Heterocyclyl Compounds

Abstract

Disclosed herein are compounds of formula (I) having the following structure that activate T cells, promote T cell proliferation, and / or have anti-tumor activity, methods of treating cancer using the compounds disclosed herein, and pharmaceutical compositions comprising said compounds. TIFF2025501098000529.tif5950

Description

[Technical Field]

[0001] Disclosed herein are compounds of formula (I) that activate T cells, promote T cell proliferation, and / or have anti-tumor activity, methods of treating cancer using the compounds disclosed herein, and pharmaceutical compositions comprising said compounds. [Background technology]

[0002] Diacylglycerol kinases (DGKs) are a family of lipid kinases that phosphorylate diacylglycerol (DAG) and convert it to phosphatidic acid (PA). As a substrate for DGKs, DAG is a product of the hydrolysis of inositol phospholipids and other phospholipids in the plasma membrane by phospholipase C (PLC) in response to activation of various cell surface receptors, including G protein-coupled receptors (GPCRs) and immunoreceptor tyrosine-based activation motif (ITAM)-bearing receptors (Rhee, Sue Goo. Annual review of biochemistry. 2001, 70.1: 281-312). DAG is one of the important intracellular second messengers that can recruit and activate many downstream effectors, including protein kinase C (PKC), protein kinase D (PKD) family members, and Ras guanine nucleotide-releasing protein (RasGRP), thereby activating the NF-κB and extracellular-regulated kinase (ERK) pathways (Merida, Isabel et al., Biochemical Journal. 2008, 409.1: 1-18; Joshi, Rohan P. et al., International Journal of Molecular Sciences. 2013, 14.4: 6649-6673). By consuming DAG, DGK controls and regulates the threshold and duration of DAG-mediated signals. The mammalian DGK family contains 10 different members, of which DGKα, DGKζ, and DGKδ are the three major subtypes that are abundantly expressed in lymphoid tissues (Joshi, Rohan P. et al., International Journal of Molecular Sciences. 2013, 14.4: 6649-6673).

[0003] Cancer immunotherapy is a type of cancer treatment that manipulates and enhances the host immune system to recognize and attack cancer cells. Most studies have focused on targeting immune checkpoint inhibitors, such as CTLA-4 and PD-1 / PD-L1, to restore exhausted CD8+ T cells within the tumor site. Peripheral T cell tolerance, which normally prevents harmful autoimmune diseases, has been shown to be controlled by tumors during the carcinogenesis process to prevent antitumor immune responses (Nussing, Simone, et al., Frontiers in Immunology. 2020, 11: 2461). T cell exhaustion, one of the most important mechanisms of T cell tolerance, has been reported to occur in tumor-infiltrating T cells, resulting in the immunosuppressive properties of the tumor microenvironment (Abe, Brian T., and Fernando Macian. Oncoimmunology. 2013, 2.2: e22679). The anergy-associated transcription factor early growth response gene 2 (Egr2) directly binds to the Dgka and Dgkz promoters and increases their expression (Zheng, Yan et al., Journal of Experimental Medicine 2012, 209.12: 2157-2163; Zheng, Yan et al., Molecular Immunology. 2013, 55.3-4: 283-291). In exhausted T cells, both DGKα and DGKζ play an important role in negatively regulating DAG signaling downstream of the TCR and reducing the intensity of TCR activation (Chen, Shelley S. et al., Frontiers in Cell and Developmental Biology. 2016, 4: 130). Therefore, DGKα and DGKζ expressed by immune cells are being investigated as potential targets for reversing the hyporesponsiveness of tumor-infiltrating T cells.Genetic deletion of DGKα or DGKζ has been shown to enhance cytokine production and T cell proliferation (Olenchock, Benjamin A. et al., Nature Immunology. 2006, 7.11: 1174-1181; Zhong, Xiao-Ping et al., Nature Immunology. 2003, 4.9: 882-890). In both mouse and human chimeric antigen receptor (CAR)-T cells, single knockout of DGKα or DGKζ exhibits superior effector function as determined by enhanced in vitro cytotoxicity and cytokine secretion when cocultured with antigen-expressing target cells (Riese, Matthew J. et al., Cancer Research. 2013, 73.12: 3566-3577; Jung, In-Young et al., Cancer Research. 2018, 78.16: 4692-4703). Furthermore, MesoCAR-transduced DGKα or DGKζ-deficient T cells have shown significantly increased anti-mesothelioma activity in vivo (Riese, Matthew J. et al., Cancer Research. 2013, 73.12: 3566-3577). - / -Mice have demonstrated enhanced tumor suppression in both in situ and subcutaneously implanted models (Wesley, Erin M. et al., Immunohorizons. 2018, 2.4: 107-118; Wee, Susan et al., AACR Cancer Res. 2019, 79(13 Suppl.): 936). In addition to their T cell regulatory function, both DGKα and DGKζ are involved in regulating NK cell activation at tumor sites (Prinz, Petra U. et al., International Journal of Cancer. 2014, 135.8: 1832-1841; Yang, Enjun et al., The Journal of Immunology. 2016, 197.3: 934-941). Furthermore, DGKζ has been found to play a key role in controlling the activation threshold of mature B cells (Wheeler, Matthew L. et al., Science Signaling. 2013, 6.297: ra91-ra91). Collectively, all these preclinical data indicate that targeted inhibition of DGKα and DGKζ may be therapeutically beneficial for promoting immunity against cancer. Although existing anti-CTLA-4 and anti-PD-1 therapies have demonstrated significant clinical benefits in subgroups of patients with various tumor types, the development of novel immunotherapies to achieve robust and durable clinical antitumor responses remains an unmet medical need. Preclinical data strongly suggest that the development of DGKα and DGKζ-targeted therapies to enhance antitumor immunity holds great promise. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Rhee, SueGoo. Annual review of biochemistry. 2001, 70.1: 281-312 [Non-patent document 2] Merida, Isabel et al., Biochemical Journal. 2008, 409.1: 1-18 [Non-patent document 3] Joshi, Rohan P. et al., International Journal of Molecular Sciences. 2013,14.4: 6649-6673 [Non-patent document 4] Nussing, Simone et al. Frontiers in Immunology. 2020, 11: 2461 [Non-Patent Document 5] Abe, Brian T. and Fernando Macian. Oncoimmunology. 2013, 2.2: e22679 [Non-patent document 6] Zheng, Yan et al., Journal of Experimental Medicine 2012, 209.12: 2157-2163 [Non-Patent Document 7] Zheng, Yan et al., Molecular Immunology. 2013, 55.3-4: 283-291 [Non-patent document 8] Chen, Shelley S. et al. Frontiers in Cell and Developmental Biology. 2016, 4: 130 [Non-Patent Document 9] Olenchock, Benjamin A. et al., Nature immunology. 2006, July 11: 1174-1181 [Non-Patent Document 10] Zhong, Xiao-Ping et al. Nature immunology. 2003, 4.9: 882-890 Summary of the Invention

[0005] The above-mentioned needs have been met by providing compounds having the novel core structure disclosed herein and exhibiting desired inhibition of DGKα and DGKζ. In some embodiments, the compounds disclosed herein exhibit dual inhibitory activity against both DGKα and DGKζ. In some embodiments, the compounds disclosed herein exhibit selective inhibitory activity against DGKα over DGKζ. In some embodiments, the compounds disclosed herein exhibit selective inhibitory activity against DGKζ over DGKα.

[0006] The present specification describes a compound of formula (I): [ka] or pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, isotopes, and prodrugs thereof, wherein the variables are as defined herein.

[0007] In some embodiments, the compound of Formula (I) is a compound of Formula (II): [ka] wherein the variables are as defined herein.

[0008] In some embodiments, the compound of Formula (II) is a compound of Formula (III): [ka] wherein the variables are as defined herein.

[0009] In some embodiments, the compound of Formula (I) is a compound of Formula (IV): [ka] wherein the variables are as defined herein.

[0010] In some embodiments, the compound of Formula (I) is a compound of Formula (V): [ka] wherein the variables are as defined herein.

[0011] In some embodiments, the compound of Formula (I) is a compound of Formula (VI): [ka] wherein the variables are as defined herein.

[0012] In one aspect, the description provides a method of inhibiting a kinase (e.g., DGKα, DGKζ, or both) in a cell expressing the kinase, comprising contacting the cell with an effective amount of a compound described herein. In one aspect, the description provides a method for treating a disease, particularly a hyperproliferative disorder (such as cancer), in a mammal (including a human).

[0013] In another aspect, the present description provides methods for preparing the compounds described herein.

[0014] Embodiments of the present invention can be more fully understood by reference to the detailed description and examples that are intended to exemplify non-limiting embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0015] definition The following terms have the meanings indicated throughout this specification.

[0016] As used in this specification (including the appended claims), the singular forms of words such as "a," "one," "a kind," and "said" include their corresponding plural forms unless the context clearly dictates otherwise.

[0017] The term "or" is used to mean, and is used interchangeably with, the term "and / or," unless context clearly indicates otherwise.

[0018] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group selected from an alkane by removing one hydrogen atom on the same carbon atom, said hydrocarbon group containing 1 to 18, such as 1 to 12, further such as 1 to 10, further such as 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. An alkyl group containing 1 to 6 carbon atoms (i.e., C 1-6Examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl. Alkyl groups may be optionally enriched with deuterium, e.g., -CD3, -CD2CD3, etc. The term "alkylene" refers to a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups derived from an alkane by removing two hydrogen atoms on the same carbon atom, said hydrocarbon group containing 1 to 6, such as 1 to 4 carbon atoms, further such as 1 to 3, further such as 1, 2 or 3 carbon atoms, including, but not limited to, methylene (-CH2-), ethylene (-CH2CH2-), 1-methylmethylene (-CH(CH3)-), or trimethylene (-CH2CH2CH2-).When alkyl groups described herein are referred to as "substituted," they may be substituted with any one or more of the substituents found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chlorine, iodine, bromine, or fluorine), alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, nitro, cyano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonate, phosphine, thiocarbonyl, sulfinyl, sulfone, sulfonamide, ketone, aldehyde, ester, urea, carbamate, oxime, hydroxylamine, alkoxyamine, aralkoxyamine, N-oxide, hydrazine, hydrazide, hydrazone, azide, isocyanate, isothiocyanate, cyanate, thiocyanate, B(OH), or O(alkyl)aminocarbonyl, aryl, heterocyclyl, or heteroaryl.

[0019] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0020] The term "haloalkyl" refers to an alkyl group in which one or more hydrogens have been replaced by one or more halogen atoms, such as fluoro, chloro, bromo, and iodo. Examples of haloalkyl include haloC 1-8 Alkyl, HaloC 1-6 Alkyl or haloC 1-4 Alkyl includes, but is not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, and the like.

[0021] The term "alkyloxy" or "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Alkoxy (e.g., C 1-6 Alkoxy or C 1-4Examples of alkoxy include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, t-butoxy, pentyloxy, hexyloxy, and the like.

[0022] The term "amino" refers to -NH2.

[0023] The term "alkenyl," as used herein, refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18 (e.g., 2 to 8, further e.g., 2 to 6) carbon atoms. Examples of alkenyl groups (e.g., C alkenyl groups) include, but are not limited to, vinyl (ethenyl or vinyl), prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.

[0024] The term "alkynyl," as used herein, refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 18 (e.g., 2 to 8, further e.g., 2 to 6) carbon atoms. Examples of alkynyl (e.g., C alkynyl) include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl.

[0025] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyl groups. By way of example, a cycloalkyl can contain 3 to 12 (e.g., 3 to 10, further for example, 3 to 8, further for example, 3 to 6, 3 to 5, or 3 to 4) carbon atoms. By way of further example, a cycloalkyl group can be selected from monocyclic groups containing 3 to 12 (e.g., 3 to 10, further for example, 3 to 8, 3 to 6) carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. In particular, saturated monocyclic cycloalkyl groups (e.g., C 3-8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In preferred embodiments, cycloalkyl is a monocyclic ring (C 3-6 Bicyclic cycloalkyls are cycloalkyls (abbreviated as cycloalkyl) and include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyls include those having 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or arranged as a bridged bicyclic ring selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. Further examples of bicyclic cycloalkyls include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.

[0026] The term "deuterated" is used herein to modify a chemical structure or organic group or radical in which one or more carbon-bonded hydrogen atoms are replaced with one or more deuterium atoms, e.g., "deuterated alkyl," "deuterated cycloalkyl," "deuterated heterocycloalkyl," "deuterated aryl," "deuterated morpholinyl," etc. For example, the term "deuterated alkyl," as defined above, refers to an alkyl group, as defined herein, in which at least one of the carbon-bonded hydrogen atoms has been replaced with deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to deuterium, and a carbon atom may be bonded to two or more deuterium atoms, and two or more carbon atoms in an alkyl group may also be bonded to deuterium.

[0027] The term "aryl," used alone or in combination with other terms, refers to an aromatic carbocyclic group having 6 to 14 carbon atoms, either in a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, the aryl group has 6 to 14 carbons, and in other embodiments, the ring portion of the aryl group contains 6 to 12, or even 6 to 10, carbon atoms. Specific aryl groups include phenyl, biphenyl, naphthyl, and the like. Aryl groups can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). In some embodiments, aryl refers to groups selected from 5- and 6-membered carbocyclic aromatic rings such as phenyl groups, bicyclic ring systems such as 7-12 membered bicyclic ring systems, such as naphthyl and indanyl, in which at least one ring is carbocyclic and aromatic, and tricyclic ring systems such as 10-15 membered tricyclic ring systems, such as fluorenyl, in which at least one ring is carbocyclic and aromatic.

[0028] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10Aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0029] The term "heteroaryl" is used herein to refer to a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), for example, 1 to 4 (or in some embodiments 1 to 3, in some embodiments 1 to 2) heteroatoms, with the remaining ring atoms being carbon; - 7-12 membered bicyclic rings containing at least one heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members, for example 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being present in the aromatic ring; and -refers to groups selected from 11-14 membered tricyclic rings containing at least one heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members, e.g., 1-4, or in some embodiments 1-3, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being present in the aromatic ring.

[0030] When the total number of S and O atoms in a heteroaryl exceeds 1, the heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in a heteroaryl is 2 or less. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is 1 or less. When a heteroaryl contains more than one heteroatom ring member, the heteroatoms may be the same or different. Nitrogen atoms in one or more rings of a heteroaryl group may be oxidized to form an N-oxide.

[0031] As used herein, the term "optionally oxidized sulfur" refers to -S-, SO, or SO2.

[0032] The terms "heteroaromatic ring" and "heteroaryl" are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic heteroaromatic ring has 5, 6, 7, 8, 9, or 10 ring members, with 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring members are carbon. In some embodiments, a monocyclic or bicyclic heteroaromatic ring is a monocyclic or bicyclic ring containing 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic heteroaromatic ring is a monocyclic 5-6 membered heteroaryl ring having 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a bicyclic 8-10 membered heteroaryl ring having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0033] Examples of heteroaryl or monocyclic or bicyclic heteroaromatic rings include (numbered from the bonding position designated priority 1): 1H-pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, or 1H-pyrazol-5-yl), pyridyl or pyridinyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, or 2,4-pyrimidinyl, 3,5-pyrimidinyl), imidazolyl (e.g., 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl), 1H-pyridyl or 1H-pyridinyl, 1H-pyridin ... 2,4-imidazole group), imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl or 1,3,4-thiadiazolyl), tetrazolyl, thienyl (e.g. thiophen-2-yl, thiophen-3-yl), triazinyl, benzothienyl, furanyl (furyl or furanyl), benzofuranyl, benzimidazolyl, indolyl (e.g. 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-5 ... 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl or 1H-indol-7-yl), isoindolyl, indolinyl, oxadiazolyl (e.g. 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl (e.g. pyrazin-2-yl), pyridazinyl, pyrrolyl, triazolyl (e.g. 1,2,3-triazolyl, 1,2,4-triazolyl or 1,3,4-triazolyl). , quinolyl (e.g., quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, or quinolin-7-yl), isoquinolyl (e.g., isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, or isoquinolin-8-yl), pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), pteridinyl, purine, 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazolyl, 1-oxa-2,5-oxadiazolyl, 1-oxa-3,4-oxadiazolyl, 1-thia-2,3-oxadiazolyl, 1-thia-2,4-oxadiazolyl, 1-thia-2,5-oxadiazolyl, 1-thia-3,4-oxadiazolyl, floridinyl (e.g., furan-2-yl, furan-3-yl), benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl (e.g., benzo[d]o quinoxalinyl (e.g., quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, or quinoxalin-8-yl), naphthyridinyl (e.g., 1,8-naphthyridin-2-yl, 1,8-naphthyridin-3-yl, or 1,8-naphthyridin-4-yl), , 2,3-dihydro-[1,4]dioxano[2,3-b]pyridinyl (e.g., 2,3-dihydro-[1,4]dioxeno[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxeno[2,3-b]pyridin-7-yl, or 2,3-dihydro-[1,4]dioxeno[2,3-b]pyridin-8-yl), furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, or benzo[d]thiazol-7-yl). -yl), benzo[d]imidazolyl (e.g., 1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-4-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, or 1H-benzo[d]imidazol-7-yl), [1,2,4]triazolo[1,5-a]pyridinyl (e.g., [1,2,4]triazolo[1,5-a]pyridin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-7-yl or [1,2,4]triazolo[1,5-a]pyridin-8-yl), 3H-imidazo[4,5-b]pyridinyl (e.g., 3H-imidazo[4,5-b]pyridin-2-yl, 3H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl or 3H-imidazo[4,5-b]pyridin-7-yl), 1H-imidazo[4,5-b]pyridyl (e.g., 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H- imidazo[4,5-b]pyridin-7-yl), [1,2,4]triazolo[1,5-a]pyridyl (e.g., [1,2,4]triazolo[1,5-a]pyridin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-7-yl or [1,2,4]triazolo[1,5-a]pyridin-8-yl), indazolyl (e.g., 1H-indazol-5-yl), 5,6,7,8-tetrahydroisoquinoline, thiazolo[5,4-b]pyridinyl (e.g., thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4- b]pyridin-5-yl, thiazolo[5,4-b]pyridin-6-yl or thiazolo[5,4-b]pyridin-7-yl), thiazolo[4,5-b]pyridinyl (e.g. thiazolo[4,5-b]pyridin-2-yl, thiazolo[4,5-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-6-yl or thiazolo[4,5-b]pyridin-7-yl), thieno[2,3-b]pyridinyl (e.g. thieno[2,3-b]pyridin-2-yl, thieno[2,3-b]pyridin-3-yl, thieno[2,3-b]pyridin-4-yl, thieno[2,3-b]pyridin-5-yl or thieno[2,3-b]pyridin-6-yl), thieno[3,2-b] Pyridyl (e.g., thieno[3,2-b]pyridin-2-yl, thieno[3,2-b]pyridin-3-yl, thieno[3,2-b]pyridin-5-yl, thieno[3,2-b]pyridin-6-yl, or thieno[3,2-b]pyridin-7-yl) is included, but is not limited to.

[0034] Additionally, a "heteroaryl" fused with a "heterocyclyl" is defined as a "heteroaryl."

[0035] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclyl containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spirocyclic, i.e., monocyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclyl groups.

[0036] The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle may be saturated or partially saturated.

[0037] Illustrative monocyclic 4- to 9-membered heterocyclyl groups include (numbered from the bond position assigned priority 1): pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholinyl ... thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, Homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiapanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl , dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, or 1,1-dioxo-thiomorpholinyl.

[0038] The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl having rings connected by one common carbon atom (called a spiro atom), containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of a spiroheterocyclyl may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Preferably, the spiroheterocyclyl has 6 to 14 members, more preferably 7 to 12 members. Depending on the number of common spiro atoms, spiroheterocyclyl is classified as monospiroheterocyclyl, dispiroheterocyclyl, or polyspiroheterocyclyl, and preferably refers to monospiroheterocyclyl or dispiroheterocyclyl, and more preferably refers to 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl.

[0039] The term "fused heterocyclyl group" refers to a 5- to 20-membered polycyclic heterocyclyl in which each ring contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members and shares an adjacent atom pair (carbon and carbon atoms or carbon and nitrogen atoms) with another ring in which the remaining ring members are carbon. One or more rings of a fused heterocyclyl group may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Preferably, the fused heterocyclyl has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of ring members, the fused heterocyclyl is classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, and preferably refers to a bicyclic or tricyclic fused heterocyclyl, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl. Representative example groups of fused heterocyclyl include, but are not limited to, octahydrocyclopenta[c]pyrrole (e.g., octahydrocyclopenta[c]pyrrol-2-yl), octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindoline (e.g., isoindolin-2-yl), and octahydrobenzo[b][1,4]dioxine.

[0040] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocycloalkyl group in which two rings in the system each share two non-linking atoms containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the remaining ring members are carbon. One or more rings of a bridged heterocyclyl may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Preferably, the bridged heterocyclyl has 6 to 14 ring members, more preferably 7 to 10 ring members. Depending on the number of ring members, the bridged heterocyclyl is classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, and preferably refers to a bicyclic, tricyclic, or tetracyclic bridged heterocyclyl, more preferably a bicyclic or tricyclic bridged heterocyclyl. Representative example groups of bridged heterocyclyl include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0041] A "cycloalkylalkyl" group is a radical of the formula: -alkyl-cycloalkyl, where alkyl and cycloalkyl are as defined above. Substituted cycloalkylalkyl groups may be substituted on the alkyl, cycloalkyl, or both the alkyl and cycloalkyl portions of the group. Representative cycloalkylalkyl groups include, but are not limited to, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl, ethylcyclohexyl, propylcyclopentyl, propylcyclohexyl, and the like.

[0042] An "aralkyl" group is a radical of the formula: -alkyl-aryl, where alkyl and aryl are as defined above. Substituted aralkyl groups may be substituted on the alkyl, aryl, or both the alkyl and aryl portions of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl, and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.

[0043] A "heterocyclylalkyl" group is a radical of the formula: -alkyl-heterocyclyl, where alkyl and heterocyclyl are as defined above. Substituted heterocyclylalkyl groups may be substituted on the alkyl, heterocyclyl, or both the alkyl and heterocyclyl portions of the group. Representative heterocyclylalkyl groups include, but are not limited to, 4-ethylmorpholinyl, 4-propylmorpholinyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0044] "Halogen" is fluorine, chlorine, bromine or iodine.

[0045] A "hydroxyalkyl" group is an alkyl group as defined above that is substituted with one or more hydroxy groups.

[0046] An "alkoxy" group is an --O-(alkyl), where alkyl is as defined above.

[0047] An "alkoxyalkyl" group is an -(alkyl)-O-(alkyl), where alkyl is as defined above.

[0048] An "amino" group is a radical of the formula: --NH.sub.2.

[0049] An "alkylamino" group is a radical of the formula: --NH-alkyl or --N(alkyl)2, where each alkyl is independently as defined above.

[0050] A "carboxy" group is a radical of the formula: --C(O)OH.

[0051] A "hydroxylamine" group has the formula: -C(O)N(R # )2, -C(O)NH(R # ) or —C(O)NH2, where R # is a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl as defined herein.

[0052] An "acylamino" group is a group of the formula: -NHC(O)(R # ) or -N(alkyl)C(O)(R # ) group, where each alkyl and R # are independently as defined above.

[0053] A "sulfonylamino" group is a group of the formula: -NHSO(R # ) or -N(alkyl)SO2(R # ), where each alkyl and R # is as defined above.

[0054] A "urea" group is a group of the formula: -N(alkyl)C(O)N(R # )2, -N(alkyl)C(O)NH(R # ), -N(alkyl)C(O)NH2, -NHC(O)N(R # )2, -NHC(O)NH(R # ) or -NH(CO)NHR # where each alkyl and R # are independently as defined above.

[0055] When groups described herein (excluding alkyl groups) are referred to as "substituted," they may be substituted with any suitable substituent or substituents. Illustrative substituents include those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chlorine, iodine, bromine, or fluorine), alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxyl, nitro, cyano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonate, phosphine, thiocarbonyl, sulfinyl, sulfone, sulfonamide, ketone, aldehyde, ester, urea, carbamate, oxime, hydroxylamine, alkoxyamine, aralkoxyamine, N-oxide, hydrazine, hydrazide, hydrazone, azide, isocyanate, isothiocyanate, cyanate, thiocyanate, oxygen (=O), B(OH), O(alkyl)aminocarbonyl, and cycloalkyl groups. and heterocyclic groups, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl); or heterocyclic groups, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl, or benzofuranyl); aryloxy, aralkoxy, heterocyclyloxy, and heterocyclylalkoxy.

[0056] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. When a compound disclosed herein has two or more asymmetric centers, it may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All possible stereoisomers are intended to be included, such as substantially pure resolved enantiomers, their racemic mixtures, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts are intended to be included. A reference to one isomer applies to any possible isomer unless otherwise specified. Unless the isomeric composition is specified, all possible isomers are included.

[0057] As used herein, the term "substantially pure" means that the target stereoisomer contains 35% by weight or less, such as 30% by weight or less, further such as 25% by weight or less, and even further such as 20% by weight or less of any one or more other stereoisomers. In some embodiments, the term "substantially pure" means that the target stereoisomer contains 10% by weight or less, such as 5% by weight or less, such as 1% by weight or less of any one or more other stereoisomers.

[0058] When compounds disclosed herein contain olefinic double bonds, such double bond, unless otherwise specified, is intended to include both E and Z geometric isomers.

[0059] When the compounds disclosed herein contain a disubstituted cyclohexyl or cyclobutyl, the substituents found on the cyclohexyl or cyclobutyl ring may adopt a cis and trans configuration, where cis means that both substituents are above the position of the two substituents on the carbon, and trans means that they are on opposite sides.

[0060] It may be advantageous to separate reaction products from one another and / or from starting materials. The products required for each step or series of steps are separated and / or purified (hereinafter, "separated") to the desired degree of homogeneity by techniques commonly used in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or flash column chromatography. Flash column chromatography may include many methods, including, for example, reverse-phase and normal-phase chromatography, size-exclusion chromatography, ion-exchange chromatography, high-pressure, medium-pressure, and low-pressure liquid flash column chromatography methods and apparatus, small-scale analytical chromatography, simulated moving bed ("SMB") chromatography, and preparative thin- or thick-layer flash column chromatography, as well as small-scale thin-layer and flash column chromatography techniques. Those skilled in the art will use the technique most likely to achieve the desired separation.

[0061] "Diastereomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, for example, via flash column chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using a chiral HPLC column.

[0062] Single stereoisomers (e.g., substantially pure enantiomers) can be obtained by resolving the racemic mixture using methods (such as the formation of diastereomers using optically active resolving agents) [Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H. et al., "Flash column chromatographic resolution of enantiomers: Selective review," J. Chromatogr., 113(3)(1975): pp. 283-302]. Racemic mixtures of the chiral compounds of the present invention can be separated and isolated by any suitable method, including (1) the formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) the formation of diastereomeric compounds with chiral derivatizing agents, separation of the diastereomers, and conversion to pure stereoisomers, or (3) the direct separation of substantially pure or enriched stereoisomers under chiral conditions. See Wainer, Irving W., ed., Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0063] "Pharmaceutically acceptable salts" refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base function with a suitable organic acid, or by reacting an acidic group with a suitable base.

[0064] "Selective inhibitory activity" or "selective" refers to the difference in the degree of inhibition of DGKα and DGKζ. In some embodiments, a "compound that exhibits selective inhibitory activity against DGKα over DGKζ" refers to a compound that exhibits a ratio of the IC50 for DGKζ to the IC50 for DGKα of about 20 or greater. In some embodiments, a "compound that exhibits selective inhibitory activity against DGKζ over DGKα" refers to a compound that exhibits a ratio of the IC50 for DGKα to the IC50 for DGKζ of about 20 or greater. In some embodiments, a "compound that exhibits selective inhibitory activity against DGKα over DGKζ" refers to a compound that exhibits an IC50 for DGKα of about 2000 nM or less and a ratio of the IC50 for DGKζ to the IC50 for DGKα of about 20 or greater. A "compound that exhibits selective inhibitory activity against DGKζ over DGKα" refers to a compound that has an IC50 against DGKζ of about 2000 nM or less and a ratio of the IC50 for DGKα to the IC50 for DGKζ of about 20 or more. A "compound that exhibits dual inhibitory activity" refers to a compound that exhibits inhibitory activity against both DGKα and DGKζ with an IC50 of 500 nM or less and a ratio of the two IC50 values ​​of 20 or less. In some embodiments, a "compound that exhibits dual inhibitory activity" refers to a compound that exhibits inhibitory activity against both DGKα and DGKζ with an IC50 of 1000 nM or less and a ratio of the two IC50 values ​​of 20 or less. In some embodiments, a "compound that exhibits dual inhibitory activity" refers to a compound that exhibits inhibitory activity against both DGKα and DGKζ with an IC50 of 2000 nM or less and a ratio of the two IC50 values ​​of 20 or less.

[0065] Furthermore, if the compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional methods for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

[0066] As defined herein, "a pharmaceutically acceptable salt thereof" includes at least one salt of a compound of formula (I) and stereoisomeric salts, such as enantiomeric and / or diastereomeric salts of a compound of formula (I).

[0067] As used herein, the terms "administration," "administering," "treating," and "treatment," when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent with a cell, and contact of a reagent with a fluid, the fluid being in contact with the cell. The terms "administration" and "treatment" further refer to in vitro and ex vivo treatment of a cell, for example, with a reagent, diagnostic agent, binding compound, or with another cell. A "subject" herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0068] The term "effective amount" or "therapeutically effective amount" refers to the amount of an active ingredient (e.g., a compound) sufficient to affect treatment of a disease, disorder, or condition when administered to a subject for treating at least one clinical symptom of the disease, disorder, or condition. A "therapeutically effective amount" may vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age and / or weight of the subject being treated. The appropriate amount in any given case may be readily apparent to one of ordinary skill in the art or may be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof effective to effect "treatment" as defined above for a disease or disorder in a subject. In the case of a combination therapy, a "therapeutically effective amount" refers to the total amount of the combined targets for effective treatment of the disease, disorder, or condition.

