 alkylene)NH(C _1-5 alkyl), -(C _1-5 alkyl lene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)( N -heterocycloalkyl), -(C _1-5 alkylene)N(C _1-5 haloalkyl)( C _1-5 alkyl), -(C _1-5 alkylene)-CO(C 1-5 alkyl _{), -(C 1-5 alkylene)CONH 2 , -(C 1-5 alkylene ) CONH} (C _1-5 alkyl), -(C _1-5 alkylene)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)CO-( N -heterocycloalkyl), -(C _1-5 alkylene)NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)NHCONH ₂ , -(C _1-5 alkylene)NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _{1 -5} alkylene)-OCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene )NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)N(C _1-5 alkyl)COO-(C _1-5 alkyl), more preferably halogen, -CN, - OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), - S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N( C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl) (C _1-5 alkyl), -( N -heterocycloalkyl), - CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl) (C _1-5 alkyl), -CO-(N-heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _{1- 5} alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(C _1-5 alkyl) (C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))( C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl) , -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkyl lene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene) -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl ), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O )(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl) , -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N - heterocycloalkyl), -(C _1-5 alkylene )-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _{1 -5} alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _{1 -5} alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -( C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _{1- 5} alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl) selected from (C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _{1- 5} haloalkyl), -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _{1 -5} haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene )-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _{1 -5} haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene) -NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkyl lene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN, - OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), - S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl ), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _{1 -5} alkyl)(C _1-5 alkyl). Even more preferably, -Y _C2 -R _C2 is -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably substituted by -CON(CH ₃ ) ₂ (preferably N- substituted) azacyclohexenyl. Preferably, azacyclohexenyl as mentioned herein is 1,2,3,6-tetrahydropyridinyl.

In another preferred embodiment, when -Y _C2 -R _C2 is heterocycloalkyl, then -Y _C2 -R _C2 is 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]des-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, or 2,7-diazas Fatigue [3.5] non-7-day.

In one particular embodiment, -Y _C2 -R _C2 is selected from:

In one particular embodiment, -Y _C2 -R _C2 is selected from:

In one particular embodiment, -Y _C2 -R _C2 is selected from:

X ₄ is N or C-R _C4 .

R _C4 is hydrogen, halo, C _1-6 alkyl, C _2-6 alkynyl, -O(C _1-6 alkyl), -S(C _1-6 alkyl), -NH(C _1-6 alkyl), -N(C _1-6 alkyl)(C _1-6 alkyl), -CO(C _1-6 alkyl), C _1-6 haloalkyl, -O(C _1-6 haloalkyl), -S(C _{1 -6} haloalkyl), -NH(C _1-6 haloalkyl), -N(C _1-6 haloalkyl, -CO(C _1-6 haloalkyl), -(C _0-3 alkylene)cycloalkyl, -O-(C _0-3 alkylene)-cycloalkyl, -CO-(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)cycloalkenyl, -O-(C _{0- 3} alkylene)-cycloalkenyl, -CO-(C _0-3 alkylene)-cycloalkenyl, -(C _0-3 alkylene)-heterocycloalkyl, -O-(C _0-3 alkylene) -Heterocycloalkyl, -CO-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-heterocycloalkenyl, -O-(C _0-3 alkylene)-heterocyclo Alkenyl, -CO-(C _0-3 alkylene)-heterocycloalkenyl, -(C _0-3 alkylene)-aryl, -O-(C _0-3 alkylene)-aryl, -CO-( C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-heteroaryl, -O-(C _0-3 alkylene)-heteroaryl and -CO-(C _0-3 alkylene)- selected from heteroaryl, preferably hydrogen, halo, C _1-6 alkyl, C _2-6 alkynyl, -O(C _1-6 alkyl), -S(C _1-6 alkyl), -NH(C _1-6 alkyl), -N(C _1-6 alkyl)(C _1-6 alkyl), -CO(C _1-6 alkyl), C _1-6 haloalkyl, -O(C _1-6 haloalkyl) , -S(C _1-6 haloalkyl),-NH(C _1-6 haloalkyl), -N(C _1-6 haloalkyl) ₂ , -CO(C _1-6 haloalkyl), -(C _{0 -3} alkylene) cycloalkyl, -O-(C _0-3 alkylene)-cycloalkyl, -CO-(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-heterocyclo Alkyl, -O-(C _0-3 alkylene)-heterocycloalkyl, -CO-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-aryl, -O-( C _0-3 alkylene)-aryl, -CO-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-heteroaryl, -O-(C _0-3 alkylene)-hetero is selected from aryl and -CO-(C _0-3 alkylene)-heteroaryl. The alkyl or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, -SH, -S(C _{1 -5} alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl) (C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , - CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N (C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -N(C _1-5 alkyl)CON(C _1-5 alkyl)( independently selected from C _1-5 alkyl), preferably halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl) )(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl) )(C _1-5 alkyl), and preferably the alkyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 halo alkyl), C _1-5 haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH (C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocyclo alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N - Heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl) , -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), - NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , - is optionally substituted with one or more groups selected from CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl) ), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO -( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _{1 -5} alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene) -OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene )-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkyl lene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _{1- 5} alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -( C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkyl lene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)- NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -( C _1-5 alkylene)-N (C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -( C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, C _{1- 5} alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _{1- 5} haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N( One or more selected from C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl) It is optionally substituted with a group.

Preferably R _C4 is hydrogen, halo, C _1-6 alkyl, C _2-6 alkynyl, -O(C _1-6 alkyl), -S(C _1-6 alkyl), -NH(C _1-6 alkyl), C _1-6 haloalkyl, -(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-cycloalkenyl, -(C _0-3 alkylene)-heterocycloalkyl , -(C _0-3 alkylene)-heterocycloalkenyl, -(C _0-3 alkylene)-aryl and -(C _0-3 alkylene)-heteroaryl, preferably hydrogen, halo , C _1-6 alkyl, C _2-6 alkynyl, -O(C _1-6 alkyl), -S(C _1-6 alkyl), -NH(C _1-6 alkyl), C _1-6 haloalkyl , -(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-aryl and -(C _0-3 alkylene)- selected from heteroaryl. The alkyl or alkynyl (preferably the alkyl) is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, - SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N (C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl ), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _{1 -5} alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)( C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -N(C _1-5 alkyl)CON( independently selected from C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -O(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), - N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and - is optionally substituted with one or more groups selected from CON(C _1-5 alkyl)(C _1-5 alkyl). The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl) ), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO -(N-heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _{1 -5} alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene) -OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene )-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkyl lene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _{1- 5} alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -( C _1-5 alkylene)-( N - heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkyl lene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)- NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -( C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -( C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, C _{1- 5} alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 haloalkyl), -S(C _{1 -5} alkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N( One or more selected from C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl) It is optionally substituted with a group.

Also preferably, R _C4 is hydrogen, halo, C _1-6 alkyl, C _2-6 alkynyl, -OC _1-6 alkyl, -SC _1-6 alkyl, -NH-C _1-6 alkyl, and C _1-6 haloalkyl, more preferably R _C4 is selected from hydrogen, halo, C _1-2 alkyl, and C _2-3 alkynyl, and even more preferably R _C4 is selected from hydrogen, halo, and is selected from C _1-2 alkyl, and even more preferably R _C4 is hydrogen or halo.

In an alternative preferred embodiment, R _C4 is -(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-cycloalkenyl, -(C _0-3 alkylene)-heterocycloalkyl , -(C _0-3 alkylene)-heterocycloalkenyl, -(C _0-3 alkylene)-aryl and -(C _0-3 alkylene)-heteroaryl, preferably -(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-aryl and -(C _0-3 alkylene)-heteroaryl. do. The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl) ), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO -( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _{1 -5} alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene) -OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene )-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkyl lene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _{1- 5} alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -( C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkyl lene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)- NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -( C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -( C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, C _{1- 5} alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _{1- 5} haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N( One or more selected from C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl) It is optionally substituted with a group. More preferably, R _C4 is selected from -(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-heterocycloalkyl, and -(C _0-3 alkylene)-heteroaryl. and is preferably selected from cycloalkyl, heterocycloalkyl, and heteroaryl. The cycloalkyl, heterocycloalkyl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 halo alkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -NH(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl) ), and -CON(C _1-5 alkyl)(C _1-5 alkyl). Even more preferably, R _C4 is selected from heterocycloalkyl, and heteroaryl. The heterocycloalkyl, or heteroaryl, is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl) , -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -NH(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl).

In an alternative preferred embodiment, R _C4 is -CH ₂ -cycloalkyl, -CH ₂ -cycloalkenyl _{, -CH 2 -heterocycloalkyl, -CH 2 -heterocycloalkenyl} , -CH ₂ -aryl and -CH ₂ -heteroaryl, preferably selected from -CH ₂ -cycloalkyl, -CH ₂ -heterocycloalkyl, -CH ₂ -aryl and -CH ₂ -heteroaryl. The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl) ), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO -( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _{1 -5} alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene) -OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene )-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkyl lene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _{1- 5} alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -( C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkyl lene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)- NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -( C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -( C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, C _{1- 5} alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _{1- 5} haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N( One or more selected from C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl) It is optionally substituted with a group. More preferably R _C4 is selected from -CH ₂ -heterocycloalkyl, and -CH ₂ -heteroaryl. The heterocycloalkyl or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), - N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and - is optionally substituted with one or more groups independently selected from CON(C _1-5 alkyl)(C _1-5 alkyl).

When R _C4 is heteroaryl, R _C4 is preferably imidazolyl, pyridazinyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or indazolyl, where heteroaryl is halogen, -CN, - OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), - S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl ), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl) )-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _{1- 5} alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl) , -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _{1- 5} alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkyl lene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N( C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene )-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl) -CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene) -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _{1- 5} alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 halo alkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl) ), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl) , and -CON(C _1-5 alkyl)(C _1-5 alkyl).

When R _C4 is heterocycloalkyl, R _C4 is preferably morpholinyl, 1,1-dioxothiomorpholinyl, azetinyl, pyrrolidinyl, piperidinyl, 6-oxo-1,6-di. hydropyridinyl, or piperazinyl, where heterocycloalkyl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _{1 -5} haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl ), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON (C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -N( C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _{1 -5} alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-NH ₂ , - (C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N( C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene) -( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _{1 -5} alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _{1- 5} alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene) -N (C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene) -N(C _1-5 alkyl)CON(C _1-5 alkyl)(independently selected from C _1-5 alkyl, preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 halo Alkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)( C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). More preferably, R _C4 is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), - N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl) (C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -N(C _1-5 alkyl)CON (C _1-5 alkyl)(C _1-5 alkyl), -(C 1-5 alkylene _{)-CN, -(C 1-5 alkylene)-OH, -(C 1-5 alkylene )} -O (C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)- S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene )-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)( C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl ), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -( C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _{1 -5} alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH- (C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 Alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _{1 -5} alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl) , -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). Even more preferably, R _C4 is optionally substituted with -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl) (preferably N -substituted) piperazinyl (preferably N-piperazinyl). Most preferably, R _C4 is -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably substituted with -CON(CH ₃ ) ₂ (preferably a ring as shown in formula (I) At an N atom different from the N atom to which the system is attached, it is preferably N-substituted) piperazinyl (preferably N-piperazinyl).

When R _C4 is heterocycloalkenyl, R _C4 is oxacyclohexenyl or azacyclohexenyl, preferably R _C4 is azacyclohexenyl, where heterocycloalkenyl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S( C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl) , -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)- CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl )CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), - (C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene )-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkyl lene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _{1- 5} alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene) -N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _{1 -5} haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _{1- 5} alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)- CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO -(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene )-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N (C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl independently selected from, preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), - N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and - is optionally substituted with one or more groups selected from CON(C _1-5 alkyl)(C _1-5 alkyl).

In an alternative embodiment when R _C4 is heterocycloalkyl, R _C4 is preferably 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- 1, 1-oxa-7-azaspiro[3.5]non-7-yl, 1-oxa-8-azaspiro[4.5]des-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, or 2,7-diazaspiro[3.5]non- 7-day.

Preferably, when X ₂ comprises cycloalkyl, _{heterocycloalkyl ,} aryl or _{heteroaryl , then 6} alkyl), -S(C _1-6 alkyl), -NH(C _1-6 alkyl), and C _1-6 haloalkyl. More preferably, when X ₂ comprises cycloalkyl, _{heterocycloalkyl} , aryl or _heteroaryl , _then

_Also preferably, when X ₄ contains cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

_Also preferably _{, if} X ₂ comprises _cycloalkyl , heterocycloalkyl, aryl or heteroaryl and Together they contain up to 12 non-hydrogen atoms, preferably up to 10 non-hydrogen atoms.

X ₅ is N or CR _C5 . Preferably, only one of X ₄ and X ₅ is N. In certain preferred embodiments, X ₄ is N and X ₅ is CR _C5 , preferably X ₄ is N and X ₅ is CH. In certain preferred embodiments, X ₄ is CR _C4 and X ₅ is N, preferably X ₄ is CH and X ₅ is N. In certain preferred embodiments, X ₄ is CR _C4 and X ₅ is CR _C5 . In certain preferred embodiments X ₄ is CH and X ₅ is CH.

R _C5 is hydrogen, halo, C _1-6 alkyl, -O(C _1-6 alkyl), -S(C _1-6 alkyl), -NH(C _1-6 alkyl), -N(C _1-6 alkyl) is selected from C _1-6 alkyl and C _1-6 haloalkyl. Preferably, R _C5 is hydrogen, halo, C _1-3 alkyl, -O(C _1-3 alkyl), -S(C _1-3 alkyl), -NH(C _1-3 alkyl), and C _{1 -3} is selected from haloalkyl. More preferably, R _C5 is selected from hydrogen, halo, C _1-3 alkyl, and C _1-3 haloalkyl.

R ₄ is Y _R5 -R _R5 .

Y _R5 is selected from a covalent bond, C _1-4 alkylene, C _2-4 alkenylene, and C _2-4 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each selected from a halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -SO(C _1-5 alkyl), -SO ₂ (C _1-5 alkyl), -S(C _1-5 haloalkyl), -SO(C _1-5 haloalkyl), -SO ₂ (C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), and -N(C _1-5 haloalkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -S(C _1-5 alkyl), - SO(C _1-5 alkyl), -SO ₂ (C _1-5 alkyl), -S(C _1-5 haloalkyl), -SO(C _1-5 haloalkyl), -SO ₂ (C _1-5 haloalkyl), -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), and -N(C _1-5 selected from haloalkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _{1 -5} alkyl), and -N(C _1-5 haloalkyl)(C _1-5 alkyl), and further wherein said alkylene, said alkenylene or said alkynylene contains One or more -CH ₂ - units are preferably each independently selected from -O-, NH-, N(C _1-5 alkyl)-, CO-, -COO-, S-, -SO-, and SO ₂ - is optionally replaced with a group selected from -O-, NH-, N(C _1-5 alkyl)-, CO-, S-, -SO-, and SO ₂ -. Preferably, Y _R5 is a covalent bond, C _1-2 alkylene, -CO-(C _1-2 alkylene)-, -(C _1-2 alkylene)-CO-, -CONH-(C _{1- 2} alkylene)-, -(C _1-2 alkylene)-CONH-, -NHCO-(C _1-2 alkylene)-, -(C _1-2 alkylene)-NHCO-, -NH-(C _1-2 alkylene)-, -(C _1-2 alkylene)-NH-, -O-(C _1-2 alkylene)-, -(C _1-2 alkylene)-O-, SO ₂ - (C _1-2 alkylene)-, -(C _1-2 alkylene)SO ₂ -, -CONH-, CON(C _1-5 alkyl)-, -NHCO-, -N(C _1-5 alkyl) is selected from CO-, -NH-, -O-, -CO-, -COO- and -SO ₂ -. C _1-2 alkylene herein is preferably the -CH ₂ - group.

R _R5 is selected from C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl, and is preferably is selected from C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. Preferably R _R5 is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. More preferably, R _R5 is selected from heterocycloalkyl, aryl, and heteroaryl. Even more preferably, R _R5 is selected from aryl and heteroaryl. Most preferably, R _R5 is heteroaryl. The alkyl, alkenyl, or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl) ), -S(C _1-5 haloalkyl), NH ₂₁ , NH(C _1-5 alkyl), NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl) , N(C _1-5 haloalkyl)(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), and CON(C _1-5 alkyl)(C _1-5 alkyl). is optionally substituted with one or more groups. The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is halogen, -CN, -OH, -C _1-5 alkyl, -C _1-5 haloalkyl, -O(C _{1 -5} alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -SO(C _1-5 alkyl), -SO ₂ (C _1-5 alkyl), -S(C _1-5 haloalkyl), -SO(C _1-5 haloalkyl), -SO ₂ (C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH (C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH (C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, -C _1-5 alkyl, -C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl) , -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 optionally substituted with one or more groups selected from haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl) do.

Preferably, Y _R5 is a covalent bond, C _1-2 alkylene, -CO-(C _1-2 alkylene)-, -(C _1-2 alkylene)-CO-, -CONH-(C _{1- 2} alkylene)-, -(C _1-2 alkylene)-CONH-, -NHCO-(C _1-2 alkylene)-, -(C _1-2 alkylene)-NHCO-, -NH-(C _1-2 alkylene)-, -(C _1-2 alkylene)-NH-, -O-(C _1-2 alkylene)-, -(C _1-2 alkylene)-O-, SO ₂ - (C _1-2 alkylene), -(C _1-2 alkylene)SO ₂ -, -CONH-, -NHCO-, -NH-, -O-, -CO- and SO ₂ -. Therefore, preferably, R ₄ is -(C _0-2 alkylene)-cycloalkyl, -CO-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-CO-cyclo Alkyl, -CONH-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-CONH-cycloalkyl, -NHCO-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-NHCO-cycloalkyl, -NH-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-NH-cycloalkyl, -O-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-O-cycloalkyl, SO ₂ -(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)SO ₂ -cyclo Alkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, SO ₂ -cycloalkyl, -(C _0-2 alkylene)-cycloalkyl Kenyl, -CO-(C _0-2 alkylene)-cycloalkenyl, -(C _0-2 alkylene)-CO-cycloalkenyl, -CONH-(C _0-2 alkylene)-cycloalkenyl, -(C _0-2 alkylene)-CONH-cycloalkenyl, -NHCO-(C _0-2 alkylene)-cycloalkenyl, -(C _0-2 alkylene)-NHCO-cycloalkenyl, -NH -(C _0-2 alkylene)-cycloalkenyl, -(C _0-2 alkylene)-NH-cycloalkenyl, -O-(C _0-2 alkylene)-cycloalkenyl, -(C _{0 -2} alkylene)-O-cycloalkenyl, SO ₂ -(C _0-2 alkylene)-cycloalkenyl, -(C _0-2 alkylene)SO ₂ -cycloalkenyl, -CONH-cycloalkenyl , -NHCO-cycloalkenyl, -NH-cycloalkenyl, -O-cycloalkenyl, -CO-cycloalkenyl, SO ₂ -cycloalkenyl, -(C _0-2 alkylene)-heterocycloalkyl, -CO-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-CO-heterocycloalkyl, -CONH-(C _0-2 alkylene)-heterocycloalkyl, -( C _0-2 alkylene)-CONH-heterocycloalkyl, -NHCO-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-NHCO-heterocycloalkyl, -NH-( C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-NH-heterocycloalkyl, -O-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-O-heterocycloalkyl, SO ₂ -(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)SO ₂ -heterocycloalkyl, -CONH-heterocycloalkyl, - NHCO- heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, SO ₂ -heterocycloalkyl, -(C _0-2 alkylene)-heterocycloalkenyl, - CO-(C _0-2 alkylene)-heterocycloalkenyl, -(C _0-2 alkylene)-CO-heterocycloalkenyl, -CONH-(C _0-2 alkylene)-heterocycloalkenyl, -(C _0-2 alkylene)-CONH-heterocycloalkenyl, -NHCO-(C _0-2 alkylene)-heterocycloalkenyl, -(C _0-2 alkylene)-NHCO- heterocycloalkenyl , -NH-(C _0-2 alkylene)-heterocycloalkenyl, -(C _0-2 alkylene)-NH-heterocycloalkenyl, -O-(C _0-2 alkylene)-heterocycloal Kenyl, -(C _0-2 alkylene)-O-heterocycloalkenyl, SO ₂ -(C _0-2 alkylene)-heterocycloalkenyl, -(C _0-2 alkylene)SO ₂ -heterocyclo Alkenyl, -CONH-heterocycloalkenyl, -NHCO- heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO-heterocycloalkenyl, SO ₂ -heterocycloalkenyl , -(C _0-2 alkylene)-aryl, -CO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-CO-aryl, -CONH-(C _0-2 alkyl len)-aryl, -(C _0-2 alkylene)-CONH-aryl, -NHCO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-NHCO-aryl, -NH- (C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-NH-aryl, -O-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-O -aryl, SO ₂ -(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl , -CO-aryl, SO ₂ -aryl, -(C _0-2 alkylene)-heteroaryl, -CO-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-CO -Heteroaryl, -CONH-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-CONH-heteroaryl, -NHCO-(C _0-2 alkylene)-heteroaryl, - (C _0-2 alkylene)-NHCO-heteroaryl, -NH-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-NH-heteroaryl, -O-(C _{0 -2} alkylene)-heteroaryl, -(C _0-2 alkylene)-O-heteroaryl, SO ₂ -(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)SO ₂ - selected from heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and SO ₂ -heteroaryl, preferably -(C _0-2 alkylene)-cycloalkyl, -CO-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-CO-cycloalkyl, -CONH-(C _0-2 alkylene )-cycloalkyl, -(C _0-2 alkylene)-CONH-cycloalkyl, -NHCO-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-NHCO-cycloalkyl, -NH-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-NH-cycloalkyl, -O-(C _0-2 alkylene)-cycloalkyl, -(C _{0- 2} alkylene)-O-cycloalkyl, SO ₂ -(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)SO ₂ -cycloalkyl, -CONH-cycloalkyl, -NHCO-cyclo Alkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, SO ₂ -cycloalkyl, -(C _0-2 alkylene)-heterocycloalkyl, -CO-(C _0-2 alkylene )-Heterocycloalkyl, -(C _0-2 alkylene)-CO-heterocycloalkyl, -CONH-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-CONH- Heterocycloalkyl, -NHCO-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-NHCO-heterocycloalkyl, -NH-(C _0-2 alkylene)-heterocyclo Alkyl, -(C _0-2 alkylene)-NH-heterocycloalkyl, -O-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-O-heterocycloalkyl, SO ₂ -(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)SO ₂ -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-hetero Cycloalkyl, -O- heterocycloalkyl, -CO-heterocycloalkyl, SO ₂ -heterocycloalkyl, -(C _0-2 alkylene)-aryl, -CO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-CO-aryl, -CONH-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-CONH-aryl, -NHCO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-NHCO-aryl, -NH-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-NH-aryl, -O -(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-O-aryl, SO ₂ -(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, SO ₂ -aryl, -(C _0-2 alkylene)-heteroaryl, -CO- (C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-CO-heteroaryl, -CONH-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene )-CONH-heteroaryl, -NHCO-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-NHCO-heteroaryl, -NH-(C _0-2 alkylene)-hetero Aryl, -(C _0-2 alkylene)-NH-heteroaryl, -O-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-O-heteroaryl, SO ₂ - (C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl , -CO-heteroaryl, and SO ₂ -heteroaryl. The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is halogen, -CN, -OH, -C _1-5 alkyl, -C _1-5 haloalkyl, -O(C _{1 -5} alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -SO(C _1-5 alkyl), -SO ₂ (C _1-5 alkyl), -S(C _1-5 haloalkyl), -SO(C _1-5 haloalkyl), -SO ₂ (C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH (C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH (C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, CN, OH, C _1-5 alkyl, C _1-5 halo Alkyl, O(C _1-5 alkyl), O(C ₁₅ haloalkyl), SH, S(C ₁₅ alkyl), S(C ₁₅ haloalkyl), NH ₂ , NH(C _1-5 alkyl), NH( C ₁₅ haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl) , and CON(C _1-5 alkyl)(C _1-5 alkyl). More preferably, R ₄ is -(C _0-2 alkylene)-aryl, -CO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-CO-aryl, -CONH -(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-CONH-aryl, -NHCO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)- NHCO-aryl, -NH-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-NH-aryl, -O-(C _0-2 alkylene)-aryl, -(C _{0 -2} alkylene)-O-aryl, SO ₂ -(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, -NH -aryl, -O-aryl, -CO-aryl, SO ₂ -aryl, -(C _0-2 alkylene)-heteroaryl, -CO-(C _0-2 alkylene)-heteroaryl, -(C _{0 -2} alkylene)-CO-heteroaryl, -CONH-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-CONH-heteroaryl, -NHCO-(C _0-2 alkyl len)-heteroaryl, -(C _0-2 alkylene)-NHCO- heteroaryl, -NH-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-NH-heteroaryl , -O-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-O-heteroaryl, SO ₂ -(C _0-2 alkylene)-heteroaryl, -(C _{0 -2} alkylene) is selected from SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and SO ₂ -heteroaryl , where the aryl or heteroaryl is halogen, -CN, -OH, -C _1-5 alkyl, -C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl ), -SH, -S(C _1-5 alkyl), -SO(C _1-5 alkyl), -SO ₂ (C _1-5 alkyl), -S(C _1-5 haloalkyl), -SO( C _1-5 haloalkyl), -SO ₂ (C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _{1 -5} alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _{1 -5} alkyl)(C _1-5 alkyl), preferably halogen, CN, OH, C _1-5 alkyl, C _1-5 haloalkyl, O(C _1-5 alkyl), O(C ₁₅ haloalkyl), SH, S(C ₁₅ alkyl), S(C ₁₅ haloalkyl), NH ₂ , NH(C _1-5 alkyl), NH(C ₁₅ haloalkyl), N(C _1-5 alkyl) (C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), and CON(C _1-5 alkyl)(C _{1- 5} alkyl).

In certain embodiments, R ₄ is -(C _0-2 alkylene)-CO-cycloalkyl, preferably -CO-cyclohexyl, and -(C _0-2 alkylene)-CO-aryl, preferably -CO-phenyl.

In certain embodiments, R ₄ is selected from -COO-(C _1-5 alkyl) or -CONH-(C _1-5 alkyl).

In one particular embodiment, R ₄ is selected from:

Preferably, Y _R5 is a covalent bond. Therefore, R ₄ is preferably selected from C _1-12 alkyl _{, C 2-12 alkenyl, C 2-12 alkynyl ,} cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl _. selected, more preferably selected from C _1-12 alkyl _{, C 2-12 alkenyl, C 2-12 alkynyl ,} cycloalkyl, heterocycloalkyl, aryl _, and heteroaryl. More preferably, R ₄ is selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. More preferably, R ₄ is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. Even more preferably, R ₄ is selected from aryl, and heteroaryl. Most preferably, R ₄ is heteroaryl. The alkyl, alkenyl, or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), SH, -S(C _1-5 alkyl) , -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _{1- 5} alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _{1- 5} alkyl) is optionally substituted with one or more groups independently selected from: The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is halogen, -CN, -OH, -C _1-5 alkyl, -C _1-5 haloalkyl, -O(C _{1 -5} alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -SO(C _1-5 alkyl), -SO ₂ (C _1-5 alkyl), -S(C _1-5 haloalkyl), -SO(C _1-5 haloalkyl), -SO ₂ (C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH (C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH (C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _{1- 5} haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), - NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl) )(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl).

Preferably, R ₄ is halogen, -CN, -OH, -C _1-5 alkyl, -C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl) , -SH, -S(C _1-5 alkyl), -SO(C _1-5 alkyl), -SO ₂ (C _1-5 alkyl), -S(C _1-5 haloalkyl), -SO(C _1-5 haloalkyl), -SO ₂ (C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _{1- 5} alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _{1- 5} alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), - O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH (C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH (C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). The 5-membered heteroaryl is preferably imidazolyl, isoxazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, 1,2,4-oxadiazolyl , 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 2,4-thiadiazolyl, or 1,3,4-thiadiazolyl. More preferably, the 5-membered heteroaryl is halogen, -CN, -OH, -C _1-5 alkyl, -C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _{1- 5} haloalkyl), -SH, -S(C _1-5 alkyl), -SO(C _1-5 alkyl), -SO ₂ (C _1-5 alkyl), -S(C _1-5 haloalkyl), -SO(C _1-5 haloalkyl), -SO ₂ (C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N (C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON independently selected from (C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -SH, -S(C _1-5 alkyl), -NH ₂ , -NH(C _1-5 alkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably C _1-5 alkyl, C _{1- 5} haloalkyl, optionally substituted with -O(C _1-5 alkyl), -SH, -S(C _1-5 alkyl), more preferably C _1-5 alkyl, optionally substituted with C _1-5 haloalkyl 1,2,4 optionally substituted with, even more preferably C _1-5 haloalkyl, preferably selected from -CH ₂ F, -CHF ₂ and CF ₃ , most preferably optionally substituted with -CHF ₂ -It is thiadiazolyl.

In one particular embodiment, R ₄ is am.

Preferably, the invention relates to compounds of formula (I) wherein W is -NHS(O) ₂ -. Accordingly, in another embodiment, the invention relates to compounds of formula (Ia):

[Formula (Ia)]

In compounds of formula (Ia) R ₁ , R ₂ , R ₃ , R ₄ , X ₁ , X ₂ , X ₃ , X ₄ , and X ₅ are as defined above for compounds of formula (I).

In a preferred embodiment, R ₂ and R ₃ together with the carbon atom to which they are attached form cyclopropyl. Therefore, preferably, the compound of formula (Ia) is a compound of formula (Ib):

[Formula (Ib)]

In compounds of formula (Ib) R ₁ , R ₄ , X ₁ , X ₂ , X ₃ , X ₄ , and X ₅ are as defined above for compounds of formula (I).

R ₁ is hydrogen, chloro, fluoro, cyano, formyl, (C _1-2 )alkyl, (C ₂ )alkenyl, (C ₂ )alkynyl (C _1-2 )haloalkyl, -(C _{1 -2} alkylene)-OH and -(C _1-2 alkylene)-O-(C _1-2 alkyl). Preferably, R ₁ is hydrogen, chloro, fluoro, cyano, formyl, (C _1-2 )alkyl, (C ₂ )alkenyl, (C ₂ )alkynyl and (C _1-2 )haloalkyl. is selected from the group consisting of More preferably, R ₁ is selected from the group consisting of cyano, (C _1-2 )haloalkyl and (C _1-2 )alkyl, preferably cyano, fluoromethyl and methyl. More preferably, R ₁ is cyano. Therefore, in a preferred embodiment, the compound of formula (Ib) is a compound of formula (Ic):

[Chemical formula (Ic)]

In compounds of formula (Ic) R ₄ , X ₁ , X ₂ , X ₃ , X _{4 ,} and

Also included within the scope of the present invention are compounds of formula (I) or compounds of formula (Ia) or compounds of formula (Ib) wherein R ₁ is methyl. In certain preferred embodiments of the invention, R ₁ is methyl. Also included within the scope of the present invention are compounds of formula (I) or compounds of formula (Ia) or compounds of formula (Ib) wherein R ₁ is fluoromethyl. In certain preferred embodiments of the invention, R ₁ is fluoromethyl.

Preferably, within the scope of the present invention, X ₁ and X ₃ are each CH. Therefore, preferably the compound of formula (I) of the invention is a compound of formula (Id):

[Chemical formula (Id)]

W, R ₁ , R ₂ , R ₃ , R ₄ , X ₂ , X ₄ , and X ₅ in compounds of formula (Id) are as defined above for compounds of formula (I).

Preferably, the invention relates to compounds of formula (I) wherein W is -NHS(O) ₂ -. Accordingly, in another embodiment, the compound of formula (Id) of the invention is a compound of formula (Ie):

[Formula (Ie)]

In compounds of formula (Ie) R ₁ , R ₂ , R ₃ , R ₄ , X ₂ , X ₄ , and X ₅ are as defined above for compounds of formula (I).

In a preferred embodiment, R ₂ and R ₃ together with the carbon atom to which they are attached form cyclopropyl. Therefore, preferably the compound of formula (Ie) of the invention is a compound of formula (If):

[Chemical formula (If)]

R ₁ , R ₄ , X ₂ , X ₄ , and X ₅ in compounds of formula (If) are as defined above for compounds of formula (I).

Within the scope of the invention, R ₁ is hydrogen, chloro, fluoro, cyano, formyl, (C _1-2 )alkyl, (C ₂ )alkenyl, (C ₂ )alkynyl and (C _1-2 ). ) is selected from the group consisting of haloalkyl. More preferably, R ₁ is selected from the group consisting of cyano, (C _1-2 )haloalkyl and (C _1-2 )alkyl, preferably cyano, fluoromethyl and methyl. More preferably, R ₁ is cyano.

Therefore, preferably the compound of formula (If) of the invention is a compound of formula (Ig):

[Formula (Ig)]

R ₄ , X ₂ , X ₄ , and X ₅ in compounds of formula (Ig) are as defined above for compounds of formula (I).

Also included within the scope of the present invention are compounds of formula (Id) or compounds of formula (Ie) or compounds of formula (If) wherein R ₁ is methyl. In certain preferred embodiments of the invention, R ₁ is methyl. Also included within the scope of the present invention are compounds of formula (Id) or compounds of formula (Ie) or compounds of formula (If) wherein R ₁ is fluoromethyl. In certain preferred embodiments of the invention, R ₁ is fluoromethyl.

As encompassed by the present invention, X ₄ is N or CR _C4 and X ₅ is N or CR _C5 . Also, as defined above, preferably only one of X ₄ and X ₅ is N. In certain embodiments of the invention, X ₅ is N. Therefore, when X ₅ is N, preferably X ₄ is CR _C4 . Accordingly, in certain preferred embodiments, the compound of formula (I) is a compound of formula (Ih):

[Formula (Ih)]

W, R _C4 , R ₁ , R ₂ , Rs, R ₄ , X ₁ , X ₂ , and X ₃ in compounds of formula (Ih) are as defined above for compounds of formula (I).

Preferably, within the scope of the present invention, W is -NHS(O) ₂ -. Therefore, preferably, the compound of formula (I) or the compound of formula (Ia) or the compound of formula (Ih) is a compound of formula (Ii):

[Formula (Ii)]

In compounds of formula (Ii) R _C4 , R ₁ , R ₂ , R ₃ , R ₄ , X ₁ , X ₂ , and X ₃ are as defined above for compounds of formula (I).

In a preferred embodiment, R ₂ and R ₃ together with the carbon atom to which they are attached form cyclopropyl. Therefore, preferably the compounds of formula (Ii) of the invention are compounds of formula (Ij):

[Formula (Ij)]

In compounds of formula (Ij) R _C4 , R ₁ , R ₄ , X ₁ , X ₂ , and X ₃ are as defined above for compounds of formula (I).

Within the scope of the invention, preferably R ₁ is hydrogen, chloro, fluoro, cyano, formyl, (C _1-2 )alkyl, (C ₂ )alkenyl, (C ₂ )alkynyl and (C _1-2 ) It is haloalkyl. More preferably, R ₁ is selected from the group consisting of cyano, (C _1-2 )haloalkyl and (C _1-2 )alkyl, preferably cyano, fluoromethyl and methyl. More preferably, R ₁ is cyano.

Therefore, preferably within the scope of the invention, the compounds of formula (I) or compounds of formula (Ib) or compounds of formula (Ic) or formula (Ih) or compounds of formula (Ii) or compounds of formula ( Compounds of Ij) are compounds of formula (Ik):

[Chemical formula (Ik)]

In compounds of formula (Ik) R _C4 , R ₄ , X ₁ , X ₂ , and X ₃ are as defined above for compounds of formula (I).

In one embodiment of the compound of formula (I) of the invention, X ₁ and X ₃ are each CH. Therefore, preferably the compounds of formula (I) of the invention are compounds of formula (IL):

[Formula (IL)]

W, R _C4 , R ₁ , R ₂ , R ₃ , R ₄ , and X ₂ in compounds of formula (IL) are as defined above for compounds of formula (I).

Preferably, within the scope of the present invention, W is -NHS(O) ₂ -. Therefore, preferably, the compound of formula (IL) of the invention is a compound of formula (Im):

[Chemical formula (Im)]

R _C4 , R ₁ , R ₂ , R ₃ , R ₄ , and X ₂ in compounds of formula (IL) are as defined above for compounds of formula (I).

Preferably, R ₂ and R ₃ together with the carbon atom to which they are attached form cyclopropyl. Therefore, preferably, the compound of formula (Im) of the invention is a compound of formula (In):

[Chemical formula (In)]

R _C4 , R ₁ , R ₄ , and X ₂ in compounds of formula (In) are as defined above for compounds of formula (I).

Within the scope of the invention, preferably R ₁ is hydrogen, chloro, fluoro, cyano, formyl, (C _1-2 )alkyl, (C ₂ )alkenyl, (C ₂ )alkynyl and (C _1-2 ) is selected from the group consisting of haloalkyl. More preferably, R ₁ is selected from the group consisting of cyano, (C _1-2 )haloalkyl and (C _1-2 )alkyl, preferably cyano, fluoromethyl and methyl. More preferably, R ₁ is cyano.

Therefore, preferably within the scope of the present invention, the compound of formula (In) is a compound of formula (Io):

[Chemical formula (Io)]

R _C4 , R ₄ , and X ₂ in compounds of formula (Io) are as defined above for compounds of formula (I).

Also included within the scope of the present invention are compounds of formula (IL) or compounds of formula (Im) or compounds of formula (In) wherein R ₁ is methyl. In certain preferred embodiments of the invention, R ₁ is methyl. Alternatively, also within the scope of the present invention are compounds of formula (IL) or compounds of formula (Im) or compounds of formula (In) wherein R ₁ is fluoromethyl. In certain preferred embodiments of the invention, R ₁ is fluoromethyl.

In one embodiment of the compounds of formula (I) of the invention, R ₄ is selected from aryl, and heteroaryl. Most preferably, R ₄ is heteroaryl. The aryl or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH , -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N( C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH2, -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). Preferably, R ₄ is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), - SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N (C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON (C _1-5 alkyl)(C _1-5 alkyl) is a 5-membered heteroaryl optionally substituted with one or more groups independently selected from: The 5-membered heteroaryl is preferably imidazolyl, isoxazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, 1,2,4-oxadiazolyl , 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl. More preferably, the 5-membered heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 halo alkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl) ), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl) , and -CON(C _1-5 alkyl)(C _1-5 alkyl)

optionally substituted with one or more groups independently selected from, preferably C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -SH, -S(C _1-5 alkyl) optionally substituted with, more preferably C _1-5 alkyl, optionally substituted with C _1-5 haloalkyl, even more preferably C _1-5 haloalkyl, preferably -CH ₂ F, -CHF ₂ and CF ₃ , most preferably 1,2,4-thiadiazolyl optionally substituted with -CHF ₂ .

Accordingly, in a preferred embodiment, the compound of formula (I) is a compound of formula (Ip):

[Chemical formula (Ip)]

W, R ₁ , R ₂ , R ₃ , X ₁ , X ₂ , X ₃ , X ₄ , and X ₅ in compounds of formula (Ip) are as defined above for compounds of formula (I).

Preferably W is -NHS(O) ₂ -. Accordingly, within the scope of the present invention, a compound of formula (Ip) is a compound of formula (Iq):

[Formula (Iq)]

In compounds of formula (Io) R ₁ , R ₂ , R ₃ , X ₁ , X ₂ , X ₃ , X ₄ , and X ₅ are as defined above for compounds of formula (I).

In a further preferred embodiment, R ₂ and R ₃ together with the carbon atoms to which they are attached form cyclopropyl. Accordingly, in a preferred embodiment, the compound of formula (Iq) of the invention is a compound of formula (Ir):

[Chemical formula (Ir)]

In compounds of formula (Ir) R ₁ , X ₁ , X ₂ , X ₃ , X _{4 ,} and

Further preferably, R ₁ is hydrogen, chloro, fluoro, cyano, formyl, (C _1-2 )alkyl, (C ₂ )alkenyl, (C ₂ )alkynyl and (C _1-2 ) is selected from the group consisting of haloalkyl. Preferably, R ₁ is selected from the group consisting of cyano, (C _1-2 )haloalkyl and (C _1-2 )alkyl, preferably cyano, fluoromethyl and methyl. More preferably, R ₁ is cyano.

Therefore, preferably within the scope of the present invention, the compound of formula (Ir) is a compound of formula (Is):

[Chemical formula (Is)]

X ₁ , X ₂ , X ₃ , X ₄ , and X ₅ in compounds of formula (Ir) are as defined above for compounds of formula (I).

Note that also included within the scope of the present invention are compounds of formula (Ip) or compounds of formula (Iq) or compounds of formula (Ir) wherein R ₁ is methyl. In certain preferred embodiments of the invention, R ₁ is methyl. It is further noted that alternatively within the scope of the present invention also included are compounds of formula (Ip) or compounds of formula (Iq) or compounds of formula (Ir) wherein R ₁ is fluoromethyl. In certain preferred embodiments of the invention, R ₁ is fluoromethyl.

Also within the scope of the present invention, preferred are embodiments in which X ₁ and X ₃ are each CH.

Accordingly, the compounds of formula (Ip) of the present invention further relate to embodiments wherein the compounds of formula (Ip) are compounds of formula (It):

[Chemical formula (It)]

W, R ₁ , R ₂ , R ₃ , X ₂ , X ₄ , and X ₅ in the compound of formula (It) are as defined above for the compound of formula (I).

Preferably W is -NHS(O) ₂ -. Therefore, also within the scope of the present invention, the compounds of formula (Iq) of the present invention further relate to embodiments wherein the compounds of formula (Iq) are compounds of formula (Iu):

[Formula (Iu)]

In compounds of formula (Iu) R ₁ , R ₂ , R ₃ , X ₂ , X ₄ , and X ₅ are as defined above for compounds of formula (I).

Preferably in the compounds of formula (Iu) R ₂ and R ₃ together with the carbon atom to which they are attached form cyclopropyl.

Accordingly, as further encompassed by the present invention, the compounds of formula (Ir) of the present invention further relate to embodiments wherein the compounds of formula (Ir) are compounds of formula (Iv):

[Formula (Iv)]

In compounds of formula (Iv) R ₁ , X ₂ , X ₄ , and X ₅ are as defined above for compounds of formula (I).

Preferably, since R ₁ is cyano, the compounds of formula (Is) of the invention further relate to embodiments in which the compounds of formula (Is) are compounds of formula (Iw):

[Chemical formula (Iw)]

X ₂ , X ₄ , and X ₅ in compounds of formula (Iw) are as defined above for compounds of formula (I).

Also included within the scope of the present invention are compounds of formula (It) or compounds of formula (Iu) or compounds of formula (Iv) wherein R ₁ is methyl. In certain preferred embodiments of the invention, R ₁ is methyl. Alternatively, also included within the scope of the present invention are compounds of formula (It) or compounds of formula (Iu) or compounds of formula (Iv) wherein R ₁ is fluoromethyl. In certain preferred embodiments of the invention, R ₁ is fluoromethyl.

As encompassed by the present invention, X ₄ is N or CR _C4 and X ₅ is N or CR _C5 . Also, as defined above, preferably only one of X ₄ and X ₅ is N. In certain embodiments of the invention, X ₅ is N. Therefore, when X ₅ is N, preferably X ₄ is CR _C4 . Accordingly, in certain preferred embodiments, the compound of formula (It) is a compound of formula (Ix):

[Formula (Ix)]

W, R _C4 , R ₁ , R ₂ , R ₃ , and X ₂ in compounds of formula (Ix) are as defined above for compounds of formula (I).

Further accordingly, preferably within the scope of the invention W is -NHS(O) ₂ -, so that in certain preferred embodiments the compound of formula (Iu) is a compound of formula (Iy):

[Formula (Iy)]

R _C4 , R ₁ , R ₂ , R ₃ , and X ₂ in compounds of formula (Iy) are as defined above for compounds of formula (I).

Preferably R ₂ and R ₃ together with the carbon atom to which they are attached form cyclopropyl. Thus further, in certain preferred embodiments, the compound of formula (Iv) is a compound of formula (Iz):

[Chemical formula (Iz)]

R _C4 , R ₁ , and X ₂ in compounds of formula (Iz) are as defined above for compounds of formula (I).

Within the scope of the invention, preferably R ₁ is hydrogen, chloro, fluoro, cyano, formyl, (C _1-2 )alkyl, (C ₂ )alkenyl, (C ₂ )alkynyl and (C _1-2 ) is selected from the group consisting of haloalkyl. More preferably, R ₁ is selected from the group consisting of cyano, (C _1-2 )haloalkyl and (C _1-2 )alkyl, preferably cyano, fluoromethyl and methyl. More preferably, R ₁ is cyano. Thus further, in certain preferred embodiments, the compound of formula (Iw) is a compound of formula (Iaa):

[Chemical formula (Iaa)]

R _C4 , and X ₂ in compounds of formula (Iaa) are as defined above for compounds of formula (I).

However, it should be noted that within the scope of the present invention also included are compounds of formula (Ix) or compounds of formula (Iy) or compounds of formula (Iz) wherein R ₁ is methyl. In certain preferred embodiments of the invention, R ₁ is methyl. It is further noted that alternatively within the scope of the present invention also included are compounds of formula (Ix) or compounds of formula (Iy) or compounds of formula (Iz) wherein R ₁ is fluoromethyl. In certain preferred embodiments of the invention, R ₁ is fluoromethyl.

Preferably, within the scope of the present invention, X ₂ is CY _C2 -R _C2 . Most preferably, -Y _C2 -R _C2 is -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably substituted with -CON(CH ₃ ) ₂ (preferably substituted with formula (I ) at an N atom different from the N atom attached to the ring system shown in ), preferably N-substituted) piperazinyl (preferably N-piperazinyl).

Therefore, preferably the compound of formula (I) of the invention is a compound of formula (Iab):

[Chemical formula (Iab)]

W, R ₁ , R ₂ , R ₃ , R ₄ , X ₁ , X ₃ , X ₄ , and X ₅ in the compound of formula (Iab) are as defined for the compound of formula (I).

Preferably W is -NHS(O) ₂ -. Therefore, preferably, the compound of formula (Ia) or compound of formula (Iab) of the invention is a compound of formula (Iac):

[Chemical formula (Iac)]

In compounds of formula (Iac) R ₁ , R ₂ , R ₃ , R ₄ , X ₁ , X ₃ , X ₄ , and X ₅ are as defined for compounds of formula (I).

Preferably, R ₂ and R ₃ together with the carbon atom to which they are attached form cyclopropyl. That is further accordingly, preferably, the compound of formula (Iac) or the compound of formula (Ib) of the invention is a compound of formula (Iad):

[Chemical formula (Iad)]

In compounds of formula (Iad) R ₁ , R ₄ , X ₁ , X ₃ , X ₄ , and X ₅ are as defined for compounds of formula (I).

Additionally, preferably R ₁ is cyano, and thus preferably the compound of formula (Ic) of the invention or the compound of formula (Iad) of the invention is a compound of formula (Iae):

[Chemical formula (Iae)]

In compounds of formula (Iae) R ₄ , X ₁ , X ₃ , X ₄ , and X ₅ are as defined for compounds of formula (I).

However, it should be noted that within the scope of the present invention also included are compounds of formula (Iab) or compounds of formula (Iac) or compounds of formula (Iad) wherein R ₁ is methyl. In certain preferred embodiments of the invention, R ₁ is methyl. Note that alternatively, also included within the scope of the present invention are compounds of formula (Iab) or compounds of formula (Iac) or compounds of formula (Iad) wherein R ₁ is fluoromethyl. In certain preferred embodiments of the invention, R ₁ is fluoromethyl.

Also within the scope of the present invention, preferred are embodiments in which X ₁ and X ₃ are each CH.

That is, the compounds of formula (Iac) of the invention are therefore preferably compounds of formula (Iag):

[Chemical formula (Iaf)]

W, R ₁ , R ₂ , R ₃ , R ₄ , X ₄ , and X ₅ in compounds of formula (Iaf) are as defined for compounds of formula (I).

Preferably W is -NHS(O) ₂ -. Accordingly further, the compounds of formula (Iad) of the invention or of formula (Iaf) as defined herein are preferably compounds of formula (Iag):

[Chemical formula (Iag)]

In compounds of formula (Iag) R ₁ , R ₂ , R ₃ , R ₄ , X ₄ , and X ₅ are as defined for compounds of formula (I).

Preferably, R ₂ and R ₃ together with the carbon atom to which they are attached form cyclopropyl. Accordingly further, the compounds of formula (Iae) or of formula (Iag) of the invention are preferably compounds of formula (Iah):

[Chemical formula (Iah)]

In compounds of formula (Iah) R ₁ , R ₄ , X ₄ , and X ₅ are as defined for compounds of formula (I).

Preferably, R ₁ is cyano. That is, further accordingly, the compound of formula (Iaf) of the invention or the compound of formula (Iah) of the invention is preferably a compound of formula (Iai):

[Chemical formula (Iaj)]

R ₄ , X ₄ , and X ₅ in compounds of formula (Iai) are as defined for compounds of formula (I).

Also included within the scope of the present invention are compounds of formula (Iaf) or compounds of formula (Iag) or compounds of formula (Iah) wherein R ₁ is methyl. In certain preferred embodiments of the invention, R ₁ is methyl. Alternatively, also included within the scope of the present invention are compounds of formula (Iaf) or compounds of formula (Iag) or compounds of formula (Iah) wherein R ₁ is fluoromethyl. In certain preferred embodiments of the invention, R ₁ is fluoromethyl.

As further encompassed by the invention, X ₄ is N or CR _C4 and X ₅ is N or CR _C5 . Also, as defined above, preferably only one of X ₄ and X ₅ is N. In certain embodiments of the invention, X ₅ is N. Therefore, when X ₅ is N, preferably X ₄ is CR _C4 .

Thus, the compounds of formula (Iab) of the present invention are preferably compounds of formula (Iaj):

[Chemical formula (Iaj)]

W, R _C4 , R ₁ , R ₂ , R ₃ , R ₄ , X ₁ , and X ₃ in compounds of formula (Iaj) are as defined for compounds of formula (I).

W is preferably -NHS(O) ₂ -. That is to say further that the compound of the formula (Iac) or the compound of the formula (Iaj) of the invention is preferably a compound of the formula (Iak):

[Chemical formula (Iak)]

In compounds of formula (Iak) R _C4 , R ₁ , R ₂ , R ₃ , R ₄ , X ₁ , and X ₃ are as defined for compounds of formula (I).

As disclosed herein, preferably R ₂ and R ₃ together with the carbon atom to which they are attached form cyclopropyl. That is to say further that the compound of the formula (Iad) or the compound of the formula (Iak) of the invention is preferably a compound of the formula (IaL):

[Chemical formula (IaL)]

R _C4 , R ₁ , R ₄ , X ₁ , and X ₃ in compounds of formula (IaL) are as defined for compounds of formula (I).

Also preferably, R ₁ is cyano. That is to say further that the compound of the formula (Iae) or the compound of the formula (IaL) of the invention is preferably a compound of the formula (Iam):

[Chemical formula (Iam)]

In compounds of formula (Iam) R _C4 , R ₄ , X ₁ , and X ₃ are as defined for compounds of formula (I).

Also included within the scope of the present invention are compounds of formula (Iaj) or compounds of formula (Iak) or compounds of formula (IaL) wherein R ₁ is methyl. In certain preferred embodiments of the invention, R ₁ is methyl. Additionally, also included within the scope of the present invention are compounds of formula (Iaj) or compounds of formula (Iak) or compounds of formula (IaL) wherein R ₁ is fluoromethyl. In certain preferred embodiments of the invention, R ₁ is fluoromethyl.

Accordingly, the compounds of formula (Iaf) of the invention are preferably compounds of formula (Ian):

[Chemical formula (Ian)]

W, R ₁ , R ₂ , R ₃ , R ₄ , and R _C4 in compounds of formula (Ian) are as defined for compounds of formula (I).

Accordingly, the compounds of formula (Iag) of the invention are preferably compounds of formula (Iao):

[Chemical formula (Iao)]

R ₁ , R ₂ , R ₃ , R ₄ , and R _C4 in compounds of formula (Iao) are as defined for compounds of formula (I).

Accordingly further, the compounds of formula (Iah) of the invention are preferably compounds of formula (Iap):

[Chemical formula (Iap)]

R ₁ , R ₄ , and R _C4 in compounds of formula (Iap) are as defined for compounds of formula (I).

Accordingly, the compounds of formula (Iai) of the invention are preferably compounds of formula (Iag):

[Formula (Iaq)]

R ₄ , and R _C4 in compounds of formula (Iaq) are as defined for compounds of formula (I).

As further encompassed by the invention, X ₄ is N or CR _C4 and X ₅ is N or CR _C5 . Also, as defined above, preferably only one of X ₄ and X ₅ is N. In certain embodiments of the invention, X ₄ is N. Therefore, when X ₄ is N, preferably X ₅ is CR _C5 .

Thus, in certain preferred embodiments of the invention, the compound of formula (I) of the invention is a compound of formula (Iar):

[Chemical formula (Iar)]

W, R ₁ , R ₂ , R ₃ , R ₄ , X ₁ , X ₂ , X ₃ , and R _C5 in compounds of formula (Iar) are as defined for compounds of formula (I).

Further accordingly, since W is preferably -NHS(O) ₂ -, in certain preferred embodiments of the invention the compounds of formula (Ia) of the invention are compounds of formula (Ias):

[Chemical formula (Ias)]

In compounds of formula (Iar) R ₁ , R ₂ , R ₃ , R ₄ , X ₁ , X ₂ , X ₃ , and R _C5 are as defined for compounds of formula (I).

Additionally, in certain preferred embodiments of the invention, the compounds of formula (Ib) of the invention are compounds of formula (Iat), since preferably R ₂ and R ₃ together with the carbon atoms to which they are attached form cyclopropyl. am:

[Chemical formula (Iat)]

In compounds of formula (Iat) R ₁ , R ₄ , X ₁ , X ₂ , X ₃ , and R _C5 are as defined for compounds of formula (I).

Additionally, since R ₁ is cyano, in certain preferred embodiments of the invention the compounds of formula (Ic) of the invention are compounds of formula (Iau):

[Chemical formula (Iau)]

In compounds of formula (Iau) R ₄ , X ₁ , X ₂ , X ₃ , and R _C5 are as defined for compounds of formula (I).

However, also included within the scope of the present invention are compounds of formula (Iar) or compounds of formula (Ias) or compounds of formula (Iat) wherein R ₁ is methyl. In certain preferred embodiments of the invention, R ₁ is methyl. Additionally, also included within the scope of the present invention are compounds of formula (Iar) or compounds of formula (Ias) or compounds of formula (Iat) wherein R ₁ is fluoromethyl. In certain preferred embodiments of the invention, R ₁ is fluoromethyl.

Accordingly, in certain preferred embodiments of the invention, the compounds of formula (Id) of the invention are compounds of formula (Iav):

[Formula (Iav)]

W, R ₁ , R ₂ , R ₃ , R ₄ , X ₂ , and R _C5 in compounds of formula (Iav) are as defined for compounds of formula (I).

Accordingly, in certain preferred embodiments of the invention, the compounds of formula (Ie) of the invention are compounds of formula (Iaw):

[Chemical formula (Iaw)]

In compounds of formula (Iaw) R ₁ , R ₂ , R ₃ , R ₄ , X ₂ , and R _C5 are as defined for compounds of formula (I).

Accordingly, in certain preferred embodiments of the invention, the compound of formula (If) of the invention is a compound of formula (Iax):

[Formula (Iax)]

In compounds of formula (Iax) R ₁ , R ₄ , X ₂ , and R _C5 are as defined for compounds of formula (I).

Accordingly, in certain preferred embodiments of the invention, the compound of formula (Ig) of the invention is a compound of formula (Iay):

[Chemical formula (Iay)]

R ₄ , X ₂ , and R _C5 in compounds of formula (Iay) are as defined for compounds of formula (I).

Accordingly, in certain preferred embodiments of the invention, the compound of formula (Ip) of the invention is a compound of formula (Iaz):

[Chemical formula (Iaz)]

W, R ₁ , R ₂ , R ₃ , X ₁ , X ₂ , X ₃ , and R _C5 in the compound of formula (Iaz) are as defined for the compound of formula (I).

Additionally, since W is -NHS(O) ₂ -, in certain preferred embodiments of the invention the compounds of formula (Iq) of the invention are compounds of formula (Iba):

[Chemical formula (Iba)]

In compounds of formula (Iba) R ₁ , R ₂ , R ₃ , X ₁ , X ₂ , X ₃ , and R _C5 are as defined for compounds of formula (I).

Additionally, in certain preferred embodiments of the invention, the compounds of formula (Ir) of the invention are compounds of formula (Ibb), since preferably R ₂ and R ₃ together with the carbon atoms to which they are attached form cyclopropyl. am:

[Chemical formula (Ibb)]

R ₁ , X ₂ , and R _C5 in compounds of formula (Ibb) are as defined for compounds of formula (I).

Additionally, since R ₁ is cyano, in certain preferred embodiments of the invention the compounds of formula (Is) of the invention are compounds of formula (Ibc):

[Chemical formula (Ibc)]

Also within the scope of the present invention, preferred are embodiments in which X ₁ and X ₃ are each CH. Accordingly, in certain preferred embodiments, the compound of formula (It) is a compound of formula (Ibd):

[Formula (Ibd)]

W, R ₁ , R ₂ , R ₃ , X ₂ , and R _C5 in compounds of formula (Ibd) are as defined for compounds of formula (I).

Accordingly, in certain preferred embodiments of the invention, the compound of formula (Iu) of the invention is a compound of formula (Ibe):

[Chemical formula (Ibe)]

In compounds of formula (Ibe) R ₁ , R ₂ , R ₃ , X ₂ , and R _C5 are as defined for compounds of formula (I).

Accordingly, in certain preferred embodiments of the invention, the compound of formula (Iv) of the invention is a compound of formula (Ibf):

[Chemical formula (Ibf)]

In compounds of formula (Ibf) R ₁ , X ₂ , and R _C5 are as defined for compounds of formula (I).

Accordingly, in certain preferred embodiments of the invention, the compound of formula (Iw) of the invention is a compound of formula (Ibg):

[Chemical formula (Ibg)]

X ₂ and R _C5 in compounds of formula (Ibf) are as defined for compounds of formula (I).

In certain embodiments of the invention, preferably X ₂ is CY _C2 -R _C2 . Most preferably, -Y _C2 -R _C2 is -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably substituted with -CON(CH ₃ ) ₂ (preferably substituted with formula (I ), preferably N-substituted, at an N atom different from the N atom attached to the ring system shown in ) (preferably N-piperazinyl).

Thus, in certain preferred embodiments of the invention, the compound of formula (Iab) of the invention is a compound of formula (Ibh):

[Chemical formula (Ibh)]

In compounds of formula (Ibh) W, R ₁ , R ₂ , R ₃ , R ₄ , X ₁ , X ₃ and R _C5 are as defined for compounds of formula (I).

Accordingly, in certain preferred embodiments of the invention, the compound of formula (Iac) of the invention is a compound of formula (Ibi):

[Chemical formula (Ibi)]

In compounds of formula (Ibi) R ₁ , R ₂ , R ₃ , R ₄ , X ₁ , X ₃ and R _C5 are as defined for compounds of formula (I).

Accordingly, in certain preferred embodiments of the invention, the compound of formula (Iad) of the invention is a compound of formula (Ibj):

[Chemical formula (Ibj)]

In compounds of formula (Ibi) R ₁ , R ₄ , X ₁ , X ₃ and R _C5 are as defined for compounds of formula (I).

Accordingly, in certain preferred embodiments of the invention, the compound of formula (Iae) of the invention is a compound of formula (Ibk):

[Chemical formula (Ibk)]

In compounds of formula (Ibi) R ₄ , X ₁ , X ₃ and R _C5 are as defined for compounds of formula (I).

Also within the scope of the present invention, preferred are embodiments in which X ₁ and X ₃ are each CH. Accordingly, in certain preferred embodiments, the compound of formula (Iaf) is a compound of formula (IbL):

[Chemical formula (IbL)]

W, R ₁ , R ₂ , R ₃ , R ₄ , and R _C5 in compounds of formula (IbL) are as defined for compounds of formula (I).

Accordingly, in certain preferred embodiments of the invention, the compound of formula (Iag) of the invention is a compound of formula (Ibm):

[Chemical formula (Ibm)]

In compounds of formula (Ibm) R ₁ , R ₂ , R ₃ , R ₄ , and R _C5 are as defined for compounds of formula (I).

Accordingly, in certain preferred embodiments of the invention, the compound of formula (Iah) of the invention is a compound of formula (Ibn):

[Chemical formula (Ibn)]

R ₁ , R ₄ , and R _C5 in compounds of formula (Ibn) are as defined for compounds of formula (I).

Accordingly, in certain preferred embodiments of the invention, the compound of formula (Iai) of the invention is a compound of formula (Ibo):

[Chemical formula (Ibo)]

R ₄ , and R _C5 in compounds of formula (Ibn) are as defined for compounds of formula (I).

In certain preferred embodiments X ₁ is CF and X ₃ is CH. Accordingly, a compound of formula (I) is a compound of formula (Ibp):

[Formula (Ibp)]

W, R ₁ , R ₂ , R ₃ , R ₄ , X ₂ , X ₄ , and X ₅ in compounds of formula (Ibp) are as defined above for compounds of formula (I).

Additionally, since W is -NHS(O) ₂ -, in certain preferred embodiments of the invention, the compound of formula (Ibp) of the invention is a compound of formula (Ibq):

[Chemical formula (Ibq)]

In compounds of formula (Ibq) R ₁ , R ₂ , R ₃ , R ₄ , X ₂ , X ₄ , and X ₅ are as defined above for compounds of formula (I).

Additionally, in certain preferred embodiments of the invention, the compounds of formula (Ibq) of the invention are compounds of formula (Ibr), since preferably R ₂ and R ₃ together with the carbon atoms to which they are attached form cyclopropyl. am:

[Chemical formula (Ibr)]

In compounds of formula (Ibr) R ₁ , R ₄ , X ₂ , X ₄ , and X ₅ are as defined above for compounds of formula (I).

Additionally, since R ₁ is cyano, in certain preferred embodiments of the invention the compounds of formula (Ibr) of the invention are compounds of formula (Ibs):

[Chemical formula (Ibs)]

R ₄ , X ₂ , X ₄ , and X ₅ in compounds of formula (Ibs) are as defined above for compounds of formula (I).

However, it is noted that compounds of formula (Ibp), (Ibq) or (Ibr) wherein R ₁ is methyl or fluoromethyl are also included within the scope of the present invention.

In certain embodiments of the invention, preferably X is CY _C2 -R _C2 . Most preferably, -Y _C2 -R _C2 is -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably substituted with -CON(CH ₃ ) ₂ (preferably substituted with formula (I ), preferably N-substituted, at an N atom different from the N atom attached to the ring system shown in ) (preferably N-piperazinyl).

Accordingly, in certain embodiments of the invention, the compound of formula (Ibp) is a compound of formula (Ibt):

[Chemical formula (Ibt)]

W, R ₁ , R ₂ , R ₃ , R ₄ , X ₄ , and X ₅ in compounds of formula (Ibt) are as defined above for compounds of formula (I).

Accordingly, in certain embodiments of the invention, the compound of formula (Ibq) is a compound of formula (Ibu):

[Chemical formula (Ibu)]

In compounds of formula (Ibu) R ₁ , R ₂ , R ₃ , R ₄ , X ₄ , and X ₅ are as defined above for compounds of formula (I).

Accordingly, in certain embodiments of the invention, the compound of formula (Ibr) is a compound of formula (Ibv).

[Formula (Ibv)]

In compounds of formula (Ibv) R ₁ , R ₄ , X ₄ , and X ₅ are as defined above for compounds of formula (I).

Accordingly, in certain embodiments of the invention, the compound of formula (Ibs) is a compound of formula (Ibw).

[Chemical formula (Ibw)]

R ₄ , X ₄ , and X ₅ in compounds of formula (Ibt) are as defined above for compounds of formula (I).

However, it is noted that compounds of formula (Ibt), (Ibu) or (Ibv) wherein R ₁ is methyl or fluoromethyl are also included within the scope of the present invention.

In certain preferred embodiments X ₄ is CR _C4 and X ₅ is CR _C5 . Accordingly, the compound of Formula (I) is, in certain embodiments, a compound of Formula (Ibx):

[Chemical formula (Ibx)]

W, R ₁ , R ₂ , R ₃ , R ₄ , R _C4 , R _C5 , X ₁ , X ₂ , and X ₃ in compounds of formula (Ibx) are as defined above for compounds of formula (I) same.

Additionally, since W is -NHS(O) ₂ -, in certain preferred embodiments of the invention the compounds of formula (Ibx) of the invention are compounds of formula (Iby):

[Chemical formula (Iby)]

In compounds of formula (Iby) R ₁ , R ₂ , R ₃ , R ₄ , R _C4 , R _C5 , X ₁ , X ₂ , and X ₃ are as defined above for compounds of formula (I).

Additionally, in certain preferred embodiments of the invention, the compounds of formula (Iby) of the invention are compounds of formula (Ibz), since preferably R ₂ and R ₃ together with the carbon atoms to which they are attached form cyclopropyl. am:

[Chemical formula (Ibz)]

In compounds of formula (Ibz) R ₁ , R ₄ , R _C4 , R _C5 , X ₁ , X ₂ , and X ₃ are as defined above for compounds of formula (I).

Additionally, since R ₁ is cyano, in certain preferred embodiments of the invention the compounds of formula (Ibz) of the invention are compounds of formula (Ica):

[Chemical formula (Ica)]

In compounds of formula (Ica) R ₄ , R _C4 , R _C5 , X ₁ , X ₂ , and X ₃ are as defined above for compounds of formula (I).

However, it is noted that compounds of formula (Ibx), (Iby) or (Ibz) wherein R ₁ is methyl or fluoromethyl are also included within the scope of the present invention.

In certain preferred embodiments X ₁ is CH and X ₃ is CH.

Accordingly, in certain embodiments of the invention, the compound of formula (Ibx) is a compound of formula (Icb):

[Chemical formula (Icb)]

W, R ₁ , R ₂ , R ₃ , R ₄ , R _C4 , R _C5 , and X ₂ in compounds of formula (Icb) are as defined above for compounds of formula (I).

Accordingly, in certain embodiments of the invention, the compound of formula (Iby) is a compound of formula (Icc):

[Chemical formula (Icc)]

R ₁ , R ₂ , R ₃ , R ₄ , R _C4 , R _C5 , and X ₂ in compounds of formula (Icc) are as defined above for compounds of formula (I).

Accordingly, in certain embodiments of the invention, the compound of formula (Ibz) is a compound of formula (Icd):

[Chemical formula (Icd)]

R ₁ , R ₄ , R _C4 , R _C5 , and X ₂ in compounds of formula (Icd) are as defined above for compounds of formula (I).

Accordingly, in certain embodiments of the invention, the compound of formula (Ica) is a compound of formula (Ice):

[Chemical formula (Ice)]

R ₄ , R _C4 , R _C5 , and X ₂ in compounds of formula (Ice) are as defined above for compounds of formula (I).

In certain preferred embodiments X ₄ is CH and X ₅ is CH.

Accordingly, in certain embodiments of the invention, the compound of formula (Icb) is a compound of formula (Icf):

[Chemical formula (Icf)]

W, R ₁ , R ₂ , R ₃ , R ₄ , and X ₂ in compounds of formula (Icf) are as defined above for compounds of formula (I).

Accordingly, in certain embodiments of the invention, the compound of formula (Icc) is a compound of formula (Icg):

[Chemical formula (Icg)]

R ₁ , R ₂ , R ₃ , R ₄ , and X ₂ in compounds of formula (Icg) are as defined above for compounds of formula (I).

Accordingly, in certain embodiments of the invention, the compound of formula (Icd) is a compound of formula (Ich):

[Chemical formula (Ich)]

R ₁ , R ₄ , and X ₂ in compounds of formula (Ich) are as defined above for compounds of formula (I).

Accordingly, in certain embodiments of the invention, the compound of formula (Icd) is a compound of formula (Ici):

[Chemical formula (Ici)]

R ₄ and X ₂ in compounds of formula (Ici) are as defined above for compounds of formula (I).

Preferred compounds of formula (I) are:

, and

or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystal form, pharmaceutically acceptable salt or prodrug thereof.

Further preferred compounds of formula (I) are

and or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystal form, pharmaceutically acceptable salt or prodrug thereof.

Further preferred compounds of formula (I) are selected from:

and .

Further preferred compounds of formula (I) are selected from:

and .

Further preferred compounds of formula (I) are selected from:

and .

Further preferred compounds of formula (I) are selected from:

and .

Further preferred compounds of formula (I) are: , preferably

As described below, the exemplified compounds, namely compounds 1 to 299, are particularly preferred. Preferably, the compound of formula (I) is ,

and

, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

The invention also includes any of these intermediates in salt (e.g., pharmaceutically acceptable salt) or non-salt form of the respective compounds, each of which is further described below in the Examples section of this specification. It relates to each of the intermediates. Such intermediates can be used in particular for the synthesis of compounds of formula (I).

The scope of the present invention is for example amino groups, which can be formed by protonation with inorganic or organic acids of atoms carrying electron lone pairs susceptible to protonation, or acidic groups with physiologically acceptable cations (e.g. It includes all pharmaceutically acceptable salt forms of the compounds of formula (I), for example as salts of carboxylic acid groups. Exemplary base addition salts include, for example: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; zinc salt; ammonium salt; Aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salt, meglumine salt, ethylenediamine salt, choline salt; Aralkyl amine salts such as N,N-dibenzylethylenediamine salt, benzathine salt, benetamine salt; Heterocyclic aromatic amine salts, such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; Quaternary ammonium salts, such as tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt or tetrabutylammonium salt; and basic amino acid salts, such as arginine salt, lysine salt, or histidine salt. Exemplary acid addition salts include, for example: inorganic acid salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate (e.g., sulfate or hydrogen sulfate), nitrate, phosphate (e.g., phosphate, hydrogen phosphate or dihydrogen phosphate), carbonate, hydrogen carbonate, perchlorate, borate or thiocyanate salt; Organic acid salts, such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, Lactate, maleate, oxalate, fumarate, tartrate, maleate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate. (ebonate), camphorate, glucoheptanoate or pivalate salt; Sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate ( tosylate), 2-naphthalenesulfonate (naphsylate), 3-phenylsulfonate, or camphorsulfonate salt; glycerophosphate salt; and acidic amino acid salts, such as aspartate or glutamate salts. Preferred pharmaceutically acceptable salts of compounds of formula (I) include hydrochloride salts, hydrobromide salts, mesylate salts, sulfate salts, tartrate salts, fumarate salts, acetate salts, citrate salts, and phosphate salts. A particularly preferred pharmaceutically acceptable salt of the compound of formula (I) is the hydrochloride salt. Accordingly, compounds of Formula (I), including any one of the specific compounds of Formula (I) described herein, include hydrochloride salts, hydrobromide salts, mesylate salts, sulfate salts, tartrate salts, fumarate salts, acetate salts, Preference is given to it in the form of the citrate salt, or phosphate salt, and particular preference is given to the compound of formula (I) in the form of the hydrochloride salt.

The present invention also relates to compounds of formula (I) comprising any of the specific compounds of formula (I) described herein in non-salt form.

Moreover, the scope of the invention includes solvates (i.e. hydrates) with water, for example, or solvates with organic solvents, for example methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO or acetonitrile. Compounds of formula (I) in any solvate form, including: All physical forms, including any amorphous or crystalline forms (i.e., polymorphs), of the compounds of formula (I) are also included within the scope of the present invention. It should be understood that such solvates and physical forms of pharmaceutically acceptable salts of compounds of formula (I) are likewise encompassed by the present invention.

Moreover, the compounds of formula (I) are

Various isomers, especially stereoisomers (including for example geometric (or cis/trans isomers), enantiomers and diastereomers) or tautomers (especially protic tautomers, for example keto/enol tautomers or thione/thiols) It may exist in the form of tautomers (including tautomers). All such isomers of the compounds of formula (I) are contemplated as being part of the present invention in mixed, pure or substantially pure form. In the case of stereoisomers, the present invention includes isolated optical isomers of the compounds according to the invention as well as any mixtures thereof (including in particular racemic mixtures/racemates). Racemates can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of the diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can also be obtained from the racemate via salt formation with an optically active acid followed by crystallization. The present invention further includes any tautomers of compounds of formula (I). It will be appreciated that some compounds may exhibit tautomerism. In such cases, the formulas provided herein explicitly represent only one of the possible tautomeric forms. Chemical formulas and chemical names as provided herein are intended to include any tautomeric form of the corresponding compound and are not limited to only the specific tautomeric form depicted by the drawing or identified by the name of the compound.

The scope of the invention also encompasses compounds of formula (I) in which one or more atoms are replaced by specific isotopes of the corresponding atom. For example, the invention encompasses compounds of formula (I) in which one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced by a deuterium atom (i.e., ² H; also referred to as “D”). Accordingly, the present invention also encompasses compounds of formula (I) rich in deuterium. Naturally occurring hydrogen is an isotopic mixture containing about 99.98 mole percent hydrogen-1 (i.e., ¹ H) and about 0.0156 mole percent deuterium ( ² H or D). The content of deuterium in one or more hydrogen positions in 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 used in the synthesis of a compound of formula (I) may be subjected to an H/D exchange reaction using, for example, heavy water (D ₂ O). Additional suitable deuteration techniques are described in Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labeled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; It is described in [Modvig A et al., J Org Chem, 79, 5861-5868, 2014]. The content of deuterium can be determined using, for example, mass spectrometry or NMR spectroscopy. Unless specifically indicated otherwise, it is preferred that the compounds of formula (I) are not rich in deuterium. Therefore, the presence of naturally occurring hydrogen atoms or ¹ H hydrogen atoms in compounds of formula (I) is preferred.

The present invention also relates to compounds of formula (I) in which one or more atoms are replaced by a positron emitting isotope of the corresponding atom, for example ¹⁸ F, ¹¹ C, ¹³ N, ¹⁵ O, ⁷⁶ Br, ⁷⁷ Br, ¹²⁰ l and/or ¹²⁴ l ) encompasses compounds of Such compounds can be used as tracers, trackers, or imaging probes in positron emission tomography (PET). Accordingly, the present invention relates to compounds of formula (I) in which (i) one or more fluorine atoms (or for example all fluorine atoms) are replaced by an ¹⁸ F atom, (ii) one or more carbon atoms (or for example all carbon atoms) are Compounds of formula (I) in which ¹¹ C atoms are replaced, (iii) compounds of formula (I) in which one or more nitrogen atoms (or for example all nitrogen atoms) are replaced by ¹³ N atoms, (iv) one or more oxygen atoms (or Compounds of formula (I) in which (e.g. all oxygen atoms) are replaced by ¹⁵ O atoms, (v) compounds of formula (I) in which one or more bromine atoms (or for example all bromine atoms) are replaced by ⁷⁶ Br atoms, ( vi) a compound of formula (I) in which one or more bromine atoms (or for example all bromine atoms) are replaced by ⁷⁷ Br atoms, (vii) in which one or more iodine atoms (or for example all iodine atoms) are replaced by ¹²⁰ I atoms Compounds of formula (I), and (viii) compounds of formula (I) in which one or more iodine atoms (or for example all iodine atoms) are replaced by ¹²⁴ I atoms. In general, it is preferred that none of the atoms of the compound of formula (I) are replaced by a specific isotope.

The invention further includes prodrugs of compounds of formula (I). Preferably, as understood herein, the term "prodrug" of a compound of formula (I) refers to a derivative of a compound of formula (I) that is metabolized into a compound of formula (I) upon administration to a subject. Said prodrugs of compounds of formula (I) may comprise modifications of the -OH, -NH ₂ or -COOH groups, respectively, when present in the compounds of formula (I), for example when administered to a subject, which preferably can be hydrolyzed to -OH, -NH ₂ or -COOH groups. For example, as known to those skilled in the art, such prodrugs may preferably include compounds of formula (I) comprising an -OH moiety wherein the -OH moiety is converted to an -OR _x moiety, wherein R _x preferably comprises a moiety selected from -CO-, -CH ₂ -O-CO, -CH ₂ -O-CO-O-, and -CH(CH ₃ )-O-COO-, and further Preferably R _x is selected from -CO-R _y , -CH ₂ -O-CO-R _y , -CH ₂ -O-CO-OR _y , and -CH(CH ₃ )-O-COO-R _y . where R _y is preferably selected from carbocyclyl, heterocyclyl, C _1-5 alkyl, -NH-(C _1-5 alkyl) or -S-(C _1-5 alkyl), where The alkyl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S (C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _{1- 5} alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _{1- 5} alkyl)(C _1-5 alkyl), wherein said carbocyclyl and heterocyclyl are each halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl. , -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). Additionally, as known for example to those skilled in the art, such prodrugs may preferably comprise compounds of formula (I) comprising a -NH ₂ moiety derivative, wherein the -NH ₂ moiety is -NHCOO- converted to the R _y moiety, where R _y is as defined above. Additionally, for example, as known to those skilled in the art, such prodrugs may preferably include compounds of formula (I) comprising a -COOH moiety derivative, wherein the -COOH group is represented by a -COOR _y moiety. converted, where R _y is as defined above. Additional examples of groups that can be derivatized to produce prodrugs are known to those skilled in the art.

pharmaceutical composition

Compounds provided herein can be administered as a compound per se or formulated into a medicine. The pharmaceutical/pharmaceutical composition may optionally include one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and/or solubility enhancers. You can.