[0069] Pharmaceutical compositions comprising the compounds disclosed herein can be administered to subjects in need thereof by oral, inhalation, rectal, parenteral, or topical administration. For oral administration, pharmaceutical compositions can be conventional solid formulations such as tablets, powders, granules, capsules, or liquid formulations such as aqueous or oily suspensions, or other liquid formulations such as other syrups, solutions, suspensions, etc. For parenteral administration, pharmaceutical compositions can be solutions, aqueous solutions, oily suspension concentrates, lyophilized powders, etc. Preferably, the pharmaceutical composition formulation is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably tablets or capsules. Pharmaceutical compositions can be single-unit dosages with precise dosages. In addition, pharmaceutical compositions can contain additional active ingredients.

[0070] All formulations of the pharmaceutical compositions disclosed herein may be prepared by conventional methods in the pharmaceutical arts. For example, an active ingredient can be mixed with one or more excipients, followed by preparation of the desired formulation. The term "pharmaceutically acceptable excipient" refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as diluents, vehicles such as water and various organic solvents, fillers such as starch and sucrose, binders such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone (PVP), humectants such as glycerin, disintegrating agents such as agar, calcium carbonate, and sodium bicarbonate, absorption enhancers such as quaternary ammonium compounds, surfactants such as cetyl alcohol, absorbent carriers such as kaolin and bentonite clay, and lubricants such as talc, calcium stearate, magnesium stearate, and polyethylene glycol. Additionally, pharmaceutical compositions may further contain other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, flavors, sweeteners, and dyes.

[0071] The term "disease" refers to any disease, ailment, illness, symptom, or indication, and is interchangeable with the terms "disorder" or "condition."

[0072] Throughout the specification and the appended claims, unless the context requires otherwise, the term "comprise" and variations thereof, such as "comprises" and "comprising," are intended to specify the presence of the subsequent feature and do not exclude the presence or addition of one or more other features. As used herein, the term "comprises" may be substituted with "contain," "include," or sometimes "have."

[0073] Throughout the specification and in the appended claims, the term "Cn-m" denotes an inclusive range, where n and m are integers and indicate the number of carbons. 1-8 , C 1-6 etc.

[0074] The term "tautomer" refers to isomeric forms of a compound that are in equilibrium with each other. The concentration of isomeric forms can vary depending on the environment in which the compound is placed, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole can exhibit the following isomeric forms, called tautomers of each other: [ka]

[0075] As will be readily understood by one skilled in the art, various functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds of formula (I) are within the scope of the invention.

[0076] Unless expressly defined elsewhere herein, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0077] It should also be noted that the compounds provided herein may contain unnatural proportions of atomic isotopes at one or more atoms. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I), sulfur-35( 35 S) or carbon-14 ( 14 C) or may be radiolabeled with deuterium ( 2 H), carbon-13( 13 C) or nitrogen-15( 15Radiolabeled, isotopically enriched compounds may be isotopically enriched with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 113, 120, 121, 132, 133, 144, 145, 150, 151, 162, 170, 181, 191, 192, 193, 194, 195, 196

[0078] The term "DGK" or "DAGK" (diacylglycerol kinase) refers to a family of enzymes that catalyze the conversion of diacylglycerol (DAG) to phosphatidic acid (PA) using ATP as a phosphate source. In unstimulated cells, DGK activity is low, and DAG is used for the biosynthesis of glycerophospholipids. However, upon activation of receptors in the phosphoinositide pathway, DGK activity increases, driving the conversion of DAG to PA. The two lipids are considered to act as biologically active lipid signaling molecules with distinct cellular targets. Therefore, DGKs play a key role in effectively functioning as switches by terminating signaling of one lipid and activating signaling of the other. See Merida I, Avila-Flores A, Merino E (January 2008). "Diacylglycerol kinases: at the hub of cell signaling," The Biochemical Journal, 409(1): 1-18. Currently, 10 members of the DGK family have been cloned and identified. All family members have a conserved catalytic domain and two cysteine-rich domains, but they are further divided into five groups depending on the presence of additional functional domains and substrate specificity. See van Blitterswijk WJ, Houssa B (October 2000), "Properties and functions of diacylglycerol kinases", Cellular Signaling, 12(9-10): 595-605. The five groups are: Type 1 - DGK-α, DGK-β, DGK-γ - contains an EF chiral motif and a recovery protein homology domain. Type 2 - DGK-δ, DGK-η, DGK-κ - contains a pleckstrin homology domain. Type 3 - DGK-ε - has specificity for arachidonic acid-containing DAG. Type 4 - DGK-ζ, DGK-ι - contains a MARCKS homology domain, ankyrin repeats, a C-terminal nuclear localization signal, and a PDZ-binding motif. Type 5 - DGK-θ - contains a third cysteine-rich domain, a pleckstrin homology domain and a proline-rich region.

[0079] As used herein, the term "treatment" means alleviating, in whole or in part, a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or slowing or halting further progression or worsening of the symptoms, or alleviating or eradicating one or more causes of the disorder, disease, or condition itself. In one embodiment, "treatment" means alleviating, in whole or in part, symptoms associated with a disorder, disease, or condition, or condition treatable or preventable by inhibition of the DGK pathway. In another embodiment, "treatment" means alleviating, in whole or in part, symptoms associated with a disorder, disease, or condition, or condition treatable or preventable by inhibition of the DGK-α pathway. In yet another embodiment, "treatment" means alleviating, in whole or in part, symptoms associated with a disorder, disease, or condition, or condition treatable or preventable by inhibition of the DGK-ζ pathway. In one embodiment, the disorder is cancer.

[0080] As used herein, "prevention" refers to a method of delaying and / or inhibiting, in whole or in part, the onset, recurrence, or spread of a disorder, disease, or condition, a method of preventing a subject from developing a disorder, disease, or condition, or a method of reducing a subject's risk of developing a disorder, disease, or condition. In another example, the disorder is a condition treatable or preventable by inhibition of the DGK pathway. In another example, the disorder is a condition treatable or preventable by inhibition of the DGK-α pathway. In another example, the disorder is a condition treatable or preventable by inhibition of the DGK-ζ pathway. In one embodiment, the disorder is cancer.

[0081] The term "subject" includes, but is not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, and is in one embodiment a mammal, and in another embodiment a human. In one embodiment, the subject is a human suffering from a liver fibrotic disorder or diabetes or metabolic syndrome that causes a liver fibrotic disorder, or a human at risk for a disease or symptom thereof that is treatable or preventable by inhibiting the JNK pathway.

[0082] As used herein, the term "compound" refers to a compound of Formula (I) and further embodiments provided herein. In one embodiment, a "compound" is a compound listed in Table 1. The term "compound" includes pharmaceutically acceptable salts, tautomers, isotopes, stereoisomers, and prodrugs of the compounds provided herein.

[0083] As used herein, unless otherwise indicated, the term "prodrug" means a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound of Formula (I). Examples of prodrugs include, but are not limited to, derivatives and metabolites of a compound that contains a biohydrolyzable moiety, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. In certain embodiments, prodrugs of compounds with carboxyl functional groups are lower alkyl esters of the carboxylic acid. Carboxylic acid esters can be conveniently formed by esterifying any carboxylic acid moiety present on the molecule. Prodrugs can generally be prepared using well-known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery 6th Edition (Donald J. Abraham, ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard, ed., 1985, Harwood Academic Publishers Gmfh).

[0084] As used herein, unless otherwise indicated, the terms "stereoisomer" or "stereoisomerically pure" mean that one stereoisomer of a compound is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. Compounds may have chiral centers and may occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms, including mixtures thereof, are included in the embodiments disclosed herein.

[0085] compound

[0086] The compounds disclosed herein have a novel core structure and exhibit desirable inhibition of DGKα and DGKζ. In some embodiments, the compounds disclosed herein exhibit dual inhibitory activity against both DGKα and DGKζ. In some embodiments, the compounds disclosed herein exhibit selective inhibitory activity against DGKα over DGKζ. In some embodiments, the compounds disclosed herein exhibit selective inhibitory activity against DGKζ over DGKα.

[0087] First aspect

[0088] The present specification describes a compound of formula (I): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, or prodrug thereof, During the ceremony, X 1 is C or N, X 2 and X 3 each is independently selected from -N- or -CH-; sign [ka] is a single or double bond, R 1 is hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, provided that X 1 is N and X 1 is connected to [ka] is a double bond, R 2 does not exist, R 4 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, or substituted or unsubstituted heteroaryl, R 5a -C(O)-, R 5a -C(O)O-, R5a -OC(O)-, R 5a -C(O)NR 5b -, R 5a -NR 5b -C(O)- or R 5a -SO2- and R 5a and R 5b are each independently hydrogen, alkyl, or cycloalkyl; R 6 is absent, hydrogen, halogen, or alkyl unsubstituted or substituted with halogen or cyano, with the proviso that R 6 The bond connecting the nitrogen to which [ka] is a double bond, R 6 does not exist, R 7 , R 9 , R 8 and R 10 each independently represents hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, —C(O)R 7a or -alkyl-C(O)R 7a and R 7a is hydrogen, alkyl, or alkoxy, where R 7 and R 9 At least one of them is not hydrogen, or R 7 and R 9 are hydrogen, and R 8 and R 10 together form a bridge containing two bridgehead atoms plus at least one -CH2- moiety, or R 8 and R 10 are hydrogen, and R 7 and R 9 together form a bridge containing two bridgehead atoms plus at least one -CH2- moiety, L 1 is a direct bond, -O-, -N(R L )-, substituted or unsubstituted alkyl, -alkylene, or -C(O)-, wherein R Lis hydrogen or alkyl, Cy 1 is unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted heteroaryl; Cy 1 optionally one, two, or three substituents R 3a is replaced by R 3a is a deuterium, alkoxy group, alkyl group, halogen, R 3b -SO2-, cycloalkyl, cyano group, R 3b -C(O)-N(R 3c )-, N(R 3b R 3c )-C(O)-, N(R 3b R 3c ), R 3b -OC(O)-, cycloalkyl or heterocyclyl; Any two R 3a are attached to the same carbon and together form a spiro ring, Any two R 3a Cy 1 forms a condensed ring with R 3a is unsubstituted or substituted with cyano, alkoxy, alkyl, halogen or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl.

[0089] In some embodiments, the compound of Formula (I) is a compound of Formula (II): [ka] wherein the variables are as defined herein.

[0090] In some embodiments, the compound of Formula (II) is a compound of Formula (III): [ka] wherein the variables are as defined herein.

[0091] In some embodiments, the compound of Formula (I) is a compound of Formula (IV): [ka] wherein the variables are as defined herein.

[0092] R 1 Definition of

[0093] In some embodiments, R 1 is hydrogen, or substituted or unsubstituted alkyl. In some embodiments, R 1 is hydrogen, or substituted or unsubstituted C 1-4 It is alkyl.

[0094] In some embodiments, R 1 is hydrogen or C optionally substituted with deuterium, halogen, hydroxy, alkoxy or cycloalkyl 1-4 In some embodiments, R 1 is hydrogen or C optionally substituted with deuterium, halogen, hydroxy, alkoxy or cycloalkyl 1-4 In some embodiments, R 1 is hydrogen or C optionally substituted with deuterium or halogen 1-3 In some embodiments, R 1 is hydrogen or C optionally substituted with deuterium 1-3 It is alkyl.

[0095] In some embodiments, R 1 is hydrogen, methyl, methyl-d3, ethyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, or cyclopropylmethyl. 1 is hydrogen, methyl, ethyl, or methyl-d3. In some embodiments, R 1 is methyl or methyl-d3. In some embodiments, R1 is methyl.

[0096] R 2 Definition of In some embodiments, R 2 is hydrogen, halogen, alkyl, alkoxy, or cyano, provided that X 1 is N and X 1 and the bond connected [ka] is a double bond, R 2 is absent. In some embodiments, R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 In some embodiments, R is alkoxy or cyano. 2 is hydrogen, F, Br, Cl, or CN. In some embodiments, R 2 is hydrogen.

[0097] In some embodiments, R 2 are hydrogen, halogen, C 1-4 Alkyl, C 1-4 alkoxy or cyano, preferably R 2 is hydrogen, F, Br, Cl or CN, more preferably R 2 is hydrogen, F or CN, and even more preferably, R 2 is hydrogen.

[0098] R 4 Definition of

[0099] In some embodiments, R 4 is hydrogen, halogen or alkyl, said alkyl optionally being halogen or -OR 4a wherein R 4a is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl, and said alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally —C 1-6 Alkyl, -C1-6 Alkoxy or -C 3-8 In some embodiments, R 4 is hydrogen, halogen or C 1-4 alkyl, said alkyl optionally being halogen or -OR 4a In some embodiments, R 4 is hydrogen, halogen or C 1-4 alkyl, said alkyl being optionally substituted with halogen.

[0100] In some embodiments, R 4 is hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, ethyl, or 2,2,2-trifluoroethyl. 4 is hydrogen.

[0101] R 5 Definition of

[0102] In some embodiments, R 5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, R 5a -C(O)-, R 5a -C(O)O-, R 5a -OC(O)-, R 5a -C(O)NR 5b -, R 5a -NR 5b -C(O)-, R 5a -SO2- or heterocyclyl, wherein the alkyl is unsubstituted or is cyano, -C(O)OR 5c , -C(O)R 5c , -C(O)NR 5c R 5d , heterocyclyl, alkoxy, hydroxy, cycloalkyl or NR 5c R 5d and each of said cycloalkyl and heterocyclyl is unsubstituted or alkyl, cyano, or alkyl substituted with halogen, cyano, —C(O)OR 5c , -C(O)R 5c , -C(O)NR 5c R5d , heterocyclyl, alkoxy, hydroxy, cycloalkyl, NR 5c R 5d or R 5c -SO2- and R 5a and R 5b are each independently hydrogen, alkyl, or cycloalkyl, and R 5c and R 5d is hydrogen or alkyl.

[0103] In some embodiments, R 5 is hydrogen, alkyl, alkenyl, or alkynyl, wherein the alkyl is unsubstituted or substituted with cyano. In some embodiments, R 5 is C 1-4 Alkyl, C 2-4 Alkenyl or C 2-4 In some embodiments, R is an alkynyl, wherein the alkyl is substituted with cyano. 5 is C 1-4 alkyl, said alkyl being substituted with cyano.

[0104] In some embodiments, R 5 is C 1-4 alkyl, wherein the alkyl is cyano, alkoxy, hydroxy, NR 5c R 5d , -NO-CH3, -S(=O)-CH3, -S(=O)2-CH3 or -S(=O)(=NH)-CH3.

[0105] In some embodiments, R 5is hydrogen, -CH2-CN, -CH2C(O)-OMe, -CH(CH3)CN, oxiran-2-ylmethyl-, prop-2-yn-1-yl, but-2-yn-1-yl, prop-1-en-2-yl, methyl, isopropyl, -CH2CH2-O-CH3, -CH2-O-CH3, -CH(CH3)-O-CH3, -CH2C(O)NH2, -CH2CH2-OH, -CH2-OH, cyclopropyl-CH2-, -CH2CH2N(CH3)2, CH3-SO2- , cyclopropyl, cyclobutyl, cyclopropyl-C(O)-, 1-cyanocyclopropyl, 2-cyanocyclopropyl, 2-cyanocyclobutyl, 3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl, 1-cyano-2-cyclopentylethan-2-yl, -CH2-N(CH3)2, -CH=NO-CH3, -CH2-S(=O)-CH3, -CH2-S(=O)2-CH3 or -CH2-S(=O)(=NH)-CH3, preferably R 5 is hydrogen, CN—CH—, —CHC(O)—OMe, —CH(CH)CN, oxiran-2-ylmethyl-, prop-2-yn-1-yl, but-2-yn-1-yl, prop-1-en-2-yl, —CH—OH, —CH(CH)CN, —CH—O—CH, —CH(CH)—O—CH, —CH—N(CH), —CH═NO—CH, —CH—S(═O)—CH, —CH—S(═O)—CH or —CH—S(═O)(═NH)—CH, more preferably R 5 is CN—CH—, prop-2-yn-1-yl, but-2-yn-1-yl or prop-1-en-2-yl, —CH—OH, —CH(CH)CN, —CH—O—CH, —CH(CH)—O—CH, —CH—N(CH), —CH═NO—CH, —CH—S(═O)—CH, —CH—S(═O)—CH or —CH—S(═O)(═NH)—CH, more preferably R 5is CN—CH—, —CH—OH, —CH(CH)CN, —CH—O—CH, —CH(CH)—O—CH, —CH—N(CH), —CH═NO—CH, —CH—S(═O)—CH, —CH—S(═O)—CH, or —CH—S(═O)(═NH)—CH, more preferably R 5 is CN-CH2-. R 6 Definition of

[0106] In some embodiments, R 6 does not exist.

[0107] In some embodiments, R 6 is absent, hydrogen, halogen, or an alkyl group that is unsubstituted or substituted with halogen or cyano, with the proviso that R 6 The bond connecting the nitrogen to which [ka] is a double bond, R 6 is absent, and in some embodiments, R 6 is hydrogen, F, Br, Cl or unsubstituted or cyano-substituted C 1-4 It is alkyl.

[0108] R 7 / R 9 、 R 8 / R 10 Definition of

[0109] In some embodiments, R 7 , R 9 , R 8 and R 10 each independently represents hydrogen, alkyl, or —C(O)R 7a wherein the alkyl is unsubstituted or substituted with halogen, cyano, hydroxy, or alkoxy; and R 7a is hydrogen, alkyl, or alkoxy, provided that R 7 and R 9 At least one of these is not hydrogen.

[0110] In some embodiments, R 7 and R 9 each independently represents hydrogen, alkyl, or —C(O)R 7a wherein the alkyl is unsubstituted or substituted with halogen, cyano, hydroxy, or alkoxy; and R 7a is hydrogen, alkyl, or alkoxy. In some embodiments, R 7 and R 9 Each of the is independently C 1-4 In some embodiments, R 7 and R 9 Each of the is independently C 1-2 It is alkyl.

[0111] In some embodiments, R 7 and R 9 are each independently hydrogen, methyl, ethyl, methoxymethyl, 1-hydroxyethyl, 2-methoxyethyl, cyanomethyl, hydroxyethyl, hydroxymethyl, methoxycarbonyl, or difluoromethyl, with the proviso that R 7 and R 9 At least one of them is not hydrogen.

[0112] In some embodiments, R 8 and R 10 are hydrogen atoms.

[0113] In some embodiments, R 7 is methyl and R 9 is methyl, or R 7 is ethyl and R 9 is ethyl, or R 7 Methyl and R 9 is ethyl, or R 7 is methyl and R 9 is methoxycarbonyl, or R 7 is hydrogen and R 9 is methyl, or R 7 is hydrogen and R9 is ethyl.

[0114] In some embodiments, R 7 and R 9 are hydrogen, and R 8 and R 10 together form a bridge that includes two bridgehead atoms plus at least one -CH2- moiety. In some embodiments, R 7 and R 9 are hydrogen, and R 8 and R 10 together form a bridge comprising two bridgehead atoms plus one -CH2- moiety. In some embodiments, R 7 and R 9 are hydrogen, and R 8 and R 10 together form a bridge containing two -CH2- moieties in addition to the two bridgehead atoms.

[0115] In some embodiments, R 8 and R 10 are hydrogen, and R 7 and R 9 together form a bridge that includes two bridgehead atoms plus at least one -CH2- moiety. In some embodiments, R 8 and R 10 are hydrogen, and R 7 and R 9 together form a bridge comprising two bridgehead atoms plus one -CH2- moiety. In some embodiments, R 8 and R 10 are hydrogen, and R 7 and R 9 together form a bridge containing two -CH2- moieties in addition to the two bridgehead atoms.

[0116] In some embodiments, R 8 and R 10 are hydrogen atoms.

[0117] In some embodiments, R 8 and R 10 are hydrogen, and R 7 is methyl and R 9 is methyl. In some embodiments, R 8 and R 10 are hydrogen, and R 7 is ethyl and R 9 is ethyl. In some embodiments, R 8 and R 10 are hydrogen, and R 7 is methyl and R 9 is ethyl. In some embodiments, R 8 and R 10 are hydrogen, and R 7 is ethyl and R 9 is methyl.

[0118] L 1 Definition of

[0119] In some embodiments, L 1 is a direct bond, -O-, -N(R L )-, -alkylene-, or -C(O)-, wherein R L is hydrogen or alkyl, and said -alkylene- is unsubstituted or substituted with halogen, alkoxy, or heterocyclyl. 1 is a direct bond, -O-, -N(R L )-, -alkylene-, or -C(O)-, and R L is hydrogen or alkyl. In some embodiments, L 1 is C 1-4 alkylene, preferably C 1-2 In some embodiments, L is alkylene. 1 is a direct bond, —CH—, —CH(CH)—, —CH(CHCH)—, —CH(CHF)—, —N(H)—, —N(CH)—, —O—, —CH(C(O)—NHCHCHOCH)—, or —C(CH)—. In some embodiments, L1 is —CH— or —CH(CH)—.

[0120] X 2 and X 3 Definition of

[0121] In some embodiments, X 2 and X 3 is independently N or CH. In some embodiments, X 2 is N and X 3 is N. In some embodiments, X 2 is N and X 3 is CH. In some embodiments, X 2 is CH and X 3 is N. In some embodiments, X 2 is CH and X 3 is CH.

[0122] Cy 1 Definition of

[0123] In some embodiments, Cy 1 is aryl, heterocyclyl, heterocyclyl, heteroaryl, or cycloalkyl, each of which is unsubstituted or contains one, two, or three substituents R 3a is substituted with R 3a is deuterium, alkoxy, alkyl, halogen, R 3b -SO2-, cycloalkyl, cyano, R 3b -C(O)-N(R 3c )-, N(R 3b R 3c )-C(O)-, N(R 3b R 3c ), R 3b -OC(O)- or heterocyclyl, wherein the alkyl portion of the alkyl or alkoxy is unsubstituted or substituted with halogen, alkoxy, hydroxy, or cyano, and the cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy; R3b and R 3c are each independently hydrogen or alkyl.

[0124] In some embodiments, Cy 1 is aryl and is unsubstituted or contains one, two, or three substituents R 3a is substituted with R 3a is deuterium, alkoxy, alkyl, halogen, R 3b -SO2-, cycloalkyl, cyano, R 3b -C(O)-N(R 3c )-, N(R 3b R 3c )-C(O)-, N(R 3b R 3c ), R 3b -OC(O)- or heterocyclyl, wherein the alkyl portion of the alkyl or alkoxy is unsubstituted or substituted with halogen, alkoxy, hydroxy, or cyano, and the cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl.

[0125] In some embodiments, Cy 1 is aryl and is unsubstituted or contains one, two, or three substituents R 3a is substituted with R 3a is alkoxy, halogen-substituted alkoxy, alkoxyalkyl-, alkyl, halogen-substituted alkyl, halogen, R 3b -SO2-, cycloalkyl, hydroxyalkyl-, cyano, R 3b -C(O)-N(R 3c )-, cyano-substituted alkyl, N(R 3b R 3c )-C(O)-, R 3b -OC(O)- or heterocyclyl, wherein said cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R3b and R 3c are each independently hydrogen or alkyl.

[0126] In some embodiments, Cy 1 is unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted heteroaryl. In some embodiments, Cy 1 optionally one, two, or three substituents R 3a is substituted with R 3a is deuterium, fluorine, bromine, chlorine, methyl, difluoromethyl, trifluoromethoxy, methoxy, methoxymethyl, trifluoromethyl, methylsulfonyl, difluoro, ethoxy, isopropyl, isopropoxy, difluoromethoxy, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl, cyclobutyl, 1-hydroxyethyl, 2-hydroxyethyl, ethyl, 1,1-difluoroethyl, cyano, dimethoxy, dichloro, acetylamino, 1-methoxyethyl, cyano and 2-(difluoromethoxy)ethyl, 1-(difluoromethoxy)ethyl, azetidin-1-yl, 2-methoxypropan-2-yl, 1-methoxycyclopropyl, oxetan-3-yl, 1-methylazetidin-3-yl, 1-hydroxyazetidin-3-yl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, or 2-fluoropropan-2-yl.

[0127] In some embodiments, Cy 1 is an aryl of 6 to 14 carbon atoms having a single ring or multiple condensed rings, which is unsubstituted or contains one, two, or three R 3a In some embodiments, the aromatic carbocyclic group is phenyl, naphthyl or anthryl, indanyl or tetrahydronaphthyl, which is unsubstituted or substituted with one, two, or three R 3ais replaced by .

[0128] In some embodiments, Cy 1 is phenyl. In some embodiments, Cy 1 is phenyl, which at the 4-position is R 3a and optionally, at another position, R 3a is replaced by .

[0129] In some embodiments, Cy 1 is naphthyl. In some embodiments, Cy 1 are naphthalen-1-yl, naphthalen-2-yl, naphthalen-3-yl, and naphthalen-4-yl.

[0130] In some embodiments, Cy 1 is benzo[d][1,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-difluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 2,2-dimethylbenzo[d][1,3]dioxol-4-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl or [ka] is.

[0131] In some embodiments, Cy 1 is a monocyclic 5- to 9-membered heterocyclyl or a bicyclic 7- to 10-membered heterocyclyl that is unsubstituted or contains one, two, or three R 3a is substituted with R 3a is deuterium, alkoxy, alkyl, halogen, R 3b-SO2-, cycloalkyl, cyano, R 3b -C(O)-N(R 3c )-, N(R 3b R 3c )-C(O)-, N(R 3b R 3c ), R 3b -OC(O)- or heterocyclyl, wherein the alkyl portion of the alkyl or alkoxy is unsubstituted or substituted with halogen, alkoxy, hydroxy or cyano, and the cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl, and preferably R 3a is alkoxy, alkoxy substituted with halogen, alkoxyalkyl-, alkyl, halogen-substituted alkyl, halogen, R 3b -SO2-, cycloalkyl, hydroxyalkyl-, cyano, R 3b -C(O)-N(R 3c )-, cyano-substituted alkyl, N(R 3b R 3c )-C(O)-, R 3b -OC(O)- or heterocyclyl, wherein said cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl. In some embodiments, the monocyclic 5- to 9-membered heterocyclyl is tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, piperidinyl, piperazinyl, or dihydropyridinyl, each of which is unsubstituted or contains one, two, or three R as disclosed herein. 3a In some embodiments, Cy is substituted with 1is tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, 1,4-dioxin-2-yl, 1,4-dioxin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl or 1,2-dihydropyridin-6-yl.

[0132] In some embodiments, Cy 1 is piperidinyl (e.g., piperidin-1-yl) or piperazinyl (e.g., piperazin-4-yl), which is substituted at the 4-position with R 3a and optionally R 3a is replaced by

[0133] In some embodiments, the bicyclic 7- to 10-membered heterocyclyl is a chroman group, preferably chroman-2-yl, chroman-3-yl, or chroman-4-yl.

[0134] In some embodiments, Cy 1 is a monocyclic 5- to 9-membered heteroaryl or a bicyclic 7- to 10-membered heteroaryl that is unsubstituted or contains one, two, or three R 3a is substituted with R 3a is deuterium, alkoxy, alkyl, halogen, R 3b -SO2-, cycloalkyl, cyano, R 3b -C(O)-N(R 3c )-, N(R 3b R 3c )-C(O)-, N(R 3b R 3c ), R 3b-OC(O)- or heterocyclyl, wherein the alkyl portion of the alkyl or alkoxy is unsubstituted or substituted with halogen, alkoxy, hydroxy or cyano, and the cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl, preferably R 3a is deuterium, alkoxy, halogen-substituted alkoxy, alkoxyalkyl-, alkyl, halogen-substituted alkyl, halogen, R 3b -SO2-, cycloalkyl, hydroxyalkyl-, cyano, R 3b -C(O)-N(R 3c )-, cyano-substituted alkyl, N(R 3b R 3c )-C(O)-, N(R 3b R 3c )-, R 3b -OC(O)- or heterocyclyl, wherein said cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl, and more preferably R 3a is selected from deuterium, fluorine, bromine, chlorine, methyl, difluoromethyl, trifluoromethoxy, methoxy, methoxymethyl, trifluoromethyl, methylsulfonyl, difluoro, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl, 1-hydroxyethyl, ethyl, 1,1-difluoroethyl, cyano, dimethoxy, dichloro, cyclopropyl-, acetamido, 1-methoxyethyl, cyanomethyl, carbamoyl, methoxycarbonyl, dimethylcarbamoyl, (difluoromethoxy)methyl, amino, 1-(difluoromethoxy)ethyl, azetidin-1-yl, 2-methoxypropan-2-yl, 1-methoxycyclopropyl, oxetan-3-yl, 1-methylazetidin-3-yl or 1-hydroxyazetidin-3-yl.

[0135] In some embodiments, the monocyclic 5- to 9-membered heteroaryl is pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is unsubstituted or contains 1, 2, or 3 R as disclosed herein. 3a In some embodiments, the monocyclic 5- to 9-membered heteroaryl is 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, pyrazin-2-yl, or pyridazin-4-yl, each of which is unsubstituted or substituted with one, two, or three of R as disclosed herein. 3a is replaced by .