The pharmaceutical composition comprises one or more solubility enhancing agents, such as poly(ethylene glycol) having a molecular weight ranging from about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600). Poly(ethylene glycol), ethylene glycol, propylene glycol, glycerol, nonionic surfactants, tyroxapol, polysorbate 80, macrogol-15-hydroxystearate (e.g. Kolliphor® HS 15, CAS 70142-34 -6), phospholipid, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclo Dextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sulfobutyl Ether-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl -γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether, hydroxypropyl methylcellulose, It may include hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

The pharmaceutical composition may also contain one or more preservatives, especially one or more antimicrobial preservatives, such as 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, thimero It may include flesh, or any combination thereof.

Pharmaceutical compositions can be formulated by techniques known to those skilled in the art, such as those disclosed in "Remington: The Science and Practice of Pharmacy", Pharmaceutical Press, ^22nd edition. Pharmaceutical compositions can be formulated in dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, 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, Includes 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 the preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and egg yolk. Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by means of a metered dose inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches, and transdermal delivery systems.

A compound of formula (I) or a pharmaceutical composition as described above comprising a compound of formula (I) may be administered to a subject by any convenient route of administration, including but not limited to one or more of the following: systemically/peripherally or to the desired site of action. Can be administered: orally (e.g., as tablets, capsules, or ingestible solutions), topically (e.g., transdermally, intranasally, ocular, buccal, and sublingually), parenterally (e.g., by injection technique or infusion). Use of techniques, for example by injection, for example subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, Subcutaneous, intraarticular, subarachnoid, or intrasternal;

For example, by implanting a depot, subcutaneously or intramuscularly), pulmonary (for example, by inhalation or aeration therapy using aerosols through the mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (intravitreal). or intracameral), rectally, or vaginally.

When the compound or pharmaceutical composition is administered parenterally, examples of such administration include one or more of the following: administering the compound or pharmaceutical composition intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, or intraurethrically. , by using intrasternal, intracardiac, intracranial, intramuscular or subcutaneous administration and/or injection techniques. For parenteral administration, the compound is best used in the form of a sterile aqueous solution that may contain other substances, such as sufficient salt or glucose to render the solution isotonic with blood. If necessary, the aqueous solution should be suitably buffered (preferably to a pH of 3 to 9). The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

The compounds or pharmaceutical compositions may also be used in the form of tablets, capsules, tablets, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications. It can be administered.

The tablets are made of microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and Granulation binders may contain excipients such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc may be included. Solid compositions of a similar type can also be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, or high molecular weight polyethylene glycol. In the case of aqueous suspensions and/or elixirs, the preparations may be prepared in combination with various sweetening or flavoring agents, coloring substances or dyes, together with emulsions and/or suspending agents and diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof. It can be.

For oral administration, the compound or pharmaceutical composition is preferably administered by oral ingestion, especially by swallowing. Accordingly, a compound or pharmaceutical composition may be administered to pass into the gastrointestinal tract through an orifice, which may also be referred to as “oral-gastrointestinal” administration.

Alternatively, the compound or pharmaceutical composition may be administered in the form of a suppository or pessary, or applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or powder. The compounds of the invention may also be administered dermally or transdermally, for example by use of a skin patch.

The compounds or pharmaceutical compositions can also be administered by sustained release systems. Suitable examples of sustained release compositions include semipermeable polymer matrices in the form of molded articles, such as films or microcapsules. Sustained release matrices include, for example, polylactide, copolymer of L-glutamic acid and gamma-ethyl-L-glutamate, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate or poly-D-(-)- Includes 3-hydroxybutyric acid. Sustained release pharmaceutical compositions also include fat trapping compounds. Accordingly, the present invention also relates to liposomes containing the compounds of the present invention.

The compounds or pharmaceutical compositions can also be administered by the pulmonary route, rectal route, or ocular route. For ophthalmic use, they may be formulated as a micronized suspension in isotonic, pH adjusted sterile saline, or preferably as a solution in isotonic, pH adjusted sterile saline, optionally in combination with a preservative such as benzalkonium chloride. It can get angry. Alternatively, they can be formulated into ointments such as petroleum jelly.

It is also contemplated to prepare dry powder formulations of the compounds of formula (I) for pulmonary administration, especially inhalation. Such dry powders can be prepared by spray drying under conditions that produce a substantially amorphous glassy powder or a substantially crystalline bioactive powder. Accordingly, dry powders of the compounds of the present invention can be prepared according to the emulsification/spray drying process.

For topical application to the skin, the compounds or pharmaceutical compositions can be prepared in the form of suitable ointments containing the active compound suspended or dissolved in a mixture with one or more of, for example, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. It can be formulated as. Alternatively, they may be suspended in a mixture of one or more of, for example, mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, 2-octyldodecanol, benzyl alcohol and water. It may be formulated as a suitable dissolving lotion or cream.

Accordingly, the present invention relates to a compound or pharmaceutical composition provided herein, wherein the corresponding compound or pharmaceutical composition is administered by any of the following: oral route; topical routes, including percutaneous, intranasal, ocular, buccal, or sublingual routes; Subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, intrasternal, cardiac. parenteral routes using injection or infusion techniques, including intraurethral, or intracranial routes; Pulmonary route, including inhalation or inhalation therapy; gastrointestinal route; intrauterine route; guided path; subcutaneous route; ophthalmic routes, including the intravitreal or intracameral routes; route to work; or vaginal route. The preferred route of administration is oral or parenteral administration. For each compound or pharmaceutical composition provided herein, it is particularly preferred that the respective compound or pharmaceutical composition is administered orally (particularly by oral ingestion).

Typically, the physician will determine the actual dosage that will be most appropriate for the individual subject. The specific dosage level and frequency of administration for any particular individual subject may vary and will vary depending on the activity of the particular compound employed, the metabolic stability and duration of action of the compound, age, weight, general health, sex, diet, mode and time of administration, It will depend on a variety of factors, including the rate of excretion, drug combination, severity of the particular condition, and the individual subject receiving treatment.

A suggested non-limiting dose of the compounds according to the invention for oral administration to humans (about 70 kg body weight) may be 0.05 to 2000 mg, preferably 0.1 mg to 1000 mg, of active ingredient per unit dose. Unit doses may be administered, for example, once to three times per day. Unit doses may also be administered 1 to 7 times per week, for example, no more than once per day. It will be appreciated that it may be necessary to routinely vary the dosage depending on the age and weight of the patient/subject as well as the severity of the condition being treated. The exact dosage and route of administration will ultimately be at the discretion of the attending physician or veterinarian.

therapeutic use

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

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

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

In a further embodiment, the invention provides an embodiment of formula (I) 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 thereof. It relates to compounds of The method of treatment comprises administering to the subject/patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate, or pharmaceutical composition thereof, as defined herein. do. In other words, in one embodiment, the invention relates to a compound of formula (I) as disclosed herein for use in treating a disease or disorder in which PARG activity is implicated.

In a further embodiment, the invention relates to a method of inhibiting cell proliferation in vitro or in vivo, comprising treating the cells with an effective amount of a compound of formula (I) as defined herein, or pharmaceutically thereof. and contacting with an acceptable salt, hydrate or solvate. Accordingly, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in inhibiting cell proliferation in vitro or in vivo.

Accordingly, 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 method of treating a proliferative disorder in a subject or patient in need thereof comprises a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate thereof, as defined herein. or administering the solvate, or pharmaceutical composition to the subject/patient. Preferably, as disclosed herein, the proliferative disorder is cancer. Accordingly, the present invention relates to a method of treating cancer in a subject or patient in need thereof. The method of treating cancer in a subject or patient in need thereof comprises a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or administering the pharmaceutical composition to the subject/patient. In certain embodiments, the cancer is a human cancer.

In one embodiment, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in treating proliferative disorders. Preferably, as disclosed herein, the proliferative disorder is cancer. Accordingly, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in treating cancer. In certain embodiments, the cancer is a human cancer.

In a further embodiment, the invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, hydrate or solvent thereof, for use in the manufacture of a medicament for the treatment of proliferative disorders. It's about cargo. In a preferred embodiment, the proliferative disorder is cancer, more preferably human cancer. Therefore, preferably the present invention relates to a compound of formula (I) as defined herein, or pharmaceutically thereof, for use in the manufacture of a medicament for the treatment of cancer, preferably for the treatment of human cancer. It relates to acceptable salts, hydrates or solvates.

In a further embodiment, the invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the manufacture of a medicament for inhibition of PARG enzyme activity. It's about. Preferably, the inhibition of PARG enzyme activity is selective inhibition of PARG enzyme activity relative to PARP1 or ARH3 enzyme activity. Accordingly, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the selective inhibition of PARG enzyme activity over PARP1 or ARH3 enzyme activity. , relates to hydrate or solvate.

The invention further provides a compound of formula (I), as defined herein, or a compound thereof, for use in the manufacture of a medicament for the treatment of diseases or disorders in which PARG activity is implicated. Pharmaceutically acceptable salts, hydrates or solvates are provided.

As understood herein, the term “proliferative disorder” is used interchangeably herein and refers to the unwanted or non-desirable growth of undesirable excessive or abnormal cells, such as neoplastic or hyperplastic growth, whether in vitro or in vivo. It relates to controlled cell proliferation. Examples of proliferative disorders include, but are not limited to, malignant neoplasms and tumors, cancer, leukemia, psoriasis, bone disease, fibroproliferative disorders (e.g., connective tissue), and atherosclerosis. Including but not limited to this. Any type of cell can be treated, including but not limited to lung, colon, breast, ovary, prostate, liver, pancreas, brain, and skin.

The anti-proliferative effect of the compounds of formula (I) of the invention has particular application in the treatment of human cancer (by inhibition of PARG enzyme activity). Anti-cancer effects include regulating cell proliferation, inhibiting angiogenesis (the formation of new blood vessels), inhibiting metastasis (the spread of a tumor from its origin), inhibiting invasion (the spread of tumor cells to adjacent normal structures), or apoptosis (programmed cell proliferation). Death) may occur through one or more mechanisms, including but not limited to promotion of death.

As defined above, antiproliferative treatment with a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof may be applied as a monotherapy or, in addition to the compounds of the invention, may be combined with conventional surgery or radiotherapy or It may involve chemotherapy. Such chemotherapy may include one or more of the following categories of antineoplastic agents:-

(i) Used in medical oncology, such as alkylating agents (e.g., cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolamide, and nitrosourea) other antiproliferative/antitumor agents and combinations thereof; antimetabolites (e.g. gemcitabine and antifolates, e.g. fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (e.g. anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); Antimitotic agents (e.g. vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxoids such as Taxol and Taxotere and polokinase inhibitors); and topoisomerase inhibitors (e.g. epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and camptothecin);

(ii) Cytostatic agents, such as antiestrogens (e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxifene), antiandrogens (e.g. bicalutamide, flutamide, niluta) mead and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g. goserelin, leuprorelin and buserelin), progestogens (e.g. megestrol acetate), aromatase inhibitors (e.g. 5oc-reductase inhibitors such as (strozole, letrozole, vorazole and exemestane) and finasteride;

(iii) Anti-invasive agents [e.g. 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)piperazine-1 -yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chern., 2004,47,6658-6661) and bosutinib (SKI-606), and metalloproteinase inhibitors such as marimastat, urokinase plasminogen activator receptor function inhibitors, or antibodies against heparanase];

(iv) Inhibitors of growth factor function: For example, these inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin™], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuxi Mab [Erbitux, C225] and any growth factor or growth factor receptor antibody disclosed by Stern et al. (Critical reviews in oncology/haematology, 2005, Vol. 54, pp1 1 -29); These inhibitors also include tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g. 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), such as lapatinib erbB2 tyrosine kinase inhibitor); 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 (e.g. Ras/Raf signaling inhibitors, e.g. farnesyl transferase inhibitors, e.g. sorafenib (BAY 43-9006), tipifarnib (R1 15777) and lonafarnib ( SCH66336)), inhibitor of cell signaling through MEK and/or AKT kinase, c-kit inhibitor, abl kinase inhibitor, PI3 kinase inhibitor, Plt3 kinase inhibitor, CSF-1R kinase inhibitor, IGF receptor (insulin-like growth factor) kinase inhibitor ; Aurora kinase inhibitors (e.g. AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;

(v) Antiangiogenic agents such as those that inhibit the effects of vascular endothelial growth factor [e.g. anti-vascular endothelial growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD6474) ), batalanib (PTK787), sunitinib (SU11248), 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 of WO 00/47212), International Patent Application No. W097/22596, WO 97/30035 , compounds such as those disclosed in WO 97/32856 and WO 98/13354 and compounds acting by other mechanisms (e.g. linomides, integrin αvβ3 function inhibitors and angiostatin)];

(vi) Vascular damaging agents, such as combretastatin A4 and international patent applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213 Compounds disclosed in (vii) endothelin receptor antagonists, such as givotentan (ZD4054) or atrasentan;

(viii) Antisense therapies, such as those targeting the targets listed above, such as ISIS 2503, an anti-ras antisense;

(ix) Gene therapy approaches, e.g. approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, gene-directed enzyme prodrug therapy (GDEPT) approaches, e.g. cytosine deaminase, thymidine kinase or bacterial nit Including approaches to increase a patient's resistance to chemotherapy or radiotherapy, such as using the roriductase enzyme and multidrug resistance gene therapy; and

(x) Immunotherapeutic approaches, e.g., in vitro and in vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4, or granulocyte-macrophage colony-stimulating factor, T cells. Approaches to reduce unresponsiveness include approaches using transfected immune cells, approaches using cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, and approaches using anti-idiotypic antibodies.

In certain embodiments, antiproliferative treatment as defined above may include conventional surgery or radiotherapy or chemotherapy in addition to the compounds of formula (I) of the invention. Such combination treatment can be achieved by administering the individual components of the treatment simultaneously, sequentially, or separately. These combination products utilize a compound of the invention within the dosage ranges described herein and other pharmaceutically active agents within the approved dosage ranges.

According to this aspect, the invention further provides a compound of formula (I) as defined herein, or a compound thereof, for use in the treatment of cancer (e.g. cancer associated with solid tumors) in combination with other anti-tumor agents. It relates to pharmaceutically acceptable salts, hydrates or solvates. The anti-tumor agent is preferably selected from the anti-tumor agents listed above.

As understood herein, the term “combination” means simultaneous, separate or sequential administration. In one aspect of the present invention, “combination” means simultaneous administration. In another aspect of the invention, “combination” means separate administration. In a further aspect of the invention “combination” means sequential administration. If administration is sequential or separate, the beneficial effects of the combination should not be lost due to delays in administering the second component.

Example

The following examples are merely illustrative of the invention and should not be construed as limiting the scope of the invention as defined by the appended claims.

Synthesis of compounds of formula (I)

The synthesis of embodiments A, B and C of compounds of formula (I) according to the invention is preferably carried out according to the general synthesis sequence as shown in Schemes 1 to 3.

In addition to the above routes described below, other routes can also be used to synthesize the target compounds according to the general general knowledge of those skilled in the art of organic synthesis. Accordingly, the transformation sequences illustrated in the schemes below are not intended to be limiting, and a variety of suitable synthesis steps can be combined to form additional synthetic sequences. Additionally, modifications of any substituents can be accomplished before and/or after the exemplified transformations. These modifications may be, for example, introduction of a protecting group, cleavage of a protecting group, reduction or oxidation of a functional group, halogenation, metallation, metal catalyzed coupling reaction, substitution or other reactions known to those skilled in the art. These transformations include those that introduce functional groups that allow further interconversion of substituents. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (e.g., Greene's Protective Groups in Organic Synthesis; Editor: P.G.M. Wuts, 5th edition, Wiley 2014). Specific examples are described in subsequent paragraphs. It is also possible that two or more consecutive steps can be carried out without work-up carried out between said steps, for example "one-pot", as is well known to those skilled in the art. It is further understood by those skilled in the art that, where appropriate, procedures similar to those reported in the general schemes below may be used to produce by-product(s) that can be used in the preparation of compounds of formula (I).

Scheme 1

Scheme 1 illustrates a preferred synthetic approach for compounds of general formula A. As will be understood by those skilled in the art, the reaction scheme also includes functionalization of the CH of Compound A with CR _C5 , for example, via bromination of the CH position (see, e.g., Kim et al, KR2012078530) followed by a palladium-catalyzed cross-coupling reaction. It can be expanded to compounds of formula (I) wherein X ₄ is N and X ₅ is CR _C5 .

In the first step, ethyl 2-chloroacetate 1 is reacted with ethyl forfmate 2 under basic conditions to yield potassium(Z)-2-chloro-3-ethoxy-3-oxoprop-1-en-1-oleate. Generates 3 . The reaction is preferably carried out in the presence of a base such as sodium ethoxide, sodium methoxide, potassium tert-butylate or sodium tert-butylate with tert-butyl methyl ether, di-isopropyl ether, diethyl ether, 1,2- It is carried out in solvents such as dimethoxyethane, dioxane, DMF, DME, THF, or mixtures of toluene, diethyl ether and EtOH. (For example, a) Stephen et al, US2017/369489; b) Murar et al, Eu. J. Med. Chern. 2017, 126, 754). The reaction is carried out at temperatures ranging from -78°C to room temperature. The reaction is preferably completed after 1 to 24 hours.

In a second step, a compound of formula 4 wherein X _{1 and} -N-1-oleate 3 is reacted to obtain the compound of formula 5 . This cyclization can be performed under acidic conditions (see, for example, Xi et al, WO2019/99311). The use of sulfuric acid in EtOH is preferably described herein. The reaction preferably proceeds at 70 to 100°C for 5 to 24 hours.

_In a third step, a compound of formula 5 _{in which} X _{1 and} It is converted to a compound of formula 6 as described above. When R ₄ is a 2-(difluoromethyl)-1,3,4-thiadiazole group, the compound of formula 5 reacts with hydrazine hydrate to produce hydrazide. This hydrazide formation can be carried out under neutral conditions (see, for example, Dong et al, J. Med. Chem. 2020, 63, 3028). Hydrazide formation is preferably carried out in EtOH, and the reaction is preferably carried out under heating or microwave conditions at 50 to 100° C. for 1 to 24 hours. The hydrazide is then reacted with ethyl 2,2-difluoroacetate to produce di-acyl hydrazine. This reaction can be carried out under basic conditions and is preferably described herein using DBU in EtOH, THF or DMF. The reaction preferably proceeds in a microwave oven or in an oil bath at room temperature to 100° C. for 0.5 to 24 hours. Finally, the diacyl hydrazine is treated with an oxygen/sulfur exchange reagent to cyclize into a compound of formula 6 where R ₄ is a 2-(difluoromethyl)-1,3,4-thiadiazole group (e.g. See Brunet et al, WO2020/127974). The use of Lawessons' reagent in toluene or THF is preferably described herein. The reaction preferably proceeds at 50 to 130°C for 0.5 to 24 hours.

In the fourth step, a compound of formula 6 _, wherein X _{1 ,} This coupling reaction can be carried out by a palladium-catalyzed CS cross-coupling reaction (see, for example, Jiang, Buchwald in 'Metal-Catalyzed Cross-Coupling Reactions', ^2nd edition.: de Meijere, Diederich , Eds.: Wiley-VCH: Weinheim, Germany, 2004]. Tris(dibenzylideneacetone) dipalladium(0), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and N-ethyl-N-isopropyl in dioxane. The use of propan-2-amine is preferably described herein. The reaction is preferably carried out in a microwave oven or in an oil bath at 80 to 100° C. for 1 to 48 hours under an argon atmosphere.

In a fifth step, a compound of formula 7 , _wherein X _{1 ,} This sulfonyl chloride formation can be accomplished by treatment with NCS, sulfonyl chloride, DCDMH, Cl ₂ , etc. in MeCN with equivalent amounts of acetic acid and water (see for example Sutton et al, WO 2021/055744). The use of DCDMH in MeCN with equivalent amounts of acetic acid and water is preferably described herein. The reaction is preferably carried out under an argon atmosphere at 0° C. to room temperature for 0.5 to 5 hours.

_{In the sixth} step, a compound of _formula 8 wherein X _{1 ,} Reaction with an amine of formula 9 as shown gives a compound of formula 10 . This reaction can be carried out under basic conditions (see, for example, Sutton et al, WO 2021/055744). The use of trimethylamine, pyridine, etc. in DCM, THF or DMF is preferably described herein. The reaction is preferably carried out under an argon atmosphere at 0° C. to room temperature for 0.5 to 24 hours.

_{In the} final step , compounds _of formula _{10 wherein} X _{1 ,} Compounds of formula A as defined for compounds of I) are obtained. This coupling reaction can be carried out by a palladium-catalyzed CN cross-coupling reaction (e.g. a) Jiang, Buchwald in 'Metal-Catalyzed Cross-Coupling Reactions', ^2nd edition.: de Meijere, Diederich , Eds.: Wiley-VCH: Weinheim, Germany, 2004; b) See Sutton, et al, WO 2021/055744). The use of cesium carbonate and Pd-PEPPSI-IHept Cl in dioxane is preferably described herein. The reaction is preferably carried out in a microwave oven or in an oil bath at 80 to 120° C. for 1 to 48 hours under an argon atmosphere. Also described herein are the preferred uses of cesium carbonate Ruphos-Pd-G3, Ruphos in dioxane or palladium acetate, Ruphos, sodium tert-butyl alcohol in THF. The reaction is preferably carried out in a microwave oven or in an oil bath at 70 to 130° C. for 1 to 24 hours under an argon atmosphere.

Scheme 2

Scheme 2 illustrates a preferred synthetic approach for compounds of general formula B. As will be appreciated _by those skilled in _the art, compounds of formula (I) _wherein there is.

In a first step, the cyano group of the compound of formula 11 where X ₁ and X ₃ are as defined for compounds of formula (I) is reduced to give the compound of formula 12 . The reaction is preferably carried out in THF in the presence of a reducing agent such as BBH ₃ .THF, BH ₃ .Me ₂ S, PtO ₂ /H ₂ , sodium tetrahydroborate, etc. (see for example Long et al, WO2018/71535 ). The reaction is carried out at temperatures ranging from 20 to 40°C. The reaction is preferably completed after 0.5 to 24 hours.

In a second step, a compound of formula 12 _, wherein X ₁ and Obtain. Acylation is preferably carried out in a solvent such as DCM, dioxane or THF in the presence of a base such as trimethylamine or N-ethyl-N-isopropylpropan-2-amine (e.g. Blaquiere et al, WO2015/ 25025). The reaction is carried out at a temperature ranging from -5°C to room temperature. The reaction is preferably completed after 1 to 24 hours.

In a third step, the compound of formula 14 where X ₁ and X ₃ are as defined for the compound of formula (I) is converted into a compound of formula 15 . The cyclization is preferably carried out in 1,2-dichloroethane, toluene or pure conditions in the presence of dehydrating reagents such as trichlorophosphate, phosphorus pentoxide and trichlorophosphate, pyridine and trifluoroacetic anhydride, etc. The reaction is carried out at temperatures ranging from 70 to 140°C. The reaction is preferably completed after 1 to 24 hours.

In the fourth step, the compound of formula 15 where X ₁ and X ₃ are as defined for the compound of formula (I) is converted into a compound of formula 16 by several synthetic steps. When R ₄ is 2-(difluoromethyl)-1,3,4-thiadiazole, the compound of formula 15 reacts with hydrazine hydrate to produce hydrazide. This hydrazide formation can be carried out under neutral conditions (see, for example, Dong et al. Med. Chern. 2020,63, 3028). Hydrazide formation is preferably carried out in EtOH, and the reaction is preferably carried out under heating or microwave conditions at 50 to 100° C. for 1 to 24 hours. The hydrazide is then reacted with ethyl 2,2-difluoroacetate to produce di-acyl hydrazine. This reaction can be carried out under basic conditions and is preferably described herein using DBU in EtOH, THF or DMF. The reaction preferably proceeds in a microwave oven or in an oil bath at room temperature to 100° C. for 0.5 to 24 hours. Finally, the diacyl hydrazine is treated with an oxygen/sulfur exchange reagent to cyclize into a compound of formula 16 where R ₄ is a 2-(difluoromethyl)-1,3,4-thiadiazole group (e.g. See Brunet et al, WO2020/127974). The use of Lawessons' reagent in toluene or THF is preferably described herein. The reaction preferably proceeds at 50 to 130°C for 0.5 to 24 hours.

In a fifth step, a compound of _formula 16 , wherein X _{1 ,} This coupling reaction can be carried out by a palladium-catalyzed CS cross-coupling reaction (see, for example, Jiang, Buchwald in 'Metal-Catalyzed Cross-Coupling Reactions', ^2nd edition.: de Meijere, Diederich , Eds.: Wiley-VCH: Weinheim, Germany, 2004]. Tris(dibenzylideneacetone) dipalladium(0), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and N-ethyl-N-isopropyl in dioxane. The use of propan-2-amine is preferably described herein. The reaction is preferably carried out in a microwave oven or in an oil bath at 80 to 100° C. for 1 to 48 hours under an argon atmosphere.

In a sixth step, a compound of formula ₁₇ , wherein X _{1 ,} This iodination can be performed by treatment with NIS, I ₂ , etc. in MeCN, THF, dioxane, DMF, etc. (see, for example, Bentley et al; WO2011/138266). The use of NIS in MeCN is preferably described herein. The reaction is preferably carried out under an argon atmosphere at 0° C. to room temperature for 0.5 to 5 hours.

In a seventh step, a compound of formula 18 _wherein X _{1 ,} This sulfonyl chloride formation can be accomplished by treatment with NCS, sulfonyl chloride, DCDMH, Cl ₂ , etc. in MeCN with equivalent amounts of acetic acid and water (see for example Sutton et al, WO 2021/055744). The use of DCDMH in MeCN with equivalent amounts of acetic acid and water is preferably described herein. The reaction is preferably carried out under an argon atmosphere at 0° C. to room temperature for 0.5 to 5 hours.

_In the _eighth step, a compound of formula 19 _{wherein X 1 ,} Reaction with an amine of formula 20 as shown gives a compound of formula 21 . This reaction can be carried out under basic conditions (see, for example, Sutton et al, WO 2021/055744). The use of trimethylamine, pyridine, etc. in DCM, THF or DMF is preferably described herein. The reaction is preferably carried out under an argon atmosphere at 0° C. to room temperature for 0.5 to 24 hours.

In the ninth step, _the compound of formula 21 , _wherein X ₁ , The reaction is preferably carried out under a hydrogen atmosphere in THF, MeOH, EtOH, dioxane or DMF in the presence of hydrogenation catalysts such as Pd/C, Pd(OH) ₂ , Raney Ni, PtO ₂ , etc. (e.g. Aissaoui et al. al, US2011/105514). The reaction is carried out at temperatures ranging from 20 to 80°C. The reaction is preferably completed after 0.5 to 24 hours.

_{In the} final step, compounds _of formula _{22 wherein} X _{1 ,} Compounds of formula B as defined for compounds of I) are obtained. This coupling reaction can be carried out by a palladium-catalyzed CN cross-coupling reaction (e.g. a) Jiang, Buchwald in 'Metal-Catalyzed Cross-Coupling Reactions', ^2nd edition.: de Meijere, Diederich , Eds.: Wiley-VCH: Weinheim, Germany, 2004; b) See Sutton, et al, WO 2021/055744). The use of cesium carbonate and Pd-PEPPSI-IHept Cl in dioxane is preferably described herein. The reaction is preferably carried out in a microwave oven or in an oil bath at 80 to 120° C. for 1 to 48 hours under an argon atmosphere. Also described herein are the preferred uses of cesium carbonate Ruphos-Pd-G3, Ruphos in dioxane or palladium acetate, Ruphos, sodium tert-butyl alcohol in THF. The reaction is preferably carried out in a microwave oven or in an oil bath at 70 to 130° C. for 1 to 24 hours under an argon atmosphere.

Scheme 3

Scheme 3 illustrates a preferred synthetic approach for compounds of general formula C. As will be appreciated by _those skilled in the art, compounds of _formula (I) wherein As will be understood by those skilled in the art, compounds _{of formula} (I ₎ wherein 2020,22,4511) can be obtained through palladium-catalyzed cross-coupling reaction.

In a first step, a compound of formula 23 where X _{1 and} Reaction with oxaborolane 24 gives the compound of formula 25 . The coupling reaction is performed using a palladium catalyst, such as tetrakis(triphenylphosphine) palladium(0) [Pd(PPh ₃ ) ₄ ], tris(dibenzylideneacetone) dipalladium(0) [Pd ₂ (dba) ₃ ] _, or _{by Pd} ( II) catalyzed by a catalyst or by [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. The reaction is preferably carried out in the presence of a base such as potassium carbonate, sodium carbonate, sodium bicarbonate or potassium phosphate in water and a solvent such as 1,2-dimethoxyethane, dioxane, DMF, DME, THF or isopropanol (e.g. For example, see Hall, Boronic Acids, 2005 Wiley VCH Verlag GmbH & Co., Weinheim, ISBN 3-527-30991-8 and references cited). The reaction is carried out at a temperature ranging from room temperature to the boiling point of the respective solvent. Additionally, the reaction can be carried out at temperatures above the boiling point using a pressure tube and microwave oven. The reaction is preferably completed after 1 to 36 hours.

In a second step , a compound of formula 25 , wherein X _{1 and} . The cyclization is preferably carried out in the presence of N-iodo-succinimide and sodium acetate in a solvent such as 1,2-dimethoxyethane, dioxane, DMF, DME, THF or MeCN (e.g. [Tang et al, Adv. Catalysis, 2016,358,2878]. The reaction is carried out in a microwave oven or in an oil bath at temperatures ranging from 80 to 100°C. The reaction is preferably completed after 1 to 36 hours.

In the third step, the compound of formula 27 where X ₁ and X ₃ are as defined for the compound of formula (I) is converted into a compound of formula 28 by several synthetic steps. When R ₄ is a 2-(difluoromethyl)-1,3,4-thiadiazole group, the compound of formula 27 reacts with hydrazine hydrate to produce hydrazide. This hydrazide formation can be carried out under neutral conditions (see, for example, Dong et al. Med. Chern. 2020.63:3028). Hydrazide formation is preferably carried out in EtOH, and the reaction is preferably carried out under heating or microwave conditions at 50 to 100° C. for 1 to 24 hours. The hydrazide is then reacted with ethyl 2,2-difluoroacetate to produce di-acyl hydrazine. This reaction can be carried out under basic conditions and is preferably described herein using DBU in EtOH, THF or DMF. The reaction preferably proceeds in a microwave oven or in an oil bath at room temperature to 100° C. for 0.5 to 24 hours. Finally, the diacyl hydrazine is treated with an oxygen/sulfur exchange reagent to cyclize into a compound of formula 28 where R ₄ is a 2-(difluoromethyl)-1,3,4-thiadiazole group (e.g. See Brunet et al, WO2020/127974). The use of Lawessons' reagent in toluene or THF is preferably described herein. The reaction preferably proceeds at 50 to 130°C for 0.5 to 24 hours.

In the fourth step, _a compound of formula 28 wherein X _{1 ,} This coupling reaction can be carried out by a palladium-catalyzed CS cross-coupling reaction (see, for example, Jiang, Buchwald in 'Metal-Catalyzed Cross-Coupling Reactions', ^2nd edition.: de Meijere, Diederich , Eds.: Wiley-VCH: Weinheim, Germany, 2004]. Tris(dibenzylideneacetone) dipalladium(0), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and N-ethyl-N-isopropyl in dioxane. The use of propan-2-amine is preferably described herein. The reaction is preferably carried out in a microwave oven or in an oil bath at 80 to 100° C. for 1 to 48 hours under an argon atmosphere.

In a fifth step, a compound of formula 29 , _wherein X _{1 ,} This iodination can be performed by treatment with NIS, I ₂ , etc. in MeCN, THF, dioxane, DMF, etc. (see, for example, Bentley et, WO2011/138266). The use of NIS in MeCN is preferably described herein. The reaction is preferably carried out under an argon atmosphere at 0° C. to room temperature for 0.5 to 5 hours.

In a sixth step, a compound of formula 30 wherein _{X 1 ,} This sulfonyl chloride formation can be accomplished by treatment with NCS, sulfonyl chloride, DCDMH, Cl ₂ , etc. in MeCN with equivalent amounts of acetic acid and water (see for example Sutton et al, WO 2021/055744). The use of DCDMH in MeCN with equivalent amounts of acetic acid and water is preferably described herein. The reaction is preferably carried out under an argon atmosphere at 0° C. to room temperature for 0.5 to 5 hours.

_In the _seventh step , the compound of formula 31 _{wherein X 1 ,} Reaction with an amine of formula 32 as shown gives a compound of formula 33 . This reaction can be carried out under basic conditions (see, for example, Sutton et al, WO 2021/055744). The use of trimethylamine, pyridine, etc. in DCM, THF or DMF is preferably described herein. The reaction is preferably carried out under an argon atmosphere at 0° C. to room temperature for 0.5 to 24 hours.

In the eighth step, _the compound of formula 33 , wherein X _{1 ,} The reaction is preferably carried out under a hydrogen atmosphere in THF, MeOH, EtOH, dioxane or DMF in the presence of hydrogenation catalysts such as Pd/C, Pd(OH) ₂ , Raney Ni, PtO ₂ , etc. (e.g. Aissaoui et al. al, US2011/105514). The reaction is carried out at temperatures ranging from 20 to 80°C. The reaction is preferably completed after 0.5 to 24 hours.

_{In the} final step , compounds _of formula _{34 wherein} X _{1 ,} Compounds of formula C as defined for compounds of I) are obtained. This coupling reaction can be carried out by a palladium-catalyzed CN cross-coupling reaction (e.g. a) Jiang, Buchwald in 'Metal-Catalyzed Cross-Coupling Reactions', ^2nd edition.: de Meijere, Diederich , Eds.: Wiley-VCH: Weinheim, Germany, 2004; b) See Sutton, et al, WO 2021/055744). The use of cesium carbonate and Pd-PEPPSI-IHept Cl in dioxane is preferably described herein. The reaction is preferably carried out in a microwave oven or in an oil bath at 80 to 120° C. for 1 to 48 hours under an argon atmosphere. Also described herein are the preferred uses of cesium carbonate Ruphos-Pd-G3, Ruphos in dioxane or palladium acetate, Ruphos, sodium tert-butyl alcohol in THF. The reaction is preferably carried out in a microwave oven or in an oil bath at 70 to 130° C. for 1 to 24 hours under an argon atmosphere.

Manufacturing example

General considerations

The abbreviations used in the following description are as follows: AcOH (acetic acid); aq. (Mercury); Ar (argon); ATM (atmospheric pressure); BH ₃ .THF (boron tetrahydrofuran complex); br. (Broad, ^1H NMR signal); B _OC2 O (di-tert-butyldicarbonate); (Cataxium APdG ₃ (mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II)); (CDCI ₃ (deuterated chloroform); CMPB ( _{cyanomethylene} trimethylphosphorane); _Cul (copper iodide); 2.2.2]octane);DAST (diethylaminosulfur trifluoride);DBU (1,8-diazabicyclo(5.4.0)undec-7-ene);d (doublet); , ¹ H NMR signal); DIBAL-H (diisobutyl aluminum hydrate); DMAP (4- NN -dimethylaminopyridine); 1,2-dimethoxyethane), DMEDA (dimethylethylenediamine); DMSO (dimethyl sulfoxide); dtbbpy ( bis(1,1) -dimethylethyl)-2,2'-bipyridine); EtOAc or EA (ethanol); FA (formic acid); [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); ¹ H NMR (proton); Nuclear magnetic resonance spectroscopy (HPLC), iPrOH ( iso -propanol) ( _potassium phosphate tribasic); lr _[ dF(CF ₃ )(dtbbpy)PF ₆ ,-di-t-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(III ) hexafluorophosphate); m ( multiplet , ¹ H NMR signal); MeCN (acetonitrile); )); MnO ₂ (manganese(IV) oxide); MS (mass spectrometry); MTBE (methyl tert- butyl ether); NaBH ₄ (sodium borohydride); NaHCO ₃ (sodium bicarbonate); Na ₂ S ₂ O ₃ (sodium thiosulfate); NCS (N-chlorosuccinimide); NH ₃ (ammonia); NH ₄ CI (ammonium fluoride); NiCl ₂ (nickel dichloride); NIS (N-iodosuccinimide); NMP (N-methylpyrrolidone); NMR (nuclear magnetic resonance); Pd/C (palladium on carbon); Pd ₂ dba ₃ (tris(dibenzylideneacetone)dipalladium); Pd(dppf)Cl ₂ (1,1-bis(diphenylphosphino)ferrocene dichloropalladium); Pd(Ph) ₃ ) ₂ Cl ₂ (bis(triphenylphosphine)palladium(II) dichloride); PE (petroleum ether); Pd-PEPPSI-IPentCl o-picolin([1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(2 -methylpyridin-1-ium-1-yl)palladium; Pd(OH) ₂ (palladium hydroxide) ₃ ) ₄ (palladium-tetrakis(triphenylphosphine); PhI(OAc) ₂ (( diacetoxyiodo)benzene); P(tBu) ₃ (tri-tert-butylphosphine); quin (quintet, 1H NMR signal); (racemic); s (single line, ¹ H NMR ^signal ); TBAF (tetrabutylammonium fluoride); BuBrettPhos-Pd-G3 ([(2-di- tert -butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-( 2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate) tBuXPhos Pd G3 (methanesulfonato(2-di-t-butylphosphino-2',4',6', -tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)) TBDMSCI or TBSCI (tert-butyldimethylsilyl chloride); tBuOH (tert-butanol); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TMSCHN ₂ (trimethylsilyl); diazomethane); TMSOTf (trimethylsilyl trifluoromethanesulfonate); UPLC (ultra-high performance liquid chromatography), wt% ); Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene); ](2'-methylamino-1,1'-biphenyl-2-yl)palladium(II)).

General Procedure: All starting materials and solvents were obtained from commercial sources or prepared according to literature references. Commercially available reagents and anhydrous solvents were used as supplied without further purification. Unless otherwise noted, all reactions were stirred. The organic solution was routinely dried with anhydrous sodium sulfate. Column chromatography was performed on pre-packed silica (100-1000 mesh, 40-63 μm) cartridges using the indicated amounts. All air and moisture-sensitive reactions were performed with oven-dried (at 120° C.) glassware under an inert atmosphere of nitrogen or argon. Compound names were generated using ChemDraw Prime (Perkin Elmer). In some cases, commonly accepted names of commercially available reagents were used in place of ChemDraw generated names.

Reverse-phase HPLC conditions for LCMS analysis of final compounds;

Method 1: SHIMADZU LCMS-2020 Kinetex EVO C18 2.1×30mm,5μm at 50℃; Mobile phase: 0.0375% TFA in water (v/v); B: 0.01875% TFA in MeCN (v/v); Flow rate maintained at 1.5 mL/min; Elution with mobile phase over 1.55 min using UV detection at 220 nm and 254 nm. Gradient information: 0-0.80 min, ramping from 95% A-5% B to 5% A-95% B; 0.80-1.20 minutes, held at 5% A-95% B; 1.20-1.21 minutes, return to 95% A-5% B, 1.21-1.55 minutes, remain at 95% A-5% B.

Method 2: SHIMADZU LCMS-2020 Kinetex EVO C18 2.1×30mm,5μm at 40℃; Mobile phase: A: 0.025% NH ₃ -H ₂ O (v/v) in water, B: MeCN; Flow rate maintained at 1.5 mL/min; Elution with mobile phase over 1.55 min using UV detection at 220 nm and 254 nm. Gradient information: 0-0.80 min, ramping from 95% A-5% B to 5% A-95% B; 0.80-1.20 minutes, held at 5% A-95% B; 1.20-1.21 minutes, return to 95% A-5% B, 1.21-1.55 minutes, remain at 95% A-5% B.

Method 3: SHIMADZU LCMS-2020 Kinetex EVO C18 2.1×30mm,5μm at 50℃; Mobile phase: 0.0375% TFA in water (v/v); B: 0.01875% TFA in MeCN (v/v); Flow rate maintained at 2.0 mL/min; Elution with mobile phase over 0.80 min using UV detection at 220 nm and 254 nm. Gradient information: 0-0.80 min, ramping from 95% A-5% B to 5% A-95% B; 0.80-1.20 minutes, held at 5% A-95% B; 1.20-1.21 minutes, return to 95% A-5% B, 1.21-1.55 minutes, remain at 95% A-5% B.

Method 4: SHIMADZU LCMS-2020 Kinetex®EVO C18 2.1×20 mm 2.6 um at 50°C; Mobile phase: 0.0375% TFA in water (v/v); B: 0.01875% TFA in MeCN (v/v); Flow rate maintained at 2.0 mL/min; Elution with mobile phase over 1.00 min using UV detection at 220 nm and 254 nm. Gradient information: 0.01-0.60 min, ramping from 95% A-5% B to 5% A-95% B; 0.61-0.78 min, maintained at 5% A-95% B; 0.78-0.79 min, return to 95% A-5% B, 0.79-0.80 min, remain 95% A-5% B.

Method 5: SHIMADZU LCMS-2020 Kinetex EVO C18 2.1×30mm,5μm at 50℃; Mobile phase: 0.0375% TFA in water (v/v); B: 0.01875% TFA in MeCN (v/v); Flow rate maintained at 2.0 mL/min; Elution with mobile phase over 0.80 min using UV detection at 220 nm and 254 nm. Gradient information: 0-0.80 min, ramping from 95% A-5% B to 5% A-95% B; 0.80-1.20 minutes, held at 5% A-95% B; 1.20-1.21 minutes, return to 95% A-5% B, 1.21-1.55 minutes, remain at 95% A-5% B.

^One H NMR spectroscopy:

¹ H NMR spectra were acquired on a Bruker Avance III spectrometer at 400 MHz using residual non-deuterated solvent as reference. The ¹ H NMR signal is specified as multiplicity/combined multiplicity as evident from the spectrum; Possible higher order effects were not considered. The chemical shift of the signal (δ) is specified in parts per million (ppm).

Salt stoichiometry :

In the present specification, especially in the examples and experimental sections for the synthesis of intermediates of the invention, where a compound is referred to in salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form is determined by the respective preparation and/or Alternatively, the information obtained through the purification process is in most cases unknown. Unless otherwise specified, suffixes to chemical names or structural formulas, for example, “hydrochloride”, “trifluoroacetate”, “sodium salt” or “x HO”, “x CF3COOH”, “x Na+” It should be understood only in salt form and not as a stoichiometric specification. This applies similarly to cases in which synthetic intermediates or exemplary compounds or salts thereof are obtained as solvates, such as hydrates, of unknown stoichiometric composition (if defined) by the described manufacturing and/or purification processes.

Preparation of intermediate 1.1

Potassium (Z)-2-chloro-3-ethoxy-3-oxoprop-1-en-1-oleate

A solution of ethyl 2-chloroacetate (10 g, 81.60 mmol, 8.70 mL) and ethyl formate (6.04 g, 81.60 mmol, 6.56 mL) in tetrahydrofuran (THF) (150 mL) at -10°C for 20 min. Stirred and then t-BuOK (11.90 g, 106.08 mmol) was added in portions to maintain the temperature of the mixture below 0-5°C. The reaction was warmed to 20° C. for 16 hours. The reaction mixture was filtered to obtain a solid which was triturated with EtOAc (50 mL) for 5 h at 20° C., filtered and the solid dried under vacuum to give potassium (Z)-2-chloro-3-ethoxy-3- Oxoprop-1-en-1-oleate (12 g, 63.61 mmol, 77.95% yield) was obtained as a yellow solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ8.88-8.24 (m, 1H), 4.16 (q, J =7.2 Hz , 2H), 1.24 (t, J =7.2 Hz , 3H).

Preparation of intermediate 1.2

Ethyl 6-bromo-8-chloroimidazo[1,2-a]pyridine-3-carboxylate

5-Bromo-3-chloro-pyridin-2-amine (2 g, 9.64 mmol) and potassium (Z)-2-chloro-3-ethoxy-3-oxoprop-1- in EtOH (100 mL) To a solution of en-1-oleate (7.27 g, 38.56 mmol) was added H ₂ SO ₄ (2.84 g, 28.92 mmol, 1.54 mL) at 20°C. The reaction mixture was heated to 90° C. for 16 hours. The reaction mixture was cooled to 20°C. EtOH was removed under reduced pressure, water (50 mL) was added and the mixture was extracted with EtAOc (3×80 mL). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give a residue which was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent 0). Purified with ∼30% ethyl acetate/petroleum ether gradient @ 80 mL/min) to give the product ethyl 6-bromo-8-chloroimidazo[1,2-a]pyridine-3-carboxylate (1.7 g, 5.21 mmol). , 54.03% yield) was obtained as a white solid.

RT 0.888 min (Method 1); m/z 304.9 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d _6,400 MHz): δ 9.24 (s, 1H), 8.301 (s, 1H), 8.05-8.04 (m, 1H), 4.40-4.35 (m, 2 H), 1.35 (t) , J =7.2 Hz , 3H).

Preparation of intermediate 1.3

6-Bromo-8-chloroimidazo[1,2-a]pyridine-3-carbohydrazide

A solution of ethyl 6-bromo-8-chloroimidazo[1,2-a]pyridine-3-carboxylate (1.7 g, 5.21 mmol, 93% purity) in EtOH (20 mL) was incubated with NH ₂ at 20°C. NH ₂ ·H ₂ O (3.26 g, 63.76 mmol, 3.16 mL, 98% purity) was added. The mixture was refluxed for 2 hours and then cooled to 20°C. The precipitated solid was separated to obtain the product 6-bromo-8-chloroimidazo[1,2-a]pyridine-3-carbohydrazide (1.5 g, 4.97 mmol, 95.49% yield) as a white solid. .

RT 0.487min (Method 1); m/z 290.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 10.68-9.40 (m, 2H), 8.32 (s, 1H), 7.92 (d, J = 1.6 Hz, 1H), 4.83-4.27 (m, 2H).

Preparation of intermediate 1.4

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

6-Bromo-8-chloroimidazo[1,2-a]pyridine-3-carbohydrazide (1.3 g, 4.31 mmol) and ethyl 2,2-difluoroacetate (110 mL) in EtOH (110 mL) To the mixture (5.35 g, 43.11 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.31 g, 8.62 mmol) was added at 20°C. The mixture was refluxed for 16 hours, then cooled to 20°C and finally concentrated to give a residue, which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 90% ethyl acetate/petroleum ether). gradient @80 mL/min) to give the product 6-bromo-8-chloro- N '-(2,2-difluoroacetyl)imidazo[1,2-a]pyridine-3-carbohydra. Zide (0.85 g, 2.17 mmol) was obtained as a white solid.

RT 0.770 min (Method 1); m/z 368.9 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 11.03-10.93 (m, 2H), 9.49 (s, 1H), 8.48 (s, 1H), 8.03 (s, 1H), 6.48 (t, J= 52.8 ㎐, 1H).

Preparation of intermediate 1.5

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

Bromo-8-chloro- N '-(2,2-difluoroacetyl)imidazo[1,2-a]pyridine-3-carbohydrazide (200.00 mg, 511.52 μmol) in toluene (4 mL) ) Lawesson's reagent (227.58 mg, 562.67 μmol) was added to the solution at 20°C. The mixture was stirred at 110°C for 2 hours. The mixture was cooled to 20° C. and concentrated to give a residue, which was triturated with MeOH (5 mL) for 30 min. After filtration, the cake was collected and the product 2-(6-bromo-8-chloro-imidazo[1,2-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4 -thiadiazole (140 mg, 382.95 μmol, 74.87% yield) was obtained as a white solid.

¹ H NMR (DMSO- d ₆ , 400 MHz): 7.54-7.84 (t, J = 53.2 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 8.64 (s, 1H), 9.61 (d, J = 1.6 Hz, 1H).

Preparation of intermediate 1.6

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

2-(6-Bromo-8-chloro-imidazo[1,2-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4- in dioxane (2 mL) _Thiadiazole (100 mg, 273.53 μmol) _, A mixture of benzylideneacetone)dipalladium(0)) (25.05 mg, 27.35 μmol) was stirred at 20°C. N ₂ was bubbled through the mixture for 5 minutes and finally phenylmethanethiol (33.97 mg, 273.53 μmol, 32.05 μL) was added. The mixture was heated to 65° C. and stirred for 16 hours. The reaction mixture was cooled to 20° C. and concentrated to give a residue, which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0-30% ethyl acetate/petroleum ether gradient @ 30 mL/min). ) to obtain the product 2-(6-benzylsulfanyl-8-chloroimidazo[1,2-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadia Sol (80 mg, 193.70 μmol, 70.81% yield) was obtained as a yellow solid.

RT 1.012 min (Method 1); m/z 408.9 (M+H) ⁺ (ESI ⁺ ).

Preparation of intermediate 1.7

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,2-a]pyridine-6-sulfonyl chloride

2-(6-benzylsulfanyl-8-chloroimidazo[1,2-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiase in MeCN (0.5 mL) 1,3-dichloro-5,5-dimethyl-diazole (20 mg, 48.91 μmol), AcOH (5.29 mg, 88.05 μmol, 5.04 μL) and H ₂ O (881.21 μg, 48.91 μmol) at 0°C. Imidazolidine-2,4-dione (17.35 mg, 88.05 μmol) was added. The mixture was stirred at 0°C for 0.5 hours. THF (3 mL) was added and the solution was dried over Na ₂ SO ₄ , filtered and concentrated to give the product 8-chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazole. -2-yl]imidazo[1,2-a]pyridine-6-sulfonyl chloride (18 mg, 46.73 μmol, 95.53% yield) was obtained as a white solid, which was used in the next step without further purification.

Preparation of Example 1

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

To a solution of 1-aminocyclopropane-1-carbonitrile (5.79 mg, 48.81 μmol, HCl) in pyridine (294.00 mg, 3.72 mmol) was added 8-chloro-3-(5-() in THF (0.3 mL) at 0°C. A solution of difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,2-a]pyridine-6-sulfonyl chloride (18.00 mg, 46.71 μmol) was added over 1 minute. It was added dropwise. The mixture was stirred at 20° C. for 16 hours. The reaction mixture was concentrated to obtain a residue, which was subjected to preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 30%-60%, 7 min) to obtain 8-chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo [1 ,2-a]pyridine-6-sulfonamide (4.34 mg, 10.07 μmol, 20.64% yield) was obtained as a gray solid.

RT 0.882 min (Method 1); m/z 430.9 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d _6,400 MHz): 9.95 (s, 1H), 8.76 (s, 1H), 8.25 (s, 1H), 7.87 (s, 1H), 7.71 (t, J = 52.8 Hz, 1H), 1.23 (s, 2H), 1.15 (s, 2H).

Preparation of Example 2

4-(6-(N-(1-cyanocyclopropyl)sulfamoyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1 ,2-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide

8-Chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo in dioxane (0.5 mL) [1,2-a]pyridine-6-sulfonamide (30 mg, 69.63 μmol), N,N-dimethylpiperazine-1-carboxamide (13.14 mg, 83.56 μmol), Pd-PEPPSI-IHept CI (6.77 mg, 6.96 μmol) and Cs ₂ CO ₃ (68.06 mg, 208.89 μmol) were degassed and purged with N ₂ (3x) and stirred at 100°C for 12 hours under N ₂ atmosphere. The mixture was concentrated under vacuum and the residue was subjected to preparative HPLC (column: Phenomenex Synergi C18 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 30%-60%, 10 min) to obtain the product 4-(6-(N-(1-cyanocyclopropyl)sulfamoyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2- I)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide (15.36 mg, 39.7% yield, 99.29% purity) was obtained as an off-white solid.

RT 0.882 min (Method 1); m/z 552.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.75 (s, 1H), 9.57 (br, 1H), 8.65 (s, 1H), 7.71 (t, J = 53.2,1H), 7.01 (s, 1H) ), 3.66-3.65 (m, 4H), 3.38-3.36 (m, 4H), 2.81 (s, 6H), 1.45-1.37 (m, 4H).

Preparation of Example 3

(R)-N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(2-methylmorpholy No) imidazo[1,2-a]pyridine-6-sulfonamide

8-Chloro-N-(1-cyanocyclopropyl)-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]imidazo in dioxane (0.5 mL) [1,2-a]pyridine-6-sulfonamide (10 mg, 23.21 μmol), (R)-2-methylmorpholine (2.82 mg, 27.85 μmol), Pd-PEPPSI-IHept Cl (2.26 mg, 2.32 μmol) ) and Cs ₂ CO ₃ (22.69 mg, 69.63 μmol) were degassed, purged with N ₂ (3x), and stirred at 100°C for 12 hours under N ₂ atmosphere. The mixture was filtered and concentrated under reduced pressure to obtain a residue, which was subjected to preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 32% -62%, 10 min) to give the product (R)-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2- Il)-8-(2-methylmorpholino)imidazo[1,2-a]pyridine-6-sulfonamide (3.22 mg, 28.00% yield) was obtained as a yellow solid.

RT 0.870 (Method 1); m/z 496.0 (M+H) ⁺ (ES ⁺ ); ¹ H NMR (400 MHz, DMSO -d 6) δ 9.71 (d, J = 1.2 Hz, 1H), 8.62 (s, 1H), 8.30 (s, 1H), 7.55 - 7.85 (t, J = 53.2 Hz, 1H), 6.98 (d, J =1.2 Hz, 1H), 4.18 - 4.32 (m, 2H), 3.98 (dd, J = 11.2,1.6 Hz, 1H), 3.74 - 3.85 (m, 2H), 2.92 (m , 1H) 2.61 - 2.67 (m, 1H), 1.35 -1.41 (m, 2H), 1.26 -1.33 (m, 2H), 1.20 (d, J = 6.4 Hz, 3H).

Preparation of Intermediate 4.1

(5-bromo-3-chloropyridin-2-yl)methanamine

To a mixture of 5-bromo-3-chloropicolonitrile (2.0 g, 9.20 mmol) in THF (10 mL) was added BH ₃ ·THF (1 M, 11.04 mL) over 5 min under ice-water cooling. The mixture was stirred at 0°C for 30 minutes and then warmed to 20°C and stirred at this temperature for an additional 30 minutes. The mixture was cooled to 0° C. and quenched by adding MeOH (10 mL) dropwise over 5 min. The mixture was heated to 70° C. and stirred at this temperature for 30 minutes. The reaction was concentrated under vacuum to give the crude product (2.2 g) as a light brown solid. The crude product was dissolved in HCl (aq. 2M, 20 mL), washed with DCM (20 mL; 2x), and the aqueous phase was finally concentrated in vacuo to give the product (5-bromo-3-chloro-2- Pyridyl)methanamine (1.5 g, 4.07 mmol, 44.26% yield, 70% purity, HCl salt) was obtained as a light brown solid.

RT 0.18 min (method 2); m/z 222.9 (M+H) ⁺ (ESI ⁺ ), ¹ H NMR (400 MHz, DMSO- d 6) δ = 8.78 (d, J = 2.0 Hz, 1H), 8.69 (br, 3H), 8.47 ( d, J = 2.0 Hz, 1H), 4.24 (d, J = 6.2 Hz, 2H).

Preparation of Intermediate 4.2

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

To a mixture of (5-bromo-3-chloro-2-pyridyl)methanamine (1.5 g, 5.82 mmol, HCl salt) in DCM (30 mL) was added DIPEA (2.25 g, 17.45 mmol) under ice-water cooling. . Ethyl 2-chloro-2-oxoacetate (952.77 mg, 6.98 mmol) was then added over 5 minutes and the mixture was stirred at 0° C. for 30 minutes. The mixture was warmed to 20° C. and stirred at this temperature for 30 minutes. The mixture was quenched with aqueous NaHCO ₃ solution (50 mL) and extracted with DCM (50 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE: EtOAc=10:1 to 1:1) to give the product ethyl 2-(((5-bromo-3-chloropyridin-2-yl)methyl)amino) -2-Oxoacetate (1300 mg, 3.64 mmol, 62.57% yield, 65.6% purity) was obtained as a white solid. RT 0.61min (Method 1); m/z 322.8 (M+H) ⁺ (ESI ⁺ ). The product was used in the next step without further purification.

Preparation of intermediate 4.3

Ethyl 6-bromo-8-chloroimidazo[1,5-a]pyridine-3-carboxylate

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

RT 0.718 min (Method 1), m/z 304.8(M+H) ⁺ (ESI ⁺ ), ^1H NMR (400 MHz, CHLOROFORM- d ) δ = 9.47 (s, 1H), 7.77(s, 1H), 7.20 (s, 1H), 4.65-4.42 (m, 2H), 1.57-1.42 (m, 3H)

Preparation of intermediate 4.4

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

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

RT 0.56 min (Method 1); m/z 290.8 (M+H) ⁺ (ESI ⁺ ); ^1H NMR (400 MHz, DMSO- d ₆ ) δ = 10.02 (s, 1H), 9.50 (s, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 4.58 (d, J = 4.0 Hz , 2H).

Preparation of intermediate 4.5

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

To a mixture of 6-bromo-8-chloroimidazo[1,5-a]pyridine-3-carbohydrazide (650 mg, 2.25 mmol) in EtOH (20 mL) was added ethyl 2,2-difluoro. Acetate (3.10 g, 22.45 mmol) and DBU (683.58 mg, 4.49 mmol) were added. The mixture was heated to 100° C. and stirred at this temperature for 16 hours. The mixture was cooled to 25° C. and concentrated under vacuum. The residue was dissolved in DCM (50 mL), washed with aqueous NH ₄ CI (30 mL; 2x) and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel (PE/EtOAc=1:1 to MeOH:EtOAc=1:10) to give the product 6-bromo-8-chloro-N'-(2,2-difluoro). Roacetyl)imidazo[1,5-a]pyridine-3-carbohydrazide (650 mg, 1.56 mmol, 69.32% yield, 88% purity) was obtained as a white solid.

RT 0.62 min (Method 1); m/z 368.8 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.95 (br, 2H), 9.44 (s, 1H), 7.81 (s, 1H), 7.59 (s, 1H), 6.38 (t, J = 53.2, 1H).

Preparation of intermediate 4.6

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

6-Bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,5-a]pyridine-3-carbohydrazide (550 mg, Lawessons reagent (665.80 mg, 1.65 mmol) was added to the mixture (1.50 mmol) under N ₂ atmosphere. The reaction was heated to 120° C. and stirred at this temperature for 2 hours. The reaction was cooled to 25°C and concentrated under vacuum. The residue was triturated with MeOH (10 mL) at 70° C. for 1 h, filtered and the cake collected and dried under vacuum to give the product 2-(6-bromo-8-chloroimidazo[1,5-a] Pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (530 mg, 1.45 mmol, 96.88% yield) was obtained as a light yellow solid.

RT 0.806 min (Method 1); m/z 366.8 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ= 9.62 (s, 1H), 8.64 (s, 1H), 8.09 (s, 1H), 7.70 (t, J = 53.2,1H).

Preparation of intermediate 4.7

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

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

RT 0.99 min (Method 1); m/z 409.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (400 MHz, CHLOROFORM-d) δ= 9.35 (s, 1H), 7.69 - 7.67 (m, 1H), 7.39 - 7.28 (m, 2H), 7.25 - 7.12 (m, 3H), 7.05 (t , J= 53.2,1H), 7.00 (s, 1H), 6.90 (s, 1H), 4.10 (s, 2H)

Preparation of intermediate 4.8

2-(6-(benzylthio)-8-chloro-1-iodimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thia Diazole

2-(6-(benzylthio)-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4- in MeCN (5 mL) To a mixture of thiadiazole (130 mg, 317.95 μmol) was added NIS (78.68 mg, 349.74 μmol) at 0°C. The mixture was stirred at 25°C for 5 hours. The reaction mixture was used directly in the next step.

RT 0.99 min (Method 1); m/z 535.0 (M+H) ⁺ (ESI ⁺ )

Preparation of intermediate 4.9

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazo[1,5-a]pyridine-6-sulfonyl chloride

2-(6-(benzylthio)-8-chloro-1-iodimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1 in MeCN (5 mL) , A mixture of 3,4-thiadiazole (170 mg, 317.95 μmol) was cooled to 0°C and then added with H ₂ O (5.73 mg, 317.95 μmol), AcOH (38.19 mg, 635.89 μmol) and 1,3-dichloro- 5,5-dimethylimidazolidine-2,4-dione (125.28 mg, 635.89 μmol) was added. The mixture was stirred at 0°C for 2 hours. The mixture was diluted with THF (8 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product 8-chloro-3-(5-(difluoromethyl)-1,3,4- Thiadiazol-2-yl)-1-iodimidazo[1,5-a]pyridine-6-sulfonyl chloride (160 mg, 219.14 μmol, 68.92% yield, 70% purity) was obtained as a light brown oil. did.

In this process, the dichloro-compound 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6 Note that it cannot be excluded that sulfonyl chloride (see intermediate 18.2) was also formed.

Preparation of Intermediate 4.10

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

To a mixture of 1-aminocyclopropane-1-carbonitrile (128.51 mg, 1.57 mmol, HCl salt) in pyridine (3 mL) was added 8-chloro-3-(5-(difluoride) in THF (2 mL) at 0°C. Romethyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazo[1,5-a]pyridine-6-sulfonyl chloride (160 mg, 313.05 μmol) was added. The mixture was stirred at 0°C for 1 hour. The reaction was concentrated under vacuum. The residue was dissolved in DCM (20 mL), washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE: EtOAc =10: 1 to 3:1) to give the product 8-chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoro). Methyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazo[1,5-a]pyridine-6-sulfonamide (110 mg, 128.43 μmol, 41.02% yield, 65% Purity) was obtained as a yellow solid.

RT 0.966 min (Method 1); m/z 556.9 (M+H) ⁺ (ESI ⁺ ); ^1H NMR (400 MHz, DMSO- d ₆ ) δ = 10.00 (s, 1H), 9.70 (br, 1H), 7.72 (t, J = 53.2,1H), 7.48 (d , J = 1.1 Hz, 1H) , 1.54 -1.48 (m, 2H), 1.42 - 1.35 (m, 2H)

Preparation of Example 4

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

8-Chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1- in THF (5 mL) DIPEA (17.41 mg, 134.71 μmol) and Pd/C (5 mg, 10% purity) in a mixture of iodoimidazo[1,5-a]pyridine-6-sulfonamide (15 mg, 26.94 μmol) at 0°C. was added. The mixture was stirred at 20° C. under H ₂ (15 psi) for 2 hours. The mixture was filtered and concentrated under vacuum. The residue was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 33%-63%, 15 min). Purified to obtain 8-chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5- a]Pyridine-6-sulfonamide (4.02 mg, 9.23 μmol, 34.25% yield, 98.9% purity, formic acid salt) was obtained as a light yellow solid.

RT 0.966 min (Method 1); m/z 431.1 (M+H) ⁺ (ESI ⁺ ); H NMR (400 MHz, METHANOL- d ₄ ) δ = 10.25 (s, 1H), 8.56 (br, 1H), 7.99 (s, 1H), 7.51 (s, 1H), 7.36 (t, J = 53.2 Hz , 1H), 1.54 - 1.50 (m, 2H), 1.50 -1.46 (m, 2 H).

Preparation of Example 5

4-(6-(N-(1-cyanocyclopropyl)sulfamoyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1 ,5-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide

8-chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4 in 1,4-dioxane (1 mL) degassed with nitrogen for 2 min. -thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide (70 mg, 162.47 μmol) mixed with N,N-dimethylpiperazine-1-carboxamide (38.31 mg) , 243.71 μmol), Cs ₂ CO ₃ (105.87 mg, 324.95 μmol) and Pd-PEPPSI-IHept Cl (15.80 mg, 16.25 μmol) were added. The mixture was stirred at 100°C for 16 hours. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: A: 0.1% TFA in water, B: MeCN; B%: 48%-68%, 7 min) to obtain 80% purity. 6 mg product was obtained. Afterwards, the 80% purity product _was subjected _to preparative HPLC (column: Waters 10 min) to give the product 4-(6-(N-(1-cyanocyclopropyl)sulfamoyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazole. -2-yl) imidazo [1,5-a] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (2.48 mg, 4.39 μmol, 2.70% yield, 97.7% purity) Obtained as a light yellow solid.

RT 0.72 min (prevention 1); m/z 552.0 (M+H) ⁺ (ESI ⁺ ); ^1H NMR (400 MHz, METHANOL- d ₄ ) δ = 9.93 (s, 1H), 7.93 (s, 1H), 7.35 (t, J = 53.2, 1H), 6.79 (s, 1H), 3.61-3.52 ( m, 4H), 3.44-3.41 (m, 4H), 2.92 (s, 6H), 1.57-1.50 (m, 2H), 1.49 -1.42 (m, 2H).

Preparation of Intermediate 6.1

1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonylchloride

A mixture of NCS (65.32 mg, 489.15 μmol, 4 eq) in MeCN (2 mL) was added at 0°C with aqueous HCl solution (2M, 244.57 μL) and 2-(6-benzylsulfanyl-8-chloroimidazo[1,5 -a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (50 mg, 122.29 μmol) was added. The mixture was warmed to 20° C. and stirred at this temperature for 1 hour. The mixture was diluted with DCM (10 mL), washed with water (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product 1,8-dichloro-3-(5-(difluoropropanol). Romethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride (50 mg, 94.13 μmol, 76.97% yield, 79% purity) Obtained as a yellow oil. The crude product was used directly in the next step without further purification.

Preparation of Example 6

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

1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6 in DCM (2 mL) -To a mixture of sulfonyl chloride (50 mg, 94.13 μmol, 79% purity) and DIPEA (24.33 mg, 188.26 μmol) was added 1-aminocyclopropane-1-carbonitrile (15.46 mg, 188.26 μmol, HCl salt) . The mixture was stirred at 20°C for 1 hour. Pyridine (148.91 mg, 1.88 mmol, 151.95 μL) was added and the mixture was stirred at 20°C for an additional 16 hours. The mixture was concentrated to obtain a residue, which was subjected to preparative HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: A: 0.1% TFA in water, B: MeCN; B%: 50%-80%, 7 min) to obtain 1,8-dichloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo [1,5-a]pyridine-6-sulfonamide (10 mg, 21.49 μmol, 66.67% yield) was obtained as a yellow solid.

RT 0.87 min (Method 1); m/z 464.9 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.91 (s, 1H), 9.71 (s, 1H), 7.71 (t, J = 53.2,1H), 7.50 (s, 1H), 1.60-1.45 ( m, 2H), 1.42-1.30 (m, 2H).

Preparation of Example 7

N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(2-oxa-7-azaspiro[ 3.5]nonan-7-yl)imidazo[1,2-a]pyridine-6-sulfonamide

8-Chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo in dioxane (0.5 mL) [1,2-a]pyridine-6-sulfonamide (10.0 mg, 23.21 μmol), 2-oxa-7-azaspiro[3.5]nonane (4.4 mg, 34.82 μmol), Pd-PEPPSI-IHept Cl (2.3 mg , 2.32 μmol) and Cs ₂ CO ₃ (22.7 mg, 69.63 μmol) were degassed and purged with nitrogen (3x) and then stirred at 100° C. for 12 h under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue, which was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN ; B%: 33%-53%, 10 min) to give the product N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazole- 2-yl)-8-(2-oxa-7-azaspiro[3.5]nonan-7-yl)imidazo[1,2-a]pyridine-6-sulfonamide (4.3 mg, 8.24 μmol) was prepared as a yellow solid. It was obtained as.

RT 0.877 (Method 1); m/z 522.1 (M+H) ⁺ (ES ⁺ ); ¹ H NMR (400 MHz, DMSO -d ₆ ) δ9.62 (s, 1H), 8.58 (s, 1H), 8.37 (s, 1H), 7.69 (t, J = 53.2 Hz, 1H), 6.97 (s , 1H), 4.39 (s, 4H), 3.55-3.53 (m, 4H), 1.97-2.01 (m, 4H), 1.28-1.24 (m, 2H), 1.22-1.18 (m, 2H).

Preparation of Example 8

N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-isobutyrylpiperazine-1 -1) Imidazo[1,2-a]pyridine-6-sulfonamide

8-Chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo in dioxane (0.5 mL) [1,2-a]pyridin-6-sulfonamide (10.0 mg, 23.21 μmol), 2-methyl-1-(piperazin-1-yl)propan-1-one (4.4 mg, 27.85 μmol,), Pd A mixture of -PEPPSI-IHept Cl (2.3 mg, 2.32 μmol) and Cs ₂ CO ₃ (22.7 mg, 69.63 μmol) was degassed and purged with nitrogen (3x) and then stirred at 100° C. for 12 hours under nitrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was subjected to preparative HPLC (column: Phenomenex C18 75*30mm*3um; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 35%-65%, 7 min) to give the product N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl) -8-(4-Isobutyrylpiperazin-1-yl)imidazo[1,2-a]pyridine-6-sulfonamide (2.3 mg, 4.16 μmol) was obtained as a light yellow solid.

RT 0.867 min (Method 1); m/z 551.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (400 MHz, MeOH- d ₄ ) δ = 9.67 (s, 1H), 8.62 (s, 1H), 8.40 (s, 1H), 7.53-7.91 (t, J = 53.2 Hz, 1H), 6.99 (d, J = 1.2 Hz, 1H), 3.76 (d, J = 4.8 Hz, 2H), 3.71 (s, 2H), 3.63 (s, 2H), 3.56 (s, 2H), 2.92-2.99 (m, 1H), 1.23-1.31 (m, 2H), 1.17-1.23 (m, 2H), 1.05 (d, J = 6.4 Hz, 6H).

Preparation of Intermediate 9.1

tert-Butyl methyl(2-(N-methylisobutyramido)ethyl)carbamate

A mixture of tert-butyl methyl(2-(methylamino)ethyl)carbamate (300.0 mg, 1.59 mmol) and Et ₃ N (322.5 mg, 3.19 mmol) in DCM (3 mL) was degassed and purified with nitrogen (3x). After purging, 2-methylpropanoyl chloride (186.8 mg, 1.75 mmol) was added dropwise at 0°C. The mixture was stirred at 20°C for 1 hour under nitrogen atmosphere, then poured into saturated aqueous NaHCO ₃ solution (10 mL) and extracted with DCM (10 mL, 3x). The combined organic layers were washed with brine (25 mL, 2x), dried over Na ₂ SO ₄ , filtered and concentrated to give the product tert-butyl methyl(2-(N-methylisobutyramido)ethyl)carbamate (300.0 mg). , 1.16 mmol) was obtained as a yellow oil.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 3.36-3.45 (m, 2H), 3.28 (t, J = 6.4 Hz, 3H) 2.99 (br s, 1H) 2.74- 2.83 (m, 5H) 1.38 ( s, 9H), 0.93-1.00 (m, 6H).

Preparation of Intermediate 9.2

N-Methyl-N-(2-(methylamino)ethyl)isobutyramide

To a solution of tert-butyl methyl(2-(N-methylisobutyramido)ethyl)carbamate (300.0 mg, 1.16 mmol) in DCM (3 mL) was added a solution of HCl in dioxane (4 M, 3 mL). Added. The mixture was stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in MeOH (2 mL) and alkaline resin (2 g) was added. The mixture was stirred at 20°C for 0.5 hours. The mixture was filtered and concentrated to give the product N-methyl-N-(2-(methylamino)ethyl)isobutyramide (116 mg, 0.73 mmol) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ3.70 (t, J = 6.0 Hz, 2 H) 3.15 (s, 3 H) 3.11 (t, J = 6.0 Hz, 2 H) 2.79- 2.87 (m, 1 H) 2.69 (s, 3 H) 1.12 (d, J = 6.8 Hz, 6 H).

Preparation of Example 9

N-(2-((6-(N-(1-cyanocyclopropyl)sulfamoyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl) imidazo[1,2-a]pyridin-8-yl)(methyl)amino)ethyl)-N-methylisobutyramide

8-Chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo in dioxane (0.5 mL) [1,2-a]pyridine-6-sulfonamide (10.0 mg, 23.21 μmol), N-methyl-N-(2-(methylamino)ethyl)isobutyramide (4.4 mg, 27.85 μmol), Pd-PEPPSI A mixture of -IHept Cl (2.3 mg, 2.32 μmol) and Cs ₂ CO ₃ (22.7 mg, 69.63 μmol) was degassed, purged with nitrogen (3x) and stirred at 100° C. for 12 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure to obtain a residue, which was subjected to preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 38%-68%, 7 min) to obtain the product N-(2-((6-(N-(1-cyanocyclopropyl)sulfamoyl)-3-(5-(difluoromethyl)-1,3,4-thia Diazol-2-yl)imidazo[1,2-a]pyridin-8-yl)(methyl)amino)ethyl)-N-methylisobutyramide (1.4 mg, 2.53 μmol) was obtained as a yellow solid.

RT 0.898 min (Method 1); m/z 553.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.85 (d, J = 1.6 Hz, 1H), 8.13 (s, 1H), 7.76 (s, 1H), 7.40 (d, J = 1.2 Hz, 1H), 7.10 (t, J = 53.2 Hz, 1H), 3.68-3.78 (m, 4H), 3.59 (s, 3H), 3.14 (s, 3H), 2.83 (m, 1H), 1.63 (s, 2H), 1.38- 1.42 (m, 2H), 1.12-1.16 (m, 6H).

Preparation of Intermediate 10.1

5-Chloro-6-vinylpyridin-3-amine

2,5-dibromo-3-chloropyridine (1.60 g, 5.90 mmol), 4,4,5,5-tetramethyl-2-vinyl-1, in dioxane (15 mL) and water (1 mL) Pd(dppf)Cl ₂ (431.5 mg, 589.67 μmol) was added to a mixture of 3,2-dioxaborolane (1.36 g, 8.85 mmol) and Na ₂ CO ₃ (1.25 g, 11.79 mmol) under nitrogen atmosphere. The mixture was stirred at 100°C for 16 hours. The mixture was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0-20% DCM/PE gradient @ 35 mL/min) to give product 5. -Bromo-3-chloro-2-vinylpyridine (1.80 g, 8.24 mmol; results of three reactions performed in parallel) was obtained as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ8.53 (d, J = 2.0 Hz, 1 H), 7.84 (d, J = 2.0 Hz, 1 H), 7.17 (dd, J = 16.8, 10.8 Hz, 1 H), 6.50 (dd, J = 17.2, 2.0 Hz, 1 H), 5.63 (dd, J = 10.4, 1.6 Hz, 1 H).

Preparation of Intermediate 10.2

Methyl 6-bromo-8-chloroimidazoline-3-carboxylate

To a solution of 5-bromo-3-chloro-2-vinylpyridine (2.20 g, 10.07 mmol) and 3-methoxy-3-oxopropanoic acid (2.38 g, 20.14 mmol) in MeCN (40 mL) was added NIS (7.93 g, 35.24 mmol) and NaOAc (2.48 g, 30.21 mmol) were added. The mixture was stirred at 100° C. for 16 hours under nitrogen atmosphere. The mixture was concentrated in vacuo to give a residue which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0-10% EtOAc/PE gradient @ 35 mL/min) to give the product methyl. 6-Bromo-8-chloroimidazoline-3-carboxylate (1.76 g, 6.10 mmol) was obtained as a yellow oil.

RT 1.053 min (Method 1); m/z 289.9 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.48 (s, 1 H), 7.42 (d, J = 4.8 Hz, 1 H), 7.10 (d, J = 1.6 Hz, 1 H), 6.63 (d, J = 4.4 Hz, 1 H), 3.85 (s, 3 H).

Preparation of Intermediate 10.3

6-Bromo-8-chloroimidazoline-3-carbohydrazide

To a solution of methyl 6-bromo-8-chloroimidazoline-3-carboxylate (1.76 g, 6.10 mmol) in EtOH (20 mL) N ₂ H ₄ ·H ₂ O (3.74 g, 73.20 mmol, 98 % purity) was added. The mixture was heated to 100° C. and stirred for 2 hours. The mixture was cooled to 25° C. and filtered. The cake was dried in vacuo to yield the product 6-bromo-8-chloroimidazoline-3-carbohydrazide (1.36 g, 4.71 mmol) as a white solid.

RT 0.808 min (Method 1); m/z 289.9 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ9.69-9.78 (m, 2H), 7.90 (br, 2H), 7.60 (d, J = 4.4 Hz, 1H), 7.41 (d, J = 1.6 Hz) , 1H), 6.72 (dd, J = 4.4, 0.4 Hz, 1H).

Preparation of Intermediate 10.4

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

Solution of 6-bromo-8-chloroimidazo[1,2-a]pyridine-3-carbohydrazide (1.36 g, 4.71 mmol) and DBU (1.43 g, 9.42 mmol) in EtOH (15 mL). Ethyl 2,2-difluoroacetate (5.84 g, 47.10 mmol) was added. The mixture was stirred at 105° C. for 16 hours. The mixture was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-50% EtOAc/PE gradient @ 36 mL/min) to give product 6. -Bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,2-a]pyridine-3-carbohydrazide (386 mg, 1.05 mmol) as a yellow solid. Obtained.

RT 0.885 min (prevention 1); m/z 368.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ(s, 1H), 10.56 (s, 1H), 9.66 (s, 1H), 7.75 (d, J = 4.8 Hz, 1H), 7.53 (d, J = 1.2 Hz, 1H), 6.80 (d, J = 4.00 Hz, 1H), 6.47 (t, J = 53.2 Hz, 1H).

Preparation of Intermediate 10.5

2-(6-bromo-8-chloroindolizin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole

Lawessons in a solution of 6-bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazoline-3-carbohydrazide (386.0 mg, 1.05 mmol) in toluene (5 mL). Reagent (468.5 mg, 1.16 mmol) was added. The mixture was stirred at 110°C for 2 hours. The mixture was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent 0-100% EtOAc/PE gradient @ 10 mL/min) to give product 2. -(6-Bromo-8-chloroindolizin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (210.0 mg, 0.58 mmol) was obtained as a yellow solid.