[0136] In some embodiments, the bicyclic 7- to 10-membered heteroaryl is indolyl, benzo[d]imidazolyl, triazolopyridinyl, imidazopyridinyl, benzoxazolyl, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, dioxinopyridinyl, quinoxalinyl, benzo[d]imidazolyl, imidazo[4,5-b]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyridyl, thieno[2,3-b]pyridyl, or thieno[3,2-b]pyridyl, each of which is unsubstituted or contains 1, 2, or 3 R as disclosed herein. 3aIn some embodiments, the bicyclic 7-10 membered heteroaryl is 1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-4-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-benzo[d]imidazol-7-yl, [1,2,4]triazolo[1,5-a]pyridin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin- 3H-imidazo[4,5-b]pyridin-7-yl, [1,2,4]triazolo[1,5-a]pyridin-8-yl, 3H-imidazo[4,5-b]pyridin-2-yl, 3H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl, 3H-imidazo[4,5-b]pyridin-7-yl, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-7-yl, benzo[d]oxazol-2-yl , benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]oxazol-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinoline quinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl, 1,8-naphthyridin-2-yl, 1,8-naphthyridin-3-yl, 1,8-naphthyridin-4-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, quinoxalin-6-yl-2,3-d2, 1H-indol-2-yl, 1H-benzo[d]imidazol-2-yl, 1-methyl-1H-benzo[d]imidazol-6-yl, 3H-imidazo[4,5-b]pyridin-2-yl, 4,5 ,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-b]pyridin-5-yl, thiazolo[5,4-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-7-yl, thiazolo[4 ,5-b]pyridin-2-yl, thiazolo[4,5-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-6-yl, thiazolo[4,5-b]pyridin-7-yl, thieno[2,3-b]pyridin-2-yl, thieno[2,3-b]pyridin-3-yl, thieno[2,3-b]pyridin-4-yl, thieno[2,3-b]pyridin-5-yl, thieno[2,3-b]pyridin-2-yl thieno[2,3-b]pyridin-6-yl, thieno[3,2-b]pyridin-2-yl, thieno[3,2-b]pyridin-3-yl, thieno[3,2-b]pyridin-5-yl, thieno[3,2-b]pyridin-6-yl, thieno[3,2-b]pyridin-7-yl, each of which is unsubstituted or contains one, two, or three R, as disclosed herein. 3a is replaced by .

[0137] In some embodiments, Cy 1 is a quinoxaline group, for example, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl, preferably quinoxalin-6-yl, which is unsubstituted or substituted with one, two, or three R 3a is substituted with R 3a is deuterium, alkoxy, alkyl, halogen, R 3b -SO2-, cycloalkyl, cyano, R 3b -C(O)-N(R 3c )-, N(R3b R 3c )-C(O)-, N(R 3b R 3c ), R 3b -OC(O)- or heterocyclyl, wherein the alkyl portion of the alkyl or alkoxy is unsubstituted or substituted with a halogen, alkoxy, hydroxy or cyano group, and the cycloalkyl or heterocyclyl is unsubstituted or substituted with an alkoxy, alkyl, halogen or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl, preferably R 3a is deuterium, alkoxy, halogen-substituted alkoxy, alkoxyalkyl-, alkyl, halogen-substituted alkyl, halogen, R 3b -SO2-, cycloalkyl, hydroxyalkyl-, cyano, R 3b -C(O)-N(R 3c )-, cyano-substituted alkyl, N(R 3b R 3c )-C(O)-, N(R 3b R 3c )-, R 3b -OC(O)- or heterocyclyl, wherein said cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl, and more preferably R 3ais selected from deuterium, fluorine, bromine, chlorine, methyl, difluoromethyl, trifluoromethoxy, methoxy, methoxymethyl, trifluoromethyl, methylsulfonyl, difluoro, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl, 1-hydroxyethyl, ethyl, 1,1-difluoroethyl, cyano, dimethoxy, dichloro, cyclopropyl-, acetamido, 1-methoxyethyl, cyanomethyl, carbamoyl, methoxycarbonyl, dimethylcarbamoyl, (difluoromethoxy)methyl, amino, 1-(difluoromethoxy)ethyl, azetidin-1-yl, 2-methoxypropan-2-yl, 1-methoxycyclopropyl, oxetan-3-yl, 1-methylazetidin-3-yl or 1-hydroxyazetidin-3-yl.

[0138] In some embodiments, Cy 1 is quinoxalin-6-yl, which is unsubstituted or contains one, two, or three R 3a is substituted with R 3a is deuterium, methyl, ethyl, isopropyl, cyanomethyl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, difluoromethyl, trifluoromethyl, 2-fluoropropan-2-yl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl, or cyclobutyl, preferably deuterium, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, or cyclopropyl. In some embodiments, Cy 1 is quinoxalin-6-yl or 3-methyl-quinoxalin-6-yl.

[0139] In some embodiments, Cy 1is benzo[d]thiazol-5-yl or benzo[d]thiazol-6-yl, each of which is unsubstituted or contains one, two, or three R 3a is substituted with R 3a is deuterium, methyl, ethyl, isopropyl, cyanomethyl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, difluoromethyl, trifluoromethyl, 2-fluoropropan-2-yl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl or cyclobutyl, preferably deuterium, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino or cyclopropyl.

[0140] In some embodiments, Cy 1 is thiazolo[5,4-b]pyridin-5-yl, thiazolo[5,4-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-7-yl, thiazolo[4,5-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-6-yl, thiazolo[4,5-b]pyridin-7-yl, each of which is unsubstituted or contains one, two, or three R 3a is substituted with R 3ais deuterium, methyl, ethyl, isopropyl, cyanomethyl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, difluoromethyl, trifluoromethyl, 2-fluoropropan-2-yl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl or cyclobutyl, preferably deuterium, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino or cyclopropyl.

[0141] In some embodiments, Cy 1 is thieno[2,3-b]pyridin-6-yl or thieno[3,2-b]pyridin-5-yl, each of which is unsubstituted or contains one, two, or three R 3a is substituted with R 3a is deuterium, methyl, ethyl, isopropyl, cyanomethyl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, difluoromethyl, trifluoromethyl, 2-fluoropropan-2-yl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl or cyclobutyl, preferably deuterium, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino or cyclopropyl.

[0142] In some embodiments, Cy 1 teeth, -phenyl, 2-(trifluoromethoxy)phenyl, 2-methoxyphenyl, 2-(methoxymethyl)phenyl, 2-(trifluoromethyl)phenyl, 4-fluoro-2-(methoxymethyl)phenyl, 4-fluoro-2-methoxyphenyl, 4-fluoro-2-methylphenyl, 2-bromo-4-fluorophenyl, 4-fluoro-2-(methylsulfonyl)phenyl, 4-methyl-2-(trifluoromethyl)phenyl, 2-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2-ethoxy-4-fluorophenyl, 4-fluoro-2-isopropoxyphenyl, 4-fluoro-2-(trifluoromethoxy)phenyl, 2-(difluoromethoxy)-4-fluorophenyl, 2-(difluoromethyl)-4-fluorophenyl, 2-cyclopropyl-4-fluorophenyl, 4-fluoro-2-(1-hydroxyethyl)phenyl, 4-cyclopropyl-2-methoxyphenyl, 2-ethyl-4-fluorophenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 2-methoxy-4-fluorophenyl fluorophenyl, 2-(1,1-difluoroethyl)-4-fluorophenyl, 2-cyano-4-fluorophenyl, 4-fluoro-3-(methoxymethyl)phenyl, 3-methyl-2-(trifluoromethyl)phenyl, 4-fluoro-2,6-dimethoxyphenyl, 2,4-difluoro-6-methoxyphenyl, 2,6-dichloro-4-fluorophenyl, 4-cyclopropylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-cyclopropylphenyl, 4-(trifluoromethyl)phenyl, 4-methylphenyl, 4-(difluoromethyl)phenyl, 4-isopropoxyphenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 4-cyclopropyl-2-fluorophenyl, 3-methoxy-4-(trifluoromethyl)phenyl, 4-fluoro-3-methoxyphenyl, 2,6-difluorophenyl, 4-(trifluoromethoxy)phenyl, 4-acetylaminophenyl, 4-fluoro-2-(1-methoxyethyl)phenyl, 2-(cyanomethyl)-4-fluorophenyl, 3,4-Difluoro-2-(trifluoromethyl)phenyl, 2-carbamoyl-4-fluorophenyl, 2-methoxycarbonyl-4-fluorophenyl, 2-(dimethylcarbamoyl)-4-fluorophenyl, 2-((difluoromethoxy)methyl)-4-fluorophenyl, 2-(1-(difluoromethoxy)ethyl)-4-fluorophenyl, 2-(azetidin-1-yl)-4-fluorophenyl, 4-fluoro-2-(2-methoxypropan-2-yl)phenyl, 3-(trifluoromethyl) phenyl, 4-fluoro-2-(1-methoxycyclopropyl)phenyl, 4-fluoro-2-(oxiran-2-yl)phenyl, 4-fluoro-2-(1-methylazetidin-3-yl)phenyl, 4-fluoro-2-(1-hydroxyazetidin-3-yl)phenyl, 4-cyclopropyl-2-methoxyphenyl, 2-ethyl-4-fluorophenyl, 2,6-difluoro-4-methoxyphenyl, 2,5-difluoro-4-methoxyphenyl, or naphthalen-2-yl, or -benzo[d][1,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-difluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,2-difluorobenzo[d][1,3]dioxan-4-yl, 2,2-dimethylbenzo[d][1,3]dioxol-4-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl or [ka] or tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, 1,4-dioxin-2-yl, 1,4-dioxin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-2-yl, piperazin-3-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl or 1,2-dihydropyridin-6-yl, or -chroman-2-yl, chroman-3-yl or chroman-4-yl, or -1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1-ethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, 5-ethyl-1-methyl-1H-pyrazol-4-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl , pyrimidin-5-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 3-methoxypyridin-2-yl, 6-isopropoxypyridin-3-yl, 2-methoxypyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 6-(difluoromethoxy)pyridin-3-yl, 3-methoxy Pyridin-4-yl, 3-(trifluoromethyl)pyridin-4-yl, 5-fluoro-3-(trifluoromethyl)pyridin-2-yl, 5-chloro-1-ethyl-1H-imidazol-2-yl, 1-ethyl-2-(trifluoromethyl)-1H-imidazol-5-yl, 1-ethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, 5-ethyl-1-methyl-1H-pyrazol-4-yl, 1-methyl-5-(trifluoro methyl)-1H-pyrazol-4-yl, 5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl, 1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl, 3-chloro-1-ethyl-1H-pyrazol-5-yl, 1-ethyl-4-methyl-1H-pyrazol-5-yl, 5-isopropoxypyridin-2-yl, 6-(trifluoromethyl)pyridin-3-yl, 3,5-difluoropyridin-2-yl, 3,5-Difluoropyridin-4-yl, 1-ethyl-4-cyano-1H-pyrazol-3-yl, 5-fluoropyridin-2-yl, pyrazin-2-yl, 3-(trifluoromethyl)pyridazin-4-yl, 6-cyclopropylpyridin-3-yl, 6-cyclobutylpyridin-3-yl, 6-isopropylpyridin-3-yl, 6-cyanopyridin-3-yl, 6-(2-cyanopropan-2-yl)pyridin-3-yl, 6-(2-hydroxypropan-2-yl)pyridin-3-yl, 6-cyclopropyl-2-fluoropyridin- 3-yl, 6-methoxypyridin-3-yl, 6-(2-fluoropropan-2-yl)pyridin-3-yl, 5-methoxypyridin-2-yl, 5-cyclopropylpyridin-2-yl, 6-(2,2-difluorocyclopropyl)pyridin-3-yl, 5-(difluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, 6-(1-fluorocyclopropyl)pyridin-3-yl, 6-(2-fluorocyclopropyl)pyridin-3-yl or 2-cyclopropylpyrimidin-5-yl, or -1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-4-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-benzo[d]imidazol-7-yl, [1,2,4]triazolo[1,5-a]pyridin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin ... 3H-imidazo[4,5-b]pyridin-7-yl, [1,2,4]triazolo[1,5-a]pyridin-8-yl, 3H-imidazo[4,5-b]pyridin-2-yl, 3H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl, 3H-imidazo[4,5-b]pyridin-7-yl, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-7-yl, benzo[d]oxazol-2-yl, benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]oxazol-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, 2-methylbenzo[d] Thiazol-6-yl, 5-fluorobenzo[d]thiazol-6-yl, 5-fluoro-2-methylbenzo[d]thiazol-6-yl, 6-fluoro-2-methylbenzo[d]thiazol-5-yl, 7-fluorobenzo[d]thiazol-6-yl, 7-fluoro-2-methylbenzo[d]thiazol-6-yl, 4-fluorobenzo[d]thiazol-5-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl, 1,8-naphthalene Phthyridin-2-yl, 1,8-naphthyridin-3-yl, 1,8-naphthyridin-4-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, 3-methylquinoxalin-6-yl, 3-methoxyquinoxalin-6-yl, quinoxalin-6-yl-2,3-d2, 1-ethyl-1H-indol-2-yl, 1-methyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-ethyl-6-(trifluoromethyl)-1H- benzo[d]imidazol-2-yl, 1-ethyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-methyl-1H-benzo[d]imidazol-6-yl, 3-ethyl-3H-imidazo[4,5-b]pyridin-2-yl, 1-ethyl-1H-imidazo[4,5-b]pyridin-2-yl, 3-cyclopropylquinoxalin-6-yl, -3-aminoquinoxalin-6-yl, 3-trifluoromethylquinoxalin-6-yl, 3-bisfluoromethylquinoxalin-6-yl, 3-(1,1-bisfluoroethyl)quinoxalin-6-yl, 2-deuterated-3-methylquinoxalin-6-yl, 2-deuterated-3-methoxyquinoxalin-6-yl, 3-methyl-5-methoxyquinoxalin-6-yl, 3-methyl-7-methoxyquinoxalin-6-yl, 3-methyl-5-trifluoromethylquinoxalin-6-yl, 3-methyl-7-trifluoromethylquinoxalin-6-yl, 1-ethyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine- 6-yl, 2,3-dimethyl-quinoxalin-6-yl, 3-ethyl-quinoxalin-6-yl, 3-chloro-quinoxalin-6-yl, 4-methoxy-quinoxalin-6-yl, 3-(difluoromethyl)quinoxalin-6-yl, 3-(1,1-difluoroethyl)quinoxalin-6-yl or 3-cyclopropyl-quinoxalin-6-yl, or cyclobutyl, cyclopentyl, cyclohexyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl or 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl, or -thiazolo[5,4-b]pyridin-5-yl, 2-methylthiazolo[5,4-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-5-yl, 2-methylthiazolo[4,5-b]pyridin-5-yl, thieno[2,3-b]pyridin-6-yl, 2-methylthieno[2,3-b]pyridin-6-yl, 2-methylthieno[3,2-b]pyridin-5-yl, 2-fluorothieno[3,2-b]pyridin-5-yl or 2-fluorothieno[2,3-b]pyridin-6-yl.

[0143] In some embodiments, Cy 1is 2-(trifluoromethoxy)phenyl, 2-methoxyphenyl, 2-(methoxymethyl)phenyl, 2-(trifluoromethyl)phenyl, 4-fluoro-2-(methoxymethyl)phenyl, 4-fluoro-2-methoxyphenyl, 4-fluoro-2-(methoxymethyl)phenyl, 4-fluoro-2-methylphenyl, 2-bromo-4-fluorophenyl, 4-fluoro-2-(methylsulfonyl)phenyl, 4-methyl-2-(trifluoromethyl)phenyl, 2-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2-ethoxy-4-fluorophenyl, 4-fluoro-2-isopropoxyphenyl, 4-fluoro-2-(trifluoromethoxy)phenyl, 2-(difluoromethoxy)-4-fluorophenyl, 2-(difluoromethoxy)-4-fluorophenyl nyl, 2-cyclopropyl-4-fluorophenyl, 4-fluoro-2-(1-hydroxyethyl)phenyl, 4-cyclopropyl-2-methoxyphenyl, 2-ethyl-4-fluorophenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 2-methoxy-4-fluorophenyl, 2-(1,1-difluoroethyl)-4-fluorophenyl, 4-fluoro-3-(methoxymethyl)phenyl, 3-methyl-2-(trifluoromethyl)phenyl, 4-fluoro-2,6-dimethoxyphenyl, 2,4-difluoro-6-methoxyphenyl, 2,6-dichloro-4-fluorophenyl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 3-methoxypyridin-2-yl, 2-methoxypyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 6-(difluoromethoxy)pyridin-3-yl, 3-methoxypyridin-4-yl, 5-fluoro-3-(trifluoromethyl)pyridin-2-yl, 5-chloro-1-ethyl-1H-imidazol-2-yl, 1-ethyl-2-(trifluoromethyl)-1H-imidazole -5-yl, 1-ethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, 5-ethyl-1-methyl-1H-pyrazol-4-yl, 1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, 5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl, 1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl, 3-chloro-1-ethyl-1H-pyrazol-5-yl, 1- Ethyl-4-methyl-1H-pyrazol-5-yl, quinolin-3-yl, quinolin-2-yl, quinoxalin-6-yl, 3-methylquinoxalin-6-yl, 3-methylquinoxalin-6-yl, 3-methylquinoxalin-6-yl, 3-cyclopropylquinoxalin-6-yl, 3-aminoquinoxalin-6-yl, 3-trifluoromethylquinoxalin-6-yl, 3-bisfluoromethylquinoxalin-6-yl, 3- (1,1-bisfluoroethyl)quinoxalin-6-yl, 2-deuterated-3-methylquinoxalin-6-yl, 2-deuterated-3-methoxyquinoxalin-6-yl, 3-methyl-5-methoxyquinoxalin-6-yl, 3-methyl-7-methoxyquinoxalin-6-yl, 3-methyl-5-trifluoromethylquinoxalin-6-yl, 3-methyl-7-trifluoromethylquinoxalin-6-yl, quinoxalin-6-yl-2,3-d2, 1-ethyl-1H-indol-2-yl, 1-methyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-ethyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-methyl-1H-benzo[d]imidazol quinoxalin-6-yl, 3-ethyl-3H-imidazo[4,5-b]pyridin-2-yl, 1-ethyl-1H-imidazo[4,5-b]pyridin-2-yl, 1-ethyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl, 3-methoxyquinoxalin-6-yl, 3-(trifluoromethyl)pyridin-4-yl, 4-cyclopropylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-cyclopropylphenyl, 4-(trifluoromethyl)phenyl, 4-methylphenyl, 4-(difluoromethyl)phenyl , 4-isopropoxyphenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 4-cyclopropyl-2-fluorophenyl, 2,4-difluorophenyl, 4-cyclopropyl-2-fluorophenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 3-methoxy-4-(trifluoromethyl)phenyl, 4-fluoro-3-methoxyphenyl, 2,6-difluorophenyl, 2,6-difluoro-4-methoxyphenyl, 2,5-difluoro-4-methoxyphenyl, naphthalen-2-yl, 3,4-dihydro-2H-benzo[ b][1,4]oxazin-6-yl, chroman-4-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 2,3-dihydro-1H-inden-1-yl, 5-isopropoxypyridin-2-yl, 6-isopropoxypyridin-3-yl, 6-(trifluoromethyl)pyridin-3-yl, 3,5-difluoropyridin-2-yl, 3,5-difluoropyridin-4-yl, 1-ethyl-4-cyano-1H-pyrazol-3-yl, quinolin-2-yl, isoquinolin-3-yl, isoquinolin-6-yl, isoquinolin-7-yl, 1,8-naphthyridin-2-yl, quinoxalin-6-yl, quinoxalin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-3-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, 2-methylbenzo[d]thiazol-6-yl, 2-fluorobenzo[d]thiazol-6-yl, 2-bromobenzo[d]thiazol-6-yl, 2-chlorobenzo[d]thiazol-6-yl, 5-methylbenzo[d]thiazol-6-yl, 5-fluorobenzo[d]thiazol-6-yl, 5-bromobenzo[d]thiazol-6-yl, 5-chlorobenzo[d]thiazol-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 4-(trifluoromethoxy)phenyl, 4-fluorophenyl, 4-acetylaminophenyl, 2-fluoro-4-(trifluoromethyl)phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 5-fluoropyridin-2-yl, pyrazin-2-yl, pyrimidin-2-yl, quinolin-7-yl, isoquinolin-7-yl, quinoxalin-6-yl, quinolin-6-yl, quinolin-7-yl, or pyrimidin-4-yl.

[0144] In some embodiments, Cy 1 is 4-fluoro-2-(trifluoromethyl)phenyl or 2-fluoro-4-(trifluoromethyl)phenyl.

[0145] Second aspect

[0146] In some embodiments, the compound of Formula (I) is a compound of Formula (V): [ka] wherein the variables are as defined herein.

[0147] In some embodiments, R 1is methyl, methyl-d3, ethyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, or cyclopropylmethyl. 1 is hydrogen, methyl, ethyl, or methyl-d3. In some embodiments, R 1 is methyl or methyl-d3. In some embodiments, R 1 is methyl.

[0148] In some embodiments, R 5 is hydrogen, CN—CH—, —CHC(O)—OMe, —CH(CH)CN, oxiran-2-ylmethyl-, prop-2-yn-1-yl, but-2-yn-1-yl, prop-1-en-2-yl, —CH—OH, —CH(CH)CN, —CH—O—CH, —CH(CH)—O—CH, —CH—N(CH), —CH═NO—CH, —CH—S(═O)—CH, —CH—S(═O)—CH, or —CH—S(═O)(═NH)—CH. In some embodiments, R 5 is CN—CH—, prop-2-yn-1-yl, but-2-yn-1-yl, or prop-1-en-2-yl, —CH—OH, —CH(CH)CN, —CH—O—CH, —CH(CH)—O—CH, —CH—N(CH), —CH═NO—CH, —CH—S(═O)—CH, —CH—S(═O)—CH, or —CH—S(═O)(═NH)—CH. In some embodiments, R 5 is CN—CH—, —CH—OH, —CH(CH)CN, —CH—O—CH, —CH(CH)—O—CH, —CH—N(CH), —CH═NO—CH, —CH—S(═O)—CH, —CH—S(═O)—CH, or —CH—S(═O)(═NH)—CH. In some embodiments, R 5 is CN-CH2-.

[0149] In some embodiments, R 7 is methyl and R9 is methyl. In some embodiments, R 7 is ethyl and R 9 is ethyl. In some embodiments, R 7 is methyl and R 9 is ethyl. In some embodiments, R 7 is ethyl and R 9 is methyl.

[0150] In some embodiments, L 1 is —CH— or —CH(CH)—. In some embodiments, L 1 is -CH(CH3)-.

[0151] In some embodiments, Cy 1 is unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted heteroaryl. In some embodiments, Cy 1 optionally one, two, or three substituents R 3a is substituted with R 3a is selected from deuterium, fluorine, bromine, chlorine, methyl, difluoromethyl, trifluoromethoxy, methoxy, methoxymethyl, trifluoromethyl, methylsulfonyl, difluoro, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl, 1-hydroxyethyl, ethyl, 1,1-difluoroethyl, cyano, dimethoxy, dichloro, cyclopropyl-, acetamido, 1-methoxyethyl, cyanomethyl, carbamoyl, methoxycarbonyl, dimethylcarbamoyl, (difluoromethoxy)methyl, amino, 1-(difluoromethoxy)ethyl, azetidin-1-yl, 2-methoxypropan-2-yl, 1-methoxycyclopropyl, oxetan-3-yl, 1-methylazetidin-3-yl or 1-hydroxyazetidin-3-yl.

[0152] In some embodiments, Cy 1is an aryl of 6 to 14 carbon atoms having a single ring or multiple condensed rings, which is unsubstituted or contains one, two, or three R 3a In some embodiments, the aromatic carbocyclic group is phenyl, naphthyl or anthryl, indanyl or tetrahydronaphthyl, which is unsubstituted or substituted with one, two, or three R 3a is replaced by .

[0153] In some embodiments, Cy 1 is phenyl. In some embodiments, Cy 1 is phenyl, which at the 4-position is R 3a and optionally, at another position, R 3a is replaced by .

[0154] In some embodiments, Cy 1 is naphthyl. In some embodiments, Cy 1 are naphthalen-1-yl, naphthalen-2-yl, naphthalen-3-yl, and naphthalen-4-yl.

[0155] In some embodiments, Cy 1 is benzo[d][1,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-difluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 2,2-dimethylbenzo[d][1,3]dioxol-4-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl or [ka] is.

[0156] In some embodiments, Cy 1 is a monocyclic 5- to 9-membered heterocyclyl or a bicyclic 7- to 10-membered heterocyclyl that is unsubstituted or contains one, two, or three R 3a is substituted with R 3a is deuterium, alkoxy, alkyl, halogen, R 3b -SO2-, cycloalkyl, cyano, R 3b -C(O)-N(R 3c )-, N(R 3b R 3c )-C(O)-, N(R 3b R 3c ), R 3b -OC(O)- or heterocyclyl, wherein the alkyl portion of the alkyl or alkoxy is unsubstituted or substituted with halogen, alkoxy, hydroxy or cyano, and the cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl, and preferably R 3a is alkoxy, alkoxy substituted with halogen, alkoxyalkyl-, alkyl, halogen-substituted alkyl, halogen, R 3b -SO2-, cycloalkyl, hydroxyalkyl-, cyano, R 3b -C(O)-N(R 3c )-, cyano-substituted alkyl, N(R 3b R 3c )-C(O)-, R 3b -OC(O)- or heterocyclyl, wherein said cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R 3b and R 3care each independently hydrogen or alkyl. In some embodiments, the monocyclic 5- to 9-membered heterocyclyl is tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, piperidinyl, piperazinyl, or dihydropyridinyl, each of which is unsubstituted or contains one, two, or three R as disclosed herein. 3a In some embodiments, Cy is substituted with 1 is tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, 1,4-dioxin-2-yl, 1,4-dioxin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl or 1,2-dihydropyridin-6-yl.

[0157] In some embodiments, Cy 1 is piperidinyl (e.g., piperidin-1-yl) or piperazinyl (e.g., piperazin-4-yl), which is substituted at the 4-position with R 3a and optionally R 3a is replaced by

[0158] In some embodiments, the bicyclic 7- to 10-membered heterocyclyl is a chroman group, preferably chroman-2-yl, chroman-3-yl, or chroman-4-yl.

[0159] In some embodiments, Cy 1 is a monocyclic 5- to 9-membered heteroaryl or a bicyclic 7- to 10-membered heteroaryl that is unsubstituted or contains one, two, or three R 3a is substituted with R 3a is deuterium, alkoxy, alkyl, halogen, R 3b-SO2-, cycloalkyl, cyano, R 3b -C(O)-N(R 3c )-, N(R 3b R 3c )-C(O)-, N(R 3b R 3c ), R 3b -OC(O)- or heterocyclyl, wherein the alkyl portion of the alkyl or alkoxy is unsubstituted or substituted with halogen, alkoxy, hydroxy or cyano, and the cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl, preferably R 3a is deuterium, alkoxy, halogen-substituted alkoxy, alkoxyalkyl-, alkyl, halogen-substituted alkyl, halogen, R 3b -SO2-, cycloalkyl, hydroxyalkyl-, cyano group, R 3b -C(O)-N(R 3c )-, cyano-substituted alkyl, N(R 3b R 3c )-C(O)-, N(R 3b R 3c )-, R 3b -OC(O)- or heterocyclyl, wherein said cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl, and more preferably R 3ais selected from deuterium, fluorine, bromine, chlorine, methyl, difluoromethyl, trifluoromethoxy, methoxy, methoxymethyl, trifluoromethyl, methylsulfonyl, difluoro, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl, 1-hydroxyethyl, ethyl, 1,1-difluoroethyl, cyano, dimethoxy, dichloro, cyclopropyl-, acetamido, 1-methoxyethyl, cyanomethyl, carbamoyl, methoxycarbonyl, dimethylcarbamoyl, (difluoromethoxy)methyl, amino, 1-(difluoromethoxy)ethyl, azetidin-1-yl, 2-methoxypropan-2-yl, 1-methoxycyclopropyl, oxetan-3-yl, 1-methylazetidin-3-yl or 1-hydroxyazetidin-3-yl.

[0160] In some embodiments, the monocyclic 5- to 9-membered heteroaryl is pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is unsubstituted or contains 1, 2, or 3 R as disclosed herein. 3a In some embodiments, the monocyclic 5- to 9-membered heteroaryl is 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, pyrazin-2-yl, or pyridazin-4-yl, each of which is unsubstituted or substituted with one, two, or three of R as disclosed herein. 3a is replaced by .

[0161] In some embodiments, the bicyclic 7- to 10-membered heteroaryl is indolyl, benzo[d]imidazolyl, triazolopyridinyl, imidazopyridinyl, benzoxazolyl, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, dioxinopyridinyl, quinoxalinyl, benzo[d]imidazolyl, imidazo[4,5-b]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyridyl, thieno[2,3-b]pyridyl, or thieno[3,2-b]pyridyl, each of which is unsubstituted or contains 1, 2, or 3 R as disclosed herein. 3aIn some embodiments, the bicyclic 7-10 membered heteroaryl is 1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-4-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-benzo[d]imidazol-7-yl, [1,2,4]triazolo[1,5-a]pyridin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin- 3H-imidazo[4,5-b]pyridin-7-yl, [1,2,4]triazolo[1,5-a]pyridin-8-yl, 3H-imidazo[4,5-b]pyridin-2-yl, 3H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl, 3H-imidazo[4,5-b]pyridin-7-yl, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-7-yl, benzo[d]oxazol-2-yl , benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]oxazol-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinoline quinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl, 1,8-naphthyridin-2-yl, 1,8-naphthyridin-3-yl, 1,8-naphthyridin-4-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, quinoxalin-6-yl-2,3-d2, 1H-indol-2-yl, 1H-benzo[d]imidazol-2-yl, 1-methyl-1H-benzo[d]imidazol-6-yl, 3H-imidazo[4,5-b]pyridin-2-yl, 4,5 ,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-b]pyridin-5-yl, thiazolo[5,4-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-7-yl, thiazolo[4 ,5-b]pyridin-2-yl, thiazolo[4,5-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-6-yl, thiazolo[4,5-b]pyridin-7-yl, thieno[2,3-b]pyridin-2-yl, thieno[2,3-b]pyridin-3-yl, thieno[2,3-b]pyridin-4-yl, thieno[2,3-b]pyridin-5-yl, thieno[2,3-b]pyridin-2-yl thieno[2,3-b]pyridin-6-yl, thieno[3,2-b]pyridin-2-yl, thieno[3,2-b]pyridin-3-yl, thieno[3,2-b]pyridin-5-yl, thieno[3,2-b]pyridin-6-yl, thieno[3,2-b]pyridin-7-yl, each of which is unsubstituted or contains one, two, or three R, as disclosed herein. 3a is replaced by .

[0162] In some embodiments, Cy 1 is a quinoxaline group, for example, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl, preferably quinoxalin-6-yl, which is unsubstituted or substituted with one, two, or three R 3a is substituted with R 3a is deuterium, alkoxy, alkyl, halogen, R 3b -SO2-, cycloalkyl, cyano, R 3b -C(O)-N(R 3c )-, N(R3b R 3c )-C(O)-, N(R 3b R 3c ), R 3b -OC(O)- or heterocyclyl, wherein the alkyl portion of the alkyl or alkoxy is unsubstituted or substituted with a halogen, alkoxy, hydroxy or cyano group, and the cycloalkyl or heterocyclyl is unsubstituted or substituted with an alkoxy, alkyl, halogen or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl, preferably R 3a is deuterium, alkoxy, halogen-substituted alkoxy, alkoxyalkyl-, alkyl, halogen-substituted alkyl, halogen, R 3b -SO2-, cycloalkyl, hydroxyalkyl-, cyano, R 3b -C(O)-N(R 3c )-, cyano-substituted alkyl, N(R 3b R 3c )-C(O)-, N(R 3b R 3c )-, R 3b -OC(O)- or heterocyclyl, wherein said cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl, and more preferably R 3ais selected from deuterium, fluorine, bromine, chlorine, methyl, difluoromethyl, trifluoromethoxy, methoxy, methoxymethyl, trifluoromethyl, methylsulfonyl, difluoro, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl, 1-hydroxyethyl, ethyl, 1,1-difluoroethyl, cyano, dimethoxy, dichloro, cyclopropyl-, acetamido, 1-methoxyethyl, cyanomethyl, carbamoyl, methoxycarbonyl, dimethylcarbamoyl, (difluoromethoxy)methyl, amino, 1-(difluoromethoxy)ethyl, azetidin-1-yl, 2-methoxypropan-2-yl, 1-methoxycyclopropyl, oxetan-3-yl, 1-methylazetidin-3-yl or 1-hydroxyazetidin-3-yl.

[0163] In some embodiments, Cy 1 is quinoxalin-6-yl, which is unsubstituted or contains one, two, or three R 3a is substituted with R 3a is deuterium, methyl, ethyl, isopropyl, cyanomethyl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, difluoromethyl, trifluoromethyl, 2-fluoropropan-2-yl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl, or cyclobutyl, preferably deuterium, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, or cyclopropyl. In some embodiments, Cy 1 is quinoxalin-6-yl or 3-methyl-quinoxalin-6-yl.

[0164] In some embodiments, Cy 1is benzo[d]thiazol-5-yl or benzo[d]thiazol-6-yl, each of which is unsubstituted or contains one, two, or three R 3a is substituted with R 3a is deuterium, methyl, ethyl, isopropyl, cyanomethyl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, difluoromethyl, trifluoromethyl, 2-fluoropropan-2-yl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl or cyclobutyl, preferably deuterium, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino or cyclopropyl.

[0165] In some embodiments, Cy 1 is thiazolo[5,4-b]pyridin-5-yl, thiazolo[5,4-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-7-yl, thiazolo[4,5-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-6-yl or thiazolo[4,5-b]pyridin-7-yl, each of which is unsubstituted or contains one, two or three R 3a is substituted with R 3ais deuterium, methyl, ethyl, isopropyl, cyanomethyl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, difluoromethyl, trifluoromethyl, 2-fluoropropan-2-yl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl or cyclobutyl, preferably deuterium, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino or cyclopropyl.

[0166] In some embodiments, Cy 1 is thieno[2,3-b]pyridin-6-yl or thieno[3,2-b]pyridin-5-yl, each of which is unsubstituted or contains one, two, or three R 3a is substituted with R 3a is deuterium, methyl, ethyl, isopropyl, cyanomethyl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, difluoromethyl, trifluoromethyl, 2-fluoropropan-2-yl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl or cyclobutyl, preferably deuterium, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino or cyclopropyl.

[0167] In some embodiments, Cy 1 teeth, -phenyl, 2-(trifluoromethoxy)phenyl, 2-methoxyphenyl, 2-(methoxymethyl)phenyl, 2-(trifluoromethyl)phenyl, 4-fluoro-2-(methoxymethyl)phenyl, 4-fluoro-2-methoxyphenyl, 4-fluoro-2-methylphenyl, 2-bromo-4-fluorophenyl, 4-fluoro-2-(methylsulfonyl)phenyl, 4-methyl-2-(trifluoromethyl)phenyl, 2-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2-ethoxy-4-fluorophenyl, 4-fluoro-2-isopropoxyphenyl, 4-fluoro-2-(trifluoromethoxy)phenyl, 2-(difluoromethoxy)-4-fluorophenyl, 2-(difluoromethyl)-4-fluorophenyl, 2-cyclopropyl-4-fluorophenyl, 4-fluoro-2-(1-hydroxyethyl)phenyl, 4-cyclopropyl-2-methoxyphenyl, 2-ethyl-4-fluorophenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 2-methoxy-4-fluorophenyl fluorophenyl, 2-(1,1-difluoroethyl)-4-fluorophenyl, 2-cyano-4-fluorophenyl, 4-fluoro-3-(methoxymethyl)phenyl, 3-methyl-2-(trifluoromethyl)phenyl, 4-fluoro-2,6-dimethoxyphenyl, 2,4-difluoro-6-methoxyphenyl, 2,6-dichloro-4-fluorophenyl, 4-cyclopropylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-cyclopropylphenyl, 4-(trifluoromethyl)phenyl, 4-methylphenyl, 4-(difluoromethyl)phenyl, 4-isopropoxyphenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 4-cyclopropyl-2-fluorophenyl, 3-methoxy-4-(trifluoromethyl)phenyl, 4-fluoro-3-methoxyphenyl, 2,6-difluorophenyl, 4-(trifluoromethoxy)phenyl, 4-acetylaminophenyl, 4-fluoro-2-(1-methoxyethyl)phenyl, 2-(cyanomethyl)-4-fluorophenyl, 3,4-Difluoro-2-(trifluoromethyl)phenyl, 2-carbamoyl-4-fluorophenyl, 2-methoxycarbonyl-4-fluorophenyl, 2-(dimethylcarbamoyl)-4-fluorophenyl, 2-((difluoromethoxy)methyl)-4-fluorophenyl, 2-(1-(difluoromethoxy)ethyl)-4-fluorophenyl, 2-(azetidin-1-yl)-4-fluorophenyl, 4-fluoro-2-(2-methoxypropan-2-yl)phenyl, 3-(trifluoromethyl)phenyl, 4- fluoro-2-(1-methoxycyclopropyl)phenyl, 4-fluoro-2-(oxiran-2-yl)phenyl, 4-fluoro-2-(1-methylazetidin-3-yl)phenyl, 4-fluoro-2-(1-hydroxyazetidin-3-yl)phenyl, 4-cyclopropyl-2-methoxyphenyl, 2-ethyl-4-fluorophenyl, 2-methoxy-4-fluorophenyl, 2,6-difluoro-4-methoxyphenyl, 2,5-difluoro-4-methoxyphenyl, or naphthalen-2-yl; or -benzo[d][1,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-difluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 2,2-dimethylbenzo[d][1,3]dioxol-4-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl or [ka] or tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, 1,4-dioxin-2-yl, 1,4-dioxin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-2-yl, piperazin-3-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl or 1,2-dihydropyridin-6-yl, or -chroman-2-yl, chroman-3-yl or chroman-4-yl, or -1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1-ethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, 5-ethyl-1-methyl-1H-pyrazol-4-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl , pyrimidin-5-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 3-methoxypyridin-2-yl, 6-isopropoxypyridin-3-yl, 2-methoxypyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 6-(difluoromethoxy)pyridin-3-yl, 3-methoxy Pyridin-4-yl, 3-(trifluoromethyl)pyridin-4-yl, 5-fluoro-3-(trifluoromethyl)pyridin-2-yl, 5-chloro-1-ethyl-1H-imidazol-2-yl, 1-ethyl-2-(trifluoromethyl)-1H-imidazol-5-yl, 1-ethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, 5-ethyl-1-methyl-1H-pyrazol-4-yl, 1-methyl-5-(trifluoro methyl)-1H-pyrazol-4-yl, 5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl, 1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl, 3-chloro-1-ethyl-1H-pyrazol-5-yl, 1-ethyl-4-methyl-1H-pyrazol-5-yl, 5-isopropoxypyridin-2-yl, 6-(trifluoromethyl)pyridin-3-yl, 3,5-difluoropyridin-2-yl, 3,5-Difluoropyridin-4-yl, 1-ethyl-4-cyano-1H-pyrazol-3-yl, 5-fluoropyridin-2-yl, pyrazin-2-yl, 3-(trifluoromethyl)pyridazin-4-yl, 6-cyclopropylpyridin-3-yl, 6-cyclobutylpyridin-3-yl, 6-isopropylpyridin-3-yl, 6-cyanopyridin-3-yl, 6-(2-cyanopropan-2-yl)pyridin-3-yl, 6-(2-hydroxypropan-2-yl)pyridin-3-yl, 6-cyclopropyl-2-fluoropyridin-3-yl pyridin-3-yl, 6-methoxypyridin-3-yl, 6-(2-fluoropropan-2-yl)pyridin-3-yl, 5-methoxypyridin-2-yl, 5-cyclopropylpyridin-2-yl, 6-(2,2-difluorocyclopropyl)pyridin-3-yl, 5-(difluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, 6-(1-fluorocyclopropyl)pyridin-3-yl, 6-(2-fluorocyclopropyl)pyridin-3-yl or 2-cyclopropylpyrimidin-5-yl, or -1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-4-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-benzo[d]imidazol-7-yl, [1,2,4]triazolo[1,5-a]pyridin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-7-yl, [1,2,4]triazolo[1,5-a]pyridin-8 -yl, 3H-imidazo[4,5-b]pyridin-2-yl, 3H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl, 3H-imidazo[4,5-b]pyridin-7-yl, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-7-yl, benzo[d]oxazol-2-yl, benzo[d]oxazol-4-yl, benzo[d]oxazol-5- yl, benzo[d]oxazol-6-yl, benzo[d]oxazol-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl quinolin-7-yl, isoquinolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl, 1,8-naphthyridin-2-yl, 1,8-naphthyridin-3-yl, 1,8-naphthyridin-4-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, 3-methylquinoxalin-6-yl, 3-methoxyquinoxalin-6-yl, quinoxalin-6-yl-2,3-d2, 1-ethyl-1H-indol-2-yl, 1-methyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl 1-ethyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-methyl-1H-benzo[d]imidazol-6-yl, 3-ethyl-3H-imidazo[4,5-b]pyridin-2-yl, 1-ethyl-1H-imidazo[4,5-b]pyridin-2-yl, 3-cyclopropylquinoxalin-6-yl, 3-aminoquinoxalin-6-yl, 3-trifluoromethylquinoxalin-6-yl, 3-bisfluoromethylquinoxalin-6-yl, 3-(1,1-bisfluoroethyl)quinoxalin-6-yl, 2-deuterated quinoxalin-3 -methylquinoxalin-6-yl, 2-deuterated-3-methoxyquinoxalin-6-yl, 3-methyl-5-methoxyquinoxalin-6-yl, 3-methyl-7-methoxyquinoxalin-6-yl, 3-methyl-5-trifluoromethylquinoxalin-6-yl, 3-methyl-7-trifluoromethylquinoxalin-6-yl, 1-ethyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dimethyl-quinoxalin-6-yl, 3-ethyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dimethyl-quinoxalin-6-yl, 3-ethyl -quinoxalin-6-yl, 3-chloro-quinoxalin-6-yl, 4-methoxy-quinoxalin-6-yl, 3-(difluoromethyl)quinoxalin-6-yl, 3-(1,1-difluoroethyl)quinoxalin-6-yl or 3-cyclopropyl-quinoxalin-6-yl, or cyclobutyl, cyclopentyl, cyclohexyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl or 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl.

[0168] In some embodiments, Cy 1are 2-(trifluoromethoxy)phenyl, 2-methoxyphenyl, 2-(methoxymethyl)phenyl, 2-(trifluoromethyl)phenyl, 4-fluoro-2-(methoxymethyl)phenyl, 4-fluoro-2-methoxyphenyl, 4-fluoro-2-(methoxymethyl)phenyl, 4-fluoro-2-methylphenyl, 2-bromo-4-fluorophenyl, 4-fluoro-2-(methylsulfonyl)phenyl, 4-methyl-2-(trifluoromethyl)phenyl, 2-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2-ethoxy-4-fluorophenyl, 4-fluoro-2-isopropoxyphenyl, 4-fluoro-2-(trifluoromethoxy)phenyl, 2-(difluoromethoxy)-4-fluorophenyl, 2-(difluoromethyl)-4-fluorophenyl , 2-cyclopropyl-4-fluorophenyl, 4-fluoro-2-(1-hydroxyethyl)phenyl, 4-cyclopropyl-2-methoxyphenyl, 2-ethyl-4-fluorophenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 2-methoxy-4-fluorophenyl, 2-(1,1-difluoroethyl)-4-fluorophenyl, 4-fluoro-3-(methoxymethyl)phenyl, 3-methyl-2-(trifluoromethyl)phenyl, 4-fluoro-2,6-dimethoxyphenyl, 2,4-difluoro-6-methoxyphenyl, 2,6-dichloro-4-fluorophenyl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 3-methoxypyridin-2-yl, 2-methoxypyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 6-(difluoromethoxy)pyridin-3-yl, 3-methoxypyridin-4-yl, 5-fluoro-3-(trifluoromethyl)pyridin-2-yl, 5-chloro-1-ethyl-1H-imidazol-2-yl, 1-ethyl-2-(trifluoromethyl)-1H-imidazole -5-yl, 1-ethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, 5-ethyl-1-methyl-1H-pyrazol-4-yl, 1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, 5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl, 1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl, 3-chloro-1-ethyl-1H-pyrazol-5-yl, 1- Ethyl-4-methyl-1H-pyrazol-5-yl, quinolin-3-yl, quinolin-2-yl, quinoxalin-6-yl, 3-methylquinoxalin-6-yl, 3-methylquinoxalin-6-yl, 3-methylquinoxalin-6-yl, 3-cyclopropylquinoxalin-6-yl, 3-aminoquinoxalin-6-yl, 3-trifluoromethylquinoxalin-6-yl, 3-bisfluoromethylquinoxalin-6-yl, 3- (1,1-bisfluoroethyl)quinoxalin-6-yl, 2-deuterated-3-methylquinoxalin-6-yl, 2-deuterated-3-methoxyquinoxalin-6-yl, 3-methyl-5-methoxyquinoxalin-6-yl, 3-methyl-7-methoxyquinoxalin-6-yl, 3-methyl-5-trifluoromethylquinoxalin-6-yl, 3-methyl-7-trifluoromethylquinoxalin-6-yl, quinoxalin-6-yl-2,3-d2, 1-ethyl-1H-indol-2-yl, 1-methyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-ethyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-methyl-1H-benzo[d]imidazol quinoxalin-6-yl, 3-ethyl-3H-imidazo[4,5-b]pyridin-2-yl, 1-ethyl-1H-imidazo[4,5-b]pyridin-2-yl, 1-ethyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl, 3-methoxyquinoxalin-6-yl, 3-(trifluoromethyl)pyridin-4-yl, 4-cyclopropylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-cyclopropylphenyl, 4-(trifluoromethyl)phenyl, 4-methylphenyl, 4-(difluoromethyl)phenyl , 4-isopropoxyphenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 4-cyclopropyl-2-fluorophenyl, 2,4-difluorophenyl, 4-cyclopropyl-2-fluorophenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 3-methoxy-4-(trifluoromethyl)phenyl, 4-fluoro-3-methoxyphenyl, 2,6-difluorophenyl, 2,6-difluoro-4-methoxyphenyl, 2,5-difluoro-4-methoxyphenyl, naphthalen-2-yl, 3,4-dihydro-2H-benzo[ b][1,4]oxazin-6-yl, chroman-4-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 2,3-dihydro-1H-inden-1-yl, 5-isopropoxypyridin-2-yl, 6-isopropoxypyridin-3-yl, 6-(trifluoromethyl)pyridin-3-yl, 3,5-difluoropyridin-2-yl, 3,5-difluoropyridin-4-yl, 1-ethyl-4-cyano-1H-pyrazol-3-yl, quinolin-2-yl, isoquinolin-3-yl, isoquinolin-6-yl, isoquinolin-7-yl, 1,8-naphthyridin-2-yl, quinoxalin-6-yl, quinoxalin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-3-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, 2-methylbenzo[d]thiazol-6-yl, 2-fluorobenzo[d]thiazol-6-yl, 2-bromobenzo[d]thiazol-6-yl, 2-chlorobenzo[d]thiazol-6-yl, 5-methylbenzo[d]thiazol-6-yl, 5-fluorobenzo[d]thiazol-6-yl, 5-bromobenzo[d]thiazol-6-yl, 5-chlorobenzo[d]thiazol-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 4-(trifluoromethoxy)phenyl, 4-fluorophenyl, 4-acetylaminophenyl, 2-fluoro-4-(trifluoromethyl)phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 5-fluoropyridin-2-yl, pyrazin-2-yl, pyrimidin-2-yl, quinolin-7-yl, isoquinolin-7-yl, quinoxalin-6-yl, quinolin-6-yl, quinolin-7-yl, or pyrimidin-4-yl.

[0169] In some embodiments, Cy 1 is 4-fluoro-2-(trifluoromethyl)phenyl or 2-fluoro-4-(trifluoromethyl)phenyl.

[0170] Third aspect

[0171] In some embodiments, the compound of Formula (I) is a compound of Formula (VI): [ka] wherein the variables are as defined herein.

[0172] In some embodiments, R 1is methyl, methyl-d3, ethyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, or cyclopropylmethyl. 1 is hydrogen, methyl, ethyl, or methyl-d3. In some embodiments, R 1 is methyl or methyl-d3. In some embodiments, R 1 is methyl.

[0173] In some embodiments, R 5 is hydrogen, CN—CH—, —CHC(O)—OMe, —CH(CH)CN, oxiran-2-ylmethyl-, prop-2-yn-1-yl, but-2-yn-1-yl, prop-1-en-2-yl, —CH—OH, —CH(CH)CN, —CH—O—CH, —CH(CH)—O—CH, —CH—N(CH), —CH═NO—CH, —CH—S(═O)—CH, —CH—S(═O)—CH, or —CH—S(═O)(═NH)—CH. In some embodiments, R 5 is CN—CH—, prop-2-yn-1-yl, but-2-yn-1-yl, or prop-1-en-2-yl, —CH—OH, —CH(CH)CN, —CH—O—CH, —CH(CH)—O—CH, —CH—N(CH), —CH═NO—CH, —CH—S(═O)—CH, —CH—S(═O)—CH, or —CH—S(═O)(═NH)—CH. In some embodiments, R 5 is CN—CH—, —CH—OH, —CH(CH)CN, —CH—O—CH, —CH(CH)—O—CH, —CH—N(CH), —CH═NO—CH, —CH—S(═O)—CH, —CH—S(═O)—CH, or —CH—S(═O)(═NH)—CH. In some embodiments, R 5 is CN-CH2-.

[0174] In some embodiments, R 7 is methyl and R9 is methyl. In some embodiments, R 7 is ethyl and R 9 is ethyl. In some embodiments, R 7 is methyl and R 9 is ethyl. In some embodiments, R 7 is ethyl and R 9 is methyl.

[0175] In some embodiments, L 1 is —CH— or —CH(CH)—. In some embodiments, L 1 is -CH(CH3)-.

[0176] In some embodiments, Cy 1 is unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted heteroaryl. In some embodiments, Cy 1 optionally one, two, or three substituents R 3a is substituted with R 3a is selected from deuterium, fluorine, bromine, chlorine, methyl, difluoromethyl, trifluoromethoxy, methoxy, methoxymethyl, trifluoromethyl, methylsulfonyl, difluoro, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl, 1-hydroxyethyl, ethyl, 1,1-difluoroethyl, cyano, dimethoxy, dichloro, cyclopropyl-, acetamido, 1-methoxyethyl, cyanomethyl, carbamoyl, methoxycarbonyl, dimethylcarbamoyl, (difluoromethoxy)methyl, amino, 1-(difluoromethoxy)ethyl, azetidin-1-yl, 2-methoxypropan-2-yl, 1-methoxycyclopropyl, oxetan-3-yl, 1-methylazetidin-3-yl or 1-hydroxyazetidin-3-yl.

[0177] In some embodiments, Cy 1is an aryl of 6 to 14 carbon atoms having a single ring or multiple condensed rings, which is unsubstituted or contains one, two, or three R 3a In some embodiments, the aromatic carbocyclic group is phenyl, naphthyl or anthryl, indanyl or tetrahydronaphthyl, which is unsubstituted or substituted with one, two, or three R 3a is replaced by .

[0178] In some embodiments, Cy 1 is phenyl. In some embodiments, Cy 1 is phenyl, which at the 4-position is R 3a and optionally, at another position, R 3a is replaced by .

[0179] In some embodiments, Cy 1 is naphthyl. In some embodiments, Cy 1 are naphthalen-1-yl, naphthalen-2-yl, naphthalen-3-yl, and naphthalen-4-yl.

[0180] In some embodiments, Cy 1 is benzo[d][1,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-difluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 2,2-dimethylbenzo[d][1,3]dioxol-4-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl or [ka] is.

[0181] In some embodiments, Cy 1 is a monocyclic 5- to 9-membered heterocyclyl or a bicyclic 7- to 10-membered heterocyclyl that is unsubstituted or contains one, two, or three R 3a is substituted with R 3a is deuterium, alkoxy, alkyl, halogen, R 3b -SO2-, cycloalkyl, cyano, R 3b -C(O)-N(R 3c )-, N(R 3b R 3c )-C(O)-, N(R 3b R 3c ), R 3b -OC(O)- or heterocyclyl, wherein the alkyl portion of the alkyl or alkoxy is unsubstituted or substituted with halogen, alkoxy, hydroxy or cyano, and the cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl, and preferably R 3a is alkoxy, alkoxy substituted with halogen, alkoxyalkyl-, alkyl, halogen-substituted alkyl, halogen, R 3b -SO2-, cycloalkyl, hydroxyalkyl-, cyano, R 3b -C(O)-N(R 3c )-, cyano-substituted alkyl, N(R 3b R 3c )-C(O)-, R 3b -OC(O)- or heterocyclyl, wherein said cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R 3b and R 3care each independently hydrogen or alkyl. In some embodiments, the monocyclic 5- to 9-membered heterocyclyl is tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, piperidinyl, piperazinyl, or dihydropyridinyl, each of which is unsubstituted or contains one, two, or three R as disclosed herein. 3a In some embodiments, Cy is substituted with 1 is tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, 1,4-dioxin-2-yl, 1,4-dioxin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl or 1,2-dihydropyridin-6-yl.

[0182] In some embodiments, Cy 1 is piperidinyl (e.g., piperidin-1-yl) or piperazinyl (e.g., piperazin-4-yl), which is substituted at the 4-position with R 3a and optionally R 3a is replaced by

[0183] In some embodiments, the bicyclic 7- to 10-membered heterocyclyl is a chroman group, preferably chroman-2-yl, chroman-3-yl, or chroman-4-yl.

[0184] In some embodiments, Cy 1 is a monocyclic 5- to 9-membered heteroaryl or a bicyclic 7- to 10-membered heteroaryl that is unsubstituted or contains one, two, or three R 3a is substituted with R 3a is deuterium, alkoxy, alkyl, halogen, R 3b-SO2-, cycloalkyl, cyano, R 3b -C(O)-N(R 3c )-, N(R 3b R 3c )-C(O)-, N(R 3b R 3c ), R 3b -OC(O)- or heterocyclyl, wherein the alkyl portion of the alkyl or alkoxy is unsubstituted or substituted with halogen, alkoxy, hydroxy or cyano, and the cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl, preferably R 3a is deuterium, alkoxy, halogen-substituted alkoxy, alkoxyalkyl-, alkyl, halogen-substituted alkyl, halogen, R 3b -SO2-, cycloalkyl, hydroxyalkyl-, cyano, R 3b -C(O)-N(R 3c )-, cyano-substituted alkyl, N(R 3b R 3c )-C(O)-, N(R 3b R 3c )-, R 3b -OC(O)- or heterocyclyl, wherein said cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl, and more preferably R 3ais selected from deuterium, fluorine, bromine, chlorine, methyl, difluoromethyl, trifluoromethoxy, methoxy, methoxymethyl, trifluoromethyl, methylsulfonyl, difluoro, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl, 1-hydroxyethyl, ethyl, 1,1-difluoroethyl, cyano, dimethoxy, dichloro, cyclopropyl-, acetamido, 1-methoxyethyl, cyanomethyl, carbamoyl, methoxycarbonyl, dimethylcarbamoyl, (difluoromethoxy)methyl, amino, 1-(difluoromethoxy)ethyl, azetidin-1-yl, 2-methoxypropan-2-yl, 1-methoxycyclopropyl, oxetan-3-yl, 1-methylazetidin-3-yl or 1-hydroxyazetidin-3-yl.

[0185] In some embodiments, the monocyclic 5- to 9-membered heteroaryl is pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is unsubstituted or contains 1, 2, or 3 R as disclosed herein. 3a In some embodiments, the monocyclic 5- to 9-membered heteroaryl is 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, pyrazin-2-yl, or pyridazin-4-yl, each of which is unsubstituted or substituted with one, two, or three of R as disclosed herein. 3a is replaced by .

[0186] In some embodiments, the bicyclic 7- to 10-membered heteroaryl is indolyl, benzo[d]imidazolyl, triazolopyridinyl, imidazopyridinyl, benzoxazolyl, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, dioxinopyridinyl, quinoxalinyl, benzo[d]imidazolyl, imidazo[4,5-b]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyridyl, thieno[2,3-b]pyridyl, or thieno[3,2-b]pyridyl, each of which is unsubstituted or contains 1, 2, or 3 R as disclosed herein. 3aIn some embodiments, the bicyclic 7-10 membered heteroaryl is 1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-4-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-benzo[d]imidazol-7-yl, [1,2,4]triazolo[1,5-a]pyridin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin- 3H-imidazo[4,5-b]pyridin-7-yl, [1,2,4]triazolo[1,5-a]pyridin-8-yl, 3H-imidazo[4,5-b]pyridin-2-yl, 3H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl, 3H-imidazo[4,5-b]pyridin-7-yl, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-7-yl, benzo[d]oxazol-2-yl , benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]oxazol-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinoline quinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl, 1,8-naphthyridin-2-yl, 1,8-naphthyridin-3-yl, 1,8-naphthyridin-4-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, quinoxalin-6-yl-2,3-d2, 1H-indol-2-yl, 1H-benzo[d]imidazol-2-yl, 1-methyl-1H-benzo[d]imidazol-6-yl, 3H-imidazo[4,5-b]pyridin-2-yl, 4,5 ,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-b]pyridin-5-yl, thiazolo[5,4-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-7-yl, thiazolo[4 ,5-b]pyridin-2-yl, thiazolo[4,5-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-6-yl, thiazolo[4,5-b]pyridin-7-yl, thieno[2,3-b]pyridin-2-yl, thieno[2,3-b]pyridin-3-yl, thieno[2,3-b]pyridin-4-yl, thieno[2,3-b]pyridin-5-yl, thieno[2,3-b]pyridin-2-yl thieno[2,3-b]pyridin-6-yl, thieno[3,2-b]pyridin-2-yl, thieno[3,2-b]pyridin-3-yl, thieno[3,2-b]pyridin-5-yl, thieno[3,2-b]pyridin-6-yl, thieno[3,2-b]pyridin-7-yl, each of which is unsubstituted or contains one, two, or three R, as disclosed herein. 3a is replaced by .

[0187] In some embodiments, Cy 1 is a quinoxaline group, for example, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl, preferably quinoxalin-6-yl, which is unsubstituted or substituted with one, two, or three R 3a is substituted with R 3a is deuterium, alkoxy, alkyl, halogen, R 3b -SO2-, cycloalkyl, cyano, R 3b -C(O)-N(R 3c )-, N(R3b R 3c )-C(O)-, N(R 3b R 3c ), R 3b -OC(O)- or heterocyclyl, wherein the alkyl portion of the alkyl or alkoxy is unsubstituted or substituted with a halogen, alkoxy, hydroxy or cyano group, and the cycloalkyl or heterocyclyl is unsubstituted or substituted with an alkoxy, alkyl, halogen or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl, preferably R 3a is deuterium, alkoxy, halogen-substituted alkoxy, alkoxyalkyl-, alkyl, halogen-substituted alkyl, halogen, R 3b -SO2-, cycloalkyl, hydroxyalkyl-, cyano, R 3b -C(O)-N(R 3c )-, cyano-substituted alkyl, N(R 3b R 3c )-C(O)-, N(R 3b R 3c )-, R 3b -OC(O)- or heterocyclyl, wherein said cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl, and more preferably R 3ais selected from deuterium, fluorine, bromine, chlorine, methyl, difluoromethyl, trifluoromethoxy, methoxy, methoxymethyl, trifluoromethyl, methylsulfonyl, difluoro, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl, 1-hydroxyethyl, ethyl, 1,1-difluoroethyl, cyano, dimethoxy, dichloro, cyclopropyl-, acetamido, 1-methoxyethyl, cyanomethyl, carbamoyl, methoxycarbonyl, dimethylcarbamoyl, (difluoromethoxy)methyl, amino, 1-(difluoromethoxy)ethyl, azetidin-1-yl, 2-methoxypropan-2-yl, 1-methoxycyclopropyl, oxetan-3-yl, 1-methylazetidin-3-yl or 1-hydroxyazetidin-3-yl.

[0188] In some embodiments, Cy 1 is quinoxalin-6-yl, which is unsubstituted or contains one, two, or three R 3a is substituted with R 3a is deuterium, methyl, ethyl, isopropyl, cyanomethyl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, difluoromethyl, trifluoromethyl, 2-fluoropropan-2-yl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl, or cyclobutyl, preferably deuterium, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, or cyclopropyl. In some embodiments, Cy 1 is quinoxalin-6-yl or 3-methyl-quinoxalin-6-yl.