RT 1.086 min (Method 1); m/z 365.9 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 9.75 (s, 1H), 7.51-7.82 (m, 3H), 6.94 (d, J = 4.0 Hz, 1H).

Preparation of Intermediate 10.6

2-(6-(benzylthio)-8-chloroindolizin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole

2-(6-Bromo-8-chloroindolizin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (210.0 mg, 575.98 μmol) in dioxane (3 mL) ), phenylmethanethiol (71.5 mg, 575.98 μmol), Pd ₂ (dba) ₃ (52.7 mg, 57.60 μmol), DIEA (148.9 mg, 1.15 mmol), and Xantphos (66.7 mg, 115.20 μmol) were degassed with nitrogen. and heated at 90°C for 2 hours under a nitrogen atmosphere. The mixture was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent 0-50% EtOAc/PE gradient @ 10 mL/min) to give product 2. -(6-(benzylthio)-8-chloroindolizin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (200.0 mg, 490.33 pmol) was obtained as a yellow solid. did.

RT 1.156 min (Method 1); m/z 408.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (400 MHz, DMSO -d ₆ ) δ7.15-7.84 (m, 9H), 6.87 (d, J = 4.52 Hz, 1H), 4.27 (s, 2H).

Preparation of Intermediate 10.7

2-(6-(benzylsulfinyl)-8-chloro-1-iodoindolizin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole

2-(6-(benzylthio)-8-chloroindolizin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (150.0 mg, 367.75) in MeCN (0.5 mL) μmol), NIS (182.0 mg, 809.05 μmol), AcOH (22.1 mg, 367.75 μmol), and H ₂ O (6.6 mg, 367.75 μmol) were added. The mixture was stirred at 20°C for 2 hours. The mixture was concentrated in _vacuo to obtain a residue, which _was subjected to preparative HPLC (column: Waters %-79%, 11 min) to give the product 2-(6-(benzylsulfinyl)-8-chloro-1-iodoindolizin-3-yl)-5-(difluoromethyl)-1, 3,4-thiadiazole (100.0 mg, 181.89 pmol) was obtained as a yellow solid.

RT 1.054 min (Method 1); m/z 550.0 (M+H) ⁺ (ESI ⁺ ).

Preparation of Intermediate 10.8

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazoline-6-sulfonyl chloride

2-(6-(benzylsulfinyl)-8-chloro-1-iodoindolizin-3-yl)-5-(difluoromethyl)-1,3,4-thiadia in MeCN (2 mL) To a mixture of sol (20.0 mg, 36.38 μmol), H ₂ O (0.7 mg, 36.38 μmol) and AcOH (4.4 mg, 72.76 μmol) were added at 0°C. The mixture was stirred at 0°C for 10 minutes. 1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (14.3 mg, 72.76 μmol) was added, and the mixture was stirred at 0°C for 2 hours. The mixture was diluted with THF (3 mL) and dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated under vacuum to obtain crude 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodimidazoline. -6-Sulfonyl chloride (20.0 mg, 19.60 μmol) was obtained as a light brown oil. The crude product was used in the next step without further purification.

Preparation of Intermediate 10.9

8-chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazoline- 6-sulfonamide

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazoline-6-sulfonyl chloride in pyridine (1 mL) (20.0 mg, 39.80 μmol) was added 1-aminocyclopropane-1-carbonitrile (16.1 mg, 196.05 μmol, HCl salt) in THF (1 mL) over 1 min at 0°C. The mixture was stirred at 0°C for 1 hour. The mixture was concentrated under vacuum to give a residue. The residue was dissolved in DCM (20 mL) and washed with brine (20 mL). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give a residue, which was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: A: 0.225% in water Formic acid, B: MeCN; B%: 45%-75%, 10 min) to give the product 8-chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1. ,3,4-thiadiazol-2-yl)-1-iodoimidazoline-6-sulfonamide (15.0 mg, 24.13 μmol, 89.4% purity) was obtained as a yellow solid.

RT 0.890 min (Method 1); m/z 555.7 (M+H) ⁺ (ESI ⁺ ).

Preparation of Example 10

8-chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazoline-6-sulfonamide

8-Chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1- in THF (5 mL) To a mixture of iodoimidazoline-6-sulfonamide (15.0 mg, 26.99 μmol), DIEA (3.5 mg, 26.99 μmol) and Pd/C (5.0 mg, 26.99 μmol, 10% purity) were added at 20°C. The mixture was stirred at 20° C. under hydrogen atmosphere (15 Psi) for 2 hours. The mixture was filtered and concentrated under vacuum to obtain a residue, which was subjected to preparative HPLC (column: Phenomenex C18 75*30mm*3um; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 40%-70 %, 7 min) to give the product 8-chloro-N-(1-cyanocyclopropyl)-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl] Imidazoline-6-sulfonamide (1.9 mg, 3.75 μmol, FA salt) was obtained as a yellow solid.

RT 0.899 min (Method 1); m/z 430.0 (M+H) ⁺ (ESI ⁺ ); ^1H NMR (400 MHz, DMSO- d ₆ ) δ10.06 (s, 1H), 8.37 (s, 2H), 7.91 (d, J = 4.4 Hz, 1H), 7.68 (t, J = 53.2 Hz, 1H ), 7.40 (d, J = 1.2 Hz, 1H), 6.98 (d, J = 4.4 Hz, 1H), 1.22-1.18 (m, 2H), 1.11-1.15 (m, 2H).

Preparation of Intermediate 11.1

Ethyl 6-(benzylthio)-8-chloroimidazo[1,2-a]pyridine-3-carboxylate

Ethyl 6-bromo-8-chloro-imidazo[1,2-a]pyridine-3-carboxylate (1.50 g, 4.94 mmol, intermediate 1.2), phenylmethanethiol (0.61 g) in dioxane (15 mL). , 4.94 mmol, 579.03 μL), DIPEA (1.28 g, 9.88 mmol, 1.72 mL), and Xantphos (0.57 g, 988.34 μmol) were added to Pd ₂ (dba) ₃ (0.45 g, 494.17 μmol). The mixture was stirred at 90° C. for 2 hours under nitrogen atmosphere. The mixture was cooled to room temperature, quenched with H ₂ O (100 mL) and extracted with EtOAc (100 mL; 2x). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent 60-100% EtOAc/PE gradient @ 100 mL/min) to give an undetermined residue. The product was obtained and purified by reverse phase flash (solvent for dissolving about 10 g of sample dissolved in 10 mL of MeOH, (column: ID95mm*H365mm Welch Ultimate Formic acid, B: MeCN; B%: 5-90% 10 min; The mixture was concentrated under reduced pressure to remove most of the MeCN, and the resulting mixture was then neutralized to pH=8 with NaHCO ₃ and extracted with EtOAc (100 mL; 2x). The combined organic layers were washed with brine (100 mL; 2x), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to obtain the product ethyl 6-benzylsulfanyl-8-chloro-imidazo[1,2-a]pyridine-3-carboxylate (1.5 g, 4.32 mmol) as a brown solid. (This reaction was performed in parallel in two batches and purified together.)

^1H NMR (DMSO- d ₆ , 400 MHz): 8.99 (d, J = 1.6 Hz, 1H), 8.31 (s, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.33- 7.18 (m, 5H), 4.41-4.32 (m, 2H), 4.29 (s, 2H), 1.34 (t, J = 7.2 Hz, 3H).

Preparation of Intermediate 11.2

Ethyl 8-chloro-6-(chlorosulfonyl)imidazo[1,2-a]pyridine-3-carboxylate

Ethyl 6-benzylsulfanyl-8-chloro-imidazo[1,2-a]pyridine-3-carboxylate (200.0 mg, 576.65 μmol), AcOH (58.9 mg, 980.31 μmol, 56.1 μmol) in MeCN (2 mL) 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (227.2 mg, 1.15 mmol) in a mixture of H ₂ O (10.4 mg, 576.65 μmol, 10.4 μL) Added at ℃. The mixture was stirred at 0°C for 0.5 hours. The mixture was diluted with THF (15 mL), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to obtain the product ethyl 8-chloro-6-chlorosulfonyl-imidazo[1,2-a]pyridine-3-carboxylate (150.0 mg, 464.18 μmol) as a yellow oil, The crude product was used directly in the next step without further purification.

Preparation of Example 11

Ethyl 8-chloro-6-(N-(1-cyanocyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3-carboxylate

To a mixture of 1-aminocyclopropanecarbonitrile (55.0 mg, 464.18 μmol, HCl salt) in pyridine (392.0 mg, 4.96 mmol, 0.4 mL) was added ethyl 8-chloro-6-chlorosulfonyl-imide in THF (1 mL). A solution of polyzo[1,2-a]pyridine-3-carboxylate (150.0 mg, 464.18 μmol) was added dropwise at 0°C. The mixture was stirred at 20°C for 2 hours, then quenched with H ₂ O (30 mL) and extracted with EtOAc (20 mL; 3x). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; 30%-60%, 10 min) to obtain ethyl product. 8-Chloro-6-[(1-cyanocyclopropyl)sulfamoyl]imidazo[1,2-a]pyridine-3-carboxylate (4.1 mg, 9.76 μmol, 99% purity, FA salt) was Obtained as a yellow solid.

RT 0.643 min (Method 1); m/z 368.8 (M+H) ⁺ (ES ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.64 (d, J = 1.2 Hz, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 7.88 (d, J = 1.2 Hz, 1H) , 4.51-4.35 (m, 2H), 1.40-1.32 (m, 5H), 1.28- 1.18 (m, 2H).

Preparation of Example 12

Ethyl 6-(N-(1-cyanocyclopropyl)sulfamoyl)-8-(4-(dimethylcarbamoyl)piperazin-1-yl)imidazo[1,2-a]pyridine-3-car voxylate

Ethyl 8-chloro-6-[(1-cyanocyclopropyl)sulfamoyl]imidazo[1,2-a]pyridine-3-carboxylate (10.0 mg, 24.11 μmol, FA) in dioxane (0.5 mL) Pd-PEPPSI-IHeptCI (2.4 mg, 2.41 μmol) was added to a mixture of salt) and Cs ₂ CO ₃ (23.6 mg, 72.32 μmol) in a glove box. The mixture was stirred at 100° C. for 3 hours under argon atmosphere. The mixture was concentrated under reduced pressure to obtain a residue, which was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 28 %-58%, 10 min) to give the product ethyl 6-[(1-cyanocyclopropyl)sulfamoyl]-8-[4-(dimethylcarbamoyl)piperazin-1-yl]imidazo[1 ,2-a]pyridine-3-carboxylate (1.6 mg, 2.83 μmol, FA salt) was obtained as an off-white solid.

RT 0.687 min (Method 1); m/z 490.1 (M+H) ⁺ (ES ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.33 (d, J = 1.2 Hz, 1H), 8.37 (s, 1H), 8.32 (s, 1H), 6.97 (d, J = 1.2 Hz, 1H) , 4.47-4.32 (m, 2H), 3.63-3.56 (m, 4H), 3.35 (br d, J = 4.8 Hz, 4H), 2.80 (s, 6H), 1.37 (t, J = 7.2 Hz, 3H) , 1.33-1.27 (m, 2H), 1.25-1.18 (m, 2H).

Preparation of Intermediate 13.1

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

MeCN (2 mL) at 0°C in a mixture of 1-methylcyclopropan-1-amine (37.80 mg, 531.49 μmol) in pyridine (1 mL) and N-methyl-2-pyrrolidone (NMP) (1 mL). Of 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazo[1,5-a]pyridine-6-sulfate Ponyl chloride (90 mg, 176.09 μmol) was added. The reaction was stirred at 0°C for 50 minutes. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL; 2x). The organic phase was collected, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give a residue which was purified by preparative TLC (PE:EtOAc = 3:1) to give the product 8-chloro-3-(5 -(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodo-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6- Sulfonamide (25 mg, 45.81 μmol, 26.01% yield) was obtained as a light yellow solid.

In this process, the dichloro compound 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ Note that it cannot be ruled out that 1,5-a]pyridine-6-sulfonamide was also formed.

RT 0.510 min (Method 3); m/z 545.8 (M+H) ⁺ (ESI ⁺ )

Preparation of Intermediate 13.2

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

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodo-N-(1-methyl) in tetrahydrofuran (3 mL) Pd/C (5 mg, 10% purity) was added to a mixture of cyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (25 mg, 45.81 μmol). The reaction was degassed three times with H ₂ (15 Psi) and then the reaction was stirred at 20° C. for 3 hours. The reaction mixture was filtered and the filtrate concentrated under vacuum to give the product 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-1-methylcyclo. Propyl)imidazo[1,5-a]pyridine-6-sulfonamide (20 mg, 30.96 μmol, 67.59% yield, 65% purity) was obtained as a brown solid.

In this process, the dichloro compound 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ Note that it cannot be ruled out that 1,5-a]pyridine-6-sulfonamide was also formed (see intermediate examples 18c and 18d).

RT 0.468 min (Method 3); m/z 420.0 (M+H) ⁺ (ESI ⁺ )

Preparation of Example 13

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

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1) in 1,4-dioxane (1 mL) degassed under nitrogen -Methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (15 mg, 35.73 μmol) and N,N-dimethylpiperazine-1-carboxamide (11.23 mg, 71.45 μmol). Pd-PEPPSI-IHept Cl (3.48 mg, 3.57 μmol) and Cs ₂ CO ₃ (23.28 mg, 71.45 μmol) were added. The mixture was stirred at 100°C for 16 hours. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by preparative TLC (EtOAc:PE = 2:1) to obtain 5 mg crude product, which was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: A: water 0.225% formic acid, B: MeCN; B%: 37%-67%, 10 min) and directly lyophilized to give the product 4-(3-(5-(difluoromethyl)-1,3 ,4-thiadiazol-2-yl)-6-(N-1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,N-dimethylpiperazine- 1-Carboxamide (1.03 mg, 1.85 μmol, 5.19% yield) was obtained as a light yellow solid.

RT 0.435 min (Method 3); m/z 541.2 (M+H) ⁺ (ESI ⁺ ); ^1H NMR (CHLOROFORM- d , 400 MHz,) 9.88 (s, 1H), 7.72 (s, 1H), 7.08 (t, J = 53.6 Hz, 1H), 6.66 (d, J = 1.1 Hz, 1H), 5.06 (s, 1H), 3.53-3.50 (m, 4H), 3.36-3.34 (m, 4H), 2.91 (s, 6H), 1.39 (s, 3H), 0.95-0.92 (m, 2H), 0.62- 0.60 (m, 2H).

Preparation of Intermediate 14.1

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-1-iodoimi Polyzo[1,5-a]pyridine-6-sulfonamide

To a mixture of pyridine (1 mL) and 1-(fluoromethyl)cyclopropan-1-amine (18.43 mg, 146.74 μmol, HCl salt) in THF (1 mL) was added 8-chloroquine in MeCN (2 mL) at 0°C. -3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazo[1,5-a]pyridine-6-sulfonyl chloride (50 mg, 97.83 μmol) was added and the mixture was stirred at 0°C for 1 hour. The mixture was quenched with water (10 mL) and extracted with EtOAc (20 mL; 2x). The organic phase was collected, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give a residue which was purified by preparative TLC (PE:EtOAc=3:1) to give the product 8-chloro-3-(5 -(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-1-iodoimidazo[1,5-a] Pyridine-6-sulfonamide (39 mg, 52.58 μmol, 53.74% yield, 76% purity) was obtained as a light yellow solid.

RT 0.487 min (Method 3); m/z 463.9 (M+H) ⁺ (ESI ⁺ )

Preparation of Intermediate 14.2

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

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl) in THF (5 mL) Pd/C (5 mg, 10% purity) was added to a mixture of -1-iodimidazo[1,5-a]pyridine-6-sulfonamide (35 mg, 62.08 μmol). The reaction was degassed three times with H ₂ (15 Psi) and then the reaction was stirred at 20° C. for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give the crude product, which was purified by preparative TLC (PE:EtOAc=1:1) to give the product 8-chloro-3-(5-(difluoromethyl )-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (10 mg, 12.49 μmol, 20.12% yield, 54.7% purity) was obtained as a brown solid.

RT 0.441 min (Method 3); m/z 437.9 (M+H) ⁺ (ESI ⁺ )

Preparation of Example 14

4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imi Polyzo[1,5-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1) in 1,4-dioxane (1 mL) degassed under nitrogen -(Fluoromethyl)cyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (10 mg, 22.84 μmol) and N,N-dimethylpiperazine-1-carboxamide (7.18 mg, 45.68 μmol) μmol), Pd-PEPPSI-IHept Cl (2.22 mg, 2.28 μmol) and Cs ₂ CO ₃ (14.88 mg, 45.68 μmol) were added to the mixture, and the mixture was stirred at 100°C for 1.5 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to obtain a residue, which was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 36%-66%, 10 min) and directly lyophilized to give the product 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)- 6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide (2.88 mg, 5.16 μmol, 22.57% yield) was obtained as a light yellow solid.

RT 0.417 min (Method 3); m/z 559.1 (M+H) ⁺ (ESI ⁺ ); ^1H NMR (CHLOROFORM- d , 400 MHz): 9.89 (s, 1H), 7.73 (s, 1H), 7.08 (t, J = 53.6 Hz, 1H), 6.65 (s, 1H), 5.50 (s, 1H) ), 4.28 (d, J = 48.4 Hz, 2H), 3.53- 3.51 (m, 4H), 3.37-3.34 (m, 4H), 2.91 (s, 6H), 1.16-1.15 (m, 2H), 0.88- 0.86 (m, 2H).

Preparation of Intermediate 18.1

2-(6-(benzylthio)-8-chloro-1-iodimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thia Diazole

2-(6-(benzylthio)-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4- in MeCN (10 mL) To a mixture of thiadiazole (900 mg, 2.20 mmol) was added NIS (1.39 g, 6.16 mmol) and AcOH (396.54 mg, 6.60 mmol, 377.66 μL). The reaction mixture was warmed to 25° C. and stirred for 16 hours. and filtered. The cake was washed with MeCN (5 mL). The filtrate was then concentrated under vacuum to give the product 2-(6-(benzylthio)-8-chloro-1-iodimidazo[1,5-a]pyridin-3-yl)-5-(difluoro Methyl)-1,3,4-thiadiazole (850 mg, 1.59 mmol) was obtained as a yellow solid.

RT 0.607 min (Method 3); m/z 534.8 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz,): 9.33 (s, 1H), 7.67 (t, J = 50.8 Hz, 1H), 7.50 (s, 1H), 7.38 (d, 2H), 7.29 (t , J = 7.2 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H), 4.34 (s, 2H)

Preparation of Intermediate 18.2

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazo[1,5-a]pyridine-6-sulfonyl Chloride and 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride

2-(6-(benzylthio)-8-chloro-1-iodimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1 in MeCN (12 mL) ,3,4-thiadiazole (850.00 mg, 1.59 mmol) was added to a mixture of AcOH (190.90 mg, 3.18 mmol, 181.81 μL), H ₂ O (57.27 mg, 3.18 mmol, 57.27 μL) and 1,3 at 0°C. -Dichloro-5,5-dimethylimidazolidine-2,4-dione (626.31 mg, 3.18 mmol) was added. The mixture was then stirred at 0°C for 1 hour. The mixture was used directly in the next step without further work-up.

RT 0.510 min (Method 3); m/z 510.8 (M+H) ⁺ (ESI ⁺ );

Preparation of Example 18a and Example 18b

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodo-N-(1-methylcyclopropyl)imidazo [1, 5-a]pyridine-6-sulfonamide and 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1 -methyl Cyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide

To a solution of 1-methylcyclopropanamine (354.84 mg, 4.99 mmol) in THF (10 mL) and H ₂ O (5 mL) was added NaHCO ₃ (1.40 g, 16.63 mmol) and the mixture was cooled to 0°C. . Then, 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazo[ 1,5-a] pyridine-6-sulfonyl chloride and 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1 A mixture of ,5-a]pyridine-6-sulfonyl chloride (850 mg, crude) was added dropwise. The resulting reaction mixture was stirred at 0°C for 1 hour, quenched with H ₂ O (30 mL) and extracted with EtOAc (60 mL; 3x). The combined organic layers were washed with brine (50 mL; 3x), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-50% EtOAc/petroleum ether gradient @ 30 mL/min) to give 8-chloro-3-(5-( difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodo-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide and 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5- The product as a mixture of a]pyridine-6-sulfonamides (430 mg, crude) was obtained as a yellow solid.

RT 0.537 min (Method 3); m/z 545.8 (M+H) ⁺ (ESI ⁺ ), m/z 453.9 (M+H) ⁺ (ESI ⁺ );

Preparation of Example 18c and Example 18d

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

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodo-N-(1-methylcyclopropyl) in THF (5 mL) ) imidazo [1,5-a] pyridine-6-sulfonamide and 1,8-dichloro-3- (5- (difluoromethyl) -1,3,4-thiadiazol-2-yl) - A mixture of N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (430 mg, crude) was added with TEA (239.18 mg, 2.36 mmol, 329.00 μL) and Pd/C( 787.90 μmol, 10% purity) was added. The reaction mixture was degassed three times with H ₂ (balloon, 15 Psi), then stirred at 25° C. under H ₂ atmosphere (balloon, 15 Psi) for 3 hours and filtered. The filtrate was concentrated under vacuum to obtain a residue, which was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 55% -70%, 10 min) and directly lyophilized to give the product 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1 -Methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (80 mg, 175.30 μmol, 92% purity) was purified as a yellow solid and the product 1,8-dichloro-3-(5-(di Fluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (120 mg) was given in yellow color. Obtained as a solid.

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

RT 0.476 min (Method 3); m/z 420.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI3,400 MHz): 10.11 (s, 1H), 7.91 (s, 1H), 7.38 (s, 1H), 7.09 (t, J= 53.6 Hz, 1H), 5.16 (s, 1H), 1.41 (s, 3H), 0.93 - 0.90 (m, 2H), 0.65 - 0.62 (m, 2H)

1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a ]Pyridine-6-sulfonamide

RT 0.509 min (Method 1); m/z 454.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz) 10.10 (s, 1H), 7.35 (s, 1H), 7.09 (t, J = 53.6 Hz, 1H), 5.17 (s, 1H), 1.41 (s, 3H), 0.96 - 0.87 (m, 2H), 0.68 - 0.60 (m, 2H)

Preparation of Example 15

N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(methoxymethyl)piperi Din- Il)imidazo[1,5-a]pyridine-6-sulfonamide

8-Chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo in dioxane (1 mL) Cs ₂ CO ₃ (68.06 mg, 208.89 mg) in a solution of [1,5-a]pyridine-6-sulfonamide (30 mg, 69.63 μmol) and 4-(methoxymethyl)piperidine (17.99 mg, 139.26 μmol). μmol) and Pd-PEPPSI-IPent Cl (6.77 mg, 6.96 μmol) were added under nitrogen atmosphere. The reaction mixture was stirred at 100° C. for 12 hours, then filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by preparative TLC (EtOAc: petroleum ether = 1:1) to obtain an impure product (22 mg), which was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm *3 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 43%-73%, 10 min) and directly lyophilized to yield product N-(1-cyanocyclopropyl). -3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-methoxymethyl)piperidin-1-yl)imidazo [1, 5-a]pyridine-6-sulfonamide (9.02 mg, 17.06 μmol, 24.49% yield, 99% purity) was obtained as a light yellow solid.

RT 0.458 min (Method 3); m/z 524.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CD ₃ OD, 400 MHz): 9.87 (s, 1H), 7.84 (s, 1H), 7.33 (t, J= 53.6 Hz, 1H), 6.74 (d, J= 1.2 Hz, 1H), 3.87 (d, J= 12.4 Hz, 2H), 3.37 (s, 3H), 3.36 (s, 2H), 3.02 - 2.93 (m, 2H), 1.99 -1.91 (m, 2H), 1.91-1.81 (m, 1H), 1.64 - 1.55 (m, 2H), 1.55 -1.49 (m, 2H), 1.49-1.42 (m, 2H).

Preparation of Example 16

N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-methoxypiperidine-1- 1) Imidazo[1,5-a]pyridine-6-sulfonamide

8-Chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo in dioxane (1 mL) Cs ₂ CO ₃ (68.06 mg, 208.89 μmol) and Pd in a solution of [1,5-a]pyridine-6-sulfonamide (30 mg, 69.63 μmol) and 4-methoxypiperidine (16.04 mg, 139.26 μmol). -PEPPSI-IPent Cl (6.77 mg, 6.96 μmol) was added. The mixture was degassed three times with N ₂ and then stirred at 100° C. for 12 hours, cooled to 20° C. and filtered. The filtrate was concentrated under vacuum to obtain a residue, which was subjected to preparative HPLC (column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 34%- 64%, 10.5 min) and directly lyophilized to give the product N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl. )-8-(4-methoxy-1-piperidyl)imidazo[1,5-a]pyridine-6-sulfonamide (11 mg, 21.59 μmol, 31.00% yield, 100% purity) as a yellow solid. Obtained.

RT 0.434 min (Method 3); m/z 510.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 9.94 (s, 1H), 7.74 (s, 1H), 7.08 (t, J = 54.0 Hz, 1H), 6.67 (s, 1H), 5.92-5.61 (br, 1H), 3.64-3.61 (m, 2H), 3.55 - 3.47 (m, 1H), 3.42 (s, 3H), 3.25 - 3.14 (m, 2H), 2.15-2.06 (m, 2H), 1.92 -1.81 ( m, 2H), 1.73-1.67 (m, 2H), 1.52 -1.49 (m, 2H).

Preparation of Example 17

N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(hydroxymethyl)piperi din-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide

8-Chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo in dioxane (1 mL) Cs ₂ CO ₃ (68.06 mg, 208.89 μmol) and Pd in a solution of [1,5-a]pyridine-6-sulfonamide (30.00 mg, 69.63 μmol) and 4-piperidylmethanol (16.04 mg, 139.26 μmol). -PEPPSI-IPent Cl (6.77 mg, 6.96 μmol) was added. The mixture was degassed three times with N ₂ and then stirred at 80° C. for 12 hours, cooled to 20° C. and filtered. The filtrate was concentrated under vacuum. The resulting residue was purified by preparative TLC (petroleum ether: EtOAc=1:1) to obtain an impure product, which was then purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 33% - 63%, 10 min) and directly lyophilized to give the product N-(1-cyanocyclopropyl)-3-(5- (difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(hydroxymethyl)-1-piperidyl)imidazo[1,5-a]pyridine- 6-Sulfonamide (5.8 mg, 10.81 μmol, 15.53% yield, 95.00% purity) was obtained as a yellow solid.

RT 0.404 min (Method 3); m/z 510.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI _3,400 MHz): 9.95 (s, 1H), 7.76 (s, 1H), 7.09 (t, J = 54.0 Hz, 1H), 6.68 (d, J = 1.4 Hz, 1H), 5.62 (s, 1H), 3.89 (d, J = 12.4 Hz, 2H), 3.65 (d, J = 6.2 Hz, 2H), 3.05 - 2.92 (td, J = 12.0,2.4 Hz, 2H), 1.97 (dd, J = 12.8,2.4 Hz, 2H), 1.88 - 1.78 (m, 1H), 1.75 -1.70 (m, 2H), 1.68 -1.63 (m, 1H), 1.63-1.60 (m, 2H), 1.56-1.52 ( m, 2H).

Preparation of Example 18

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(hydroxymethyl)piperidin-1-yl)-N-(1 -Methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ Cs ₂ CO ₃ (23.28 mg, 71.46 μmol) and Pd- in a solution of 1,5-a]pyridine-6-sulfonamide (10 mg, 23.82 μmol) and 4-piperidylmethanol (4.12 mg, 35.73 μmol) PEPPSI-IPent Cl (2.32 mg, 2.38 μmol) was added and the mixture was degassed with N ₂ three times, then stirred at 100° C. for 30 min, cooled to 20° C. and filtered. The filtrate was concentrated under vacuum to obtain a residue, which was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B% : 35%-65%, 10 min) and directly lyophilized to produce product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4- (Hydroxymethyl)-1-piperidyl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (6.4 mg, 11.94 μmol, 50.12% yield, 93% Purity) was obtained as a yellow solid.

RT 0.450 min (Method 3); m/z 499.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI _3,400 MHz): 9.83 (s, 1H), 7.71 (s, 1H), 7.08 (t, J = 54.4 Hz, 1H), 6.64 (s, 1H), 5.01 (s, 1H) , 3.82 (d, J = 12.4 Hz, 2H), 3.64 (d, J = 6.0 Hz, 2H), 2.93 (t, J = 12.0 Hz, 2H), 2.04-1.96 (m, 2H), 1.81 -1.76 ( m, 1H), 1.65-1.58 (m, 2H), 1.39 (s, 3H), 0.95 (s, 2H), 0.64-0.55 (m, 2H).

Preparation of Example 19

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2-hydroxypropan-2-yl)piperidin-1-yl )-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ Cs ₂ CO ₃ (23.28 mg, 71.45 μmol) and Pd-PEPPSI-IPent Cl (2.32 mg, 2.38 μmol) were added. The mixture was degassed three times with N ₂ and then stirred at 100° C. for 1 hour, cooled to 20° C. and filtered. The filtrate was concentrated under vacuum to obtain a residue, which was subjected to preparative HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; 45%-75%, 10 min) and directly lyophilized to give the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-1-hydroxy-1-methyl -Ethyl)-1-piperidyl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (1 mg, 1.71 μmol, 7.16% yield, 97.7% purity, FA salt) was obtained as a yellow solid.

RT 0.474 min (Method 3); m/z 527.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.56 (s, 1H), 8.49-8.39 (br, 1H), 8.38-8.33 (br, 1H), 7.94 (s, 1H), 7.66 (t, J = 52.4 Hz, 1H), 6.66 (s, 1H), 4.36-4.04 (m, 1H), 3.84 (d, J = 12.2 Hz, 2H), 2.83 (t, J = 11.2 Hz, 2H), 1.90-1.83 (m, 2H), 1.58-1.49 (m, 2H), 1.49 (s, 1H), 1.15 (s, 3H), 1.10 (s, 6H), 0.72 (s, 2H), 0.44 (s, 2H)

Preparation of Example 20

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

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ Cs ₂ CO ₃ (23.28 mg, 71.45 μmol) in a solution of 1,5-a]pyridine-6-sulfonamide (10 mg, 23.82 μmol) and 4-(methoxymethyl)piperidine (4.62 mg, 35.73 μmol). ) and Pd-PEPPSI-IPent Cl (2.32 mg, 2.38 μmol) were added. The mixture was degassed three times with N ₂ and then stirred at 100° C. for 30 min and filtered. The filtrate was concentrated under vacuum and the residue was obtained, which was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150 * 50 mm * 3 um; mobile phase: A: 0.225% formic acid in water, B: MeCN; B% : 35%-65%, 10 min) and directly lyophilized to produce product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4- (methoxymethyl)-1-piperidyl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (4.73 mg, 9.02 pmol, 37.85% yield, 97.7% Purity) was obtained as a yellow solid.

RT 0.499 min (Method 3); m/z 513.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI ₃ 400 _MHz ): 9.83 (s, 1H), 7.70 (s, 1H), 7.08 (t, J = 54.0 Hz, 1H), 6.63 (d, J = 1.2 Hz, 1H), 5.02 ( s, 1H), 3.84-3.74 (m, 2H), 3.40 (s, 3H), 3.35 (d, J = 6.0 Hz, 2H), 2.98-2.86 (m, 2H), 1.99-1.92 (m, 2H) , 1.88 (s, 1H), 1.59-1.58 (m, 2H), 1.38 (s, 3H), 0.97-0.91 (m, 2H), 0.63-0.57 (m, 2H).

Preparation of Example 21

1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(methoxymethyl)piperidin-1-yl)- N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide

Dioxane (1 mL) 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo Cs ₂ CO ₃ (64.55 mg, 198.11) in a solution of [1,5-a]pyridine-6-sulfonamide (30 mg, 66.04 μmol) and 4-(methoxymethyl)piperidine (12.80 mg, 99.05 μmol). μmol) and Pd-PEPPSI-IPent Cl (6.42 mg, 6.60 μmol) were added. The mixture was degassed three times with N ₂ and then stirred at 100° C. for 30 min, cooled to 20° C. and filtered. The filtrate was concentrated under vacuum. The resulting residue was purified by preparative TLC (petroleum ether: EtOAc=0:1) to obtain an impure product, which was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: A: Further purification with 0.225% formic acid in water, B: MeCN; B%: 60%-90%, 10 min) and lyophilization gave the product 1-chloro-3-(5-(difluoromethyl)-1,3. ,4-thiadiazol-2-yl)-8-(4-(methoxymethyl)-1-piperidyl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine- 6-Sulfonamide (5.6 mg, 9.44 μmol, 14.30% yield, 100% purity, FA salt) was obtained as a yellow solid.

RT 0.543 min (Method 3); m/z 547.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.59 (d, J = 0.8 Hz, 1H), 8.50 (s, 1H), 8.37 (s, 1H), 7.68 (t, J = 53.2 Hz, 1H) , 6.80 (d, J = 0.8 ㎐, 1H), 3.46 (s, 2H), 3.28 (s, 2H), 3.27 (s, 3H), 2.73 (t, J = 11.4 ㎐, 2H), 1.88-1.81 ( m, 2H), 1.80-1.72 (m, 1H), 1.58-1.46 (m, 2H), 1.16 (s, 3H), 0.77-0.69 (m, 2H), 0.49-0.42 (m, 2H).

Preparation of Example 22

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(1-hydroxyethyl)piperidin-1-yl)-N- (1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide

1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imi in dioxane (1 mL) Cs ₂ CO ₃ (28.69 mg; 88.04 μmol) and Pd-PEPPSI-IPent Cl (4.28 mg, 4.40 μmol) were added under nitrogen atmosphere. The mixture was stirred at 100°C for 16 hours, then cooled to 20°C and filtered. The filtrate was concentrated under vacuum. The resulting residue was purified by preparative TLC (EtOAc: petroleum ether = 3:1) to obtain an impure product, which was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10 μm; mobile phase: A: Further purification (0.225% formic acid in water, B: MeCN; B%: 43%-73%, 10 min) and direct lyophilization gave the product 3-(5-(difluoromethyl)-1,3,4- Thiadiazol-2-yl)-8-(4-(1-hydroxyethyl)piperidin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine- 6-Sulfonamide (1.4 mg, 2.59 μmol, 5.89% yield, 95.82% purity) was obtained as a yellow solid.

RT 0.472 min (Method 3); m/z 513.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CD ₃ OD, 400 MHz): 9.79 (s, 1H), 7.83 (s, 1H), 7.33 (t, J = 53.6 Hz, 1H), 6.70 (s, 1H), 3.87 (d, J = 12.4 Hz, 2H), 3.61 (t, J = 6.0 Hz, 1H), 2.96-2.84 (m, 2H), 2.06 (d, J = 10.8 Hz, 1H), 1.85 (d, J = 12.8 Hz, 1H) ), 1.66 -1.60 (m, 1H), 1.59-1.48 (m, 2H), 1.26 (s, 3H), 1.23 (d, J= 6.4 Hz, 3H), 0.86-0.81 (m, 2H), 0.53- 0.48 (m, 2H).

Preparation of Example 23

Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(1-hydroxyethyl)piperidin-1-yl)- N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide

1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imi in dioxane (1 mL) Pd-PEPPSI-IPent Cl (7.49 mg) in a solution of polyzo[1,5-a]pyridine-6-sulfonamide (35 mg, 77.04 μmol) and 1-(4-piperidyl)ethanol (19.91 mg, 154.08 μmol) , 7.70 μmol) and Cs ₂ CO ₃ (75.30 mg, 231.12 μmol) were stirred at 100° C. for 20 min, then cooled to 20° C. and the filtrate was concentrated under vacuum. The residue was obtained and subjected to preparative HPLC (column: Phenomenex luna C18 150 * 25 mm * 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 50%-80%, 10 min) Purified and directly lyophilized to produce the product 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(1-hydroxyethyl) Piperidin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (2.9 mg, 5.14 μmol, 6.67% yield, 97.16% purity) was obtained as yellow Obtained as a solid.

RT 0.493 min (Method 3); m/z 547.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.59 (s, 1H), 8.49 (s, 1H), 7.68 (t, J = 52.8 Hz, 1H), 6.79 (s, 1H), 4.45 (d, J = 4.4 Hz, 1H), 3.49 (d, J = 11.2 Hz, 2H), 3.47-3.42 (m, 1H), 2.69 (t, J = 11.2 Hz, 1H), 1.96 (d, J = 12.0 Hz, 1H), 1.72 (d, J= 11.6 Hz, 1H), 1.63- 1.47 (m, 2H), 1.41-1.32 (m, 1H), 1.17 (s, 3H), 1.10 (d, J = 6.2 Hz, 3H) ), 0.76-0.70 (m, 2H), 0.49-0.43 (m, 2H).

Preparation of Example 24

1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(2-hydroxypropan-2-yl)piperidine -1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide

1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)—N-(1-methylcyclopropyl)imi in dioxane (1 mL) Cs ₂ CO ₃ in a solution of polyzo[1,5-a]pyridine-6-sulfonamide (20 mg, 44.02 μmol) and 2-(4-piperidyl)propan-2-ol (9.46 mg, 66.04 μmol) (43.03 mg, 132.07 μmol) and Pd-PEPPSI-IPent Cl (4.28 mg, 4.40 μmol) were added. The mixture was degassed three times with N ₂ and then stirred at 100° C. for 30 min, cooled to 20° C. and filtered. The filtrate was concentrated under vacuum. The resulting residue was purified by preparative TLC (EtOAc: petroleum ether = 1:0) to obtain an impure product, which was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10 μm; mobile phase: A: Further purification with 0.225% formic acid in water, B: MeCN; B%: 50%-80%, 10 min) and direct lyophilization gave the product 1-chloro-3-(5-(difluoromethyl)-1, 3,4-thiadiazol-2-yl)-8-(4-(1-hydroxy-1-methyl-ethyl)-1-piperidyl)-N-(1-methylcyclopropyl)imidazo[ 1,5-a]pyridine-6-sulfonamide (3.91 mg, 6.18 μmol, 14.03% yield, 95.9% purity, FA salt) was obtained as a yellow solid.

RT 0.507 min (Method 3); m/z 561.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.59 (s, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 7.07 (t, J = 53.2 Hz, 1H), 6.79 (s, 1H), 4.41 -4.02 (m, 1H), 3.52 (d, J = 11.4 Hz, 2H), 2.67 (t, J = 11.4 Hz, 2H), 1.86 (d, J = 12.0 Hz, 2H), 1.67- 1.51 (m, 2H), 1.47-1.36 (m, 1H), 1.17 (s, 3H), 1.11 (s, 6H), 0.79-0.68 (m, 2H), 0.52-0.40 (m, 2H)

Preparation of Example 25a

1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imidazo [1 ,5-a]pyridine-6-sulfonamide

NaHCO ₃ (240.23 mg, 2.86 mmol, 111.22 μL) in a mixture of 1-(fluoromethyl)cyclopropanamine (179.54 mg, 1.43 mmol, HCl salt) in water (3 mL) and THF (3 mL) at 0°C. was added followed by 1,8-dichloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]imidazo[1,5-a) in THF (3 mL). ] A solution of pyridine-6-sulfonyl chloride (400 mg, 953.19 μmol) was added dropwise. The resulting mixture was stirred at 0°C for 20 min, quenched with H ₂ O (25 mL) and extracted with EtOAc (30 mL; 2x). The combined organic layers were washed with brine (50 mL; 2x), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash). ® Silica flash column, eluent 0-50% EtOAc/petroleum ether gradient @ 30 mL/min) to give the product 1,8-dichloro-3-[5-(difluoromethyl)-1,3,4- Thiadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]imidazo[1,5-a]pyridine-6-sulfonamide (180 mg, 343.01 μmol, 35.99% yield, 90% Purity) was obtained as a yellow solid.

RT 0.52 min (Method 1); m/z 471.8&173.8 (M+H) ⁺ (ESI ⁺ ); ^1H NMR (DMSO- d ₆ , 400 MHz): 9.80 (s, 1H), 9.03 (s, 1H), 7.71 (t, J = 53.2 Hz , 1H), 7.48 (s, 1H), 4.25 (d, J = 52.8 Hz, 2H), 0.91 -0.89 (m, 2H), 0.83 -0.77 (m, 2H).

Preparation of Example 25

4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl) Sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide

1,8-dichloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-[1-(fluoromethyl) in dioxane (2 mL) In a mixture of cyclopropyl]imidazo[1,5-a]pyridine-6-sulfonamide (50 mg, 105.87 μmol), Cs ₂ CO ₃ (68.99 mg, 211.73 μmol), N,N -dimethylpiperazine-1- Carboxamide (33.29 mg, 211.73 μmol) and Pd-PEPPSI-IPent Cl (9.11 mg, 10.59 μmol) were added. The reaction mixture was degassed with N ₂ three times, stirred at 100° C. for 1 hour, and filtered. The filtrate was concentrated under vacuum to obtain a residue, which was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: A: 0.221% NH ₃ .H ₂ O in water, B: MeCN; B%: 43%-73%, 10 min) and directly lyophilized to give product 4-[1-chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazole-2. -yl]-6-[[1 (fluoromethyl)cyclopropyl]sulfamoyl]imidazo[1,5-a]pyridin-8-yl]-N,N-dimethyl-piperazine-1-carboxamide (12.4 mg, 20.49 μmol, 19.36% yield, 98% purity) was obtained as a yellow solid.

RT 0.494 min (Method 2); m/z 593.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 9.90 (s, 1H), 7.07 (t, J = 54.0 Hz, 1H), 6.73 (s, 1H), 5.46 (s, 1H), 4.27 (d, J = 48.4 Hz, 2H), 3.55-3.51 (m, 4H), 3.22-3.16 (m, 4H), 2.90 (s, 6H), 1.15-1.14 (m, 2H), 0.89-0.87 (m, 2H)

Preparation of Example 26

tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfa moyl)imidazo[1,5-a]pyridin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate

8-chloro-3-(5-( _{difluoromethyl} )-1,3,4-thiadiazol-2-yl)-N-( tert-butyl 4-(4,4,5,5-tetra) in a mixture of 1-(fluoromethyl)cyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (80 mg, 182.71 μmol) Methyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (169.49 mg, 548.14 μmol) and K ₃ PO ₄ (46.54 mg, 219.25 μmol) was added. The mixture was degassed and purged with N ₂ (3x), then cataCXium A-Pd-G3 (13.31 mg, 18.27 μmol) was added. The mixture was stirred at 60° C. for 16 hours under N ₂ atmosphere. The reaction mixture was extracted with EtOAc (10 mL, 3x). The combined organic layers were washed with brine (30 mL) and concentrated under vacuum. The residue was subjected to preparative TLC (petroleum ether: ethyl acetate = 2/1) and preparative HPLC (column: Phenomenex Synergi C18 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B %: 40%-70%, 10 min) and directly lyophilized to give the product tert-butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl )-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-3,6-dihydropyridin-1(2H)- The carboxylate (23.85 mg, 37.12 μmol, 20.32% yield, 94% purity) was obtained as a yellow solid.

RT 0.516 min (Method 3); m/z 585.3 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 10.14 (s, 1H), 7.86 (s, 1H), 7.20 (s, 1H), 7.09 (t, J = 56.0 Hz, 1H), 6.36 (s, 1H) , 5.49 (s, 1H), 4.29 (d, J = 48.0 Hz, 2H), 4.20-4.18 (m, 2H), 3.73 (t, J = 8.0 Hz, 2H), 2.63-2.57 (m, 2H), 1.53 (s, 9H), 1.18-1.13 (m, 2H), 0.91- 0.88 (m, 2H).

Preparation of Example 27

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8-(1,2,3, 6-Tetrahydropyridin-4-yl)imidazo[1,5-a]pyridine-6-sulfonamide

tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N- in HCl/dioxane (4 M, 1 mL) (1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (20 mg, 34.21 μmol) of the solution was stirred at 25°C for 1 hour. The reaction mixture was concentrated under vacuum to give the crude product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl). -8-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5-a]pyridine-6-sulfonamide (25 mg, crude, HCl salt) was obtained as a yellow solid. did. The crude product (5 mg) was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 11%-41%, 10 min ) and then lyophilized to obtain a product with 85% purity. This material was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: A: 0.1% trifluoroacetic acid in water, B: MeCN; B%: 11%-44%, 10 min). Further purification and direct lyophilization gave the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)- 8-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5-a]pyridine-6-sulfonamide (3.06 mg, 4.86 μmol, 56.34% yield, TFA salt) was obtained as a yellow Obtained as a solid.

RT 0.343 min (Method 3); m/z 485.2 (M+H) ⁺ (ESI ⁺ ), ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.86 (s, 1H), 8.93 (s, 1H), 8.92-8.90 (m, 1H) , 8.11 (s, 1H), 7.69 (t, J = 52.0 Hz, 1H), 7.32 (d, J = 0.8 Hz, 1H), 6.49 (s, 1H), 4.24 (d, J = 40.0 Hz, 2H) , 3.89 (s, 2H), 3.43 (t, J = 8.0 Hz, 2H), 2.80 -2.72 (m, 2H), 0.90-0.85 (m, 2H), 0.84-0.74 (m, 2H).

Preparation of Example 28

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1 ,5-a]pyridin-8-yl)-N,N-dimethyl-3,6-dihydropyridin-1(2H)-carboxamide

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl) in THF (0.5 mL) and H ₂ O (0.25 mL) )Cyclopropyl)-8-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5-a]pyridine-6-sulfonamide (20 mg, 41.28 μmol, HCl salt) K ₂ CO ₃ (17.11 mg, 123.83 μmol) and dimethylcarbamic acid chloride (6.66 mg, 61.92 μmol, 5.69 μL) were added to the solution at 0°C. The mixture was stirred at 25°C for 1 hour, then diluted with water (15 mL) and extracted with EtOAc (15 mL, 3x). The organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazole- 2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,N-dimethyl-3,6- Dihydropyridine-1(2H)-carboxamide (23 mg, 39.30 μmol, 90.26% yield, 90% purity) was obtained as a yellow solid. 7 mg of the crude product was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 35%-65%, 10 min) It was further purified and directly lyophilized to obtain 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoro Methyl) cyclopropyl) sulfamoyl) imidazo [1,5-a] pyridin-8-yl) -N, N-dimethyl-3,6-dihydropyridine-1 (2H) -carboxamide (3.81 mg, 6.51 μmol, 54.4% yield, 95% purity) was obtained as a yellow solid.

RT 0.458 min (Method 3); m/z 556.3 (M+H) ⁺ (ESI ⁺ ), ¹ H NMR (CDCI _3,400 MHz): 10.14 (s, 1H), 7.88 (s, 1H), 7.22 (s, 1H), 7.09 (t , J = 52.0 Hz, 1H), 6.38 (s, 1H), 5.54 (s, 1H), 4.29 (d, J = 48.0 Hz, 1H), 4.08-4.06 (m, 2H), 3.55 (t, J= 8.0 Hz, 2H), 2.92 (s, 6H), 2.70-2.68 (m, 2H), 1.17-1.13 (m, 2H), 0.90-0.87 (m, 2H).

Preparation of Example 29

4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl) Sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,N-dimethyl-3,6-dihydropyridine-1( 2H )-carboxamide

4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclo in MeCN (0.5 mL) Propyl) sulfamoyl) imidazo [1,5-a] pyridin-8-yl) -N, N-dimethyl-3,6-dihydropyridine-1 (2H) -carboxamide (16 mg, 28.80 μmol) 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (5.67 mg, 28.80 μmol) was added to the mixture at 0°C. The mixture was stirred at 20° C. for 16 hours and then concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%:45%-75%, 10 min) and directly By lyophilization, the product 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl )Cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,N-dimethyl-3,6-dihydropyridine-1(2H)-carboxamide (2.77 mg, 4.51 μmol, 15.65% yield, 96% purity) was obtained as a yellow solid.

RT 0.479 min (Method 3); m/z 590.3 (M+H) ⁺ (ESI ⁺ ), ¹ H NMR (CDCl ₃ , 400 MHz): 10.13 (d, J = 1.2 Hz, 1H), 7.12 (d, J = 1.2 Hz, 1H), 7.09 (t, J = 52.0 Hz, 1H), 5.89 (s, 1H), 5.54 (s, 1H), 4.29 (d, J = 48.0 Hz, 2H), 4.02-3.99 (m, 2H), 3.56 (t , J = 8.0 Hz, 2H), 2.91 (s, 6H), 2.62-2.53 (m, 2H), 1.17-1.13 (m, 2H), 0.90 (t, J = 8.0 Hz, 2H).

Preparation of Example 30

tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo [1,5-a]pyridin-8-yl)piperazine-1-carboxylate

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ 1,5-a]pyridine-6-sulfonamide (100 mg, 238.18 μmol) in a mixture of tert-butyl piperazine-1-carboxylate (106.09 mg, 476.35 μmol), Cs ₂ CO ₃ (155.21 mg, 476.35 μmol) μmol) and Pd-PEPPSI-IPentCl o-picolin (20.49 mg, 23.82 μmol) were added and the reaction mixture was degassed with N ₂ (3x). The mixture was stirred at 100° C. for 1 hour, then filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by preparative TLC (petroleum ether: EtOAc = 0/1) to give the product tert-butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazole- 2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)piperazine-1-carboxylate (130 mg, 182.57 μmol, 76.65% yield, 80% purity) was obtained as a yellow solid.

RT 0.653 min (Method 3); m/z 514.0 (M+H) ⁺ (ES ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 9.88 (s, 1H), 7.71 (s, 1H), 7.08 (t, J =53.6 Hz, 1H), 6.65 (s, 1H), 5.04 (s, 1H) , 3.72-3.70 (m, 4H), 3.31-3.29 (m, 4H), 1.52 (s, 9H), 1.39 (s, 3H), 0.95-0.90 (m, 2H), 0.62-0.59 (m, 2H) .

Preparation of Example 31

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

tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N- in HCl/dioxane (4 M, 2 mL) A mixture of (1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)piperazine-1-carboxylate (50 mg, 87.77 μmol) was stirred at 25°C for 1 hour. did. The reaction mixture was concentrated under vacuum to obtain a residue, which was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 11% -41%, 10 min) and directly lyophilized to produce the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl )-8-(piperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide (12.90 mg, 26.38 μmol, 30.05% yield, 96% purity, FA salt) was obtained as a yellow solid. did.

RT 0.360 min (Method 3); m/z 470.1 (M+H) ⁺ (ESI ⁺ ), ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.58 (s, 1H), 8.43 (s, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.67 (t, J =53.2 Hz, 1H), 6.67 (s, 1H), 3.26 (s, 4H), 3.01 (s, 4H), 1.15 (s, 3H), 0.73-0.71 ( m, 2H), 0.50-0.38 (m, 2H).

Preparation of Example 32

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclo Profile) imidazo[1,5-a]pyridine-6-sulfonamide

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl) in THF (2 mL) and H ₂ O (1 mL) NaHCO ₃ (aq., 53.67 mg, 638.94 μmol) in a mixture of -8-(piperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide (30 mg, 63.89 μmol, FA salt) , 24.85 μL) and isobutyryl chloride (13.62 mg, 127.79 μmol, 13.35 μL) were added at 0°C, and the mixture was stirred at 0°C for 15 min. The mixture was poured into water (7 mL) and extracted with EtOAc (12 mL; 2x). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give a residue, which was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water , B: MeCN; B%: 41%-71%, 10 min) and directly lyophilized to give the product 3-(5-(difluoromethyl)-1,3,4-thiadiazole-2- 1)-8-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (5.98 mg, 10.97 μmol, 17.17% yield, 96.39% purity) was obtained as a yellow solid.

RT 0.498 min (method 3), m/z 540.2(M+H) ⁺ (ESI ⁺ ), ¹ H NMR (CDCl ₃ , 400 MHz) 9.90 (s, 1H), 7.73 (s, 1H), 7.08 (t , J =53.6 Hz, 1H), 6.66 (s, 1H), 5.08 (s, 1H), 3.91-3.81 (m, 4H), 4.00-3.65 (m, 2H), 3.65- 3.32 (m, 2H), 2.88-2.85 (m, 1H), 1.40 (s, 3H), 1.20 (d, J = 6.8 Hz, 6H), 0.95-0.92 (m, 2H), 0.65-0.55 (m, 2H).

Preparation of Example 33

tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo [1,5-a]pyridin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate

8-chloro-3-(5-( _{difluoromethyl} )-1,3,4-thiadiazol-2-yl)-N-( 1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (50 mg, 119.09 μmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3, K ₃ PO ₄ (30.33 mg, 142.91 μmol) was added to a solution of 2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (110.47 mg, 357.26 μmol). Added. The mixture was degassed with N ₂ (3x). Then, cataCXium A-Pd-G3 (8.6 mg, 11.91 μmol) was added. The mixture was stirred at 60°C for 16 hours, cooled to room temperature and dissolved in MeOH (1 mL). The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 60%-90%, 10 min); It was then lyophilized to give the product tert-butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl) Sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (35.21 mg, 60.27 μmol, 50.61% yield, 97% purity) was obtained as a yellow solid.

RT 0.567 min (Method 3); m/z 567.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 10.13 (s, 1H), 7.85 (s, 1H), 7.21 (s, 1H), 7.09 (t, J = 53.6 Hz, 1H), 6.35 (s, 1H) , 5.13 (s, 1H), 4.21-4.19 (m, 2H), 3.73 (t, J = 5.2 Hz, 2H), 2.63-2.61 (m, 2H), 1.53 (s, 9H), 1.39 (s, 3H) ), 0.92 (t, J = 6.0 Hz, 2H), 0.62 (t, J = 6.4 Hz, 2H).

Preparation of Example 34

tert-Butyl 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfa moyl)imidazo[1,5-a]pyridin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate

tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl) in MeCN (1.5 mL) ) NCS (49.49 mg) in a solution of sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (140 mg, 247.06 μmol) , 370.60 μmol) was added and the mixture was stirred at 20°C for 16 hours. The reaction was quenched with NaHCO ₃ (10 mL). The resulting mixture was then extracted with EtOAc (30 mL; 3x). The combined organic layers were washed with brine (20 mL; 3x), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 36 mg of crude product. 15 mg of this crude product was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 65%-95%, 10 min ) and lyophilized to produce the product tert-butyl-4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N -(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (4.28 mg, 6.79 μmol, 6.6% yield, 95.3% purity) was obtained as a yellow solid.

RT 0.598 min (Method 3); m/z 601.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 10.12 (d, J = 1.4 Hz, 1H), 7.11 (d, J = 1.2 Hz, 1H), 7.09 (t, J = 53.6 Hz, 1H), 5.88 (s , 1H), 5.15 (s, 1H), 4.16-4.14 (m, 2H), 3.75 (t, J = 5.2 Hz, 2H), 2.58-2.39 (m, 2H), 1.53 (s, 9H), 1.39 ( s, 3H), 0.92 (t, J = 6.4 Hz, 2H), 0.62 (t, J = 6.8 Hz, 2H).

Preparation of Example 35

1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(1,2,3, 6-Tetrahydropyridin-4-yl)imidazo[1,5-a]pyridine-6-sulfonamide formate

tert-Butyl 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6 in HCl/dioxane (4 M, 0.2 mL) -(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (35 mg, 58.23 μmol) of the solution was stirred at 20°C for 1 hour. The mixture was concentrated to give 35 mg crude product. 10 mg of this crude product was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 15%-45%, 10 min ) and lyophilized to produce 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8. -(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5-a]pyridine-6-sulfonamide formate (3.1 mg, 5.44 μmol, 32.7% yield, 96% purity, FA salt) was obtained as a yellow solid.

RT 0.376 min (Method 3); m/z 501.3 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.83 (d, J = 1.6 Hz, 1H), 8.73-8.42 (m, 1H), 8.25 (s, 1H), 7.69 (t, J = 53.6 Hz, 1H), 7.12 (d, J = 1.2 Hz, 1H), 5.92 (s, 1H), 3.52-3.50 (m, 2H), 3.11 (t, J = 5.6 Hz, 2H), 2.34 (s, 2H), 1.19 (s, 3H), 0.73 (t, J = 6.4 Hz, 2H), 0.49- 0.46 (m, J, 2H).

Preparation of Example 36

4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imi Polyzo[1,5-a]pyridin-8-yl)-N,N-dimethyl-3,6-dihydropyridine-1(2H)-carboxamide

1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1- in THF (0.6 mL) and H ₂ O (0.3 mL) of methylcyclopropyl)-8-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5-a]pyridine-6-sulfonamide (20 mg, 36.56 μmol, FA salt) K ₂ CO ₃ (16.55 mg, 119.77 μmol) and dimethylcarbamic acid chloride (6.44 mg, 59.88 μmol, 5.50 μL) were added to the solution. The mixture was stirred at 0°C for 1 hour, diluted with H ₂ O (5 mL) and extracted with EtOAc (5 mL, 3x). The organic layer was washed with brine (5 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 48%-78%, 10 min) and lyophilized. The product 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl ) imidazo [1,5-a] pyridin-8-yl) -N, N-dimethyl-3,6-dihydropyridine-1 (2H) -carboxamide (5.38 mg, 9.31 μmol, 25.46% yield, 99% purity) was obtained as a yellow solid.

RT 0.498 min (Method 3); m/z 572.4 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 10.12 (d, J = 0.8 Hz, 1H), 7.12 (d, J = 0.8 Hz, 1H), 7.09 (t, J = 53.6 Hz, 1H), 5.88 (s, 1H), 5.19 (s, 1H), 4.01-3.99 (m, 2H), 3.57 (t, J = 5.2 Hz, 2H), 2.91 (s, 6H), 2.57-2.54 (m, 2H), 1.39 (s, 3H), 0.92 (t, J = 6.0 Hz, 2H), 0.62 (t, J = 5.6 Hz, 2H).

Preparation of Example 37

1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8-(2- Oxa-7-azaspiro[3.5]nonan-7-yl)imidazo[1,5-a]pyridine-6-sulfonamide

1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-() in 1,4-dioxane (4 mL) 2-oxa-7-azaspiro[3.5]nonane (162 mg, 1.27 mmol) in a mixture of fluoromethyl)cyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (200 mg, 0.423 mmol) ), Cs ₂ CO ₃ (414 mg, 1.27 mmol) and Pd-PEPPSI-IPentCl o-picolin (36 mg, 0.0423 mmol) were added. The reaction mixture was degassed with N ₂ (3x) and stirred at 90° C. for 1 hour. It was then filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by preparative TLC (petroleum: EtOAc =3/1), and the crude product (32 mg) was further triturated with MeOH (2 mL) for 10 minutes at 20°C to give the product 1-chloro-3. -(5-difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8-(2-oxa-7-azaspiro [3.5]nonan-7-yl)imidazo[1,5-a]pyridine-6-sulfonamide (25.55 mg, 44.9 μmol, 10.61% yield, 100% purity) was obtained as a yellow solid.

RT 0.515 min (Method 3); m/z 563.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz,) 9.87 (s, 1H), 7.07 (t, J = 53.6 Hz, 1H), 6.69 (s, 1H), 5.58 (s, 1H), 4.53 (s, 4H) , 4.26 (d, J = 48.4 Hz, 2H), 3.29-2.94 (m, 4H), 2.17 (m, 4H), 1.17-1.13 (m, 2H), 0.89-0.86 (m, 2H).

Preparation of Example 38

1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(2-oxa-7- Azaspiro[3.5]nonan-7-yl)imidazo[1,5-a]pyridine-6-sulfonamide

1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imi in dioxane (1 mL) A mixture of polyzo[1,5-a]pyridine-6-sulfonamide (40 mg, 88.05 μmol), 2-oxa-7-azaspiro[3.5]nonane (22.40 mg, 176.09 μmol), Cs ₂ CO ₃ (86.06 mg, 264.14 μmol) and Pd-PEPPSI-IPentCl o-picolin (7.58 mg, 8.80 μmol) were added. The reaction mixture was degassed with N ₂ (3x) and the mixture was stirred at 90° C. for 1 hour. It was then filtered and the filtrate was concentrated under vacuum.

The residue was purified by preparative TLC (petroleum ether: EtOAc = 0:1) and lyophilized to give the product 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2. -yl)-N-(1-methylcyclopropyl)-8-(2-oxa-7-azaspiro[3.5]nonan-7-yl)imidazo[1,5-a]pyridine-6-sulfonamide ( 15.58 mg, 27.55 μmol, 31.29% yield, 96.39% purity) was obtained as a yellow solid.

RT 0.509 min (Method 3); m/z 545.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 9.87 (s, 1H), 7.68 (t, J =53.2 Hz, 1H), 6.70 (s, 1H), 5.09 (s, 1H), 4.54 (s, 4H) , 3.10-3.05 (m, 4H), 2.25-2.10 (m, 4H), 1.39 (s, 3H), 0.94-0.91 (m, 2H), 0.66-0.59 (m, 2H).

Preparation of Example 39

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(1,2,3,6-tetrahydro Pyridin-4-yl)imidazo[1,5-a]pyridine-6-sulfonamide

tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N- in HCl/dioxane (4 M, 1.5 mL) (1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate (40 mg, 70.59 μmol) The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under vacuum to give the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(1, 2,3,6-Tetrahydropyridin-4-yl)imidazo[1,5-a]pyridine-6-sulfonamide (45 mg, crude, HCl salt) was obtained as a yellow solid.

RT 0.351 min (Method 3); m/z 467.1 (M+H) ⁺ (ESI ⁺ ), ¹ H NMR (DMSO- d _6,400 MHz): 9.88 (s, 1H), 9.27 (d, J = 0.8 Hz, 1H), 8.58 (s , 1H), 8.13 (s, 1H), 7.69 (t, J = 53.2 Hz, 1H), 7.38 (d, J = 0.8 Hz, 1H), 6.49 (s, 1H), 3.92-3.87 (m, 2H) , 3.45-3.35 (m, 2H), 2.85-2.72 (m, 2H), 1.18 (s, 3H), 0.74-0.72 (m, 2H), 0.49- 0.45 (m, 2H).

Preparation of Example 40

4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo [1, 5-a]pyridin-8-yl)-N,N-dimethyl-5,6-dihydropyridin-1(2H)-carboxamide

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl) in THF (2 mL) and H ₂ O (1 mL) K ₂ in a mixture of -8-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5-a]pyridine-6-sulfonamide (45 mg, 96.46 μmol, HCl salt) CO ₃ (39.99 mg, 289.37 μmol) and dimethylcarbamate chloride (15.56 mg, 144.69 μmol, 13.30 μL) were added at 0°C. The mixture was stirred at 0°C for 15 min, poured into water (10 mL) and extracted with EtOAc (15 mL; 2x). The combined organic layers were then dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 40%-70%, 10 min) and directly freeze-dried to obtain the product 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfa Moyl) imidazo [1,5-a] pyridin-8-yl) -N, N-dimethyl-5,6-dihydropyridine-1 (2H) -carboxamide (12.1 mg, 22.06 μmol, 22.87% yield) , 98% purity) was obtained as a yellow solid.

RT 0.494 min (Method 3); m/z 538.1 (M+H) ⁺ (ESI ⁺ ), ¹ H NMR (CDCl _3,400 MHz): 10.13 (s, 1H), 7.87 (s, 1H), 7.22 (d, J = 1.2 Hz, 1H ), 7.09 (t, J = 53.2 Hz, 1H), 6.38 (s, 1H), 5.09 (s, 1H), 4.10-3.95 (m, 2H), 3.65-3.45 (m, 2H), 2.92 (s, 6H), 2.70-2.58 (m, 2H), 1.39 (s, 3H), 0.93-0.91 (m, 2H), 0.68-0.58 (m, 2H).

The following general procedure applies to the synthesis of the compounds described below.

General procedure 1 (Buchwald coupling): To a solution of chloro compound (1.00 eq) in 1,4-dioxane (500 mg/mL) add amine substrate (1 to 3 eq, free base or salt) and Cs ₂ CO ₃ ( 2 to 4 eq) was added. The mixture was degassed with N2 (3x) or placed in a glove box. Then Pd-PEPPSI-IPentCl o-picolin (0.05 to 0.1 eq) was added. The mixture was stirred under N ₂ for 1 to 16 hours at 80 to 100° C. outside the glove box. The reaction mixture was then cooled to room temperature, diluted with H ₂ O and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC (reverse phase) or preparative TLC or SiO ₂ column chromatography (normal phase) to obtain the corresponding product.

General Procedure 2 (Boc Cleavage): To a solution of Boc-protected compound in DCM (0.1 g/mL) add TFA (1/5 to 1/3 volume of DCM) or HCl/dioxane (4N, 1 volume of DCM). /5 to 1/3) was added at 0°C and the mixture was stirred at 0°C for 2 to 16 hours. The resulting residue was purified by reverse phase preparative HPLC (reverse phase) or preparative TLC or SiO ₂ column chromatography (normal phase) to obtain the corresponding product.

General procedure 3 (bromination or iodination): Mixture of substrate (1 eq) in CHCl ₃ (0.01 to 0.1 g/mL) or MeCN (0.01 to 0.1 g/mL) with CHCl ₃ (0.01 to 0.1 g/mL) or MeCN. NBS (0.8 to 1.1 eq) or NIS (0.8 to 1.1 eq) (0.01 to 0.1 g/mL) was added dropwise at 0°C. The mixture was stirred and concentrated under reduced pressure for 0.5 hours at room temperature. The resulting residue was purified by reverse phase preparative HPLC (reverse phase) or preparative TLC or SiO ₂ column chromatography (normal phase) to obtain the corresponding product.

General Procedure 4 (Amine Transesterification): Addition of amine substrate (1 to 10 eq) to a mixture of ester substrate (1 eq) in EtOH (10 to 100 mg/mL) and H ₂ O (1/10 to 1/3 volume of EtOH). eq, free base or HCl salt) was added. The mixture was stirred at 20 to 100° C. for 2 to 20 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC (reverse phase) or preparative TLC or SiO ₂ column chromatography (normal phase) to obtain the corresponding product.

General Procedure 5 (Amide Formation Using Peptide Coupling Reagents): Add HATU (1 to 2 eq) and DIEA (1.5 to 2 eq) to a solution of acid substrate (1 eq) in DMF (20 to 100 mg/mL). did. The mixture was stirred at 20° C. for 30 min and amine substrate (1.2-1.5 eq, free base or HCl salt) was added. The reaction was stirred at 20°C for 1-16 hours, then diluted with ice/H ₂ O and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC (reverse phase) or preparative TLC or SiO ₂ column chromatography (normal phase) to obtain the corresponding product.

General procedure ₆ (Suzuki coupling with eq), to a solution of borate ester or borate acid substrate (1 to 4 eq) and Cs ₂ CO ₃ (2 to 4 eq) was added Xantphos Pd G4 (0.1 to 0.2 eq). The reaction mixture was degassed and purged with N ₂ (3x), stirred at 80-100° C. for 2-16 hours and concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC (reverse phase) or preparative TLC or SiO ₂ column chromatography (normal phase) to obtain the corresponding product.

Alternatively, after 2-16 hours at 80-100°C, the reaction mixture was cooled to room temperature, diluted with H ₂ O and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC (reverse phase) or preparative TLC or SiO ₂ column chromatography (normal phase) to obtain the corresponding product.

General Procedure 7 (Hydrogenation): Pd/C (m = 1/10 to 1/5 mg of substrate mass, 10% purity) to a solution of olefin substrate (1 eq) in THF (2.5 to 50 g/mL) was added to N Added under ₂ . The suspension was degassed under vacuum and purged with H ₂ (3x). The mixture was stirred under H ₂ atmosphere (15 psi) at 20 to 50°C for 2 to 16 hours, then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC (reverse phase) or preparative TLC or SiO ₂ column chromatography (normal phase) to obtain the corresponding product.

General procedure 8 (Sonogashira coupling 1): CuI (0.05 to 0.3 eq) in a solution of bromide or iodide (1 eq) in DMF or dioxane or DMF/MeOH (1 to 100 mg/mL), K ₂ CO ₃ (2 to 4 eq) or TEA (1/2 to 1 V of solvent) and Pd(PPh ₃ ) ₂ Cl ₂ or Pd(dppf)Cl ₂ (0.05 to 0.3 eq) were added. The reaction mixture was degassed and purged with N ₂ (3x). Alkyne substrate (1-3 eq) was then added to the mixture. The reaction mixture was stirred at 80 to 150°C for 0.5 to 16 hours under N ₂ atmosphere, then poured into water and extracted with EtOAc (3x). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC (reverse phase) or preparative TLC or SiO ₂ column chromatography (normal phase) to obtain the corresponding product.

General procedure 9 (saponification): To a mixture of ester substrate (1 eq) in MeOH (10 to 200 mg/mL) and H ₂ O (1/3 to 1/1 volume of MeOH) was added LiOH or LiOH·H ₂ O( 2 to 10 eq) was added. The mixture was stirred at 20 to 80° C. for 1 to 16 hours. Post-treatment procedure 1: The pH of the reaction mixture was adjusted to 1 to 6 by adding an aqueous hydrochloric acid solution (1N) and then extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was used in the next step without further purification. Post-treatment 2: The pH of the reaction mixture was adjusted to 1 to 6 by adding an aqueous hydrochloric acid solution (1N). The resulting residue was purified by reverse phase preparative HPLC (reverse phase) or preparative TLC or SiO ₂ column chromatography (normal phase) to obtain the corresponding product.

General Procedure 10 (Sonogashira Coupling 2): P(t-Bu) ₃ (0.2 eq, 10% w/w in hexane) to a solution of bromide or iodide substrate (1 eq) in MeCN (50 mg/mL) ), TEA or DABCO (2 eq) and allyl(chloro)palladium (0.1 eq) were added. The reaction mixture was degassed and purged with N ₂ (3x) before the alkyne substrate (2 eq) was added to the mixture. The reaction mixture was stirred under N ₂ atmosphere at room temperature for 1 to 16 hours and concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC (reverse phase) or preparative TLC or SiO ₂ column chromatography (normal phase) to obtain the corresponding product.

Alternatively, after stirring, the reaction mixture was diluted with H ₂ O and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC (reverse phase) or preparative TLC or SiO ₂ column chromatography (normal phase) to obtain the corresponding product.

General Procedure 11 (TBS Cleavage): To a solution of TBS protected compound in MeOH (0.5 g/mL) was added KF (2 eq). The mixture was stirred at room temperature for 1 to 16 hours and then concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC (reverse phase) or preparative TLC or SiO ₂ column chromatography (normal phase) to obtain the corresponding product.

General Procedure 12 (Amide Formation Using Acyl Glorides): To a solution of the amine substrate (1 eq) in THF (20-100 mg/mL) was added NaHCO ₃ (saturated solution, 20-100 mg/mL) or TEA (1.5-100 mg/mL). 2 eq) was added. The mixture was stirred at 0° C. for 2 minutes and acyl chloride (1.2-1.5 eq) was added to the mixture. The reaction was stirred at 20° C. for 0.5-1 hour, then diluted with ice-H ₂ O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC (reverse phase) or preparative TLC or SiO ₂ column chromatography (normal phase) to obtain the corresponding product.

General Procedure 13 (Steel Coupling): To a solution of tin substrate (1 eq) in dioxane (V = 15 mg/mL) halogenated substrate (1.5 eq), K ₂ CO ₃ (2 eq) and Pd(dppf)Cl ₂ (0.1 eq) was added. The reaction mixture was degassed and purged with N ₂ (3x). The reaction mixture was stirred at 80°C for 16 hours under N ₂ atmosphere, then poured into water and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by reversed phase preparative HPLC (reverse phase).

General Procedure 14 (Ester Formation): A solution of acid substrate (1 eq), DMAP (0.5 eq) and DCC (2 eq) in DCM (20 to 100 mg/mL) is stirred at room temperature for 1 to 3 hours and alcohol substrate (1 to 2 eq) was added. The mixture was stirred at room temperature for 1 to 16 hours. The resulting mixture was diluted with ice/H ₂ O and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC (reverse phase) or preparative TLC or SiO ₂ column chromatography (normal phase) to obtain the corresponding product.

Preparation of Example 41.a

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

To a mixture of 1-methylcyclopropanamine (78.20 mg, 726.90 μmol, HCl salt) in NaHCO ₃ (aq., sat., 3 mL) was added 8-chloro-3-(5-(difluoro) in THF (1.5 mL). Romethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,2-a]pyridine-6-sulfonyl chloride (140 mg, 363.45 μmol) was added dropwise at 0°C. The mixture was stirred at 15°C for 2 hours. The reaction mixture was quenched with H ₂ O (30 mL) and extracted with EtOAc (30 mL, 3x). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent 20-40% ethyl acetate/petroleum @ 75 mL/min) to give the product 8-chloro-3-(5- (difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (50 mg, 119.09 μmol, 32.77% yield) was obtained as a white solid.

RT 0.809 min (Method 1); m/z 420.1 (M+H) ⁺ (ESI+); ¹ H NMR (DMSO- d ₆ , 400 MHz) 9.99 (d, J = 1.2 Hz, 1H), 8.81 (s, 1H), 8.58 (s, 1H), 7.94 (d, J = 1.2 Hz, 1H), 7.73 (t, J = 53.2 Hz, 1H), 1.17-1.20 (m, 3H), 0.67-0.76 (m, 2H), 0.45-0.53 (m, 2H).

Preparation of Example 41

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

A solution of N,N-dimethylpiperazine-1-carboxamide (14.98 mg, 95.27 μmol) in dioxane (0.5 mL) was dissolved in 8-chloro-3-(5-(difluoromethyl)-1,3, 4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (20 mg, 47.64 μmol), Cs ₂ CO ₃ (31.04 mg , 95.27 μmol) and Pd-PEPPSI-IPentCl o-picolin (2.05 mg, 2.38 μmol) were added in the glove box. The mixture was stirred under Ar for 2 hours at 100° C. outside the glove box, cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with MeOH (3 mL), filtered and the filtrate was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: A: 0.225% formic acid in water, B : MeCN; B%: 32%-62%, 7 min) and directly lyophilized to obtain product 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazole-2- 1)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide (3.05 mg , 5.42 μmol, 11.37% yield, 96% purity) was obtained as a light yellow solid.

RT 0.896 min (Method 1); m/z 541.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d _6,400 MHz): 9.67 (s, 1H), 8.63 (s, 1H), 8.32-8.50 (m, 1H), 7.71 (t, J = 53.2 Hz, 1H), 7.02 ( s, 1H), 3.64 (br, 4H), 3.35-3.37 (m, 4H), 2.81 (s, 6H), 1.14 (s, 3H), 0.66-0.77 (m, 2H), 0.39-0.52 (m, 2H).

Preparation of Example 42

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(2-oxa-7-azaspiro[3.5 ]nonan-7-yl)imidazo[1,2-a]pyridine-6-sulfonamide

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ 2-oxa-7-azaspiro[3.5]nonane (25.19 mg, 104.45 μmol, TFA salt) in a solution of 1,2-a]pyridine-6-sulfonamide (30 mg, 69.63 μmol), Cs ₂ CO ₃ ( 68.06 mg, 208.89 μmol) was added. In the glove box, Pd-PEPPSI-IPentCl o-picolin (3.00 mg, 3.48 μmol) was added. The mixture was then stirred under Ar for 1 hour at 100° C. outside the glove box, cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 31%-61%, 10 min) and directly freeze-dried to produce the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(2-oxa- 7-Azaspiro[3.5]nonan-7-yl)imidazo[1,2-a]pyridine-6-sulfonamide (7.35 mg, 13.67 μmol, 19.64% yield, 94.99% purity) was obtained as a light yellow solid. .

RT 0.918 min (Method 1); m/z 511.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz) 9.88 (d, J = 1.6 Hz, 1H), 8.18 (s, 1H), 6.95-7.24 (m, 2H), 5.06 (s, 1H), 4.54 (s, 4H) ), 3.49-3.60 (m, 4 H), 2.11-2.21 (m, 4H), 1.35 (s, 3H), 0.87-0.95 (m, 2H), 0.55-0.62 (m, 2H).

Preparation of Intermediate 43.1

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,2-a]pyridine-6-sulfonyl bromide

Three batches were run in parallel and mixed for work-up.

2-(6-(benzylthio)-8-chloroimidazo[1,2-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4- in MeCN (10 mL) 1,3-dibromo-5,5 in a mixture of thiadiazole (1 g, 2.45 mmol), AcOH (293.74 mg, 4.89 mmol, 279.75 μL), H ₂ O (88.12 mg, 4.89 mmol, 88.12 μL) -Dimethylimidazolidine-2,4-dione (2.80 g, 9.78 mmol) was added at 0°C and the mixture was stirred at 0°C for 0.5 h. Three batches were combined. The resulting mixture was quenched with ice/water (90 mL) and extracted with DCM (90 mL, 3x). The combined organic layers were washed with brine (50 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate (10% DCM added) = 5/1 to 1/1) to give the product 8-chloro-3-[5-(difluoromethyl )-1,3,4-thiadiazol-2-yl]imidazo[1,2-a]pyridine-6-sulfonyl bromide (3.15 g, 7.33 mmol, 99.73%) was obtained as a yellow solid.

RT 0.770 min (Method 1); m/z 430.7 (M+H) ⁺ (ESI ⁺ )

Preparation of Compound 43

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

Three batches were run in parallel and mixed for work-up.