[0189] In some embodiments, Cy 1is benzo[d]thiazol-5-yl or benzo[d]thiazol-6-yl, each of which is unsubstituted or contains one, two, or three R 3a is substituted with R 3a is deuterium, methyl, ethyl, isopropyl, cyanomethyl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, difluoromethyl, trifluoromethyl, 2-fluoropropan-2-yl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl or cyclobutyl, preferably deuterium, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino or cyclopropyl.

[0190] In some embodiments, Cy 1 is thiazolo[5,4-b]pyridin-5-yl, thiazolo[5,4-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-7-yl, thiazolo[4,5-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-6-yl or thiazolo[4,5-b]pyridin-7-yl, each of which is unsubstituted or contains one, two or three R 3a is substituted with R 3ais deuterium, methyl, ethyl, isopropyl, cyanomethyl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, difluoromethyl, trifluoromethyl, 2-fluoropropan-2-yl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl or cyclobutyl, preferably deuterium, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino or cyclopropyl.

[0191] In some embodiments, Cy 1 is thieno[2,3-b]pyridin-6-yl or thieno[3,2-b]pyridin-5-yl, each of which is unsubstituted or contains one, two, or three R 3a is substituted with R 3a is deuterium, methyl, ethyl, isopropyl, cyanomethyl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, difluoromethyl, trifluoromethyl, 2-fluoropropan-2-yl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl or cyclobutyl, preferably deuterium, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino or cyclopropyl.

[0192] In some embodiments, Cy 1 teeth, -phenyl, 2-(trifluoromethoxy)phenyl, 2-methoxyphenyl, 2-(methoxymethyl)phenyl, 2-(trifluoromethyl)phenyl, 4-fluoro-2-(methoxymethyl)phenyl, 4-fluoro-2-methoxyphenyl, 4-fluoro-2-methylphenyl, 2-bromo-4-fluorophenyl, 4-fluoro-2-(methylsulfonyl)phenyl, 4-methyl-2-(trifluoromethyl)phenyl, 2-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2-ethoxy-4-fluorophenyl, 4-Fluoro-2-isopropoxyphenyl, 4-fluoro-2-(trifluoromethoxy)phenyl, 2-(difluoromethoxy)-4-fluorophenyl, 2-(difluoromethyl)-4-fluorophenyl, 2-cyclopropyl-4-fluorophenyl, 4-fluoro-2-(1-hydroxyethyl)phenyl, 4-cyclopropyl-2-methoxyphenyl, 2-ethyl-4-fluorophenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 2-methoxy-4-fluorophenyl, 2-(1,1-difluoroethyl)- 4-Fluorophenyl, 2-cyano-4-fluorophenyl, 4-fluoro-3-(methoxymethyl)phenyl, 3-methyl-2-(trifluoromethyl)phenyl, 4-fluoro-2,6-dimethoxyphenyl, 2,4-difluoro-6-methoxyphenyl, 2,6-dichloro-4-fluorophenyl, 4-cyclopropylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-cyclopropylphenyl, 4-(trifluoromethyl)phenyl, 4-methylphenyl, 4-(difluoromethyl)phenyl, 4-isopropanol xyphenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 4-cyclopropyl-2-fluorophenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 3-methoxy-4-(trifluoromethyl)phenyl, 4-fluoro-3-methoxyphenyl, 2,6-difluorophenyl, 4-(trifluoromethoxy)phenyl, 4-acetylaminophenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 4-fluoro-2-(1-methoxyethyl)phenyl, 2-(cyanomethyl)-4-fluorophenyl, 3,4-Difluoro-2-(trifluoromethyl)phenyl, 2-carbamoyl-4-fluorophenyl, 2-methoxycarbonyl-4-fluorophenyl, 2-(dimethylcarbamoyl)-4-fluorophenyl, 2-((difluoromethoxy)methyl)-4-fluorophenyl, 2-(1-(difluoromethoxy)ethyl)-4-fluorophenyl, 2-(azetidin-1-yl)-4-fluorophenyl, 4-fluoro-2-(2-methoxypropan-2-yl)phenyl, 3-(trifluoromethyl)phenyl, 4-fluoro-2-(1-methoxycyclopropyl)phenyl nyl, 4-fluoro-2-(oxiran-2-yl)phenyl, 4-fluoro-2-(1-methylazetidin-3-yl)phenyl, 4-fluoro-2-(1-hydroxyazetidin-3-yl)phenyl, 4-cyclopropyl-2-methoxyphenyl, 2-ethyl-4-fluorophenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 2-methoxy-4-fluorophenyl, 2,6-difluoro-4-methoxyphenyl, 2,5-difluoro-4-methoxyphenyl, 3-methoxy-4-(trifluoromethyl)phenyl or naphthalen-2-yl, or -benzo[d][1,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-difluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 2,2-dimethylbenzo[d][1,3]dioxol-4-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl or [ka] or tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, 1,4-dioxin-2-yl, 1,4-dioxin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-2-yl, piperazin-3-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl or 1,2-dihydropyridin-6-yl, or -chroman-2-yl, chroman-3-yl or chroman-4-yl, or -1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1-ethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, 5-ethyl-1-methyl-1H-pyrazol-4-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl , pyrimidin-5-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 3-methoxypyridin-2-yl, 6-isopropoxypyridin-3-yl, 2-methoxypyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 6-(difluoromethoxy)pyridin-3-yl, 3-methoxy Pyridin-4-yl, 3-(trifluoromethyl)pyridin-4-yl, 5-fluoro-3-(trifluoromethyl)pyridin-2-yl, 5-chloro-1-ethyl-1H-imidazol-2-yl, 1-ethyl-2-(trifluoromethyl)-1H-imidazol-5-yl, 1-ethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, 5-ethyl-1-methyl-1H-pyrazol-4-yl, 1-methyl-5-(trifluoro methyl)-1H-pyrazol-4-yl, 5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl, 1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl, 3-chloro-1-ethyl-1H-pyrazol-5-yl, 1-ethyl-4-methyl-1H-pyrazol-5-yl, 5-isopropoxypyridin-2-yl, 6-(trifluoromethyl)pyridin-3-yl, 3,5-difluoropyridin-2-yl, 3,5-Difluoropyridin-4-yl, 1-ethyl-4-cyano-1H-pyrazol-3-yl, 5-fluoropyridin-2-yl, pyrazin-2-yl, 3-(trifluoromethyl)pyridazin-4-yl, 6-cyclopropylpyridin-3-yl, 6-cyclobutylpyridin-3-yl, 6-isopropylpyridin-3-yl, 6-cyanopyridin-3-yl, 6-(2-cyanopropan-2-yl)pyridin-3-yl, 6-(2-hydroxypropan-2-yl)pyridin-3-yl, 6-cyclopropyl-2-fluoropyridine -3-yl, 6-methoxypyridin-3-yl, 6-(2-fluoropropan-2-yl)pyridin-3-yl, 5-methoxypyridin-2-yl, 5-cyclopropylpyridin-2-yl, 6-(2,2-difluorocyclopropyl)pyridin-3-yl, 5-(difluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, 6-(1-fluorocyclopropyl)pyridin-3-yl, 6-(2-fluorocyclopropyl)pyridin-3-yl or 2-cyclopropylpyrimidin-5-yl, or -1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-4-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-benzo[d]imidazol-7-yl, [1,2,4]triazolo[1,5-a]pyridin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-7-yl, [1,2,4]triazolo[1,5-a]pyridin-8 -yl, 3H-imidazo[4,5-b]pyridin-2-yl, 3H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl, 3H-imidazo[4,5-b]pyridin-7-yl, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-7-yl, benzo[d]oxazol-2-yl, benzo[d]oxazol-4-yl, benzo[d]oxazol-5- yl, benzo[d]oxazol-6-yl, benzo[d]oxazol-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl quinolin-7-yl, isoquinolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl, 1,8-naphthyridin-2-yl, 1,8-naphthyridin-3-yl, 1,8-naphthyridin-4-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, 3-methylquinoxalin-6-yl, 3-methoxyquinoxalin-6-yl, quinoxalin-6-yl-2,3-d2, 1-ethyl-1H-indol-2-yl, 1-methyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl , 1-ethyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-methyl-1H-benzo[d]imidazol-6-yl, 3-ethyl-3H-imidazo[4,5-b]pyridin-2-yl, 1-ethyl-1H-imidazo[4,5-b]pyridin-2-yl, 3-cyclopropylquinoxalin-6-yl, 3-aminoquinoxalin-6-yl, 3-trifluoromethylquinoxalin-6-yl, 3-bisfluoromethylquinoxalin-6-yl, 3-(1,1-bisfluoroethyl)quinoxalin-6-yl, 2-deuterated quinoxalin-3- Methylquinoxalin-6-yl, 2-deuterated-3-methoxyquinoxalin-6-yl, 3-methyl-5-methoxyquinoxalin-6-yl, 3-methyl-7-methoxyquinoxalin-6-yl, 3-methyl-5-trifluoromethylquinoxalin-6-yl, 3-methyl-7-trifluoromethylquinoxalin-6-yl, 1-ethyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dimethyl-quinoxalin-6-yl, 3-ethyl- quinoxalin-6-yl, 3-chloro-quinoxalin-6-yl, 4-methoxy-quinoxalin-6-yl, 3-(difluoromethyl)quinoxalin-6-yl, 3-(1,1-difluoroethyl)quinoxalin-6-yl or 3-cyclopropyl-quinoxalin-6-yl, or cyclobutyl, cyclopentyl, cyclohexyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl or 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl.

[0193] In some embodiments, Cy 1are 2-(trifluoromethoxy)phenyl, 2-methoxyphenyl, 2-(methoxymethyl)phenyl, 2-(trifluoromethyl)phenyl, 4-fluoro-2-(methoxymethyl)phenyl, 4-fluoro-2-methoxyphenyl, 4-fluoro-2-(methoxymethyl)phenyl, 4-fluoro-2-methylphenyl, 2-bromo-4-fluorophenyl, 4-fluoro-2-(methylsulfonyl)phenyl, 4-methyl-2-(trifluoromethyl)phenyl, 2-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2-ethoxy-4-fluorophenyl, 4-fluoro-2-isopropoxyphenyl, 4-fluoro-2-(trifluoromethoxy)phenyl, 2-(difluoromethoxy)-4-fluorophenyl, 2-(difluoromethyl)-4-fluorophenyl , 2-cyclopropyl-4-fluorophenyl, 4-fluoro-2-(1-hydroxyethyl)phenyl, 4-cyclopropyl-2-methoxyphenyl, 2-ethyl-4-fluorophenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 2-methoxy-4-fluorophenyl, 2-(1,1-difluoroethyl)-4-fluorophenyl, 4-fluoro-3-(methoxymethyl)phenyl, 3-methyl-2-(trifluoromethyl)phenyl, 4-fluoro-2,6-dimethoxyphenyl, 2,4-difluoro-6-methoxyphenyl, 2,6-dichloro-4-fluorophenyl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 3-methoxypyridin-2-yl, 2-methoxypyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 6-(difluoromethoxy)pyridin-3-yl, 3-methoxypyridin-4-yl, 5-fluoro-3-(trifluoromethyl)pyridin-2-yl, 5-chloro-1-ethyl-1H-imidazol-2-yl, 1-ethyl-2-(trifluoromethyl)-1H-imidazole -5-yl, 1-ethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, 5-ethyl-1-methyl-1H-pyrazol-4-yl, 1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, 5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl, 1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl, 3-chloro-1-ethyl-1H-pyrazol-5-yl, 1- Ethyl-4-methyl-1H-pyrazol-5-yl, quinolin-3-yl, quinolin-2-yl, quinoxalin-6-yl, 3-methylquinoxalin-6-yl, 3-methylquinoxalin-6-yl, 3-methylquinoxalin-6-yl, 3-cyclopropylquinoxalin-6-yl, 3-aminoquinoxalin-6-yl, 3-trifluoromethylquinoxalin-6-yl, 3-bisfluoromethylquinoxalin-6-yl, 3- (1,1-bisfluoroethyl)quinoxalin-6-yl, 2-deuterated-3-methylquinoxalin-6-yl, 2-deuterated-3-methoxyquinoxalin-6-yl, 3-methyl-5-methoxyquinoxalin-6-yl, 3-methyl-7-methoxyquinoxalin-6-yl, 3-methyl-5-trifluoromethylquinoxalin-6-yl, 3-methyl-7-trifluoromethylquinoxalin-6-yl, quinoxalin-6-yl-2,3-d2, 1-ethyl-1H-indol-2-yl, 1-methyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-ethyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-methyl-1H-benzo[d]imidazol quinoxalin-6-yl, 3-ethyl-3H-imidazo[4,5-b]pyridin-2-yl, 1-ethyl-1H-imidazo[4,5-b]pyridin-2-yl, 1-ethyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl, 3-methoxyquinoxalin-6-yl, 3-(trifluoromethyl)pyridin-4-yl, 4-cyclopropylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-cyclopropylphenyl, 4-(trifluoromethyl)phenyl, 4-methylphenyl, 4-(difluoromethyl)phenyl , 4-isopropoxyphenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 4-cyclopropyl-2-fluorophenyl, 2,4-difluorophenyl, 4-cyclopropyl-2-fluorophenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 3-methoxy-4-(trifluoromethyl)phenyl, 4-fluoro-3-methoxyphenyl, 2,6-difluorophenyl, 2,6-difluoro-4-methoxyphenyl, 2,5-difluoro-4-methoxyphenyl, naphthalen-2-yl, 3,4-dihydro-2H-benzo[ b][1,4]oxazin-6-yl, chroman-4-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 2,3-dihydro-1H-inden-1-yl, 5-isopropoxypyridin-2-yl, 6-isopropoxypyridin-3-yl, 6-(trifluoromethyl)pyridin-3-yl, 3,5-difluoropyridin-2-yl, 3,5-difluoropyridin-4-yl, 1-ethyl-4-cyano-1H-pyrazol-3-yl, quinolin-2-yl, isoquinolin-3-yl, isoquinolin-6-yl, isoquinolin-7-yl, 1,8-naphthyridin-2-yl, quinoxalin-6-yl, quinoxalin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-3-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, 2-methylbenzo[d]thiazol-6-yl, 2-fluorobenzo[d]thiazol-6-yl, 2-bromobenzo[d]thiazol-6-yl, 2-chlorobenzo[d]thiazol-6-yl, 5-methylbenzo[d]thiazol-6-yl, 5-fluorobenzo[d]thiazol-6-yl, 5-bromobenzo[d]thiazol-6-yl, 5-chlorobenzo[d]thiazol-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 4-(trifluoromethoxy)phenyl, 4-fluorophenyl, 4-acetylaminophenyl, 2-fluoro-4-(trifluoromethyl)phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 5-fluoropyridin-2-yl, pyrazin-2-yl, pyrimidin-2-yl, quinolin-7-yl, isoquinolin-7-yl, quinoxalin-6-yl, quinolin-6-yl, quinolin-7-yl, or pyrimidin-4-yl.

[0194] In some embodiments, Cy 1 is 4-fluoro-2-(trifluoromethyl)phenyl or 2-fluoro-4-(trifluoromethyl)phenyl.

[0195] Fourth aspect

[0196] In some embodiments, the compound of formula (I) is a compound of formula (VI) as described above.

[0197] In some embodiments, R 1 is methyl, methyl-d3, ethyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, or cyclopropylmethyl.1 is hydrogen, methyl, ethyl, or methyl-d3. In some embodiments, R 1 is methyl or methyl-d3. In some embodiments, R 1 is methyl.

[0198] In some embodiments, R 5 is hydrogen, CN—CH—, —CHC(O)—OMe, —CH(CH)CN, oxiran-2-ylmethyl-, prop-2-yn-1-yl, but-2-yn-1-yl, prop-1-en-2-yl, —CH—OH, —CH(CH)CN, —CH—O—CH, —CH(CH)—O—CH, —CH—N(CH), —CH═NO—CH, —CH—S(═O)—CH, —CH—S(═O)—CH, or —CH—S(═O)(═NH)—CH. In some embodiments, R 5 is CN—CH—, prop-2-yn-1-yl, but-2-yn-1-yl, or prop-1-en-2-yl, —CH—OH, —CH(CH)CN, —CH—O—CH, —CH(CH)—O—CH, —CH—N(CH), —CH═NO—CH, —CH—S(═O)—CH, —CH—S(═O)—CH, or —CH—S(═O)(═NH)—CH. In some embodiments, R 5 is CN—CH—, —CH—OH, —CH(CH)CN, —CH—O—CH, —CH(CH)—O—CH, —CH—N(CH), —CH═NO—CH, —CH—S(═O)—CH, —CH—S(═O)—CH, or —CH—S(═O)(═NH)—CH. In some embodiments, R 5 is CN-CH2-.

[0199] In some embodiments, R 7 is methyl and R 9 is methyl. In some embodiments, R 7 is ethyl and R 9 is ethyl. In some embodiments, R 7is methyl and R 9 is ethyl. In some embodiments, R 7 is ethyl and R 9 is methyl.

[0200] In some embodiments, L 1 is —CH— or —CH(CH)—. In some embodiments, L 1 is -CH(CH3)-.

[0201] In some embodiments, Cy 1are 2-(trifluoromethoxy)phenyl, 2-methoxyphenyl, 2-(methoxymethyl)phenyl, 2-(trifluoromethyl)phenyl, 4-fluoro-2-(methoxymethyl)phenyl, 4-fluoro-2-methoxyphenyl, 4-fluoro-2-(methoxymethyl)phenyl, 4-fluoro-2-methylphenyl, 2-bromo-4-fluorophenyl, 4-fluoro-2-(methylsulfonyl)phenyl, 4-methyl-2-(trifluoromethyl)phenyl, 2-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2-ethoxy-4-fluorophenyl, 4-fluoro-2-isopropoxyphenyl, 4-fluoro-2-(trifluoromethoxy)phenyl, 2-(difluoromethoxy)-4-fluorophenyl, 2-(difluoromethyl)-4-fluorophenyl , 2-cyclopropyl-4-fluorophenyl, 4-fluoro-2-(1-hydroxyethyl)phenyl, 4-cyclopropyl-2-methoxyphenyl, 2-ethyl-4-fluorophenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 2-methoxy-4-fluorophenyl, 2-(1,1-difluoroethyl)-4-fluorophenyl, 4-fluoro-3-(methoxymethyl)phenyl, 3-methyl-2-(trifluoromethyl)phenyl, 4-fluoro-2,6-dimethoxyphenyl, 2,4-difluoro-6-methoxyphenyl, 2,6-dichloro-4-fluorophenyl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 3-methoxypyridin-2-yl, 2-methoxypyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 6-(difluoromethoxy)pyridin-3-yl, 3-methoxypyridin-4-yl, 5-fluoro-3-(trifluoromethyl)pyridin-2-yl, 5-chloro-1-ethyl-1H-imidazol-2-yl, 1-ethyl-2-(trifluoromethyl)-1H-imidazole -5-yl, 1-ethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, 5-ethyl-1-methyl-1H-pyrazol-4-yl, 1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, 5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl, 1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl, 3-chloro-1-ethyl-1H-pyrazol-5-yl, 1- Ethyl-4-methyl-1H-pyrazol-5-yl, quinolin-3-yl, quinolin-2-yl, quinoxalin-6-yl, 3-methylquinoxalin-6-yl, 3-methylquinoxalin-6-yl, 3-methylquinoxalin-6-yl, 3-cyclopropylquinoxalin-6-yl, 3-aminoquinoxalin-6-yl, 3-trifluoromethylquinoxalin-6-yl, 3-bisfluoromethylquinoxalin-6-yl, 3- (1,1-bisfluoroethyl)quinoxalin-6-yl, 2-deuterated-3-methylquinoxalin-6-yl, 2-deuterated-3-methoxyquinoxalin-6-yl, 3-methyl-5-methoxyquinoxalin-6-yl, 3-methyl-7-methoxyquinoxalin-6-yl, 3-methyl-5-trifluoromethylquinoxalin-6-yl, 3-methyl-7-trifluoromethylquinoxalin-6-yl, quinoxalin-6-yl-2,3-d2, 1-ethyl-1H-indol-2-yl, 1-methyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-ethyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-methyl-1H-benzo[d]imidazol quinoxalin-6-yl, 3-ethyl-3H-imidazo[4,5-b]pyridin-2-yl, 1-ethyl-1H-imidazo[4,5-b]pyridin-2-yl, 1-ethyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl, 3-methoxyquinoxalin-6-yl, 3-(trifluoromethyl)pyridin-4-yl, 4-cyclopropylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-cyclopropylphenyl, 4-(trifluoromethyl)phenyl, 4-methylphenyl, 4-(difluoromethyl)phenyl , 4-isopropoxyphenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 4-cyclopropyl-2-fluorophenyl, 2,4-difluorophenyl, 4-cyclopropyl-2-fluorophenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 3-methoxy-4-(trifluoromethyl)phenyl, 4-fluoro-3-methoxyphenyl, 2,6-difluorophenyl, 2,6-difluoro-4-methoxyphenyl, 2,5-difluoro-4-methoxyphenyl, naphthalen-2-yl, 3,4-dihydro-2H-benzo[ b][1,4]oxazin-6-yl, chroman-4-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 2,3-dihydro-1H-inden-1-yl, 5-isopropoxypyridin-2-yl, 6-isopropoxypyridin-3-yl, 6-(trifluoromethyl)pyridin-3-yl, 3,5-difluoropyridin-2-yl, 3,5-difluoropyridin-4-yl, 1-ethyl-4-cyano-1H-pyrazol-3-yl, quinolin-2-yl, isoquinolin-3-yl, isoquinolin-6-yl, isoquinolin-7-yl, 1,8-naphthyridin-2-yl, quinoxalin-6-yl, quinoxalin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-3-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, 2-methylbenzo[d]thiazol-6-yl, 2-fluorobenzo[d]thiazol-6-yl, 2-bromobenzo[d]thiazol-6-yl, 2-chlorobenzo[d]thiazol-6-yl, 5-methylbenzo[d]thiazol-6-yl, 5-fluorobenzo[d]thiazol-6-yl, 5-bromobenzo[d]thiazol-6-yl, 5-chlorobenzo[d]thiazol-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 4-(trifluoromethoxy)phenyl, 4-fluorophenyl, 4-acetylaminophenyl, 2-fluoro-4-(trifluoromethyl)phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 5-fluoropyridin-2-yl, pyrazin-2-yl, pyrimidin-2-yl, quinolin-7-yl, isoquinolin-7-yl, quinoxalin-6-yl, quinolin-6-yl, quinolin-7-yl, or pyrimidin-4-yl.

[0202] In some embodiments, Cy 1 is 4-fluoro-2-(trifluoromethyl)phenyl or 2-fluoro-4-(trifluoromethyl)phenyl.

[0203] Common synthetic forms

[0204] The compounds disclosed herein (including salts thereof) can be prepared using known organic synthesis techniques, and can be synthesized according to any of a number of possible synthetic routes.

[0205] The reactions for preparing the compounds disclosed herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent may be substantially non-reactive with the starting materials, intermediates, or products at the temperature at which the reaction is carried out, for example, at a temperature within the range of room temperature to the boiling point of the solvent. A given reaction can be carried out in one solvent or a mixture of solvents.

[0206] The selection of an appropriate protecting group can be readily determined by one of ordinary skill in the art.

[0207] The reaction can be detected according to any suitable method known in the art, such as NMR, UV, HPLC, LC-MS, and TLC. The compound may be purified by a variety of methods, including HPLC and normal phase silica gel flash column chromatography.

[0208] Chiral analytical HPLC is used for retention time analysis of different chiral examples, and the conditions are divided into the following methods according to the column, mobile phase, and solvent ratio used. Preparation of isochiral examples can be carried out by techniques known to those skilled in the art. The newly formed carbon-nitrogen bond does not assign absolute configuration.

[0209] The compounds disclosed herein can be prepared according to the following Forms I and II.

[0210] Form I [ka]

[0211] In Form I, compound 1 is reacted with ethyl 3-bromo-2-oxopropionate by a cyclization reaction under heating conditions to give compound 2. Compound 2 is reacted with a suitable chiral secondary amine by a nucleophilic aromatic substitution reaction to give compound 3, which is used to give compound 4 by a Pd-catalyzed CO coupling reaction with a suitable Pd catalyst (e.g., Pd2(dba)3) and a ligand (e.g., tBuXPhos) under basic conditions (e.g., K2CO3, Cs2CO3). Compound 4 is then reacted with a suitable R 1 -X to give compound 5. Compound 5 is reduced using a reducing agent (such as NaBH) to give compound 6 in the form of an alcohol. The hydroxyl group of compound 6 is chlorinated by treatment with a chlorinating agent (such as SOCl) to give compound 7. Compound 7 is converted to the corresponding compound 8 by treatment with a cyanating agent such as TMSCN under basic conditions (such as CsCO or nBuNF). Compound 8 is deprotected under acidic conditions (such as a solution of TFA or 4 M HCl in 1,4-dioxane) to give compound 9. Tertiary amine compound 10 is prepared from N-alkylation of secondary amine compound 9 by reductive alkylation with an aldehyde or ketone, or by phosphonium salt-mediated alkylation of the amine with the corresponding alcohol (Florencio Zaragoza and Henrik Stephensen, J. Org. Chem. 2001, 66, 2518-2521). Compound 10 is halogenated with an electrophilic halogenating reagent (NBS, NCS, selectfluor, etc.) to give compound 11 (R 2 is F, Cl or Br). Compound 11 (R 2 where R is Br) can also be obtained by Pd-catalyzed coupling reaction with Zn(CN) and 2,4,6-trimethylboroxine to give compound 12 (R 2 is CN or Me).

[0212] Form II [ka]

[0213] Form II is an alternative route to the target compound with a similar reaction. In Form II, secondary amines and commercially available compounds 1b are N-alkylated by reductive alkylation with aldehydes or ketones, or by phosphonium salt-mediated alkylation of the amine with the corresponding alcohol to prepare tertiary amine compounds 2b (Florencio Zaragoza and Henrik Stephensen, J. Org. Chem. 2001, 66, 2518-2521). Compound 2b is deprotected using acidic conditions (e.g., TFA or 4M HCl in 1,4-dioxane) to give compound 2b'. Compound 2 is reacted with compound 2b' via a nucleophilic aromatic substitution reaction to give compound 3b, which is then used to give compound 4b via a Pd-catalyzed CO coupling reaction with an appropriate Pd catalyst (e.g., Pd2(dba)3) and ligand (e.g., tBuXPhos) under basic conditions (e.g., KOH). Compound 4b is reacted with an appropriate R1-X under basic conditions (such as K2CO3, Cs2CO3, etc.) to give compound 5b. Compound 5b is reduced using a reducing agent (such as NaBH4) to give compound 6b in the form of an alcohol. The hydroxyl group of compound 6b is chlorinated by treatment with a chlorinating agent (such as SOCl2) to give compound 7b. Compound 7b is converted to the corresponding compound 10 by treatment with a cyanating agent (such as TMSCN) under basic conditions (such as Cs2CO3 or nBu4NF).

[0214] Form III [ka]

[0215] In Form III, compound 7c is prepared by oxidizing compound 6 using an oxidizing agent (e.g., a Dess-Martin reagent such as MnO). Compound 7c is condensed with O-methylhydroxylamine hydrochloride under basic conditions (e.g., CHCOONa, KCO) to give compound 8c. Compound 8c is converted to the corresponding target compound using a reaction similar to that described in Scheme I. Compound 7 is alkynylated by a Pd-catalyzed CC coupling reaction using an appropriate Pd catalyst (e.g., Pd(OAc)) and ligand (e.g., X-Phos) under basic conditions (e.g., CsCO) to give compound 8d. Compound 8d is converted to the corresponding target compound using a reaction similar to that described in Scheme I. [Example]

[0216] Example The following examples are intended to be illustrative only and should not be construed as limiting in any way. Experimental methods in the examples described below are conventional unless otherwise specified. Reagents and materials were commercially available unless otherwise specified. All solvents and chemicals used were of analytical grade or chemical purity. All solvents were redistilled before use. All anhydrous solvents were prepared according to standard or reference methods. Silica gel (100-200 mesh) for flash column chromatography and silica gel (GF254) for thin-layer flash column chromatography (TLC) were purchased from Tsingdao Haiyang Chemical Co., Ltd. or Yantai Chemical Co., Ltd., China. Unless otherwise specified, all were eluted with petroleum ether (60-90°C) / ethyl acetate (v / v) and developed with iodine or molybdenum phosphate ethanol solution. All extraction solvents were dried over anhydrous Na2SO4 unless otherwise specified. 1H NMR spectra were recorded on a Bruck-400 nuclear magnetic resonance spectrometer with TMS (tetramethylsilane) as the internal standard. LC / MS data were recorded using an Agilent 1100 high-performance liquid flash column chromatography-ion trap mass spectrometer (LC-MSD trap) equipped with a diode array detector (DAD) detecting at 214 nm and 254 nm and an ion trap (ESI source). All compound names, except for those of the reagents, were generated from ChemDraw®.

[0217] synthesis

[0218] [Table 2]

[0219] [Table 3]

[0220] [Table 4-1] [Table 4-2] [Table 4-3]

[0221] Intermediate 1: 2-(8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile

[0222] Step A: Ethyl 8-bromo-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate [ka] To a stirred solution of 4-bromo-6-chloropyridazin-3-amine (4.16 g, 20 mmol) in DMF (40 mL) is added ethyl 2-bromo-2-oxoacetate (7.8 g, 40 mmol). After the addition, the reaction mixture is stirred overnight under N2. The reaction mixture is poured into ice water (150 mL), stirred for 30 minutes, and filtered. The filter cake is collected and dried to give the title compound (4.5 g, 74%). MS: M / e 304 / 305 (M+1) + .