To a mixture of 1-(fluoromethyl)cyclopropan-1-amine (705.83 mg, 5.62 mmol, HCl salt) in saturated NaHCO ₃ (7 mL) was added 8-chloro-3-(5-() in THF (5 mL). Difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,2-a]pyridine-6-sulfonyl bromide (1.05 g, 2.44 mmol) was added, and the mixture was stirred at 15 °C. It was stirred at ℃ for 1 hour. Three batches were combined. The resulting mixture was diluted with H ₂ O (60 mL) and extracted with EtOAc (60 mL, 2x). The combined organic layers were then washed with brine (30 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 2/1) to obtain 1.7 g of impure product. 50 mg was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water; B: MeCN; B%: 41%-61%, 10 min) and directly By lyophilization, the product 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imidazo [1,2-a]pyridine-6-sulfonamide (17.49 mg, 39.95 μmol, 8.06% yield) was obtained as a white solid.

RT 0.784 min (Method 1); m/z 438.1 (M+H) ⁺ (ESI+); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.97 (d, J = 1.6 Hz, 1H), 9.08-8.90 (m, 1H), 8.79 (s, 1H), 7.94 (d, J = 1.6 Hz, 1H), 7.71 (t, J = 53.2 Hz, 1H), 4.24 (d, J = 48.4 Hz, 1H), 0.92-0.84 (m, 2H), 0.83-0.76 (m, 2H).

Preparation of Example 44

4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imi Polyzo[1,2-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide

In a glove box, to a solution of N,N-dimethylpiperazine-1-carboxamide (14.36 mg, 91.36 μmol) in dioxane (0.5 mL) was added 8-chloro-3-(5-(difluoromethyl)- 1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (20 mg, 45.68 μmol) , Cs ₂ CO ₃ (29.77 mg, 91.36 μmol) and Pd-PEPPSI-IPentCl o-picolin (1.97 mg, 2.28 μmol) were added. The mixture was stirred under Ar for 2 hours outside the glove box at 100°C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with MeOH (3 mL), filtered and the filtrate was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN ; B%: 29%-59%, 7 min) and directly lyophilized to give the product 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl). -6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide ( 5.73 mg, 10.16 μmol, 22.23% yield, 99% purity) was obtained as a light yellow solid.

RT 0.887 min (Method 1); m/z 559.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.65 (s, 1H), 8.67-8.82 (m, 1H), 8.62 (s, 1H), 7.71 (t, J = 53.2 Hz, 1H), 7.02 ( s, 1H), 4.23 (d, J = 48.8 Hz, 2H), 3.63 (br, 4H), 3.36 (br, 4H), 2.81 (s, 6H), 0.81-0.88 (m, 2H), 0.74-0.81 (m, 2H).

Preparation of Example 45

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-((dimethyl(oxo)-l6-sulfaneylidene)amino)piperi Din-1-yl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide

In the glove box, 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ Dimethyl(piperidin-4-ylimiro)-λ ⁶ -sulfanone (13.35 mg, 53.59 μmol, 2 HCl salt) in a mixture of 1,2-a]pyridine-6-sulfonamide (15 mg, 35.73 μmol). ), Pd-PEPPSI-IPentCl o-picolin (1.74 mg, 1.79 μmol) and Cs ₂ CO ₃ (46.56 mg, 142.91 μmol) were added. The mixture was stirred under Ar for 2 h outside the glove box at 100°C, cooled to room temperature, diluted with H ₂ O (30 mL) and extracted with EtOAc (30 mL, 3x). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 29%-59%, 10 min) and directly lyophilized to obtain the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-((dimethyl(oxo)-l6-sulfaneyl) den) amino) piperidin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a] pyridine-6-sulfonamide (6.53 mg, 11.67 μmol, 32.66% yield, 100% Purity) was obtained as a yellow solid.

RT 0.904 min (Method 1); m/z 560.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz) 9.61 (d, J = 1.2 Hz, 1H), 8.58 (s, 1H), 8.39 (s, 1H), 7.69 (t, J = 53.2 Hz, 1H), 6.97 (s, 1H), 4.11-4.23 (m, 2H), 3.44-3.52 (m, 1H), 3.30 (s, 6H), 3.15-3.23 (m, 2H), 1.81-1.96 (m, 2H), 1.56-1.71 (m, 2H), 1.13 (s, 3H), 0.68-0.74 (m, 2H), 0.41-0.46 (m, 2H).

Preparation of Example 46

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(6-(hydroxymethyl)-3-azabicyclo[3.1.1]heptane-3 -1)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide

In the glove box, 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl) in dioxane (0.6 mL) ) (3-azabicyclo[3.1.1]heptan-6-yl)methanol (29.23 mg, 178.64 μmol, HCl salt), Pd-PEPPSI-IPentCl o-picoline (5.79 mg, 5.95 μmol) and Cs ₂ CO ₃ (116.40 mg, 357.27 μmol) were added. The mixture was stirred under Ar for 2 hours outside the glove box at 100°C. The reaction mixture was cooled to room temperature, diluted with H ₂ O (30 mL) and extracted with EtOAc (30 mL, 3x). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 29%-59%, 10 min) and directly lyophilized to obtain the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(6-(hydroxymethyl)-3-azabicyclo[3.1 .1]heptan-3-yl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (6.53 mg, 11.67 μmol, 32.66% yield, 100% purity) Obtained as a yellow solid.

RT 1.010 min (Method 1); m/z 511.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz) 9.45-9.52 (m, 1H), 8.52-8.57 (m, 1H), 8.30-8.43 (m, 1H), 7.54-7.87 (m, 1H), 6.61- 6.67 (m, 1H), 4.18-4.24 (m, 1H), 3.96- 4.13 (m, 3H), 3.67-3.71 (m, 1H), 3.39-3.43 (m, 1H), 2.35-2.45 (m, 3H) ), 1.82-2.08 (m, 1H), 1.38-1.51 (m, 1H), 1.16 (d, J = 2.4 Hz, 3H), 0.69-0.76 (m, 2H), 0.41-0.47 (m, 2H).

Preparation of Example 47

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8-(2-oxa-7- Azaspiro[3.5]nonan-7-yl)imidazo[1,2-a]pyridine-6-sulfonamide

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl in dioxane (0.5 mL) ) 2-oxa-7-azaspiro[3.5]nonane (24.79 mg, 102.78 μmol, TFA salt) and Cs in a solution of imidazo[1,2-a]pyridine-6-sulfonamide (30 mg, 68.52 μmol) ₂ CO ₃ (66.97 mg, 205.55 μmol) was added. In the glove box, Pd-PEPPSI-IPentCl o-picolin (2.95 mg, 3.43 μmol) was added. The mixture was stirred under Ar for 1 hour at 100° C. outside the glove box, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 38%-68%, 10 min) and directly freeze-dried to produce the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8-( 2-Oxa-7-azaspiro[3.5]nonan-7-yl)imidazo[1,2-a]pyridine-6-sulfonamide (4.9 mg, 9.27 μmol, 13.53% yield, 100% purity) was obtained as a yellow solid. It was obtained as.

RT 0.855 min (Method 1); m/z 529.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz) 9.88 (d, J = 1.6 Hz, 1H), 8.18 (s, 1H), 6.93-7.24 (m, 2H), 5.46 (s, 1H), 4.54 (s) , 4H), 4.25 (d, J = 48.8 Hz, 2H), 3.51-3.61 (m, 4H), 2.10-2.18 (m, 4H), 1.09-1.18 (m, 2H), 0.83-0.88 (m, 2H) )

Preparation of Compound 48

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(4-(methylthio)piperidine- 1-1) imidazo[1,2-a]pyridine-6-sulfonamide

8-chloro-3-(5-(difluoromethyl)-1,3,4 in a solution of 4-(methylthio)piperidine (53.92 mg, 321.54 μmol, HCl salt) in dioxane (1 mL) -thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (90 mg, 214.36 μmol) and Cs ₂ CO ₃ (209.53 mg, 643.08 μmol) was added. In the glove box, Pd-PEPPSI-IPentCl o-picolin (9.22 mg, 10.72 μmol) was added. The mixture was stirred under Ar ₂ at 100° C. outside the glove box for 2 h, then cooled to room temperature, diluted with H ₂ O (30 mL) and extracted with EtOAc (30 mL, 3x). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 51%-81%, 10 min) and directly lyophilized to obtain the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(4-(methyl Thio)piperidin-1-yl)imidazo[1,2-a]pyridine-6-sulfonamide (25 mg, 48.07 μmol, 22.42% yield, 98.95% purity) was obtained as a yellow solid.

RT 0.634 min (Method 3); m/z 515.3 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz) 9.87 (d, J = 1.6 Hz, 1H), 8.17 (s, 1H), 6.95-7.24 (m, 2H), 5.05 (s, 1H), 4.18-4.28 (m , 2H), 3.10-3.20 (m, 2H), 2.79-2.92 (m, 1H), 2.15-2.25 (m, 5H), 1.85-1.98 (m, 2H), 1.36 (s, 3H), 0.87-0.95 (m, 2H), 0.56-0.62 (m, 2H)

Preparation of Example 49

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(4-(S-methylsulfomidoyl) ) piperidin-1-yl)imidazo[1,2-a]pyridine-6-sulfonamide

3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclopropyl)-8-(4-methylsulfa) in EtOH (0.5 mL) Phl(OAc) ₂ (50.07 mg, 155.45 μmol) and ammonium carbamate in a mixture of nyl-1-piperidyl)imidazo[1,2-a]pyridine-6-sulfonamide (20 mg, 38.86 μmol) (6.07 mg, 77.73 μmol) was added. The mixture was stirred at 20°C for 16 hours, then diluted with H ₂ O (20 mL) and extracted with EtOAc (20 mL, 2x). The combined organic layers were washed with brine (20 mL, 2x), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 24%-54%, 10 min) and directly lyophilized to produce the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(4-(S -Methylsulfomidoyl)piperidin-1-yl)imidazo[1,2-a]pyridine-6-sulfonamide (12.51 mg, 22.93 μmol, 58.99% yield, 100% purity) was obtained as a yellow solid. did.

RT 0.780 min (Method 1); m/z 546.1 (M+H) ⁺ (ESI ⁺ ); ^1H NMR (CDCl ₃ , 400 MHz) 9.92 (d, J = 1.2 Hz, 1H), 8.19 (s, 1H), 6.96-7.26 (m, 2H), 5.30 (s, 1H), 4.61 (t, J = 12.4 Hz, 2H), 3.14-3.30 (m, 1H), 2.94-3.06 (m, 5H), 2.33-2.50 (m, 2H), 2.08-2.22 (m, 2H), 1.37 (s, 3H) , 0.89-0.99 (m, 2H), 0.56-0.65 (m, 2H)

Preparation of Example 50

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(4-(methylsulfonyl)piperidine -1-1) imidazo[1,2-a]pyridine-6-sulfonamide

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(4-(methyl) in DCM (0.5 mL) m-CPBA (15.39 mg, 75.78 μmol, 85% purity) was added to a solution of thio) piperidin-1-yl) imidazo [1,2-a] pyridine-6-sulfonamide (20 mg, 38.86 μmol). was added and the mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with NaS ₂ O ₃ (aq., sat., 20 mL) and extracted with EtOAc (20 mL, 2x). The combined organic layers were washed with brine (20 mL, 2x), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting residue _was subjected _to preparative HPLC (column: Waters min) and directly lyophilized to produce the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-( 4-(methylsulfonyl)piperidin-1-yl)imidazo[1,2-a]pyridine-6-sulfonamide (2.13 mg, 3.78 μmol, 9.73% yield, 97% purity) as a light yellow solid. Obtained.

RT 0.679 min (Method 3); m/z 547.2 (M+H) ⁺ (ESI ⁺ ); ^1H NMR (CDCl ₃ , 400 MHz) 9.93 (d, J = 1.6 Hz, 1H), 8.20 (s, 1H), 6.96-7.26 (m, 2H), 5.09 (s, 1H), 4.53-4.65 ( m, 2H), 3.07-3.18 (m, 1H), 2.96-3.06 (m, 2H), 2.93 (s, 3H), 2.35-2.46 (m, 2H), 2.11-2.26 (m, 2H), 1.39 ( s, 3H), 0.90-0.97 (m, 2H), 0.57-0.65 (m, 2H).

Preparation of Example 51

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(4-(methylsulfinyl)piperidine -1-1) imidazo[1,2-a]pyridine-6-sulfonamide

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(4-(methyl) in DCM (0.5 mL) m-CPBA (11.24 mg, 55.38 μmol, 85% purity) was added to a solution of thio) piperidin-1-yl) imidazo [1,2-a] pyridine-6-sulfonamide (30 mg, 58.29 μmol). was added and the mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with Na ₂ S ₂ O ₃ (aq., sat., 20 mL) and extracted with EtOAc (20 mL*2). The combined organic layers were washed with brine (20 mL*2), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a residue, which was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 um; Mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 33%-63%, 10 min) and lyophilized to give product 3-(5-(difluoromethyl)-1,3,4. -thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(4-(methylsulfinyl)piperidin-1-yl)imidazo[1,2-a]pyridine-6 -Sulfonamide (5.96 mg, 11.10 μmol, 19.04% yield, 98.822% purity) was obtained as a yellow solid.

RT 0.679 min (Method 1); m/z 531.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz) 8.89 (d, J = 1.2 Hz, 1H), 8.17 (s, 1H), 7.23-6.96 (m, 2H), 5.34 (s, 1H), 4.52-4.44 (m , 2H), 3.13-3.06 (m, 1H), 2.86-2.84 (m, 2H), 2.64 (s, 3H), 2.34-2.33 (m, 1H), 2.10-2.02 (m, 3H), 1.36 (s) , 3H), 0.93-0.90 (m, 2H), 0.60-0.57 (m, 2H)

The compounds listed in the table below were prepared according to the corresponding general procedures or, where specified, starting from the corresponding intermediates or examples in a manner analogous to the relevant example. Note that one skilled in the art can select the correct intermediates and reaction conditions to obtain any compound listed in the table below (or in any other table of the present application for compound synthesis that references any general procedure).

Compound 55 appears to contain two isomers according to the following structure:

Preparation of Example 70a

Tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo [1,2-a]pyridin-8-yl)-3,6-dihydropyridine-1( 2H )-carboxylate

tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1 in n-BuOH (5 mL) (2H)-carboxylate (220.94 mg, 714.53 μmol), 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1 -Methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (200 mg, 476.35 μmol), mixture of CataCXium A-Pd-G ₃ and K ₃ PO ₄ aqueous solution (1.5 M, 317.57 μL) Degassed, purged with N ₂ (3x) and stirred at 60°C for 16 hours under N ₂ atmosphere. The mixture was cooled to 20°C, poured into water (20 mL) and filtered. The resulting solid was triturated with PE:EA=3:1 at 20° C. for 10 minutes. After filtration, the solid was dried under vacuum to obtain 170 mg of crude product. 10 mg of this crude product was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 54%-84% , 7 min) and directly lyophilized to give the product tert-butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N- (1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (6.05 mg, 10.68 μmol, 38.08 % yield, 100% purity) was obtained as a yellow solid.

RT 0.991 min (Method 1); m/z 567.2 (M+H) ⁺ (ES ⁺ ); ¹ H NMR (CDCl _3,400 MHz) 10.22 (d, J = 1.6 Hz, 1H), 8.28 (s, 1H), 7.67 (d, J = 1.6 Hz, 1H), 6.95-7.25 (m, 2H), 5.13 (s, 1H), 4.20-4.30 (m, 2H), 3.75 (t, J = 5.6 Hz, 2H), 2.70-2.80 (m, 2H), 1.52 (s, 9H), 1.37 (s, 3H) , 0.86-0.95 (m, 2H), 0.58-0.64 (m, 2H)

Preparation of Example 70

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(1,2,3,6-tetrahydro Pyridin-4-yl)imidazo[1,2-a]pyridine-6-sulfonamide

tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl) in DCM (2 mL) )Sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (150 mg, 264.72 μmol) in HCl/dioxane (4 M, 2 mL) was added and the mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give 90 mg of crude product. 15 mg of this crude product was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 10%-40%, 10 min ) and directly lyophilized to produce the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(1 ,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine-6-sulfonamide hydrochloride (3.69 mg, 7.91 μmol, 18.94% yield, 100% purity, HCl salt) Obtained as a yellow solid.

RT 0.767 min (Method 1); m/z 467.1 (M+H) ⁺ (ES ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz) 10.23 (d, J = 1.6 Hz, 1 H), 8.27 (s, 1 H), 7.70 (d, J = 1.6 Hz, 1 H), 6.98-7.27 (m, 2 H), 5.09-5.21 (m, 1 H), 3.72-3.78 (m, 2 H), 3.27 (t, J = 5.6 Hz, 2 H), 2.69-2.78 (m, 2 H), 1.38 (s) , 3 H), 0.90-0.94 (m, 2 H), 0.59-0.65 (m, 2 H).

Preparation of Example 71

4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo [1, 2-a]pyridin-8-yl)-N,N-dimethyl-3,6-dihydropyridin-1(2H)-carboxamide

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(1,2, In a solution of 3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine-6-sulfonamide (20 mg, 42.87 μmol), DIEA (11.08 mg, 85.74 μmol, 14.93 μL) and dimethyl Carbamic acid chloride (3.69 mg, 34.30 μmol, 3.15 μL) was added and the mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 44%-74%, 7min) Purified and directly lyophilized to produce the product 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl) Sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethyl-3,6-dihydropyridine-1(2H)-carboxamide (3.82 mg, 7.11 μmol, 16.57% Yield) was obtained as a white solid.

RT 0.620 min (Method 3); m/z 538.2 (M+H) ⁺ (ES ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz) 9.99 (d, J = 1.6 Hz, 1 H), 8.75 (s, 1 H), 8.45-8.55 (m, 1 H), 7.56-7.87 (m, 2) H), 7.40 (s, 1 H), 4.00 (d, J = 1.6 Hz, 2 H), 3.42-3.46 (m, 2H), 2.81 (s, 6 H), 2.70-2.80 (m, 3 H) , 1.14 (s, 3 H), 0.68-0.75 (m, 2 H), 0.43-0.50 (m, 2 H)

Preparation of Example 72

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-N -(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1] in DMF (1 mL) ,2-a]pyridine-6-sulfonamide (30 mg, 71.45 μmol) in a solution of K ₂ CO ₃ (39.50 mg, 285.81 μmol), Pd(dppf)Cl ₂ (5.23 mg, 7.15 μmol) and CuI (1.36 μmol). mg, 7.15 μmol) was added. The reaction mixture was degassed and purged with N ₂ (3x), then 2-methylbut-3-yn-2-ol (6.61 mg, 78.60 μmol, 7.68 μL) was added. The reaction mixture was then stirred at 100°C for 2 hours under N ₂ atmosphere and then concentrated under reduced pressure. The resulting residue was diluted with MeOH (3 mL), filtered and the filtrate was subjected to preparative HPLC (column: Phenomenex Synergi C18 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 34%-64%, 10 min) and directly lyophilized to give the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-( 3-hydroxy-3-methylbut-1-yn-1-yl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (7.42 mg, 15.87 μmol, 22.21% yield, 100% purity) was obtained as an off-white solid.

RT 0.980 min (Method 1); m/z 468.1 (M+H) ⁺ (ES ⁺ ); ¹ H NMR (400 MHz, DMSO -d ₆ ) 9.99 (d, J = 1.6 Hz, 1 H), 8.75 (s, 1 H), 8.37-8.62 (m, 1 H), 7.53-7.86 (m, 2 H), 5.73 (s, 1 H), 1.55 (s, 6 H), 1.15 (s, 3 H), 0.67-0.74 (m, 2 H), 0.41-0.49 (m, 2 H).

Preparation of Example 73

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-hydroxy-3-methylbutyl)-N-(1-methylcyclopropyl) Imidazo[1,2-a]pyridine-6-sulfonamide

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-hydroxy-3-methylbut-1-yne- in EtOH (1 mL) Pd/C (5 mg, 10% purity) in a solution of 1-yl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (10 mg, 21.39 μmol) was added under N ₂ . The suspension is degassed under vacuum; Purged with H ₂ (3x) and stirred at 20° C. for 2 hours under H ₂ (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Waters By direct lyophilization, the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-hydroxy-3-methylbutyl)-N-(1 -Methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (0.89 mg, 1.89 μmol, 8.82% yield, 100% purity) was obtained as a light yellow solid.

RT 0.889 min (Method 1); m/z 472.0 (M+H) ⁺ (ES ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) 10.16 (d, J = 1.6 Hz, 1 H), 8.27 (s, 1 H), 7.63 (s, 1 H), 7.105 (t, J = 53.2 Hz, 1 H ), 5.13 (s, 1 H), 3.20-3.30 (m, 2 H), 1.97-2.03 (m, 2 H), 1.36 (s, 9 H), 0.86-0.92 (m, 2 H), 0.55- 0.63 (m, 2 H).

Preparation of Example 74

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imidazo[1,2-a]pyridine -6-sulfonamide

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl) in MeOH (2 mL) Pd/C (25 mg, 114.20 μmol, 10% purity), DIEA (44.28 mg, 342.59 μmol, 59.67 μL) in a solution of imidazo[1,2-a]pyridine-6-sulfonamide (50 mg, 114.20 μmol) ) was added under N ₂ . The suspension was degassed under vacuum, purged with H ₂ (3x) and stirred at 20° C. under H ₂ (15 psi) for 24 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water; B: MeCN; B%: 29%-59%, 10 min) purified and directly lyophilized to produce the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imidazo [1,2-a]pyridine-6-sulfonamide (1.31 mg, 3.25 μmol, 2.84% yield, 100% purity) was obtained as a yellow solid.

RT 0.557 min (Method 3); m/z 403.9 (M+H) ⁺ (ES ⁺ ); ¹ H NMR (DMSO- d _6,400 MHz): 10.03 (s, 1H), 8.92 (br, 1H), 8.75 (s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.85-7.56 ( m, 2H), 4.235 (d, J = 48.8 Hz, 2H), 0.76- 0.85 (m, 4H).

Preparation of Intermediate 75.1

Ethyl 8-chloro-6-(chlorosulfonyl)imidazo[1,2-a]pyridine-3-carboxylate

Ethyl 6-(benzylthio)-8-chloroimidazo[1,2-a]pyridine-3-carboxylate (500 mg, 1.44 mmol), AcOH (329.80 μL, 5.77 mmol) in MeCN (5 mL); To a mixture of H ₂ O (103.89 μL, 5.77 mmol) was added sulfuryl dichloride (504.46 μL, 5.05 mmol) at 0°C. The mixture was stirred at 0° C. for 0.5 h, then diluted with DCM (30 mL), washed with ice-H ₂ O (30 mL), brine (30 mL), dried over Na ₂ SO ₄ and filtered. Concentration under reduced pressure at 20°C gave the product ethyl 8-chloro-6-(chlorosulfonyl)imidazo[1,2-a]pyridine-3-carboxylate (450 mg, 1.39 mmol, 96.59% yield) as a yellow oil. It was obtained as. The crude product was used directly in the next step without purification.

RT 0.724 min (Method 1); m/z 322.7 (M+H) ⁺ (ESI+)

Preparation of Example 75

Ethyl 8-chloro-6-(N-(1-cyanocyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3-carboxylate

A mixture of 1-aminocyclopropane-1-carbonitrile (165.11 mg, 1.39 mmol, HCl salt) in pyridine (561.99 μL, 6.96 mmol) with ethyl 8-chloro-6-(chlorosulfonyl) in THF (5 mL). Imidazo[1,2-a]pyridine-3-carboxylate (450 mg, 1.39 mmol) was added dropwise at 0°C. The mixture was stirred at 20° C. for 16 hours, then cooled to room temperature, quenched with H ₂ O (30 mL) and extracted with EtOAc (30 mL, 3x). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 30-60% ethyl acetate/petroleum ether @ 75 mL/min) and concentrated to give the product ethyl 8-chloro-6-( N-(1-Cyanocyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3-carboxylate (0.3 g, 813.46 μmol, 58.42% yield) was obtained as a white solid.

RT 0.834 min (Method 1); m/z 369.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d _6,400 MHz): 9.71 (d, J = 1.6 Hz, 1H), 9.67-9.39 (m, 1H), 8.51 (s, 1H), 7.95 (d, J = 1.6 Hz, 1H), 4.48-4.39 (m, 2H), 1.54-1.46 (m, 2H), 1.44-4.34 (m, 5H).

Preparation of Example 76

Ethyl 8-chloro-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3-carboxylate.

To a solution of 1-methylcyclopropan-1-amine (1.20 g, 11.14 mmol, HCl salt) in NaHCO ₃ (aq., sat., 30 mL) was added ethyl 8-chloro-6-(chloro) in THF (15 mL). Sulfonyl)imidazo[1,2-a]pyridine-3-carboxylate (1.8 g, 5.57 mmol) was added dropwise at 0°C. The mixture was stirred at 15°C for 2 hours and then quenched with H ₂ O (50 mL) and extracted with EtOAc (50 mL, 3x). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent 25-40% ethyl acetate/petroleum ether @ 100 mL/min) and concentrated to give the product ethyl 8-chloro-6. -(N-(1-Methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3-carboxylate (0.6 g, 1.68 mmol, 30.10% yield) was obtained as a white solid.

^1H NMR (DMSO- d _6,400 MHz): 9.62 (d, J = 1.6 Hz, 1H), 8.52 (s, 1H), 8.46 (s, 1H), 7.85-7.95 (m, 1H), 4.41 ( q, 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H), 1.16 (s, 3H), 0.65-0.74 (m, 2H), 0.40-0.52 (m, 2H).

Preparation of Intermediate 77.1

8-Chloro-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3-carboxylic acid

Ethyl 8-chloro-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3-carboxylate in MeOH (2 mL) and H ₂ O (2 mL) To a solution of (400 mg, 1.12 mmol), LiOH (160.63 mg, 6.71 mmol) was added in one portion. The reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was acidified to pH=4 with 1M aqueous hydrochloric acid solution. The white precipitate was filtered, collected and dried under reduced pressure to give the product 8-chloro-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3-carboxylic acid (280 mg, 679.28 μmol, 60.76% yield, 80% purity) was obtained as a yellow solid.

RT 0.559 min (Method 1); m/z 330.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.66 (s, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 7.88 (s, 1H), 1.15 (s, 3H), 0.64- 0.73 (m, 2H), 0.41-0.50 (m, 2H).

Preparation of Example 77

8-chloro-N-isobutyl-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3-carboxamide

A mixture of 8-chloro-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3-carboxylic acid (40 mg, 121.30 μmol) in DMF (1 mL) HATU (55.35 mg, 145.56 μmol) and DIPEA (31.35 mg, 242.60 μmol) were added. The mixture was stirred at 15°C for 10 minutes. Then, 2-methylpropan-1-amine (17.74 mg, 242.60 μmol) was added and the mixture was stirred at 15°C for 16 hours. The reaction mixture was cooled to room temperature, quenched with H ₂ O (30 mL) and extracted with EtOAc (30 mL, 3x). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO ₂ , petroleum ether: EtOAc = 0:1) to give the product 8-chloro-N-isobutyl-6-(N-(1-methylcyclopropyl)sulfamoyl)imide. Polyzo[1,2-a]pyridine-3-carboxamide (45 mg, 116.92 μmol, 96.39% yield) was obtained as a white solid.

¹ H NMR (DMSO- d ₆ , 400 MHz): 9.96 (d, J = 1.2 Hz, 1H), 8.78 (t, J = 5.2 Hz, 1H), 8.53 (s, 1H), 8.44 (s, 1H) , 7.80 (s, 1H), 3.15 (t, J = 6.4 Hz, 2H), 1.76-1.93 (m, 1H), 1.14 (s, 3H), 0.93 (d, J = 6.4 Hz, 6H), 0.68 ( s, 2H), 0.41-0.53 (m, 2H).

Preparation of Example 78

N-isobutyl-6-(N-(1-methylcyclopropyl)sulfamoyl)-8-(2-oxa-7-azaspiro[3.5]nonan-7-yl)imidazo[1,2-a] Pyridine-3-carboxamide

8-chloro-N-isobutyl-6-(N-(1-methylcyclopropyl) in a solution of 2-oxa-7-azaspiro[3.5]nonane (13.22 mg, 103.93 μmol) in dioxane (0.5 mL) Sulfamoyl)imidazo[1,2-a]pyridine-3-carboxamide (20 mg, 51.96 μmol), Cs ₂ CO ₃ (33.86 mg, 103.93 μmol) and Pd-PEPPSI-IPentCl o-picolin (2.24 mg, 2.60 μmol) was added in the glove box. The mixture was stirred under Ar outside the glove box for 16 hours at 90°C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with MeOH (3 mL), filtered, and the filtrate was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: A: 0.225% formic acid in water, B : MeCN; B%: 31%-61%, 7 min) and directly lyophilized to obtain the product N-isobutyl-6-(N-(1-methylcyclopropyl)sulfamoyl)-8-(2-oxa). -7-Azaspiro[3.5]nonan-7-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.53 mg, 1.10 μmol, 2.12% yield, 99% purity) was obtained as an off-white solid. did.

RT 0.867 min (Method 1); m/z 476.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.58 (s, 1H), 8.65 (t, J = 5.6 Hz, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 6.85 (s, 1H), 4.39 (s, 4H), 3.47-3.51 (m, 4H), 3.08-3.15 (m, 2H), 1.94-2.00 (m, 4H), 1.79-1.90 (m, 1H), 1.09 (s, 3H), 0.92 (d, J = 6.8 Hz, 6H), 0.61-0.71 (m, 2H), 0.37-0.45 (m, 2H).

Preparation of Example 79

Methyl 6-(N-(1-methylcyclopropyl)sulfamoyl)-8-(2-oxa-7-azaspiro[3.5]nonan-7-yl)imidazo[1,2-a]pyridine-3- carboxylate

Methyl 8-chloro-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3-carboxylate (30 mg, 87.26 μmol) in dioxane (0.5 mL) , 2-oxa-7-azaspiro[3.5]nonane (31.57 mg, 130.90 μmol, TFA salt), Cs ₂ CO ₃ (85.30 mg, 261.79 μmol), Pd-PEPPSI-IPentCl o-picolin (3.75 mg, 4.36 μmol) μmol) of the mixture was degassed and purged with N ₂ (3x). The reaction mixture was stirred at 100°C for 12 h under N ₂ atmosphere, then cooled to room temperature, diluted with H ₂ O (30 mL) and extracted with EtOAc (20 mL, 2x). The combined organic layers were washed with brine (30 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by preparative-TLC (SiO ₂ , petroleum ether/EtOAc = 2/1) to obtain the product methyl 6-(N-(1-methylcyclopropyl)sulfamoyl)-8-(2-oxa- 7-Azaspiro[3.5]nonan-7-yl)imidazo[1,2-a]pyridine-3-carboxylate (16 mg, 36.82 μmol, 42.20% yield) was obtained as a yellow solid.

RT 0.834 min (Method 1); m/z 435.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 9.43 (d, J = 1.6 Hz, 1H), 8.20 (s, 1H), 6.84 (d, J = 1.6 Hz, 1H), 4.88 (s, 1H), 4.45 (s, 4H), 3.90 (s, 3H), 3.38-3.46 (m, 4H), 2.01-2.13 (m, 4H), 1.24 (s, 3H), 0.73-0.81 (m, 2H), 0.45-0.51 (m, 2H)

Preparation of Example 80

Ethyl 8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3-carboxyl rate

To a solution of N,N-dimethylpiperazine-1-carboxamide (131.81 mg, 838.43 μmol) in dioxane (1 mL) was added ethyl 8-chloro-6-(N-(1-methylcyclopropyl)sulfamoyl). Imidazo[1,2-a]pyridine-3-carboxylate (100 mg, 279.48 μmol), Pd-PEPPSI-IPentCl o-picolin (12.03 mg, 13.97 μmol), Cs ₂ CO ₃ (182.12 mg, 558.95 μmol) was added in the glove box. The mixture was stirred under Ar ₂ at 100° C. outside the glove box for 2 hours. The mixture was quenched with cold water (50 mL) and extracted with EtOAc (50 mL, 3x). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by preparative-TLC (SiO ₂ , DCM/MeOH = 15/1) to obtain the product ethyl 8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N- (1-Methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3-carboxylate (100 mg, 188.06 μmol, 67.29% yield, 90% purity) was obtained as a brown oil.

RT 0.845 min (Method 1); m/z 479.3 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 9.54 (s, 1H), 8.26 (s, 1H), 6.91 (s, 1H), 5.02 (s, 1H), 3.47-3.42(q, 2 H), 3.61 -3.60 (m, 4H), 3.53-3.52 (m, 4H), 2.89 (s, 6H), 1.44(t, 3H),1.31 (s, 3H), 0.87-0.85 (m, 2H), 0.57-0.54 (m, 2H).

Preparation of Intermediate 81.1

8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3-carboxylic acid .

Ethyl 8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imi in MeOH (0.1 mL), H ₂ O (0.02 mL). LiOH·H ₂ O (2.37 mg, 56.42 μmol) was added to a solution of polyzo[1,2-a]pyridine-3-carboxylate (10 mg, 18.81 μmol). The mixture was stirred at 20°C for 3 hours. The pH of the reaction was then adjusted to 1-2 with 1M aqueous hydrochloric acid solution, and the solution was extracted with EtOAc (10 mL, 3x). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 20%-50%, 7 min) and directly By lyophilization, the product 8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3 -Carboxylic acid (3.45 mg, 7.66 μmol, 40.72% yield, 100% purity) was obtained as a yellow solid.

RT 0.794 min (Method 1); m/z 451.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.64 (s, 1H), 8.24-8.20 (m, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 6.84 (s, 1H), 3.56-3.55 (m, 4H), 3.30-3.33 (m, 4H), 2.79 (s, 6H), 1.10 (s, 3H), 0.69-0.66 (m, 2H), 0.43-0.40 (m, 2H).

Preparation of Example 81

Methyl 8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3-carboxyl rate

8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1] in MeOH (0.15 mL) and toluene (0.5 mL) ,2-a]TMSCHN ₂ (2 M, 22.20 μL) was added to a solution of pyridine-3-carboxylic acid (10 mg, 22.20 μmol). The mixture was stirred at 20° C. for 2 hours and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 28%-58%, 7 min) Direct freeze-drying yields the product methyl 8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine. -3-Carboxylate (5.36 mg, 11.54 μmol, 51.98% yield, 100% purity) was obtained as a yellow gum.

RT 0.856 min (Method 1); m/z 465.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 9.52 (s, 1H), 8.26 (s, 1H), 6.93 (s, 1H), 5.17 (s, 1H), 3.97 (s, 3H), 3.61-3.59 ( m, 4H), 3.52-3.51 (m, 4H), 2.88 (s, 6H), 1.31 (s, 3H), 0.86-0.83 (m, 2H), 0.56-0.53 (m, 2H).

Preparation of Example 82

8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-N-(oxetan-3-yl)imidazo [1, 2-a]pyridine-3-carboxamide

8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine in DMF (0.5 mL) DIEA (8.61 mg, 66.59 μmol, 11.60 μL) in a mixture of -3-carboxylic acid (20 mg, 44.39 μmol), oxetan-3-amine (3.89 mg, 53.27 μmol), and HATU (25.32 mg, 66.59 μmol). ) was added. The mixture was stirred at 20°C for 1 hour. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL, 3x). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting mixture was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm* 10μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 20%-50%, 10 min) and directly frozen. Dry to give the product 8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-N-(oxetan-3-yl)imidazo [1,2-a]pyridine-3-carboxamide (5.89 mg, 11.32 μmol, 25.50% yield, 97.180% purity) was obtained as a light yellow solid.

RT 0.770 min (Method 1); m/z 506.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.56 (d, J = 1.6 Hz, 1 H), 9.29 (d, J = 6.8 Hz, 1 H), 8.43 (s, 1 H), 8.27 (s , 1 H), 6.89 (d, J = 1.6 Hz, 1 H), 5.01-5.12 (m, 1 H), 4.81 (t, J = 6.8 Hz, 2 H), 4.62 (t, J = 6.48 Hz, 2 H), 3.53-3.60 (m, 4 H), 3.30-3.34 (m, 4 H), 2.79 (s, 6 H), 1.09 (s, 3 H), 0.61-0.71 (m, 2 H), 0.36-0.46 (m, 2H)

The compounds listed in the table below were prepared according to the corresponding general procedures or, where specified, starting from the corresponding intermediates or examples in a manner analogous to the relevant example.

Preparation of Intermediate 96.1

6-Amino-5-bromo-pyridine-3-sulfonyl chloride

Two batches were run in parallel and combined for post-processing.

A solution of 3-bromopyridin-2-amine (10 g, 57.80 mmol) in sulfurochloric acid (67.35 g, 578.00 mmol, 38.49 mL) was stirred at 140°C for 1 hour. The reaction mixture was cooled to 0°C and poured into ice-water (500 mL). The resulting mixture (two batches combined together) was filtered. The solid was collected, dried under reduced pressure and triturated with petroleum ether: EtOAc (1:1, 100 mL) at 20°C for 2 hours. The mixture was then filtered and the solid was collected and dried under reduced pressure. The crude compound was triturated with HCl/dioxane (4N, 110 mL) at 20°C for 1 hour and filtered to obtain the product 6-amino-5-bromo-pyridine-3-sulfonyl chloride (26.5 g, 97.11 mmol, 72.91 % yield, 99.5% purity) was obtained as a white solid.

RT 0.817 min (Method 1); m/z 272.9 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 8.25 (d, J = 1.6 Hz. 1H), 8.12 (d, J = 1.6 Hz. 1H).

Preparation of Intermediate 96.2

6-Amino-5-bromo-N-(1-methylcyclopropyl)pyridine-3-sulfonamide

Two batches were run in parallel and combined for post-processing.

To a mixture of 6-amino-5-bromo-pyridine-3-sulfonyl chloride (12.9 g, 47.51 mmol) in DCM (130 mL) was added TEA (14.42 g, 142.53 mmol, 19.84 mL) at 0°C. Then, 1-methylcyclopropan-1-amine (5.62 g, 52.26 mmol, HCl salt) was added in portions. The reaction mixture was stirred at 15°C for 1 hour and concentrated under reduced pressure. The residue (two batches) was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 4/5) to give the product 6-amino-5-bromo-N-(1-methyl Cyclopropyl)pyridine-3-sulfonamide (22 g, 68.19 mmol, 71.76% yield, 94.9% purity) was obtained as a white solid.

RT 0.735 min (Method 1); m/z 305.9 (M+H) ⁺ (ESI+); ¹ H NMR (DMSO- d ₆ , 400 MHz): 8.27 (d, J= 2.0 Hz. 1H), 7.92 (d, J= 2.0 Hz. 1H), 7.85 (s, 1H), 7.16 (br, 2H) , 1.09 (s, 3H), 0.62 (t, J= 4.8 Hz. 2H), 0.40 (t, J= 5.2 Hz, 2H).

Preparation of Intermediate 96.3

8-Bromo-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide

6-Amino-5-bromo-N-(1-methylcyclopropyl)pyridine-3-sulfonamide (12) in 2-chloroacetaldehyde/H ₂ O (260.27 g, 1.33 mol, 213.34 mL, 40% purity) g, 39.19 mmol) was stirred at 100°C for 1 hour. The resulting mixture was cooled to room temperature and diluted with H ₂ O (300 mL). The mixture was extracted with EtOAc (200 mL, 3x). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na ₂ SO ₄ , filtered and dried under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 4/5) to produce the product 8-bromo-N-(1-methylcyclopropyl)imidazo[1,2-a. ]Pyridine-6-sulfonamide (12.9 g, 39.07 mmol, 99.68% yield, 100% purity) was obtained as a white solid.

RT 0.628 min (Method 1); m/z 329.9 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.25 (d, J = 1.6 Hz, 1H), 8.32 (s, 1H), 8.25 (d, J = 1.2 Hz, 1H), 7.77 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 1.13 (s, 3H), 0.67 (t, J = 4.8 Hz. 2H), 0.44 (t, J = 5.2 Hz, 2H).

Preparation of intermediate 96.4

N,N-dimethyl-4-(6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)piperazine-1-carboxamide

To a solution of N,N-dimethylpiperazine-1-carboxamide (476.11 mg, 3.03 mmol) in dioxane (5 mL) was added 8-bromo-N-(1-methylcyclopropyl)imidazo[1,2. -a]pyridine-6-sulfonamide (0.5 g, 1.51 mmol), Cs ₂ CO ₃ (986.73 mg, 3.03 mmol) and Pd-PEPPSI-IPentCl (65.15 mg, 75.71 μmol) were added in the glove box. The mixture was then stirred under Ar outside the glove box for 2 hours at 100°C. The reaction mixture was cooled to room temperature, quenched with H ₂ O (50 mL) and extracted with EtOAc (50 mL; 3x). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 60-100% ethyl acetate/petroleum @ 75 mL/min) to give the product N,N-dimethyl-4-(6- (N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)piperazine-1-carboxamide (0.3 g, 738.00 μmol, 48.74% yield) was obtained as a brown solid. It was obtained as.

RT 0.716 min (Method 1); m/z 407.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO-d ₆ , 400 MHz): 8.76 (s, 1H), 8.16 (s, 1H), 8.10 (d, J = 1.2 Hz, 1H), 7.61 (d, J = 1.2 Hz, 1H) , 6.66 (s, 1H), 3.60-3.56 (m, 4H), 3.32-3.28 (m, 4H), 2.80 (s, 6H), 1.11 (s, 3H), 0.71-0.65 (m, 2H), 0.37 -0.44 (m, 2H).

Preparation of Intermediate 96.5

4-(3-iodo-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-car Voxamide

N,N-dimethyl-4-(6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)piperazine-1- in MeCN (30 mL) To a solution of carboxamide (2.75 g, 6.77 mmol) was added a solution of NIS (1.67 g, 7.44 mmol) in MeCN (20 mL) at 0°C. The reaction mixture was stirred at 15°C for 0.5 hours and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Phenomenex luna C18 150*40mm* 15 μm; mobile phase: A: 0.225% formic acid in water; B: MeCN; B%: 37%-67%, 10 min) The impure product was obtained, which was further purified by flash silica gel column (ISCO®; 24 g SepaFlash® silica flash column, eluent 50-100% ethyl acetate/petroleum ether gradient @ 45 mL/min) to give product 4- (3-iodo-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide (2.1 g, 3.94 mmol, 58.31% yield, 100% purity) was obtained as an off-white solid.

RT 0.673 min (Method 1); m/z 533.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 8.44 (d, J = 1.2 Hz, 1H), 7.72 (s, 1H), 6.72 (s, 1H), 5.04 (s, 1H), 3.70-3.55 (m, 4H), 3.54-3.45 (m, 4H), 2.89 (s, 6H), 1.32 (s, 3H), 0.85 (t, J = 6.4 Hz, 2H), 0.56 (t, J = 6.4 Hz, 2H)

Preparation of Intermediate 96.6

4-(3-bromo-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-car Voxamide

Intermediate 96.2 was prepared according to General Procedure 3 and obtained in 29.86% yield.

RT 0.759 min (Method 1); m/z 487.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 8.33 (s, 1H), 8.21 (s, 1H), 7.82 (s, 1H), 6.79 (s, 1H), 3.62 (s, 4H), 3.33 ( s, 4H), 2.80 (s, 6H), 1.12 (s, 3H), 0.61 -0.72 (m, 2H), 0.39-0.47 (m, 2H).

Preparation of Intermediate 96.7

tert-butyl ((3-bromo-8-(4-(dimethylcarbamoyl)piperazin-1-yl)imidazo[1,2-a]pyridin-6-yl)sulfonyl)(1-methyl Cyclopropyl)carbamate

4-(3-Bromo-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethyl in DCM (1.5 mL) To a mixture of piperazine-1-carboxamide (100 mg, 206.02 μmol), Boc ₂ O (67.44 mg, 309.03 μmol, 70.99 μL) and DMAP (5.03 mg, 41.20 μmol) were added sequentially. The reaction mixture was stirred at 20°C for 2 hours and concentrated under reduced pressure. The resulting residue was purified by preparative-TLC (SiO ₂ , PE: EA = 0:1) to obtain the product tert-butyl ((3-bromo-8-(4-(dimethylcarbamoyl)piperazine-1 -yl) imidazo [1,2-a] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamate (71 mg, 119.43 μmol, 57.97% yield, 98.49% purity) as a colorless oil. Obtained.

RT 0.811 min (Method 1);m/z 585.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 8.51 (s, 1H), 7.64 (s, 1H), 6.79 (s, 1H), 3.70-3.60 (m, 4H), 3.60-3.50 (m, 4H), 2.89 (s, 6H), 1.59 (s, 3H), 1.41 (s, 9H), 1.12- 0.94 (m, 4H).

Preparation of intermediate 96.8

tert-Butyl ((8-(4-(dimethylcarbamoyl)piperazin-1-yl)-yl)-3-(5-methylpyridin-2-yl)imidazo[1,2-a]pyridine- 6-yl)sulfonyl)(1-methylcyclopropyl)carbamate

tert-Butyl ((3-bromo-8-(4-(dimethylcarbamoyl)piperazin-1-yl)imidazo[1,2-a]pyridin-6-yl) in dioxane (1 mL) 2-(dibutyl(pentyl)stannyl)-5-methylpyridine (23.50 mg, 61.48 μmol) in a solution of sulfonyl)(1-methylcyclopropyl)carbamate (12 mg, 20.49 μmol), K ₂ CO ₃ (5.67 mg, 40.99 μmol) and Pd(PPh ₃ ) ₄ (2.37 mg, 2.05 μmol) were added successively. The reaction mixture was degassed, purged with N ₂ (3x) and stirred at 80° C. for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative-HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 58%-88%, 10 min). Purification product tert-butyl ((8-(4-(dimethylcarbamoyl)piperazin-1-yl)-3-(5-methylpyridin-2-yl)imidazo[1,2-a]pyridine- 6-yl)sulfonyl)(1-methylcyclopropyl)carbamate (12 mg, 20.08 μmol, 97.96% yield, 100% purity) was obtained as an off-white solid.

RT 1.003 min (Method 1); m/z 598.3 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 10.28 (d, J = 1.2 Hz, 1H), 8.51 (s, 1H), 8.07 (s, 1H), 7.65 (d, J = 8 Hz, 1H), 7.58 (dd, J = 2.0 Hz, J = 8 Hz, 1H), 6.93 (d, J = 1.2 Hz, 1H), 3.65-3.50 (m, 8H), 2.90 (s, 6H), 2.40 (s, 3H) , 1.64 (s, 3H), 1.34 (s, 9H), 1.25-1.24 (m, 2H), 1.10-0.95 (m, 2H).

Preparation of Example 96

N,N-dimethyl-4-(6-(N-(1-methylcyclopropyl)sulfamoyl)-3-(5-methylpyridin-2-yl)imidazo[1,2-a]pyridine-8- 1) Piperazine-1-carboxamide

tert-Butyl ((8-(4-(dimethylcarbamoyl)piperazin-1-yl)-3-(5-methylpyridin-2-yl)imidazo[1,2-a) in DCM (3 mL) ] To a solution of pyridin-6-yl)sulfonyl)(1-methylcyclopropyl)carbamate (12 mg, 20.08 μmol) was added TFA (1.54 g, 13.51 mmol). The reaction mixture was stirred at 15°C for 1 hour and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 35%-65%, 9 min) to obtain the product. N,N-dimethyl-4-(6-(N-(1-methylcyclopropyl)sulfamoyl)-3-(5-methylpyridin-2-yl)imidazo[1,2-a]pyridine-8- 1) Piperazine-1-carboxamide (1.63 mg, 3.26 μmol, 16.24% yield, 99.55% purity) was obtained as an off-white solid.

RT 0.692 min (Method 1); m/z 498.3 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 10.18 (d, J = 1.6 Hz, 1H), 8.56 (s, 1H), 8.05 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.60 (dd, J = 1.6 Hz, J = 8.4 Hz, 1H), 6.81 (d, J = 1.2 Hz, 1H), 5.0 (s, 1H), 3.65-3.55 (m, 4H), 3.55-3.48 (m, 4H), 2.90 (s, 6H), 2.40 (s, 3H), 1.33 (s, 3H), 0.91 (t, J = 6 Hz, 2H), 0.56 (t, J = 6 Hz, 2H).

Preparation of Example 97

N,N-dimethyl-4-(6-(N-(1-methylcyclopropyl)sulfamoyl)-3-(6-methylpyridin-3-yl)imidazo[1,2-a]pyridine-8- 1) Piperazine-1-carboxamide

4-(3-bromo-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-8 in dioxane (1.5 mL) and H ₂ O (0.3 mL) -yl)-N,N-dimethylpiperazine-1-carboxamide (15 mg, 30.90 μmol), (6-methyl-3-pyridyl)boronic acid (8.46 mg, 61.81 μmol) and Cs ₂ CO ₃ ( Xantphos Pd G4 (5.95 mg, 6.18 μmol) was added to the solution (20.14 mg, 61.81 μmol). The reaction mixture was degassed and purged with N ₂ (3x), stirred at 80° C. for 16 hours and then concentrated under reduced pressure. The resulting residue was subjected to preparative-HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water; B: MeCN; B%: 19%-49%; 10 min) Purified product N,N-dimethyl-4-(6-(N-(1-methylcyclopropyl)sulfamoyl)-3-(6-methylpyridin-3-yl)imidazo[1,2-a]pyridine -8-yl)piperazine-1-carboxamide (6.93 mg, 13.79 μmol, 44.62% yield, 99.01% purity) was obtained as a white solid.

RT 0.722 min (Method 1); m/z 498.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 8.69 (s, 1H), 8.42 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.37 (d, J = 8.0,1H), 6.68 (s, 1H), 4.97 (s, 1H), 3.75-3.60 (m, 4H), 3.58-3.48 (m, 4H), 2.90 (s, 6H), 2.69 (s, 3H) , 1.30 (s, 3H), 0.82 (t, J = 6.0 Hz, 2H), 0.53 (t, J = 6.4 Hz, 2H).

Preparation of Example 98

4-(3-ethyl-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carbox amides

N,N-dimethyl-4-(6-(N-(1-methylcyclopropyl)sulfamoyl)-3-vinylimidazo[1,2-a]pyridin-8-yl) in THF (2 mL) To a solution of piperazine-1-carboxamide (5 mg, 11.56 μmol) was added Pd/C (2 mg, 10% purity) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ (3x). The mixture was stirred under H ₂ (15 psi) at 20° C. for 3 hours and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative-HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: A: 0.225% formic acid in water; B: MeCN; 18%-48%, 10 min). Purified product 4-(3-ethyl-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethylpiperazine-1 -Carboxamide (2.98 mg, 6.86 μmol, 59.32% yield, 100% purity) was obtained as an off-white solid.

RT 0.663 min (Method 1); m/z 435.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 8.22 (d, J = 1.2 Hz, 1H), 7.42 (s, 1H), 6.61 (d, J = 1.2 Hz, 1H), 5.08 (s, 1H), 3.70 -3.60 (m, 4H), 3.60-3.47 (m, 4H), 2.95- 2.80 (s, 8H), 1.42 (t, J = 7.6 Hz, 3H), 1.29 (s, 3H), 0.83 (t, J = 5.6 Hz, 2H), 0.52 (t, J = 5.2 Hz, 2H).

Preparation of Example 99

N,N-dimethyl-4-(3-(3-methylbut-1-yn-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a] Pyridin-8-yl)piperazine-1-carboxamide

4-(3-Bromo-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethyl in DMF (1.5 mL) CuI (588.54 μg, 3.09 μmol), K ₂ CO ₃ (17.08 mg, 123.61 μmol) and Pd(PPh ₃ ) ₂ Cl ₂ (2.17 mg) in a solution of piperazine-1-carboxamide (15 mg, 30.90 μmol). , 3.09 μmol) was added. The reaction mixture was degassed and purged with N ₂ (3x). 3-Methylbut-1-yne (2.32 mg, 33.99 μmol, 3.48 μL) was then added to the mixture via injection syringe. The reaction mixture was stirred at 110° C. for 16 hours under N ₂ atmosphere, then poured into water (5 mL) and extracted with EtOAc (5 mL, 3x). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was subjected to preparative-HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: A: 0.225% formic acid in water; B: MeCN; B%: 48%-78%, 7 min) to produce the product N,N-dimethyl-4-(3-(3-methylbut-1-yn-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[ 1,2-a]pyridin-8-yl)piperazine-1-carboxamide (3.35 mg, 7.09 μmol, 22.94% yield, 100% purity) was obtained as an off-white solid.

RT 0.849 min (Method 1); m/z 473.3 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 8.50 (d, J = 1.6 Hz, 1H), 7.73 (s, 1H), 6.67 (d, J = 1.6 Hz, 1H), 4.93 (s, 1H), 3.70 -3.58 (m, 4H), 3.58-3.45 (m, 4H), 3.00- 2.92 (m, 1H), 2.89 (s, 6H), 1.36 (d, J = 6.8 Hz, 6H), 1.32 (s, 3H) ), 0.86 (t, J = 6.0 Hz, 2H), 0.55 (t, J = 5.2 Hz, 2H).

Preparation of Intermediate 100.1

N,N-dimethyl-4-(6-(N-(1-methylcyclopropyl)sulfamoyl)-3-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridin-8-yl) Piperazine-1-carboxamide

4-(3-iodo-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethyl in DMF (2 mL) CuI (1.61 mg, 8.45 μmol), DIPEA (5.46 mg, 42.26 μmol, 7.36 μL) and Pd(PPh ₃ ) ₄ (1.63 mg, 1.41 μL) were added to a solution of piperazine-1-carboxamide (15 mg, 28.17 μmol). μmol) was added. The reaction mixture was degassed and purged with N ₂ (3x). Ethynyltrimethylsilane (3.32 mg, 33.81 μmol, 4.68 μL) was then added to the mixture via injection syringe. The mixture was stirred at 80° C. for 4 hours under N ₂ atmosphere, then poured into water (10 mL) and extracted with EtOAc (5 mL, 3x). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was subjected to preparative-HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water; B: MeCN; B%: 54%-84%, 10 min) Purified product N,N-dimethyl-4-(6-(N-(1-methylcyclopropyl)sulfamoyl)-3-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridine-8 -yl)piperazine-1-carboxamide (12 mg, 20.29 μmol, 72.02% yield, 85% purity) was obtained as a brown solid.

RT 0.938 min (Method 1); m/z 503.3 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 8.52 (d, J = 1.2 Hz, 1H), 7.84 (s, 1H), 6.73 (s, 1H), 4.96 (s, 1H), 3.70-3.58 (m, 4H), 3.58-3.45 (m, 4H), 2.89 (s, 6H), 1.32 (s, 3H), 0.90-0.80 (m, 2H), 0.60-0.50 (m, 2H), 0.08 (s, 9H) .

Preparation of Example 100

4-(3-ethynyl-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-car Voxamide

N,N-dimethyl-4-(6-(N-(1-methylcyclopropyl)sulfamoyl)-3-((trimethylsilyl)ethynyl)imidazo[1,2-a] in MeOH (0.5 mL) To a solution of pyridin-8-yl)piperazine-1-carboxamide (6 mg, 11.94 μmol) was added K ₂ CO ₃ (4.95 mg, 35.81 μmol). The reaction mixture was stirred at 20°C for 2 hours and concentrated under reduced pressure. The resulting residue _was subjected _to preparative-HPLC (column: Waters 8 min) to obtain the product 4-(3-ethynyl-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N- Dimethylpiperazine-1-carboxamide (0.65 mg, 1.51 μmol, 12.65% yield, 100% purity) was obtained as an off-white gum.

RT 0.814 min (Method 1); m/z 431.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 8.56 (d, J = 1.2 Hz, 1H), 7.86 (s, 1H), 6.72 (s, 1H), 4.98 (s, 1H), 3.85 (s, 1H) , 3.70-3.60 (m, 4H), 3.58-3.45 (m, 4H), 2.89 (s, 6H), 1.32 (s, 3H), 0.85 (t, J = 5.6 Hz, 2H), 0.56 (t, J = 6.0 Hz, 2H).

Preparation of Example 101

N,N-dimethyl-4-(6-(N-(1-methylcyclopropyl)sulfamoyl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine- 8-day) piperazine-1-carboxamide

4-(3-iodo-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N- in dioxane (2 mL) CuI (715.44 ug, 3.76 μmol), TEA (727.00 mg, 7.18 mmol) and Pd ₂ (dba) ₃ (3.44 mg, 3.76 μmol) in a solution of dimethylpiperazine-1-carboxamide (20 mg, 37.57 μmol). was added. The reaction mixture was degassed and purged with N ₂ (3x). Prop-1-yne (1 M in THF, 45.08 μL) was then added. The reaction mixture was stirred at 20°C for 16 h under N ₂ , poured into water (10 mL) and extracted with EA (10 mL, 3x). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative-HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water; B: MeCN; B%: 42%-72%; 10 min) Product N,N-dimethyl-4-(6-(N-(1-methylcyclopropyl)sulfamoyl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine -8-yl)piperazine-1-carboxamide (15 mg, 33.74 μmol, 89.82% yield, 100% purity) was obtained as a white solid.

RT 0.825 min (Method 1); m/z 445.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 8.54 (d, J = 1.2 Hz, 1H), 7.73 (s, 1H), 6.67 (d, J = 1.2 Hz, 1H), 5.01 (s, 1H), 3.70 -3.55 (m, 4H), 3.55-3.45 (m, 4H), 2.89 (s, 6H), 2.24 (s, 3H), 1.31 (s, 3H), 0.84 (t, J = 6.0 Hz, 2H), 0.55 (t, J = 6.4 Hz, 2H).

Preparation of Example 102

N,N-dimethyl-4-(6-(N-(1-methylcyclopropyl)sulfamoyl)-3-propylimidazo[1,2-a]pyridin-8-yl)piperazine-1-car Voxamide

N,N-dimethyl-4-(6-(N-(1-methylcyclopropyl)sulfamoyl)-3-(prop-1-yn-1-yl)imidazo[1, To a solution of 2-a]pyridin-8-yl)piperazine-1-carboxamide (8 mg, 18.00 μmol) was added Pd/C (4 mg, 10% purity) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ (3x). The mixture was stirred under H2 (15 psi) at 20° C. for 3 hours, then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative-HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water; B: MeCN; B%: 25%-55%; 10 min) Purification resulted in the product N,N-dimethyl-4-(6-(N-(1-methylcyclopropyl)sulfamoyl)-3-propylimidazo[1,2-a]pyridin-8-yl)piperazine- 1-Carboxamide (4.05 mg, 9.03 μmol, 50.17% yield, 100% purity) was obtained as an off-white solid.

RT 0.746 min (Method 1); m/z 449.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 8.23 (s, 1H), 7.42 (s, 1H), 6.60 (s, 1H), 5.00 (s, 1H), 3.70-3.55 (m, 4H), 3.55- 3.45 (m, 4H), 2.89 (s, 6H), 2.84 (t, J =7.2 Hz , 2H), 1.90-1.75 (m, 2H), 1.29 (s, 3H), 1.06 (t, J = 7.6 Hz) , 3H), 0.84 (t, J = 6.0 Hz, 2H), 0.52 (t, J = 6.4 Hz, 2H).

Preparation of Example 103

N,N-dimethyl-4-(6-(N-(1-methylcyclopropyl)sulfamoyl)-3-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)piperazine -1-carboxamide

4-(3-iodo-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethyl in DMF (1 mL) Diphenyl(trifluoromethyl)sulfonium;trifluoromethanesulfonate (6.84 mg, 16.90 μmol) and copper (1.43 mg, 22.54 μmol) in a solution of piperazine-1-carboxamide (6 mg, 11.27 μmol). ) was added. The reaction mixture was stirred at 60° C. under N ₂ for 2 hours, then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: A: 0.225% formic acid in water; B: MeCN; B%: 41%-71%; 10 min ) and purified to produce the product N,N-dimethyl-4-(6-(N-(1-methylcyclopropyl)sulfamoyl)-3-(trifluoromethyl)imidazo[1,2-a]pyridine-8 -yl)piperazine-1-carboxamide (1.55 mg, 3.27 μmol, 28.99% yield, 100% purity) was obtained as a yellow gum.

RT 0.908 min (Method 1); m/z 475.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 8.44 (s, 1H), 7.96 (s, 1H), 6.80 (s, 1H), 5.00 (s, 1H), 3.70-3.60 (m, 4H), 3.60- 3.45 (m, 4H), 2.90 (s, 6H), 1.33 (s, 3H), 0.84 (t, J = 6.0 Hz, 2H), 0.57 (t, J = 6.0 Hz, 2H).

The compounds listed in the table below were prepared according to the corresponding general procedures or, where specified, starting from the corresponding intermediates or examples in a manner analogous to the relevant example.

Alternative Preparation of Intermediate 10.7

2-(6-(benzylthio)-8-chloro-1-iodoindolizin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole

2-(6-(benzylthio)-8-chloroindolizin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (700 mg, 172 mg) in ACN (10 mL) NIS (42472 mg, 1.89 mmol) was added to the solution of (mmol). The mixture was stirred at 50° C. for 2 hours and concentrated under vacuum. The crude product was triturated with MeOH (10 mL) at 20°C for 5 min and the precipitate was filtered. The cake was dried under vacuum to give the product 2-(6-(benzylthio)-8-chloro-1-iodoindolizin-3-yl)-5-(difluoromethyl)-1,3,4-thiadia. The sol (700 mg, 1.31 mmol, 76.41% yield) was obtained as a yellow solid.

RT 0.812 min (Method 3); m/z 533.8 (M+H) ⁺ (ESI ⁺ ).

Preparation of Intermediate 113.1

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazoline-6-sulfonyl chloride and 1,8-dichloro -3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazoline-6-sulfonyl chloride

2-(6-(benzylthio)-8-chloro-1-iodoindolizin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole in ACN (3 mL) 1,3-dichloro-5,5-dimethyl-imida in a solution of (250 mg, 468.35 μmol), AcOH (112.50 mg, 1.87 mmol, 107.15 μL) and H ₂ O (33.75 mg, 1.87 mmol, 33.75 μL). Zolidine-2,4-dione (276.82 mg, 1.41 mmol) was added at 0°C. The reaction was stirred at 0° C. for 15 minutes to dissolve 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodimidazoline-6. -Obtain a mixture of sulfonyl chloride and 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazoline-6-sulfonyl chloride and was used directly in the next step.

Preparation of Intermediate 113.2

8-chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazoline- 6-sulfonamide and 1,8-dichloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imida Jolin-6-sulfonamide

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazoline-6-sulfonyl chloride and 1,8-dichloro A mixture of -3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazoline-6-sulfonyl chloride was dissolved in Py (1 mL) and MeCN (3 mL). It was added dropwise to a solution of 1-aminocyclopropanecarbonitrile hydrochloride (165.96 mg, 1.40 mmol) at 0°C. The mixture was allowed to warm to 20° C., stirred for 1 hour, and poured into HCl solution (1 N, 30 mL). The aqueous phase was extracted with ethyl acetate (10 mL, 2x). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent 0-25% ethyl acetate/petroleum ether gradient @ 12 mL/min) to give the product 8-chloro-N-(1- Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazoline-6-sulfonamide and 1,8- Dichloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazoline-6-sulfonamide (130 mg , crude) was obtained as a yellow solid.

RT 0.890 min (Method 1); m/z 555.9 & 463.9 (M+H) ⁺ (ESI ⁺ ).

Preparation of Examples 113 and 114

4-(6-(N-(1-cyanocyclopropyl)sulfamoyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)indolizine-8 -yl)-N,N-dimethylpiperazine-1-carboxamide and 4-(1-chloro-6-(N-(1-cyanocyclopropyl)sulfamoyl)-3-(5-(difluoro Romethyl)-1,3,4-thiadiazol-2-yl)indolizin-8-yl)-N,N-dimethylpiperazine-1-carboxamide

8-Chloro-N-(1-cyanocyclopropyl)-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1 in dioxane (1 mL) -iodo-imidazoline-6-sulfonamide and 1,8-dichloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadia Zol-2-yl)imidazoline-6-sulfonamide (100 mg, crude), N,N-dimethylpiperazine-1-carboxamide (31.12 mg, 197.93 μmol), Cs ₂ CO ₃ (117.25 mg , 359.88 μmol) and Pd-PEPPSI-IPentCl o-picolin (17.50 mg, 17.99 μmol) were degassed and purged with Ar ₂ (3x) in a glove box. The mixture was then stirred outside the glove box under Ar atmosphere at 80°C for 26 hours. The mixture was filtered and the mother liquor was concentrated in vacuo. The resulting residue was purified by preparative TLC (SiO ₂ , petroleum ether:ethyl acetate=1:1) to give two impure products.

Impure product 1 was purified by preparative TLC (SiO ₂ , petroleum ether: ethyl acetate = 0:1) and directly lyophilized to give product 4-(6-(N-(1-cyanocyclopropyl)sulfamoyl). -3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)indolizin-8-yl)-N,N-dimethylpiperazine-1-carboxamide (2.3 mg, 4.12 μmol, 2.29% yield, 98.511% purity) was obtained as a yellow solid.

RT 0.585 min (Method 3); m/z 551.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.97 (s, 1H), 9.32 (br, 1H), 7.84 (d, J = 4.4 Hz, 1H), 7.52-7.79 (m, 1H), 6.96 ( d, J = 4.8 Hz, 1H), 6.79 (s, 1H), 3.36-3.38 (m, 4H), 3.22 (s, 4H), 2.80 (s, 6H), 1.44-1.49 (m, 2H), 1.35 -1.40 (m, 2H)

The impure product 2 was subjected to preparative HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 42%-72%, 10 min), followed by 10 min. Purified by HPLC _{( column} : Waters The product 4-(1-chloro-6-(N-(1-cyanocyclopropyl)sulfamoyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2- I)indolizin-8-yl)-N,N-dimethylpiperazine-1-carboxamide (1.73 mg, 2.96 μmol, 1.64% yield, 99.99% purity) was obtained as a yellow solid.

RT 0.587 min (Method 3); m/z 585.0 (M+H) ⁺ (ESI ⁺ ); iH NMR (DMSO- d ₆ , 400 MHz): 9.98 (s, 1H), 9.06-9.19 (m, 1H), 7.90 (s, 1H), 7.46-7.74 (m, 1H), 6.91 (s, 1H) , 3.41 (s, 4H), 3.08-3.12 (m, 4H), 2.82 (s, 6H), 1.44-1.46 (m, 2H), 1.39-1.41 (m, 2H).

Preparation of Example 115

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodo-N-(1-methylcyclopropyl)imidazoline-6 -Sulfonamides

8-chloro-3-(5-(difluoromethyl)-1,3 in a solution of 1-methylcyclopropanamine (30.05 mg, 279.35 μmol, HCl salt) in NMP (0.5 mL) and pyridine (0.5 mL) ,4-thiadiazol-2-yl)-1-iodoimidazoline-6-sulfonyl chloride and 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4- The crude product of thiadiazol-2-yl)imidazoline-6-sulfonyl chloride (95 mg, crude) was added at 0°C. The reaction was stirred at 20°C for 2 hours and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 61%-91%, 10 min) and directly By lyophilization, the product 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodo-N-(1-methylcyclopropyl)imi Dazoline-6-sulfonamide (25 mg, 45.89 μmol, 24.64% yield) was obtained as a brown solid.

RT 0.668 min (Method 3); m/z 544.8 (M+H)+ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz,): 10.19 (d, J = 1.2 Hz, 1H), 8.45 (s, 1H), 8.18 (s, 1H), 7.82 -7.66 (m, 1H), 7.43 (d, J = 1.2 Hz, 1H), 1.18 -1.16 (m, 3H), 0.73 -0.68 (m, 2H), 0.48 -0.43 (m, 2H).

Preparation of Example 116

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazoline-6-sulfonamide

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodo-N-(1-methylcyclopropyl) in MeOH (0.5 mL) ) Pd/C (5 mg, 10% purity) was added to a solution of imidazoline-6-sulfonamide (23 mg, 42.22 μmol). The mixture was degassed, purged with H ₂ (3x) and stirred under H ₂ (15 Psi) at 20° C. for 16 hours. The mixture was filtered to remove insoluble matter and the filtrate was concentrated under vacuum to give the product 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N- (1-Methylcyclopropyl)imidazoline-6-sulfonamide (10 mg, 23.87 μmol, 56.55% yield) was obtained as a gray solid.

RT 0.625 min (Method 3); m/z 418.9 (M+H) ⁺ (ESI ⁺ ).

Preparation of Example 117

4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)indolizine-8- I)-N,N-dimethylpiperazine-1-carboxamide

N,N-dimethylpiperazine-1-carboxamide (7.51 mg, 47.75 μmol), 8-chloro-3-(5-(difluoromethyl)-1,3,4- in dioxane (0.5 mL) Thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazoline-6-sulfonamide (10 mg, 23.87 μmol), Cs ₂ CO ₃ (15.56 mg, 47.75 μmol) and Pd-PEPPSI- A mixture of IPentCl o-picolin (1 mg, 1.03 μmol) was degassed and purged with Ar (3x) in a glove box. The mixture was then stirred outside the glove box under Ar atmosphere at 100°C for 16 hours and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*30 mm*5 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 40%-70%, 8 min) and directly By lyophilization, the product 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)indole Lysin-8-yl)-N,N-dimethylpiperazine-1-carboxamide (1.28 mg, 2.32 μmol, 9.74% yield, 98% purity) was obtained as a yellow solid.

RT 0.575 min (Method 3); m/z 540.1 (M+H)+ (ESI+); ¹ H NMR (DMSO- d ₆ , 400 MHz,): 9.89 (s, 1H), 8.27 (s, 1H), 7.81 (d, J = 4.8 Hz, 1H), 7.79-7.50 (m, 1H), 6.93 (d, J = 4.4 Hz, 1H), 6.79 (s, 1H), 3.39-3.35 (m, 4H), 3.19 (brs, 4H), 2.80 (s, 6H), 1.13 (s, 3H), 0.70 ( s, 2H), 0.43 (d, J = 1.6 Hz, 2H).

Preparation of Example 118

1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imidazoline- 6-sulfonamide

The crude product 8-chloro-3-(5-(difluoromethyl) was added to a solution of 1-(fluoromethyl)cyclopropanamine (45.26 mg, 360.47 μmol, HCl salt) in pyridine (1 mL) and NMP (0.5 mL). Romethyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazoline-6-sulfonyl chloride and 1,8-dichloro-3-(5-(difluoromethyl) -1,3,4-thiadiazol-2-yl)imidazoline-6-sulfonyl chloride (95 mg, crude) was added at 0°C. The mixture was stirred at 20° C. for 2 hours and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 57%-58%, 10 min) and directly frozen. Dry to give the product 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imi Dazoline-6-sulfonamide (25 mg, 53.04 μmol, 28.48% yield) was obtained as a brown solid.

RT 0.633 min (Method 3); m/z 472.8 (M+H)+ (ESI+); ¹ H NMR (DMSO- d _6,400 MHz,): 10.18 (d, J = 1.2 Hz, 1H), 8.85 (s, 1H), 8.19 (s, 1H), 7.83-7.53 (m, 1H), 7.45 (d, J = 1.2 Hz, 1H), 4.32-4.16 (m, 2H), 0.88-0.84 (m, 2H), 0.81-0.77 (m, 2H).

Preparation of Example 119

4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)indole Lysin-8-yl)-N,N-dimethylpiperazine-1-carboxamide

1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl) in dioxane (0.5 mL) Cyclopropyl)imidazoline-6-sulfonamide (25 mg, 53.04 μmol), N,N-dimethylpiperazine-1-carboxamide (16.68 mg, 106.09 μmol), Cs ₂ CO ₃ (34.57 mg, 106.09 μmol) ) and Pd-PEPPSI-IPentCl o-picoline (1 mg, 1.03 μmol) were degassed and purged with Ar (3x) in a glove box. The mixture was then stirred outside the glove box under Ar atmosphere at 100°C for 16 hours. The mixture was concentrated under vacuum. The residue was diluted with MeOH (3 mL), filtered, and the filtrate was subjected to preparative HPLC (column: Phenomenex Luna C18 100*30 mm*5 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B %: 37%-67%, 8 min) and directly lyophilized to give product 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6. -(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)indolizin-8-yl)-N,N-dimethylpiperazine-1-carboxamide (0.91 mg, 1.53 μmol, 2.88% yield, 93.47% purity) was obtained as a yellow solid.

RT 0.563 min (Method 3); m/z 558.0 (M+H)+ (ESI+); ¹ H NMR (DMSO- d _6,400 MHz,): 9.86 (s, 1H), 8.66 (s, 1H), 7.81 (d, J = 4.8 Hz, 1H), 7.79-7.51 (m, 1H), 6.93 (d, J = 4.8 Hz, 1H), 6.79 (d, J = 1.2 Hz, 1H), 4.39-4.08 (m, 2H), 3.37 (t, J = 5.2 Hz, 4H), 3.19 (t, J = 4.8 Hz, 4H), 2.80 (s, 6H), 0.81 (d, J = 4.4 Hz, 2H), 0.76 (d, J = 4.4 Hz, 2H)

Preparation of Example 120

4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl) Sulfamoyl)indolizin-8-yl)-N,N-dimethylpiperazine-1-carboxamide

1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl) in dioxane (0.5 mL) Pd-PEPPSI-IPentCl o-P in a solution of cyclopropyl)imidazoline-6-sulfonamide (20 mg, 42.44 μmol) and N,N-dimethylpiperazine-1-carboxamide (6.67 mg, 42.44 μmol). Choline (4.13 mg, 4.24 μmol) and Cs ₂ CO ₃ (27.65 mg, 84.87 μmol) were added under N ₂ . The mixture was stirred at 80° C. for 5 hours and concentrated under vacuum. The residue was diluted with MeOH (3 mL), filtered, and the filtrate was purified by preparative TLC (SiO ₂ , petroleum ether/ethyl acetate = 0:1) and directly lyophilized to give the product 4-(1-chloro- 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)indolizine-8 -yl)-N,N-dimethylpiperazine-1-carboxamide (3.48 mg, 5.74 μmol, 13.52% yield, 97.595% purity) was obtained as a yellow solid.

RT 0.492 min (0.8 min method 3); m/z 592.1 (M+H)+ (ESI+); ¹ H NMR (CDCl ₃ ,400 MHz,): 10.11 (d, J = 1.2 Hz, 1H), 7.33 (s, 1H), 7.20-6.93 (m, 1H), 6.82 (d, J = 0.8 Hz, 1H ), 5.46 (s, 1H), 4.34-4.20 (m, 2H), 3.83-2.96 (m, 8H), 2.90 (s, 6H), 1.18-1.12 (m, 2H), 0.88-0.83 (m, 2H) ).

Preparation of Intermediate 121.1

1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazoline-6-sulfonyl bromide

2-(6-(benzylthio)-8-chloro-1-iodoindolizin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole in ACN (4 mL) 1,3-dibromo-5,5-dimethylimidazole in a solution of (400 mg, 749.37 μmol), AcOH (90.00 mg, 1.50 mmol, 85.71 μL) and water (27.01 mg, 1.50 mmol, 27.01 μL). Dean-2,4-dione (428.52 mg, 1.50 mmol) was added at 0°C. The mixture was stirred at 0° C. for 2 hours and then poured into water (20 mL). The aqueous phase was extracted with DCM (10 mL, 2x). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo at 20°C. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 20/1) to give the product 1-bromo-8-chloro-3-(5-(difluoromethyl)-1. ,3,4-thiadiazol-2-yl)imidazoline-6-sulfonyl bromide (260 mg, 512.26 μmol, 68.36% yield) was obtained as a brown solid.

Preparation of Example 121

1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imi Dazoline-6-sulfonamide

In a solution of 1-(fluoromethyl)cyclopropanamine (50.21 mg, 399.87 μmol, HCl salt), NaHCO ₃ (215.17 mg, 2.56 mmol, 99.62 μL), H ₂ O (2 mL) in THF (2 mL). 1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazoline-6-sulfonyl bromide (260 mg, 512.26 μmol) ) was added at 0°C. The mixture was stirred at 0° C. for 2 hours and then poured into water (20 mL). The aqueous phase was extracted with EtOAc (10 mL, 2x). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 10/1) to give the product 1-bromo-8-chloro-3-(5-(difluoromethyl)-1. ,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imidazoline-6-sulfonamide (100 mg, 193.89 μmol, 37.85% yield) as a yellow solid. Obtained.

¹ H NMR (DMSO- d ₆ , 400 MHz): 10.09 (d, J = 1.2 Hz, 1H), 8.83 (s, 1H), 8.14 (s, 1H), 7.78-7.49 (m, 1H), 7.41 ( d, J = 1.2 Hz, 1H), 4.30 (d, J = 48.4), 0.84-0.74 (m, 4H)

Preparation of Example 122

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-1-(3- Methyl-3-(methylamino)but-1-yn-1-yl)imidazoline-6-sulfonamide

1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoro Methyl) cyclopropyl) imidazoline-6-sulfonamide (10 mg, 19.39 μmol), allyl (chloro) palladium (354.74 ug, 1.94 μmol), P(t-Bu) ₃ (7.85 mg, 3.88 μmol, 9.10 μL) , 10% w/w hexane solution) and TEA (3.92 mg, 38.78 μmol, 5.40 μL) were degassed and purged with N ₂ (3x). Next, N,2-dimethylbut-3-yn-2-amine (3.77 mg, 38.78 μmol, 3.23 μL) was added to the mixture via injection syringe. The mixture was stirred at 20°C for 1 hour. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 18%-48%, 10 min) and directly lyophilized. The product 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-1-( 3-methyl-3-(methylamino)but-1-yn-1-yl)imidazoline-6-sulfonamide (3.06 mg, 5.29 μmol, 27.30% yield, 100% purity, FA salt) as a white solid. Obtained.

RT 0.409 min (Method 4); m/z 554.0 (M+Na)+ (ESI+); ¹ H NMR (DMSO- d ₆ , 400 MHz,): 10.10 (d, J = 1.2 Hz, 1H), 8.86 (br s, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 7.82- 7.54 (m, 1H), 7.44 (d, J = 1.2 Hz, 1H), 4.39-4.12 (m, 2H), 2.39 (s, 3H), 1.37 (s, 6H), 0.91-0.84 (m, 2H) , 0.83-0.77 (m, 2H).

Preparation of intermediate 123.1

1-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-8-chloro-3-(5-(difluoromethyl)-1,3,4-thia Diazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imidazoline-6-sulfonamide

1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoro Methyl) cyclopropyl) imidazoline-6-sulfonamide (70 mg, 135.72 μmol), Cul (2.58 mg, 13.57 μmol), TEA (363.50 mg, 3.59 mmol, 0.5 mL) and Pd[P(t-Bu) ₃ ] ₂ A mixture of Cl ₂ (10.02 mg, 13.57 μmol) was degassed and purged with N ₂ (3x). Then, tert-butyldimethyl(prop-2-yn-1-yloxy)silane (46.23 mg, 271.45 μmol, 55.04 μL) was added to the mixture via injection syringe. The mixture was stirred at 100° C. for 16 hours under N ₂ atmosphere and then poured into water (30 mL). The aqueous phase was extracted with EtOAc (10 mL, 2x). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative TLC (SiO ₂ , petroleum ether: ethyl acetate = 3:1) and directly lyophilized to give the product 1-(3-((tert-butyldimethylsilyl)oxy)prop-1-yne-. 1-yl)-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imi Dazoline-6-sulfonamide (10 mg, 16.52 μmol, 12.18% yield) was obtained as a yellow solid.

RT 0.593 min (Method 4); m/z 605.1 (M+H)+ (ESI+).

Preparation of Example 123

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-1-(3- Hydroxyprop-1-yn-1-yl)imidazoline-6-sulfonamide

1-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-8-chloro-3-(5-(difluoromethyl)-1 in MeOH (0.2 mL) ,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imidazoline-6-sulfonamide (10 mg, 16.52 μmol) in a solution of KF (1.92 mg, 33.05 μmol) was added. The mixture was stirred at 20° C. for 4 hours and then concentrated under vacuum. The residue was diluted with MeOH (3 mL), filtered, and the filtrate _was subjected _to preparative HPLC (column: Waters ; B%: 25%-55%, 8 min) and directly lyophilized to give the product 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl. )-N-(1-(fluoromethyl)cyclopropyl)-1-(3-hydroxyprop-1-yn-1-yl)imidazoline-6-sulfonamide (1.27 mg, 2.59 μmol, 15.66 % yield, 100% purity) was obtained as a yellow solid.

RT 0.438 min (Method 4); m/z 513.0 (M+Na) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz,): 10.09 (d, J = 1.2 Hz, 1H), 8.85 (br, 1H), 8.11 (s, 1H), 7.67 (t, J = 53.2 Hz, 1H ), 7.46 (d, J = 1.2 Hz, 1H), 5.33 (t, J = 6.0 Hz, 1H), 4.36 (d, J = 6.0 Hz, 2H), 4.31-4.18 (d, J = 48.4 Hz, 2H) ), 0.89-0.86 (m, 2H), 0.81-0.78 (m, 2H).

Preparation of Intermediate 124.1

tert-Butyl3-((8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl )Cyclopropyl)sulfamoyl)indolizin-1-yl)methylene)azetidine-1-carboxylate

1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-( Fluoromethyl)cyclopropyl)imidazoline-6-sulfonamide (60 mg, 116.33 μmol), tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxabo Rolan-2-yl)methylene)azetidine-1-carboxylate (41.21 mg, 139.60 μmol,) and Pd(dppf)Cl ₂ (8.47 mg, 11.63 μmol), K ₃ PO ₄ (1.5 M in water, 155.11 μL) of the solution was degassed, purged with N ₂ (3x) and stirred at 60° C. for 4 hours under N ₂ atmosphere. To this mixture was added tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine-1-carboxylate (41.21 mg, 139.60 μmol), K ₃ PO ₄ (1.5 M in water, 100 μL) and Pd(dppf)Cl ₂ (8.47 mg, 11.63 μmol) were added and the reaction was stirred at 60° C. for an additional 4 hours. Again, tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine-1-carboxylate (41.21 mg) was added to the mixture. , 139.60 μmol) and Pd(dppf)Cl ₂ (8.47 mg, 11.63 μmol) were added and the reaction was stirred at 60°C for an additional 4 h. The mixture was poured into water (10 mL) and the aqueous layer was extracted with EtOAc (5 mL, 2x). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative TLC (SiO ₂ , petroleum ether:ethyl acetate = 3:2) to give the product tert-butyl 3-((8-chloro-3-(5-(difluoromethyl)-1,3 ,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)indolizin-1-yl)methylene)azetidine-1-carboxylate (17 mg, 28.14 μmol, 24.19% yield) was obtained as a yellow solid.

RT 0.538 min (Method 4); m/z 503.9 (M-Boc+H) ⁺ (ESI).

Preparation of Intermediate 124.2

tert-Butyl 3-((8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl )Cyclopropyl)sulfamoyl)indolizin-1-yl)methyl)azetidine-1-carboxylate

tert-Butyl 3-((8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-( Pd/C (10 mg, 10% purity) in a solution of 1-(fluoromethyl)cyclopropyl)sulfamoyl)indolizin-1-yl)methylene)azetidine-1-carboxylate (20 mg, 33.11 μmol) ) was added under N ₂ atmosphere. The suspension was degassed and purged with H ₂ (3x) and then stirred at 20° C. for 2 hours. The mixture was filtered and the filtrate concentrated under vacuum to give the product tert-butyl 3-((8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)- 6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)indolizin-1-yl)methyl)azetidine-1-carboxylate (5 mg, 8.25 μmol, 24.92% yield) was purified as a yellow solid. It was obtained as.

RT 0.529 min (Method 4); m/z 506.2 (M-BocH)+ (ESI+).

Preparation of Example 124

1-(azetidin-3-ylmethyl)-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoro Romethyl)cyclopropyl)imidazoline-6-sulfonamide

tert-Butyl 3-((8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-( 1-(fluoromethyl)cyclopropyl)sulfamoyl)indolizin-1-yl)methyl)azetidine-1-carboxylate (15 mg, 24.75 μmol) and 2,6-dimethylpyridine (21.22 mg, 197.99 μmol) , 23.06 μL), TMSOTf (33.00 mg, 148.50 μmol, 26.83 μL) was added dropwise at 0°C. The mixture was stirred at 20° C. for 1.5 hours and then concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 13%-43%, 8 min) and directly lyophilized. The product 1-(azetidin-3-ylmethyl)-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1- (Fluoromethyl)cyclopropyl)imidazoline-6-sulfonamide (0.6 mg, 1.14 μmol, 4.61% yield, 96.24% purity, FA salt) was obtained as a yellow solid.

RT 0.366 min (Method 4); m/z 506.0 (M+H)+ (ESI+); ¹ H NMR (DMSO- d ₆ , 400 MHz,): 10.08 (d, J = 1.2 Hz, 1H), 8.40 (s, 1H), 7.86-7.78 (m, 1H), 7.75 (s, 1H), 7.34 (d, J = 1.2 Hz, 1H), 4.35-4.15 (m, 2H), 3.85-3.81 (m, 2H), 3.61-3.57 (m, 2H), 3.13-3.05 (m, 2H), 2.60 (s) , 1H), 0.88-0.82 (m, 2H), 0.82-0.76 (m, 2H).

Preparation of Example 125

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-1-isobutyl Midazoline-6-sulfonamide

1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoro A mixture of methyl)cyclopropyl)imidazoline-6-sulfonamide (20 mg, 38.78 μmol), Pd ₂ (dba) ₃ (3.55 mg, 3.88 μmol) and XPhos (3.70 mg, 7.76 μmol) was added to isobutylzinc ( II) Bromide (0.5 M, 310.22 μL) was added under N ₂ . The mixture was then stirred at 80° C. for 1 hour under N ₂ atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was reversed phase flash (ISCO®20 g Flash column Welch Ultimate ) was purified. The resulting impure product was then subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 65%-95%, 58 min ) and direct lyophilization to obtain another impure product, which was further purified by preparative TLC (SiO ₂ , petroleum ether: ethyl acetate = 3:1) to give the product 8-chloro-3-(5 -(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-1-isobutylimidazoline-6-sulfonamide ( 1.58 mg, 3.04 μmol, 7.84% yield, 94.8% purity) was obtained as a white solid.

RT 0.596 min (Method 4); m/z 492.9 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz,): 10.10 (s, 1H), 8.80 (s, 1H), 7.81 (s, 1H), 7.67 (t, J = 53.2 Hz, 1H), 7.32 (s , 1H), 4.26 (t, J = 48.8 Hz, 1H), 2.93 (d, J = 6.8 Hz, 2H), 1.95-1.99 (m, 1H), 0.96 (d, J = 6.4 Hz, 6H), 0.87 (t, J = 4.8 Hz, 2H), 0.81 (t, J = 4.0 Hz, 2H).

Preparation of Example 126

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imidazoline-6-sulfonamide

1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoro Pd/C (5 mg, 10% purity) and DIPEA (5.01 mg, 38.78 μmol, 6.75 μL) were added to a solution of methyl) cyclopropyl) imidazoline-6-sulfonamide (20 mg, 38.78 μmol) in N ₂ atmosphere. It was added below. The suspension was degassed and purged three times with H ₂ . The reaction was then stirred at 30° C. for 2 hours, filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 40%-70%, 10 min) and directly By lyophilization, the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imidazoline-6- Sulfonamide (960.00 ug, 2.37 μmol, 6.11% yield, 99.29% purity) was obtained as a white solid.

RT 0.558 min (Method 3); m/z 402.9 (M+H)+ (ESI+); ¹ H NMR (CDCl ₃ , 400 MHz,): 10.39 (s, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.34 (dd, J = 9.6) ,1.6 Hz, 1H), 7.20-6.93 (m, 1H), 6.77 (d, J = 4.4 Hz, 1H), 5.47 (s, 1H), 4.29 (d, J = 48.4 Hz, 2H), 1.16-1.10 (m, 2H), 0.88-0.83 (m, 2H)

Preparation of Example 127

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-1-isobutylimidazoline-6 -Sulfonamides

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl) in MeOH (1 mL) Pd/C (5 mg, 10% purity) and DIPEA (2.62 mg, 20.29 μmol, 3.53 μL) were added to a solution of -1-isobutylimidazoline-6-sulfonamide (10 mg, 20.29 μmol) in N ₂ atmosphere. It was added below. The suspension was degassed and purged with H ₂ (3x). The mixture was then stirred at 30° C. for 1 hour, filtered and the filtrate was concentrated under vacuum. The resulting crude product was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 70%-100%, 10 min) and directly freeze-dried to obtain the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-1-iso. Butylimidazoline-6-sulfonamide (960.00 ug, 1.91 μmol, 9.43% yield, 91.39% purity) was obtained as a yellow solid.

RT 0.470 min (Method 3); m/z 458.9 (M+H)+ (ESI+); ¹ H NMR (CDCl ₃ , 400 MHz,): 10.33 (s, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.29 (s, 1H), 7.25 (d, J = 9.2 Hz, 1H), 7.05 (t, J = 53.2 Hz, 1H), 5.43 (s, 1H), 4.29 (d, J = 48.0 Hz, 2H), 2.67 (d, J = 6.8 Hz, 2H), 2.00-1.92 (m, 1H) ), 1.16-1.11 (m, 2H), 0.98 (d, J = 6.4 Hz, 6H), 0.91-0.86 (m, 2H).

Preparation of intermediate 128.1

Tert-Butyl4-(8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl) Cyclopropyl)sulfamoyl)indolizin-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate

1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluo) in dioxane (0.5 mL) Romethyl)cyclopropyl)imidazoline-6-sulfonamide (30 mg, 58.17 μmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (25.18 mg, 81.43 μmol), Pd(dppf)Cl ₂ (4.26 mg, 5.82 μmol), K ₂ CO ₃ (16.08 mg , 116.33 μmol) and H ₂ O (0.025 mL) was degassed and purged with N ₂ (3x). The mixture was then stirred at 80°C for 2 hours under N ₂ atmosphere and poured into water (10 mL). The aqueous phase was extracted with EtOAc (5 mL, 2x). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative TLC (SiO ₂ , petroleum ether:ethyl acetate = 2:1) to give the product tert-butyl 4-(8-chloro-3-(5-(difluoromethyl)-1,3, 4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)indolizin-1-yl)-5,6-dihydropyridin-1(2H) -Carboxylate (12.75 mg, 20.63 μmol, 35.46% yield) was obtained as a yellow solid.

RT 0.656 min (Method 3); m/z 561.9 (M-56+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz,): 10.34 (d, J = 1.6 Hz, 1H), 7.34 (d, J = 1.2 Hz, 1H), 7.31 (s, 1H), 7.08-6.92 (m , 1H), 5.75 (br s, 1H), 5.46 (s, 1H), 4.33 (t, J = 48.4 Hz, 2H), 4.11-4.08 (m, 2H), 3.68 (t, J = 5.6 Hz, 2H) ), 2.51-2.47 (m, 2H), 1.52 (s, 9H), 1.14 (br d, J = 4.0 Hz, 2H), 0.90 -0.87 (m,2H).

Preparation of Example 128

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-1-(1, 2,3,6-Tetrahydropyridin-4-yl)imidazoline-6-sulfonamide

tert-Butyl 4-(8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1) in DCM (0.5 mL) -(Fluoromethyl)cyclopropyl)sulfamoyl)indolizin-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate (10.00 mg, 16.18 μmol) was added to a solution of TFA (1.5 mL). ) was added. The mixture was stirred at 20° C. for 1 hour and then concentrated under vacuum. The residue was purified by preparative HPLC (column: Welch Ultimate C18 150*25mm*5μm; mobile phase: A: 0.225% TFA in water, B: MeCN; B%: 21%-51%, 10 min) and directly lyophilized. The product 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-1-( 1,2,3,6-Tetrahydropyridin-4-yl)imidazoline-6-sulfonamide (1.6 mg, 3.09 μmol, 19.09% yield, 99.99% purity, TFA salt) was obtained as a white solid.

RT 0.390 min (Method 4); m/z 518.0 (M+H)+ (ESI+); ¹ H NMR (DMSO- d _6,400 MHz,): 10.13 (d, J = 1.2 Hz, 1H), 8.89 (d, J = 3.2 Hz, 1H), 8.84 (s, 1H), 7.82-7.80 (m , 1H), 7.80-7.52 (m, 1H), 7.43 (d, J = 1.2 Hz, 1H), 5.80 (br, 1H), 4.27 (d, J = 48.4 Hz, 2H), 3.79 (d, J = 1.2 Hz, 2H), 3.44-3.35 (m, 2H), 2.69-2.61 (m, 2H), 0.95-0.75 (m, 4H).

Preparation of Example 129

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(2-oxa-7-azaspiro[3.5 ]nonane-7-yl)imidazo[1,5-a]pyridine-6-sulfonamide

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ 2-oxa-7-azaspiro[3.5]nonane (24.23 mg, 190.54 μmol), Cs ₂ CO ₃ (93.12 mg, 285.81 μmol) and Pd-PEPPSI-IPentCl o-picolin (8.20 mg, 9.53 μmol) were added. The reaction mixture was degassed with N ₂ (3x) and the mixture was stirred at 90° C. for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by preparative TLC (ethyl acetate) to give impure product, which was further triturated with MeOH (1 mL) to give product 3-(5-(difluoromethyl)-1,3 ,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(2-oxa-7-azaspiro[3.5]nonan-7-yl)imidazo[1,5-a ]Pyridine-6-sulfonamide (9.89 mg, 19.15 μmol, 20.10% yield, 98.86% purity) was obtained as a yellow solid.

RT 0.473 min (Method 4); m/z 511.3 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 9.84 (s, 1H), 7.70 (s, 1H), 7.08 (t, J =53.6 Hz, 1H), 6.63 (d, J = 1.2 Hz, 1H), 5.06 (s, 1H), 4.54 (s, 4H), 3.26-3.23 (m, 4H), 2.16-2.13 (m, 4H), 1.39 (s, 3H), 0.94-0.91 (m, 2H), 0.60 (d) , J = 1.6 Hz, 2H).

Preparation of Example 130

4-(7-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imi Polyzo[1,5-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide

4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl in MeCN (0.5 mL) ) NCS (2.47 mg, 18.50 μmol) was added to a mixture of imidazo [1,5-a] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (20 mg, 37.00 μmol). Added at ℃. The mixture was then stirred at 25°C for 1 hour. The resulting solution was purified by preparative TLC (ethyl acetate:petroleum ether=1:0) and concentrated under vacuum to give the product 4-(7-chloro-3-(5-(difluoromethyl)-1,3,4 -thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,N-dimethylpiperazine-1 -Carboxamide (3.30 mg, 5.62 μmol, 15.19% yield, 98% purity) was obtained as a yellow solid.

RT 0.583 min (Method 4); m/z 574.9 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 10.20 (s, 1H), 7.85 (s, 1H), 7.09 (t, J = 53.2 Hz, 1H), 5.45 (s, 1H), 3.47-3.45 (m, 4H), 3.46-3.44 (m, 4H), 2.92 (s, 6H), 1.34 (s, 3H), 0.99-0.97 (m, 2H), 0.66-0.53 (m, 2H).

Preparation of Example 131

4-(1,7-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclo Propyl) sulfamoyl) imidazo [1,5-a] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide

4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclo in MeCN (0.5 mL) NCS (10.76 mg, 80.56 mg) in a mixture of propyl) sulfamoyl) imidazo [1,5-a] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (30 mg, 53.71 μmol) μmol) was added at 0°C. The reaction mixture was then stirred for 16 hours. After filtration, the filtrate was concentrated under vacuum at low temperature. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.025% formic acid in water, B: MeCN; B%: 42%-72%, 10 min) and directly freeze-dried to produce the product 4-(1,7-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- (Fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (9.9 mg, 15.62 μmol, 29.08% yield) , 99% purity) was obtained as a yellow solid.

RT 0.506 min (Method 4), m/z 628.9(M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 10.23 (s, 1H), 7.08 (t, J =53.6 Hz, 1H), 5.77 (s, 1H), 4.28-4.16 (d, J =48.8 Hz, 2H) , 3.68-3.59 (m, 4H), 3.44-3.39 (m, 2H), 3.14-3.12 (m, 2H), 2.91 (s, 6H), 1.23-1.22 (m, 2H), 0.91-0.89 (m, 2H).

Preparation of Example 132

4-(7-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl) Sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide

4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclo in MeCN (1 mL) NCS (5.74 mg, 42.96 mg) in a mixture of propyl) sulfamoyl) imidazo [1,5-a] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (30 mg, 53.71 μmol) μmol) was added at 0°C. The reaction mixture was stirred for 16 hours. After filtration, the filtrate was concentrated under vacuum at low temperature. The resulting residue was purified by preparative TLC (ethyl acetate: petroleum ether = 1:0), concentrated under vacuum and directly lyophilized to give the product 4-(7-chloro-3-(5-(difluoromethyl) -1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl) -N,N-dimethylpiperazine-1-carboxamide (8.03 mg, 13.27 μmol, 24.71% yield, 98% purity) was obtained as a yellow solid.

RT 0.451 min (Method 4); m/z 593.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 10.18 (s, 1H), 7.85 (s, 1H), 7.08 (t, J =54.0 Hz, 1H), 5.82 (s, 1H), 4.29-4.17 (d, J =48.8 Hz, 2H), 3.48-3.46 (m, 8H), 2.92 (s, 6H), 1.22-1.20 (m, 2H), 0.90-0.86 (m, 2H).

Preparation of Example 133.a

tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo [1,5-a]pyridin-8-yl)piperidine-1-carboxylate

tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl) in MeOH (3 mL) )Sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate (80 mg, 141.18 μmol) in a mixture of Pd(OH) ₂ (24 mg, 34.18 μmol, 20% purity) and Pd/C (24 mg, 141.18 μmol, 10% purity) were added. The reaction was degassed with H ₂ (3x) and then stirred at 50° C. for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by preparative TLC (ethyl acetate:petroleum ether=1:1) to give the product tert-butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazole -2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)piperidine-1-carboxylate (38 mg, 58.81 μmol, 41.65% yield, 88% purity) was obtained as a yellow solid.

RT 0.573 min (Method 4); m/z 591.2 (M+Na) ⁺ (ESI ⁺ ).

Preparation of Example 133

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

tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-( A mixture of 1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)piperidine-1-carboxylate (20 mg, 35.17 μmol) was stirred at 25°C for 1 hour. did. The reaction mixture was concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%:12%-42%, 8 min) and directly lyophilized to obtain the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(piperidine- 4-day) Imidazo[1,5-a]pyridine-6-sulfonamide (1.07 mg, 2.04 μmol, 5.80% yield, 89.49% purity, FA salt) was obtained as a yellow solid.

RT 0.374 min (Method 1); m/z 469.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.80 (s, 1H), 8.63-8.51 (m, 1H), 8.49 (s, 1H), 8.17 (s, 1H) 7.68 (t, J = 53.2 Hz) , 1H), 7.23 (s, 1H), 3.25-3.23 (m, 2H), 3.15-3.10 (m, 1H), 2.91-2.85 (m, 2H), 1.98-1.95 (m, 2H), 1.81-1.73 (m, 2H), 1.14 (s, 3H), 0.71 (br, 2H), 0.46 (br, 2H).

Preparation of Example 134

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

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl) in THF (0.5 mL) and H ₂ O (0.5 mL) -8-(piperidin-4-yl)imidazo[1,5-a]pyridine-6-sulfonamide (10 mg, 21.34 μmol) in a mixture of K ₂ CO ₃ (8.85 mg, 64.03 μmol) and dimethyl Carbamic acid chloride (3.44 mg, 32.01 μmol, 2.94 μL) was added at 0°C. The mixture was stirred at 0°C for 15 min, poured into water (10 mL) and extracted with EtOAc (15 mL; 2x). The organic layer was separated, mixed, dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 36%-66%, 8 min) and directly freeze-dried to obtain the product 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl ) Imidazo [1,5-a] pyridin-8-yl) -N, N-dimethylpiperidine-1-carboxamide (1.64 mg, 2.70 μmol, 12.66% yield, 88.90% purity) as a yellow solid. Obtained.

RT 0.496 min (Method 4); m/z 540.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d _6,400 MHz): 9.79 (s, 1H), 8.45 (s, 1H), 8.19 (s, 1H), 7.69 (t, J = 53.6 Hz, 1H), 7.26 (s, 1H), 3.72 (d, J = 13.6 Hz, 2H), 3.32-3.24 (m, 1H), 2.95 (t, J = 12.4 Hz, 2H), 2.78 (s, 6H), 1.94 (d, J = 12.4 ㎐, 2H), 1.72-1.68 (m, 2H), 1.11 (s, 3H), 0.72-0.69 (m, 2H), 0.46-0.44 (m, 2H).

Preparation of Example 135.1

1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride

2-(6-Benzylsulfanyl-8-chloro-imidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4- in ACN (10 mL) A mixture of thiadiazole (1 g, 2.45 mmol) at 0°C with AcOH (293.73 mg, 4.89 mmol, 279.75 μL), water (88.14 mg, 4.89 mmol, 88.14 μL) and 1,3-dibromo-5; 5-Dimethyl-imidazolidine-2,4-dione (2.80 g, 9.78 mmol) was added. The reaction was then stirred at 0°C for 2 hours. The resulting mixture was concentrated under vacuum (at 20°C). The residue was diluted with DCM (30 mL), washed with ice water (20 mL; 4x), separated, dried over Na ₂ SO ₄ and concentrated in vacuo (at 20°C). The crude product (1.6 g) was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0-15% ethyl acetate/petroleum @ 50 mL/min) to give the product 1-bromo-8. -Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride (800 mg, 1.10 mmol, 44.90% yield, 69.8% purity) was obtained as a light yellow solid.

¹ H NMR (CDCl ₃ , 400 MHz): 10.32 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 1.2 Hz, 1H), 7.11 (t, J = 53.6 Hz, 1H).

Preparation of Example 135.2

1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imi Polyzo[1,5-a]pyridine-6-sulfonamide

NaHCO ₃ (660.79 mg, 7.87 mmol, 305.92 μL) was added to a mixture of 1-(fluoromethyl)cyclopropanamine (217.29 mg, 1.73 mmol, HCl) in THF (8 mL) and H ₂ O (8 mL) at 0°C. It was added from . Then, 1-bromo-8-chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]imidazo[1,5- a]Pyridine-6-sulfonyl bromide (800 mg, 1.57 mmol) was added dropwise over 10 minutes and stirred at 0°C for 2 hours. The resulting mixture was quenched with saturated brine (30 mL) and extracted with EtOAc (30 mL; 3x). The combined organic layers were separated, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0-20% ethyl acetate/petroleum @ 30 mL/min) to give the product 1-bromo-8-chloro-3- (5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imidazo[1,5-a]pyridine-6 -Sulfonamide (200 mg, 348.34 μmol, 22.14% yield, 90% purity) was obtained as a light yellow solid.

RT 0.497 min (Method 1); m/z 517.8 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 10.16 (s, 1H), 7.38 (s, 1H), 7.09 (t, J = 53.2 Hz, 1H), 5.59 (s, 1H), 4.31 (d, J = 48.4 Hz, 2H), 1.19 -1.10 (m, 2H), 0.95 -0.88 (m, 2H).

Preparation of Example 135

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-1-(3- Methoxyprop-1-yn-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide

1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoro Methyl) cyclopropyl) imidazo [1,5-a] pyridine-6-sulfonamide (100 mg, 193.52 μmol), 3-methoxyprop-1-yne (27.13 mg, 387.04 μmol, 31.91 μL), allyl A mixture of (chloro)palladium (7.08 mg, 19.35 μmol), tri-tert-butylphosphane (78.30 mg, 38.70 μmol, 90.84 μL, 10% purity) and DABCO (43.42 mg, 387.04 μmol, 42.56 μL) was degassed and N Purged ₂ (3x). The mixture was then stirred at 25° C. for 1 hour, filtered and the filtrate was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-55% ethyl acetate/petroleum ether @ 20 mL/min) to give impure product, which was purified with MeOH ( 3 mL) at 20°C for 5 minutes. After filtration, the filtrate was concentrated directly to give the product 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl )Cyclopropyl)-1-(3-methoxyprop-1-yn-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide (115 mg, 225.04 μmol, 23.26% yield, 99 % purity) was obtained as a yellow solid.

RT 0.485min (Method 1); m/z 506.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 10.15 (d, J = 1.2 Hz, 1H), 7.41 (d, J = 1.2 Hz, 1H), 7.09 (t, J = 56.0 Hz, 1H), 5.56 (s , 1H), 4.45 (s, 2H), 4.31 (d, J = 48.0 Hz, 2H), 3.52 (s, 3H), 1.17-1.12 (m, 2H), 0.93-0.90 (m, 2H).

Preparation of Example 136

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-1-(3- Methoxy propyl)imidazo[1,5-a]pyridine-6-sulfonamide and Example 137 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)- N-(1-(fluoromethyl)cyclopropyl)-1-(3-methoxypropyl)imidazo[1,5-a]pyridine-6-sulfonamide

8-Chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl] in MeOH (0.5 mL) -1-(3-methoxyprop-1-inyl)imidazo[1,5-a]pyridine-6-sulfonamide (20 mg, 39.53 μmol) was added to a solution of Pd/C (5 mg, 10% purity). ) and DIEA (5.11 mg, 39.53 μmol, 6.89 μL) were added. The reaction was degassed with H ₂ (3x) and the mixture was stirred under H ₂ (15 psi, 1 atm) at 50° C. for 16 hours. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 42%-72%, 10 min) and frozen. Dry to give the product 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-1- (3-methoxypropyl)imidazo[1,5-a]pyridine-6-sulfonamide (3.98 mg, 7.49 μmol, 18.95% yield, 96% purity) as a yellow solid and 8-chloro-3-(5 -(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-1-(3-methoxypropyl)imidazo[1 ,5-a]pyridine-6-sulfonamide (4.28 mg, 8.55 μmol, 21.63% yield, 95% purity) was obtained as a yellow solid.

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

RT 0.522 min (Method 1); m/z 510.1 (M+H) ⁺ (ESI ⁺ ); ^1H NMR (CDCl ₃ , 400 MHz): 10.08 (d, J = 1.2 Hz, 1H), 7.25 (d, J = 0.8 Hz, 1H), 7.08 (t, J = 56.0 Hz, 1H), 5.50 (s , 1H), 4.32 (d, J = 48.0 Hz, 1H), 3.52 (t, J = 8.0 Hz, 2H), 3.38 (s, 3H), 3.31 (t, J = 8.0 Hz, 2H), 2.15-2.04 (m, 2H), 1.16-1.12 (m, 2H), 0.92-0.88 (m, 2H).

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

RT 0.492 min (Method 1); m/z 475.8 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 10.11 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.25 (dd, J = 1.2,8.0 Hz, 1H), 7.08 (t, J = 56.0 Hz, 1H), 5.50 (s, 1H), 4.29 (d, J = 48.0 Hz, 2H), 3.43 (t, J = 8.0 Hz, 2H), 3.36 (s, 3H), 3.05 (t, J = 8.0 Hz, 2H), 2.12-2.05 (m, 2H), 1.15-1.11 (m, 2H), 0.89-0.86 (m, 2H).

Preparation of intermediate 138.1

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

2-(6-(benzylthio)-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4 in dioxane (30 mL) -Phenylmethanol (2.12 g, 19.57 mmol, 2.03 mL), Cs ₂ CO ₃ (3.19 g, 9.78 mmol) and t-BuBrettPhos Pd G3 (417.94 mg, 489.15 μmol) in a solution of thiadiazole (2 g, 4.89 mmol). ) was added. The reaction mixture was stirred at 100° C. under N ₂ for 16 hours. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent 0-20% ethyl acetate/petroleum ether @ 40 mL/min) to give the product 2-(8-(benzyloxy)- 6-(benzylthio)imidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (700 mg, 1.44mmol, 29.40% yield) , 98.731% purity) was obtained as a yellow solid.

RT 0.754 min (method 1), m/z 480.8 (M+H) ⁺ (ESI ⁺ ), ¹ H NMR (CDCl _3,400 MHz): 9.22 (s, 1H), 7.77 (s, 1H), 7.47 - 7.44 (m, 4H), 7.43-7.38 (m, 1H), 7.34-7.29 (m, 5H), 7.07 (t, J = 52.0 Hz, 1H), 6.24 (s, 1H), 5.12 (s, 2H) , 4.13 (s, 2H).

Preparation of intermediate 138.2

6-(benzylthio)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridin-8-ol

2-(8-(benzyloxy)-6-(benzylthio)imidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3 in TFA (3 mL) A solution of 4-thiadiazole (300 mg, 624.28 μmol) was stirred at 70°C for 24 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in EtOAc (25 mL) and washed with brine. The organic phase was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 2/1) to give the product 6-(benzylthio)-3-(5-(difluoromethyl)-1,3,4-thiadiazole- 2-yl)imidazo[1,5-a]pyridin-8-ol (150 mg, 291.99 μmol, 46.77% yield, 76% purity) was obtained as a yellow solid.

RT 0.471 min (Method 1); m/z 390.8 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 9.22 (s, 1H), 7.78 (s, 1H), 7.37-7.35 (m, 2H), 7.30 (m, 1H), 7.23-7.21 (m, 2H), 7.07 (t, J = 52.0 Hz, 1H), 6.31 (s, 1H), 4.17 (s, 2H).

Preparation of intermediate 138.3

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

6-(benzylthio)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine- in DMF (1 mL) To a mixture of 8-ol (40 mg, 102.45 μmol) was added K ₂ CO ₃ (28.32 mg, 204.90 μmol) and 1-bromo-3-methoxypropane (31.35 mg, 204.90 μmol). The reaction was heated to 80° C. and stirred for 16 hours. The reaction mixture was diluted with 20 mL H ₂ O and extracted with EtOAc (10 mL, 3x). The organic layers were separated, combined, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 2/1) to give the product 2-(6-(benzylthio)-8-(3-methoxypropoxy)imidazo[1,5-a]. Pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (40 mg, 68.32 μmol, 53.35% yield, 79% purity) was obtained as a yellow solid.

RT 0.537 min (Method 1); m/z 463.0 (M+H) ⁺ (ESI ⁺ ); ^1H NMR (DMSO- d ₆ , 400 MHz): 8.96 (s, 1H), 7.80 (s, 1H), 7.65 (t, J = 52.0 Hz, 1H), 7.40-7.38 (m, 1H), 7.30- 7.25 (m, 2H), 7.23-7.19 (m, 2H), 6.70 (s, 1H), 4.33 (s, 2H), 4.26 (t, J = 8.0 Hz, 2H), 3.53 (t, J = 8.0 Hz) , 2H), 3.28 (s, 3H), 2.06-2.01 (m, 2H).

Preparation of intermediate 138.4

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-methoxypropoxy)imidazo[1,5-a]pyridine-6- Sulfonyl chloride and 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-methoxypropoxy)imidazo [1, 5-a]pyridine-6-sulfonyl chloride

2-(6-(benzylthio)-8-(3-methoxypropoxy)imidazo[1,5-a]pyridin-3-yl)- in AcOH (0.4 mL) and H ₂ O (0.2 mL) A mixture of 5-(difluoromethyl)-1,3,4-thiadiazole (20 mg, 43.24 μmol) at 0°C with NCS (23.10 mg, 172.96 μmol) and 1,3-dichloro-5,5- Dimethylimidazolidine-2,4-dione (25.56 mg, 129.72 μmol) was added. The mixture was stirred at 20° C. for 6 h, then diluted with DCM (15 mL), washed with brine (10 mL; 4x), dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude mixture product 3-( 5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-methoxypropoxy)imidazo[1,5-a]pyridine-6-sulfonyl chloride and 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-methoxypropoxy)imidazo[1,5-a ]Pyridine-6-sulfonyl chloride (17 mg, crude) was obtained as a yellow solid. The crude mixture product was used directly in the next step without further purification.

Preparation of Example 138

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-methoxypropoxy)-N-(1-methylcyclopropyl)imidazo[ 1,5-a]pyridine-6-sulfonamide and Example 139 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-( 3-methoxypropoxy)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide

To a mixture of 1-methylcyclopropanamine (5.88 mg, 54.69 μmol, HCl) in DCM (0.5 mL) was added DIEA (10.60 mg, 82.03 μmol, 14.29 μL), 3-(5-(difluoromethyl) at -10°C. )-1,3,4-thiadiazol-2-yl)-8-(3-methoxypropoxy)imidazo[1,5-a]pyridine-6-sulfonyl chloride and 1-chloro-3- (5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-methoxypropoxy)imidazo[1,5-a]pyridine-6-sulfonyl Chloride (17 mg, crude) was added. The mixture was stirred at 20° C. for 16 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with MeOH (3 mL), filtered, and the filtrate was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B %:45%-75%, 10 min) and lyophilized to produce the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3- Methoxypropoxy)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (4.81 mg, 9.95 μmol, 36.41% yield, 98% purity) as a light yellow solid. and 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-methoxypropoxy)-N-(1-methylcyclo Propyl)imidazo[1,5-a]pyridine-6-sulfonamide (2.0 mg, crude) was obtained as a yellow solid.

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

RT 0.536 min (Method 1); m/z 474.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.55 (s, 1H), 8.44 (s, 1H), 7.94 (s, 1H), 7.69 (t, J = 52.0 Hz, 1H), 6.80 (s, 1H), 4.32 (t, J = 8.0 Hz, 2H), 3.56 (t, J = 8.0 Hz, 2H), 3.28 (s, 3H), 2.11 (t, J = 8.0 Hz, 2H), 1.17 (s, 3H), 0.75-0.73 (m, 2H), 0.48-0.45 (m, 2H).

1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-methoxypropoxy)-N-(1-methylcyclopropyl )Imidazo[1,5-a]pyridine-6-sulfonamide

RT 0.496 min (Method 1); m/z 508.0 (M+H) ⁺ (ESI ⁺ ).

Preparation of Intermediate 140.1

2-(6-(benzylthio)-8-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl )-1,3,4-thiadiazole

6-(benzylthio)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine- in toluene (2 mL) To a solution of 8-ol (60 mg, 153.68 μmol) was added tetrahydro-2H-pyran-4-ol (31.39 mg, 307.35 μmol, 30.77 μL) and CMBP (74.18 mg, 307.35 μmol). The mixture was degassed and purged with N ₂ (3x). The mixture was stirred at 100° C. for 16 hours and then diluted with EtOAc (45 mL). The organic layer was washed with brine (20 mL; 2x), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by preparative TLC (petroleum ether: ethyl acetate = 3/1) to give the product 2-(6-(benzylthio)-8-((tetrahydro-2H-pyran-4-yl)oxy). Imidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (40 mg, 65.75 μmol, 42.78% yield, 78% purity) Obtained as a yellow solid.

RT 0.578 min (Method 1); m/z 475.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 9.25 (s, 1H), 7.73 (s, 1H), 7.38-7.36 (m, 2H), 7.33-7.29 (m, 2H), 7.27-7.23 (m, 1H) ), 7.07 (t, J = 52.0 Hz, 1H), 6.11 (s, 1H), 4.53-4.47 (m, 1H), 4.16 (s, 2H), 4.03-3.97 (m, 2H), 3.63-3.57 ( m, 2H), 2.05-1.99 (m, 2H), 1.88-1.80 (m, 2H).

Preparation of Intermediate 140.2

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,5 -a]pyridine-6-sulfonyl chloride and 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((tetrahydro-2H -Pyran-4-yl)oxy)imidazo[1,5-a]pyridine-6-sulfonyl chloride

2-(6-benzylsulfanyl-8-tetrahydropyran-4-yloxy-imidazo[1,5-a]pyridin-3-yl)- in AcOH (0.6 mL) and H ₂ O (0.3 mL) 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione in a mixture of 5-(difluoromethyl)-1,3,4-thiadiazole (40 mg, 84.29 μmol) (49.82 mg, 252.87 μmol) was added at 0°C. The mixture was stirred at 20° C. for 6 hours and then diluted with DCM (15 mL). The organic layer was washed with brine (20 mL; 2x), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was used directly in the next step.

Preparation of Example 140

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-((tetrahydro-2H-pyran-4- I) oxy) imidazo [1,5-a] pyridine-6-sulfonamide and Example 141 1-chloro-3- (5- (difluoromethyl) -1,3,4-thiadiazole-2 -yl)-N-(1-methylcyclopropyl)-8-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,5-a]pyridine-6-sulfonamide

DIEA (34.40 mg, 266.15 μmol, 46.36 μL) and 3-(5-(difluoromethyl)-1 in a mixture of 1-methylcyclopropanamine (19.09 mg, 177.44 μmol, HCl salt) in DCM (0.5 mL). ,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,5-a] Pyridine-6-sulfonamide (20 mg, 44.36 μmol) and 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1- A mixture of methylcyclopropyl)-8-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,5-a]pyridine-6-sulfonamide (20 mg, 41.21 μmol) was incubated at -10°C. It was added from . The mixture was stirred at 20° C. for 1 hour and then concentrated under vacuum. The crude product was diluted with MeOH (3 mL), filtered, and the filtrate was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 49%-79%, 10 min) and lyophilized to give the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1 -Methylcyclopropyl)-8-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,5-a]pyridine-6-sulfonamide (2.25 mg, 4.22 μmol, 9.51% yield, 91 % purity) as a light yellow solid and the product 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl) -8-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,5-a]pyridine-6-sulfonamide (2.66 mg, 4.60 μmol, 10.38% yield, 90% purity) was obtained as yellow Obtained as a solid.

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-((tetrahydro-2H-pyran-4- 1) Oxy) imidazo [1,5-a] pyridine-6-sulfonamide

RT 0.511 min (Method 1); m/z 486.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 9.81 (s, 1H), 7.86 (s, 1H), 7.09 (t, J = 52.0 Hz, 1H), 6.61 (s, 1H), 5.16 (s, 1H) , 4.82-4.79 (m, 1H), 4.07-4.02 (m, 2H), 3.71-3.65 (m, 2H), 2.20-2.14 (m, 2H), 2.02-1.94 (m, 2H), 1.39 (s, 3H), 0.94 (t, J = 4.0 Hz, 2H), 0.63-0.60 (m, 2H).

1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-((tetrahydro-2H- Pyran-4-yl)oxy)imidazo[1,5-a]pyridine-6-sulfonamide

RT 0.509 min (Method 1); m/z 520.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 9.78 (s, 1H), 7.08 (t, J = 52.0 Hz, 1H), 6.57 (s, 1H), 5.07 (s, 1H), 4.91-4.81 (m, 1H), 4.09-4.03 (m, 2H), 3.77-3.72 (m, 2H), 2.18-2.10 (m, 2H), 2.02-1.94 (m, 2H), 1.40 (s, 3H), 0.93 (t, J = 4.0 Hz, 2H), 0.64-0.61 (m, 2H).

Preparation of intermediate 142.1

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

2-(6-(benzylthio)-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4 in dioxane (5 mL) -Cs ₂ CO ₃ (398.43 mg, 1.22 mmol) and t-Bu Pd-G3 (52.24 mg, 61.14 μmol) was added. The mixture was degassed, purged with N ₂ (3x) and stirred at 100° C. for 16 hours under N ₂ atmosphere. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-70% petroleum ether/ethyl acetate @ 20 mL/min) to give the product 2-(6-(benzylthio)- 8-(3-methoxypropoxy)imidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (120 mg, 168.64 μmol) , 27.58% yield, 65% purity) was obtained as a yellow solid.

RT 0.565 min (Method 1); m/z 462.9 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 9.20 (s, 1H), 7.72 (s, 1H), 7.38-7.36 (m, 2H), 7.32-7.29 (m, 2H), 7.26-7.22 (m, 1H) ), 7.07 (t, J = 56.0 Hz, 1H), 6.20 (s, 1H), 4.17 (s, 2H), 4.14 (t, J = 4.0 Hz, 2H), 3.59 (t, J = 4.0 Hz, 2H) ), 3.39 (s, 3H), 2.15-2.13 (m, 2H).

Preparation of Intermediate 142.2

2-(6-(benzylthio)-1-iodo-8-(3-methoxypropoxy)imidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)- 1,3,4-thiadiazole

2-(6-(benzylthio)-8-(3-methoxypropoxy)imidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl) in MeCN (1.5 mL) To a mixture of -1,3,4-thiadiazole (70.00 mg, 151.34 μmol) was added NIS (51.07 mg, 227.01 μmol) and AcOH (27.26 mg, 454.02 μmol, 25.97 μL). The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was used directly in the next step.

Preparation of intermediate 142.3

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodo-8-(3-methoxypropoxy)imidazo[1,5-a ]Pyridine-6-sulfonyl chloride

2-(6-(benzylthio)-1-iodo-8-(3-methoxypropoxy)imidazo[1,5-a]pyridin-3-yl)-5-( To a mixture of difluoromethyl)-1,3,4-thiadiazole (70 mg, 118.96 μmol, stoichiometric, reaction mixture from previous step) H ₂ O (4.29 mg, 237.92 μmol, 4.29 μL) at 0°C. , AcOH (14.29 mg, 237.92 μmol, 13.61 μL) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (46.87 mg, 237.92 μmol) were added. The mixture was then stirred at 0°C for 2 hours. The reaction mixture was used directly in the next step.

Preparation of Example 142

N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodo-8-(3-methoxy Propoxy)imidazo[1,5-a]pyridine-6-sulfonamide

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)- in a mixture of 1-aminocyclopropanecarbonitrile (30.53 mg, 371.84 μmol) in pyridine (1.5 mL) 1-iodo-8-(3-methoxypropoxy)imidazo[1,5-a]pyridine-6-sulfonyl chloride (70 mg, 123.95 μmol, stoichiometric amount, reaction mixture from previous step) was incubated at 0°C. It was added from . The mixture was stirred at 0°C for 1 hour. The resulting mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL, 3x). The combined organic layers were washed with brine (60 mL), separated, dried and concentrated under vacuum. The resulting residue was purified by preparative TLC (petroleum ether: ethyl acetate = 1/1) to give the product N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3, 4-thiadiazol-2-yl)-1-iodo-8-(3-methoxypropoxy)imidazo[1,5-a]pyridine-6-sulfonamide (15 mg, 22.12 μmol, 17.84% Yield, 90% purity) was obtained as a yellow solid.

RT 0.491 min (Method 1); m/z 611.0 (M+H) ⁺ (ESI ⁺ ).

Preparation of Example 143

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

N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodo-8 in MeOH (3 mL) Pd/C (5 mg, 10% purity) was added to a mixture of -(3-methoxypropoxy)imidazo[1,5-a]pyridine-6-sulfonamide (15 mg, 24.57 μmol). The reaction mixture was degassed with H ₂ (balloon, 15 psi) (3x) and then stirred at 20° C. for 2 hours. The reaction was filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 22%-52%, 10 min) to give product N -(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-methoxypropoxy)imidazo[ 1,5-a]pyridine-6-sulfonamide (1.9 mg, 3.92 μmol, 15.96% yield, 100% purity) was obtained as a light yellow solid.

RT 0.511 min (Method 1); m/z 485.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (400 MHz, DMSO- d ₆ ): 9.60 (s, 1H), 7.95 (s, 1H), 7.81 (t, J = 50.8 Hz, 1H), 6.76 (s, 1H), 4.34 (t, J = 6.4 Hz, 2H), 3.55 (t, J = 6.0 Hz, 2H), 3.28 (s, 3H), 2.12-2.09 (m, 2H), 1.40 (br, 2H), 1.31 (br, 2H).

Preparation of Example 146a

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-fluoro-N-(1-(fluoromethyl)cyclopropyl)imi Polyzo[1,5-a]pyridine-6-sulfonamide

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl) in DMF (1 mL) Selectfluor (24.27 mg, 68.52 μmol) was added to a solution of imidazo[1,5-a]pyridine-6-sulfonamide (10 mg, 22.84 μmol). The mixture was degassed with N ₂ (3x) and stirred at 70° C. for 1.5 hours. The mixture was cooled to room temperature, diluted with EtOAc (10 mL) and washed with water (5 mL; 3x). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue, which was purified by preparative TLC (petroleum ether: ethyl acetate = 3:1) to give the product 8-chloro-3- (5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-fluoro-N-(1-(fluoromethyl)cyclopropyl)imidazo[1,5- a]Pyridine-6-sulfonamide (5 mg, 9.87 μmol, 28.82% yield, 90% purity) was obtained as a yellow solid.

RT 0.511 min (Method 1); m/z 455.9 (M+H) ⁺ (ESI ⁺ )

Preparation of Example 146

4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-fluoro-6-(N-(1-(fluoromethyl)cyclopropyl ) Sulfamoyl) imidazo [1,5-a] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-fluoro-N-(1-(fluoro) in dioxane (1 mL) Romethyl)cyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (5 mg, 10.97 μmol), N,N-dimethylpiperazine-1-carboxamide (6.90 mg, 43.88 μmol), and Pd-PEPPSI-IPentCl o-picolin (1.07 mg, 1.10 μmol) was added to a solution of Cs ₂ CO ₃ (10.72 mg, 32.91 μmol). The mixture was degassed with N ₂ (3x) and stirred at 100° C. for 30 min. The mixture was cooled to 20° C., filtered and the filtrate was evaporated. The residue was subjected to preparative TLC (petroleum ether: ethyl acetate = 0: 1) and preparative HPLC (column: Unisil 3-100 C18 Ultra 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 38%-68%, 10 min) and then lyophilized to give the product 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazole-2- 1)-1-fluoro-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,N-dimethylpiperazine -1-Carboxamide (6 mg, 8.85 μmol, 80.63% yield, 85% purity) was obtained as a yellow solid.

RT 0.486min (Method 1); m/z 577.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI ₃ 400 MHz): 9.76 (s, 1H), 7.01 (t, J = 54.0 Hz, 1H), 6.53 (s, 1H), 5.45 (s, 1H), 4.29 (d, J = 48.4 ㎐, 2H), 3.50 (t, J = 4.4 ㎐, 4H), 3.25 (t, J = 4.4 ㎐, 4H), 2.90 (s, 6H), 1.18-1.14 (m, 2H), 0.89 (t, J = 6.4 Hz, 1H)

Preparation of Example 147

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-1-methylimida Crude[1,5-a]pyridine-6-sulfonamide

1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluo) in dioxane (1 mL) In a solution of romethyl)cyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (20 mg, 38.70 μmol), H ₂ O (0.1 mL), K ₂ CO ₃ (10.70 mg, 77.40 μmol) , 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (3.5 M, 5.53 μL, 50% purity) and Pd(dppf)Cl ₂ (2.83 mg, 3.87 μmol) ) was added. The mixture was degassed, purged with N ₂ (3x) and stirred at 80° C. for 16 hours. After filtration, the filtrate was evaporated. The resulting residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; 30%-60%, 10 min) and directly freeze-dried to produce the product 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl) -1-Methylimidazo[1,5-a]pyridine-6-sulfonamide (13 mg, 28.48 μmol, 49.06% yield, 99% purity) was obtained as a light yellow solid.

RT 0.460 min (Method 1);m/z 451.9(M+H) ⁺ (ESI ⁺ ); ¹ HNMR (DMSO- d ₆ , 400 MHz): 9.77 (s, 1H), 8.95 (s, 1H), 7.6 (t, J = 53.2 Hz, 1H), 7.33 (s, 1H), 4.25 (d, J = 48.4 Hz, 2H), 2.78 (s,3H), 0.85-0.76 (m,4H).

Preparation of Example 148

4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)- 1-methylimidazo[1,5-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl in dioxane (0.5 mL) )-1-methylimidazo[1,5-a]pyridine-6-sulfonamide (13 mg, 28.77 μmol) in a solution of N,N-dimethylpiperazine-1-carboxamide (9.05 mg, 57.54 μmol) ), Pd-PEPPSI-IPentCl o-picolin (2.48 mg, 2.88 μmol) and Cs ₂ CO ₃ (18.75 mg, 57.54 μmol) were added. The reaction mixture was degassed with N ₂ (3x) and stirred at 100° C. for 30 min. After filtration, the filtrate was evaporated to obtain a residue, which was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; 38 %-68%, 10 min) and directly lyophilized to give the product 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N -(1-(fluoromethyl)cyclopropyl)sulfamoyl)-1-methylimidazo[1,5-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide ( 0.5 mg, 7.68e-1 μmol, 2.67% yield, 88% purity) was obtained as a yellow solid.

RT 0.453min (Method 1); m/z 573.2(M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.57 (s, 1H), 8.44 (s, 1H), 7.66 (t, J =53.2 Hz, 1H), 6.78 (s, 1H), 4.21 (d, J = 49.2 Hz, 2H), 3.46-3.44(m, 4H), 3.07-3.05 (m, 4H), 2.80 (s, 6H), 2.71 (s, 3H), 0.84-0.80(m, 2H), 0.78 -0.76 (m, 2H).

Preparation of intermediate 149.1

(5-bromo-3-chloropyridin-2-yl)methanamine hydrochloride

To a mixture of 5-bromo-3-chloropicolonitrile (2.0 g, 9.20 mmol) in tetrahydrofuran (10 mL) was added BH ₃ .THF (1 M, 11.04 mL) at 0°C. The mixture was stirred at 0°C for 30 minutes and then warmed to 20°C and stirred at this temperature for an additional 30 minutes. The mixture was cooled to 0°C and quenched by adding methanol (10 mL) dropwise over 5 minutes. The mixture was heated to 70° C. and stirred at this temperature for 30 minutes. The reaction was concentrated under vacuum to give the crude product (2.2 g) as a light brown solid. The crude product was dissolved in HCl (aq. 2M, 20 mL) and washed with dichloromethane (20 mL; 2x). The aqueous phase was concentrated in vacuo to give the product (5-bromo-3-chloropyridin-2-yl)methanamine hydrochloride (1.5 g, 4.07 mmol, 44.26% yield, 70% purity, HCl salt) as a light brown solid. Obtained.

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

Preparation of intermediate 149.2

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

To a mixture of (5-bromo-3-chloro-2-pyridyl)methanamine (1.5 g, 5.82 mmol, HCl salt) in dichloromethane (30 mL) was added DIPEA (2.25 g, 17.45 mmol) at 0°C. did. Ethyl 2-chloro-2-oxoacetate (952.77 mg, 6.98 mmol) was then added over 5 minutes and the mixture was stirred at 0° C. for 30 minutes. The mixture was warmed to 20° C. and stirred at this temperature for 30 minutes. The mixture was quenched with aqueous NaHCO ₃ solution (50 mL) and extracted with dichloromethane (50 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1 to 1:1) to give the product ethyl 2-(((5-bromo-3-chloropyridin-2-yl)methyl) Amino)-2-oxoacetate (1300 mg, 3.64 mmol, 62.57% yield, 65.6% purity) was obtained as a white solid.

RT 0.61 min (Method 1); m/z 322.8 (M+H) ⁺ (ESI ⁺ ).

Preparation of intermediate 149.3

Ethyl 6-bromo-8-chloroimidazo[1,5-a]pyridine-3-carboxylate

Pentaoxidation in a mixture of ethyl 2-(((5-bromo-3-chloropyridin-2-yl)methyl)amino)-2-oxoacetate (1300 mg, 4.04 mmol) in POCI ₃ (15 mL) at 0°C. Phosphorus (2.87 g, 20.21 mmol) was added. The mixture was heated to 110° C. and stirred at this temperature for 5 hours. The mixture was cooled to 25° C. and concentrated under vacuum. The residue was dissolved in ethyl acetate (50 mL) and washed with water (30 mL) and saturated NaHCO ₃ solution (30 mL). It was then finally concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent 0-30% ethyl acetate/petroleum ether gradient @ 30 mL/min) to give the product ethyl 6-bromo-8-chloro. Imidazo[1,5-a]pyridine-3-carboxylate (900 mg, 2.97 mmol, 73.34% yield) was obtained as a white solid.

RT 0.718 min (Method 1), m/z 304.8(M+H) ⁺ (ESI ⁺ ), 1H NMR (CDCI _3,400 MHz): 9.47 (s, 1H), 7.77 (s, 1H), 7.20 (s) , 1H), 4.65-4.42 (m, 2H), 1.57-1.42 (m, 3H).

Preparation of intermediate 149.4

6-Bromo-8-chloroimidazo[1,5-a]pyridine-3-carboxamide

A solution of ethyl 6-bromo-8-chloro-imidazo[1,5-a]pyridine-3-carboxylate (3 g, 9.88 mmol) in NH ₃ /MeOH (7 M, 59.30 mL) was incubated at 25°C. It was stirred for 16 hours. The mixture was filtered, washed with MeOH (5 mL) and the product 6-bromo-8-chloroimidazo[1,5-a]pyridine-3-carboxamide (2.6 g, 9.47 mmol, 95.83% yield) was obtained as a white solid. It was obtained as.

RT 0.45 min (Method 3); m/z 275.9 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI _3,400 MHz) δ: 9.62 (s, 1H), 7.66 (s, 1H), 7.32 (s, 1H), 7.16 (s, 1H), 5.55 (s, 1H).

Preparation of Intermediate 149.5

6-Bromo-8-chloroimidazo[1,5-a]pyridine-3-carbothioamide

To a suspension of 6-bromo-8-chloro-imidazo[1,5-a]pyridine-3-carboxamide (4 g, 14.57 mmol) in toluene (40 mL) was added TFA (1.66 g, 14.57 mmol, 1.08 mmol). mL) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with toluene (40 mL). Lawesson reagent (17.68 g, 43.72 mmol) was added and the reaction mixture was stirred at 110°C for 16 hours. The mixture was concentrated under reduced pressure and the residue was triturated with MeOH (60 mL) at 50° C. for 1 hour. After filtration, the filter cake was collected and dried under reduced pressure to give the product 6-bromo-8-chloroimidazo[1,5-a]pyridine-3-carbothioamide (3.94 g, 12.84 mmol, 88.10% yield, 94.68% purity) was obtained as a brown solid.

^1H NMR (DMSO _- d6 , 400 MHz) δ : 10.76 (s, 1H), 9.84 (s, 1H), 9.71 (s, 1H), 7.84 (s, 1H), 7.65 (s, 1H).

Preparation of Intermediate 149.6.

Ethyl 2-(6-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)thiazole-5-carboxylate

6-Bromo-8-chloro-imidazo[1,5-a]pyridine-3- in a solution of ethyl 2-chloro-3-oxo-propanoate (4.77 g, 31.67 mmol) in toluene (15 mL). Carbothioamide (2 g, 6.88 mmol) and MgSO ₄ (1.66 g, 13.77 mmol) were added. The mixture was stirred at 100° C. for 16 hours, then filtered and the filtrate was concentrated under reduced pressure. The residue was triturated in MeOH (20 mL) at 17°C for 8 h, the precipitate filtered and dried under reduced pressure to give the product ethyl 2-(6-bromo-8-chloroimidazo[1,5-a]pyridine. -3-yl)thiazole-5-carboxylate (2 g, 4.52 mmol, 87.424% yield) was obtained as a brown solid.

RT 0.702 min; m/z 385.8 (M+H) ⁺ (ESI ⁺ ); ^1H NMR (CDCI _3,400 ㎒) 9.74 (s, 1H), 8.44 (s, 1H), 7.72 (s, 1H), 7.11 (s, 1H), 4.41 -4.36 (q, J = 7.2 ㎐, 2H ), 1.41-1.37 (t, J = 7.2 Hz, 3H).

Preparation of intermediate 149.7

(2-(6-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)thiazol-5-yl)methanol

of ethyl 2-(6-bromo-8-chloro-imidazo[1,5-a]pyridin-3-yl)thiazole-5-carboxylate (1000 mg, 2.59 mmol) in THF (30 mL). DIBAL-H (1 M, 10.35 mL) was added dropwise to the solution over 6 min under N ₂ at -20°C. The reaction mixture was stirred at -20°C for 2 hours and at 0°C for an additional 2 hours. The reaction mixture was quenched with NH ₄ CI (aq., sat., 4 mL) and MeOH (4 mL), then filtered through silica gel and washed with THF (20 mL; 3x). The filtrate was collected, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was triturated in MeOH (15 mL). The precipitate was filtered and dried under vacuum to obtain the product [2-(6-bromo-8-chloro-imidazo[1,5-a]pyridin-3-yl)thiazol-5-yl]methanol (490 mg, 1.42 mmol, 54.98% yield, 100% purity) was obtained as a yellow solid.

RT 0.450 min (Method 4); m/z 345.9 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI _3,400 MHz) 9.75 (s, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.06 (s, 1H), 5.96 (s, 2H).

Preparation of intermediate 149.8

2-(6-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)thiazole-5-carbaldehyde

[2-(6-bromo-8-chloro-imidazo[1,5-a]pyridin-3-yl)thiazol-5-yl]methanol (500 mg) in 1,2-dichloroethane (7 mL) , 1.45 mmol) was added to MnO ₂ (1.26 g, 14.51 mmol). The reaction mixture was stirred at 80° C. for 20 min, filtered and the cake was washed with DCM (20 mL, 3x). The filtrate was collected, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the product 2-(6-bromo-8-chloro-imidazo[1,5-a]pyridin-3-yl)thiazol-5. -Carbaldehyde (327 mg, 931.66 μmol, 64.21% yield, 97.610% purity) was obtained as a yellow solid.

RT 0.495 min (Method 4); m/z 343.9 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI _3,400 MHz) δ : 10.01 (s, 1H), 9.83 (s, 1H), 8.48 (s, 1H), 7.81 (s, 1H), 7.18 (s, 1H).

Preparation of intermediate 149.9

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

A solution of 2-(6-bromo-8-chloro-imidazo[1,5-a]pyridin-3-yl)thiazole-5-carbaldehyde (327 mg, 954.47 μmol) in DCM (15 mL) A solution of DAST (1.54 g, 9.54 mmol, 1.26 mL) in DCM (0.6 mL) was added dropwise under N ₂ at -15°C. The mixture was stirred at -15°C for 2 hours, at 0°C for an additional 2 hours and at 20°C for an additional 3 hours. The mixture was quenched at -15°C with NH ₄ CI (aq., sat, 5 mL), diluted with water (40 mL) and extracted with DCM (20 mL, 3x). The organic phase was separated, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the product 2-(6-bromo-8-chloro-imidazo[1,5-a]pyridin-3-yl)-5. -(Difluoromethyl)thiazole (360 mg, crude) was obtained as a yellow solid.

RT 0.542 min (Method 4); m/z 366.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI _3,400 MHz) δ : 9.73-9.72 (m, 1H), 8.05-8.04 (t, J = 2.0 Hz, 1H), 7.75 (m, 1H), 7.12-6.84 (m, 2H) .

Preparation of Intermediate 149.10

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

2-(6-Bromo-8-chloro-imidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)thiazole in 1,4-dioxane (4 mL) DIEA (197.97 mg, 1.53 mmol, 266.80 μL) and phenylmethane in a solution of 234 mg, 510.59 μmol, 79.555% purity), Pd ₂ (dba) ₃ (46.76 mg, 51.06 μmol) and Thiol (63.42 mg, 510.59 μmol, 59.83 μL) was added under N ₂ . The mixture was degassed with N ₂ (3x) and stirred at 100° C. for 1 hour under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 10:1) to give the product 2-(6-benzylsulfanyl-8-chloro-imidazo[1,5-a]pyridin-3-yl)- 5-(difluoromethyl)thiazole (140 mg, 338.10 μmol, 66.22% yield, 98.504% purity) was obtained as a yellow solid.

RT 0.595 min (Method 4); m/z 408.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI _3,400 MHz) 9.43 (s, 1H), 8.00 (s, 1H), 7.68 (s, 1H), 7.34-7.30 (m, 5H), 6.97 (t, J = 55.2 Hz, 1H ), 6.90 (s, 1H), 4.15 (s, 2H).

Preparation of intermediate 149.11

2-(6-(benzylthio)-8-chloro-1-iodimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)thiazole

2-(6-Benzylsulfanyl-8-chloro-imidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)thiazole (74 mg, 181.42) in MeCN (3 mL) NIS (40.82 mg, 181.42 μmol) was added to the solution. The mixture was stirred at 25°C for 16 hours, then AcOH (32.68 mg, 544.27 μmol, 31.13 μL) was added at 25°C and the mixture was stirred for an additional 1 hour. The reaction mixture of 2-(6-(benzylthio)-8-chloro-1-iodimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)thiazole was purified without purification. It was used in the next step.

RT 0.766 min (Method 3); m/z 533.9 (M+H) ⁺ (ESI ⁺ ).

Preparation of Intermediate 149.12

8-chloro-3-(5-(difluoromethyl)thiazol-2-yl)-1-iodoimidazo[1,5-a]pyridine-6-sulfonyl chloride

2-(6-(benzylthio)-8-chloro-1-iodimidazo[1,5-a]pyridin-3-yl)-5-(difluoro) in MeCN (3 mL) at 0°C. To the previous suspension of methyl)thiazole (78 mg, 146.13 μmol, stoichiometric amount) was added AcOH (17.55 mg, 292.25 μmol, 16.71 μL), H ₂ O (5.27 mg, 292.25 μmol, 5.27 μL) and 1,3-dichlorofluoroethylene. -5,5-Dimethyl-imidazolidine-2,4-dione (57.58 mg, 292.25 μmol) was added successively. The mixture was stirred at 0°C for 1 hour. 8-Chloro-3-(5-(difluoromethyl)thiazol-2-yl)-1-iodoimidazo[1,5-a]pyridine-6-sulfonyl chloride (74.35 mg, theoretical weight) The reaction mixture was used directly in the next step without purification.

RT 0.684 min (Method 3); m/z 509.8 (M+H) ⁺ (ESI ⁺ );

Preparation of Example 149

8-chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)thiazol-2-yl)-1-iodoimidazo[1,5-a]pyridine-6 -Sulfonamides

8-chloro-3-(5-(difluoromethyl) in a solution of 1-aminocyclopropane-1-carbonitrile (51.98 mg, 438.38 μmol, HCl salt) in pyridine (2.94 g, 37.17 mmol, 3 mL) The reaction mixture containing thiazol-2-yl)-1-iodimidazo[1,5-a]pyridine-6-sulfonyl chloride (74.35 mg, crude, theoretical weight) was incubated at 0°C for 3 min. It was added dropwise. The mixture was stirred at 0°C for 1 hour, quenched with water (5 mL) and extracted with EtOAc (15 mL; 3x). The organic layers were separated, combined, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 2:1) to give the product 8-chloro-N-(1-cyanocyclopropyl)-3-[5-(difluoromethyl)thiazole- 2-yl]-1-iodo-imidazo[1,5-a]pyridine-6-sulfonamide (64 mg, 97.79 μmol, 66.92% yield, 84.915% purity) was obtained as a yellow solid.

RT 0.611 min (Method 4); m/z 555.8 (M+H) ⁺ (ESI ⁺ ); ^1H NMR (CDCI ₃ , 400 MHz) δ :10.37 (s, 1H), 8.11 (s, 1H), 7.32-7.31 (d, J = 1.2 Hz, 1H), 7.13 (s, 1H), 7.13-6.85 (t, J = 55.6 Hz, 1H), 1.67-1.62 (m, 2H), 1.27-1.24 (m, 2H).

Preparation of Example 150

8-chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)thiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide

8-Chloro-N-(1-cyanocyclopropyl)-3-[5-(difluoromethyl)thiazol-2-yl]-1-iodo-imidazo[1, Pd/C (50.00 mg, 46.98 μmol, 10% purity) was added to a solution of 5-a]pyridine-6-sulfonamide (50 mg, 89.97 μmol). The reaction was degassed with H ₂ (balloon, 15 psi, 3x) and stirred at 25° C. for 1 hour. The mixture was filtered, washed with MeOH (3 mL; 2x) and the filtrate was concentrated under reduced pressure to give the product 8-chloro-N-(1-cyanocyclopropyl)-3-[5-(difluoromethyl)thia. Zol-2-yl]imidazo[1,5-a]pyridine-6-sulfonamide (26 mg, 28.43 μmol, 31.60% yield) was obtained as a yellow solid.

RT 0.558 min (Method 3); m/z 430.1 (M+H) ⁺ (ESI ⁺ );

Preparation of Example 151

4-(6-(N-(1-cyanocyclopropyl)sulfamoyl)-3-(5-(difluoromethyl)thiazol-2-yl)imidazo[1,5-a]pyridine-8 -1)-N,N-dimethylpiperazine-1-carboxamide

N,N-dimethylpiperazine-1-carboxamide (10.97 mg, 69.79 μmol) and 8-chloro-N-(1-cyanocyclopropyl)-3-[5-(di In a solution of fluoromethyl)thiazol-2-yl]imidazo[1,5-a]pyridine-6-sulfonamide (15 mg, 34.90 μmol), Cs ₂ CO ₃ (22.74 mg, 69.79 μmol) and Pd- PEPPSI-IPentCl o-picolin (1.70 mg, 1.74 μmol) was added under N ₂ and the mixture was stirred at 100° C. for 5 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 0:1) to obtain an impure product, which was purified by preparative-HPLC (column: Phenomenex Synergi C18 150*25 mm*10 μm; mobile phase: A : 0.225% formic acid in water, B: MeCN; B%: 40%-70%, 10 min) and directly lyophilized to give the product 4-(6-(N-(1-cyanocyclopropyl)sulfa. moyl)-3-(5-(difluoromethyl)thiazol-2-yl)imidazo[1,5-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide (4.98 mg, 8.16 μmol, 23.38% yield) was obtained as a yellow solid.

RT 0.552 min (Method 3); m/z 551.1 (M+H) ⁺ (ESI ⁺ ); ^1H NMR (400 MHz, DMSO- d ₆ ) 9.67 (s, 1H), 8.42 (s, 1H), 8.32 (s, 1H), 7.90 (s, 1H), 7.50 (t, J = 54.8 Hz, 1H ), 6.61 (s, 1H), 3.38-3.36 (m, 4H), 3.35- 3.30 (m, 4H), 2.80 (s, 6H), 1.33-1.26 (m, 2H), 1.25-1.18 (m, 2H) ).

Preparation of Example 152

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

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ Pd(PPh ₃ ) ₄ (5.50 mg, 4.76 μmol) in a solution of 1,5-a]pyridine-6-sulfonamide (20 mg, 47.64 μmol) and (tributylstannyl)methanol (152.95 mg, 476.35 μmol). was added. The mixture was degassed with N ₂ (3x) and stirred at 100° C. for 16 hours under N ₂ atmosphere. The reaction mixture was cooled to 20° C., filtered and the filtrate was concentrated under vacuum. The residue was first subjected to preparative TLC (petroleum ether: ethyl acetate = 0:1) and then to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*25 mm*5 μm; mobile phase: A: 0.225% formic acid in water , B: MeCN; B%: 30%-50%, 10 min) and directly lyophilized to give the product 3-(5-(difluoromethyl)-1,3,4-thiadiazole-2. -yl)-8-(hydroxymethyl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (20 mg, 28.89 μmol, 60.64% yield, 60% purity ) was obtained as a yellow solid.

RT 0.443 min (Method 1); m/z 415.9 (M+H) ⁺ (ESI ⁺ )

Preparation of intermediate 152.1

8-(((tert-butyldimethylsilyl)oxy)methyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclo Profile) imidazo[1,5-a]pyridine-6-sulfonamide

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(hydroxymethyl)-N-(1-methylcyclopropyl) in THF (1 mL) Imidazole (2.95 mg, 43.33 μmol) in a solution of imidazo[1,5-a]pyridine-6-sulfonamide (15 mg, 21.66 μmol, 60% purity) and TBSCI (6.53 mg, 43.33 μmol, 5.31 μL). was added. The mixture was stirred at 20° C. for 16 hours, then diluted with EtOAc (20 mL) and washed with water (30 mL; 3x). The organic layer was collected, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 5:1) to give the product 8-(((tert-butyldimethylsilyl)oxy)methyl)-3-(5-(difluoromethyl)-1. ,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (15 mg, 21.24 μmol, 98.04% yield, 75 % purity) was obtained as a yellow solid.

RT 0.631 min (Method 1); m/z 530.1 (M+H) ⁺ (ESI ⁺ ).

Alternative Preparation of Example 152

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

8-(((tert-butyldimethylsilyl)oxy)methyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazole- in HCl/dioxane (4 M, 3.00 mL) A solution of 2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (15 mg, 28.32 μmol) was stirred at 20°C for 1 hour. The reaction mixture was concentrated under vacuum to give a residue, which was triturated with MeOH (0.5 mL) at 20° C. for 1 hour. After filtration, the cake was collected and dried under vacuum to give the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(hydroxymethyl)-N- (1-Methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (8.14 mg, 18.24 μmol, 64.42% yield, 93.1% purity) was obtained as a yellow solid.

RT 0.405 min (Method 1); m/z 416.0 (M+H) ⁺ (ESI ⁺ ); ^1H NMR (DMSO- d ₆ , 400 MHz): 9.82 (s, 1H), 8.56 (s, 1H), 7.98 (s, 1H), 7.69 (t, J = 53.4 Hz, 1H), 7.41 (d, J = 1.4 Hz, 1H), 5.80 (t, J = 5.6 Hz, 1H), 4.85 (d, J = 5.6 Hz, 2H), 1.19 (s, 3H), 0.70 (t, J = 5.6 Hz, 2H) , 0.46 (dd, J = 6.4 Hz, 4.8 Hz, 2H).

Preparation of intermediate 153

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imidazo[1,5-a]pyridine -6-sulfonamide

Three batches were run in parallel and combined for post-processing.

1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N- in HFIP (15 mL) and THF (15 mL) (1-(Fluoromethyl)cyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (500 mg, 967.60 μmol) was mixed with Pd/C (160 mg, 10% purity) and DIEA ( 250.11 mg, 1.94 mmol, 337.08 μL) was added. The reaction mixture was degassed with H ₂ (15 psi, 3x) and stirred at 40° C. for 16 hours. The three reaction mixtures were combined, diluted with EtOAc (50 mL), filtered and concentrated under vacuum. The resulting residue was dissolved in EtOAc (50 mL). The organic layer was washed with NaHCO ₃ (aq., sat., 30 mL) and brine (30 mL), and the organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 1.15 g of crude mixture.

50 mg of this crude residue was purified by preparative TLC (petroleum ether: ethyl acetate = 3:1) to give the product 3-(5-(difluoromethyl)-1,3,4-thiadiazole-2. -I)-N-(1-(fluoromethyl)cyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (11.4 mg, 28.26 μmol, 24.75% yield, 100% purity) was obtained as a white solid. It was obtained as.

RT 0.440 min (Method 1); m/z 403.9 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI _3,400 MHz): 10.20 (s, 1H), 7.81 (s, 1H), 7.98 (s, 1H), 7.76 (dd, J = 9.6 Hz, 0.8 Hz, 1 H), 7.36 ( dd, J = 10.8 Hz, 1.2 Hz, 1H), 7.09 (t, J = 53.6 Hz, 1H), 5.50 (s, 1H), 4.29 (d, J = 48.4 Hz), 1.15-1.11 (m, 2H) , 0.90-0.87 (dd, J= 6.4 Hz, 4.8 Hz, 2H).

The compounds listed in the table below were prepared according to the corresponding general procedures or, where specified, starting from the corresponding intermediates in a similar manner to the related compounds.

Preparation of Example 168

Oxetan-3-yl 8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine -3-carboxylate

8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine in DCM (0.5 mL) A solution of -3-carboxylic acid (10 mg, 22.20 μmol), oxetan-3-ol (1.97 mg, 26.64 μmol), DMAP (542.35 μg, 4.44 μmol) and DCC (5.50 mg, 26.64 μmol, 5.39 μL). was stirred at 20°C for 1 hour. The solution was quenched with water (10 mL) and extracted with DCM (10 mL; 3x). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue _{was subjected} to preparative-HPLC (column: Waters Purified and directly lyophilized to produce oxetan-3-yl 8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo [1,2-a]pyridine-3-carboxylate (0.9 mg, 1.71 μmol, 7.68% yield, 96% purity) was obtained as a yellow gum.

RT 0.769 min (Method 1); m/z 507.3 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI _3,400 MHz) 9.46 (s, 1H), 8.34 (s, 1H), 6.94 (s, 1H), 5.76-5.69 (m, 1H), 5.04-5.00 (m, 2H), 4.85 -4.81 (m, 2H), 3.62-3.60 (m, 4H), 3.53- 3.51 (m, 4H), 2.89 (s, 6H), 1.31 (s, 3H), 0.86-0.83 (m, 2H), 0.57 -0.54 (m, 2H).

Preparation of intermediate 169.1

tert-Butyl (8-chloro-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-3-yl)carbamate

8-chloro-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine- in t-BuOH (2.33 g, 31.37 mmol, 3 mL) and toluene (3 mL) TEA (214.80 mg, 2.12 mmol, 295.46 μL) was added to a solution of 3-carboxylic acid (280 mg, 849.11 μmol), followed by DPPA (467.35 mg, 1.70 mmol, 367.99 μL). The reaction mixture was degassed and purged with N ₂ (3x) and the mixture was stirred at 90° C. for 4 hours under N ₂ atmosphere. The mixture was poured into NaHCO ₃ (aq., sat., 10 mL) and extracted with EtOAc (10 mL, 3x). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 20-50% ethyl acetate/petroleum ether gradient @ 30 mL/min) to give the impure product, which was separated. Further purified by solvent HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 34%-64%; 10 min) and directly lyophilized. The product tert-butyl (8-chloro-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-3-yl)carbamate (75 mg, 187.09 μmol, 22.03% yield, 100% purity) was obtained as a yellow solid.

RT 0.768 min (Method 1); m/z 401.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d _6,400 MHz): 9.90 (s, 1H), 8.62 (s, 1H), 8.37 (s, 1 H), 7.66 (s, 1H), 7.57 (s, 1H), 1.48 (s, 9H), 1.12 (s, 3H), 0.64-0.73 (m, 2H), 0.41- 0.50 (m, 2H).

Preparation of intermediate 169.2

tert-Butyl (8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3 -1) Carbamate

tert-butyl (8-chloro-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-3-yl)carbamate (75) in dioxane (2 mL) mg, 187.09 μmol) in solution of Cs ₂ CO ₃ (121.91 mg, 374.18 μmol), N,N-dimethylpiperazine-1-carboxamide (58.83 mg, 374.18 μmol) and Pd-PEPPSI-IPentCl o-picolin. (8.05 mg, 9.35 μmol) was added. The reaction mixture was degassed and purged with N ₂ (3x) and then stirred at 100° C. for 4 hours under N ₂ atmosphere. The mixture was poured into water (5 mL) and extracted with EtOAc (5 mL, 3x). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was subjected to preparative-HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 34%-64%; 10 min). Purified and directly lyophilized to produce the product tert-butyl (8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1, 2-a]pyridin-3-yl)carbamate (20 mg, 36.52 μmol, 19.52% yield, 95.26% purity) was obtained as a white solid.

RT 0.839 min (Method 1); m/z 522.3 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDC ₃ , 400 MHz): 8.21 (s, 1H), 7.52 (s, 1H), 6.65 (s, 1H), 6.25 (br, 1H), 4.93 (s, 1H), 3.70-3.58 ( m, 4H), 3.57-3.45 (m,4H), 2.89 (s, 6H), 1.56 (s, 9H), 1.30 (s, 3H), 0.85 (t, J =6 Hz, 2H), 0.85 (t , J =6 Hz, 2H).