[0223] Step B: Ethyl 8-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate [ka]

[0224] A mixture of ethyl 8-bromo-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (3.04 g, 10 mmol), tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (2.57 g, 12 mmol), and DIPEA (2.58 g, 20 mmol) in CHCN (40 mL) was stirred at 80 °C overnight. The reaction mixture was poured into HO (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated. The resulting residue was further purified by flash column chromatography to give the title compound (3.87 g, 89%). MS: M / e 438 (M+1). + .

[0225] Step C: 8-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-2-carboxylic acid [ka]

[0226] To a stirred solution of ethyl 8-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (41.4 mg, 0.1 mmol) in 1,4-dioxane (40 mL) was added aqueous KOH (1.48 g, 26.55 mmol, in 10 mL HO), followed by the addition of Pd(dba) (0.4 g, 0.44 mmol) and t-BuXPhos (0.376 g, 0.885 mmol) under N. After the addition, the reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was poured into HO (100 mL) and extracted with EtOAc (50 mL × 2). The combined organic layer was discarded, and the aqueous layer was acidified with aqueous citric acid to pH=3-4, and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated to give the target compound (4.45 g, crude, 100%). MS: M / e 392 (M+1)+.

[0227] Step D: Methyl 8-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-2-carboxylate [ka]

[0228] A mixture of 8-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-2-carboxylic acid (8.85 mmol), MeI (3.77 g, 26.55 mmol), and CsCO (8.6 g, 26.55 mmol) in 1,4-dioxane (50 mL) is stirred at 90 °C for 2 days in a sealed tube. The reaction mixture is poured into HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers are washed with brine, dried over NaSO, and concentrated. The resulting residue is purified by flash column chromatography to give the title compound (2.2 g, 59%).1 H NMR(400 MHz, CDCl3) δ 7.96(s, 1H), 5.88(s, 1H), 4.91(s, 1H), 4.53(s, 1H), 4.35(s, 1H), 3.95(s, 3H), 3.86 - 3.73(m, 4H), 3.66 - 3.41(m, 2H), 1.49(s, 9H), 1.31 - 1.19(m, 6H) ppm. MS: M / e 420(M+1) + .

[0229] Step E: tert-Butyl (2R,5S)-4-(2-(hydroxymethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0230] To a stirred solution of methyl 8-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-2-carboxylate (1.1 g, 2.63 mmol) in EtOH (20 mL) is added NaBH (0.3 g, 7.88 mmol). After the addition, the reaction is stirred at 70 °C for 2 days. The reaction mixture is diluted with HO (20 mL) and extracted with EtOAc (20 mL × 4). The combined organic layers are washed with brine, dried over NaSO, and concentrated to give the title compound (500 mg, 49%). MS: M / e 392 (M+1) + .

[0231] Step F: tert-Butyl (2R,5S)-4-(2-(chloromethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0232] To a stirred solution of tert-butyl (2R,5S)-4-(2-(hydroxymethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (200 mg, 0.512 mmol) in CHCl (10 mL) is added SOCl (122 mg, 1.02 mmol). After the addition, the reaction is stirred for 1 h. The reaction mixture was washed with aqueous NaHCO, brine, dried over NaSO, and concentrated to give the title compound (170 mg, 81%). MS: M / e 410 (M+1). + .

[0233] Step G: tert-Butyl (2R,5S)-4-(2-(cyanomethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0234] A mixture of tert-butyl (2R,5S)-4-(2-(chloromethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (270 mg, 0.66 mmol), TMSCN (130 mg, 1.32 mmol), and CsCO (645 mg, 1.98 mmol) in CHCN (5 mL) is stirred at 70 °C overnight. The reaction mixture was diluted with EtOAc (15 mL), washed with HO, brine, dried over NaSO, concentrated, and purified by flash column chromatography to give the title compound (100 mg, 38%). MS: M / e 401 (M+1). + .

[0235] Step H: 2-(8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0236] To a stirred solution of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (100 mg, 0.24 mmol) in CHCl (5 mL) was added TFA (1 mL). After the addition, the reaction was stirred for 3 h. The reaction mixture was concentrated to give a residue, which was basified with aqueous NaCO and extracted with CHCl (15 mL × 6). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the target compound (70 mg, 94%). MS: M / e 301 (M+1). +

[0237] Intermediate 2: (2R,5S)-1-benzyl-2,5-diethylpiperazine [ka]

[0238] Step A: Methyl (R)-2-(benzylamino)butanoate [ka]

[0239] To a solution of methyl (R)-2-aminobutanoate (100.0 g, 0.85 mol) in CHCN (1000 mL) was added benzyl bromide (146.1 g, 0.85 mol) under N atmosphere at 0 °C. The reaction was stirred overnight at room temperature and concentrated under reduced pressure. The resulting residue was dissolved in EA (1000 mL) and washed with water (1000 mL × 3). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (PE:EA = 10:1) to give the title compound (106 g, 60%). MS: M / e 208 (M+1) + .

[0240] Step B: Methyl (R)-2-((S)-N-benzyl-2-((tert-butoxycarbonyl)amino)butanamido)butanoate [ka]

[0241] To a solution of methyl (R)-2-(benzylamino)butanoate (117.0 g, 0.56 mol), (S)-2-((tert-butoxycarbonyl)amino)butanoic acid (170.5 g, 0.84 mmol), and 4-methylmorpholine (113.1 g, 1.12 mmol) in DCM (2000 mL) at 0 °C, HATU (319.0 g, 0.84 mmol) was added. The reaction was stirred overnight at room temperature, quenched with water, and washed with water (1500 mL × 2). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (PE:EA = 10:1) to give the title compound product (178 g, 80%). MS: M / e 393 (M+1). + .

[0242] Step C: Methyl (R)-2-((S)-2-amino-N-benzylbutanamido)butanoate [ka]

[0243] To a solution of methyl (R)-2-((S)-N-benzyl-2-((tert-butoxycarbonyl)amino)butanamido)butanoate (178 g, 0.45 mol) in 1,4-dioxane (100 mL) was added HCl (400 mL, 4 M in 1,4-dioxane) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 h and concentrated in vacuo to give the crude product (200 g, crude). MS: M / e 293 (M+1). + .

[0244] Step D: (3S,6R)-1-benzyl-3,6-diethylpiperazine-2,5-dione [ka]

[0245] To a solution of methyl (R)-2-((S)-2-amino-N-benzylbutanamido)butanoate (200 g, crude) in EA (1000 mL) is added aqueous NaHCO3 (300 mL) at room temperature. The reaction mixture is stirred at room temperature for an additional 2 h. The organic layer is concentrated under reduced pressure. The resulting residue is triturated with MTBE to give the title compound (61 g, 52% for two steps, ee: 97%). MS: M / e 261 (M+1) + .

[0246] Step E: (2R,5S)-1-benzyl-2,5-diethylpiperazine [ka]

[0247] To a solution of LiAlH4 (26.5 g, 0.69 mol) in THF (1000 mL) is slowly added (3S,6R)-1-benzyl-3,6-diethylpiperazine-2,5-dione (61.0 g, 0.23 mol) in THF (500 mL) at 0 °C. The resulting mixture is stirred at room temperature for 2 h and then at 80 °C overnight. The reaction is slowly quenched with water (27 mL) at 0 °C. 1N aqueous NaOH solution (54 mL) and water (81 mL) are then added sequentially. The resulting mixture is stirred for 2 h. The formed white precipitate is removed by filtration. The filter cake is washed with EA (500 mL). The combined filtrates are evaporated. The resulting residue is dissolved in toluene. The solvent is removed under vacuum to dryness to give the title compound (51 g, 95%). MS: M / e 233 (M+1) + .

[0248] Compound A1: 2-(8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0249] A mixture of 2-(8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (80 mg, 0.27 mmol), 1-(quinoxalin-6-yl)ethan-1-ol (139 mg, 0.8 mmol), (cyanomethyl)trimethylphosphonium iodide (194 mg, 0.8 mmol), and DIPEA (348 mg, 2.7 mmol) in CHCN (4 mL) was stirred at 100 °C for 6 h in a sealed tube. The reaction mixture was diluted with EtOAc (10 mL), washed with brine, dried over NaSO, and concentrated. The resulting residue was purified by preparative TLC (CHCl:MeOH=10:1) to give the title compound A1 (47 mg). Another compound A1 (47 mg) was separated into compound A1a (16 mg) and compound A1b (17 mg) by chiral preparative HPLC. The chiral separation conditions were as follows: [Table 5]

[0250] Compound A1: 1 H NMR(400 MHz, DMSO-d6) δ 8.93(s, 2H), 8.15 - 7.92(m, 3H), 7.87(s, 1H), 5.52(s, 1H), 5.29 - 4.55(m, 1H), 4.04(s, 2H), 3.97 - 3.75(m, 1H), 3.61(s, 3H), 3.58 - 3.50(m, 1H), 3.28(s, 1H), 3.01 - 2.65(m, 2.5H), 2.10(d, J = 12.0 Hz, 0.5H), 1.42-1.31(m, 4.5H), 1.12(s, 3H), 0.97(d, J = 5.8 Hz, 1.5H) ppm. MS: M / e 457(M+1) + .

[0251] Compound A1a (early peak): 1 H NMR(400 MHz, DMSO-d6) δ 8.96-8.91(m, 2H), 8.17 - 7.94(m, 3H), 7.87(s, 1H), 5.52(s, 1H), 5.21(s, 1H), 4.04(s, 2H), 3.98-3.89(m, 1H), 3.61(s, 3H), 3.32-3.23(m, 1.5H), 3.02 - 2.74(m, 3.5H), 1.41-1.29(m, 6H), 1.00-0.94(m, 3H) ppm. MS: M / e 457(M+1) + .

[0252] Compound A1b (later peak): 1 H NMR(400 MHz, DMSO-d6) δ 8.96-8.90(m, 1H), 8.17 - 7.92(m, 3H), 7.87(s, 1H), 5.53(s, 1H), 4.67(s, 1H), 4.04(s, 2H), 3.84-3.76(m, 1H), 3.68 - 3.49(m, 5H), 2.78-2.70(m, 1H), 2.14-2.07(m, 1H), 1.42-1.35(m, 3H), 1.18-1.08(m, 6H) ppm. MS: M / e 457(M+1) + .

[0253] Compound A2: 2-(8-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0254] Step A: 2-(8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0255] A solution of (2R,5S)-4-(2-(cyanomethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-tert-butylcarboxylate (570 mg, 1.43 mmol) and TFA (2 mL) in DCM (10 mL) was stirred at room temperature for 1 h. The reaction was poured into aqueous NaHCO (saturated, 10 mL) and then extracted with organic solvent (DCM:MeOH = 10:1). The organic layer was dried over NaSO and concentrated to dryness to give the title compound (420 mg, 98%), which was used directly in the next step without further purification. MS: M / e 301 (M+1). + .

[0256] Step B: 2-(8-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0257] A solution of 2-(8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (210 mg, 0.70 mmol), 1-(3-methylquinoxalin-6-yl)ethan-1-ol (165 mg, 0.88 mmol), (cyanomethyl)trimethylphosphonium iodide (510 mg, 2.10 mmol) and DIPEA (903 mg, 7 mmol) in MeCN (4 ml) is stirred at 100° C. for 2 days. The reaction is diluted with EA (15 ml) and washed with brine (10 ml). The organic layer is concentrated to dryness. The residue was purified by flash column chromatography to give the title compound A2 (290 mg), which was separated into compound A2a (106 mg) and compound A2b (87 mg) by chiral preparative HPLC. The chiral separation conditions were as follows: [Table 6]

[0258] Compound A2a (early peak): 1 H NMR(400 MHz, DMSO-d6) δ 8.81(s, 1H), 8.02(d, J = 8.6 Hz, 1H), 7.92(s, 1H), 7.88 - 7.81(m, 2H), 5.53(s, 1H), 4.67(s, 1H), 4.03(s, 2H), 3.76(q, J = 6.6 Hz, 1H), 3.61(s, 3H), 3.54(d, J = 12.5 Hz, 2H), 3.31 - 3.27(m, 1H), 2.75-2.70(m, 1H), 2.70(s, 3H), 2.11(d, J = 11.6 Hz, 1H), 1.37(d, J = 6.5 Hz, 3H), 1.12(dd, J = 6.2, 3.8 Hz, 6H) ppm. MS: M / e 471(M+1) + .

[0259] Compound A2b (later peak): 1H NMR(400 MHz, DMSO-d6) δ 8.82(s, 1H), 8.05(d, J = 8.6 Hz, 1H), 7.95(d, J = 1.5 Hz, 1H), 7.89-7.84(m, 2H), 5.52(s, 1H), 5.20(s, 1H), 4.03(s, 2H), 3.89(q, J = 6.5 Hz, 1H), 3.61(s, 3H), 3.31-3.26(m, 2H), 2.95(dd, J = 11.6, 3.7 Hz, 1H), 2.87-2.76(m, 2H), 2.70(s, 3H), 1.33(dd, J = 12.1, 6.5 Hz, 6H), 0.96(d, J = 6.5 Hz, 3H) ppm. MS: M / e 471(M+1) + .

[0260] Compound A3: 8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-(hydroxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0261] Step A: 6-(1-bromoethyl)quinoxaline [ka]

[0262] A stirred solution of 1-(quinoxalin-6-yl)ethan-1-ol (200 mg, 1.15 mmol) in aqueous HBr (5 mL) is stirred at 60 °C for 4 h. The reaction mixture is basified with aqueous NaHCO3 to pH = 8-9 and extracted with EtOAc (20 mL × 3). The combined organic layers are washed with brine, dried over Na2SO4, and concentrated. The resulting residue is purified by flash column chromatography to give the title compound (100 mg, 37%), which solidifies on standing for 2 h. MS: M / e 237 / 239 (M+1) + .

[0263] Step B: 8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-2-(hydroxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0264] To a stirred solution of tert-butyl (2R,5S)-4-(2-(hydroxymethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (39 mg, 0.1 mmol) in CHCl (5 mL) is added TFA (2 mL). The mixture is then stirred for 2 hours. The reaction mixture is concentrated to give the title compound, which is used directly in the next step. MS: M / e 292 (M+1) + .

[0265] Step C: 8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-(hydroxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0266] A mixture of 8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-2-(hydroxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one (crude, 0.1 mmol), DIPEA (39 mg, 0.3 mmol), and 6-(1-bromoethyl)quinoxaline (28 mg, 0.12 mmol) in CHCN (5 mL) is stirred at 70 °C overnight. The reaction mixture is poured into HO (15 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers are washed with brine, dried over NaSO, concentrated, and purified by preparative TLC (CHCl:MeOH = 10:1) to give the title compound. 1H NMR(400 MHz, DMSO-d6) δ 9.03 - 8.96(m, 2H), 8.23 ​​- 7.98(m, 3H), 7.81(s, 1H), 5.54(d, J = 9.6 Hz, 1H), 5.22(s, 1H), 4.52(s, 2H), 4.05 - 3.82(m, 1H), 3.68(s, 3H), 3.65 - 3.55(m, 1H), 3.08 - 2.76(m, 2.5H), 2.16(d, J = 12.8 Hz, 0.5H), 1.51 - 1.33(m, 4.5H), 1.17(s, 3H), 1.05 - 0.98(m, 1.5H) ppm. MS: M / e 448(M+1) + .

[0267] Compound A4: 8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-(methoxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0268] Step A: tert-Butyl (2R,5S)-4-(2-(methoxymethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0269] A mixture of tert-butyl (2R,5S)-4-(2-(chloromethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (41 mg, 0.1 mmol) in MeOH (5 mL) is stirred at 50° C. overnight. The reaction mixture is concentrated to give the title compound, which is used directly in the next step. MS: M / e 406 (M+1). + .

[0270] Step B: 8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-2-(methoxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0271] To a stirred solution of tert-butyl (2R,5S)-4-(2-(methoxymethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (crude, 0.1 mmol) in CHCl (5 mL) is added TFA (2 mL). The mixture is then stirred for 1 h. The reaction mixture is concentrated to give a residue, which is washed with aqueous KCO and extracted with EtOAc (10 mL × 3). The combined organic layers are washed with brine, dried over NaSO, and concentrated to give the title compound (30 mg, 100%). MS: M / e 306 (M+1). + .

[0272] Step C: 8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-(methoxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0273] A mixture of 8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-2-(methoxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one (30 mg, 0.1 mmol), 1-(quinoxalin-6-yl)ethan-1-ol (52.2 mg, 0.3 mmol), (cyanomethyl)trimethylphosphonium iodide (73 mg, 0.3 mmol), and DIPEA (90 mg, 0.7 mmol) in CHCN (3 mL) was stirred at 100 °C for 6 h in a sealed tube. The reaction mixture was diluted with EtOAc (10 mL), washed with brine, dried over NaSO, and concentrated. The resulting residue was purified by preparative TLC (CHCl:MeOH = 10:1) to give the title compound A1 (15 mg). 1 H NMR(400 MHz, DMSO-d6) δ 9.06 - 8.95(m, 2H), 8.22 - 7.98(m, 3H), 7.95(s, 1H), 5.56(d, J = 6.8 Hz, 1H), 4.82 - 4.75(m, 1H), 4.50 - 4.37(m, 3H), 4.03 - 3.81(m, 1H), 3.68(s, 3H), 3.65 - 3.55(m, 1H), 3.35(s, 3H), 3.07 - 2.75(m, 2H), 2.16(d, J = 12 Hz, 1H), 1.51 - 1.34(m, 4.5H), 1.17(s, 3H), 1.02(d, J = 5.6 Hz, 1.5H) ppm. MS: M / e 462(M+1) + .

[0274] Compound A5: 8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-(1-methoxyethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0275] Step A: tert-Butyl (2R,5S)-4-(2-formyl-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0276] To a stirred solution of tert-butyl (2R,5S)-4-(2-(hydroxymethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate in CHCl (10 mL) at room temperature, Dess-Martin periodinane (152 mg, 0.358 mmol) is added. After the addition, the reaction mixture is stirred for 20 minutes. The reaction mixture is quenched with aqueous NaHCO and extracted with CHCl (10 mL × 2). The combined organic layers are washed with brine, dried over NaSO, and concentrated to give the title compound, which is used directly in the next step without further purification. MS: M / e 390 (M+1). + .

[0277] Step B: tert-Butyl (2R,5S)-4-(2-(1-hydroxyethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0278] To a solution of tert-butyl (2R,5S)-4-(2-formyl-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (crude, 0.179 mmol) in anhydrous THF (5 mL) was added MeMgBr (3.0 M, 0.12 mL) at 0 °C. After the addition, the reaction was stirred for 2 h. The mixture was quenched with aqueous NH4Cl and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound (23 mg, 32%). MS: M / e 406 (M+1) + .

[0279] Step C: tert-Butyl (2R,5S)-4-(2-(1-chloroethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0280] To a solution of tert-butyl (2R,5S)-4-(2-(1-hydroxyethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (23 mg, 0.056 mmol) in CHCl (5 mL) was added SOCl (13.5 mg, 0.114 mmol), and the mixture was stirred for 1 h. The reaction mixture was washed with aqueous NaHCO and extracted with CHCl (5 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound, which was used directly in the next step without further purification. MS: M / e 424 (M+1). + .

[0281] Step D: tert-Butyl (2R,5S)-4-(2-(1-methoxyethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0282] A mixture of tert-butyl (2R,5S)-4-(2-(1-chloroethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (crude, 0.056 mmol) in MeOH (5 mL) is stirred at 60° C. overnight. The mixture is concentrated to give the title compound (26 mg, crude), which is used directly in the next step without further purification. MS: M / e 420 (M+1) + .

[0283] Step E: 8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-(1-methoxyethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0284] To a stirred solution of tert-butyl (2R,5S)-4-(2-(1-methoxyethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (26 mg, 0.056 mmol) in CHCl (5 mL) is added TFA (2 mL). The mixture is then stirred for 2 h. The mixture is concentrated to give a residue, which is washed with aqueous NaHCO and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the de-Boc intermediate, which was dissolved in CH3CN (3 mL) and added with 1-(quinoxalin-6-yl)ethan-1-ol (29.2 mg, 0.168 mmol), (cyanomethyl)trimethylphosphonium iodide (40.8 mg, 0.168 mmol), and DIPEA (90 mg, 0.7 mmol). After the addition, the mixture was stirred in a sealed tube at 100 °C overnight. The reaction mixture was diluted with EtOAc (10 mL), washed with brine, dried over Na2SO4, and concentrated. The resulting residue was purified by preparative TLC (CH2Cl2:MeOH = 10:1) to give the title compound (2 mg). 1 H NMR(400 MHz, DMSO-d6) δ 8.93(s, 2H), 8.15 - 7.92(m, 3H), 7.83(d, J = 15.2 Hz, 1H), 5.48(s, 1H), 4.42-4.31(m, 1H), 3.98 - 3.76(m, 1H), 3.62(s, 3H), 3.60 - 3.48(m, 1H), 3.26 - 3.15(m, 3H), 3.01 - 2.64(m, 3H), 2.19 - 1.94(m, 2H), 1.51 - 1.30(m, 8H), 1.13(s, 3H), 1.01 - 0.93(m, 1H) ppm. MS: M / e 476(M+1) + .

[0285] Compound A6: 2-(8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)propanenitrile [ka]

[0286] Step A: tert-Butyl (2R,5S)-4-(2-(1-cyanoethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0287] A mixture of tert-butyl (2R,5S)-4-(2-(1-chloroethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (73 mg, 0.172 mmol), TMSCN (51 mg, 0.516 mmol), and CsCO (168 mg, 0.516 mmol) in CHCN (5 mL) is stirred at 70 °C overnight. The reaction mixture is poured into H0 (10 mL) and extracted with EtOAc (15 mL × 2). The combined organic layers are washed with brine, dried over NaSO, and concentrated. The resulting residue is purified by preparative TLC (EtOAc) to give the title compound (15 mg, 21%). MS: M / e 415 (M+1). + .

[0288] Compound B: 2-(8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)propanenitrile [ka]

[0289] To a stirred solution of tert-butyl (2R,5S)-4-(2-(1-cyanoethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (15 mg, 0.036 mmol) in CHCl (5 mL) is added TFA (2 mL). The mixture is then stirred for 2 h. The mixture is concentrated to give a residue, which is washed with aqueous NaHCO and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the de-Boc intermediate, which was dissolved in CH3CN (3 mL) and added with 1-(quinoxalin-6-yl)ethan-1-ol (18.9 mg, 0.11 mmol), (cyanomethyl)trimethylphosphonium iodide (26.7 mg, 0.11 mmol), and DIPEA (47 mg, 0.36 mmol). After the addition, the mixture was stirred in a sealed tube at 100 °C overnight. The reaction mixture was diluted with EtOAc (10 mL), washed with brine, dried over Na2SO4, and concentrated. The resulting residue was purified by preparative TLC (CH2Cl2:MeOH = 10:1) to give the title compound (5 mg). 1 H NMR(400 MHz, DMSO-d6) δ 8.97 - 8.90(m, 2H), 8.15 - 7.92(m, 3H), 5.69(s, 1H), 4.27 - 3.93(m, 1H), 3.88(s, 3H), 3.83 - 3.75(m, 1H), 3.64 - 3.49(m, 1H), 2.99 - 2.77(m, 2H), 2.78 - 2.64(m, 3H), 2.14 - 1.94(m, 2H), 1.70 - 1.43(m, 2H), 1.40 - 1.32(m, 5H), 1.13(s, 3H), 1.02 - 0.95(m, 1H) ppm. MS: M / e 471(M+1) + .

[0290] Compound A7: 8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-((dimethylamino)methyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0291] Step A: tert-Butyl (2R,5S)-4-(2-((dimethylamino)methyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0292] A mixture of tert-butyl (2R,5S)-4-(2-(chloromethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (40.8 mg, 0.1 mmol) in a solution of dimethylamine in THF (2.0 M, 3 mL) is stirred for 3 hours. The reaction mixture is concentrated to give the title compound, which is used directly in the next step without further purification. MS: M / e 419 (M+1). + .

[0293] Step B: 8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-((dimethylamino)methyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0294] To a stirred solution of tert-butyl (2R,5S)-4-(2-((dimethylamino)methyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (crude, 0.1 mmol) in CHCl (5 mL) was added TFA (1 mL). After stirring for 2 h, TLC (CHCl:MeOH = 10:1) indicated the reaction was complete. The reaction mixture was concentrated to give a residue, which was dissolved in CHCN (5 mL) and 6-(1-bromoethyl)quinoxaline (35.5 mg, 0.15 mmol) and DIPEA (51.6 mg, 0.4 mmol) were added. After the addition, the reaction mixture was stirred at 70 °C overnight. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 2), then the aqueous layer was concentrated to give a residue that was purified by preparative HPLC to give the title compound (14 mg, 28%). 1 H NMR(400 MHz, CD3OD) δ 9.00(s, 2H), 8.53(dd, J = 16.0, 1.6 Hz, 1H), 8.27(d, J = 8.8 Hz, 1H), 8.20(d, J = 3.2 Hz, 1H), 8.12(d, J = 8.8 Hz, 1H), 5.87(d, J = 4.8 Hz, 1H), 5.22 - 5.14(m, 1H), 5.07(s, 1H), 4.80 - 4.63(m, 3H), 3.88 - 3.72(m, 5H), 3.69 - 3.60(m, 1H), 3.25 - 3.15(m, 4H), 3.06(d, J = 2.4 Hz, 3H), 2.10(t, J = 7.6Hz, 3H), 1.47(d, J = 6.0 Hz, 3H), 1.42(dd, J = 6.8, 1.6 Hz, 3H) ppm. MS: M / e 475(M+1) + .

[0295] Compound A8: 8-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-(methoxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0296] Step A: Ethyl 8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate [ka]

[0297] A mixture of ethyl 8-bromo-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (2.5 g, 8.3 mmol), (2R,5S)-1-benzyl-2,5-diethylpiperazine (Intermediate 2) (2.0 g, 8.6 mmol), and DIPEA (3.2 g, 24.9 mmol) in MeCN (25 mL) was stirred at 90 °C for 16 h. The mixture was diluted with EtOAc (25 mL), washed with brine (25 mL × 3), dried, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound (2.7 g, 71%). MS: M / e 456 (M+1). + .

[0298] Step B: Ethyl 8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-2-carboxylate [ka]

[0299] A mixture of ethyl 8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (2.17 g, 4.79 mmol), Pd2(dba)3 (650 mg, 0.71 mmol), t-BuXPhos (600 mg, 1.41 mmol), and KOH (3 M, 4.5 mmol) in 1,4-dioxane (25 mL) is stirred at 100 °C for 2 h. The mixture is diluted with aqueous NaHCO3 (15 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers are washed with brine (20 mL × 2), dried, and concentrated. The resulting residue is purified by flash column chromatography to give the title compound (1.0 g, 48%). MS: M / e 438 (M+1). + .

[0300] Step C: Ethyl 8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-2-carboxylate [ka]

[0301] A mixture of ethyl 8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-2-carboxylate (1.0 g, 2.28 mmol), iodomethane (1.0 g, 7.04 mmol), and CsCO (2.3 g, 7.07 mmol) in dioxane (10 mL) is stirred at 70 °C for 16 h. The mixture is filtered, and the filtrate is diluted with EtOAc (20 mL), washed with brine (10 mL × 2), dried over NaSO, concentrated, and purified by flash column chromatography to give the title compound (540 mg, 52%). MS: M / e 452 (M+1). + .

[0302] Step D: 8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-2-(hydroxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0303] To a stirred solution of ethyl 8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-2-carboxylate (540 mg, 1.2 mmol) in the mixed solvent THF / EtOH (1:1, 20 mL) is added NaBH (273 mg, 7.2 mmol) portionwise at room temperature. The resulting mixture is stirred at 60 °C for 3 days. The mixture is treated with saturated aqueous NaHCO (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers are washed with brine (20 mL × 3), dried over NaSO, and concentrated. The resulting crude product is purified by flash column chromatography to give the title compound (344 mg, 70%). MS: M / e 410 (M+1) + .

[0304] Step E: tert-Butyl (2R,5S)-2,5-diethyl-4-(2-(hydroxymethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)piperazine-1-carboxylate [ka]

[0305] A mixture of 8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-2-(hydroxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one (340 mg, 0.83 mmol), Pd / C (100 mg), and di-tert-butyl dicarbonate (280 mg, 1.29 mmol) in MeOH (10 mL) is stirred under H at room temperature for 16 h. The mixture is filtered, and the filtrate is concentrated. The resulting residue is purified by flash column chromatography to give the title compound (280 mg, 80%). MS: M / e 420 (M+1). + .

[0306] Step F: tert-Butyl (2R,5S)-4-(2-(chloromethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-diethylpiperazine-1-carboxylate [ka]

[0307] To a stirred solution of tert-butyl (2R,5S)-2,5-diethyl-4-(2-(hydroxymethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)piperidine-1-carboxylate (280 mg, 0.67 mmol) in CHCl (5 mL) is added SOCl (160 mg, 1.33 mmol). The resulting mixture is stirred at room temperature for 1 h. The mixture is concentrated to dryness, treated with saturated aqueous NaHCO (5 mL), and extracted with DCM (5 ml × 3). The combined organic layers are washed with brine (10 mL × 2), dried over NaSO, and concentrated. The resulting crude product is purified by flash column chromatography to give the title compound (270 mg, 92%). MS: M / e 438 (M+1). + .

[0308] Step G: tert-Butyl (2R,5S)-2,5-diethyl-4-(2-(methoxymethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)piperazine-1-carboxylate [ka]

[0309] tert-Butyl (2R,5S)-4-(2-(chloromethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-diethylpiperazine-1-carboxylate (120 mg, 0.27 mmol) was added to a solution of CHONa in MeOH (5.4 M, 4 mL), and the mixture was stirred at 70 °C for 3 h. The mixture was diluted with EtOAc (20 mL), washed with brine (5 mL × 3), dried over NaSO, concentrated, and purified by flash column chromatography to give the title compound (100 mg, 83%). MS: M / e 434 (M+1). + .