Preparation of intermediate 169.3

4-(3-amino-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxylic amides

tert-Butyl (8-(4-(dimethylcarbamoyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfa in MeOH (0.5 mL) and H ₂ O (0.5 mL) A mixture of moyl)imidazo[1,2-a]pyridin-3-yl)carbamate (8 mg, 15.34 μmol) was stirred at 120°C for 2 hours under a microwave, and the reaction mixture was concentrated under reduced pressure. The resulting residue was subjected to preparative-HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 6%-36%; 10 min). Purification and direct lyophilization yielded the product 4-(3-amino-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethyl. Piperazine-1-carboxamide (0.85 mg, 2.02 μmol, 13.15% yield, 100% purity) was obtained as an off-white solid.

RT 0.616 min (Method 1); m/z 422.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI _3,400 MHz): 8.36 (s, 1H), 7.22 (s, 1H), 6.55 (s, 1H), 4.95 (s, 1H), 3.68-3.57 (m, 4H), 3.57- 3.46 (m, 4H), 3.18-3.41 (m, 2H), 2.88 (s, 6H), 1.30 (s, 3H), 0.84 (t, J =5.6 Hz, 2H), 0.53 (t, J =6.4 Hz) , 2H).

Preparation of Example 169

4-(3-(2-chloroacetamido)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethyl Piperazine-1-carboxamide

4-[3-amino-6-[(1-methylcyclopropyl)sulfamoyl]imidazo[1,2-a]pyridin-8-yl]-N in THF (2 mL) and water (1 mL); To a solution of N-dimethyl-piperazine-1-carboxamide (10 mg, 0.0237 mmol) and NaHCO ₃ (10 mg, 0.119 mmol) was added 2-chloroacetyl chloride (4.0 mg, 0.0356 mmol) at 0°C. . The reaction mixture was stirred at 20°C for 2 hours and poured into water (5 mL). The aqueous phase was extracted with EtOAc (5 mL, 3x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative-HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 21%-51%; 10 min) Product 4-(3-(2-chloroacetamido)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N- Dimethylpiperazine-1-carboxamide (11 mg, 0.0218 mmol, 91.99% yield, 98.8% purity) was obtained as a white solid.

RT 0.709 min (Method 1); m/z 498.2 (M+H) ⁺ (ESI ⁺ ); ^1H NMR (CDCI ₃ , 400 MHz): 8.37 (br, 1H), 8.08 (s, 1H), 7.59 ( s , 1H), 6.68 (s, 1H), 5.08 (s, 1H), 4.35 (s, 2H), 3.65-3.55 (m, 4H), 3.55-3.45 (m, 4H), 2.89 (s, 6H), 1.30 (s, 3H), 0.84 (s, 2H), 0.55(s, 2H).

Preparation of Example 170

4-(3-(2-cyanoacetamido)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N- Dimethylpiperazine-1-carboxamide

4-(3-(2-chloroacetamido)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl) in THF (2 mL) To a solution of -N,N-dimethylpiperazine-1-carboxamide (9.0 mg, 0.0181 mmol) and trimethylsilylformonitrile (5.4 mg, 0.0542 mmol) was added TBAF (0.054 mL, 0.0542 mmol). The reaction mixture was stirred at 25°C for 16 hours, then poured into water (5 mL) and extracted with EtOAc (5 mL, 3x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative-HPLC (column: Phenomenex luna C18 150* 25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 17%-47%; 10 min) Product 4-(3-(2-cyanoacetamido)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N -Dimethylpiperazine-1-carboxamide (2.4 mg, 0.00475 mmol, 26.26% yield, 96.2% purity) was obtained as an off-white solid.

RT 0.765 min (Method 1); m/z 489.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI ₃ , 400 MHz): 9.23 (br s, 1H), 8.26 (s, 1H), 7.62 (s, 1H), 6.64 (s, 1H), 5.62 (s, 1H), 3.80 (s) , 2H), 3.55-3.40 (m, 8H), 2.89 (s, 6H), 1.26 (s, 3H), 0.83 (t, J =5.6 Hz, 2H), 0.52 (t, J =5.2 Hz, 2H) .

Preparation of Intermediate 171.1

tert-Butyl N-[8-[4-(dimethylcarbamoyl)piperazin-1-yl]-3-iodo-imidazo[1,2-a]pyridin-6-yl]sulfonyl-N- (1-methylcyclopropyl)carbamate

4-(3-iodo-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethyl in DCM (30 mL) To a mixture of piperazine-1-carboxamide (2.1 g, 3.94 mmol) was added Boc ₂ O (1.29 g, 5.92 mmol, 1.36 mL) and DMAP (96.38 mg, 788.88 μmol). The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/1 to 0/1) followed by preparative-HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: A: 0.225% in water NH ₄ HCO ₃ , B: MeCN; B%: 48%-68%; lyophilized to yield product tert-butyl ((8-(4-(dimethylcarbamoyl)piperazin-1-yl) )-3-iodimidazo[1,2-a]pyridin-6-yl)sulfonyl)(1-methylcyclopropyl)carbamate (1.1 g, 1.74 mmol, 44.00% yield, 99.8% purity) Obtained as a white solid.

RT 0.807 min (Method 1); m/z 633.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d _6,400 MHz): 8.35 (s, 1H), 7.85 (s, 1H), 6.59 (s, 1H), 3.62-3.50 (m, 4H), 3.30 (s, 4H), 2.78 (s, 6H), 1.52 (s, 3H), 1.28 (s, 9H), 1.01- 0.96 (m, 4H).

Preparation of Intermediate 171.2

tert-butyl ((8-(4-(dimethylcarbamoyl)piperazin-1-yl)-3-(1-ethoxyvinyl)imidazo[1,2-a]pyridin-6-yl)sulfonyl )(1-methylcyclopropyl)carbamate

tert-butyl ((8-(4-(dimethylcarbamoyl)piperazin-1-yl)-3-iodimidazo[1,2-a]pyridin-6-yl) in dry toluene (0.5 mL) Sulfonyl)(1-methylcyclopropyl)carbamate (20 mg, 31.62 μmol), tributyl(1-ethoxyvinyl)stanane (13.70 mg, 37.94 μmol, 12.81 μL) and Pd(PPh ₃ ) ₄ ( 3.65 mg, 3.16 μmol) was stirred under N ₂ at 100° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product tert-butyl ((8-(4-(dimethylcarbamoyl)piperazin-1-yl)-3-(1-ethoxyvinyl)imidazo[1,2- a]pyridin-6-yl)sulfonyl)(1-methylcyclopropyl)carbamate (18 mg, 31.21 μmol, 98.71% yield) was obtained as a yellow oil, which was used directly in the next step without further purification.

RT 0.662 min (Method 5); m/z 577.2 (M+H) ⁺ (ESI ⁺ ).

Preparation of Example 171

4-(3-acetyl-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carbox amides

tert-Butyl ((8-(4-(dimethylcarbamoyl)piperazin-1-yl)-3-(1-ethoxyvinyl)imidazo[1,2-a]pyridine- in acetone (0.5 mL) To a solution of 6-yl)sulfonyl)(1-methylcyclopropyl)carbamate (18 mg, 31.21 μmol) was added HCl (12 N, 13.00 μL). The mixture was stirred at 20°C for 1 hour, then diluted with H ₂ O (30 mL) and extracted with EtOAc (20 mL, 2x). The combined organic layers were washed with brine (30 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 30%-60%, 7 min). Purification and direct lyophilization yielded the product 4-(3-acetyl-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethyl. Piperazine-1-carboxamide (3.61 mg, 7.63 μmol, 24.44% yield, 94.77% purity) was obtained as a yellow solid.

RT 0.820 min (Method 1); m/z 449.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI ₃ , 400 MHz) 9.83 (d, J = 1.2 Hz, 1 H), 8.30 (s, 1 H), 7.01 (d, J = 1.2 Hz, 1 H), 5.05 (s, 1 H) ), 3.57-3.66 (m, 4 H), 3.49-3.57 (m, 4 H), 2.90 (s, 6 H), 2.64 (s, 3 H), 1.33 (s, 3 H), 0.81-0.92 ( m, 2 H), 0.53-0.61 (m, 2 H).

Preparation of intermediate 172.1

tert-butyl ((3-acetyl-8-(4-(dimethylcarbamoyl)piperazin-1-yl)imidazo[1,2-a]pyridin-6-yl)sulfonyl)(1-methylcyclo Profile) Carbamate

tert-Butyl ((8-(4-(dimethylcarbamoyl)piperazin-1-yl)-3-(1-ethoxyvinyl)imidazo[1,2-a]pyridine- in acetone (0.5 mL) To a solution of 6-yl)sulfonyl)(1-methylcyclopropyl)carbamate (50 mg, 86.70 μmol) was added HCl (1 N, 433.50 μL). The mixture was stirred at 20°C for 1 hour, then diluted with H ₂ O (20 mL) and extracted with EtOAc (20 mL, 2x). The combined organic layers were washed with brine (20 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH = 10/1) to give the product tert-butyl ((3-acetyl-8-(4-(dimethylcarbamoyl)piperazin-1-yl)imidazo[1 ,2-a]pyridin-6-yl)sulfonyl)(1-methylcyclopropyl)carbamate (40 mg, 72.91 μmol, 84.09% yield) was obtained as a yellow solid.

RT 0.846 min (Method 1); m/z 549.2 (M+H) ⁺ (ESI ⁺ ).

Preparation of Intermediate 172.2

tert-butyl ((8-(4-(dimethylcarbamoyl)piperazin-1-yl)-3-(1-hydroxyethyl)imidazo[1,2-a]pyridin-6-yl)sulfonyl )(1-methylcyclopropyl)carbamate

tert-butyl ((3-acetyl-8-(4-(dimethylcarbamoyl)piperazin-1-yl)imidazo[1,2-a]pyridine- in THF (0.2 mL) and MeOH (0.2 mL) NaBH ₄ (10.34 mg, 273.40 μmol) was added to a solution of 6-yl)sulfonyl)(1-methylcyclopropyl)carbamate (30 mg, 54.68 μmol). The resulting mixture was stirred at 20°C for 1 hour, then diluted with H ₂ O (20 mL) and extracted with EtOAc (20 mL, 2x). The combined organic layers were washed with brine (20 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the product tert-butyl ((8-(4-(dimethylcarbamoyl)piperazine-1 -yl)-3-(1-hydroxyethyl)imidazo[1,2-a]pyridin-6-yl)sulfonyl)(1-methylcyclopropyl)carbamate (30 mg, 54.48 μmol, 99.63% Yield) was obtained as a yellow solid.

RT 0.581 min (Method 5); m/z 551.3 (M+H) ⁺ (ESI ⁺ ).

Preparation of Example 172

4-(3-(1-hydroxyethyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethylpipe Razine-1-carboxamide

tert-Butyl ((8-(4-(dimethylcarbamoyl)piperazin-1-yl)-3-(1-hydroxyethyl)imidazo[1,2-a]pyridine- in DCM (0.3 mL) To a solution of 6-yl)sulfonyl)(1-methylcyclopropyl)carbamate (8 mg, 14.53 μmol) was added HCl/dioxane (4 M, 240.00 μL). The mixture was stirred at 20°C for 1 hour, then diluted with H ₂ O (20 mL) and extracted with EtOAc (20 mL, 2x). The combined organic layers were washed with brine (20 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 12%-42%, 10 min) and directly By lyophilization, the product 4-(3-(1-hydroxyethyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N, N-dimethylpiperazine-1-carboxamide (1.93 mg, 4.16 μmol, 28.64% yield, 97.131% purity) was obtained as a yellow solid.

RT 0.705 min (Method 1); m/z 451.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI _3,400 MHz) 8.65 (d, J = 1.2 Hz, 1 H), 7.53 (s, 1 H), 6.68 (s, 1 H), 5.20-5.27 (m, 1 H), 4.97 (s, 1 H), 3.53-3.63 (m, 4 H), 3.46-3.53 (m, 5 H), 2.88 (s, 6 H), 1.80 (d, J = 6.4 Hz, 3 H), 1.30 ( s, 3 H), 0.81-0.88 (m, 2 H), 0.50-0.56 (m, 2 H).

Preparation of Example 173

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclo Profile) imidazo[1,2-a]pyridine-6-sulfonamide

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ 2-methyl-1-(piperazin-1-yl)propan-1-one (17 mg, 0.107 mmol) in a solution of 1,2-a]pyridin-6-sulfonamide (30 mg, 0.0715 mmol), Cs ₂ CO ₃ (47 mg, 0.143 mmol) was added at room temperature. Pd-PEPPSI-IPentCl o-picolin (3.5 mg, 0.00357 mmol) was then added to this solution in the glove box. The mixture was stirred under Ar outside the glove box for 1 hour at 100°C. The reaction mixture was cooled to room temperature, diluted with H ₂ O (20 mL) and extracted with EtOAc (20 mL, 2x). The combined organic layers were washed with brine (20 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 40%-70%, 10 min) and directly By lyophilization, the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-isobutyrylpiperazin-1-yl)-N-( 1-Methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (3.0 mg, 0.00553 mmol, 7.74% yield) was obtained as an off-white solid.

RT 0.619 min (Method 5); m/z 540.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI ₃ , 400 MHz) 9.92 (s, 1 H), 8.19 (s, 1 H), 6.96-7.24 (m, 2 H), 5.11 (s, 1 H), 3.93 (s, 2 H) ), 3.82 (s, 2 H), 3.67 (s, 2 H), 3.59 (s, 2 H), 2.84- 2.91 (m, 1 H), 1.37 (s, 3 H), 1.19 (d, J = 6.8 Hz, 6 H), 0.89-0.94 (m, 2 H), 0.57-0.62 (m, 2 H).

Preparation of intermediate 174.1

Ethyl 6-(N-(tert-butoxycarbonyl)-N-(1-methylcyclopropyl)sulfamoyl)-8-chloroimidazo[1,2-a]pyridine-3-carboxylate

of ethyl 8-chloro-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridine-3-carboxylate (120 mg, 0.335 mmol) in DCM (1.5 mL) Boc ₂ O (95 mg, 0.436 mmol) and DMAP (8.2 mg, 0.0671 mmol) were added to the solution. The reaction was stirred at 20°C for 1 hour, then diluted with H ₂ O (20 mL) and extracted with EtOAc (20 mL, 2x). The organic layer was washed with brine (20 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the product ethyl 6-(N-(tert-302 butoxycarbonyl)-N-(1- Methylcyclopropyl)sulfamoyl)-8-chloroimidazo[1,2-a]pyridine-3-carboxylate (120 mg, 0.262 mmol, 78.14% yield) was obtained as a yellow solid.

RT 0.994 min (Method 1); m/z 458.1 (M+H) ⁺ (ESI ⁺ ).

Preparation of Intermediate 174.2

tert-Butyl ((8-chloro-3-(hydroxymethyl)imidazo[1,2-a]pyridin-6-yl)sulfonyl)(1-methylcyclopropyl)carbamate

Ethyl 6-(N-(tert-butoxycarbonyl)-N-(1-methylcyclopropyl)sulfamoyl)-8-chloroimidazo[1,2-a]pyridine-3- in THF (1 mL) To a solution of carboxylate (130 mg, 0.284 mmol) was added dropwise DIBAL-H (1 M, 1.1 mL, 1.14 mmol) in THF at -78°C. The reaction mixture was slowly warmed to 20° C. and stirred for 1 hour. The reaction mixture was then diluted with saturated NH ₄ CI (20 mL) and extracted with EtOAc (20 mL, 2x). The combined organic layers were washed with brine (20 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate/petroleum ether @ 60 mL/min) to give the product tert-butyl ((8-chloro-3- (Hydroxymethyl)imidazo[1,2-a]pyridin-6-yl)sulfonyl)(1-methylcyclopropyl)carbamate (80 mg, 0.192 mmol, 67.76% yield) was obtained as a yellow solid. .

RT 0.592 min (Method 5); m/z 416.0 (M+H) ⁺ (ESI ⁺ ).

Preparation of intermediate 174.3

tert-Butyl ((8-chloro-3-(methoxymethyl)imidazo[1,2-a]pyridin-6-yl)sulfonyl)(1-methylcyclopropyl)carbamate

tert-Butyl ((8-chloro-3-(hydroxymethyl)imidazo[1,2-a]pyridin-6-yl)sulfonyl)(1-methylcyclopropyl)carbamate in DMF (0.5 mL) (80 mg, 0.192 mmol) was added NaH (12 mg, 0.289 mmol, 60% purity) and Mel (0.036 mL, 0.577 mmol) at 0°C. The mixture was stirred at 20°C for 1 hour, then diluted with NH ₄ CI (aq. sat., 20 mL) and extracted with EtOAc (20 mL, 2x). The organic layer was washed with brine (20 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-20% EtOAc/petroleum ether gradient @ 60 mL/min) to give the product tert-butyl ((8-chloro-3 -(methoxymethyl)imidazo[1,2-a]pyridin-6-yl)sulfonyl)(1-methylcyclopropyl)carbamate (50 mg, 0.116 mmol, 60.46% yield) was obtained as a yellow solid. did.

RT 0.636 min ( Method 5 ); m/z 430.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz) 8.84 (d, J = 1.6 Hz, 1 H), 7.87 (s, 1 H), 7.68 (d, J = 1.6 Hz, 1 H), 4.89 (s, 2 H), 3.26 (s, 3 H), 1.50 (s, 3 H), 1.33 (s, 9 H), 0.87-1.13 (m, 4 H).

Preparation of intermediate 174.4

tert-butyl ((8-(4-(dimethylcarbamoyl)piperazin-1-yl)-3-(methoxymethyl)imidazo[1,2-a]pyridin-6-yl)sulfonyl)( 1-methylcyclopropyl)carbamate

tert-butyl ((8-chloro-3-(methoxymethyl)imidazo[1,2-a]pyridin-6-yl)sulfonyl)(1-methylcyclopropyl)carba in dioxane (0.5 mL) N,N-dimethylpiperazine-1-carboxamide (14 mg, 0.0872 mmol) and Cs ₂ CO ₃ (38 mg, 0.116 mmol) were added to a solution of mate (25 mg, 0.0582 mmol) at room temperature. Pd-PEPPSI-IPentCl o-picolin (2.8 mg, 0.00291 mmol) was then added to this solution in the glove box. The mixture was stirred under Ar outside the glove box for 1 hour at 100°C. The reaction mixture was cooled to room temperature, diluted with H ₂ O (20 mL) and extracted with EtOAc (20 mL, 2x). The combined organic layers were washed with brine (20 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the product tert-butyl ((8-(4-(dimethylcarbamoyl)piperazine-1 -yl)-3-(methoxymethyl)imidazo[1,2-a]pyridin-6-yl)sulfonyl)(1-methylcyclopropyl)carbamate (30 mg, 0.0545 mmol, 93.69% yield) was obtained.

RT 0.865 min (Method 1); m/z 551.2 (M+H) ⁺ (ESI ⁺ ).

Preparation of Example 174

4-(3-(methoxymethyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethylpiperazine- 1-carboxamide

tert-Butyl ((8-(4-(dimethylcarbamoyl)piperazin-1-yl)-3-(methoxymethyl)imidazo[1,2-a]pyridine-6- in DCM (0.5 mL) To a mixture of 1) sulfonyl) (1-methylcyclopropyl) carbamate (30 mg, 0.0545 mmol) was added HCl/dioxane (4 N, 0.50 mL). The reaction mixture was stirred at 20° C. for 1 hour and then concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 22%-52%, 10 min) and directly 4-(3-(methoxymethyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethyl by freeze-drying Piperazine-1-carboxamide (3.8 mg, 0.00835 mmol, 15.33% yield) was obtained as an off-white solid.

RT 0.506 min (Method 5); m/z 451.3 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI ₃ , 400 MHz) 8.48 (d, J = 1.2 Hz, 1 H), 7.62 (s, 1 H), 6.71 (s, 1 H), 4.99 (s, 1 H), 4.77 (s , 2 H), 3.56-3.65 (m, 4 H), 3.48-3.56 (m, 4 H), 3.36 (s, 3 H), 2.89 (s, 6 H), 1.30 (s, 3 H), 0.82 -0.88 (m, 2 H), 0.51-0.57 (m, 2 H).

Preparation of Example 175

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(N,S-dimethylsulfomidoyl)piperidin-1-yl )-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl) in dioxane (0.5 mL) at room temperature. In a solution of imidazo[1,2-a]pyridin-6-sulfonamide (30 mg, 0.0715 mmol) was added methyl(methylimino)(piperidin-4-yl)-λ6-sulfanone (23 mg, 0.107 mmol). mmol, HCl salt), Cs ₂ CO ₃ (70 mg, 0.214 mmol) were added. Pd-PEPPSI-IPentCl o-picolin (3.5 mg, 0.00357 mmol) was then added to this mixture in a glove box at room temperature. The mixture was stirred under Ar ₂ outside the glove box for 1 hour at 100°C. The reaction mixture was purified by preparative TLC (PE/EtOAc=1/1) to give the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4 -(N,S-dimethylsulfonimidoyl)piperidin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (2.2 mg, 0.00367 mmol) , 5.14% yield) was obtained as a yellow gum.

RT 0.765 min (Method 1); m/z 560.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI ₃ , 400 MHz) 9.83 (d, J = 1.6 Hz, 1 H), 8.11 (s, 1 H), 6.87-7.17 (m, 2 H), 5.08 (s, 1 H), 4.39 -4.58 (m, 2 H), 3.10-3.22 (m, 1 H), 2.76-2.91 (m, 8 H), 2.26-2.40 (m, 2 H), 1.97-2.10 (m, 2 H), 1.29 (s, 3 H), 0.83-0.87 (m, 2 H), 0.49-0.56 (m, 2 H).

Preparation of Example 176a

tert-Butyl 6-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo [1,5-a]pyridin-8-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate

tert-Butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (63 mg, 0.298 mmol) and 8-chloro-3-(5-(difluoromethyl) in dioxane (1.5 mL) In a solution of -1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (50 mg, 0.119 mmol) Cs ₂ CO ₃ (78 mg, 0.238 mmol) was added. The mixture was degassed with N ₂ (3x) and then Pd-PEPPSI-IPentCl o-picolin (12 mg, 0.0119 mmol) was added. The mixture was stirred at 90° C. for 2 h under N ₂ and purified by preparative TLC (petroleum ether/EtOAc = 2/1) to give the product tert-butyl 6-(3-(5-(difluoromethyl)-1, 3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2,6-diazas Pyro[3.4]octane-2-carboxylate (20 mg, 0.0336 mmol, 28.19% yield) was obtained as a yellow solid.

RT 0.524 min (Method 1); m/z 596.4 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz) 9.38 (s, 1 H), 8.33 (s, 1 H), 8.18 (s, 1 H), 7.49-7.82 (m, 1 H), 6.13 (s, 1 H), 3.91-3.98 (m, 2 H), 3.82-3.90 (m, 4 H), 3.68 (t, J = 6.8 Hz, 2 H), 2.22-2.30 (m, 2 H), 1.39 (s) , 9 H), 1.19 (s, 3 H), 0.73 (m, 2 H), 0.39-0.50 (m, 2 H).

Preparation of Example 176

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(2,6-diazaspiro[3.4] octane-6-yl)imidazo[1,5-a]pyridine-6-sulfonamide

tert-Butyl 6-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl) in DCM (1 mL) ) Sulfamoyl) imidazo [1,5-a] pyridin-8-yl) -2,6-diazaspiro [3.4] octane-2-carboxylate (20 mg, 0.0336 mmol) in a solution of TFA (0.67 mL, 9.00 mmol) was added. The mixture was stirred at 20° C. for 1 hour and then concentrated under reduced pressure. The residue was stirred with MTBE at 20° C. for 1 minute. The resulting suspension was left for a while and then the supernatant was discarded (3x). The solid was collected and dried under vacuum. The residue was dissolved in water (10 mL) and directly lyophilized to give the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclo Propyl)-8-(2,6-diazaspiro[3.4]octan-6-yl)imidazo[1,5-a]pyridine-6-sulfonamide (4.8 mg, 0.00713 mmol, 21.25% yield, TFA salt) ) was obtained as a yellow solid.

RT 0.362 min (Method 1); m/z 496.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d _6,400 MHz) 9.41 (s, 1 H), 8.50-8.83 (m, 2 H), 8.38 (s, 1 H), 8.15 (s, 1 H), 7.51-7.84 ( m, 1 H), 6.13 (s, 1 H), 4.09-4.17 (m, 2 H), 3.91- 4.02 (m, 4 H), 3.67-3.76 (m, 2 H), 2.34 (m, 2 H) ), 1.20 (s, 3 H), 0.70-0.77 (m, 2 H), 0.43-0.49 (m, 2 H).

Preparation of Example 177a

tert-Butyl 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl) Cyclopropyl) sulfamoyl) imidazo [1,5-a] pyridin-8-yl) piperazine-1-carboxylate

1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl) in dioxane (1.5 mL) in a solution of cyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (25 mg, 52.93 μmol) and tert-butyl piperazine-1-carboxylate (23.58 mg, 105.87 μmol, HCl salt). Pd-PEPPSI-IPentCl o-picolin (2.57 mg, 2.65 μmol) and Cs ₂ CO ₃ (51.74 mg, 158.80 μmol) were added and the mixture was degassed with N ₂ (3x). The mixture was then stirred at 90° C. for 5 hours, cooled to room temperature, filtered and the filtrate concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether/EtOAc = 2/1) to give the product tert-butyl 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadia Zol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)piperazine-1-carboxylate ( 20 mg, 28.94 μmol, 54.66% yield, 90% purity) was obtained as a yellow solid.

RT 0.549 min (Method 5); m/z 622.3 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz) 9.67 (s, 1H), 8.94 (s, 1H), 7.76 (t, J = 52.8 Hz, 1H), 6.92 (s, 1H), 4.29 (d, J = 48.4 Hz, 2H), 3.67-3.65 (m, 4H), 3.15-3.12 (m, 4H), 1.51 (s, 9H), 0.96-0.90 (m, 2H), 0.86-0.83 (m, 2H).

Preparation of Example 177b

1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8-(piperazine -1-1) imidazo[1,5-a]pyridine-6-sulfonamide formate

tert-Butyl 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl) in HCl/dioxane (1 mL, 4.00 mmol, 4N) -6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)piperazine-1-carboxylate (30 mg, 48.23 μmol) The mixture was stirred at 25° C. for 1 hour and concentrated under vacuum to give the crude product (30 mg). 15 mg was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 15%-45%, 10 min) and lyophilized. The product 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8-( Piperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide formate (3.21 mg, 5.43 μmol, 25.51% yield, 96% purity, FA salt) was obtained as a yellow solid.

RT 0.367 min (Method 3); m/z 522.3 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.59 (s, 1H), 8.91 (br, 1H), 8.23 (d, J = 1.6 Hz, 1H), 7.70 (t, J = 53.2,1H), 6.81 (s, 1H), 4.23 (t, J = 48.4,2H), 3.75-3.02 (m, 4H), 3.02-2.96 (m, 4H), 0.90-0.85 (m, 2H), 0.81-0.76 (m , 2H).

Preparation of Example 177

4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl) Sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N-methylpiperazine-1-carboxamide

1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N in THF (0.2 mL) and NaHCO ₃ (aq., sat, 1.5 mL) -(1-(fluoromethyl)cyclopropyl)-8-(piperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide (15 mg, 28.74 μmol) Bamate chloride (5.37 mg, 57.47 μmol) was added at 0°C. The mixture was stirred at 20°C for 30 min, then diluted with DCM (10 mL), washed with water (5 mL; 3x) and separated. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuo. The residue was subjected to preparative TLC (petroleum ether: EtOAc = 1/1) and preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B% : 37%-67%, 10 min) to obtain an impure product, which was further purified by trituration with MeOH (0.5 mL, 20°C, 5 min). The solid was collected by filtration and dissolved in MeCN (1 mL). Water (15 mL) was added to the solution and lyophilized to obtain the product 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6. -(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N-methylpiperazine-1-carboxamide (6.04 mg, 10.36 μmol, 36.05% yield, 99.3% purity) was obtained as a yellow solid.

RT 0.452 min (Method 5); m/z 579.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz) 9.60 (s, 1H), 8.88 (s, 1H), 7.69 (t, J = 52.8 Hz, 1H), 6.84 (s, 1H), 6.59-6.57 (m , 1H), 4.22 (d, J = 48.4 Hz, 2H), 3.62-3.52 (m, 4H), 3.14-2.99 (m, 4H), 2.61 (d, J = 4.4 Hz, 3H), 0.90-0.84 ( m, 2H), 0.81-0.75 (m, 2H).

Preparation of Example 178a

(S)-tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfa moyl)imidazo[1,5-a]pyridin-8-yl)-2-methylpiperazine-1-carboxylate

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo in dioxane (3 mL) [ 1,5-a]pyridine-6-sulfonamide (100 mg, 0.238 mmol), tert-butyl (S)-2-methylpiperazine-1-carboxylate (191 mg, 0.953 mmol), Pd-PEPPSI- A mixture of IPentCl o-picolin (23 mg, 0.0238 mmol), Cs ₂ CO ₃ (233 mg, 0.715 mmol) was degassed and purged with N ₂ (3x). The mixture was stirred at 95° C. for 4 hours under N ₂ atmosphere, cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: EtOAc = 2/1) to give the product (S)-tert-butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadia Zol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-methylpiperazine-1-carboxylate ( 65 mg, 0.105 mmol, 43.95% yield) was obtained as a yellow solid.

RT 0.537 min (Method 5); m/z 528.2 (M-56+H)+ (ESI+); ¹ H NMR (CDCI _3,400 MHz,): 9.87 (s, 1H), 7.73 (s, 1H), 7.09 (t, J = 54 Hz, 1H), 6.65 (s, 1H), 5.08 (s, 1H) ), 4.47-4.44 (m, 1H), 4.07 (d, J = 13.2 Hz, 1H), 3.62-3.34 (m, 2H), 3.37 (t, J = 12.8 Hz, 1H), 3.08-2.94 (m, 2H), 1.52 (s, 9H), 1.47 (d, J= 6.8 Hz, 3H), 1.39 (s, 3H), 0.94 (s, 2H), 0.61 (s, 2H).

Preparation of Example 178

(S)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(3-methylpiperazine- 1-1) imidazo[1,5-a]pyridine-6-sulfonamide formate

(S)-tert-butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl in HCl/dioxane (2.0 mL, 0.0857 mmol, 4 N) )-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-methylpiperazine-1-carboxylate (50 mg, 0.0857 mmol ) The solution was stirred at 20°C for 1 hour. After concentration under reduced pressure, the crude product was triturated with MeOH (0.5 mL) at 20°C for 5 min. The solid was collected by filtration and subjected to preparative HPLC (column: Phenomenex Luna C18 150*25 mm*5 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 18%-48%, 10 min ) and directly lyophilized to obtain the product (S)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl )-8-(3-methylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide formate (35 mg, 0.0661 mmol, 77.15% yield, FA salt) as a yellow solid. Obtained.

RT 0.358 min (Method 3); m/z 484.3 (M+H)+ (ESI+); ¹ H NMR (CDCI _3,400 MHz): 9.87 (s, 1H), 8.31 (s, 1H), 7.70 (s, 1H), 7.09 (t, J = 54 Hz, 1H), 6.70 (s, 1H) , 5.44-5.38 (m, 1H), 3.66 (t, J= 15.2 Hz, 2H), 310 3.63-3.25 (m, 3H), 3.12 (t, J= 11.6 Hz, 1H), 2.83 (t, J= 11.6 Hz, 1H), 1.38 (s, 3H), 1.32 (d, J = 6.4 Hz, 3H), 0.95-0.92 (m, 2H), 0.61-0.58 (m, 2H).

Preparation of Example 179

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

(S)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclo in THF (0.5 mL) and water (0.5 mL) In a solution of propyl)-8-(3-methylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide formate (20 mg, 0.0378 mmol, FA salt), NaHCO ₃ (25 mg, 0.302 mmol) and 2-methylpropanoyl chloride (8.0 mg, 0.0755 mmol) were added. The mixture was stirred at 0°C for 1 hour and then diluted with water (20 mL) and extracted with EtOAc (50 mL, 3x). The combined organic layers were washed with brine (25 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 44%-74%, 10 min) and directly frozen. Dry to produce (S)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-isobutyryl-3-methylpiperazine-1 -yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (3.1 mg, 0.00558 mmol, 14.77% yield) was obtained as a yellow solid.

RT 0.487 min (Method 3); m/z 554.4 (M+H)+ (ESI+); ¹ H NMR (CDC ₃ , 400 MHz): 9.89 (s, 1H), 7.74 (s, 1H), 7.09 (t, J= 54 Hz, 1H), 6.66 (s, 1H), 5.11 (s, 1H) , 5.06-486 (m, 0.5H), 4.78-4.56 (m, 0.5H), 4.47- 4.21 (m, 0.5H), 4.07-3.83 (m, 0.5H), 3.62-3.75 (m, 2.5H) , 3.16-3.32 (m, 0.5H), 2.90-3.11 (m, 2H), 2.77- 2.88 (m, 1H), 1.49 (br d, J = 7.60 Hz, 2H), 1.40 (s, 3H), 1.21 (br d, J = 6.64 Hz, 7H), 0.94 (br s, 2H), 0.61 (s, 2H).

Preparation of Example 180a

(S)-tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfa moyl)imidazo[1,5-a]pyridin-8-yl)-2-ethylpiperazine-1-carboxylate

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ 1,5-a]pyridine-6-sulfonamide (30 mg, 0.0715 mmol) in a mixture of (S)-tert-butyl 2-ethylpiperazine-1-carboxylate (31 mg, 0.143 mmol), Cs ₂ CO ₃ (70 mg, 0.214 mmol) and Pd-PEPPSI-IPentCl o-picolin (7.0 mg, 0.00715 mmol) were added. The reaction mixture was degassed with N ₂ (3x), stirred at 98° C. for 1 hour and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by preparative TLC (petroleum ether: ethyl acetate = 1:1) to give the product (S)-tert-butyl 4-(3-(5-(difluorofluoroethylene) Romethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)- 2-Ethylpiperazine-1-carboxylate (25 mg, 0.0387 mmol, 54.14% yield, 92.4% purity) was obtained as a yellow solid.

RT 0.597 min (Method 4); m/z 620.2 (M+Na) ⁺ (ESI ⁺ ); ^1H NMR (CDCI ₃ , 400 MHz): 9.87 (s, 1H), 7.72 (s, 1H), 7.08 (t, J = 54.0 Hz, 1H), 6.65 (s, 1H), 5.09 (s, 1H) , 4.30-4.14 (m, 2H), 3.70-3.49 (m, 2H), 3.38-3.19 (m, 1H), 3.11-2.88 (m, 2H), 2.15-2.07 (m, 1H), 1.79-1.71 ( m, 1H), 1.51 (s, 9H), 1.39 (s, 3H), 1.00 (t, J= 7.2 Hz, 3H), 0.96-0.90 (m, 2H), 0.64-0.57 (m, 2H).

Preparation of Example 180

(S)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-ethylpiperazin-1-yl)-N-(1- Methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide formate

(S)-tert-butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6 in DCM (0.5 mL) and TFA (0.1 mL) A solution of -(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-ethylpiperazine-1-carboxylate (25 mg, 0.0402 mmol) was stirred at 25°C for 1 hour. The mixture was concentrated under vacuum to obtain a residue, which was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 um; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 12%- 42%, 15 min) and directly lyophilized to obtain the product (S)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3- Ethylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide formate (9.4 mg, 0.0168 mmol, 41.79% yield, 97.8% purity, FA salt) was obtained as a yellow solid.

RT 0.366 min (Method 4); m/z 498.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.58 (s, 1H), 8.43 (br, 1H), 8.23 (s, 1H), 7.96 (s, 1H), 7.67 (t, J= 53.2 Hz, 1H), 6.67 (s, 1H), 3.63-3.58 (m, 2H), 3.11- 3.04 (m, 1H), 3.02-2.94 (m, 1H), 2.89-2.78 (m, 2H), 2.54-2.56 ( m, 1H), 1.46-1.42 (m, 2H), 1.15 (s, 3H), 0.96 (t, J = 7.6 Hz, 3H), 0.77-0.67 (m, 2H), 0.47-0.42 (m, 2H) .

Preparation of Example 181a

(R)-tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfa moyl)imidazo[1,5-a]pyridin-8-yl)-2-ethylpiperazine-1-carboxylate

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ (R)-tert-butyl 2-ethylpiperazine-1-carboxylate (31 mg, 0.143 mmol) in a solution of 1,5-a]pyridine-6-sulfonamide (30 mg, 0.0715 mmol), Cs ₂ CO ₃ (70 mg, 0.214 mmol) and Pd-PEPPSI-IPentCl o-picolin (7.0 mg, 0.00715 mmol) were added. The reaction mixture was degassed with N ₂ (3x), then stirred at 98° C. for 1 hour and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by preparative TLC (petroleum ether: ethyl acetate = 1:1) to give the product (R)-tert-butyl 4-(3-(5-(difluoro) Romethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)- 2-Ethylpiperazine-1-carboxylate (20 mg, 0.0333 mmol, 46.56% yield, 99.4% purity) was obtained as a yellow solid.

RT 0.591 min (Method 4), m/z 620.1 (M+Na) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI _3,400 MHz) 9.87 (s, 1H), 7.72 (s, 1H), 7.08 (t, J = 53.6 Hz, 1H), 6.64 (s, 1H), 5.09 (s, 1H), 4.28-4.14 (m, 2H), 3.70-3.49 (m, 2H), 3.38- 3.19 (m, 1H), 3.11-2.88 (m, 2H), 2.15-2.07 (m, 1H), 1.82-1.71 (m) , 1H), 1.51 (s, 9H), 1.39 (s, 3H), 1.00 (t, J = 7.6 Hz, 3H), 0.96-0.90 (m, 2H), 0.64-0.58 (m, 2H).

Preparation of Example 181

(R)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-ethylpiperazin-1-yl)-N-(1- Methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide formate

(R)-tert-butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6 in DCM (0.2 mL) and TFA (0.04 mL) A mixture of -(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-ethylpiperazine-1-carboxylate (20 mg, 0.0335 mmol) was stirred at 25°C for 1 hour. The mixture was concentrated under vacuum to give a residue, which was subjected to preparative HPLC (column: Phenomenex luna C18 150 *25 mm* 10 um; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 13%- 43%, 10 min) and directly lyophilized to produce the product (R)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3- Ethylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide formate (7.6 mg, 0.0133 mmol, 39.57% yield, 95.6% purity, FA salt) was obtained as a yellow solid.

RT 0.363 min (Method 4); m/z 498.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.57 (s, 1H), 8.43 (br, 1H), 8.19 (s, 1H), 7.97 (s, 1H), 7.67 (t, J = 53.2 Hz, 1H), 6.67 (d, J = 0.8 Hz, 1H), 3.63-3.60 (m, 2H), 3.11-3.04 (m, 1H), 3.02-2.94 (m, 1H), 2.89-2.78 (m, 2H) , 2.56 (br d, J = 10.8 Hz, 1H), 1.51-1.42 (m, 3142H), 1.14 (s, 3H), 0.96 (t, J= 7.6 Hz, 3H), 0.75-0.69 (m, 2H) , 0.47-0.42 (m, 2H).

Preparation of intermediate 182.1

tert-Butyl 4-((2-(dimethylamino)ethyl)(methyl)carbamoyl)piperazine-1-carboxylate

To a solution of N ¹ ,N ¹ ,N ² -trimethylethane-1,2-diamine (80 mg, 0.783 mmol) and DIEA (0.27 mL, 1.57 mmol) in DCM (4 mL), tert- A solution of butyl 4-(chlorocarbonyl)piperazine-1-carboxylate (234 mg, 0.94 mmol) was added at 0°C. The reaction mixture was stirred at 20° C. for 15 minutes and then concentrated under vacuum. The resulting residue was diluted with saturated NaHCO ₃ (20 mL) and extracted with EtOAc (20 mL, 2x). The combined organic layers were washed with brine (20 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give tert-butyl 4-((2-(dimethylamino)ethyl)(methyl)carbamoyl. ) Piperazine-1-carboxylate (200 mg, 0.496 mmol, 63.37% yield) was obtained as a white solid.

¹ H NMR (CDCl ₃ , 400 MHz) 3.40-3.45 (m, 4H), 3.30-3.37 (m, 2H), 3.13-3.21 (m, 4H), 2.89 (s, 3H), 2.49-2.57 (m, 2H), 2.29 (s, 6H), 1.46 (s, 9H).

Preparation of intermediate 182.2

N-(2-(dimethylamino)ethyl)-N-methylpiperazine-1-carboxamide hydrochloride

of tert-butyl 4-((2-(dimethylamino)ethyl)(methyl)carbamoyl)piperazine-1-carboxylate (80 mg, 0.254 mmol) in HCl/dioxane (1.5 mL, 0.254 mmol) The mixture was stirred at 25°C for 2 hours. The resulting mixture was concentrated under vacuum. The residue was triturated with MTBE at 20°C for 1 minute. The resulting suspension was left for a while and the supernatant was then discarded (3x). The solid was collected and dried under reduced pressure to produce N-(2-(dimethylamino)ethyl)-N-methylpiperazine-1-carboxamideN-(2-(dimethylamino)ethyl)-N-methylpiperazine-1 -Carboxamide hydrochloride (46 mg, 0.165 mmol, 64.89% yield, HCl salt) was obtained as a colorless oil.

Preparation of Example 182

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

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl) in 1,4-dioxane (1 mL) N-(2-(dimethylamino)ethyl)-N-methylpiperazine-1-carboxamide (36) was added to a mixture of imidazo[1,5-a]pyridine-6-sulfonamide (30 mg, 0.0715 mmol). mg, 0.143 mmol, HCl salt), Cs ₂ CO ₃ (47 mg, 0.143 mmol) and Pd-PEPPSI-IPentCl o-picolin (7.0 mg, 0.00715 mmol) were added. The mixture was degassed, purged with N ₂ (3x) and stirred at 100° C. for 2 hours under N ₂ atmosphere. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm* 10 um; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 15%-45%, 10 min) and directly frozen. Dry to give the product 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo [1,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N-methylpiperazine-1-carboxamide (5.8 mg, 0.00956 mmol, 13.38% yield) was obtained as yellow Obtained as a solid.

RT 0.361 min (Method 4); m/z 598.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI _3,400 MHz) 9.88 (s, 1H), 7.71 (s, 1H), 7.08 (t, J = 53.6 Hz, 1H), 6.67 (s, 1H), 5.27 (s, 1H), 3.51-3.55 (m, 4H), 3.44 (t, J = 6.8 Hz, 2H), 3.33-3.37 (m, 4H), 2.98 (s, 3H), 2.68 (t, J = 7.2 Hz, 2H), 2.41 (s, 6H), 1.38 (s, 3H), 0.91-0.95 (m, 2H), 0.57-0.62 (m, 2H)

Preparation of Example 183a

tert-Butyl 3-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo [1,5-a]pyridin-8-yl)-3,6-diazabicyclo[3.2.1]octane-6-carboxylate

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo in dioxane (1 mL) [ 1,5-a]pyridine-6-sulfonamide (50 mg, 0.119 mmol), tert-butyl 3,6-diazabicyclo[3.2.1]octane-6-carboxylate (51 mg, 0.238 mmol), A mixture of Pd-PEPPSI-IPentCl o-picolin (12 mg, 0.0119 mmol) and Cs ₂ CO ₃ (116 mg, 0.357 mmol) was degassed, purged with N ₂ (3x) and incubated with N ₂ for 4 h at 95°C. It was stirred under atmosphere. The reaction mixture was then cooled to room temperature and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether/EtOAc = 1/1) to give the product tert-butyl 3-(3-(5-(difluoromethyl)-1,3,4-thiadiazole-2- 1)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-3,6-diazabicyclo[3.2.1]octane-6- The carboxylate (13 mg, 0.0199 mmol, 16.68% yield) was obtained as a yellow solid.

RT 0.516 min (Method 3); m/z 596.1 (M+H) ⁺ (ESI ⁺ );

Preparation of Example 183

8-(3,6-diazabicyclo[3.2.1]octan-3-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N -(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide formate

At room temperature, tert-butyl 3-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- of methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (10 mg, 0.0168 mmol) TFA (0.1 mL, 1.32 mmol) was added to the solution. The reaction mixture was stirred at 25° C. for 1 hour and then concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water; B%: 11%-41%, 5 min) to obtain product 8-(3 ,6-Diazabicyclo[3.2.1]octan-3-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1- Methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide formate (2.3 mg, 0.00408 mmol, 24.29% yield, FA salt) was obtained as a yellow solid.

RT 0.338 min (Method 3); m/z 496.1 (M+H) ⁺ (ESI ⁺ );

¹ H NMR (D ₂ 0,400 MHz): 9.42 (s, 1H), 8.39 (s, 1H), 7.84 (s, 1H), 7.28 (t, J = 53.6 Hz, 1H), 6.59 (s, 1H), 4.29 (s, 1H), 3.92 (d, J = 12.4 Hz, 1H), 3.71 (d, J = 11.6 Hz, 2H), 3.46-3.31 (m, 1H), 3.24 (d, J = 12.6 Hz, 1H) ), 3.11 (d, J= 12.0 Hz, 1H), 2.90 (s, 1H), 2.12 (s, 2H), 1.13 (s, 3H), 0.72 (m, 2H), 0.46 (m, 2H).

Note that the compounds may be of isomeric composition.

Preparation of Example 184a

tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfa moyl)imidazo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1- in water (0.2 mL) and t-BuOH (2.0 mL) (Fluoromethyl) cyclopropyl) imidazo [1,5-a] pyridine-6-sulfonamide (100 mg, 0.228 mmol) in a solution of K ₃ PO ₄ (48 mg, 0.228 mmol), cataCXium A-Pd- G3 (17 mg, 0.0228 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H -Pyridine-1-carboxylate (212 mg, 0.685 mmol) was added at room temperature. The mixture was stirred at 60°C for 16 hours and then diluted with water (20 mL) and extracted with EtOAc (50 mL, 3x). The combined organic layers were washed with brine (25 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/EtOAc = 2/1) to give the product tert-butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazole-2- 1)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-5,6-dihydropyridin-1(2H) -Carboxylate (160 mg, 0.271 mmol, 118.63% yield) was obtained as a yellow solid.

RT 0.517 min (Method 3); m/z 585.1 (M+H) ⁺ (ESI ⁺ )

Preparation of Example 184b

tert-Butyl 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl) Cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate

tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoro) in MeCN (2 mL) In a solution of methyl) cyclopropyl) sulfamoyl) imidazo [1,5-a] pyridin-8-yl) -5,6-dihydropyridine-1 (2H) -carboxylate (160 mg, 0.271 mmol) NCS (181 mg, 1.35 mmol) was added at 20°C. The mixture was stirred at 20° C. for 16 hours, then diluted with NaHCO ₃ (aq., sat, 20 mL) and extracted with EtOAc (30 mL, 3x). The combined organic layers were washed with brine (30 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/EtOAc = 2/1) to give the product tert-butyl 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadia zol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine- 1(2H)-carboxylate (100 mg, 0.145 mmol, 53.66% yield) was obtained as a yellow solid.

RT 0.540 min (Method 3); m/z 619.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI _3,400 MHz): 10.13 (d, J = 0.88 Hz, 1H), 7.22-6.95 (m, 2H), 5.88 (brs, 1H), 5.54 (s, 1H), 4.28 (d, J = 48.4 Hz, 2H), 4.12 (m, 2H), 3.74 (t, J = 5.4 Hz, 2H), 2.50 (br s, 2H), 1.53 (s, 9H), 1.12-1.20 (m, 2H) , 0.86-0.93 (m, 2H).

Preparation of Example 184

1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8-(1, 2,3,6-Tetrahydropyridin-4-yl)imidazo[1,5-a]pyridine-6-sulfonamide formate

tert-Butyl 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6 in HCl/dioxane (2.0 mL, 0.162 mmol) -(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate A solution of (100 mg, 0.162 mmol) was stirred at 25° C. for 1 hour and then concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 15%-45%, 10 min) to obtain the product. 1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8-(1, 2,3,6-Tetrahydropyridin-4-yl)imidazo[1,5-a]pyridine-6-sulfonamide formate (27 mg, 0.0467 mmol, 28.92% yield, FA salt) was obtained as a yellow solid. did.

RT 0.540 min (Method 3); m/z 519.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 9.82 (s, 1H), 8.26 (s, 1H), 7.70 (t, J= 53.2 Hz, 1H), 7.13 (s, 1H), 5.92 (brs, 1H) , 4.24 (d, J = 48.6 Hz, 2H), 3.54 (brs, 2H), 3.13 (br s, 2H), 2.40 (br s, 2H), 0.82-0.92 (m, 2H), 0.70-0.81 (m , 2H).

Preparation of Example 185

1-Chloro-8-(4-cyclopropylpiperazin-1-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1 -(Fluoromethyl)cyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide formate

1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl) in dioxane (1 mL) 1-cyclopropylpiperazine (16.03 mg, 127.04 μmol), Cs ₂ CO ₃ (41.39 mg, 127.04 μmol) and Pd-PEPPSI-IPentCl o-picolin (6.18 mg, 6.35 μmol) were added. The mixture was degassed with N ₂ (3x), stirred at 90° C. for 20 min under nitrogen atmosphere, cooled to 25° C., filtered and the filtrate concentrated in vacuo. The residue was purified by preparative TLC (EtOAc: petroleum ether = 1:1) to obtain an impure product, which was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 20%-50%, 10 min) and directly lyophilized to give the product 1-chloro-8-(4-cyclopropylpiperazine-1- 1)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imidazo[1,5- a]Pyridine-6-sulfonamide formate (5.55 mg, 9.01 μmol, 14.18% yield, 98.67% purity, FA salt) was obtained as a yellow solid.

RT 0.354 min (Method 3), m/z 562.2(M+H) ⁺ (ESI ⁺ ), ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.58 (d, J = 0.8 Hz, 1H), 8.89 ( br s, 1H), 8.25 (s, 1H) 7.68 (t, J = 53.2 Hz, 1H), 6.79 (d, J = 0.8 Hz, 1H), 4.22 (d, J = 48.8 Hz, 2H), 3.13- 2.94 (m, 4H), 2.90-2.71 (m, 4H), 1.82-1.69 (m, 1H), 0.92-0.82 (m, 2H), 0.81-0.72 (m, 2H), 0.53-0.42 (m, 2H) ), 0.42-0.31 (m, 2H).

Preparation of Example 186a

tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfa moyl)imidazo[1,5-a]pyridin-8-yl)piperazine-1-carboxylate

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl in dioxane (2 mL) ) tert-butyl piperazine-1-carboxylate (42.54 mg, 228.39 μmol), Cs ₂ CO ₃ ( 74.41 mg, 228.39 μmol) and Pd-PEPPSI-IPentCl o-picolin (11.11 mg, 11.42 μmol) were added at room temperature. The mixture was degassed with N ₂ (3x), stirred at 90° C. for 1 hour under nitrogen atmosphere, cooled to 25° C. and filtered. The filtrate was concentrated under vacuum to obtain a residue, which was purified by preparative TLC (EtOAc: petroleum ether = 2:1) to give the product tert-butyl 4-(3-(5-(difluoromethyl)-1 ,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)piperazine -1-Carboxylate (50 mg, 75.73 μmol, 33.16% yield, 89% purity) was obtained as a yellow solid.

RT 0.531 min (method 3), m/z 588.2(M+H) ⁺ (ESI ⁺ ), ¹ H NMR (CDCl ₃ , 400 MHz): 9.89 (s, 1H), 7.72 (s, 1H), 7.08 ( t, J = 53.6 Hz, 1H), 6.64 (s, 1H), 5.49 (s, 1H), 4.27 (d, J = 48.4 Hz, 2H), 3.76-3.64 (m, 4H), 3.39-3.23 (m , 4H), 1.52 (s, 9H), 1.20-1.13 (m, 2H), 0.93-0.84 (m, 2H).

Preparation of Example 187

3-(5-(difluomethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8-(piperazin-1-yl) Imidazo[1,5-a]pyridine-6-sulfonamide formate

tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N- in HCl/dioxane (4 M, 1 mL) A solution of (1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)piperazine-1-carboxylate (45 mg, 76.58 μmol) was incubated at 25°C. Stirred for 1 hour and concentrated under vacuum. The residue was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 12%-42%, 10 min). Purification and direct lyophilization resulted in the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8- (Piperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide (22.23 mg, 40.19 μmol, 52.48% yield, 96.45% purity, FA salt) was obtained as a yellow solid.

RT 0.324 min (Method 3); m/z 488.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d _6,400 MHz): 9.56 (s, 1H), 8.92-8.71 (m, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.67 (t, J = 53.2 ㎐, 1H), 6.67 (s, 1H), 4.22 (d, J = 48.4 ㎐, 2H), 3.25-3.20 (m, 4H), 3.05-2.92 (m, 4H), 0.88-0.81 (m, 2H) , 0.80-0.74 (m, 2H).

Preparation of Example 188

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8-(4-isobutyryl pipe Razin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl) in THF (0.5 mL) and H ₂ O (0.5 mL) ) Cyclopropyl)-8-(piperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide (15 mg, 30.77 μmol, FA salt) in a solution of NaHCO ₃ (25.85 mg, 307.68 μmol), followed by isobutyryl chloride (4.92 mg, 46.15 μmol, 4.82 μL) at 0°C. The mixture was stirred at 25°C for 1 hour, then poured into water (10 mL) and extracted with EtOAc (10 mL; 2x). The organic layer was collected, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: EtOAc = 1:1) to give an impure product, which was further purified by trituration with MeOH (2 mL) at 25° C. for 20 min. After filtration, the cake was collected and dried under vacuum to give the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclo. Propyl)-8-(4-isobutyrylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide (6.43 mg, 11.35 μmol, 36.90% yield, 98.46% purity) was obtained as yellow Obtained as a solid.

RT 0.485 min (Method 3); m/z 558.3 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 9.91-9.90 (m, 1H), 7.74 (s, 1H), 7.08 (t, J =53.2 Hz, 1H), 6.65 (d, J = 1.2 Hz, 1H) , 5.50 (s, 1H), 4.27 (d, J= 48.8 Hz, 2H), 3.98-3.75 (m, 4H), 3.45-3.25 (m, 4H), 2.90-2.78 (m, 1H), 1.20 (d , J = 6.8 Hz, 6H), 1.18-1.14 (m, 2H), 0.90- 0.86 (m, 2H).

Preparation of Example 189a

tert-Butyl 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfa moyl)imidazo[1,5-a]pyridin-8-yl)piperazine-1-carboxylate

1,8-dichloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclopropyl)imi in dioxane (2 mL) In a solution of polyzo[1,5-a]pyridine-6-sulfonamide (50 mg, 0.110 mmol), tert-butyl piperazine-1-carboxylate (41 mg, 0.220 mmol), Pd-PEPPSI-IPentCl o- Picolin (11 mg, 0.0110 mmol) and Cs ₂ CO ₃ (90 mg, 0.275 mmol) were added. The mixture was degassed with N ₂ (3x), stirred at 90° C. for 1 hour under nitrogen atmosphere, cooled to 25° C. and filtered. The filtrate was concentrated under vacuum to give a residue, which was purified by preparative TLC (EtOAc:petroleum ether = 2:1) to give the product tert-butyl 4-(1-chloro-3-(5-(difluoro). methyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)piperazine -1-Carboxylate (18 mg, 0.0275 mmol, 24.99% yield) was obtained as a yellow solid.

RT 0.535 min (method 3), m/z 604.0(M+H) ⁺ (ESI ⁺ ), ¹ H NMR (CDCl ₃ , 400 MHz): 9.90 (s, 1H), 7.08 (t, J = 54.0 Hz, 1H), 6.73 (s, 1H), 5.07 (s, 1H), 3.84-3.58 (m, 4H), 3.24-3.02 (m, 4H), 1.51 (s, 9H), 1.39 (s, 3H), 0.94 -0.90 (m, 2H), 0.63-0.61 (m, 2H).

Preparation of Example 189

1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(piperazin-1-yl )Imidazo[1,5-a]pyridine-6-sulfonamide formate

tert-Butyl 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6 in HCl/dioxane (4 M, 1 mL) A solution of -(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)piperazine-1-carboxylate (12 mg, 0.0199 mmol) was reacted at 25°C. Stirred for 16 hours. The reaction mixture was concentrated under vacuum to obtain a residue, which was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B% : 15%-45%, 10 min) and directly lyophilized to obtain the product 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N -(1-methylcyclopropyl)-8-(piperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide formate (7.26 mg, 0.0132 mmol, 66.45% yield, FA salt) was obtained as a yellow solid.

RT 0.340 min (Method 3); m/z 504.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d _6,400 MHz): 9.61 (s, 1H), 8.61-8.44 (m, 1H), 8.20 (s, 1H), 7.69 (t, J= 53.2 Hz, 1H), 6.81 ( s, 1H), 3.08-3.02 (m, 4H), 3.02-2.97 (m, 4H), 1.18 (s, 3H), 0.82-0.66 (m, 2H), 0.56-0.36 (m, 2H).

Preparation of Example 190a

tert-Butyl 2-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfa moyl)imidazo[1,5-a]pyridin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate

1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imi in dioxane (0.5 mL) tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (47 mg, 0.220 mmol) in a solution of polyzo[1,5-a]pyridine-6-sulfonamide (50 mg, 0.110 mmol) ), Cs ₂ CO ₃ (108 mg, 0.330 mmol) and Pd-PEPPSI-IPentCl o-picolin (11 mg, 0.0110 mmol) were added at room temperature. The mixture was degassed with N ₂ (3x), stirred at 98° C. for 1 hour under nitrogen atmosphere, cooled to 25° C. and filtered.

The filtrate was concentrated under vacuum to obtain a residue, which was purified by preparative TLC (EtOAc: petroleum ether = 1:1) to give the product tert-butyl 2-(1-chloro-3-(5-(difluoro). methyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2 ,6-Diazaspiro[3.4]octane-6-carboxylate (32 mg, 0.0486 mmol, 44.14% yield) was obtained as a yellow solid.

RT 0.531 min (method 3), m/z 630.3(M+H) ⁺ (ESI ⁺ ), ¹ H NMR (CDCl ₃ , 400 MHz): 9.82 (s, 1H), 7.08 (t, J = 53.6 Hz, 1H), 6.60 (s, 1H), 5.08 (s, 1H), 4.04-3.98 (m, 2H), 3.98-3.91 (m, 2H), 3.61 (s, 2H), 3.51 (t, J = 6.8 Hz) , 2H), 2.29 (t, J = 6.8 Hz, 2H), 1.46 (s, 9H), 1.39 (s, 3H), 0.97-0.90 (m, 2H), 0.65-0.55 (m, 2H).

Preparation of Example 190

1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(2,6-diazas Pyro[3.4]octane-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide formate

tert-Butyl 2-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1) in DCM (0.5 mL) -Methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (32 mg, 0.0486 mmol) solution TFA (0.1 mL, 0.250 mmol) was added at 0°C. The mixture was stirred at 25° C. for 30 minutes and then concentrated under vacuum. The residue was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 16%-46%, 10 min). Purified and directly lyophilized to produce the product 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8- (2,6-diazaspiro[3.4]octan-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide formate (9.97 mg, 0.0167 mmol, 34.47% yield, FA salt) was obtained as a yellow Obtained as a solid.

RT 0.340 min (Method 3); m/z 530.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.55 (s, 1H), 9.01-8.11 (m, 2H), 7.69 (t, J = 53.2 Hz, 1H), 6.67 (s, 1H), 3.93- 3.79 (m, 4H), 3.64-3.58 (m, 4H), 2.26 (t, J = 6.8 Hz, 2H), 1.18 (s, 3H), 0.77-0.67 (m, 2H), 0.49-0.39 (m, 2H).

Preparation of Example 191a

(S)-tert-Butyl 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methyl Cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-methylpiperazine-1-carboxylate

1,8-dichloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclopropyl)imi in dioxane (2 mL) (S)-tert-butyl 2-methylpiperazine-1-carboxylate (88 mg, 0.440 mmol) in a solution of polyzo[1,5-a]pyridine-6-sulfonamide (50 mg, 0.110 mmol); Cs ₂ CO ₃ (108 mg, 0.330 mmol) and Pd-PEPPSI-IPentCl o-picolin (11 mg, 0.0110 mmol) were added. The mixture was degassed with N ₂ (3x), stirred at 98° C. for 1 hour under nitrogen atmosphere, cooled to 25° C. and filtered. The filtrate was concentrated under vacuum to obtain a residue, which was purified by preparative TLC (ethyl acetate:petroleum ether = 1:1) to give the product (S)-tert-butyl 4-(1-chloro-3-(5) -(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridine-8 -yl)-2-methylpiperazine-1-carboxylate (10 mg, 0.0121 mmol, 10.96% yield, 74.56% purity) was obtained as a yellow solid.

RT 0.552 min (Method 4), m/z 618.2 (M+H) ⁺ (ESI ⁺ ).

Preparation of Example 191

(S)-1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(3- Methylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide formate

(S)-tert-butyl 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-( in DCM (1.5 mL) TFA in a solution of N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-methylpiperazine-1-carboxylate (8.0 mg, 0.00965 mmol) (0.3 mL) was added. The mixture was stirred at 25° C. for 1 hour and then concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 um; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 16%-46%, 10 min) and directly By lyophilization, the product (S)-1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8 -(3-methylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide formate (1.38 mg, 0.00243 mmol, 25.17% yield, 99.28% purity, FA salt) as a yellow solid. It was obtained as.

RT 0.377 min (Method 4); m/z 518.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 9.91 (s, 1H), 8.26 (s, 1H), 7.08 (t, J = 53.6 Hz, 1H), 6.81 (s, 1H), 5.44 (s, 1H) , 3.56-3.26 (m, 5H), 3.18-3.03 (m, 1H), 2.88- 2.69 (m, 1H), 1.38 (s, 3H), 1.35 (d, J= 6.0 Hz, 3H), 0.96-0.90 (m, 2H), 0.65-0.58 (m, 2H).

Preparation of Example 192a

(R)-tert-Butyl 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methyl Cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-methylpiperazine-1-carboxylate

1,8-dichloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclopropyl)imi in dioxane (2 mL) (R)-tert-butyl 2-methylpiperazine-1-carboxylate (88 mg, 0.440 mmol) in a solution of polyzo[1,5-a]pyridine-6-sulfonamide (50 mg, 0.110 mmol); Cs ₂ CO ₃ (108 mg, 0.330 mmol) and Pd-PEPPSI-IPentCl o-picolin (11 mg, 0.0110 mmol) were added. The mixture was degassed with N ₂ (3x), stirred at 98° C. for 1 hour under N ₂ atmosphere, cooled to 25° C. and filtered. The filtrate was concentrated under vacuum to give a residue, which was purified by preparative TLC (ethyl acetate:petroleum ether = 1:1) to give the product (R)-tert-butyl 4-(1-chloro-3-(5). -(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridine-8 -yl)-2-methylpiperazine-1-carboxylate (10 mg, 0.0148 mmol, 13.45% yield, 91.50% purity) was obtained as a yellow solid.

RT 0.546 min (Method 4), m/z 618.2 (M+H) ⁺ (ESI ⁺ ).

Preparation of Example 192

(R)-1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(3- Methylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide 2,2,2-trifluoroacetate

(R)-tert-butyl 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-( in DCM (1.5 mL) TFA in a solution of N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-methylpiperazine-1-carboxylate (8.0 mg, 0.0118 mmol) (0.5 mL) was added. The mixture was stirred at 25° C. for 1 hour and concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 um; mobile phase: A: 0.1% TFA in water, B: MeCN; B%: 25%-55%, 10 min) and directly lyophilized to produce (R)-1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl) -8-(3-methylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide 2,2,2-trifluoroacetate (7.33 mg, 0.00978 mmol, 82.56% yield, 99.51% purity, 2 TFA salts) was obtained as a yellow solid.

RT 0.383 min (Method 4); m/z 518.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 10.01 (br, 1H), 9.94 (s, 1H), 9.37 (br, 1H), 7.09 (t, J = 53.6 Hz, 1H), 6.89 (s, 1H) , 5.93 (s, 1H), 3.85-3.70 (m, 1H), 3.69- 3.51 (m, 3H), 3.50-3.24 (m, 2H), 3.19-3.03 (m, 1H), 1.51 (d, J = 6.4 Hz, 3H), 1.35 (s, 3H), 1.01-0.82 (m, 2H), 0.66-0.49 (m, 2H).

Preparation of Intermediate 193.1

1,8-dichloro-3-(5-(difluoromethyl)thiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride

2-(6-(benzylthio)-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)thiazole (65 mg, 159.36) in MeCN (2 mL) AcOH (19.14 mg, 318.72 μmol, 18.23 μL) and H ₂ O (5.74 mg, 318.72 μmol, 5.74 μL) were added to the mixture of μmol) at room temperature. The mixture was cooled to -10°C and sulfuryl dichloride (75.28 mg, 557.75 μmol, 55.76 μL) was added. The reaction mixture was stirred at -10°C for 1 hour and then quenched with ice water (8 mL). The yellow precipitate was collected by filtration and dried under vacuum to give the crude product 1,8-dichloro-3-(5-(difluoromethyl)thiazol-2-yl)imidazo[1,5-a]pyridine- 6-Sulfonyl chloride (65 mg, crude) was obtained and used directly in the next step without further purification.

Preparation of Example 193

1,8-dichloro-3-(5-(difluoromethyl)thiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imidazo[1,5-a]pyridine-6 -Sulfonamides

To a mixture of 1-(fluoromethyl)cyclopropanamine (22.50 mg, 138.83 μmol, HCl salt) in DCM (1 mL) was added DIEA (46.31 mg, 358.29 μmol, 62.41 μL) and 1,8-dichloro-3-[ 5-(difluoromethyl)thiazol-2-yl]imidazo[1,5-a]pyridine-6-sulfonyl chloride (50 mg, 119.43 μmol) was added at -10°C. The reaction mixture was stirred at -10°C for 2 hours, then quenched with brine (5 mL) and NaHCO ₃ (aq., sat., 5 mL) and extracted with EtOAc (12 mL; 2x). The organic layers were separated, combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/EtOAc = 3/1) to give the product 1,8-dichloro-3-[5-(difluoromethyl)thiazol-2-yl]-N-[1- (Fluoromethyl)cyclopropyl]imidazo[1,5-a]pyridine-6-sulfonamide (35 mg, 69.65 μmol, 58.32% yield, 93.79% purity) was obtained as a yellow solid.

RT 0.531 min (Method 3); m/z 471.0 (M+H) ⁺ (ESI ⁺ )

Preparation of Example 194

4-(1-chloro-3-(5-(difluoromethyl)thiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo [1, 5-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide

and Example 195

4-(3-(5-(difluoromethyl)thiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a] Pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide

1,8-dichloro-3-[5-(difluoromethyl)thiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]imidazo[1, 5-a]pyridine-6-sulfonamide (20 mg, 42.44 μmol), N,N-dimethylpiperazine-1-carboxamide (13.34 mg, 84.87 μmol), Pd-PEPPSI-IPentCl o-picoline (3.65 μmol) mg, 4.24 μmol) and Cs ₂ CO ₃ (41.48 mg, 127.31 μmol) were degassed with N ₂ (3x). The mixture was then stirred at 90° C. for 1 hour, then cooled to room temperature, filtered and the filtrate concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether: EtOAc = 0: 1) to give the product 4-(1-chloro-3-(5-(difluoromethyl)thiazol-2-yl)-6-(N -(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide (2.64 mg, 4.22 μmol) , 9.94% yield, 94.74% purity) was obtained as a yellow solid, and the impure fraction (10 mg, 80% purity) was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase). : A: 0.225% formic acid in water, B: MeCN; 38%-68%, 10 min) and directly lyophilized to obtain product 4-(3-(5-(difluoromethyl)thiazole-2 -yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-car Boxamide (0.87 mg, 0.00149 mmol, 8.33% yield) was obtained as a yellow solid.

4-(1-chloro-3-(5-(difluoromethyl)thiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo [1, 5-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide

RT 0.492 min (Method 3); m/z 592.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 9.95 (s, 1H), 8.07 (s, 1H), 6.97 (t, J =55.2 Hz, 1H), 6.60 (s, 1H), 5.45 (s, 1H) , 4.26 (d, J =52.4 Hz, 2H), 3.62-3.43 (m, 4H), 3.27-3.06 (m, 4H), 2.90 (s, 6H), 1.13-1.12 (m, 2H), 0.87-0.84 (m, 2H).

4-(3-(5-(difluoromethyl)thiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a] Pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide

RT 0.459 min (Method 3), m/z 558.3(M+H) ⁺ (ESI ⁺ ); ^1H NMR (CDCl ₃ , 400 MHz), 9.94 (s, 1H), 8.07 (s, 1H), 7.63 (s, 1H), 6.97 (t, J =53.2 Hz, 1H), 6.53 (s, 1H) , 5.45 (s, 1H), 4.26 (d, J = 48.4 Hz, 2H), 3.61-3.43 (m, 4H), 3.42-3.22 (m, 4H), 2.91 (s, 6H), 1.14-1.11 (m , 2H), 0.86-0.81 (m, 2H).

Preparation of Example 196

1-Chloro-3-(5-(difluoromethyl)thiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8-(2-oxa-7-azaspiro[3.5 ]nonane-7-yl)imidazo[1,5-a]pyridine-6-sulfonamide

1,8-dichloro-3-[5-(difluoromethyl)thiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]imidazo[1, A mixture of 5-a]pyridine-6-sulfonamide (15 mg, 31.83 μmol), 2-oxa-7-azaspiro[3.5]nonane (8.10 mg, 63.65 μmol), CS ₂ CO ₃ (31.11 mg, 95.48 μmol) ) and Pd-PEPPSI-IPentCl o-picoline (2.74 mg, 3.18 μmol) were added and the reaction mixture was degassed with N ₂ (3x). The mixture was stirred at 90° C. for 30 minutes and then cooled to room temperature, filtered and concentrated in vacuo. The residue was subjected to preparative TLC (EtOAc: petroleum ether = 3:1) followed by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water; B: MeCN; B %:50%-80%, 10 min) and lyophilized to obtain the product 1-chloro-3-[5-(difluoromethyl)thiazol-2-yl]-N-[1-(fluoromethyl ) Cyclopropyl]-8-(2-oxa-7-azaspiro[3.5]nonan-7-yl)imidazo[1,5-a]pyridine-6-sulfonamide (1.71 mg, 2.83 μmol, 8.89% yield) , 93.04% purity) was obtained as a yellow solid.

RT 0.514 min (Method 3), m/z 562.3(M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCI _3,400 MHz), 9.92 (s, 1H), 8.06 (s, 1H), 6.97 (t, J =55.2 Hz, 1H), 6.56 (s, 1H), 5.44 (s, 1H) , 4.53 (s, 4H), 4.25 (d, J = 48.4,2H), 3.16-2.93 (m, 4H), 2.31-2.06 (m, 4H), 1.13-1.11 (m, 2H), 0.87-0.82 ( m, 2H).

Preparation of Example 197a

(R)-tert Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl )imidazo[1,5-a]pyridin-8-yl)-2-methylpiperazine-1-carboxylate

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ tert-butyl tert-butyl (R)-2-methylpiperazine-1-carboxylate (153 mg, 0.762 mmol) in a mixture of 1,5-a]pyridine-6-sulfonamide (80 mg, 0.191 mmol) , Cs ₂ CO ₃ (217 mg, 0.667 mmol) and Pd-PEPPSI-IPentCl o-picolin (19 mg, 0.0191 mmol) were added. The mixture was degassed and purged with N ₂ (3x) and then stirred at 90° C. for 2 hours under N ₂ atmosphere. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether: EtOAc=2:1) to give the product tert-butyl (R)-4-(3-(5-(difluoromethyl)-1,3,4-thiadia Zol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-methylpiperazine-1-carboxylate ( 28 mg, 0.0437 mmol, 31.85% yield) was obtained as a yellow solid.

RT 0.539 min (Method 3); m/z 584.4 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz) 9.87 (s, 1H), 7.73 (s, 1H), 7.08 (t, J =53.6 Hz, 1H), 6.64 (s, 1H), 5.10 (s, 1H), 4.46 (br s, 1H), 4.08 (d, J = 12.8 Hz, 1H), 3.62- 3.53 (m, 2H), 3.40-3.33 (m, 1H), 3.07-2.95 (m, 2H), 1.51 (s) , 9H), 1.47 (d, J = 6.8 Hz, 3H), 1.39 (s, 3H), 0.97-0.90 (m, 2H), 0.65-0.57 (m, 2H).

Preparation of Example 197

(R)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(3-methylpiperazine- 1-1) imidazo[1,5-a]pyridine-6-sulfonamide formate

tert-Butyl (R)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl) in HCl/dioxane (1.0 mL, 4.00 mmol, 4N) -6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-methylpiperazine-1-carboxylate (28 mg, 0.0480 mmol) The mixture was stirred at 25° C. for 1 hour and then concentrated under vacuum. The crude product was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 12%-42%, 10 min) purified and directly lyophilized to produce (R)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8. -(3-Methylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide formate (1.4 mg, 0.00258 mmol, 5.38% yield, FA salt) was obtained as a yellow solid.

RT 0.369 min (Method 3); m/z 484.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 9.87 (s, 1H), 8.30 (br 1H), 7.70 (s, 1H), 7.08 (t, J = 53.6 Hz, 1H), 6.69 (s, 1H), 5.35 (s, 1H), 3.69-3.61 (m, 2H), 3.32-3.27 (m, 2H), 3.12-3.06 (m, 2H), 2.81-2.76 (m, 1H), 1.38 (s, 3H), 1.29 (d, J = 6.4 Hz, 3H), 0.95- 0.92 (m, 2H), 0.61- 0.58 (m, 2H).

Preparation of Example 198

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

(R)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclo in THF (0.5 mL) and water (0.5 mL) Propyl)-8-(3-methylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide (22 mg, 0.0414 mmol) was added to a mixture of 2-methylpropanoyl chloride (8.8 mg, 0.0827 mmol) and NaHCO ₃ (3.5 mg, 0.0414 mmol) were added at 0°C. The reaction mixture was stirred at 0°C for 15 min, then quenched with water (6 mL) and extracted with EtOAc (6 mL; 2x). The organic layers were separated, combined, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude product was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 45%-75%, 10 min) purified and directly lyophilized to produce (R)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-isobutyryl-3- Methylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (3.3 mg, 0.00578 mmol, 13.98% yield) was obtained as a yellow solid. .

RT 0.483 min (method 1), m/z 554.4(M+H) ⁺ (ESI ⁺ ), ¹ H NMR (CDCl ₃ , 400 MHz) 9.88 (s, 1H), 7.74 (br, 1H), 7.08 (t , J = 53.6 Hz, 1H), 6.65 (s, 1H), 5.09 (s, 1H), 5.00-4.46 (m, 1H), 4.39-3.88 (m, 1H), 3.68- 3.61 (m, 2H), 3.02-2.97 (m, 2H), 2.96-2.86 (m, 1H), 1.49-1.48 (m, 1H), 1.39 (s, 3H), 1.27-1.05 (m, 9H), 0.97-0.89 (m, 2H) ), 0.58-0.63 (m, 2H).

Preparation of Example 199

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8-(2-oxa-7- Azaspiro[3.5]nonan-7-yl)imidazo[1,5-a]pyridine-6-sulfonamide

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl in dioxane (0.5 mL) ) 2-oxa-7-azaspiro[3.5]nonane (17 mg, 0.137 mmol) in a mixture of imidazo[1,5-a]pyridine-6-sulfonamide (30 mg, 0.0685 mmol), Pd-PEPPSI- IPentCl o-picolin (5.9 mg, 0.00685 mmol) and Cs ₂ CO ₃ (67 mg, 0.206 mmol) were added. The reaction mixture was degassed with N ₂ (3x), stirred at 90° C. for 30 min and then concentrated in vacuo. The resulting residue was diluted with MeOH (3 mL), filtered and the filtrate was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 40%-70%, 10 min) and directly lyophilized to give the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-( 1-(fluoromethyl)cyclopropyl)-8-(2-oxa-7-azaspiro[3.5]nonan-7-yl)imidazo[1,5-a]pyridine-6-sulfonamide (2.8 mg, 0.00518 mmol, 7.55% yield) was obtained as a yellow solid.

RT 0.458 min (Method 1); m/z 529.3 (M+H) ⁺ (ESI ⁺ ), ¹ H NMR (CDCl ₃ , 400 MHz) 9.85 (s, 1H), 7.70 (s, 1H), 7.08 (t, J = 54.0 Hz, 1H) , 6.61 (s, 1H), 5.47(s, 1H), 4.54(s, 4H), 4.26 (d, J = 48.4 Hz, 2H), 3.27- 3.24 (m, 4H), 2.16-2.14 (m, 4H) ), 1.18-1.14 (m, 2H), 0.88-0.85(m, 2H).

Preparation of Example 200

1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8-(4- Isobutyrylpiperazine-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide

1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N in THF (0.5 mL) and H ₂ O (0.25 mL) at 0°C. Solution of -(1-(fluoromethyl)cyclopropyl)-8-(piperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide (15 mg, 28.74 μmol, FA sale) To was added K ₂ CO ₃ (11.92 mg, 86.21 μmol) followed by isobutyryl chloride (6.12 mg, 57.47 μmol, 6.00 μL). The mixture was stirred at 25°C for 1 hour and then diluted with brine (15 mL) and extracted with EtOAc (7 mL, 3x). The organic layers were separated, combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 40%-70%, 10 min) By lyophilization, the product 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8 -(4-Isobutyrylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide (5.26 mg, 8.53 μmol, 29.68% yield, 96% purity) was obtained as a yellow solid. .

RT 0.499 min (Method 3); m/z 592.3 (M+H) ⁺ (ESI ^{+); 1} H NMR (CDCl ₃ , 400 MHz): 9.92 (s, 1H), 7.09 (t, J = 53.6 Hz, 1H), 6.73 (s, 1H), 5.52 (s, 1H), 4.27 (d, J = 48.4 Hz, 2H), 3.65-3.41 (m, 4H), 3.27-3.17 (m, 4H), 2.88-2.81 (m, 1H), 1.20 (s, 3H), 1.19 (s, 3H), 1.18-1.14 (m, 2H), 0.91-0.82 (m, 2H).

The compounds listed in the table below were prepared according to the corresponding general procedures or, where specified, starting from the corresponding intermediates in a similar manner to the related compounds.

Preparation of Example 278

4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imi Polyzo[1,5-a]pyridin-8-yl)-N-(2-(dimethylamino)ethyl)-N-methylpiperazine-1-carboxamide

1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imi in dioxane (1 mL) In a solution of polyzo[1,5-a]pyridine-6-sulfonamide (30 mg, 0.0660 mmol), N-(2-(dimethylamino)ethyl)-N-methylpiperazine-1-carboxamide hydrochloride ( 33 mg, 0.132 mmol, HCl salt), Cs ₂ CO ₃ (54 mg, 0.165 mmol) and Pd-PEPPSI-IPentCl o-picolin (6.4 mg, 0.0066 mmol) were added. The mixture was degassed and purged with N ₂ (3x) and then stirred at 100° C. for 2 hours under N ₂ atmosphere. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 20%-50%, 10 min) and frozen. Dry to give the product 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfa Moyl) imidazo [1,5-a] pyridin-8-yl) -N- (2- (dimethylamino) ethyl) -N-methylpiperazine-1-carboxamide (5.4 mg, 0.00821 mmol, 12.4% Yield) was obtained as a yellow solid.

RT 0.415 min (Method 4); m/z 632.3 (M+H) ⁺ (ESI ⁺ ), ¹ H NMR (CDCl _3,400 MHz): 9.89 (s, 1H), 7.08 (t, J = 53.6 Hz, 1H), 6.76 (s, 1H) ), 5.34 (br, 1H), 3.61-3.51 (m,4H), 3.48 (t, J = 6.8 Hz, 2H), 3.25-3.15 (m, 4H), 2.98 (s, 3H), 2.76 (t, J = 6.8 Hz, 2H), 2.47 (s, 6H), 1.38 (s, 3H), 0.94-0.90 (m, 2H), 0.63-0.58 (m, 2H).

Preparation of Example 279a

tert-Butyl-3-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imi polyzo[1,5-a]pyridin-8-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo in tert-butanol (2 mL) A solution of [1,5-a]pyridine-6-sulfonamide (100 mg, 0.238 mmol) was added to water (0.2 mL), K ₃ PO ₄ (51 mg, 0.238 mmol), and cataCXium A-Pd-G3 (17 mg). , 0.0238 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2 -N-8-carboxylate (240 mg, 0.715 mmol) was added. The mixture was stirred at 60° C. for 16 hours under N ₂ atmosphere. The resulting mixture was concentrated and the residue was purified by preparative TLC (petroleum ether: ethyl acetate = 2:1) to give the product tert-butyl-3-(3-(5-(difluoromethyl)-1,3, 4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-8-azabicyclo[3.2.1 ]Oct-2-ene-8-carboxylate (35 mg, 0.0555 mmol, 23.3% yield) was obtained as a yellow solid.

RT 0.550 min (Method 4); m/z 593.1 (M+H) ⁺ (ESI ⁺ ), ¹ H NMR (DMSO- d _6,400 MHz): 9.84 (s, 1H), 8.50 (s, 1H), 8.03 (s, 1H), 7.69 (t, J = 53.2 Hz, 1H), 7.26 (s, 1H), 6.86 (d, J = 5.2 Hz, 1H), 4.46-4.52 (m, 1H), 4.35-4.43 (m, 1H), 3.03- 3.18 (m, 1H), 2.28-2.35 (m, 1H), 2.01-2.12 (m, 2H), 1.75-1.88 (m,2H), 1.41 (s, 9H), 1.15 (s, 3H), 0.67- 0.74 (m, 2H), 0.48-0.44 (m, 2H).

Preparation of Example 279b

tert-Butyl-3-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl) Sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate

tert-Butyl-3-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclo Solution of propyl) sulfamoyl) imidazo [1,5-a] pyridin-8-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate (35 mg, 0.0591 mmol) NCS (13 mg, 0.094 mmol) was added at 25°C. The mixture was stirred at 25°C for 18 hours. NCS (6.5 mg, 0.0472 mmol) was added to the solution and the mixture was stirred for 16 hours. The resulting solution was diluted with water (10 mL) and extracted with EtOAc (15 mL, 3x). The combined organic phases were washed with brine (15 mL, 2x), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo to give the product tert-butyl-3-(1-chloro-3-(5-( difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl )-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (32 mg, 0.0459 mmol, 77.77% yield) was obtained as a yellow solid.

RT 0.577 min (Method 4); m/z 571.0 (M-56+H) ⁺ (ESI ⁺ ), ¹ H NMR (DMSO -d _6,400 MHz): 9.83 (s, 1H), 8.56 (s, 1H), 7.70 (t, J = 53.2 Hz, 1H), 7.10 (s, 1H), 6.25 (d, J = 5.2 Hz, 1H), 4.45 (t, J = 5.2 Hz, 1H), 4.37-4.28 (m, 1H), 2.26-2.16 ( m, 2H), 2.08-2.00 (m, 2H), 1.96-2.03 (m, 2H), 1.43 (s, 9H), 1.23 (s, 3H), 0.72 (m, 2H), 0.47 (m, 2H) .

Preparation of Example 279

8-azabicyclo[3.2.1]oct-2-en-3-yl)-1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl) -N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide formate

tert-Butyl-3-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)- in TFA (1.0 mL) and DCM (0.5 mL) 6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxyl A solution of rate (25 mg, 0.0399 mmol) was stirred at 25°C for 1 hour. The mixture was concentrated and the residue was subjected to reverse-phase HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 14%-44%, 10 min) Purification gave the product 8-azabicyclo[3.2.1]oct-2-en-3-yl)-1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2 -yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide formate (5.0 mg, 0.00867 mmol, 21.76% yield, FA salt) was obtained as a yellow solid. .

RT 0.393 min (Method 4); m/z 527.1 (M+H) ⁺ (ESI ⁺ ), ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.84 (s, 1H), 8.57 (br, 1H), 8.31 (s, 1H), 7.70 (t, J = 53.2 Hz, 1H), 7.15 (s, 1H), 6.17 (d, J = 5.2 Hz, 1H), 3.89-3.82 (m, 2H), 2.89-2.78 (m, 1H), 2.14- 2.24 (m, 1H), 2.11-1.99 (m, 2H), 1.92-1.81 (m, 2H), 1.19 (s, 3H), 0.74-0.72 (m, 2H), 0.52-0.50 (m, 2H).

Preparation of Intermediate 280.1

Benzyl 4-(2-chloropropanoyl)piperazine-1-carboxylate

To a solution of benzyl piperazine-1-carboxylate (2.00 g, 9.08 mmol) in DCM (20 mL) was added TEA (2.5 mL, 18.2 mmol) and 2-chloropropanoyl chloride (1.27 g, 9.99 mmol). After addition at 100°C, the mixture was stirred at 25°C for 1 hour. The resulting mixture was concentrated under vacuum to afford the crude product benzyl 4-(2-chloropropanoyl)piperazine-1-carboxylate (2.10 g, crude, 80.8% purity based on LMCS) as a white solid.

RT 0.385 min (Method 4); m/z 311.2 (M+H) ⁺ (ESI ⁺ ), ¹ H NMR (CDCl ₃ , 400 MHz): 7.40-7.27 (m, 5H), 5.12 (s, 2H) 3.80-3.50 (m, 4H), 3.49-3.32 (m, 4H), 3.39 (q, J = 6.8 Hz, 1H), 1.65 (d, J = 6.8 Hz, 3H).

Preparation of Intermediate 280.2

Benzyl 4-(dimethylalanyl)piperazine-1-carboxylate formate

To a solution of benzyl 4-(2-chloropropanoyl)piperazine-1-carboxylate (500 mg, 1.30 mmol, 80.8% purity) in MeCN (5 mL) was added dimethylamine hydrochloride (159 mg, 1.95 mmol, HCl salt) was added. The mixture was stirred at 80° C. for 16 hours. The resulting mixture was filtered, and the filtrate was concentrated under vacuum to obtain a residue, which was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water , B: MeCN; B%: 0%-30%, 10 min) and directly lyophilized to give the product benzyl 4-(dimethylalanyl)piperazine-1-carboxylate (70 mg, 0.184 mmol, 14.1%). Yield, 96.0% purity, FA salt) was obtained as a colorless oil.

RT 0.253 min (Method 4); m/z 320.2 (M+H) ⁺ (ESI ⁺ ), ¹ H NMR (DMSO- d ₆ , 400 MHz): 8.30 (br, 1H), 7.57-7.16 (m, 5H), 5.10 (s, 2H) , 3.72-3.51 (m, 9H), 2.14 (s, 6H), 1.00 (d, J = 6.6 Hz, 3H).

Preparation of Intermediate 280.3

2-(dimethylamino)-1-(piperazin-1-yl)propan-1-one

Benzyl 4-(dimethylalanyl)piperazine-1-carboxylate formate (50 mg, 0.131 mmol, 96.0% purity, FA) in a suspension of Pd/C (20 mg, 10% purity) in MeOH (2 mL). salt) was added. The suspension was degassed under vacuum and purged with H ₂ (3x) and the mixture was stirred at 25° C. for 4 hours under H ₂ atmosphere. The suspension was filtered through a pad of Celite and the cake was washed with MeOH (3 mL, 4x). The combined filtrates were concentrated in vacuo to give the crude product 2-(dimethylamino)-1-(piperazin-1-yl)propan-1-one (34 mg, 0.110 mmol, 83.80% yield) as a colorless oil. , which was used in the next step without further purification.

RT 0.060 min (Method 4); m/z 186.2 (M+H) ⁺ (ESI ⁺ ).

Preparation of Example 280

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

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ 2-(dimethylamino)-1-(piperazin-1-yl)propan-1-one (33 mg, 0.179 mmol) in a solution of 1,5-a]pyridine-6-sulfonamide (30 mg, 0.0715 mmol) ), Cs ₂ CO ₃ (70 mg, 0.21 mmol) and Pd-PEPPSI-IPentCl o-picolin (7.0 mg, 0.00715 mmol) were added. The mixture was degassed and purged with N ₂ (3x) and then stirred at 100° C. for 16 hours under N ₂ atmosphere. The reaction mixture was cooled to 25° C. and filtered. The filtrate was concentrated under vacuum to obtain a residue, which was subjected to preparative HPLC (column: Phenomenex C18 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 14%- 44%, 10 min) and directly lyophilized to give the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(dimethylalanyl) ) Piperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a] pyridine-6-sulfonamide formate (3.76 mg, 0.00609 mmol, 8.53% yield, 99.63% purity, FA salt) was obtained as a yellow solid.

RT 0.337 min (Method 4); m/z 569.3 (M+H) ⁺ (ESI ⁺ ), ¹ H NMR (CDCl ₃ , 400 MHz): 9.88 (s, 1H), 8.37 (s, 1H), 7.72 (s, 1H), 7.08 (t , J = 53.6 Hz, 1H), 6.69 (s, 1H), 5.56 (br, 1H), 4.16-4.01 (m, 2H), 3.98 (q, J = 6.8 Hz, 1H), 3.85-3.70 (m, 2H), 3.45-3.32 (m, 3H), 3.28-3.17 (m, 1H), 2.52 (s, 6H), 1.38 (s, 3H), 1.34 (d, J = 6.8 Hz, 3H), 0.96-0.88 (m, 2H), 0.63-0.55 (m, 2H).

Preparation of Intermediate 281.1

Benzyl 4-(1-methylazetidine-3-carbonyl)piperazine-1-carboxylate formate

To a solution of 1-methylazetidine-3-carboxylic acid (300 mg, 2.61 mmol) in DMF (15 mL) was added HATU (604 mg, 1.59 mmol) and DIEA (0.33 mL, 1.99 mmol). The mixture was stirred at 25°C for 30 minutes, then benzyl piperazine-1-carboxylate (175 mg, 0.794 mmol) was added and the mixture was stirred at 25°C for 16 hours. The resulting mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL; 2x) and washed with brine (30 mL; 3x). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under vacuum to give a residue, which was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 0%-28%, 10 min) and directly lyophilized to give the product benzyl 4-(1-methylazetidine-3-carbonyl)piperazine- 1-Carboxylate formate (50 mg, 0.120 mmol, 15.07% yield, FA salt) was obtained as a brown solid.

RT 0.249 min (Method 4); m/z 318.2 (M+H) ⁺ (ESI ⁺ ), ¹ H NMR (DMSO- d ₆ , 400 MHz): 7.46-7.34 (m, 5H), 5.10 (s, 2H), 4.43-4.01 (m, 2H), 3.98-3.82 (m, 1H), 3.65-3.55 (m, 2H), 3.55-3.46 (m, 2H), 3.44-3.38 (m, 4H), 3.14-3.07 (m, 2H), 2.81 ( s, 3H).

Preparation of Intermediate 281.2

(1-methylazetidin-3-yl)(piperazin-1-yl)methanone

Benzyl 4-(1-methylazetidine-3-carbonyl)piperazine-1-carboxylate formate (50 mg, 0.137 mg) in a suspension of Pd/C (17 mg, 10% purity) in MeOH (2 mL). mmol, FA salt) was added. The suspension was degassed under vacuum and purged with H ₂ (3x) and the mixture was stirred at 25° C. for 4 hours under H ₂ atmosphere. The suspension was filtered through a pad of Celite and the cake was washed with MeOH (3 mL, 4x). The combined filtrates were concentrated under vacuum to give the crude product (1-methylazetidin-3-yl)(piperazin-1-yl)methanone (38 mg, 0.124 mmol, 90.78% yield) as a colorless oil. This was used in the next step without further purification.

RT 0.060 min (Method 4); m/z 184.2 (M+H) ⁺ (ESI ⁺ )

Preparation of Example 281

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-(1-methylazetidine-3-carbonyl)piperazin-1-yl )-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide formate

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ (1-methylazetidin-3-yl)(piperazin-1-yl)methanone (33.0 mg, 0.179 mmol) in a solution of 1,5-a]pyridin-6-sulfonamide (30.0 mg, 0.0715 mmol) , Cs ₂ CO ₃ (70 mg, 0.21 mmol) and Pd-PEPPSI-IPentCl o-picolin (7.0 mg, 0.00715 mmol) were added. The mixture was degassed and purged with N ₂ (3x) and then the mixture was stirred at 100° C. for 16 hours under N ₂ atmosphere. The reaction mixture was cooled to 25° C. and filtered. The filtrate was concentrated under vacuum to obtain a residue, which was subjected to preparative HPLC (column: Unisil 3-100 C18 Ultra 150*25 mm*10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B% : 13%-43%, 10 min) and directly lyophilized to produce the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4- (1-methylazetidine-3-carbonyl)piperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide formate (12.94 mg, 0.022 mmol, 28.61% yield, 96.78% purity, FA salt) was obtained as a yellow solid.

RT 0.337 min (Method 4); m/z 567.2 (M+H) ⁺ (ESI ⁺ ), ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.60 (s, 1H), 8.44 (br, 1H), 8.21 (s, 1H), 8.05 (s, 1H), 7.67 (t, J= 53.2 Hz, 1H), 6.68 (s, 1H), 3.75-3.71 (m, 2H), 3.55- 3.54 (m, 3H), 3.55-3.54 (m, 2H) ), 3.52-3.31 (m, 2H), 3.30-3.25 (m, 4H), 2.29 (s, 3H), 1.15 (s, 3H), 0.75- 0.68 (m, 2H), 0.47-0.41 (m, 2H) ).

Preparation of Example 282a

tert -Butyl (R)-4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-( Fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a] pyridin-8-yl) -2-methylpiperazine-1-carboxylate

1,8-dichloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-[1-(fluoromethyl) in dioxane (1 mL) In a solution of cyclopropyl]imidazo[1,5-a]pyridine-6-sulfonamide (50.0 mg, 0.106 mmol) was added tert-butyl rac-(2R)-2-methylpiperazine-1-carboxylate (42.0 mg, 0.106 mmol). mg, 0.212 mmol) followed by Cs ₂ CO ₃ (103 mg, 0.318 mmol) and Pd-PEPPSI-IPentCl (10.0 mg, 0.0106 mmol). The mixture was degassed, purged with N ₂ (3x) and stirred at 100° C. for 1 hour. The resulting mixture was cooled to 20°C, diluted with EtOAc (10 mL) and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by preparative TLC to give the product tert-butyl (R)-4-(1-chloro-3-(5-(difluoromethyl)-1,3, 4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-methylpipe Razine-1-carboxylate (10.0 mg, 0.0138 mmol, 13.05% yield, 87.91% purity) was obtained as a yellow solid.

RT 0.855 min (Method 2); m/z 636.0 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 9.90 (s, 1H), 7.08 (t, J = 53.6 Hz, 1H), 6.71 (s, 1H), 5.59 (s, 1H), 4..45-4.57 (m, 1H), 4.28 (d, J = 48.4 Hz, 2H), 4.02-3.94 (m, 1H), 3.65-3.53 (m, 2H), 3.19-3.07 (m, 2H), 2.70-2.58 (m , 1H), 1.51 (s, 9H), 1.39 (d, J = 6.8 Hz, 3H), 1.19-1.14 (m, 2H), 0.91-0.87 (m, 2H).

Preparation of Example 282

( R )-1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8 -(3-methylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide bis(2,2,2-trifluoroacetate)

tert-Butyl (R)-4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-( in DCM (1 mL) N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-methylpiperazine-1-carboxylate (10.0 mg, 0.0157 mmol) TFA (0.20 mL, 2.63 mmol) was added to the solution, and the mixture was stirred at 22°C for 1 hour. The mixture was concentrated in vacuo at 32°C. The residue was dissolved in MeCN (2 mL), filtered and the filtrate was subjected to preparative HPLC (column: Welch : 20%-50%, 8 min) and directly lyophilized to obtain the product (R)-1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2- 1)-N-(1-(fluoromethyl)cyclopropyl)-8-(3-methylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide bis(2,2 ,2-trifluoroacetate) (4.3 mg, 0.0056 mmol, 35.69% yield, 99.46% purity, 2TFA salt) was obtained as a yellow solid.

RT 0.370 min (Method 1); m/z 536.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (400 MHz, DMSO- d ₆ ): 9.62 (s, 1H), 9.21-9.02 (m, 1H), 8.90 (s, 1H), 8.79 - 8.65 (m, 1H), 7.69 (t, J = 52.8 Hz, 1H), 6.94- 6.87 (m, 1H), 4.23 (t, J = 48.4, 2H), 3.57-3.51 (m, 5H), 3.07-2.98 (m, 1H), 2.89 - 2.81 (m , 1H), 1.30 (d, J = 6.4 Hz, 3H), 0.90-0.85 (m, 2H), 0.82-0.76 (m, 2H).

Preparation of Example 283.1

tert-Butyl (2R,6R)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl ) Sulfamoyl) imidazo [1,5-a] pyridin-8-yl) -2,6-dimethylpiperazine-1-carboxylate

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ 1,5-a]pyridine-6-sulfonamide (50.0 mg, 0.119 mmol) and tert-butyl (2R,6R)-2,6-dimethylpiperazine-1-carboxylate (51.0 mg, 0.238 mmol) Cs ₂ CO ₃ (116 mg, 0.357 mmol) and Pd-PEPPSI-IPentCl o-picolin (12.0 mg, 0.0119 mmol) were added to the mixture. The mixture was degassed and purged with N ₂ (3x) and then stirred at 100° C. for 4 hours under N ₂ atmosphere. The reaction mixture was 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 (2R,6R)-4-(3-(5-(difluoromethyl)-1,3,4 -thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2,6-dimethylpiperazine-1 -Carboxylate (15.0 mg, 0.0246 mmol, 20.65% yield) was obtained as a yellow solid.

RT 0.498 min (Method 4); m/z 598.1 (M+H) ⁺ (ESI ⁺ );

Preparation of Example 283

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3R,5R)-3,5-dimethylpiperazin-1-yl)-N -(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide formate

tert-Butyl (2R,6R)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N- in DCM (1 mL) TFA in a solution of (1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (15.0 mg, 0.0246 mmol) (0.2 mL) was added at 20°C and the mixture was stirred at 20°C for 2 hours. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 13%-43%, 10 min) and frozen. Dry to give the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3R,5R)-3,5-dimethylpiperazin-1-yl )-N-(1-Methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide formate (1.6 mg, 0.0028 mmol, 11.52% yield, FA salt) was obtained as a yellow solid.

RT 0.333 min (Method 4); m/z 498.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 9.88 (s, 1H), 8.47 (s, 1H), 7.70 (s, 1H), 7.09 (t, J = 53.6 Hz, 1H), 6.71 (s, 1H) , 5.49 (br s, 1H), 3.60-3.72 (m, 2H), 3.36-3.45 (m, 2H), 3.20-3.28 (m, 2H), 1.49 (d, J= 6.0 Hz, 6H), 1.38 ( s, 3H), 0.96-0.90 (m, 2H), 0.63-0.56 (m, 2H).

Preparation of intermediate 284.1

tert-Butyl (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl ) Sulfamoyl) imidazo [1,5-a] pyridin-8-yl) -2,6-dimethylpiperazine-1-carboxylate

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate (15 mg, 0.0715 mmol) in a mixture of 1,5-a]pyridine-6-sulfonamide (30 mg, 0.0715 mmol) ), Cs ₂ CO ₃ (70 mg, 0.214 mmol) and Pd-PEPPSI-IPentCl o-picolin (7.0 mg, 0.00715 mmol) were added. The reaction mixture was degassed with N ₂ (3x) and then stirred at 98° C. for 1 hour. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 1:2) to give the product tert-butyl (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4 -thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2,6-dimethylpiperazine-1 -Carboxylate (16 mg, 0.0238 mmol, 33.34% yield) was obtained as a yellow solid.

RT 0.573 min (Method 4); m/z 598.1 (M+H ⁺ ) (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 9.74 (s, 1H), 7.83 (s, 1H), 7.08 (t, J = 53.6 Hz, 1H), 6.36 (s, 1H), 5.06 (s, 1H) , 4.20-4.37 (m, 2H), 4.14-4.11 (m, 2H), 3.67- 3.48 (m, 2H), 1.52 (s, 9H), 1.40 (s, 3H), 1.34 (d, J = 6.8 Hz) , 6H), 0.98-0.96 (m, 2H), 0.63-0.58 (m, 2H)

Preparation of Example 284

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

tert-Butyl (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl) in DCM (0.5 mL) and TFA (0.1 mL) -6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (16 mg, 0.0322 mmol) solution was stirred at 25°C for 1 hour. The mixture was concentrated under vacuum to obtain a residue, which was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 14%- 44%, 10 min) and directly lyophilized to give the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)- 3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide formate (4.0 mg, 0.00725 mmol, 22.56% yield, FA salt) was obtained as a yellow solid.

RT 0.362 min (Method 4); m/z 498.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.57 (s, 1H), 8.43 (s, 1H), 8.22 (s, 1H), 7.89 (s, 1H), 7.67 (t, J = 53.2 Hz, 1H), 6.66 (s, 1H), 3.30-3.27 (m, 2H), 3.26- 3.22 (m, 2H), 3.06-3.01 (m, 2H), 1.23 (d, J = 6.4 Hz, 6H), 1.15 (s, 3H), 0.77-0.67 (m, 2H), 0.45-0.47 (m, 2H).

Preparation of intermediate 285.1

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

6-Bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,5-a]pyridine-3-carbohydrazide (2000 mg, Burgess reagent (3890 mg, 16.3 mmol) was added to the solution (5.44 mmol), and the reaction mixture was stirred at 65°C for 16 hours. The mixture was cooled to 20° C. and concentrated to give a residue, which was triturated with MeOH (5 mL) for 30 min. After filtration, the cake was collected and dried to give the product 2-(6-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3, 4-Oxadiazole (750 mg, 2.10 mmol, 38.53% yield) was obtained as a yellow solid.

RT 0.449 min (Method 4); m/z 350.9 (M+H) ⁺ (ESI ⁺ ); H NMR (CDCl ₃ , 400 MHz): 9.52 (s, 1H), 7.93 (s, 1H), 7.28 (s, 1H), 7.10-6.85 (t, J = 51.6 Hz, 1H).

Preparation of Intermediate 285.2

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

2-(6-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3 in 1,4-dioxane (15 mL) , Phenylmethanethiol (0.49 mL, 4.22 mmol), Pd ₂ (dba) ₃ (386 mg, 0.422 mmol), Xantphos (244 mg, 0.422 mmol) and DIEA (2.2 mL, 12.6 mmol) was added at 25°C and the reaction mixture was stirred at 100°C for 1 hour under N ₂ atmosphere. After cooling, the reaction mixture was diluted with DCM (20 mL) and filtered through a pad of silica gel. The filtrate was collected and concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (Phenomenex luna C18 150*25mm* 10um; mobile phase: 0.225% formic acid in water; B: 61%-91%, 10min). Product 2-(6-(benzylthio)-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (710 mg, 1.81 mmol, 42.88% yield) was obtained as a white solid.

RT 0.483 min (Method 4); m/z 393.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz) δ 9.17 (s, 1H), 7.85 (s, 1H), 7.37-7.34 (m, 2H), 7.34-7.28 (m, 2H), 7.26-7.18 (m, 1H) ), 7.03 (s, 1H), 6.96 (t, J= 51.6 Hz, 1H), 4.19 (s, 2H).

Preparation of Intermediate 285.3

8-chloro-3-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)imidazo[1,5 -a]pyridine-6-sulfonamide

2-(6-benzylsulfanyl-8-chloro-imidazo[1,5-a]pyridin-3-yl)-5 in AcOH (3.0 mL, 1.02 mmol) and H ₂ O (1.5 mL, 0.509 mmol) In a solution of -(difluoromethyl)-1,3,4-oxadiazole (200 mg, 0.509 mmol), 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (2.5 eq, 251 mg, 1.27 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 0.5 h. The mixture was quenched with H ₂ O (5 mL) at 0° C. and extracted with DCM (10 mL×3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product, which was used in the next step without further purification.

To a solution of 1-(fluoromethyl)cyclopropanamine hydrochloride (102 mg, 0.81 mmol) in DCM (20 mL) was added dropwise DIEA (0.19 mL, 1.08 mmol) at -15°C. Then 8-chloro-3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]imidazo[1,5-a]pyridine-6- in DCM (5 mL) A solution of sulfonyl chloride (200 mg, 0.542 mmol) was added dropwise at -15°C and the reaction mixture was stirred at -15°C for 1 hour. The reaction mixture was diluted with DCM (10 mL) and extracted with H ₂ O (10 mL×3). The combined organic layers were concentrated under reduced pressure to obtain a residue, which was purified by preparative TLC (petroleum ether:EtOAc=2:1) to give the product 8-chloro-3-[5-(difluoromethyl)-1,3. ,4-oxadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]imidazo[1,5-a]pyridine-6-sulfonamide (50 mg, 0.106 mmol, 19.48% yield ) was obtained as a white solid.

RT 0.376 min (Method 1); m/z 422.1 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl _3,400 MHz): 9.89 (s, 1H), 8.00 (s, 1H), 7.43 (s, 1H), 7.12 (t, J = 51.2 Hz, 1H), 5.89 (s, 1H) , 4.31 (d, J = 48.4 Hz, 2H), 1.08 - 1.04 (m, 2H), 0.85 - 0.82 (m, 2H).

Preparation of Example 285

4-(3-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imi Polyzo[1,5-a]pyridin-8-yl)-N,N-dimethylpiperazine-1-carboxamide

8-Chloro-3-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl in dioxane (1 mL) ) N,N-dimethylpiperazine-1-carboxamide (15 mg, 0.0948 mmol) in a solution of imidazo[1,5-a]pyridine-6-sulfonamide (20 mg, 0.047 mmol) followed by Cs ₂ CO ₃ (46 mg, 0.142 mmol) and Pd-PEPPSI-IPentCl o-picolin (4.6 mg, 0.0047 mmol) were added in the glovebox at 25°C. Outside the glovebox, the reaction mixture was heated to 100° C. and stirred for 1.33 hours. The mixture was cooled to 25°C, diluted with EtOAc (15 mL), filtered and the filter cake was washed with EtOAc (3 mL, 3x). The filtrate was concentrated in vacuo and the residue was purified by preparative TLC (SiO ₂ , petroleum ether: ethyl acetate = 0:1) to give the product 4-(3-(5-(difluoromethyl)-1,3, 4-oxadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-N,N- Dimethylpiperazine-1-carboxamide (1.2 mg, 0.00208 mmol, 4.38% yield) was obtained as a yellow solid.

RT 0.597 min (Method 4); m/z 543.0 (M+H) ⁺ (ESI ⁺ ); 1H NMR (CDCl _3,400 MHz): 9.65 (s, 1H), 7.81 (s, 1H), 6.98 (t, J = 51.6 Hz, 1H), 6.68 (s, 1H), 5.51 (s, 1H), 4.27 (d, J = 48.4 Hz, 2H), 3.54-3.51 (m, 4H), 3.39-3.36 (m, 4H), 2.92 (s, 6H), 1.27-1.25 (m, 2H), 0.89-0.87 ( m, 2H).

Preparation of Intermediate 286.1

tert -Butyl (S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl) Cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-methylpiperazine-1-carboxylate

8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl in dioxane (1 mL) ) tert-butyl (S)-2-methylpiperazine-1-carboxylate (46 mg, 0.228 mmol) in a solution of imidazo[1,5-a]pyridine-6-sulfonamide (50 mg, 0.114 mmol) ) followed by the addition of Cs ₂ CO ₃ (112 mg, 0.343 mmol) and Pd-PEPPSI-IPentCl o-picolin (11 mg, 0.011 mmol) at 22°C. The mixture was degassed and purged with N ₂ (3x), then heated to 100° C. and stirred for 1 hour. The resulting mixture was cooled to 22°C, diluted with EtOAc (10 mL), filtered and the filter cake was washed with EtOAc (3 mL, 3x). The combined filtrates were concentrated in vacuo. The residue was purified by preparative TLC (SiO ₂ , petroleum ether:ethyl acetate = 2:1) to give the product tert-butyl (S)-4-(3-(5-(difluoromethyl)-1,3, 4-thiadiazol-2-yl)-6-(N-(1-(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-methylpipe Razine-1-carboxylate (42 mg, 0.0619 mmol, 54.18% yield, 88.63% purity) was obtained as a yellow solid.

RT 0.800 min (method 2); m/z 602.0 (M+H) ⁺ (ESI ⁺ );

Preparation of Example 286

(S)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-8-(3- Methylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide

tert-Butyl (S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1) in DCM (2 mL) TFA in a solution of -(fluoromethyl)cyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-methylpiperazine-1-carboxylate (42 mg, 0.070 mmol) (0.4 mL) was added at 22°C. The reaction mixture was stirred at 22°C for 0.5 hours. The resulting mixture was concentrated in vacuo. The residue _was subjected _to preparative HPLC (column: Welch purified and directly lyophilized to obtain the product (S)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclo Propyl)-8-(3-methylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide (9.5 mg, 0.0188 mmol, 26.97% yield, 99.7% purity) as a yellow solid. Obtained.

RT 0.345 min (Method 4); m/z 502.2 (M+H)+ (ESI+); ¹ H NMR (DMSO- d ₆ , 400 MHz): 9.55 (s, 1H), 8.80 (br s, 1H), 7.98 (s, 1H), 7.67 (t, J = 53.2 Hz, 1H), 6.68 (s , 1H), 4.22 (d, J = 48.4 Hz, 2H), 3.63-3.51 (m, 2H), 3.03-2.92 (m, 3H), 2.82-2.75 (m, 1H), 2.48-2.44 (m, 1H) ), 1.06 (d, J = 6.0 Hz, 3H), 0.88-0.81 (m, 2H), 0.80-0.74 (m, 2H).

Preparation of Intermediate 287.1

tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo [1,5-a]pyridin-8-yl)-2-(trifluoromethyl)piperazine-1-carboxylate

8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[ 1,5-a]pyridine-6-sulfonamide (30 mg, 0.0715 mmol), tert-butyl 2-(trifluoromethyl)piperazine-1-carboxylate (36 mg, 0.143 mmol), Cs ₂ CO A mixture of ₃ (70 mg, 0.214 mmol) and Pd-PEPPSI-IPentCl o-picolin (7.0 mg, 0.00715 mmol) was degassed with N ₂ (3x) and stirred at 100°C for 1 hour. The resulting mixture was 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 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazole-2 -yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-(trifluoromethyl)piperazine-1-carboxyl Rate (10 mg, 0.0138 mmol, 19.30% yield) was obtained as a yellow solid.

RT 0.579 min (Method 4); m/z 638.2 (M+H) ⁺ (ESI ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): 9.91 (s, 1H), 7.78 (s, 1H), 7.08 (t, J =53.6 Hz, 1H), 6.69 (s, 1H), 5.10 (br, 1H) , 4.87-4.56 (m, 1H), 4.16-4.09 (m, 2H), 3.65-3.47 (m, 2H), 3.13-3.01 (m, 2H), 1.40 (s, 3H), 1.26 (s, 9H) , 0.95-0.93- (m, 2H), 0.65-0.57 (m, 2H).

Preparation of Example 287

3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-8-(3-(trifluoromethyl)piperazine -1-1) imidazo[1,5-a]pyridine-6-sulfonamide

tert-Butyl 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N- in DCM (0.2 mL) and TFA (0.04 mL) (1-methylcyclopropyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-(trifluoromethyl)piperazine-1-carboxylate (10 mg, 0.016 mmol) The solution was stirred at 25°C for 1 hour. The mixture was concentrated under vacuum and the residue was obtained, which was subjected to preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 34%- 64%, 10 min) and directly lyophilized to give the product 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl). -8-(3-(trifluoromethyl)piperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide (0.60 mg, 0.001 mmol, 6.6% yield) was obtained as a yellow solid. did.

RT 0.411 min (Method 4); m/z 538.3 (M+H) ⁺ (ESI ⁺ ); ^1H NMR (DMSO- d _6,400 MHz): 9.91 (s, 1H), 7.71 (s, 1H), 7.09 (t, J = 53.2 Hz, 1H), 6.69 (s, 1H), 5.10 ( s, 1H), 3.86-3.80 (m, 1H), 3.68-3.58 (m, 2H), 3.39-3.30 (m, 1H), 3.23-3.16 (m, 1H), 3.15-3.02 (m, 2H), 1.40 ( s, 3H), 0.98-0.89 (m, 2H), 0.62-0.59 (m, 2H).

The compounds listed in the table below were prepared according to the corresponding general procedures or, where specified, starting from the corresponding intermediates in a similar manner to the related compounds.

The compounds listed in the table below were prepared according to the corresponding general procedures or, where specified, starting from the corresponding intermediates in a similar manner to the related compounds.

Table 1 below provides an overview of the compounds described in the Examples section:

[Table 1]

Biological Evaluation of Exemplary Compounds

Exemplary compounds of formula (I) were tested one or more times in selected biological and/or physicochemical assays. When tested more than once, data are reported as the mean value or median, where the mean, also referred to as the arithmetic mean, represents the sum of the values divided by the number of times tested, and the median represents the values when ranked in ascending or descending order. It represents the middle number of a group of people. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two intermediate values. The in vitro pharmacological, pharmacokinetic and physicochemical properties of compounds can be determined according to the following assays and methods.

PARG protein expression and purification

A codon-optimized gene encoding human PARG (448-976 [H446G, L447S, L473S, N479S, S802A, R811K, M841I, S858P, I916T, T924D, D927K, C963S, A967T]) was synthesized by Genscript and N-terminal thrombin protease. It was cloned into pET15b (Ncol/BamHI) with a cleavable 6His-TwinStrep tag. Protein expression in E. coli BL21(DE3) was induced by adding 0.2 mM IPTG to shake flask cultures grown at 37°C to OD600=0.8. Growth was continued for an additional 20 hours at 30°C, then harvested by centrifugation and the cell pellets were stored at -80°C.

Proteins were purified by IMAC and SEC: frozen cell pellets (typically 40 g wet weight) were incubated with 1 mg of bovine pancreas DNase I (Sigma-Aldrich) and protease inhibitors (Roche Complete™ EDTA-free protease inhibitor tablets). was resuspended by homogenization in 5 volumes of Buffer A (25 mM Tris/HCI pH 8.0, 200 mM NaCl, 2 mM DTT) supplemented with , and passed through a Constant Systems BasicZ homogenizer to dissolve. The lysate was clarified by centrifugation at 25,000 g for 60 min at 4°C, and the lysate supernatant was loaded into 5 ml StrepTrap HP (Cytiva) pre-equilibrated with Buffer A. The column was washed with buffer A (~10 CV) and then with buffer B (~5 CV) containing 1 M KCl, and then the protein was eluted with buffer A containing 2.5 mM d-desthiobiotin. Pooled fractions containing 6HisTwinStrep-TEV-hPARG were incubated with TEV protease overnight at 4°C. hPARG was separated from uncleaved material and thrombin protease by gel filtration using a Superdex75 sizing column (GE Healthcare) pre-equilibrated with SEC buffer (15mM Tris/HCI pH 8.5, 100mM NaCl, 2mM DTT). Pooled fractions containing pure hPARG were concentrated to 10 mg/mL using a 10k MWCO spin concentrator (VivaSpin) and then used immediately for crystallization or snap frozen in liquid nitrogen and stored at -80°C.

PARG enzyme IC ₅₀ black

PARG enzyme incubated with compound or vehicle (DMSO) in 384-well plates for 15 min or 2 h. After addition of the PARG substrate ADP-ribose-pNP, the absorbance intensity of the plate was read at 405 nm. Vehicle (DMSO) with high absorbance intensity indicates no inhibition of the enzymatic reaction, whereas low control (no enzyme) with low absorbance intensity indicates complete inhibition of the enzymatic reaction.

ingredient:

hPARG: peak protein, 30 nM

Substrate: ADP-pNP, 800 μM, Jena Bioscience catalog # NU-955

Response time: 60 minutes

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

Temperature: 30℃

Total volume: 30 μL

Control group:

0% inhibition control: DMSO

100% inhibition control: no enzyme

The protocol used for enzyme reaction and detection is as follows:

One. Transfer 100 nL of final concentration of test compound or vehicle (DMSO) to the appropriate well of the microtiter plate.

2. Centrifuge the plate at 1000 rpm for 1 minute.

3. Transfer 14.6 µL of 2x final concentration of enzyme in assay buffer or assay buffer alone to the appropriate well.

4. Centrifuge the plate at 1000 rpm for 1 minute.

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

6. Transfer 15.4 μL of 2x substrate in assay buffer to all test wells.

7. Centrifuge the plate at 1000 rpm for 1 minute.

8. Plates are read on a plate reader (e.g. Spark Tecan).

The absorbance IC ₅₀ values of compounds of formula (I) in Examples 1 to 299 are provided in Table 2 below.

Cellular PAR chain assay

The ability of compounds to inhibit PARG in response to DNA damage was assessed using U2OS cells pretreated with the compounds for 1 h followed by 1 h treatment with or without the DNA alkylating agent temozolomide (TMZ). Cells were harvested, fixed in 70% ethanol, rehydrated with glucose and EDTA in PBS, and blocked with PBS 1% BSA and 0.01% Tween-20 (PBT) for 1 hour. Cells were incubated with mouse monoclonal antibody against poly(ADP) ribose (PAR) polymer for 2 h at room temperature. Cells were washed and incubated with anti-mouse Alexa-488 conjugated secondary antibody for 1 hour at room temperature. The DNA content of cells was determined using propidium iodide staining (staining overnight at 4°C). The fluorescence intensity of cells was assessed by flow cytometry (Beckmann's Cytoflex) and the percentage of PAR chain positive cells (gated relative to TMZ+DMSO treated controls) was determined. PAR chain EC ₅₀ values were generated by fitting the % PAR chain positive cells to the concentration of the compound using a 4-parameter log-logistic function:

PAR chain EC ₅₀ values for compounds of formula (I) of Examples 1 to 25 are provided in Table 2 below.

Cell viability assay

NCIH-460, a PARG-inhibition sensitive cell line, and U2OS, a PARG-inhibition non-sensitive cell line, were plated at 1000 cells/well and 2000 cells/well, respectively, in a 96-well white plate with a transparent flat bottom. After 24 hours, compounds were added in duplicate using a Tecan digital dispenser (D300e). The outer wells of the plate were excluded. After 96 hours of incubation, 150 μl of growth medium was removed and 50 μl of Cell Titer-Gio (Promega) was added per well. After incubation for 10 minutes, luminescence was read using a plate reader (Tecan). The mean values of the samples were normalized to the DMSO treated control samples. Curves were fitted as % of control versus logarithm of compound concentration using the four parameter log-logistic function:

PARGi (NCIH-460 and U2OS) cell viability EC ₅₀ values for compounds of formula (I) of Examples 1 to 299 are provided in Table 2 below.

Table 2: Inhibition of PARG and cellular activity by compounds according to the invention.

IC ₅₀ (50% inhibitory concentration of maximal effect) values are expressed in μM, with blank spaces indicating that the compound was not tested in the respective assay.

① Example number

③ IC ₅₀ (μM) determined in the PARG enzyme assay (PARG protein and 15 min incubation) described in the PARG enzyme IC ₅₀ assay .

④ IC ₅₀ (μM) determined in the PARG enzyme assay (PARG protein and 2-hour incubation) described in the PARG enzyme IC ₅₀ assay .

⑤ EC ₅₀ (μM) determined in the cellular assay described in Cellular PAR chain analysis (conditions with TMZ treatment)

⑥ EC ₅₀ (μM) determined in the cellular assay described in Cellular PAR chain analysis (conditions without TMZ treatment)

⑦ EC ₅₀ (μM) determined in NCIH-460 cells as described in Cell Viability Assay

⑧ EC ₅₀ (μM) determined in U2OS cells as described in Cell Viability Assay

[Table 2]

Additional tests

Kinetic solubility assay

The kinetic solubility assay uses the shake flask method followed by HPLC-UV analysis. For exemplary compounds, dynamic solubility was measured according to the following protocol:

One) Samples were weighed and dissolved in 100% DMSO to make a 10 mM stock solution. Approximately 100 μL of stock solution is required to perform this assay.

2) Test compounds and controls (10 mM in DMSO, 10 μL/tube) were added to buffer (490 μL/well) placed on Minni-Uniprep filters. Buffers were manufactured according to customer requirements.

3) Dynamic solubility Vortex the sample for 2 minutes.

4) Incubate and shake the solubility solution on an orbital shaker for 24 hours at room temperature.

5) If samples were directly filtered with a syringe-less filter device, 200 μL of each solubility solution was transferred to a 96-deep well for analysis.

6) Determine the test compound concentration in the filtrate using HPLC-UV.

7) After injecting three UV standard solutions into HPLC from low to high concentration, K.S. The supernatant was tested. Test samples are injected in duplicate.

Bidirectional transmittance of Caco2

Bidirectional permeability assays in Caco-2 cells were performed for exemplary compounds of Formula (I) according to the following protocol:

1. Caco-2 cells purchased from ATCC were seeded on polyethylene membranes (PET) in ⁹⁶ -well BD insert plates at ¹ Media was refreshed every to 5 days.

2. The integrity of the monolayer is confirmed by performing a Lucifer yellow rejection assay.

3. The quality of the monolayer was assessed by measuring unidirectional (A→B) permeability of fenoterol/nadolol (low-permeability marker), propranolol/metopronolol (high-permeability marker), and bidirectional permeability of digoxin (P-glycoprotein matrix marker) in duplicate wells. Measure and verify.

4. Standard analysis conditions for test compounds:

-Test concentration: 2 μM (DMSO≤1%);

- repetition: n=2;

- Direction: two-way transport including A→B and B→A;

- Incubation time: single time point, 2 hours;

- Transport buffer: HBSS containing 10mM HEPES, pH7.40±0.05;

- Incubation conditions: 37±1°C, 5% CO2, relative saturated humidity.

5. The dosing solution is spiked and mixed with transport buffer and stop solution (containing the appropriate internal standard (IS)) as a T0 sample.

6. At the end of incubation, sample solution is taken from both donor and recipient wells and immediately mixed with the stop solution.

7. All samples, including T0 samples, donor samples, and recipient samples, are analyzed using LC/MS/MS. The concentration of the test compound is expressed as the ratio of the peak area of the analyte to the IS without a standard curve.

Microsome metabolic stability (MMS) assay

The stability of exemplary compounds was measured in a microsomal metabolic stability assay as follows:

One) Test compounds will be incubated at 37°C with 1 μM liver microsomes (pooled from multiple donors) in the presence of the NADPH regeneration system at 0.5 mg/ml microsomal protein.

2) Positive controls include testosterone (3A4 substrate), propafenone (2D6), and diclofenac (2C9). These will be incubated with microsomes in the presence of the NADPH regeneration system.

3) Time samples (0, 5, 15, 30, 45, and 60 min) will be removed and immediately mixed with cold acetonitrile containing the internal standard (IS). Test compounds incubated for 60 minutes with microsomes without the NADPH regeneration system will also be included.

4) Single point for each test condition (n=1).

5) Samples will be analyzed by LC/MS/MS; Disappearance of test compounds will be assessed based on peak area ratio of analyte/IS (no standard curve).

6) Excel data summary, calculated intrinsic clearances and t½ values will be provided.

7) Calculate microsome clearance using the equation:

int(min) = 0.693/half-life/mg microsomal protein weight per mL: 40 g/kg, 30 g/kg, 32 g/kg, 20 g/kg and 88 g for rats, monkeys, dogs, humans and mice. /kg. CLint(mic) to calculate total liver clearance: microsomal protein/g liver weight: 45 mg/g for 5 species. int(liver) = CLint(mic) * mg microsomal protein/g liver weight * g liver weight/kg body weight.

In vitro metabolic stability of test compounds in CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys, and human cryopreserved hepatocytes.

1. Test compounds (1 μM) are incubated with cryopreserved hepatocytes (0.5 × 10 ⁶ cells per mL) in duplicate (n=2) at 37°C using a 96-well plate format.

2. Time points are 0, 15, 30, 60 and 90 minutes on separate plates with cell-free media control samples also incubated at 0 and 90 minutes. At each time point the reaction will be stopped by adding the organic solution containing the internal standard (IS).

3. Positive controls 7-ethoxycoumarin and 7-hydroxycoumarin are included in parallel.

4. Samples are analyzed by LC-MS/MS. Disappearance of test compounds is assessed based on the peak area ratio of analyte/IS (no standard curve).

Additional embodiments of the invention are disclosed in the numbered sections below.

One. Compounds of formula (I):

[Formula (I)]

or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystal form, pharmaceutically acceptable salt or prodrug thereof:

In the above equation

R ₁ is hydrogen, chloro, fluoro, cyano, formyl, (C _1-2 )alkyl, (C ₂ )alkenyl, (C ₂ )alkynyl (C _1-2 )haloalkyl, -(C _{1 -2} alkylene)-OH and -(C _1-2 alkylene)-O-(C _1-2 alkyl), preferably where R ₁ is hydrogen, chloro, fluoro, cyano , formyl, (C _1-2 )alkyl, (C ₂ )alkenyl, (C ₂ )alkynyl and (C _1-2 )haloalkyl;

R ₂ and R ₃ are independently each (C _1-2 )alkyl or (C _1-2 )haloalkyl, or R ₂ and R ₃ together with the carbon atom to which they are attached form cyclopropyl;

W is -NHS(O) _y- , -S(O) _y NH-, -NHS(O)(NH)-, -NHS(O)(NCH ₃ )-, -S(O)(NH)-NH -, -S(O)(NCH ₃ )-NH-, where y is 1 or 2;

X ₁ and X ₃ are independently selected from the group consisting of N, CH, and CF;

X ₂ is N or CY _C2 -R _C2 ,

where Y _C2 is a covalent bond, selected from C _1-5 alkylene, C _2-5 alkenylene, C _2-5 alkynylene, cycloalkylene and heterocycloalkylene, wherein said alkylene, said alkenylene and said Alkynylene is halogen, CN, OH, O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, SH, S(C ₁₅ alkyl), -S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N( C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), CON(C _{1 -5} alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), NHCO-(C _1-5 alkyl), N(C _1-5 alkyl)-CO-(C _1-5 alkyl ), NHCONH ₂ , NHCONH-(C _1-5 alkyl), NHCON(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 alkyl)CONH ₂ , N(C _1-5 alkyl) CONH-(C _1-5 alkyl), and N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, CN, OH, O( optional with one or more groups selected from C _1-5 alkyl), SH, S(C ₁₅ alkyl), NH ₂ , NH(C _1-5 alkyl), and N(C _1-5 alkyl)(C _1-5 alkyl) and further, wherein the alkylene, the alkenylene, or one or more -CH ₂ - units contained in the alkynylene are each -O-, NH-, N(C _1-5 alkyl)-, CO-, optionally replaced with a group selected from S-, -SO-, and SO ₂ -, and further wherein said cycloalkylene and said heterocycloalkylene are each halogen, CN, OH, C _1-5 alkyl, C _1-5 Haloalkyl, O(C _1-5 alkyl), -O(C _1-5 haloalkyl), SH, S(C ₁₅ alkyl), -S(C _1-5 haloalkyl), NH ₂ , NH(C _{1 -5} alkyl), -NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), - (N- heterocycloalkyl), -CO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), NHCO-(C _1-5 alkyl), N(C _1-5 alkyl)-CO-(C _1-5 alkyl), NHCONH ₂ , NHCONH-(C _1-5 alkyl), NHCON (C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 alkyl)CONH ₂ , N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and N(C _{1- 5} alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)OH, -(C _1-5 alkylene )O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)SH, -(C _1-5 alkylene) S(C ₁₅ alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)NH ₂ , -(C _1-5 alkylene)NH( C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)(C _1-5 alkyl ), -(C _1-5 alkylene)N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)( N -heterocycloalkyl), -(C _{1- 5} alkylene)N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)CONH ₂ , -(C _1-5 alkylene)CONH(C _1-5 alkyl), -(C _1-5 alkylene)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _{1- 5} alkylene)CO-( N -heterocycloalkyl), -(C _1-5 alkylene)NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl) -CO-(C _1-5 alkyl), -(C _1-5 alkylene)NHCONH ₂ , -(C _1-5 alkylene)NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene )NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)N(C _{1 -5} alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl) independently selected, preferably halogen, CN, OH, C _1-5 alkyl, O(C _1-5 alkyl), SH, S(C ₁₅ alkyl), NH ₂ , NH(C _1-5 alkyl), and N( optionally substituted with one or more groups selected from C _1-5 alkyl)(C _1-5 alkyl),

Preferably wherein Y _C2 is selected from a covalent bond, C _1-5 alkylene, C _2-5 alkenylene, and C _2-5 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each halogen , CN, OH, O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, SH, S(C ₁₅ alkyl), -S(C _1-5 haloalkyl ), NH ₂ , NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl) (C _1-5 alkyl), -(N- heterocycloalkyl), -CO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), CON(C _1-5 alkyl)(C _{1 -5} alkyl), -CO-( N -heterocycloalkyl), NHCO-(C _1-5 alkyl), N(C _1-5 alkyl)-CO-(C _1-5 alkyl), NHCONH ₂ , NHCONH- (C _1-5 alkyl), NHCON(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 alkyl)CONH ₂ , N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, CN, OH, O(C _1-5 alkyl), optionally substituted with one or more groups selected from SH, S(C ₁₅ alkyl), NH ₂ , NH(C _1-5 alkyl), and N(C _1-5 alkyl)(C _1-5 alkyl), and further comprising: The alkylene, the alkenylene, or one or more -CH _2- units contained in the alkynylene are each -O-, NH-, N(C _1-5 alkyl)-, CO-, S-, -SO-, and SO _2- ,

where R _C2 is hydrogen, halo, -OH, -NH ₂ , -SH, -CN, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

wherein the alkyl, alkenyl, or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _{1 -5} alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _{1- 5} alkyl)(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _{1- 5} alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), - P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), and -P(O )(O(C _1-5 alkyl))(C _1-5 alkyl), preferably halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _{1- 5} haloalkyl), C _1-5 haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl),

wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S( O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl) (C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _{1- 5} alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(N- heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl) , -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(C _{1-5 alkyl)(C 1-5 alkyl} ), -P(O)(O(C _1-5 alkyl))(O(C _{1 -5} alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene) -OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene )-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkyl lene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S( O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _{1- 5} alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O (C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene) -NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkyl lene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _{1 -5} alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene) -CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene )-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO- (C _1-5 alkyl), -(C _1-5 alkylene)-N(C 1-5 alkyl _{)-CO-(C 1-5 alkyl), -(C 1-5 alkylene )} -NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _{1 -5} alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _{1 -5} alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl , C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -(C _1-5 alkylene)-OH, -(C _1-5 alkylene) -O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _{1- 5} haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N( C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkyl ren)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _{1 -5} alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), - O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH (C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _{1- 5} alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl);

X ₄ is N or CR _C4 ,

where R _C4 is hydrogen, halo, C _1-6 alkyl, C _2-6 alkynyl, -O(C _1-6 alkyl), -S(C _1-6 alkyl), -NH(C _1-6 alkyl) , -N(C _1-6 alkyl)(C _1-6 alkyl), -CO(C _1-6 alkyl), C _1-6 haloalkyl, -O(C _1-6 haloalkyl), -S(C _1-6 haloalkyl), -NH(C _1-6 haloalkyl), -N(C _1-6 haloalkyl) ₂ , -CO-(C _1-6 haloalkyl), -(C _0-3 alkylene )-cycloalkyl, -O-(C _0-3 alkylene)-cycloalkyl, -CO-(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-heterocycloalkyl, - O-(C _0-3 alkylene)-heterocycloalkyl, -CO-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-aryl, -O-(C _{0- 3} alkylene)-aryl, -CO-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-heteroaryl, -O-(C _0-3 alkylene)-heteroaryl, and -CO-(C _0-3 alkylene)-heteroaryl,

Here, the alkyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH( C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-(N-heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N (C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _{1 -5} alkyl), preferably halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _{1- 5} alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)( C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)( C _1-5 alkyl) is optionally substituted with one or more groups selected from

wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _{1- 5} alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), - ( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), - CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _{1- 5} alkyl), and -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene )-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkyl lene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-NH2, -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _{1- 5} alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -( C _1-5 alkylene)-( N - heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkyl lene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)- NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -( C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -( C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, C _{1- 5} alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _{1- 5} haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N( One or more selected from C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl) optionally substituted with a group;

X ₅ is N or CR _C5 ,

where R _C5 is hydrogen, halo, C _1-6 alkyl, -O(C _1-6 alkyl), -S(C _1-6 alkyl), -NH(C _1-6 alkyl), -N(C _{1- 6} alkyl)(C _1-6 alkyl) and C _1-6 haloalkyl;

R ₄ is Y _R5 -R _R5 ,

wherein Y _R5 is selected from a covalent bond, C _1-4 alkylene, C _2-4 alkenylene, and C _2-4 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each selected from a halogen, CN, OH, O(C _1-5 alkyl), O(C _1-5 haloalkyl)SH, S(C _1-5 alkyl), S(C _1-5 haloalkyl)NH ₂ , NH(C _1-5 alkyl) ), NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), and N(C _1-5 haloalkyl)(C _1-5 alkyl). optionally substituted with one or more groups, and further wherein the alkylene, the alkenylene, or one or more -CH ₂ - units included in the alkynylene are -O-, NH-, N(C _1-5 alkyl)-, optionally replaced with a group selected from CO-, -COO-, S-, -SO-, and SO ₂ -,

where R _R5 is selected from C _1-12 alkyl, C _1-12 alkenyl, C _2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

where the alkyl, alkenyl, or alkynyl is halogen, CN, OH, O(C _1-5 alkyl), O(C _1-5 haloalkyl), SH, S(C _1-5 alkyl), S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _{1- 5} haloalkyl)(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), and CON(C _1-5 alkyl)(C _1-5 alkyl). wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is halogen, CN, OH, C _1-5 alkyl, C _1-5 haloalkyl, O(C _1-5 alkyl), O(C _{1- 5} haloalkyl), SH, S(C _1-5 alkyl), S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), NH(C _1-5 haloalkyl), N( C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), and CON(C _1-5 alkyl)(C _1-5 alkyl).

2. The compound of item 1, wherein R ₁ is selected from the group consisting of cyano, cyano, (C _1-2 )alkyl, and (C _1-2 )haloalkyl.

3. The compound according to item 1 or 2, wherein R ₁ is selected from the group consisting of cyano, methyl and fluoromethyl.

4. The compound according to any one of items 1 to 3, wherein R ₁ is cyano.

5. The compound according to any one of items 1 to 4, wherein R ₂ and R ₃ together with the carbon atom to which they are attached form cyclopropyl.

6. The compound according to any one of items 1 to 5, wherein W is -NHS(O) ₂ -.

7. The compound according to any one of items 1 to 6, wherein X ₁ and X ₃ are each CH.

8. The compound according to any one of items 1 to 7, wherein X ₂ is CY _C2 -R _C2 .

9. The method of item 8, where -Y _C2 -R _C2 is -OC _1-12 alkyl, -NH-C _1-12 alkyl, -N(C _1-5 alkyl)-C _1-12 alkyl, -OC _{2- 12} alkenyl, -NH-C _2-12 alkenyl, -N(C _1-5 alkyl)-C _2-12 alkenyl, -OC _2-12 alkynyl, -NH-C _2-12 alkynyl, - N(C _1-5 alkyl)-C _2-12 alkynyl, -(C _0-3 alkylene)-cycloalkyl, -CO-(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-CO-cycloalkyl, -CONH-(C _0-3 alkylene)-cycloalkyl, (C _0-3 alkylene)-CONH-cycloalkyl, -NHCO-(C _0-3 alkylene)- Cycloalkyl, -(C _0-3 alkylene)-NHCO-cycloalkyl, -NH-(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-NH-cycloalkyl, -O -(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)- O-cycloalkyl, -SO ₂ -(C _0-3 alkylene)-cycloalkyl, -(C _0-3 Alkylene)-SO ₂ -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, -SO ₂ -cycloalkyl, -(C _0-3 alkylene)-heterocycloalkyl, -CO-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-CO-heterocycloalkyl,-CONH-(C _{0- 3} alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene) -NHCO-heterocycloalkyl, -NH-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-NH-heterocycloalkyl, -O-(C _0-3 alkylene) -Heterocycloalkyl, -(C _0-3 alkylene)-O-cycloalkyl, -SO ₂ -(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-SO ₂ - Heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O- heterocycloalkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, -(C _0-3 alkylene)-aryl, -CO-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-CO-aryl, -CONH-(C _0-3 alkylene)-aryl , -(C _0-3 alkylene)-CONH-aryl, -NHCO-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-NHCO-aryl, -NH-(C _{0- 3} alkylene)-aryl, -(C _0-3 alkylene)-NH-aryl, -O-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-O-aryl, - SO ₂ -(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, - CO-aryl, -SO ₂ -aryl, -(C _0-3 alkylene)-heteroaryl, -CO-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-CO- Heteroaryl, -CONH-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-CONH-heteroaryl, -NHCO-(C _0-3 alkylene)-heteroaryl, -( C _0-3 alkylene)-NHCO-heteroaryl, -NH-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-NH-heteroaryl, -O-(C _{0- 3} alkylene)-heteroaryl, -(C _0-3 alkylene)-O-heteroaryl, -SO ₂ -(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and -SO ₂ -heteroaryl, wherein the alkyl, Alkenyl, or alkynyl, is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , NH(-C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl) )(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), - N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl) , -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)( C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O) (C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), and -P(O)(O( independently selected from C _1-5 alkyl))(C _1-5 alkyl), preferably halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl) , -C _1-5 haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH( C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), wherein the cycloalkyl, hetero Cycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl) , -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)( C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl ), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _{1 -5} alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _{1 -5} alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N( C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), - P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)- CN, -(C _1-5 alkylene)OH-, -(C _{1 -5} alkylene)O-(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)SH-, -(C _1-5 alkylene)S-(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O) (C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P( O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl) ), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)NH(-C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)N(-C _{1 -5} alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)N(-C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N - heterocycloalkyl), -(C _1-5 alkylene)N(-C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)CONH(-C _1-5 alkyl), -(C _1-5 alkylene)CON(-C _{1- 5} alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl) , -(C _1-5 alkylene)N(-C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkyl len)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)NHCON(-C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)N( -C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)N(-C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)N( -C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, - O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -(C _1-5 alkylene)- OH, -(C _1-5 alkylene)-O(C _1-5 alkyl) , -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -(C _{1- 5} alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH( C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl) , -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , CONH (-C _1-5 alkyl), and CON(-C _1-5 alkyl)(C _1-5 alkyl).

10. The method of item 8 or 9, wherein -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -CO-(C _0-3 alkylene)-heterocycloalkyl, -(C _{0 -3} alkylene)-CO-heterocycloalkyl, -CONH-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(C _{0 -3} alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-NHCO-heterocycloalkyl, -NH-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene )-NH-heterocycloalkyl, -O-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-O-cycloalkyl, -SO ₂ -(C _0-3 alkylene )-heterocycloalkyl, -(C _0-3 alkylene)-SO ₂ -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl , -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, -(C _0-3 alkylene)-aryl, -CO-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene )-CO-aryl, -CONH-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-CONH-aryl, -NHCO-(C _0-3 alkylene)-aryl, -( C _0-3 alkylene)-NHCO-aryl, -NH-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-NH-aryl, -O-(C _0-3 alkylene )-aryl, -(C _0-3 alkylene)-O-aryl, -SO ₂ -(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-SO ₂ -aryl, -CONH -aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-3 alkylene)-heteroaryl, -CO-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-CO-heteroaryl, -CONH-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-CONH-hetero Aryl, -NHCO-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-NHCO-heteroaryl, -NH-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-NH-heteroaryl, -O-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-O-heteroaryl, -SO ₂ -(C _{0- 3} alkylene)-heteroaryl, -(C _0-3 alkylene)-SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO -heteroaryl, and -SO ₂ -heteroaryl, wherein the heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O (C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N =S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _{1 -5} haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-(N-heterocycloalkyl ), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON (C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)- CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 halo alkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), - (C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O _{)(C 1-5 alkyl)(C 1-5 alkyl), -(C 1-5 alkylene )} -P(O)( O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl ), -(C _1-5 alkylene)-NH2, -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 halo alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _{1 -5} haloalkyl), -(C _1-5 alkylene)-( N - heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl) , -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl ), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -( C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _{1 -5} alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, - CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -(C _1-5 alkylene)-OH , -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _{1- 5} alkylene)-S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)( C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH( C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _{1- 5} alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, - O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -NH2, -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl) ), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl).

11. The method of any one of items 8 to 10, wherein -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH- Heterocycloalkyl, -O- heterocycloalkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, -(C _0-3 alkylene)aryl, -CONH-aryl, -NHCO-aryl, -NH- Aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-3 alkylene)-heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, - is selected from O-heteroaryl, -CO-heteroaryl, and -SO ₂ -heteroaryl, wherein the heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _{1 -5} haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl) ), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _{1 -5} alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl) ), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO -( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _{1 -5} alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P (O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)- CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)- O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene) -S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _{1 -5} alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene )-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl) )(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene) -NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl )(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C 1-5 alkyl ₎ , -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene) -CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _{1 -5} alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON( C _1-5 alkyl)(C _1-5 alkyl), -(C 1-5 alkylene _{)-N(C 1-5 alkyl)CONH 2 , -(C 1-5 alkylene ) -N} (C _{1- 5} alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl) independently selected, preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -SH , -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N (C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _{1 -5} alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _{1- 5} alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -NH ₂ , -NH(C _{1 -5} alkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), Compounds optionally substituted with one or more groups selected from -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl).

12. The method of any one of items 8 to 11, wherein -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-aryl, and -(C _0-3 alkylene)-heteroaryl, wherein the heterocycloalkyl, aryl, or heteroaryl is halogen, CN, OH, C _1-5 alkyl, C _1-5 haloalkyl, O(C _1-5 alkyl), -O(C _1-5 haloalkyl), SH, S(C _1-5 alkyl), S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), and CON(C _1-5 alkyl)(C _1-5 alkyl).

13. The method according to any one of items 8 to 12, wherein -Y _C2 -R _C2 is selected from heterocycloalkyl, aryl, and heteroaryl, preferably heterocycloalkyl and heteroaryl, more preferably heterocycloalkyl, wherein the heterocycloalkyl, aryl, or heteroaryl is halogen, CN, OH, C _1-5 alkyl, C _1-5 haloalkyl, O(C _1-5 alkyl), -O(C _1-5 haloalkyl) , SH, S(Cis haloalkyl), S(Cis alkyl), NH ₂ , NH(C _1-5 alkyl), NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _{1- 5} alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), and CON(C _{1- 5} alkyl)(C _1-5 alkyl).

14. The method according to any one of items 8 to 13, wherein -Y _C2 -R _C2 is optionally substituted aryl, preferably -Y _C2 -R _C2 is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl ), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _{1- 5} haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _{1- 5} alkyl), which is phenyl optionally substituted with one or more groups independently selected from alkyl).

15. The method of any one of items 8 to 13, wherein -Y _C2 -R _C2 is optionally substituted heteroaryl, preferably where -Y _C2 -R _C2 is imidazolyl, pyridazinyl, thiazolyl, pyri. dinyl, pyrimidinyl, pyrazinyl, or indazolyl, where heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), - O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH (C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _{1- 5} alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl).

16. The method of any one of items 8 to 13, wherein -Y _C2 -R _C2 is optionally substituted heterocycloalkyl, preferably wherein -Y _C2 -R _C2 is morpholinyl, 1,1-dioxothio. morpholinyl, azetinyl, pyrrolidinyl, piperidinyl, 6-oxo-1,6-dihydropyridinyl, or piperazinyl, where heterocycloalkyl is halogen, CN, OH, C _1-5 alkyl , C _1-5 haloalkyl, O(C _1-5 alkyl), -O(C _1-5 haloalkyl), SH, S(C _1-5 alkyl), S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _{1 -5} alkyl), -CO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), and CON(C _1-5 alkyl)(C _1-5 alkyl). Compounds, optionally substituted.

17. The method of item 16, where -Y _C2 -R _C2 is halogen, CN, OH, C _1-5 alkyl, C _1-5 haloalkyl, O(C _1-5 alkyl), -O(C _1-5 halo alkyl), SH, S(C _1-5 alkyl), S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), NH(C _1-5 haloalkyl), N(C _{1 -5} alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl) ), and CON(C _1-5 alkyl)(C _1-5 alkyl), preferably piperazinyl, wherein -Y _C2 -R _C2 is CO(C _{1- 5} alkyl), CONH ₂ , CONH(C _1-5 alkyl), and CON(C _1-5 alkyl)(C _1-5 alkyl) optionally substituted (preferably N-substituted) piperazinyl ( Preferably N-piperazinyl), more preferably where -Y _C2 -R _C2 is CON(C _1-5 alkyl)(C _1-5 alkyl), preferably -CON(CH ₃ ) ₂ A compound which is piperazinyl (preferably N-piperazinyl) substituted (preferably at an N atom different from the N atom attached to the ring system shown in formula (I), preferably N-substituted) .

18. In item 16, -Y _C2 -R _C2 is 2-oxaspiro[3.5]non-6-en-7-yl, 2-oxaspiro[3.5]non-7-yl, 2-oxa-8- Oxaspiro[4.5]dec-8-yl, 9-oxa-3-oxaspiro[5.5]undec-3-yl, 2-oxa-6-oxaspiro[3.4]oct-6-yl, 1-oxa- 7-oxaspiro[3.5]non-7-yl, 1-oxa-8-oxaspiro[4.5]des-8-yl, 6-oxa-2-oxaspiro[3.3]hept-2-yl, 2,8 -dioxaspiro[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-oxaspiro[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, or 2,7-dioxaspiro[3.5]non-7-yl.

_{19. The method} of _any one _of items ₁ to ₁₆ , wherein _-6 alkyl, -NH-C _1-6 alkyl, C _1-6 haloalkyl, -(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-aryl, and -(C _0-3 alkylene)-heteroaryl, wherein the alkyl is halogen, CN, OH, O(C _1-5 alkyl), O(C _{1- 5} haloalkyl), SH, S(C _1-5 alkyl), O(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), NH(C _1-5 haloalkyl), N( C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), and CON(C _1-5 alkyl)(C _1-5 alkyl), wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is halogen, CN, OH, C _1-5 alkyl, C _{1 -5} haloalkyl, O(C _1-5 alkyl), O(C _1-5 haloalkyl), SH, S(C _1-5 haloalkyl), S(C _1-5 alkyl), NH ₂ , NH( C _1-5 alkyl), NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), and CON(C _1-5 alkyl)(C _1-5 alkyl).

20. The method of item 19, wherein R _C4 is hydrogen, halo, C _1-6 alkyl, C _2-6 alkynyl, -OC _1-6 alkyl, -SC _1-6 alkyl, -NH-C _1-6 alkyl, and C _1-6 haloalkyl, preferably where R _C4 is selected from hydrogen, halo, C _1-2 alkyl, and C _2-3 alkynyl, more preferably where R _C4 is hydrogen, halo , and C _1-2 alkyl, even more preferably wherein R _C4 is hydrogen or halo.

21. The method of item 19, wherein R _C4 is -(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-aryl, and -(C _0-3 alkylene)-heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 halo Alkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH2, -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), .

22. The method of item 19 or 21, wherein R _C4 is -(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-heterocycloalkyl, and -(C _0-3 alkylene)- heteroaryl, preferably where R _C4 is selected from cycloalkyl, heterocycloalkyl, and heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S( C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -NH(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl) A compound wherein the compound is optionally substituted with one or more independently selected groups.

23. Item 21, wherein R _C4 is selected from heterocycloalkyl and heteroaryl, wherein said heterocycloalkyl or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , - NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -NH(C _1-5 haloalkyl)(C _{1 -5} alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl).

24. Item 19, wherein R _C4 is selected from -CH ₂ -cycloalkyl, -CH ₂ -heterocycloalkyl, -CH ₂ -aryl, and -CH ₂ -heteroaryl, more preferably wherein R _C4 is -CH ₂ -heterocycloalkyl, and -CH ₂ -heteroaryl, wherein the cycloalkyl, heterocycloalkyl or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 halo Alkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)( optionally substituted with one or more groups independently selected from C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), compound.

25. Item 23, wherein R _C4 is heteroaryl, preferably wherein R _C4 is imidazolyl, pyridazinyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or indazolyl, wherein said heteroaryl Aryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S( C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl).

26. Item 23, wherein R _C4 is heterocycloalkyl, preferably wherein R _C4 is morpholinyl, 1,1-dioxothiomorpholinyl, azetinyl, pyrrolidinyl, piperidinyl, 6- oxo-1,6-dihydropyridinyl, or piperazinyl, wherein the heterocycloalkyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -SH, -S(C _{1- 5} alkyl), -NH ₂ , -NH(C _1-5 alkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl).

27. Item 26, wherein R _C4 is piperazinyl, preferably where R _C4 is -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably -CON(CH ₃ ) ₂ A compound which is piperazinyl (preferably N-piperazinyl) substituted (preferably at an N atom different from the N atom attached to the ring system shown in formula (I), preferably N-substituted) .

28. Item 23, wherein R _C4 is heterocycloalkyl, preferably R _C4 is 2-oxaspiro[3.5]non-6-en-7-yl, 2-oxaspiro[3.5]non-7-yl , 2-oxa-8-oxaspiro[4.5]dec-8-yl, 9-oxa-3-oxaspiro[5.5]undec-3-yl, 2-oxa-6-oxaspiro[3.4]oct-6 -yl, 1-oxa-7-oxaspiro[3.5]non-7-yl, 1-oxa-8-oxaspiro[4.5]dec-8-yl, 6-oxa-2-oxaspiro[3.3]hept- 2-yl, 2,8-dioxaspiro[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-oxaspiro[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, or 2,7-dioxaspiro[3.5]non-7 -One person, compound.

_{29. The method} of any one of items 1 to 28, wherein when X ₂ comprises cycloalkyl, heterocycloalkyl, aryl, or heteroaryl _, then ₆ alkyl, -OC _1-6 alkyl, -SC _1-6 alkyl, -NH-C _1-6 alkyl, and C _1-6 haloalkyl; Preferably wherein R _C4 is selected from hydrogen and halo.

30. _The method of any one of items 1 to 28, wherein when X ₄ comprises cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, then Compounds containing none of the following.

31. _{The method} of any one of items 1 to 28, wherein if X ₂ comprises cycloalkyl, heterocycloalkyl, aryl or heteroaryl and -Y _C2 -R _C2 together comprise up to 12 non-hydrogen atoms, preferably up to 10 non-hydrogen atoms.

32. _{The method} of _any one _of items 1 to _{31 ,} wherein Compounds selected from C _1-3 alkyl, and C _1-3 haloalkyl, preferably wherein R _C5 is selected from hydrogen, halo, C _1-3 alkyl, and C _1-3 haloalkyl.

33. The method of any one of items 1 to 32, wherein Y _R5 is a covalent bond, C _1-2 alkylene, -CO-(C _1-2 alkylene), -(C _1-2 alkylene)-CO-, -CONH-(C _1-2 alkylene)-, -(C _1-2 alkylene)-CONH-, -NHCO-(C _1-2 alkylene)-, -(C _1-2 alkylene)-NHCO -, -NH-(C _1-2 alkylene)-, -(C _1-2 alkylene)-NH-, -O-(C _1-2 alkylene)-, -(C _1-2 alkylene) -O-, SO ₂ -(C _1-2 alkylene)-, -(C _1-2 alkylene)SO ₂ -, -CONH-, CON(C _1-5 alkyl)-, -NHCO-, -N (C _1-5 alkyl)CO-, -NH-, -O-, -CO-, -COO- and -SO ₂ -.

34. The method of any one of items 1 to 33, wherein R _R5 is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, preferably wherein R _R5 is selected from heterocycloalkyl, aryl, and heteroaryl and , more preferably wherein R _R5 is selected from aryl, and heteroaryl, and most preferably wherein R _R5 is heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from halogen, CN, OH. , C _1-5 alkyl, C _1-5 haloalkyl, O(C _1-5 alkyl), O(C _1-5 haloalkyl), SH, S(C _1-5 alkyl), S(C _1-5 Haloalkyl), NH ₂ , NH(C _1-5 alkyl), NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl) )(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), and CON(C _1-5 alkyl)(C _1-5 alkyl). .

35. The method of any one of items 1 to 34, wherein Y _R5 is a covalent bond, C _1-2 alkylene, -CO-(C _1-2 alkylene)-, -(C _1-2 alkylene)-CO- , -CONH-(C _1-2 alkylene)-, -(C _1-2 alkylene)-CONH-, -NHCO-(C _1-2 alkylene), -(C _1-2 alkylene)-NHCO -, -NH-(C _1-2 alkylene), -(C _1-2 alkylene)-NH-, -O-(C _1-2 alkylene), -(C _1-2 alkylene)-O -, -SO ₂ -(C _1-2 alkylene)-, -(C _1-2 alkylene)-SO ₂ -, -CONH-, -NHCO-, -NH-, -O-, -CO- and A compound selected from -SO ₂ -.

36. The method of item 34 or 35, wherein R ₄ is -(C _0-2 alkylene)-cycloalkyl, -CO-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)- CO-cycloalkyl, -CONH-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-CONH-cycloalkyl, -NHCO-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-NHCO-cycloalkyl, -NH-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-NH-cycloalkyl, -O-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-O-cycloalkyl, -SO ₂ -(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene) -SO ₂ -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, -SO ₂ -cycloalkyl, -(C _0-2 alkylene)-heterocycloalkyl, -CO-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-CO-heterocycloalkyl, -CONH-(C _0-2 alkylene )-Heterocycloalkyl, -(C _0-2 alkylene)-CONH-heterocycloalkyl, -NHCO-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-NHCO- Heterocycloalkyl, -NH-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-NH-heterocycloalkyl, -O-(C _0-2 alkylene)-heterocyclo Alkyl, -(C _0-2 alkylene)-O-heterocycloalkyl, -SO ₂ -(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-SO ₂ -heterocyclo Alkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, -(C _{0- 2} alkylene)-aryl, -CO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-CO-aryl, -CONH-(C _0-2 alkylene)-aryl, - (C _0-2 alkylene)-CONH-aryl, -NHCO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-NHCO-aryl, -NH-(C _0-2 alkyl lene)-aryl, -(C _0-2 alkylene)-NH-aryl, -O-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-O-aryl, -SO ₂ -(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO- Aryl, -SO ₂ -aryl, -(C _0-2 alkylene)-heteroaryl, -CO-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-CO-heteroaryl , -CONH-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-CONH-heteroaryl, -NHCO-(C _0-2 alkylene)-heteroaryl, -(C _{0 -2} alkylene)-NHCO-heteroaryl, -NH-(C _0-2 alkylene)heteroaryl, -(C _0-2 alkylene)-N H-heteroaryl, -O-(C _0-2 alkyl len)heteroaryl, -(C _0-2 alkylene)-O-heteroaryl, -SO ₂ -(C _0-2 alkylene)heteroaryl, -(C _0-2 alkylene)-SO ₂ -heteroaryl , -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and -SO ₂ -heteroaryl, wherein the cycloalkyl, heterocycloalkyl , aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), - SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N (C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON (C _1-5 alkyl)(C _1-5 alkyl).