[0310] Step H: 8-((2S,5R)-2,5-diethylpiperazin-1-yl)-2-(methoxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0311] To a stirred solution of tert-butyl (2R,5S)-2,5-diethyl-4-(2-(methoxymethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)piperazine-1-carboxylate (100 mg, 0.23 mmol) in CHCl (5 mL) is added TFA (1 mL). The resulting mixture is stirred at room temperature for 3 h. The mixture is concentrated, and the resulting residue is treated with saturated aqueous NaHCO to pH > 8. The mixture is extracted with DCM (5 mL × 3). The combined organic layers are washed with brine (5 mL × 2), dried over NaSO, and concentrated to give the title compound (35 mg, 45%). MS: M / e 334 (M+1) + .

[0312] Step I: 8-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-(methoxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0313] A mixture of 8-((2S,5R)-2,5-diethylpiperazin-1-yl)-2-(methoxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one (35 mg, 0.1 mmol), 1-(quinoxalin-6-yl)ethan-1-ol (55 mg, 0.3 mmol), (cyanomethyl)trimethylphosphonium iodide (100 mg, 0.41 mmol), and DIPEA (150 mg, 1.16 mmol) in MeCN (1 mL) was stirred at 100° C. for 16 h. The resulting mixture was diluted with EtOAc (5 mL), washed with brine (2 mL × 3), dried, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound A8, which was separated into compound A8a (6 mg) and compound A8b (7 mg) by preparative HPLC (Method B).

[0314] Compound A8a (early peak): 11H NMR (400 MHz, CD3OD) δ 8.88 (dd, J = 4.4, 1.6 Hz, 2H), 8.12 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 8.00 (dd, J = 8.8, 1.6 Hz, 1H), 7.79 (s, 1H), 5.61 (s, 1H), 4.47 (s, 2H), 4.07 (q, J = 6.4 Hz, 1H), 3.74 (s, 3H), 3.40 - 3.31 (m, 6H), 3.15 - 3.03 (m, 1H), 3.02 - 2.92 (m, 1H), 2.50 - 2.35 (m, 1H), 2.24 - 2.04 (m, 1H), 1.97 - 1.81 (m, 1H), 1.70 - 1.52 (m, 2H), 1.46 (d, J = 6.4 Hz, 3H), 0.94 (t, J = 7.2 Hz, 3H), 0.66 (t, J = 7.2 Hz, 3H). MS: M / e 490 (M+1) + .

[0315] Compound A8a (slower peak): 1 1H NMR (400 MHz, CD3OD) δ 8.91 - 8.83 (m, 2H), 8.14 - 8.05 (m, 2H), 8.02 (d, J = 8.8 Hz, 1H), 7.79 (s, 1H), 5.60 (s, 1H), 4.48 (s, 2H), 3.92 (q, J = 6.4 Hz, 1H), 3.74 (s, 3H), 3.56 (d, J = 12.8 Hz, 1H), 3.39 (s, 3H), 3.30 - 3.29 (m, 2H), 3.23 (d, J = 10.8 Hz, 1H), 2.77 (d, J = 12.8 Hz, 1H), 2.36 (d, J = 12.0 Hz, 1H), 2.06 - 1.86 (m, 1H), 1.80 - 1.66 (m, 2H), 1.65 - 1.55 (m, 1H), 1.43 (d, J = 6.8 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H), 0.55 (t, J = 7.2 Hz, 3H). MS: M / e 490 (M+1) + .

[0316] Compound A9: ((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-2-carbaldehyde O-methyloxime [ka]

[0317] Step A: tert-Butyl (2R,5S)-2-ethyl-4-(2-formyl-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-5-methylpiperazine-1-carboxylate [ka]

[0318] To a solution of tert-butyl (2R,5S)-2-ethyl-4-(2-(hydroxymethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-5-methylpiperazine-1-carboxylate (200 mg, 0.5 mmol) in DCM (10 mL) at room temperature, MnO2 (2.0 g, 23 mmol) is added and the mixture is stirred at room temperature for 16 hours. The mixture is filtered and the filtrate is concentrated to dryness to give the title compound (180 mg, 90%). MS: M / e 404 (M+1). + .

[0319] Step B: tert-Butyl (2R,5S)-2-ethyl-4-(2-((methoxyimino)methyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-5-methylpiperazine-1-carboxylate [ka]

[0320] A mixture of tert-butyl (2R,5S)-2-ethyl-4-(2-formyl-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-5-methylpiperazine-1-carboxylate (120 mg, 0.3 mmol), O-methylhydroxylamine hydrochloride (120 mg, 1.4 mmol), and CHCOONa (150 mg, 1.8 mmol) in a mixed solvent of HO / THF (1 / 2, 5 mL) was stirred at room temperature for 20 h. The mixture was diluted with EtOAc (20 mL), washed with brine (10 mL × 2), dried over NaSO, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound (100 mg, 77%). MS: M / e 433 (M+1). + .

[0321] Step C: 8-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-2-carbaldehyde O-methyloxime [ka]

[0322] To a solution of tert-butyl (2R,5S)-2-ethyl-4-(2-(methoxyimino)methyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-5-methylpiperazine-1-carboxylate (80 mg, 0.185 mmol) in DCM, TFA (2 mL) was added and the mixture was stirred at room temperature for 2 h. The mixture was concentrated, treated with saturated aqueous NaHCO3 (2 mL), and extracted with DCM (2 mL × 3). The combined organic layers were washed with brine (2 mL × 2), dried over Na2SO4, and concentrated to give the title compound (55 mg, 89%). MS: M / e 333 (M+1). + .

[0323] Step D: ((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-2-carbaldehyde O-methyloxime [ka]

[0324] A mixture of 8-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-2-carbaldehyde O-methyloxime (30 mg, 0.09 mmol), 1-(quinoxalin-6-yl)ethan-1-ol (45 mg, 0.26 mmol), (cyanomethyl)trimethylphosphonium iodide (65 mg, 0.26 mmol), and DIPEA (75 mg, 0.58 mmol) in MeCN (1 mL) is stirred at 100° C. for 16 h. The resulting mixture is diluted with EtOAc (10 mL), washed with brine (5 mL × 3), dried, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound A9, which was separated by preparative HPLC (Method B) into compound A9a (3 mg), compound A9b (7 mg), compound A9c (3 mg) and compound A9d (5 mg).

[0325] Compound A9a (first peak). 1H NMR(400 MHz, CD3OD) δ 8.88(dd, J = 5.2, 2.0 Hz, 2H), 8.12(d, J = 8.4 Hz, 1H), 8.06(d, J = 7.2 Hz, 2H), 8.04 - 7.99(m, 2H), 5.65(s, 1H), 4.12 - 4.04(m, 1H), 3.89(s, 3H), 3.75(s, 3H), 3.38 - 3.32(m, 2H), 3.06(dd, J = 11.6, 4.0 Hz, 1H), 2.97 - 2.89(m, 1H), 2.88 - 2.66(m, 1H), 2.52 - 2.39(m, 1H), 1.69 - 1.58(m, 2H), 1.50 - 1.39(m, 6H), 0.71(t, J = 7.2 Hz, 3H). MS: M / e 489(M+1) + .

[0326] Compound A9b (No. 2). 1 H NMR(400 MHz, CD3OD) δ 8.88(dd, J = 5.2, 1.6 Hz, 2H), 8.29(s, 1H), 8.12(d, J = 8.8 Hz, 1H), 8.08 - 7.99(m, 2H), 7.39(s, 1H), 5.67(s, 1H), 4.14 - 4.01(m, 4H), 3.77(s, 3H), 3.39 - 3.32(m, 2H), 3.05(dd, J = 11.6, 3.6 Hz, 1H), 2.93(d, J = 12.0 Hz, 1H), 2.89 - 2.61(m, 1H), 2.51 - 2.41(m, 1H), 1.72 - 1.57(m, 2H), 1.52 - 1.40(m, 6H), 0.73(t, J = 7.2 Hz, 3H). MS: M / e 489(M+1) + .

[0327] Compound A9c: (No. 3). 11H NMR (400 MHz, CD3OD) δ 8.92 - 8.84 (m, 2H), 8.16 - 7.98 (m, 5H), 5.64 (s, 1H), 3.99 - 3.85 (m, 4H), 3.75 (s, 3H), 3.64 - 3.54 (m, 1H), 3.42 - 3.32 (m, 1H), 3.28 - 3.21 (m, 1H), 2.96 - 2.67 (m, 2H), 2.26 (d, J = 10.8 Hz, 1H), 1.84 - 1.69 (m, 1H), 1.68 - 1.55 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H), 1.23 (d, J = 6.8 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H). MS: M / e 489 (M+1) + .

[0328] Compound A9d (the 4th peak): 1 1H NMR (400 MHz, CD3OD) δ 8.87 (dd, J = 6.0, 1.6 Hz, 2H), 8.30 (s, 1H), 8.12 - 8.06 (m, 2H), 8.06 - 8.01 (m, 1H), 7.43 (s, 1H), 5.65 (s, 1H), 4.06 (s, 3H), 3.94 (q, J = 6.4 Hz, 1H), 3.77 (s, 3H), 3.59 (d, J = 11.2 Hz, 1H), 3.34 - 3.31 (m, 1H), 3.24 (d, J = 10.4 Hz, 1H), 2.93 - 2.64 (m, 2H), 2.27 (d, J = 12.0 Hz, 1H), 1.84 - 1.69 (m, 1H), 1.69 - 1.57 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H), 1.24 (d, J = 6.4 Hz, 3H), 1.09 (t, J = 7.2 Hz, 3H). MS: M / e 489 (M+1) + .

[0329] Compound A10: 8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-2-((methylsulfinyl)methyl)imidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0330] Step A: tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-2-((methylthio)methyl)-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)piperazine-1-carboxylate [ka]

[0331] To a stirred solution of tert-butyl (2R,5S)-4-(2-(chloromethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (40.9 mg, 0.1 mmol) in THF (5 mL) was added EtN (101 mg, 1 mmol), followed by the addition of sodium methylthiolate (20% in HO, 0.5 mL). After the addition, the reaction mixture was stirred overnight. The reaction mixture was poured into HO (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound, which was used directly in the next step without further purification. MS: M / e 422 (M+1). + .

[0332] Step B: tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-2-((methylsulfinyl)methyl)-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)piperazine-1-carboxylate [ka]

[0333] To a stirred solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-2-((methylthio)methyl)-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)piperazine-1-carboxylate (crude, 0.1 mmol) in CHCl (5 mL) was added m-CPBA (25.8 mg, 0.15 mmol). After stirring for 2 h, the reaction mixture was washed with aqueous NaHCO, brine, dried over NaSO, and concentrated. The resulting residue was purified by preparative TLC (CHCl:MeOH=10:1) to give the title compound (26 mg, 60%). MS: M / e 438 (M+1). + .

[0334] Step C: 8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-2-((methylsulfinyl)methyl)imidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0335] To a stirred solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-2-((methylsulfinyl)methyl)-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)piperazine-1-carboxylate (26 mg, 0.06 mmol) in CHCl (5 mL) is added TFA (1 mL). After addition, the reaction mixture is stirred for 4 h. The reaction mixture was concentrated to give a residue, which was dissolved in EtOAc (20 mL), washed with aqueous NaCO, brine, dried over NaSO, and concentrated to give the de-Boc intermediate, which was dissolved in CHCN (3 mL) and added with 1-(quinoxalin-6-yl)ethan-1-ol (31.3 mg, 0.18 mmol), (cyanomethyl)trimethylphosphonium iodide (43.7 mg, 0.18 mmol), and DIPEA (77.4 mg, 0.6 mmol). After the addition, the reaction mixture was stirred overnight at 100 °C in a sealed tube. The reaction mixture was poured into H O (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine, dried over NaSO, and concentrated. The resulting residue was purified by preparative TLC (CH Cl : MeOH = 10:1) to give the title compound (4 mg). 1 H NMR(400 MHz, CD3OD) δ 8.91 - 8.83(m, 2H), 8.14 - 8.00(m, 3H), 7.86 - 7.81(m, 1H), 5.63(s, 1H), 5.22-4.39(m, 2H), 4.28 - 4.04(m, 2H), 4.02 - 3.79(m, 1H), 3.75(s, 3H), 3.72 - 3.65(m, 1H), 3.50 - 3.42(m, 0.5H), 3.14 - 2.83(m, 2H), 2.68 - 2.60(m, 3H), 2.21(d, J = 12 Hz, 0.5H), 1.52 - 1.40(m, 4.5H), 1.27 - 1.17(m, 3H), 1.06(d, J = 6.4 Hz, 1.5H) ppm. MS: M / e 494(M+1) +

[0336] Compound A11: 8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-2-((methylsulfonyl)methyl)imidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0337] Step A: tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-2-((methylsulfonyl)methyl)-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)piperazine-1-carboxylate [ka]

[0338] To a stirred solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-2-((methylthio)methyl)-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)piperazine-1-carboxylate (63 mg, 0.15 mmol) in CHCl (15 mL) is added m-CPBA (78 mg, 0.45 mmol). After the addition, the reaction is stirred for 2 days. The reaction mixture is washed with aqueous NaCO, brine, dried over NaSO, and concentrated. The resulting residue was purified by preparative TLC (CHCl:MeOH=10:1) to give the title compound (8 mg, 12%). MS: M / e 454 (M+1) + .

[0339] Step B: 8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-2-((methylsulfonyl)methyl)imidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0340] To a stirred solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-2-((methylsulfonyl)methyl)-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)piperazine-1-carboxylate (8 mg, 0.018 mmol) in CHCl (5 mL) was added TFA (1 mL). After the addition, the reaction mixture was stirred for 4 h. The reaction mixture was concentrated to give a residue, which was treated with aqueous NaCO and extracted with CHCl:IPA (3:1, 10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the de-Boc intermediate, which was dissolved in CH3CN (3 mL) and added with 1-(quinoxalin-6-yl)ethan-1-ol (9.2 mg, 0.053 mmol), (cyanomethyl)trimethylphosphonium iodide (12.8 mg, 0.053 mmol), and DIPEA (23.22 mg, 0.18 mmol). After the addition, the reaction mixture was stirred in a sealed tube at 100 °C overnight. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The resulting residue was purified by preparative TLC (CH2Cl2:MeOH = 10:1) to give the title compound (4 mg). 1 H NMR(400 MHz, CD3OD) δ 9.06 - 8.82(m, 2H), 8.19 - 8.00(m, 3H), 7.92(s, 1H), 5.66(s, 1H), 4.48(s, 2H), 3.80 - 3.68(m, 5H), 3.27 - 3.19(m, 2H), 2.98(s, 3H), 1.52-1.42(m, 3H), 1.39-1.35(m, 9H) ppm. MS: M / e 510(M+1) + .

[0341] Compound A12: 8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-2-((S-methylsulfonimido)methyl)imidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0342] Step A: N-(((8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)methyl)(methyl)(oxo)-16-sulfinylene)-2,2,2-trifluoroacetamide [ka]

[0343] To a stirred mixture of 8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-2-((methylsulfinyl)methyl)imidazo[1,2-b]pyridazin-6(5H)-one (69 mg, 0.14 mmol), PhI(OAc) (69 mg, 0.21 mmol), MgO (22.4 mg, 0.54 mmol), and Rh(OAc) (6.2 mg, 0.014 mmol) in CHCl (10 mL) under N was added 2,2,2-trifluoroacetamide (31.6 mg, 0.28 mmol). After the addition, the reaction mixture was stirred for 2 days. The reaction mixture was filtered, and the filtrate was concentrated and purified by preparative TLC (CH2Cl2:MeOH=10:1) to give the title compound (14 mg, 17%). MS: M / e 605 (M+1). + .

[0344] Step B: 8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-2-((S-methylsulfonimido)methyl)imidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0345] To a stirred solution of N-(((8-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)methyl)(methyl)(oxo)-16-sulfinylene)-2,2,2-trifluoroacetamide (14 mg, 0.023 mmol) in MeOH (5 mL) is added KCO (16 mg, 0.12 mmol). After the addition, the reaction mixture is stirred for an additional 30 minutes. The reaction mixture is concentrated to give a residue that is purified by preparative HPLC to give the title compound (0.8 mg). 1 H NMR(400 MHz, CD3OD) δ 8.91 - 8.84(m, 2H), 8.13 - 8.03(m, 3H), 7.90 - 7.86(m, 1H), 5.64(s, 1H), 4.63 - 4.45(m, 2H), 4.07 - 3.93(m, 1H), 3.88 - 3.78(m, 1H), 3.75(s, 3H), 3.73 - 3.65(m, 2H), 3.02(d, J = 2.8 Hz, 3H), 2.97 - 2.72(m, 3H), 2.21(d, J = 10.4 Hz, 1H), 1.50 - 1.41(m, 4.5H), 1.28 - 1.17(m, 4.5H) ppm. MS: M / e 509(M+1) + .

[0346] Compound A13: 2-(8-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile. [ka]

[0347] Step A: Benzyl-L-alanine methyl ester [ka]

[0348] To a suspension of L-alanine methyl ester hydrochloride (50 g, 0.36 mol) and K2CO3 (150 g, 1.08 mol) in MeCN (500 mL) was added BnBr (80 g, 0.47 mol) dropwise at room temperature, and the resulting mixture was stirred at room temperature for 16 h. The mixture was filtered. The filter cake was washed with EtOAc (200 mL × 3). The organics were combined and concentrated. The resulting residue was diluted with EtOAc (500 mL), washed with saturated aqueous NaHCO3 (200 mL), brine (200 mL × 3), dried, and concentrated. The resulting oil was purified by flash column chromatography to give the title compound (28.0 g, 40%). MS: M / e 194 (M+1) + .

[0349] Step B: N-benzyl-N-((R)-2-((tert-butoxycarbonyl)amino)butanoyl)-L-alanine methyl ester [ka]

[0350] To a mixture of benzyl-L-alanine methyl ester (27.0 g, 140 mmol), (R)-2-((tert-butoxycarbonyl)amino)butanoic acid (31.2 g, 154 mmol), and DIPEA (36.5 g, 280 mmol) in CHCl (300 mL) was added HATU (60.0 g, 158 mmol) portionwise at 0 °C. The resulting mixture was stirred at room temperature for 20 h. The mixture was washed with saturated aqueous NaHCO (100 mL × 2), brine (100 mL × 2), dried over NaSO, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound (45 g, 85%). MS: M / e 379 (M+1). + .

[0351] Step C: N-((R)-2-aminobutanoyl)-N-benzyl-L-alanine methyl ester [ka]

[0352] To a solution of N-benzyl-N-((R)-2-((tert-butoxycarbonyl)amino)butanoyl)-L-alanine methyl ester (41.0 g, 108.5 mmol) in EtOAc (300 mL) is added HCl (100 mL, 4 M in dioxane) at room temperature, and the mixture is stirred at room temperature for 3 days. The mixture is concentrated to dryness to give the title compound (38.0 g, crude), which is used directly in the next step. MS: M / e 279 (M+1) + .

[0353] Step D: (3R,6S)-1-benzyl-3-ethyl-6-methylpiperazine-2,5-dione [ka]

[0354] To a mixture of N-((R)-2-aminobutanoyl)-N-benzyl-L-alanine methyl ester hydrochloride (38.0 g, crude) in the mixed solvent EA / HO (200 mL / 50 mL) is added NaHCO (55 g, 650 mmol) portionwise at room temperature. The resulting mixture is stirred at room temperature for 5 h. The layers are separated. The aqueous layer is extracted with EtOAc (100 mL × 3). The combined organic layers are washed with brine (200 mL × 3), dried over NaSO, and concentrated. The resulting residue is purified by flash column chromatography to give the title compound (24 g, 88% for two steps). MS: M / e 247 (M+1) + .

[0355] Step E: (2S,5R)-1-benzyl-5-ethyl-2-methylpiperazine [ka]

[0356] A solution of borane in THF (1 M, 480 mL) is slowly added to (3R,6S)-1-benzyl-3-ethyl-6-methylpiperazine-2,5-dione (23.6 g, 95.9 mmol) over 15 minutes. The resulting mixture is stirred at 70° C. for 72 hours. The mixture is cooled to 0° C. and MeOH (100 mL) is slowly added, followed by HCl (5 M, 40 mL). A large amount of gas bubbles are generated. After stirring for 30 minutes, the mixture is heated at 70° C. for 2 hours. The mixture is concentrated to dryness and purified by flash column chromatography to give the title compound (21.5 g, crude), which is used directly in the next step. MS: M / e 219 (M+1) + .

[0357] Step F: tert-Butyl (2R,5S)-4-benzyl-2-ethyl-5-methylpiperazine-1-carboxylate [ka]

[0358] To a solution of (2S,5R)-1-benzyl-5-ethyl-2-methylpiperazine (19.5 g, crude) in THF (150 mL) was added KCO (24.5 g, 177 mmol) and HO (50 mL) at room temperature, followed by the dropwise addition of di-tert-butyl dicarbonate (20.0 g, 91.7 mmol). The resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with EtOAc (200 mL), washed with brine (100 mL × 3), dried over NaSO, concentrated, and purified by flash column chromatography to give the title compound (23.8 g, 86% for two steps). MS: M / e 319 (M+1). + .

[0359] Step G: tert-Butyl (2R,5S)-2-ethyl-5-methylpiperazine-1-carboxylate [ka]

[0360] A mixture of tert-butyl (2R,5S)-4-benzyl-2-ethyl-5-methylpiperazine-1-carboxylate (23.8 g, 74.8 mmol), Pd / C (3.0 g), and AcOH (2 mL) in MeOH (400 mL) was stirred under H at room temperature for 16 h. The mixture was filtered, and the filtrate was concentrated. The resulting oil was treated with aqueous NaOH (5 M, 50 mL) and extracted with CHCl (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over NaSO, and concentrated to dryness to give the title compound (14.3 g, 84%). 1 H NMR(400 MHz, DMSO-d6) δ 3.42 - 3.23(m, 1H), 3.04(d, J = 12.0 Hz, 1H), 2.64 - 2.46(m, 3H), 2.15 - 2.05(m, 1H), 1.99(dd, J = 12.8, 1.6 Hz, 1H), 1.41 - 1.24(m, 1H), 1.16 - 1.01(m, 1H), 0.97(s, 9H), 0.60(d, J = 6.8 Hz, 3H), 0.36(t, J = 7.6 Hz, 3H). MS: M / e 229(M+1) + .

[0361] Step H: Ethyl 8-((2S,5R)-4-(tert-butoxycarbonyl)-5-ethyl-2-methylpiperazin-1-yl)-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate [ka]

[0362] A mixture of ethyl 8-bromo-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (5.0 g, 16.6 mmol), tert-butyl (2R,5S)-2-ethyl-5-methylpiperazine-1-carboxylate (4.0 g, 17.5 mmol), and DIPEA (6.5 g, 50.5 mmol) in MeCN (40 mL) was stirred at 90 °C for 20 h. The mixture was treated with saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (50 mL × 3). The extracts were combined, washed with brine (50 mL × 2), dried, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound (6.61 g, 88%). MS: M / e 452 (M+1). + .

[0363] Step I: 8-((2S,5R)-4-(tert-butoxycarbonyl)-5-ethyl-2-methylpiperazin-1-yl)-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-2-carboxylic acid [ka]

[0364] A mixture of ethyl 8-((2S,5R)-4-(tert-butoxycarbonyl)-5-ethyl-2-methylpiperazin-1-yl)-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (5.0 g, 11.1 mmol), Pd(dba) (2.0 g, 2.2 mmol), t-BuXPhos (1.9 g, 4.4 mmol), and KOH (3 M, 9.0 mL) in dioxane (90 mL) was stirred at 100 °C for 2 h. Additional KOH solution (30 mL, 3 M) was added, and the mixture was stirred at 50 °C for 1 h. The mixture was extracted with DCM (50 mL × 3). The aqueous layer was acidified to pH < 5 with citric acid and extracted with DCM / MeOH (5 / 1, 50 mL × 5). The combined organic layers were washed with brine (100 mL x 2), dried and concentrated to give the title compound (5.5 g, crude). MS: M / e 406 (M+1). + .

[0365] Step J: Methyl 8-((2S,5R)-4-(tert-butoxycarbonyl)-5-ethyl-2-methylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-2-carboxylate [ka]

[0366] A mixture of 8-((2S,5R)-4-(tert-butoxycarbonyl)-5-ethyl-2-methylpiperazin-1-yl)-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-2-carboxylic acid (5.5 g, crude), iodomethane (9.5 g, 66.9 mmol), and CsCO (15.0 g, 46.1 mmol) in dioxane (60 mL) is stirred at 70 °C for 16 h. The mixture is diluted with EtOAc (100 mL), and the suspension is filtered. The filtrate is concentrated and purified by flash column chromatography to give the title compound (1.5 g, 27% over two steps). MS: M / e 434 (M+1). + .

[0367] Step K: tert-Butyl (2R,5S)-2-ethyl-4-(2-(hydroxymethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-5-methylpiperazine-1-carboxylate [ka]

[0368] To a stirred solution of methyl 8-((2S,5R)-4-(tert-butoxycarbonyl)-5-ethyl-2-methylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-2-carboxylate (1.4 g, 3.23 mmol) in the mixed solvent THF / MeOH (1:3, 20 mL) is added NaBH (1.0 g, 26.3 mmol) portionwise at room temperature. The resulting mixture is stirred at 60 °C for 16 h. An additional 4.0 g of NaBH is added over 47 h (1.0 g of NaBH over 5 h at 60 °C, 1.0 g over 40 h at 40 °C, and 2.0 g over 2 h at 60 °C). All starting material is consumed. The mixture was diluted with EtOAc (20 mL) and the suspension was filtered through a pad of diatomaceous earth to remove solids. The filtrate was concentrated, and the residue was treated with HO (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over NaSO, and concentrated. The resulting crude product was purified by flash column chromatography to give the title compound (710 mg, 54%). MS: M / e 406 (M+1). + .

[0369] Step L: tert-Butyl (2R,5S)-4-(2-(chloromethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2-ethyl-5-methylpiperazine-1-carboxylate [ka]

[0370] To a stirred solution of tert-butyl (2R,5S)-2-ethyl-4-(2-(hydroxymethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-5-methylpiperazine-1-carboxylate (700 mg, 1.72 mmol) in CHCl (5 mL) is added SOCl (415 mg, 3.5 mmol). The resulting mixture is stirred at room temperature for 2 h. The mixture is quenched with saturated NaHCO solution (5 mL) and extracted with DCM (5 mL × 3). The combined organic layers are washed with brine (5 mL × 2), dried over NaSO, and concentrated to dryness to give the title compound (700 mg, 95%). MS: M / e 424 (M+1). + .

[0371] Step M: tert-Butyl (2R,5S)-4-(2-(cyanomethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2-ethyl-5-methylpiperazine-1-carboxylate [ka]

[0372] A mixture of tert-butyl (2R,5S)-4-(2-(chloromethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2-ethyl-5-methylpiperazine-1-carboxylate (600 mg, 1.42 mmol), TMSCN (281 mg, 2.84 mmol), and CsCO (1.39 g, 4.26 mmol) in MeCN (10 mL) was stirred at 70 °C for 16 h. The mixture was diluted with EtOAc (20 mL), filtered, and the filtrate was washed with brine (10 mL × 3), dried over NaSO, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography to give the title compound (320 mg, 54%). MS: M / e 415 (M+1). + .

[0373] Step N: 2-(8-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0374] To a stirred solution of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2-ethyl-5-methylpiperazine-1-carboxylate (320 mg, 0.77 mmol) in CHCl (5 mL) is added TFA (1 mL). The resulting mixture is stirred at room temperature for 3 h. The mixture is concentrated, and the resulting residue is treated with saturated aqueous NaHCO to pH > 8. The mixture is extracted with DCM (5 mL × 3). The combined organic layers are washed with brine (5 mL × 2), dried over NaSO, and concentrated to give the title compound (210 mg, 86%). MS: M / e 315 (M+1) + .

[0375] Step O: 2-(8-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0376] A mixture of 2-(8-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (100 mg, 0.32 mmol), 1-(quinoxalin-6-yl)ethan-1-ol (140 mg, 0.8 mmol), (cyanomethyl)trimethylphosphonium iodide (311 mg, 1.28 mmol), and DIPEA (250 mg, 1.94 mmol) in MeCN (1 mL) is stirred at 100° C. for 16 h. The resulting mixture is diluted with EtOAc (5 mL), washed with brine (2 mL × 3), dried, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound A13, which was separated by preparative HPLC (Method B) into compound A13a (5 mg) and compound A13b (5 mg).

[0377] Compound A13a (early peak): 1 H NMR(400 MHz, CDCl3) δ 9.02 - 8.77(m, 2H), 8.14 - 7.83(m, 2H), 7.40 - 7.29(m, 1H), 5.74 - 5.56(m, 1H), 4.32 - 3.94(m, 1H), 3.78 - 3.70(m, 5H), 3.33 - 3.21(m, 1H), 3.15 - 2.75(m, 2H), 2.54 - 2.06(m, 1H), 1.99 - 1.84(m, 1H), 1.65 - 1.52(m, 5H), 1.42(d, J = 5.2Hz, 3H), 0.77 - 0.45(m, 3H). MS: M / e 471(M+1) + .

[0378] Compound A13b (later peak): 1H NMR(400 MHz, CDCl3) δ 9.03 - 8.78(m, 2H), 8.42 - 7.84(m, 3H), 7.43 - 7.30(m, 1H), 5.76 - 5.58(m, 1H), 4.02 - 3.81(m, 1H), 3.80 - 3.75(m, 2H), 3.72(s, 3H), 3.62 - 3.39(m, 2H), 3.28 - 3.09(m, 1H), 2.89 - 2.72(m, 1H), 2.31 - 2.05(m, 2H), 1.95 - 1.69(m, 1H), 1.60 - 1.55(m, 5H), 1.46 - 1.26(m, 3H), 1.21 - 1.00(m, 3H). MS: M / e 471(M+1) + .