37. The method of item 36, wherein R ₄ is -(C _0-2 alkylene)aryl, -CO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-CO-aryl, - CONH-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-CONH-aryl, -NHCO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene) -NHCO-aryl, -NH-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-NH-aryl, -O-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-O-aryl, -SO ₂ -(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-SO ₂ -aryl, -CONH-aryl, -NHCO-aryl , -NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-2 alkylene)-heteroaryl, -CO-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-CO-heteroaryl, -CONH-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-CONH-heteroaryl, -NHCO-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-NHCO-heteroaryl, -NH-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)- NH-heteroaryl, -O-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-O-heteroaryl, -SO ₂ -(C _0-2 alkylene)-heteroaryl , -(C _0-2 alkylene)-SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and -SO ₂ -heteroaryl, wherein the aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O( C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl).

38. The method of any one of items 1 to 32, wherein R ₄ is selected from C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; , preferably R ₄ is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, more preferably R ₄ is selected from aryl, and heteroaryl, and even more preferably R ₄ is heteroaryl. , where the alkyl, alkenyl, or alkynyl is halogen, CN, OH, O(C _1-5 alkyl), O(C _1-5 haloalkyl), SH, S(C _1-5 alkyl), S( C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _{1 -5} haloalkyl)(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), and CON(C _1-5 alkyl)(C _1-5 alkyl); substituted, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is halogen, CN, OH, C _1-5 alkyl, C _1-5 haloalkyl, O(C _1-5 alkyl), O(C _{1 -5} haloalkyl), SH, S(C _1-5 alkyl), S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), NH(C _1-5 haloalkyl), N (C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), and CON(C _{1- 5} alkyl)(C _1-5 alkyl).

39. The method of item 37 or 38, wherein R ₄ is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 halo alkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl) ), and -CON(C _1-5 alkyl)(C _1-5 alkyl).

40. The method of item 39, wherein the 5-membered heteroaryl is imidazolyl, isoxazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, 1,2,4- is selected from oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl, and preferably the 5-membered heteroaryl is halogen, -CN , -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -SH, -S(C _1-5 alkyl), -NH ₂ , -NH(C _{1- 5} alkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -SH, -S(C _1-5 optionally substituted with alkyl), more preferably C _1-5 alkyl, optionally substituted with C _1-5 haloalkyl, even more preferably optionally substituted with C _1-5 haloalkyl, preferably A compound selected from -CH ₂ F, -CHF ₂ and CF ₃ , most preferably 1,2,4-thiadiazolyl optionally substituted with -CHF ₂ .

41. A pharmaceutical composition comprising the compound of any one of items 1 to 40, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.

42. A compound of any one of items 1 to 40, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of item 41, for use in therapy.

43. The compound for use or the pharmaceutical composition for use according to item 42, for use in a method of treating a disease or disorder in which PARG activity is implicated.

44. The compound for use or the pharmaceutical composition for use according to item 42 for use in a method of treating a proliferative disorder.

45. A compound for use or a pharmaceutical composition for use according to item 44, wherein the proliferative disorder is cancer, preferably human cancer.

Additional embodiments of the invention are disclosed in the numbered paragraphs below.

One. Compounds of formula (I):

[Formula (I)]

or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystal form, pharmaceutically acceptable salt or prodrug thereof:

In the above equation

R ₁ is selected from the group consisting of hydrogen, chloro, fluoro, cyano, formyl, (C _1-2 )alkyl, (C ₂ )alkenyl, (C ₂ )alkynyl and (C _1-2 )haloalkyl. being selected;

R ₂ and R ₃ are independently each (C _1-2 )alkyl or (C _1-2 )haloalkyl, or R ₂ and R ₃ together with the carbon atom to which they are attached form cyclopropyl;

W is -NHS(O) _y- , -S(O) _y NH-, -NHS(O)(NH)-, -NHS(O)(NCH ₃ )-, -S(O)(NH)-NH -, -S(O)(NCH ₃ )-NH-, where y is 1 or 2;

X ₁ and X ₃ are independently selected from the group consisting of N, CH, and CF;

X ₂ is N or CY _C2 -R _C2 ,

Y _C2 is selected from a covalent bond, C _1-5 alkylene, C _2-5 alkenylene, and C _2-5 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each selected from halogen, CN, OH, Independent of O(C _1-5 alkyl), SH, S(C _1-5 alkyl), NH ₂ , NH(C _1-5 alkyl), and N(C _1-5 alkyl)(C _1-5 alkyl) is optionally substituted with one or more selected from, and further, wherein the alkylene, the alkenylene and the one or more -CH ₂ - units included in the alkynylene are -O-, NH-, N(C _1-5 alkyl )-, CO-, S-, -SO-, and SO ₂ -,

where R _C2 is hydrogen, halo, -OH, -NH ₂ , -SH, -CN, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

wherein the alkyl, alkenyl, or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _{1 -5} alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl),

Here, the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _{1 -5} haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _{1- 5} haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), is optionally substituted with one or more groups independently selected from -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl);

X ₄ is N or CR _C4 ,

where R _C4 is hydrogen, halo, C _1-6 alkyl, C _2-6 alkynyl, -O(C _1-6 alkyl), -S(C _1-6 alkyl), -NH(C _1-6 alkyl) , -N(C _1-6 alkyl)(C _1-6 alkyl), -CO(C _1-6 alkyl), C _1-6 haloalkyl, -O(C _1-6 haloalkyl), -S(C _1-6 haloalkyl), -NH(C _1-6 haloalkyl), -N(C _1-6 haloalkyl) ₂ , -CO-(C _1-6 haloalkyl), -(C _0-3 alkylene )-cycloalkyl, -O-(C _0-3 alkylene)-cycloalkyl, -CO-(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-heterocycloalkyl, - O-(C _0-3 alkylene)-heterocycloalkyl, -CO-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-aryl, -O-(C _{0- 3} alkylene)-aryl, -CO-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-heteroaryl, -O-(C _0-3 alkylene)-heteroaryl and - CO-(C _0-3 alkylene)-heteroaryl,

Here, the alkyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), - Independent of N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl) is optionally substituted with one or more groups selected as,

wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _{1 -5} haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _{1 -5} alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl);

X ₅ is N or CR _C5 ,

where R _C5 is hydrogen, halo, C _1-6 alkyl, -O(C _1-6 alkyl), -S(C _1-6 alkyl), -NH(C _1-6 alkyl), -N(C _{1- 6} alkyl)(C _1-6 alkyl) and C _1-6 haloalkyl;

R ₄ is Y _R5 -R _R5 ,

wherein Y _R5 is selected from a covalent bond, C _1-4 alkylene, C _2-4 alkenylene, and C _2-4 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each selected from a halogen, CN, OH, O(C _1-5 alkyl), O(C _1-5 haloalkyl)SH, S(C _1-5 alkyl), S(C _1-5 haloalkyl)NH ₂ , NH(C _1-5 alkyl) ), NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), and N(C _1-5 haloalkyl)(C _1-5 alkyl). is optionally substituted with one or more groups, and further wherein the alkylene, the alkenylene, or one or more -CH ₂ - units included in the alkynylene are -O-, NH-, N(C _1-5 alkyl)-, CO, respectively. -, - optionally replaced with a group independently selected from COO-, S-, -SO-, and SO ₂ -,

where R _R5 is selected from C _1-12 alkyl, C _1-12 alkenyl, C _2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

wherein the alkyl, alkenyl, or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 Haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl) (C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). .

2. The compound of paragraph 1, wherein R ₁ is cyano.

3. The compound of paragraph 1 or 2, wherein R ₂ and R ₃ together with the carbon atom to which they are attached form cyclopropyl.

4. The compound of any of paragraphs 1 to 3, wherein W is -NHS(O) _2- .

5. The compound of any one of paragraphs 1 to 4, wherein X ₁ and X ₃ are each CH.

_{6. The method} of any one _{of paragraphs} 1 _{to 5} , wherein _1-5 alkyl)-C _1-12 alkyl, -OC _2-12 alkenyl, -NH-C _2-12 alkenyl, -N(C _1-5 alkyl)-C _2-12 alkenyl, -OC _{2 -12} alkynyl, -NH-C _2-12 alkynyl, -N(C _1-5 alkyl)-C _2-12 alkynyl, -(C _0-3 alkylene)-cycloalkyl, -CO-(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-CO-cycloalkyl, -CONH-(C _0-3 alkylene)-cycloalkyl, (C _0-3 alkylene)-CONH -Cycloalkyl, -NHCO-(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-NHCO-cycloalkyl, -NH-(C _0-3 alkylene)-cycloalkyl, - (C _0-3 alkylene)-N H-cycloalkyl, -O-(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-O-cycloalkyl, SO ₂ -(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)SO ₂ -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, - CO-cycloalkyl, SO ₂ -cycloalkyl, -(C _0-3 alkylene)-heterocycloalkyl, -CO-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene) -CO-heterocycloalkyl, -CONH-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(C _0-3 alkylene) -Heterocycloalkyl, -(C _0-3 alkylene)-NHCO- Heterocycloalkyl, -NH-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-NH-hetero Cycloalkyl, -O-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-O-cycloalkyl, SO ₂ -(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)SO ₂ -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl , SO ₂ -heterocycloalkyl, -(C _0-3 alkylene)-aryl, -CO-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-CO-aryl, -CONH -(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-CONH-aryl, -NHCO-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)- NHCO-aryl, -NH-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-NH-aryl, -O-(C _0-3 alkylene)-aryl, -(C _{0 -3} alkylene)-O-aryl, SO ₂ -(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, -NH -aryl, -O-aryl, -CO-aryl, SO ₂ -aryl, -(C _0-3 alkylene)-heteroaryl, -CO-(C _0-3 alkylene)-heteroaryl, -(C _{0 -3} alkylene)-CO-heteroaryl, -CONH-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-CONH-heteroaryl, -NHCO-(C _0-3 alkyl len)-heteroaryl, -(C _0-3 alkylene)-NHCO-heteroaryl, -NH-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-NH-heteroaryl , -O-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-O-heteroaryl, SO ₂ -(C _0-3 alkylene)-heteroaryl, -(C _{0 -3} alkylene) is selected from SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and SO ₂ -heteroaryl , where the alkyl, alkenyl, or alkynyl is halogen, CN, OH, O(C _1-5 alkyl), O(C _1-5 haloalkyl), -C _1-5 haloalkyl, SH, S(C _1-5 alkyl), S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _{1- 5} alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), and CON(C _1-5 alkyl)(C _1-5 alkyl), wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is halogen, CN, OH, C _1-5 alkyl, C _{1 -5} haloalkyl, O(C _1-5 alkyl), O(C _1-5 haloalkyl), SH, S(C _1-5 alkyl), S(C _1-5 haloalkyl), NH ₂ , NH( C _1-5 alkyl), NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), -optionally substituted with one or more groups independently selected from -CO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), and CON(C _1-5 alkyl)(C _1-5 alkyl);

Preferably where -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -CO-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene) -CO-heterocycloalkyl, -CONH-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(C _0-3 alkylene) -Heterocycloalkyl, -(C _0-3 alkylene)-NHCO-heterocycloalkyl, -NH-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-NH-hetero Cycloalkyl, -O-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-O-cycloalkyl, -SO ₂ -(C _0-3 alkylene)-heterocycloalkyl , -(C _0-3 alkylene)-SO ₂ -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-hetero Cycloalkyl, -SO ₂ -heterocycloalkyl, -(C _0-3 alkylene)-aryl, -CO-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-CO-aryl , -CONH-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-CONH-aryl, -NHCO-(C _0-3 alkylene)-aryl, -(C _0-3 alkyl lene)-NHCO-aryl, -NH-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-NH-aryl, -O-(C _0-3 alkylene)-aryl, - (C _0-3 alkylene)-O-aryl, -SO ₂ -(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-SO ₂ -aryl, -CONH-aryl, -NHCO -aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-3 alkylene)-heteroaryl, -CO-(C _0-3 alkylene)-hetero Aryl, -(C _0-3 alkylene)-CO-heteroaryl, -CONH-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-CONH-heteroaryl, -NHCO- (C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-NHCO-heteroaryl, -NH-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene )-NH-heteroaryl, -O-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-O-heteroaryl, -SO ₂ -(C _0-3 alkylene)- Heteroaryl, -(C _0-3 alkylene)-SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and -SO ₂ -heteroaryl, wherein the heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl) ), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl),

More preferably where -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O- Heterocycloalkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, -(C _0-3 alkylene)aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-3 alkylene)-heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO -heteroaryl, and -SO ₂ -heteroaryl, wherein the heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O (C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -NH ₂ , -NH(C _1-5 alkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _{1 -5} alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl),

Even more preferably where -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-aryl, and -(C _0-3 alkylene)- is selected from heteroaryl, wherein the heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), - O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH (C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _{1- 5} alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl),

Even more preferably where -Y _C2 -R _C2 is selected from heterocycloalkyl, aryl, and heteroaryl, preferably heterocycloalkyl and heteroaryl, more preferably heterocycloalkyl, wherein said heterocycloalkyl, Aryl, or heteroaryl, is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH , -S(C _1-5 haloalkyl), -S(C _1-5 alkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N( C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl).

7. According to paragraph 6, -Y _C2 -R _C2 is optionally substituted aryl, preferably -Y _C2 -R _C2 is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 halo Alkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)( Independent from C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl) or -Y _C2 -R _C2 is optionally substituted heteroaryl, preferably -Y _C2 -R _C2 is imidazolyl, pyridazinyl, thiazolyl, pyri. dinyl, pyrimidinyl, pyrazinyl, or indazolyl, where heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), - O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH (C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _{1- 5} alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), or

or -Y _C2 -R _C2 is optionally substituted heterocycloalkyl, preferably -Y _C2 -R _C2 is morpholinyl, 1,1-dioxothiomorpholinyl, azetinyl, pyrrolidinyl, pipe. Ridinyl, 6-oxo-1,6-dihydropyridinyl,

or piperazinyl, wherein heterocycloalkyl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 halo alkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl) ), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl).

8. The method of paragraph 6 or 7, where -Y _C2 -R _C2 is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O( C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl) ), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), optionally substituted with one or more groups independently selected from piperazinyl, and is preferred. Specifically, -Y _C2 -R _C2 is CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). optionally substituted (preferably N-substituted) piperazinyl (preferably N-piperazinyl), more preferably -Y _C2 -R _C2 is -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably -CON(CH ₃ ) ₂ (preferably at an N atom different from the N atom attached to the ring system shown in formula (I), preferably N-substituted ) a compound that is piperazinyl (preferably N-piperazinyl).

_{9. The method of any} one of paragraphs 1 _{to 8 ,} wherein _-6 alkyl, -NH-C _1-6 alkyl, C _1-6 haloalkyl, -(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-aryl, and -(C _0-3 alkylene)-heteroaryl, wherein the alkyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O (C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -O(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH( C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH( C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), wherein said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl Silver halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 haloalkyl), -S(C _1-5 alkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl) )(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl) )(C _1-5 alkyl),

Preferably where R _C4 is hydrogen, halo, C _1-6 alkyl, C _2-6 alkynyl, -OC _1-6 alkyl, -SC _1-6 alkyl, -NH-C _1-6 alkyl, and C _{1 -6} haloalkyl, preferably where R _C4 is selected from hydrogen, halo, C _1-2 alkyl, and C _2-3 alkynyl, more preferably where R _C4 is hydrogen, halo, and C _1-2 alkyl, even more preferably wherein R _C4 is hydrogen or halo.

11. _{The method} of _any one of paragraphs ₁ to _{10 ,} wherein Compounds selected from C _1-3 alkyl, and C _1-3 haloalkyl, preferably wherein R _C5 is selected from hydrogen, halo, C _1-3 alkyl, and C _1-3 haloalkyl.

12. The method of any one of paragraphs 1 to 11, wherein R ₄ is -(C _0-2 alkylene)-cycloalkyl, -CO-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkyl lene)-CO-cycloalkyl, -CONH-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-CONH-cycloalkyl, -NHCO-(C _0-2 alkylene)- Cycloalkyl, -(C _0-2 alkylene)-NHCO-cycloalkyl, -NH-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-N H-cycloalkyl, - O-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-O-cycloalkyl, SO ₂ -(C _0-2 alkylene)-cycloalkyl, -(C _0-2 Alkylene)SO ₂ -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, SO ₂ -cycloalkyl, -(C _{0- 2} alkylene)-heterocycloalkyl, -CO-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-CO-heterocycloalkyl, -CONH-(C _0-2 alkyl lene)-heterocycloalkyl, -(C _0-2 alkylene)-CONH-heterocycloalkyl, -NHCO-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-NHCO -Heterocycloalkyl, -NH-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-NH-heterocycloalkyl, -O-(C _0-2 alkylene)-hetero Cycloalkyl, -(C _0-2 alkylene)-O-heterocycloalkyl, SO ₂ -(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)SO ₂ -heterocycloalkyl , -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, SO ₂ -heterocycloalkyl, -(C _0-2 alkyl len)-aryl, -CO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-CO-aryl, -CONH-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-CONH-aryl, -NHCO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-NHCO-aryl, -NH-(C _0-2 alkylene) -aryl, -(C _0-2 alkylene)-NH-aryl, -O-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-O-aryl, SO ₂ -(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, SO ₂ -aryl, -(C _0-2 alkylene)-heteroaryl, -CO-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-CO-heteroaryl, -CONH-( C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-CONH-heteroaryl, -NHCO-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene) -NHCO-heteroaryl, -NH-(C _0-2 alkylene)heteroaryl, -(C _0-2 alkylene)-NH-heteroaryl, -O-(C _0-2 alkylene)heteroaryl, - (C _0-2 alkylene)-O-heteroaryl, SO ₂ -(C _0-2 alkylene)heteroaryl, -(C _0-2 alkylene)SO ₂ -heteroaryl, -CONH-heteroaryl, - is selected from NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and SO ₂ -heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is halogen, CN, OH, C _1-5 alkyl, C _1-5 haloalkyl, O(C _1-5 alkyl), O(Cis haloalkyl), SH, S(C _1-5 alkyl), S(C _1-5 Haloalkyl), NH ₂ , NH(C _1-5 alkyl), NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl) )(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), and CON(C _1-5 alkyl)(C _1-5 alkyl),

Preferably here R ₄ is -(C _0-2 alkylene)aryl, -CO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-CO-aryl, -CONH-( C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-CONH-aryl, -NHCO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-NHCO- Aryl, -NH-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-NH-aryl, -O-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-O-aryl, -SO ₂ -(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, -NH -aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-2 alkylene)-heteroaryl, -CO-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-CO-heteroaryl, -CONH-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-CONH-heteroaryl, -NHCO-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-NHCO-heteroaryl, -NH-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-NH-hetero Aryl, -O-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-O-heteroaryl, -SO ₂ -(C _0-2 alkylene)-heteroaryl, -( C _0-2 alkylene)-SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and -SO ₂ -hetero is selected from aryl, wherein the aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _{1- 5} haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), or

or where R ₄ is selected from C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, preferably where R ₄ is cycloalkyl , heterocycloalkyl, aryl, and heteroaryl, more preferably wherein R ₄ is selected from aryl, and heteroaryl, and even more preferably wherein R ₄ is heteroaryl, wherein the alkyl, alkenyl , or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), - Independent of N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl) is optionally substituted with one or more groups selected from , wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _{1 -5} alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl) , -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl),

Preferably where R ₄ is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), - SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N (C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON 5-membered heteroaryl optionally substituted with one or more groups independently selected from (C _1-5 alkyl)(C _1-5 alkyl), preferably wherein the 5-membered heteroaryl is imidazolyl, isoxazolyl, pyrazolyl. , 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadia is selected from zolyl, or 1,3,4-thiadiazolyl, preferably wherein the 5-membered heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -SH, -S(C _1-5 alkyl), -NH ₂ , -NH(C _1-5 alkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), optionally substituted with one or more groups independently selected from -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -SH, -S(C _1-5 alkyl), more preferably C _1-5 alkyl, C _1- optionally substituted with ₅ haloalkyl, even more preferably optionally substituted with C _1-5 haloalkyl, preferably selected from -CH ₂ F, -CHF ₂ and CF ₃ , preferably -CHF ₂ A compound that is optionally substituted 1,2,4-thiadiazolyl.

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

14. A compound of any one of paragraphs 1 to 12, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of paragraph 13, for use in therapy.

15. Use according to paragraph 14, for use in a method of treating a disease or disorder in which PARG activity is implicated, or for use in a method of treating a proliferative disorder, preferably the proliferative disorder is cancer, preferably a human cancer. Compounds for or pharmaceutical compositions for use.

Claims (40)

Compounds of formula (I):
[Formula (I)]

or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystal form, pharmaceutically acceptable salt or prodrug thereof:
In the above equation
R ₁ is hydrogen, chloro, fluoro, cyano, formyl, (C _1-2 )alkyl, (C ₂ )alkenyl, (C ₂ )alkynyl (C _1-2 )haloalkyl, -(C _{1 -2} alkylene)-OH and -(C _1-2 alkylene)-O-(C _1-2 alkyl);
R ₂ and R ₃ are independently each (C _1-2 )alkyl or (C _1-2 )haloalkyl, or R ₂ and R ₃ together with the carbon atom to which they are attached form cyclopropyl;
W is -NHS(O) _y- , -S(O) _y NH-, -NHS(O)(NH)-, -NHS(O)(NCH ₃ )-, -S(O)(NH)-NH -, -S(O)(NCH ₃ )-NH-, where y is 1 or 2;
X ₁ and X ₃ are independently selected from the group consisting of N, CH, C(C _1-2 alkyl), C-Cl and CF;
X ₂ is N or CY _C2 -R _C2 ,
where Y _C2 is selected from a covalent bond, C _1-5 alkylene, C _2-5 alkenylene, C _2-5 alkynylene, cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene, where The alkylene, the alkenylene and the alkynylene are each halogen, CN, OH, O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, SH, S ( C ₁₅ alkyl), -S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _{1 -5} alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), NHCO-(C _1-5 alkyl), N(C _1-5 alkyl)-CO -(C _1-5 alkyl), NHCONH ₂ , NHCONH-(C _1-5 alkyl), NHCON(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 alkyl)CONH ₂ , N (C _1-5 alkyl)CONH-(C _1-5 alkyl), and N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen , CN, OH, O(C _1-5 alkyl), SH, S(C ₁₅ alkyl), NH ₂ , NH(C _1-5 alkyl), and N(C _1-5 alkyl)(C _1-5 alkyl) ), and further wherein the alkylene, the alkenylene or the one or more -CH ₂ - units included in the alkynylene are -O-, NH-, N(C _1-5 alkyl)-, CO-, S-, -SO-, and SO ₂ -, and further wherein said cycloalkylene, said cycloalkenylene, said heterocycloalkylene and said heterocycloalkenylene. are each halogen, CN, OH, C _1-5 alkyl, C _1-5 haloalkyl, O(C _1-5 alkyl), -O(C _1-5 haloalkyl), SH, S(C ₁₅ alkyl), -S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), CON( C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), NHCO-(C _1-5 alkyl), N(C _1-5 alkyl)-CO-(C _{1- 5} alkyl), NHCONH ₂ , NHCONH-(C _1-5 alkyl), NHCON(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 alkyl)CONH ₂ , N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CN, - (C _1-5 alkylene)OH, -(C _1-5 alkylene)O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -( C _1-5 alkylene)SH, -(C _1-5 alkylene)S(C ₁₅ alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _{1- 5} alkylene)NH ₂ , -(C _1-5 alkylene)NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _{1- 5} alkylene)N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _{1 -5} alkylene)( N -heterocycloalkyl), -(C _1-5 alkylene)N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO (C _1-5 alkyl), -(C _1-5 alkylene)CONH ₂ , -(C _1-5 alkylene)CONH(C _1-5 alkyl), -(C _1-5 alkylene)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)CO-( N -heterocycloalkyl), -(C _1-5 alkylene)NHCO-(C _1-5 alkyl) , -(C _1-5 alkylene)N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)NHCONH ₂ , -(C _1-5 alkylene) NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 Alkyl)CONH ₂ , -(C _1-5 alkylene)N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)N(C _1-5 alkyl) CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, CN, OH, C _1-5 alkyl, O(C _1-5 alkyl), SH, S(C ₁₅ alkyl), NH ₂ , NH(C _1-5 alkyl), and N(C _1-5 alkyl)(C _1-5 alkyl),
where R _C2 is hydrogen, halo, -OH, -NH ₂ , -SH, -CN, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, cycloalkyl, cycloalkenyl, heterocyclo selected from alkyl, heterocycloalkenyl, aryl, and heteroaryl,
wherein the alkyl, alkenyl, or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _{1 -5} alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _{1- 5} alkyl)(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _{1- 5} alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), - P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), and -P(O )(O(C _1-5 alkyl))(C _1-5 alkyl), preferably halogen, -CN, -OH, -O(C _1-5 alkyl)-, -O(C _{1 -5} haloalkyl)-, C _1-5 haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl) ), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO (C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _{1- 5} haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N( C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON (C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-( C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -S(O) (C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), and -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), preferably halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, -SH, -S( C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 Alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl) ), and -CON(C _1-5 alkyl)(C _1-5 alkyl),
wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _{1 -5} alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S( O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 halo alkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO( C _1-5 alkyl), -CO(C _1-5 haloalkyl), -CO-cycloalkyl, -COO(C _1-5 alkyl), -COO(C _1-5 haloalkyl), -COO-cycloalkyl , -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _{1- 5} alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _{1 -5} alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _{1- 5} alkyl), -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O (C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene )-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _{1- 5} haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _{1 -5} haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl) , -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl)) (C _1-5 alkyl), -(C _1-5 alkylene _{)-P(O)(C 1-5 alkyl)(C 1-5 alkyl), -(C 1-5 alkylene )} -P(O )(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _{1- 5} alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _{1 -5} haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl) (C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _{1- 5} alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 haloalkyl), -(C _1-5 alkyl lene)-CO-cycloalkyl, -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)- CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C 1-5 alkyl _{)-CO-(C 1-5 alkyl), -(C 1-5 alkylene )} -NHCONH ₂ , -( C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkyl lene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)- OCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _{1 -5} alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O )(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _{1- 5} alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , - NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _{1 -5} alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -COO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON (C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-( C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , - OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl) ), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, - (C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S (O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH )(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene) -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _{1- 5} alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N (C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene )-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON( C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _{1- 5} alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _{1 -5} alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene )-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene) -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH- (C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 Alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl) )(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl ), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl ), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH -(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-( C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _{1-5 alkyl)(C 1-5 alkyl} ), -P(O)(C _1-5 alkyl)(C _1-5 alkyl ), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl) , -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _{1- 5} alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O ) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)( N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _{1 -5} alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _{1 -5} alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _{1- 5} alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene) -N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _{1 -5} haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _{1- 5} alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)- CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO -(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene )-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N (C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl ), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl) , -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl) , -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , - (C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N( C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl) , -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _{1- 5} alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _{1- 5} haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N( C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)( optionally substituted with one or more groups selected from C _1-5 alkyl);
X ₄ is N or CR _C4 ,
where R _C4 is hydrogen, halo, C _1-6 alkyl, C ₂ -6 alkynyl, -O(C _1-6 alkyl), -S(C _1-6 alkyl), -NH(C _1-6 alkyl) , -N(C _1-6 alkyl)(C _1-6 alkyl), -CO(C _1-6 alkyl), C _1-6 haloalkyl, -O(C _1-6 haloalkyl), -S(C _1-6 haloalkyl), -NH(C _1-6 haloalkyl), -N(C _1-6 haloalkyl) ₂ , -CO(C _1-6 haloalkyl), -(C _0-3 alkylene) Cycloalkyl, -O-(C _0-3 alkylene)-cycloalkyl, -CO-(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)cycloalkenyl, -O-( C _0-3 alkylene)-cycloalkenyl, -CO-(C _0-3 alkylene)-cycloalkenyl, -(C _0-3 alkylene)-heterocycloalkyl, -O-(C _0-3 alkylene)-heterocycloalkyl, -CO-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-heterocycloalkenyl, -O-(C _0-3 alkylene) -Heterocycloalkenyl, -CO-(C _0-3 alkylene)-heterocycloalkenyl, -(C _0-3 alkylene)-aryl, -O-(C _0-3 alkylene)-aryl, - CO-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-heteroaryl, -O-(C _0-3 alkylene)-heteroaryl, and -CO-(C _0-3 alkylene)-heteroaryl,
Here, the alkyl or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, -SH, -S( C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 Alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl ), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -N(C _1-5 alkyl)CON(C _1-5 alkyl) )(C _1-5 alkyl), preferably halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S (C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _{1- 5} alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _{1- 5} alkyl)(C _1-5 alkyl),
wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _{1 -5} alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _{1- 5} alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-( C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _{1 -5} alkyl), and -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkyl lene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _{1- 5} alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _{1- 5} alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _{1 -5} alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene )-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene) -NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), - selected from N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl) optionally substituted with one or more groups;
X ₅ is N or CR _C5 ,
where R _C5 is hydrogen, halo, C _1-6 alkyl, -O(C _1-6 alkyl), -S(C _1-6 alkyl), -NH(C _1-6 alkyl), -N(C _{1- 6} alkyl)(C _1-6 alkyl) and C _1-6 haloalkyl;
R ₄ is Y _R5 -R _R5 ,
wherein Y _R5 is selected from a covalent bond, C _1-4 alkylene, C _2-4 alkenylene, and C _2-4 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each selected from a halogen, -CN , -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -SO(C _1-5 alkyl), -SO ₂ (C _1-5 alkyl), -S(C _1-5 haloalkyl), -SO(C _1-5 haloalkyl), -SO ₂ (C _1-5 haloalkyl), -NH ₂ , -NH( C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), and -N(C _1-5 haloalkyl)(C _{1- 5} alkyl), and further wherein one or more -CH ₂ - units comprised in said alkylene, said alkenylene or said alkynylene are each -O-, NH-, N( C _1-5 alkyl)-, CO-, -COO-, S-, -SO-, and SO ₂ -,
where R _R5 is selected from C _1-12 alkyl, C _1-12 alkenyl, C _2-12 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl,
wherein the alkyl, alkenyl, or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is halogen, -CN, -OH, - C _1-5 alkyl, -C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -SO (C _1-5 alkyl), -SO ₂ (C _1-5 alkyl), -S(C _1-5 haloalkyl), -SO(C _1-5 haloalkyl), -SO ₂ (C _1-5 halo alkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _{1 -5} haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). A compound optionally substituted with a group. The method of claim 1, wherein R ₁ is hydrogen, chloro, fluoro, cyano, formyl, (C _1-2 )alkyl, (C ₂ )alkenyl, (C ₂ )alkynyl and (C _1-2 ) A compound selected from the group consisting of haloalkyl. The method according to claim 1 or 2, wherein R ₁ is chloro, fluoro, cyano, formyl, (C _1-2 )alkyl, (C ₂ )alkenyl, (C ₂ )alkynyl and (C _{1- 2} ) A compound selected from the group consisting of haloalkyl. The compound according to any one of claims 1 to 3, wherein R ₁ is selected from the group consisting of cyano, (C _1-2 )alkyl, and (C _1-2 )haloalkyl. 5. The compound according to any one of claims 1 to 4, wherein R ₁ is selected from the group consisting of cyano, methyl and fluoromethyl. 6. The compound according to any one of claims 1 to 5, wherein R ₁ is cyano. 6. The compound according to any one of claims 1 to 5, wherein R ₁ is methyl. 6. The compound according to any one of claims 1 to 5, wherein R ₁ is fluoromethyl. 10. The compound according to any one of claims 1 to 9, wherein R ₂ and R ₃ together with the carbon atom to which they are attached form cyclopropyl. 10. The method according to any one of claims 1 to 9, wherein W is -NHS(O) ₂ -, preferably wherein the left side of W as defined herein is a carbon carrying R ₁ , R ₂ and R ₃ A compound wherein the compound is attached to an atom and the right side of W, as defined herein, is attached to the ring system shown in formula (I). 11. The compound according to any one of claims 1 to 10, wherein X ₁ and X ₃ are independently selected from the group consisting of N, CH and CF. 12. The compound according to any one of claims 1 to 11, wherein X ₁ and X ₃ are each CH. 13. The method according to any one of claims 1 to 12, wherein Y _C2 is selected from a covalent bond, C _1-5 alkylene, C _2-5 alkenylene, C _2-5 alkynylene, cycloalkylene and heterocycloalkylene. is selected, wherein the alkylene, the alkenylene and the alkynylene are each selected from halogen, CN, OH, O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, SH, S(C ₁₅ alkyl), -S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), N(C _1-5 alkyl )(C _1-5 alkyl), N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), CONH ₂ , CONH( C _1-5 alkyl), CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), NHCO-(C _1-5 alkyl), N(C _1-5 Alkyl)-CO-(C _1-5 alkyl), NHCONH ₂ , NHCONH-(C _1-5 alkyl), NHCON(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 alkyl) CONH ₂ , N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), Preferably halogen, CN, OH, O(C _1-5 alkyl), SH, S(C ₁₅ alkyl), NH ₂ , NH(C _1-5 alkyl), and N(C _1-5 alkyl)(C _1-5 alkyl), and further wherein one or more -CH ₂ - units included in the alkylene, alkenylene or alkynylene are -O-, NH-, N( C _1-5 alkyl)-, CO-, S-, -SO-, and SO ₂ -, and further wherein said cycloalkylene and said heterocycloalkylene are each halogen, CN, OH. , C _1-5 alkyl, C _1-5 haloalkyl, O(C _1-5 alkyl), -O(C _1-5 haloalkyl), SH, S(C ₁₅ alkyl), -S(C _1-5 haloalkyl), NH ₂ , NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), N(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 halo Alkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), CONH ₂ , CONH(C _1-5 alkyl), CON(C _1-5 alkyl)( C _1-5 alkyl), -CO-( N -heterocycloalkyl), NHCO-(C _1-5 alkyl), N(C _1-5 alkyl)-CO-(C _1-5 alkyl), NHCONH ₂ , NHCONH-(C _1-5 alkyl), NHCON(C _1-5 alkyl)(C _1-5 alkyl), N(C _1-5 alkyl)CONH ₂ , N(C _1-5 alkyl)CONH-(C _{1 -5} alkyl), and N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene )OH, -(C _1-5 alkylene)O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene) SH, -(C _1-5 alkylene)S(C ₁₅ alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)NH ₂ , -(C _1-5 alkylene)NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)( N -heterocycloalkyl), -(C _1-5 alkylene)N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl) , -(C _1-5 alkylene)CONH ₂ , -(C _1-5 alkylene)CONH(C _1-5 alkyl), -(C _1-5 alkylene)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)CO-( N -heterocycloalkyl), -(C _1-5 alkylene)NHCO-(C _1-5 alkyl), -(C _1-5 Alkylene)N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)NHCONH ₂ , -(C _1-5 alkylene)NHCONH-(C _1-5 Alkyl), -(C _1-5 alkylene)NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene) N(C _1-5 alkyl)CONH ₂ , -( C _1-5 alkylene)N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)N(C _1-5 alkyl)CON(C _1-5 alkyl) )(C _1-5 alkyl), preferably halogen, CN, OH, C _1-5 alkyl, O(C _1-5 alkyl), SH, S(C ₁₅ alkyl), NH ₂ , NH (C _1-5 alkyl), and N(C _1-5 alkyl)(C _1-5 alkyl). _{14. The method according to} any one _of claims 1 _{to 13} , _wherein (C _1-5 alkyl)-C _1-12 alkyl, -OC _2-12 alkenyl, -NH-C _2-12 alkenyl, -N(C _1-5 alkyl)-C _2-12 alkenyl, - OC _2-12 alkynyl, -NH-C _2-12 alkynyl, -N(C _1-5 alkyl)-C _2-12 alkynyl, (C _0-3 alkylene)-cycloalkyl, -CO-( C _0-3 alkylene) cycloalkyl, (C _0-3 alkylene)-CO-cycloalkyl, -CONH-(C _0-3 alkylene) cycloalkyl, -(C _0-3 alkylene)-CONH- Cycloalkyl, -NHCO-(C _0-3 alkylene)cycloalkyl, (C _0-3 alkylene)-NHCO-cycloalkyl, -NH-(C _0-3 alkylene)cycloalkyl, -(C _{0- 3} alkylene)-NH-cycloalkyl, -O-(C _0-3 alkylene)cycloalkyl, -(C _0-3 alkylene)-O-cycloalkyl, -SO ₂ -(C _0-3 alkylene )Cycloalkyl, -(C _0-3 alkylene)-SO ₂ -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, -SO ₂ -cycloalkyl, (C _0-3 alkylene)-cycloalkenyl, -CO-(C _0-3 alkylene)cycloalkenyl, (C _0-3 alkylene)-CO-cycloalkenyl, -CONH-(C _0-3 alkylene)cycloalkenyl, -(C _0-3 alkylene)-CONH-cycloalkenyl, -NHCO-(C _0-3 alkylene)cycloalkenyl, (C _{0- 3} alkylene)-NHCO-cycloalkenyl, -NH-(C _0-3 alkylene)cycloalkenyl, -(C _0-3 alkylene)-NH-cycloalkenyl, -O-(C _0-3 alkylene) cycloalkenyl, -(C _0-3 alkylene)-O-cycloalkenyl, -SO ₂ -(C _0-3 alkylene) cycloalkenyl, -(C _0-3 alkylene)-SO ₂ -cycloalkenyl, -CONH-cycloalkenyl, -NHCO-cycloalkenyl, -NH-cycloalkenyl, -O-cycloalkenyl, -CO-cycloalkenyl, -SO ₂ -cycloalkenyl, - (C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-CO-heterocycloalkyl, -CONH-(C _0-3 Alkylene)heterocycloalkyl, -(C _0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-NHCO- Heterocycloalkyl, -NH-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-NH-heterocycloalkyl, -O-(C _0-3 alkylene) heterocycloalkyl, -(C _0-3 alkylene)-O-heterocycloalkyl, -SO ₂ -(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-SO ₂ -heterocycloalkyl, - CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, -(C _0-3 alkylene )-Heterocycloalkenyl, -CO-(C _0-3 alkylene)heterocycloalkenyl, -(C _0-3 alkylene)-CO-heterocycloalkenyl, -CONH-(C _0-3 alkylene ) Heterocycloalkenyl, -(C _0-3 alkylene)-CONH-heterocycloalkenyl, -NHCO-(C _0-3 alkylene)heterocycloalkenyl, -(C _0-3 alkylene)-NHCO -Heterocycloalkenyl, -NH-(C _0-3 alkylene)heterocycloalkenyl, -(C _0-3 alkylene)-NH-heterocycloalkenyl, -O-(C _0-3 alkylene) Heterocycloalkenyl, -(C _0-3 alkylene)-O-heterocycloalkenyl, -SO ₂ -(C _0-3 alkylene)heterocycloalkenyl, -(C _0-3 alkylene)-SO ₂ -heterocycloalkenyl, -CONH-heterocycloalkenyl, -NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO-heterocycloalkenyl, -SO ₂ -Heterocycloalkenyl, (C _0-3 alkylene)aryl, -CO-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-CO-aryl, -CONH-(C _{0- 3} alkylene)aryl, -(C _0-3 alkylene)-CONH-aryl, -NHCO-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-NHCO-aryl, -NH- (C _0-3 alkylene)aryl, -(C _0-3 alkylene)-NH-aryl, -O-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-O-aryl , -SO ₂ -(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-3 alkylene)heteroaryl, -CO-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-CO-hetero Aryl, -CONH-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-CONH-heteroaryl, -NHCO-(C _0-3 alkylene)heteroaryl, -(C _{0- 3} alkylene)-NHCO-heteroaryl, -NH-(C _0-3 alkylene)heteroaryl, (C _0-3 alkylene)-NH-heteroaryl, -O-(C _0-3 alkylene)hetero Aryl, -(C _0-3 alkylene)-O-heteroaryl, -SO ₂ -(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-SO ₂ -heteroaryl, -CONH is selected from -heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and -SO ₂ -heteroaryl, preferably -Y _C2 -R _C2 is - OC _1-12 alkyl, -NH-C _1-12 alkyl, -N(C _1-5 alkyl)-C _1-12 alkyl, -OC _2-12 alkenyl, -NH-C _2-12 alkenyl, - N(C _1-5 alkyl)-C _2-12 alkenyl, -OC _2-12 alkynyl, -NH-C _2-12 alkynyl, -N(C _1-5 alkyl)-C _2-12 alkynyl , (C _0-3 alkylene)-cycloalkyl, -CO-(C _0-3 alkylene)cycloalkyl, (C _0-3 alkylene)-CO-cycloalkyl, -CONH-(C _0-3 alkyl lene)cycloalkyl, -(C _0-3 alkylene)-CONH-cycloalkyl, -NHCO-(C _0-3 alkylene)cycloalkyl, (C _0-3 alkylene)-NHCO-cycloalkyl, -NH -(C _0-3 alkylene)cycloalkyl, -(C _0-3 alkylene)-NH-cycloalkyl, -O-(C _0-3 alkylene)cycloalkyl, -(C _0-3 alkylene) -O-cycloalkyl, -SO ₂ -(C _0-3 alkylene)cycloalkyl, -(C _0-3 alkylene)-SO ₂ -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, - NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, -SO ₂ -cycloalkyl, -(C _0-3 alkylene)-heterocycloalkyl, -CO-(C _0-3 alkylene)hetero Cycloalkyl, -(C _0-3 alkylene)-CO-heterocycloalkyl, -CONH-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-NHCO-heterocycloalkyl, -NH-(C _0-3 alkylene)heterocycloalkyl, -(C _{0 -3} alkylene)-NH-heterocycloalkyl, -O-(C _0-3 alkylene) heterocycloalkyl, -(C _0-3 alkylene)-O-cycloalkyl, -SO ₂ -(C _{0- 3} alkylene)heterocycloalkyl, -(C _0-3 alkylene)-SO ₂ -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-hetero Cycloalkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, (C _0-3 alkylene)aryl, -CO-(C _0-3 alkylene)aryl, -(C _0-3 alkylene) -CO-aryl, -CONH-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-CONH-aryl, -NHCO-(C _0-3 alkylene)aryl, -(C _{0- 3} alkylene)-NHCO-aryl, -NH-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-NH-aryl, -O-(C _0-3 alkylene)aryl, - (C _0-3 alkylene)-O-aryl, -SO ₂ -(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-SO ₂ -aryl, -CONH-aryl, -NHCO- Aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO2-aryl, -(C _0-3 alkylene)heteroaryl, -CO-(C _0-3 alkylene)heteroaryl, -( C _0-3 alkylene)-CO-heteroaryl, -CONH-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-CONH-heteroaryl, -NHCO-(C _0-3 Alkylene)heteroaryl, -(C _0-3 alkylene)-NHCO- heteroaryl, -NH-(C _0-3 alkylene)heteroaryl, (C _0-3 alkylene)-NH-heteroaryl, - O-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-O-heteroaryl, -SO ₂ -(C _0-3 alkylene)heteroaryl, -(C _0-3 alkyl ren) is selected from -SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and -SO ₂ -heteroaryl, wherein the alkyl, alkenyl, or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _{1 -5} alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _{1- 5} alkyl)(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _{1- 5} alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), - P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), and -P(O )(O(C _1-5 alkyl))(C _1-5 alkyl), preferably halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _{1- 5} haloalkyl), -C _1-5 haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl) , -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO( C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), wherein Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _{1- 5} alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O) (C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl) , -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _{1 -5} alkyl), -CO(C _1-5 haloalkyl), -CO-cycloalkyl, -COO(C _1-5 alkyl), -COO(C _1-5 haloalkyl), -COO-cycloalkyl, - CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl ), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _{1- 5} alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl) ), -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)- CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 halo alkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), - (C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O _{)(C 1-5 alkyl)(C 1-5 alkyl), -(C 1-5 alkylene )} -P(O)( O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl ), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl ), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 haloalkyl), -(C _1-5 alkylene) -CO-cycloalkyl, -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON( C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _{1- 5} alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _{1 -5} alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene )-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene) -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH- (C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl). 15. The method according to any one of claims 1 to 14, wherein -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -CO-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-CO-heterocycloalkyl, -CONH-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-CONH-heterocycloalkyl, -NHCO- (C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-NHCO-heterocycloalkyl, -NH-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkyl lene)-NH-heterocycloalkyl, -O-(C _0-3 alkylene) heterocycloalkyl, (C _0-3 alkylene)-O-cycloalkyl, (C _0-3 alkylene)-O-hetero Cycloalkyl, -SO ₂ -(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-SO ₂ -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO- heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, -(C _0-3 alkylene)-heterocycloalkenyl, -CO-(C _{0 -3} alkylene)heterocycloalkenyl, -(C _0-3 alkylene)-CO-heterocycloalkenyl, -CONH-(C _0-3 alkylene)heterocycloalkenyl, -(C _0-3 alkyl len)-CONH-heterocycloalkenyl, -NHCO-(C _0-3 alkylene)heterocycloalkenyl, -(C _0-3 alkylene)-NHCO-heterocycloalkenyl, -NH-(C _{0- 3} alkylene)heterocycloalkenyl, -(C _0-3 alkylene)-NH-heterocycloalkenyl, -O-(C _0-3 alkylene) heterocycloalkenyl, (C _0-3 alkylene) -O-heterocycloalkenyl, -SO ₂ -(C _0-3 alkylene)heterocycloalkenyl, -(C _0-3 alkylene)-SO ₂ -heterocycloalkenyl, -CONH-heterocycloalkenyl , -NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO-heterocycloalkenyl, -SO ₂ -heterocycloalkenyl, -(C _0-3 alkylene )aryl, -CO-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-CO-aryl, -CONH-(C _0-3 alkylene)aryl, -(C _0-3 alkyl lene)-CONH-aryl, -NHCO-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-NHCO-aryl, -NH-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-NH-aryl, -O-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-O-aryl, -SO ₂ -(C _0-3 alkylene) Aryl, -(C _0-3 alkylene)-SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -( C _0-3 alkylene)heteroaryl, -CO-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-CO-heteroaryl, -CONH-(C _0-3 alkylene) Heteroaryl, -(C _0-3 alkylene)-CONH-heteroaryl, -NHCO-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-NHCO-heteroaryl, -NH- (C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-NH-heteroaryl, -O-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)- O-heteroaryl, -SO ₂ -(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH -heteroaryl, -O-heteroaryl, -CO-heteroaryl, and -SO ₂ -heteroaryl, preferably -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl , -CO-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-CO-heterocycloalkyl, -CONH-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-NHCO-heterocycloalkyl, -NH-(C _{0 -3} alkylene)heterocycloalkyl, -(C _0-3 alkylene)-NH-heterocycloalkyl, -O-(C _0-3 alkylene) heterocycloalkyl, (C _0-3 alkylene)-O -cycloalkyl, -SO ₂ -(C _0-3 alkylene)heterocycloalkyl, -(C _0-3 alkylene)-SO ₂ -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl , -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, -(C _0-3 alkylene)aryl, -CO-(C _0-3 alkyl len)aryl, -(C _0-3 alkylene)-CO-aryl, -CONH-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-CONH-aryl, -NHCO-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-NHCO-aryl, -NH-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-NH-aryl, - O-(C _0-3 alkylene)aryl, -(C _0-3 alkylene)-O-aryl, -SO ₂ -(C _0-3 alkylene)aryl, -(C _0-3 alkylene)- SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-3 alkylene)heteroaryl, -CO -(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-CO-heteroaryl, -CONH-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene) -CONH-heteroaryl, -NHCO-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-NHCO-heteroaryl, -NH-(C _0-3 alkylene)heteroaryl, - (C _0-3 alkylene)-NH-heteroaryl, -O-(C _0-3 alkylene)heteroaryl, -(C _0-3 alkylene)-O-heteroaryl, -SO ₂ -(C _{0 -3} alkylene)heteroaryl, -(C _0-3 alkylene)-SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO -heteroaryl, and -SO ₂ -heteroaryl, wherein the heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 Haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N - Heterocycloalkyl), -CO(C _1-5 alkyl), -CO(C _1-5 haloalkyl), -CO-cycloalkyl, -COO(C _1-5 alkyl), -COO(C _1-5 halo alkyl), -COO-cycloalkyl, -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl) , -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON( C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _{1 -5} alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl) ), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl) , -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkyl lene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N (C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _{1- 5} alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _{1- 5} alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)- N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _{1- 5} haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 haloalkyl) , -(C _1-5 alkylene)-CO-cycloalkyl, -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -( C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 Alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkyl len)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl ), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl) , -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -( C _1-5 alkylene)-OCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 optionally with one or more groups independently selected from alkylene)-NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl) Substituted compounds. 16. The method according to any one of claims 1 to 15, wherein -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, - NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, -(C _0-3 alkylene)-heterocycloalkenyl, -CONH-heterocycloalkenyl , -NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO-heterocycloalkenyl, -SO ₂ -heterocycloalkenyl, -(C _0-3 alkylene )aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-3 alkylene)heteroaryl, -CONH-hetero is selected from aryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and -SO ₂ -heteroaryl, preferably -Y _C2 -R _C2 is -(C _0-3 alkylene) -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO ₂ - Heterocycloalkyl, -(C _0-3 alkylene)aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _{0 -3} alkylene)heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and -SO ₂ -heteroaryl, where The heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O( C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S (O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl) )(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _{1 -5} alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), - CO(C _1-5 haloalkyl), -CO-cycloalkyl, -COO(C _1-5 alkyl), -COO(C _1-5 haloalkyl), -COO-cycloalkyl, -CONH ₂ , -CONH( C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N (C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _{1- 5} alkyl), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON(C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _{1-5 alkyl)(C 1-5 alkyl} ), -P(O)(O(C _1-5 alkyl)) (O(C _1-5 alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _{1 -5} alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -( C _1-5 alkylene)-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkyl lene)-S(O)(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 Alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _{1 -5} alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -( C _1-5 alkylene)-N (C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl) , -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _{1 -5} alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 haloalkyl), -(C _1-5 alkylene)-CO-cycloalkyl, -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl) (C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -( C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)- NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _{1 -5} alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _{1- 5} alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH-(C _1-5 alkyl ), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _1-5 alkyl), and -( A compound optionally substituted with one or more groups independently selected from C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _1-5 alkyl). 17. The method according to any one of claims 1 to 16, wherein -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-heterocycloalkenyl, - (C _0-3 alkylene)aryl, and -(C _0-3 alkylene)heteroaryl, preferably -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)aryl, and -(C _0-3 alkylene)heteroaryl, wherein the heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is halogen, -CN, - OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), - S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _1-5 alkyl), -S(O)(N( C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl) (C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CO(C _1-5 haloalkyl), -CO-cycloalkyl, -COO(C _{1- 5} alkyl), -COO(C _1-5 haloalkyl), -COO-cycloalkyl, -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl ), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH -(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-( C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _{1-5 alkyl)(C 1-5 alkyl} ), -OCONH ₂ , -OCONH-(C _1-5 alkyl), -OCON( C _1-5 alkyl)(C _1-5 alkyl), -NHCOO(C _1-5 alkyl), -N(C _1-5 alkyl)COO-(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -P(O)(O(C _{1- 5} alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _{1 -5} alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-S(O)(C _1-5 alkyl), -( C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(NH)(C _1-5 alkyl), -(C _{1 -5} alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)( C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), -(C _1-5 alkylene )-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N (C _1-5 alkyl)(C _1-5 alkyl ), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkyl lene)-CO(C _1-5 haloalkyl), -(C _1-5 alkylene)-CO-cycloalkyl, -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene) -CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _{1 -5} alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON( C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _{1- 5} alkyl)CONH-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-OCONH ₂ , -(C _1-5 alkylene)-OCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-OCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NHCOO(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)COO-(C _{1- 5} alkyl), which is optionally substituted with one or more groups independently selected from: According to any one of claims 1 to 12,
Y _C2 is selected from a covalent bond, C _1-5 alkylene, C _2-5 alkenylene, and C _2-5 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each halogen, CN, OH , O(C _1-5 alkyl), SH, S(C ₁₅ alkyl), NH ₂ , NH(C _1-5 alkyl), and N(C _1-5 alkyl)(C _1-5 alkyl) independently optionally substituted with one or more groups selected, and further wherein the alkylene, the alkenylene or the one or more -CH ₂ - units contained in the alkynylene are -O-, NH-, N(C _1-5 alkyl)- , CO-, S-, -SO-, and SO ₂ -,
where R _C2 is hydrogen, halo, -OH, -NH ₂ , -SH, -CN, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,
wherein the alkyl, alkenyl, or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _{1 -5} alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _{1- 5} alkyl)(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S(O)(NH)(C _{1- 5} alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl)(C _1-5 alkyl), - P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _1-5 alkyl)), and -P(O )(O(C _1-5 alkyl))(C _1-5 alkyl), preferably halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _{1- 5} haloalkyl), C _1-5 haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl),
wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(O)(C _1-5 alkyl), -S(O) ₂ (C _1-5 alkyl), -S( O)(NH)(C _1-5 alkyl), -S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -N=S(O)(C _1-5 alkyl) (C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _{1- 5} alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(N- heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl) , -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), -N(C _1-5 alkyl)CON(C _1-5 alkyl) )(C _1-5 alkyl), -P(O)(C _1-5 alkyl)(C _1-5 alkyl), -P(O)(O(C _1-5 alkyl))(O(C _{1- 5} alkyl)), -P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)- OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene) -SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene )-S(O)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O) ₂ (C _1-5 alkyl), -(C _1-5 alkylene)-S(O )(NH)(C _1-5 alkyl), -(C _1-5 alkylene)-S(O)(N(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(O( C _1-5 alkyl)), -(C _1-5 alkylene)-P(O)(O(C _1-5 alkyl))(C _1-5 alkyl), -(C _1-5 alkylene)- NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene )-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _{1- 5} alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)- CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene) -CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-( C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , - (C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _{1- 5} alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _{1- 5} alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -)(C _1-5 haloalkyl), -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)- O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 halo alkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _1-5 alkylene)-S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _{1 -5} alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene )-N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _{1- 5} alkyl)(C _1-5 alkyl), more preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O (C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH( C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). _{19. The method of claim 18 , wherein} C _1-12 alkyl, -OC _2-12 alkenyl, -NH-C _2-12 alkenyl, -N(C _1-5 alkyl)-C _2-12 alkenyl, -OC _2-12 alkynyl, - NH-C _2-12 alkynyl, -N(C _1-5 alkyl)-C _2-12 alkynyl, -(C _0-3 alkylene)-cycloalkyl, -CO-(C _0-3 alkylene) -cycloalkyl, -(C _0-3 alkylene)-CO-cycloalkyl, -CONH-(C _0-3 alkylene)-cycloalkyl, (C _0-3 alkylene)-CONH-cycloalkyl, -NHCO -(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-NHCO-cycloalkyl, -NH-(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkyl lene)-NH-cycloalkyl, -O-(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-O-cycloalkyl, -SO ₂ -(C _0-3 alkylene) -cycloalkyl, -(C _0-3 alkylene)-SO ₂ -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, -SO ₂ -cycloalkyl, -(C _0-3 alkylene)-heterocycloalkyl, -CO-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-CO-hetero Cycloalkyl, -CONH-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(C _0-3 alkylene)-heterocycloalkyl , -(C _0-3 alkylene)-NHCO-heterocycloalkyl, -NH-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-NH-heterocycloalkyl, - O-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-O-cycloalkyl, -SO ₂ -(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene) -SO ₂ -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, - SO ₂ -heterocycloalkyl, -(C _0-3 alkylene)-aryl, -CO-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-CO-aryl, -CONH- (C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-CONH-aryl, -NHCO-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-NHCO -aryl, -NH-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-NH-aryl, -O-(C _0-3 alkylene)-aryl, -(C _{0- 3} alkylene)-O-aryl, -SO ₂ -(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, - NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-3 alkylene)-heteroaryl, -CO-(C _0-3 alkylene)-heteroaryl, -( C _0-3 alkylene)-CO-heteroaryl, -CONH-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-CONH-heteroaryl, -NHCO-(C _{0- 3} alkylene)-heteroaryl, -(C _0-3 alkylene)-NHCO-heteroaryl, -NH-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-NH- Heteroaryl, -O-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-O-heteroaryl, -SO ₂ -(C _0-3 alkylene)-heteroaryl, - (C _0-3 alkylene)-SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and -SO ₂ - heteroaryl, wherein the alkyl, alkenyl, or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -C _{1- 5} haloalkyl, -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 halo alkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), wherein the cycloalkyl, heterocycloalkyl, Aryl, or heteroaryl, is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH , -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N( C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). 20. The method of claim 18 or 19, wherein -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -CO-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-CO-heterocycloalkyl, -CONH-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-CONH-heterocycloalkyl, -NHCO-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-NHCO-heterocycloalkyl, -NH-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkyl lene)-NH-heterocycloalkyl, -O-(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-O-cycloalkyl, -SO ₂ -(C _0-3 alkyl len)-heterocycloalkyl, -(C _0-3 alkylene)-SO ₂ -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocyclo Alkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, -(C _0-3 alkylene)-aryl, -CO-(C _0-3 alkylene)-aryl, -(C _0-3 alkyl lene)-CO-aryl, -CONH-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-CONH-aryl, -NHCO-(C _0-3 alkylene)-aryl, - (C _0-3 alkylene)-NHCO-aryl, -NH-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-NH-aryl, -O-(C _0-3 alkyl lene)-aryl, -(C _0-3 alkylene)-O-aryl, -SO ₂ -(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-SO ₂ -aryl, - CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-3 alkylene)-heteroaryl, -CO-(C _{0- 3} alkylene)-heteroaryl, -(C _0-3 alkylene)-CO-heteroaryl, -CONH-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-CONH- Heteroaryl, -NHCO-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-NHCO-heteroaryl, -NH-(C _0-3 alkylene)-heteroaryl, -( C _0-3 alkylene)-NH-heteroaryl, -O-(C _0-3 alkylene)-heteroaryl, -(C _0-3 alkylene)-O-heteroaryl, -SO ₂ -(C _{0 -3} alkylene)-heteroaryl, -(C _0-3 alkylene)-SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, - is selected from CO-heteroaryl, and -SO ₂ -heteroaryl, wherein the heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, - O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH( C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). 21. The method according to any one of claims 18 to 20, wherein -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, - NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, -(C _0-3 alkylene)aryl, -CONH-aryl, -NHCO-aryl, - NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-3 alkylene)-heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl , -O-heteroaryl, -CO-heteroaryl, and -SO ₂ -heteroaryl, wherein the heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -NH ₂ , -NH(C _{1 -5} alkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), and -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). 22. The method according to any one of claims 18 to 21, wherein -Y _C2 -R _C2 is -(C _0-3 alkylene)-heterocycloalkyl, -(C _0-3 alkylene)-aryl, and -( C _0-3 alkylene)-heteroaryl, wherein the heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O( C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl ), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl) with one or more groups independently selected from Compounds, optionally substituted. 23. The method according to any one of claims 18 to 22, wherein -Y _C2 -R _C2 is selected from heterocycloalkyl, aryl, and heteroaryl, preferably heterocycloalkyl and heteroaryl, more preferably heterocycloalkyl. Becomes, where the heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _{1 -5} haloalkyl), -SH, -S(C _1-5 haloalkyl), -S(C _1-5 alkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _{1- 5} haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), and -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). 24. The method according to any one of claims 18 to 23, wherein -Y _C2 -R _C2 is optionally substituted aryl, preferably -Y _C2 -R _C2 is halogen, -CN, -OH, C _1-5 alkyl. , C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 halo alkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _{1 -5} haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _{1 -5} alkyl), or phenyl optionally substituted with one or more groups independently selected from
or -Y _C2 -R _C2 is optionally substituted heteroaryl, preferably -Y _C2 -R _C2 is imidazolyl, pyridazinyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or indazolyl. , where heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH , -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N( C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), or
or -Y _C2 -R _C2 is optionally substituted heterocycloalkyl, preferably -Y _C2 -R _C2 is morpholinyl, 1,1-dioxothiomorpholinyl, azetinyl, pyrrolidinyl, pipe. ridinyl, 6-oxo-1,6-dihydropyridinyl, or piperazinyl, where heterocycloalkyl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O (C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH( C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). A compound optionally substituted with a group. 25. The method according to any one of claims 18 to 24, wherein -Y _C2 -R _C2 is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl ), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl) , -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CO( p is optionally substituted with one or more groups independently selected from C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl) perazinyl, and preferably -Y _C2 -R _C2 is CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _{1 -5} alkyl) is optionally substituted (preferably N-substituted) piperazinyl (preferably N-piperazinyl), more preferably -Y _C2 -R _C2 is CON(C _1-5 alkyl)(C _1-5 alkyl), preferably substituted with -CON(CH ₃ ) ₂ (preferably at an N atom different from the N atom attached to the ring system shown in formula (I), preferably A compound that is N-substituted) piperazinyl (preferably N-piperazinyl). _{26. The method} according to any one of claims 1 to _{25 , wherein} ), -S(C _1-6 alkyl), -NH(C _1-6 alkyl), -N(C _1-6 alkyl)(C _1-6 alkyl), -CO(C _1-6 alkyl), C _1-6 haloalkyl, -O(C _1-6 haloalkyl), -S(C _1-6 haloalkyl), -NH(C _1-6 haloalkyl), -N(C _1-6 haloalkyl, - CO(C _1-6 haloalkyl), -(C _0-3 alkylene)cycloalkyl, -O-(C _0-3 alkylene)-cycloalkyl, -CO-(C _0-3 alkylene)-cyclo Alkyl, -(C _0-3 alkylene)-heterocycloalkyl, -O-(C _0-3 alkylene)-heterocycloalkyl, -CO-(C _0-3 alkylene)-heterocycloalkyl, -( C _0-3 alkylene)-aryl, -O-(C _0-3 alkylene)-aryl, -CO-(C _0-3 alkylene)-aryl, -(C _0-3 alkylene)-heteroaryl , -O-(C _0-3 alkylene)-heteroaryl, and -CO-(C _0-3 alkylene)-heteroaryl;
Here, the alkyl or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), C _1-5 haloalkyl, -SH, -S( C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 Alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl)-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl ), -N(C _1-5 alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -N(C _1-5 alkyl)CON(C _1-5 alkyl) )(C _1-5 alkyl), preferably halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S (C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _{1- 5} alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _{1- 5} alkyl)(C _1-5 alkyl), wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is halogen, -CN, - OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), - S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl ), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -( N -heterocycloalkyl), -CO(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), -CON(C _1-5 alkyl)(C _1-5 alkyl), -CO-( N -heterocycloalkyl), -NHCO-(C _1-5 alkyl), -N(C _1-5 alkyl) )-CO-(C _1-5 alkyl), -NHCONH ₂ , -NHCONH-(C _1-5 alkyl), -NHCON(C _1-5 alkyl)(C _1-5 alkyl), -N(C _{1- 5} alkyl)CONH ₂ , -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _1-5 alkyl) , -(C _1-5 alkylene)-CN, -(C _1-5 alkylene)-OH, -(C _1-5 alkylene)-O(C _1-5 alkyl), -(C _1-5 alkylene)-O(C _1-5 haloalkyl), -(C _1-5 alkylene)-SH, -(C _1-5 alkylene)-S(C _1-5 alkyl), -(C _{1- 5} alkylene)-S(C _1-5 haloalkyl), -(C _1-5 alkylene)-NH ₂ , -(C _1-5 alkylene)-NH(C _1-5 alkyl), -(C _1-5 alkylene)-NH(C _1-5 haloalkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkyl lene)-N(C _1-5 alkyl)(C _1-5 haloalkyl), -(C _1-5 alkylene)-( N -heterocycloalkyl), -(C _1-5 alkylene)-N( C _1-5 haloalkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-CO(C _1-5 alkyl), -(C _1-5 alkylene)-CONH ₂ , -(C _1-5 alkylene)-CONH(C _1-5 alkyl), -(C _1-5 alkylene)-CON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene )-CO-( N -heterocycloalkyl), -(C _1-5 alkylene)-NHCO-(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl) -CO-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCONH ₂ , -(C _1-5 alkylene)-NHCONH-(C _1-5 alkyl), -(C _1-5 alkylene)-NHCON(C _1-5 alkyl)(C _1-5 alkyl), -(C _1-5 alkylene)-N(C _1-5 alkyl)CONH ₂ , -(C _1-5 alkylene) -N(C _1-5 alkyl)CONH-(C _1-5 alkyl), and -(C _1-5 alkylene)-N(C _1-5 alkyl)CON(C _1-5 alkyl)(C _{1- 5} alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 halo alkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl) ), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl) , and -CON(C _1-5 alkyl)(C _1-5 alkyl). _{27. The method} according to _any one _{of claims} 1 to 26, wherein SC _1-6 alkyl, -NH-C _1-6 alkyl, C _1-6 haloalkyl, -(C _0-3 alkylene)-cycloalkyl, -(C _0-3 alkylene)-heterocycloalkyl, - (C _0-3 alkylene)-aryl, and -(C _0-3 alkylene)-heteroaryl, wherein the alkyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -O(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), - NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , - is optionally substituted with one or more groups independently selected from CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), wherein said cycloalkyl, heterocycloalkyl, aryl, or Heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S (C _1-5 haloalkyl), -S(C _1-5 alkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _{1- 5} alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _{1- 5} alkyl)(C _1-5 alkyl). 28. The method of claim 27, wherein R _C4 is hydrogen, halo, C _1-6 alkyl, C _2-6 alkynyl, -OC _1-6 alkyl, -SC _1-6 alkyl, -NH-C _1-6 alkyl, and C _1-6 haloalkyl, preferably R _C4 is selected from hydrogen, halo, C _1-2 alkyl, and C _2-3 alkynyl, more preferably R _C4 is hydrogen, halo, and C _1-2 alkyl, and even more preferably R _C4 is hydrogen or halo. _{29. The method} according _to any one _of claims 1 to 28, _wherein NH—C _1-3 alkyl, and C _1-3 haloalkyl, preferably wherein R _C5 is selected from hydrogen, halo, C _1-3 alkyl, and C _1-3 haloalkyl. 30. The method according to any one of claims 1 to 29, wherein R _R5 is selected from C _1-12 alkyl, C _1-12 alkenyl, C _2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. selected,
wherein the alkyl, alkenyl, or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, -C _1-5 alkyl, -C _{1 -5} haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -SO(C _1-5 alkyl), - SO ₂ (C _1-5 alkyl), -S(C _1-5 haloalkyl), -SO(C _1-5 haloalkyl), -SO ₂ (C _1-5 haloalkyl), -NH ₂ , -NH (C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _{1- 5} alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH , C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S (C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl) , -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl) Compounds that are optionally substituted with one or more groups selected from: The method according to any one of claims 1 to 29, wherein R ₄ is -(C _0-2 alkylene)-cycloalkyl, -CO-(C _0-2 alkylene)-cycloalkyl, -(C _{0- 2} alkylene)-CO-cycloalkyl, -CONH-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-CONH-cycloalkyl, -NHCO-(C _0-2 alkylene )-cycloalkyl, -(C _0-2 alkylene)-NHCO-cycloalkyl, -NH-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-NH-cycloalkyl, -O-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-O-cycloalkyl, SO ₂ -(C _0-2 alkylene)-cycloalkyl, -(C _{0- 2} alkylene)SO ₂ -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, SO ₂ -cycloalkyl, -(C _{0 -2} alkylene)-cycloalkenyl, -CO-(C _0-2 alkylene)-cycloalkenyl, -(C _0-2 alkylene)-CO-cycloalkenyl, -CONH-(C _0-2 alkylene)-cycloalkenyl, -(C _0-2 alkylene)-CONH-cycloalkenyl, -NHCO-(C _0-2 alkylene)-cycloalkenyl, -(C _0-2 alkylene)- NHCO-cycloalkenyl, -NH-(C _0-2 alkylene)-cycloalkenyl, -(C _0-2 alkylene)-NH-cycloalkenyl, -O-(C _0-2 alkylene)- Cycloalkenyl, -(C _0-2 alkylene)-O-cycloalkenyl, SO ₂ -(C _0-2 alkylene)-cycloalkenyl, -(C _0-2 alkylene)SO ₂ -cycloal Kenyl, -CONH-cycloalkenyl, -NHCO-cycloalkenyl, -NH-cycloalkenyl, -O-cycloalkenyl, -CO-cycloalkenyl, SO ₂ -cycloalkenyl, -(C _0-2 alkylene)-heterocycloalkyl, -CO-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-CO-heterocycloalkyl, -CONH-(C _0-2 alkylene )-Heterocycloalkyl, -(C _0-2 alkylene)-CONH-heterocycloalkyl, -NHCO-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-NHCO- Heterocycloalkyl, -NH-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-NH-heterocycloalkyl, -O-(C _0-2 alkylene)-heterocyclo Alkyl, -(C _0-2 alkylene)-O-heterocycloalkyl, SO ₂ -(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)SO ₂ -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, SO ₂ -heterocycloalkyl, -(C _0-2 alkylene )-Heterocycloalkenyl, -CO-(C _0-2 alkylene)-heterocycloalkenyl, -(C _0-2 alkylene)-CO-heterocycloalkenyl, -CONH-(C _0-2 alkyl len)-heterocycloalkenyl, -(C _0-2 alkylene)-CONH-heterocycloalkenyl, -NHCO-(C _0-2 alkylene)-heterocycloalkenyl, -(C _0-2 alkylene )-NHCO-heterocycloalkenyl, -NH-(C _0-2 alkylene)-heterocycloalkenyl, -(C _0-2 alkylene)-NH-heterocycloalkenyl, -O-(C _{0- 2} alkylene)-heterocycloalkenyl, -(C _0-2 alkylene)-O-heterocycloalkenyl, SO ₂ -(C _0-2 alkylene)-heterocycloalkenyl, -(C _0-2 Alkylene)SO ₂ -heterocycloalkenyl, -CONH-heterocycloalkenyl, -NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO-heterocycloalkenyl , SO ₂ -heterocycloalkenyl, -(C _0-2 alkylene)-aryl, -CO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-CO-aryl, - CONH-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-CONH-aryl, -NHCO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene) -NHCO-aryl, -NH-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-NH-aryl, -O-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-O-aryl, SO ₂ -(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, - NH-aryl, -O-aryl, -CO-aryl, SO ₂ -aryl, -(C _0-2 alkylene)-heteroaryl, -CO-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-CO-heteroaryl, -CONH-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-CONH-heteroaryl, -NHCO-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-NHCO-heteroaryl, -NH-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-NH-hetero Aryl, -O-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-O-heteroaryl, SO ₂ -(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene) selected from SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and SO ₂ -heteroaryl wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is halogen, -CN, -OH, -C _1-5 alkyl, -C _1-5 haloalkyl, - O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -SO(C _1-5 alkyl), -SO ₂ (C _{1- 5} alkyl), -S(C _1-5 haloalkyl), -SO(C _1-5 haloalkyl), -SO ₂ (C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl) ), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably halogen, -CN, -OH, C _1-5 alkyl , C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 halo alkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _{1 -5} haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl); Compound substituted with. 32. The method according to any one of claims 1 to 31, wherein R ₄ is -(C _0-2 alkylene)-cycloalkyl, -CO-(C _0-2 alkylene)-cycloalkyl, -(C _{0- 2} alkylene)-CO-cycloalkyl, -CONH-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-CONH-cycloalkyl, -NHCO-(C _0-2 alkylene )-cycloalkyl, -(C _0-2 alkylene)-NHCO-cycloalkyl, -NH-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-NH-cycloalkyl, -O-(C _0-2 alkylene)-cycloalkyl, -(C _0-2 alkylene)-O-cycloalkyl, -SO ₂ -(C _0-2 alkylene)-cycloalkyl, -(C _{0 -2} alkylene) -SO ₂ -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, -SO ₂ -cycloalkyl, - (C _0-2 alkylene)-heterocycloalkyl, -CO-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-CO-heterocycloalkyl, -CONH-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-CONH-heterocycloalkyl, -NHCO-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkyl lene)-NHCO- heterocycloalkyl, -NH-(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)-NH-heterocycloalkyl, -O-(C _0-2 alkyl lene)-heterocycloalkyl, -(C _0-2 alkylene)-O-heterocycloalkyl, -SO ₂ -(C _0-2 alkylene)-heterocycloalkyl, -(C _0-2 alkylene)- SO ₂ -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO ₂ -heterocycloalkyl, -(C _0-2 alkylene)-aryl, -CO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-CO-aryl, -CONH-(C _0-2 alkylene )-aryl, -(C _0-2 alkylene)-CONH-aryl, -NHCO-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-NHCO-aryl, -NH-( C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-NH-aryl, -O-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-O- Aryl, -SO ₂ -(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-SO ₂ -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O- Aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-2 alkylene)-heteroaryl, -CO-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene) -CO-heteroaryl, -CONH-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-CONH-heteroaryl, -NHCO-(C _0-2 alkylene)-heteroaryl , -(C _0-2 alkylene)-NHCO-heteroaryl, -NH-(C _0-2 alkylene)heteroaryl, -(C _0-2 alkylene)-NH-heteroaryl, -O-(C _0-2 alkylene)heteroaryl, -(C _0-2 alkylene)-O-heteroaryl, -SO ₂ -(C _0-2 alkylene)heteroaryl, -(C _0-2 alkylene)-SO is selected from ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and -SO ₂ -heteroaryl, wherein the cycloalkyl , heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 halo alkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl) ), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl) , and -CON(C _1-5 alkyl)(C _1-5 alkyl). 33. The method according to any one of claims 1 to 32, wherein R ₄ is -(C _0-2 alkylene)-aryl, -CO-(C _0-2 alkylene)-aryl, -(C _0-2 alkyl lene)-CO-aryl, -CONH-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-CONH-aryl, -NHCO-(C _0-2 alkylene)-aryl, - (C _0-2 alkylene)-NHCO-aryl, -NH-(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-NH-aryl, -O-(C _0-2 alkyl len)-aryl, -(C _0-2 alkylene)-O-aryl, -SO ₂ -(C _0-2 alkylene)-aryl, -(C _0-2 alkylene)-SO ₂ -aryl, - CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO ₂ -aryl, -(C _0-2 alkylene)-heteroaryl, -CO-(C _{0- 2} alkylene)-heteroaryl, -(C _0-2 alkylene)-CO-heteroaryl, -CONH-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-CONH- Heteroaryl, -NHCO-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-NHCO-heteroaryl, -NH-(C _0-2 alkylene)-heteroaryl, -( C _0-2 alkylene)-NH-heteroaryl, -O-(C _0-2 alkylene)-heteroaryl, -(C _0-2 alkylene)-O-heteroaryl, -SO ₂ -(C _{0 -2} alkylene)-heteroaryl, -(C _0-2 alkylene)-SO ₂ -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, - is selected from CO-heteroaryl, and -SO ₂ -heteroaryl, wherein the aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _{1 -5} alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _{1- 5} alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), and -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl). 33. The method of any one of claims 1 to 32, wherein R ₄ is selected from C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. is selected, preferably R ₄ is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, more preferably R ₄ is selected from aryl, and heteroaryl, and even more preferably R ₄ is selected from heteroaryl. aryl, wherein the alkyl, alkenyl, or alkynyl is halogen, -CN, -OH, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), SH, -S(C _{1 -5} alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl) (C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl) (C _1-5 alkyl), wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _{1 -5} haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl), -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 halo optionally with one or more groups independently selected from alkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl) Substituted compounds. The method of claim 34, wherein R ₄ is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -O(C _1-5 haloalkyl) , -SH, -S(C _1-5 alkyl), -S(C _1-5 haloalkyl), -NH ₂ , -NH(C _1-5 alkyl), -NH(C _1-5 haloalkyl), -N(C _1-5 alkyl)(C _1-5 alkyl), -N(C _1-5 haloalkyl)(C _1-5 alkyl), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl) is a 5-membered heteroaryl optionally substituted with one or more groups independently selected from: imidazolyl, isoxazolyl, Pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4- thiadiazolyl, or 1,3,4-thiadiazolyl, preferably wherein the 5-membered heteroaryl is halogen, -CN, -OH, C _1-5 alkyl, C _1-5 haloalkyl, -O (C _1-5 alkyl), -SH, -S(C _1-5 alkyl), -NH ₂ , -NH(C _1-5 alkyl), -N(C _1-5 alkyl)(C _1-5 alkyl ), -CONH ₂ , -CONH(C _1-5 alkyl), and -CON(C _1-5 alkyl)(C _1-5 alkyl), preferably C _{1 -5} alkyl, C _1-5 haloalkyl, -O(C _1-5 alkyl), -SH, -S(C _1-5 alkyl), more preferably C _1-5 alkyl, C optionally substituted with _1-5 haloalkyl, even more preferably optionally substituted with C _1-5 haloalkyl, preferably selected from -CH ₂ F, -CHF ₂ and CF ₃ , most preferably - A compound that is 1,2,4-thiadiazolyl optionally substituted with CHF ₂ . According to paragraph 1,



and ,
or a pharmaceutically acceptable salt, hydrate or solvate thereof. A pharmaceutical composition comprising the compound of any one of claims 1 to 36 or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier. A compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of claim 37, for use in therapy. 39. A compound for use or a pharmaceutical composition for use according to claim 38 for use in a method of treating a disease or disorder in which PARG activity is implicated. 39. A compound for use or a pharmaceutical composition for use according to claim 38, for use in a method of treating a proliferative disorder, preferably wherein the proliferative disorder is cancer, preferably human cancer.