[0379] Compound A14: 2-(8-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0380] Step A: tert-Butyl (2R,5S)-4-(2-(cyanomethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-diethylpiperazine-1-carboxylate [ka]

[0381] A mixture of tert-butyl (2R,5S)-4-(2-(chloromethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-diethylpiperazine-1-carboxylate (150 mg, 0.35 mmol), TMSCN (69 mg, 0.69 mmol), and CsCO (300 mg, 0.90 mmol) in MeCN (4 mL) is stirred at 70 °C for 24 h. The mixture is diluted with EtOAc (10 mL), washed with brine (5 mL × 3), dried over NaSO, concentrated, and purified by flash column chromatography to give the title compound (92 mg, 71%). MS: M / e 429 (M+1). + .

[0382] Step B: 2-(8-((2S,5R)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0383] To a stirred solution of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-diethylpiperazine-1-carboxylate (92 mg, 0.21 mmol) in CHCl (5 mL) is added TFA (1 mL). The resulting mixture is stirred at room temperature for 3 h. The mixture is concentrated, and the resulting residue is treated with saturated aqueous NaHCO to pH > 8. The mixture is extracted with DCM (5 mL × 3). The combined organic layers are washed with brine (5 mL × 2), dried over NaSO, and concentrated to give the title compound (40 mg, 58%). MS: M / e 329 (M+1). + .

[0384] Step C: 2-(8-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0385] A mixture of 2-(8-((2S,5R)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (40 mg, 0.12 mmol), 1-(quinoxalin-6-yl)ethan-1-ol (55 mg, 0.3 mmol), (cyanomethyl)trimethylphosphonium iodide (100 mg, 0.41 mmol), and DIPEA (150 mg, 1.16 mmol) in MeCN (1 mL) is stirred at 100° C. for 16 h. The resulting mixture is diluted with EtOAc (5 mL), washed with brine (2 mL × 3), dried, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound A14, which was separated by preparative HPLC (Method B) into compound A14a (12 mg) and compound A14b (19 mg).

[0386] Compound A14a (early peak): 11H NMR (400 MHz, CD3OD) δ 8.96 - 8.81 (m, 2H), 8.12 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 8.03 - 7.97 (m, 1H), 7.78 (s, 1H), 5.62 (s, 1H), 4.07 (q, J = 6.4 Hz, 1H), 3.92 (s, 2H), 3.73 (s, 3H), 3.38 - 3.31 (m, 3H), 3.08 (d, J = 12.0 Hz, 1H), 2.96 (dd, J = 12.0, 3.2 Hz, 1H), 2.43 (d, J = 8.8 Hz, 1H), 2.24 - 2.05 (m, 1H), 2.00 - 1.79 (m, 1H), 1.70 - 1.51 (m, 2H), 1.46 (d, J = 6.4 Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H), 0.68 (t, J = 7.2 Hz, 3H) ppm. MS: M / e 485 (M+1) + .

[0387] Compound A14b (the slower peak): 1 1H NMR (400 MHz, CD3OD) δ 8.87 (dd, J = 6.8, 1.6 Hz, 2H), 8.12 - 8.06 (m, 2H), 8.02 (dd, J = 8.8, 1.2 Hz, 1H), 7.79 (s, 1H), 5.60 (s, 1H), 3.98 - 3.85 (m, 3H), 3.73 (s, 3H), 3.56 (d, J = 13.2 Hz, 1H), 3.30 - 3.29 (m, 2H), 3.23 (d, J = 9.6 Hz, 1H), 2.83 - 2.70 (m, 1H), 2.37 (d, J = 12.4 Hz, 1H), 2.08 - 1.90 (m, 1H), 1.80 - 1.53 (m, 3H), 1.43 (d, J = 6.4 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H), 0.56 (t, J = 7.2 Hz, 3H) ppm. MS: M / e 485 (M+1) + .

[0388] Compound A15: 2-(8-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0389] Step A: Ethyl 8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate [ka]

[0390] To a solution of 8-methylbromo-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (310 mg, 1 mmol) and DIPEA (258 mg, 2 mmol) in CHCN (6 mL) was added (2R,5S)-1-benzyl-2,5-diethylpiperazine (300 mg, 1 mmol). The reaction was stirred at 70 °C for 16 h. The mixture was then cooled to room temperature, diluted with water, extracted with EA (60 mL × 3), washed with brine, dried over NaSO, filtered, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound (220 mg, 48%). MS: M / e 456 (M+1). + .

[0391] Step B: 8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-6-(benzyloxy)imidazo[1,2-b]pyridazine-2-carboxylic acid [ka]

[0392] To a solution of BnOH (432 mg, 4 mmol) in DMSO (300 mL) is added 60% NaH (320 mg, 8 mmol). The mixture is stirred at room temperature for 30 min. Then, a solution of ethyl 8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (910 mg, 2 mmol) in DMSO (2 mL) is added and heated at 80 °C overnight. The mixture is cooled to room temperature, diluted with water, and washed with EA. The aqueous layer is collected, treated with 2N HCl to pH = 3, extracted with EA (60 mL × 3), washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (1.3 g, crude). MS: M / e 500 (M+1) + .

[0393] Step C: Ethyl 8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-6-(benzyloxy)imidazo[1,2-b]pyridazine-2-carboxylate [ka]

[0394] To a mixture of 8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-6-(benzyloxy)imidazo[1,2-b]pyridazine-2-carboxylic acid (1.35 g, crude) in 1,4-dioxane (8 mL) is added CsCO (1.3 g, 4 mmol) and iodoethane (620 mg, 4 mmol). The reaction is heated at 80 °C overnight. The mixture is cooled to room temperature, diluted with water, extracted with EA (60 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated. The residue is purified by flash column chromatography (EA:PE = 1:3) to give the title compound (0.57 g, crude). MS: M / e 528 (M+1) + .

[0395] Step D: (8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-6-(benzyloxy)imidazo[1,2-b]pyridazin-2-yl)methanol [ka]

[0396] To a mixture of ethyl 8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-6-(benzyloxy)imidazo[1,2-b]pyridazine-2-carboxylate (570 mg, crude) in THF (10 mL) is added dropwise a solution of LiAlH in THF (2.2 mL, 2.2 mmol). The reaction is stirred at room temperature for 2 h. The reaction is quenched with water, extracted with EA (60 mL × 3), washed with brine, dried over NaSO, filtered and concentrated. The residue is purified by flash column chromatography (EA:PE = 1:3) to give the title compound (0.48 g, crude). MS: M / e 486 (M+1) + .

[0397] Step E: 2-(8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-6-(benzyloxy)imidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0398] To a mixture of (8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-6-(benzyloxy)imidazo[1,2-b]pyridazin-2-yl)methanol (480 mg, crude) in DCM (6 mL) is added SOCl (104 mg, 0.88 mmol). The reaction is stirred at room temperature for 0.5 h, quenched with water, extracted with DCM (60 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated. The residue is dissolved in CHCN (10 mL), and CsCO (858 mg, 2.64 mmol) and TMSCN (350 mg, 3.52 mmol) are added. The reaction is heated at 70 °C under N overnight. The mixture was cooled to room temperature, diluted with water, extracted with EA (60 mL × 2), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (EA:PE = 1:3) to give the title compound (360 mg, crude). MS: M / e 495 (M+1). + .

[0399] Step F: 2-(8-((2S,5R)-2,5-diethylpiperazin-1-yl)-6-hydroxyimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0400] To a mixture of 2-(8-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-6-(benzyloxy)imidazo[1,2-b]pyridazin-2-yl)acetonitrile (100 mg, crude) in MeOH (5 mL) is added 10% Pd / C (10 mg) and one drop of TFA. The reaction is stirred under H (balloon) at room temperature for 4 hours. The mixture is filtered through a diatomaceous earth pad mixture and washed with MeOH. The filtrate is collected, treated with 7M NH in MeOH, and further concentrated. The resulting residue is purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound (35 mg, crude).

[0401] Step G: 2-(8-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0402] To a solution of 2-(8-((2S,5R)-2,5-diethylpiperazin-1-yl)-6-hydroxyimidazo[1,2-b]pyridazin-2-yl)acetonitrile (35 mg, 0.1 mmol), 1-(quinoxalin-6-yl)ethan-1-ol (35 mg, 0.2 mmol), and (cyanomethyl)trimethylphosphonium iodide (48 mg, 0.2 mmol) in CHCN (3 mL) is added DIPEA (38 mg, 0.3 mmol). The mixture is sealed in a vial and heated at 105 °C for 16 h. Additional (cyanomethyl)trimethylphosphonium iodide (48 mg, 0.2 mmol) is added and heated at 105 °C for 18 h. The mixture is then cooled to RT, diluted with water, extracted with EA (60 mL), washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC (DCM:MeOH = 15:1) and preparative HPLC (Method A) to give the title compound (1 mg). 1H NMR(400 MHz, CD3OD) δ 8.92 - 8.82(m, 2H), 8.15 - 7.90(m, 3H), 7.55(s, 1H), 5.72(s, 1H), 4.12 - 4.02(m, 0.5H), 3.97 - 3.86(m, 0.5H), 3.89(s, 2H), 3.62 - 3.44(m, 1H), 3.26 - 3.15(m, 1H), 3.12 - 2.94(m, 2H), 2.82 - 2.74(m, 1H), 2.47 - 2.30(m, 1H), 2.22 - 2.08(m, 0.5H), 2.00 - 1.90(m, 0.5H), 1.87 - 1.56(m, 3H), 1.49 - 1.40(m, 3H), 1.05(t, J = 7.6 Hz, 1.5H), 0.94(t, J = 7.6 Hz, 1.5H), 0.66(t, J = 7.6 Hz, 1.5H), 0.54(t, J = 7.6 Hz, 1.5H) ppm. MS: M / e 471(M+1) + .

[0403] Compound A16: 8-((2S,5R)-5-ethyl-4-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methylpiperazin-1-yl)-2-(methoxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0404] Step A: tert-Butyl (2R,5S)-2-ethyl-4-(2-(methoxymethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-5-methylpiperazine-1-carboxylate [ka]

[0405] tert-Butyl (2R,5S)-4-(2-(chloromethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2-ethyl-5-methylpiperazine-1-carboxylate (100 mg, 0.23 mmol) is added to a solution of CHONa in MeOH (5.4 M, 1 mL), and the mixture is stirred at 70 °C for 1 h. The mixture is diluted with HO (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers are washed with brine (10 mL × 2), dried over NaSO, and concentrated. The resulting residue is purified by flash column chromatography to give the title compound (75 mg, 78%). MS: M / e 420 (M+1) + .

[0406] Step B: 8-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-2-(methoxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0407] To a stirred solution of tert-butyl (2R,5S)-2-ethyl-4-(2-(methoxymethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-5-methylpiperazine-1-carboxylate (75 mg, 0.18 mmol) in CHCl (2 mL) is added TFA (1 mL). The resulting mixture is stirred at room temperature for 3 h. The mixture is concentrated, and the resulting residue is treated with saturated aqueous NaHCO to pH > 8. The mixture is extracted with DCM (5 mL × 3). The combined organic layers are washed with brine (5 mL × 2), dried over NaSO, and concentrated to give the title compound (52 mg, 90%). MS: M / e 320 (M+1) + .

[0408] Step C: 8-((2S,5R)-5-ethyl-4-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methylpiperazin-1-yl)-2-(methoxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one [ka]

[0409] A mixture of 8-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-2-(methoxymethyl)-5-methylimidazo[1,2-b]pyridazin-6(5H)-one (52 mg, 0.16 mmol), 1-(2-fluoro-4-(trifluoromethyl)phenyl)ethan-1-ol (85 mg, 0.40 mmol), (cyanomethyl)trimethylphosphonium iodide (155 mg, 0.64 mmol), and DIPEA (129 mg, 1.0 mmol) in MeCN (1 mL) is stirred at 100° C. for 16 h. The resulting mixture is diluted with EtOAc (5 mL), washed with brine (2 mL × 3), dried, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound A16, which was separated by preparative HPLC (Method B) into compound A16a (1 mg) and compound A16b (2 mg).

[0410] Compound A16a (early peak): 1H NMR(400 MHz, CDCl3) δ 7.74 - 7.58(m, 1H), 7.47 - 7.39(m, 1H), 7.38 - 7.28(m, 2H), 5.70 - 5.54(m, 1H), 4.51 - 4.41(m, 2H), 4.31 - 4.15(m, 1H), 3.72(s, 3H), 3.43(s, 3H), 3.29 - 3.10(m, 1H), 3.04 - 2.92(m, 1H), 2.81 - 2.66(m, 1H), 2.47 - 2.32(m, 1H), 2.06 - 1.99(m, 1H), 1.91 - 1.81(m, 1H), 1.62 - 1.53(m, 4H), 1.37 - 1.30(m, 4H), 0.82 - 0.55(m, 3H). MS: M / e 510(M+1) + .

[0411] Compound A16b (later peak): 1 H NMR(400 MHz, CDCl3) δ 7.86 - 7.61(m, 1H), 7.47 - 7.37(m, 1H), 7.37 - 7.27(m, 2H), 5.75 - 5.57(m, 1H), 4.52 - 4.42(m, 2H), 4.10 - 3.94(m, 1H), 3.72(s, 3H), 3.49 - 3.40(m, 4H), 3.16 - 3.00(m, 1H), 2.86 - 2.69(m, 1H), 2.19 - 2.11(m, 1H), 2.04 - 1.97(m, 1H), 1.89 - 1.67(m, 1H), 1.62 - 1.51(m, 5H), 1.33 - 1.26(m, 3H), 1.21 - 0.98(m, 3H). MS: M / e 510(M+1) + .

[0412] Compound A17: 2-(8-((2S,5R)-5-ethyl-4-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile. [ka]

[0413] A mixture of 2-(8-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (45 mg, 0.14 mmol), 1-(2-fluoro-4-(trifluoromethyl)phenyl)ethan-1-ol (65 mg, 0.31 mmol), (cyanomethyl)trimethylphosphonium iodide (100 mg, 0.41 mmol), and DIPEA (100 mg, 0.7 mmol) in MeCN (1 mL) is stirred at 100° C. for 16 h. The resulting mixture is diluted with EtOAc (5 mL), washed with brine (2 mL × 3), dried, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound A17, which was separated by preparative HPLC (Method B) into compound A17a (3 mg) and compound A17b (4 mg).

[0414] Compound A17a (early peak): 1 H NMR(400 MHz, CDCl3) δ 7.73 - 7.61(m, 1H), 7.47 - 7.40(m, 1H), 7.40 - 7.28(m, 2H), 5.80 - 5.58(m, 1H), 4.30 - 4.16(m, 1H), 3.80 - 3.68(m, 5H), 3.28 - 3.12(m, 1H), 3.04 - 2.88(m, 1H), 2.83 - 2.67(m, 1H), 2.48 - 2.28(m, 1H), 2.15 - 1.95(m, 1H), 1.94 - 1.78(m, 1H), 1.63 - 1.48(m, 4H), 1.39 - 1.30(m, 4H), 0.85 - 0.53(m, 3H). MS: M / e 505(M+1) + .

[0415] Compound A17b (later peak): 1H NMR(400 MHz, CDCl3) δ 7.83 - 7.62(m, 1H), 7.48 - 7.26(m, 3H), 5.77 - 5.58(m, 1H), 4.15 - 3.93(m, 1H), 3.81 - 3.68(m, 5H), 3.51 - 3.35(m, 1H), 3.27 - 3.02(m, 1H), 2.89 - 2.68(m, 1H), 2.25 - 1.95(m, 2H), 1.92 - 1.66(m, 1H), 1.60 - 1.52(m, 4H), 1.36 - 1.22(m, 4H), 1.22 - 0.96(m, 3H). MS: M / e 505(M+1) + .

[0416] Compound A18: 2-(8-((2S,5R)-5-ethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2-methylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0417] A mixture of 2-(8-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (44 mg, 0.14 mmol), 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol (63 mg, 0.30 mmol), (cyanomethyl)trimethylphosphonium iodide (98 mg, 0.40 mmol), and DIPEA (100 mg, 0.7 mmol) in MeCN (1 mL) was stirred at 100° C. for 24 h. The resulting mixture was diluted with EtOAc (5 mL), washed with brine (2 mL × 3), dried, and concentrated. The resulting residue was purified by flash column chromatography to give the crude product, which was further purified by preparative HPLC (Method A) to give the title compound (6 mg, 9%). 1H NMR(400 MHz, CD3OD) δ 8.14 - 8.01(m, 1H), 7.79(s, 1H), 7.47 - 7.30(m, 2H), 5.71 - 5.58(m, 1H), 4.22 - 3.99(m, 1H), 3.97 - 3.88(m, 2H), 3.73(s, 3H), 3.59 - 3.42(m, 1H), 3.30 - 3.16(m, 2H), 3.07 - 2.89(m, 1H), 2.88 - 2.71(m, 1H), 2.39 - 1.98(m, 1H), 1.82 - 1.48(m, 2H), 1.47 - 1.29(m, 3H), 1.29 - 1.15(m, 3H), 1.14 - 0.73(m, 3H). MS: M / e 505(M+1) + .

[0418] Compound A19: 2-(8-((2S,5R)-4-(1-(3-(difluoromethyl)quinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0419] A solution of 2-(8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (80 mg, 0.267 mmol), 1-(3-(difluoromethyl)quinoxalin-6-yl)ethan-1-ol (120 mg, 0.533 mmol), (cyanomethyl)trimethylphosphonium iodide (130 mg, 0.533 mmol), and DIPEA (103 mg, 0.801 mmol) in CHCN (2 mL). The mixture was degassed three times under N atmosphere. The mixture was then stirred at 105 °C for 24 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH=15:1) to give the title compound (55 mg, 41%). 1H NMR(400 MHz, CD3OD) δ 9.13(d, J = 4.3 Hz, 1H), 8.21-8.10(m, 3H), 7.78(s, 1H), 6.99(td, J = 54.5, 3.6 Hz, 1H), 5.62(s, 1H), 4.68-4.52(m, 1H), 4.00(q, J = 6.6 Hz, 0.5H), 3.93(d, J = 2.7 Hz, 2H), 3.85(q, J = 6.4 Hz, 0.5H), 3.73(s, 3H), 3.72-3.64(m, 1H), 3.46(dd, J = 12.9, 3.2 Hz, 0.5H), 3.30-3.23(m, 0.5H), 3.09(dd, J = 11.7, 3.8 Hz, 0.5H), 2.97-2.83(m, 2H), 2.20(d, J = 12.1 Hz, 0.5H), 1.47-1.39(m, 4H), 1.23(t, J = 7.3 Hz, 3.5H), 1.07(d, J = 6.5 Hz, 1.5H) ppm. MS: M / e 507(M+1) + .

[0420] Compound A20: 2-(8-((2S,5R)-4-(1-(3-methoxyquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0421] Step A: 7-Bromo-2-methoxyquinoxaline [ka]

[0422] To a solution of 7-bromo-2-chloroquinoxaline (12 g, 49.3 mmol) in CHOH (150 mL) was added KCO (13.6 g, 98.6 mmol). The reaction mixture was refluxed for 2 h. After filtration, the organic layer was concentrated to give the title compound (9.2 g, 79%). MS: M / e 239 (M+1). + .

[0423] Step B: 1-(3-methoxyquinoxalin-6-yl)ethan-1-one [ka]

[0424] To a solution of 7-bromo-2-methoxyquinoxaline (4.0 g, 16.81 mmol) and tributyl(1-ethoxyvinyl)stannane (12.14 g, 33.61 mmol) in toluene (70 mL) was added Pd(PPh3)2Cl2 (2.36 g, 3.36 mmol). The reaction mixture was stirred at 90 °C under N2 for 8 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with EA (60 mL × 2). The organic layers were combined, washed with brine (50 mL × 2), dried, and concentrated to dryness. The resulting oil was diluted with THF (50 mL). To the above solution was then added HCl (6 mL, 4 M, in 1,4-dioxane) dropwise, and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EA (50 mL), treated with saturated aqueous NaHCO to pH 8, washed with brine (30 mL × 3), dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography (PE:EA = 8:1) to give the title compound (1.2 g, 35%). MS: M / e 203 (M+1). +

[0425] Step C: 1-(3-methoxyquinoxalin-6-yl)ethan-1-ol [ka]

[0426] To a solution of 1-(3-methoxyquinoxalin-6-yl)ethan-1-one (800 mg, 3.94 mmol) in CHOH (15 mL) was added NaBH (165 mg, 4.33 mmol). The reaction was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NH Cl, extracted with EA (35 mL × 2), washed with brine, dried over Na SO , filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (PE:EA = 5:1) to give the title compound (630 mg, 78%). MS: M / e 205 (M+1). +

[0427] Step D: 2-(8-((2S,5R)-4-(1-(3-methoxyquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0428] A solution of 2-(8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (304 mg, 1.01 mmol), 1-(3-methoxyquinoxalin-6-yl)ethan-1-ol (310 mg, 1.52 mmol), (cyanomethyl)trimethylphosphonium iodide (491 mg, 2.02 mmol), and DIPEA (391 mg, 3.03 mmol) in CHCN (2 mL) was degassed three times under N atmosphere. The mixture was then stirred at 105 °C for 24 h. The reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by preparative TLC (DCM:MeOH=15:1) to give the title compound (255 mg, 52%). 1H NMR(400 MHz, CD3OD) δ 8.43(d, J = 5.0 Hz, 1H), 7.96(dd, J = 12.4, 8.5 Hz, 1H), 7.84(d, J = 6.2 Hz, 1H), 7.78(s, 1H), 7.75(d, J = 8.5 Hz, 1H), 5.62(s, 1H), 5.10-4.50(m, 1H), 4.10(d, J = 5.5 Hz, 3H), 3.93(d, J = 2.4 Hz, 2H), 3.89-3.77(m, 1H), 3.73(s, 3H), 3.69-3.63(m, 1H), 3.44-3.34(m, 1H), 3.07(dd, J = 11.8, 3.9 Hz, 0.5H), 2.97-2.71(m, 2H), 2.22(d, J = 12.2 Hz, 0.5H), 1.42(dd, J = 15.1, 6.5 Hz,4.5H), 1.22(dd, J = 14.7, 6.5 Hz, 3H), 1.04(d, J = 6.5 Hz, 1.5H) ppm. MS: M / e 487(M+1) + .

[0429] Compound A21: 2-(8-((2S,5R)-4-(1-(3-chloroquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0430] Step A: 2-(8-((2S,5R)-4-(1-(3-hydroxyquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0431] To a solution of 2-(8-((2S,5R)-4-(1-(3-methoxyquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (130 mg, 0.267 mmol) in DCM (5 mL) was added BBr3 (5.35 mL, 1 M, 5.35 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with DCM (30 mL × 2). The organic layers were combined, washed with brine (50 mL × 2), dried, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH = 20:1) to give the title compound (80 mg, 63%). MS: M / e 473(M+1) + .

[0432] Step B: 2-(8-((2S,5R)-4-(1-(3-chloroquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0433] A solution of 2-(8-((2S,5R)-4-(1-(3-hydroxyquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (80 mg, 0.169 mmol) in POCl (5 mL) was stirred at 80 °C for 2 h. The reaction mixture was poured into HO (30 mL) and extracted with DCM (30 mL × 2). The organic layers were combined, washed with brine (50 mL × 2), dried over NaSO, and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM:MeOH = 15:1) to give the title compound (9 mg, 11%). 1H NMR(400 MHz, CD3OD) δ 8.83(d, J = 4.3 Hz, 1H), 8.11(dd, J = 11.6, 8.7 Hz, 1H), 8.05-7.95(m, 2H), 7.78(s, 1H), 5.62(s, 1H), 4.78-4.48(m, 1H), 4.05-3.94(m, 0.5H), 3.93(d, J = 2.3 Hz, 2H), 3.87-3.76(m, 0.5H), 3.74(s, 3H), 3.71-3.64(m,1.5H), 3.49-3.42(m, 0.5H), 3.13-3.06(m, 0.5H), 2.95-2.66(m, 2H), 2.20(d, J = 12.4 Hz, 0.5H), 1.48-1.38(m, 4H), 1.22(dd, J = 12.2, 6.5 Hz, 4H), 1.06(d, J = 6.5 Hz, 1H) ppm. MS: M / e 491(M+1) + .

[0434] Compound A22: 2-(8-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-7-fluoro-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0435] To a mixture of 2-(8-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (47 mg, 0.1 mmol) in CHCN (2 mL) was added Select F reagent (53 mg, 0.15 mmol). The mixture was stirred at room temperature for 16 h. The reaction was diluted with water, extracted with DCM (60 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by preparative TLC (DCM:MeOH=15:1) to give the title compound (4 mg, 8.3%). 1 H NMR(400 MHz, CD3OD) δ 8.81 - 8.76(m, 1H), 8.07 - 7.90(m, 3H), 7.78(s, 1H), 4.82 - 4.68(m, 0.5H), 4.56- 4.44(m, 0.5H), 4.15 - 3.85(m, 4.5H), 3.83 - 3.71(m, 3.5H), 3.63 - 3.51(m, 1H), 3.25 - 3.16(m, 0.5H), 2.96 - 2.79(m, 1H), 2.76(s, 3H), 2.24 - 2.12(m, 0.5H), 1.49 - 1.40(m, 4H), 1.27 - 1.18(m, 4H), 1.12 - 1.04(m, 1H) ppm. MS: M / e 489(M+1) + .

[0436] Compound A23: 2-(cyanomethyl)-8-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-7-carbonitrile [ka]

[0437] Step A: 2-(7-bromo-8-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0438] To a mixture of 2-(8-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (200 mg, 0.425 mmol) in CHCN (10 mL) is added a solution of NBS (80 mg, 0.43 mmol) in CHCN (1 mL). The mixture is stirred at room temperature for 2 h. The reaction is diluted with water, extracted with DCM (60 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The residue is purified by preparative TLC (DCM:MeOH=15:1) to give the title compound (130 mg, 55%). MS: M / e 549 (M+1). + .

[0439] Step B: 2-(cyanomethyl)-8-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-7-carbonitrile [ka]

[0440] To a mixture of 2-(7-bromo-8-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (130 mg, 0.236 mmol) in DMF (5 mL) is added Zn(CN) (83 mg, 0.71 mmol) and Pd(PPh) (82 mg, 0.071 mmol). The mixture is heated under reduced pressure in a nitrogen atmosphere. 2 The mixture was stirred at 100° C. for 16 h under reduced pressure. The reaction mixture was cooled to room temperature, diluted with water, extracted with DCM (60 mL × 2), washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative TLC (DCM:MeOH = 15:1) to give the title compound (26 mg, 22%). 1 H NMR(400 MHz, CD3OD) δ 8.81 - 8.76(m, 1H), 8.09 - 7.90(m, 3H), 7.86(s, 1H), 4.22 - 4.08(m, 0.5 H), 4.01 - 3.86(m, 3H), 3.83 - 3.69(m, 4H), 3.25 - 3.16(m, 1H), 3.06 - 2.89(m, 2H), 2.83 - 2.75(m, 4H), 2.26 - 2.19(m, 0.5H), 1.66(d, J = 6.4 Hz, 1.5H), 1.50 - 1.38(m, 4.5H), 1.17(d, J = 6.8 Hz, 1.5H), 1.01(d, J = 6.8 Hz, 1.5H) ppm. MS: M / e 496(M+1) + .

[0441] Compound A24: 2-(8-((2S,5R)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0442] A solution of 2-(8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (300 mg, 1.00 mmol), 1-(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethan-1-ol (270 mg, 1.50 mmol), (cyanomethyl)trimethylphosphonium iodide (729 mg, 3.00 mmol) and DIEA (1.29 g, 10.00 mmol) in MeCN (6 ml) is stirred at 100° C. overnight. The reaction is diluted with EA (20 ml) and washed with brine (10 ml). The organic layer is concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (0-5% MeOH / DCM) and then by preparative HPLC to give the title compound (3.42 mg, FA salt). 1 H NMR(400 MHz, DMSO-d6) δ 8.18(s, 0.37H), 7.86(s, 1H), 6.86-6.76(m, 3H), 5.52(d, J = 3.9 Hz, 1H), 4.22(d, J = 5.8 Hz, 4H), 4.04(s, 2H), 3.61(s, 3H), 3.51 - 3.40(m, 2H), 3.38-3.35(m, 1H), 3.23(d, J = 13.0 Hz, 1H), 2.87-2.80(m, 1H), 2.74(d, J = 11.5 Hz, 0.5H), 2.58(d, J = 8.6 Hz, 0.5H), 2.54-2.52(m, 0.5H), 2.14(d, J = 11.9 Hz, 0.5H), 1.26(d, J = 6.5 Hz, 1.5H), 1.20(dd, J = 9.3, 6.6 Hz, 3H), 1.11(d, J = 6.3 Hz, 1.5H), 1.03(d, J = 6.2 Hz, 1.5H), 0.88(d, J = 6.5 Hz, 1.5H) ppm. MS: M / e 463(M+1) + .

[0443] Compound A25: 2-(8-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0444] A solution of 2-(8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (150 mg, 0.50 mmol), 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethan-1-ol (125 mg, 0.60 mmol), (cyanomethyl)trimethylphosphonium iodide (365 mg, 1.50 mmol) and DIEA (645 mg, 5 mmol) in MeCN (4 ml) is stirred at 100° C. overnight. The reaction is diluted with EA (20 ml) and washed with brine (10 ml). The organic layer is concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (0-5% MeOH / DCM) to give the title compound A25, which was separated into compound A25a (22 mg) and compound A25b (23 mg) by preparative HPLC (Method B) and then by chiral preparative HPLC. The chiral separation conditions were as follows: [Table 7]

[0445] Compound A25: 11H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 0.24H), 7.86 (s, 1H), 6.87 - 6.76 (m, 3H), 5.52 (d, J = 3.0 Hz, 1H), 4.04 (s, 2H), 3.90 (d, J = 5.2 Hz, 2H), 3.61 (s, 3H), 3.50 - 3.37 (m, 4H), 3.23 (d, J = 9.7 Hz, 0.5H), 2.87 - 2.79 (m, 1H), 2.73 (d, J = 11.0 Hz, 0.5H), 2.58 (d, J = 8.0 Hz, 0.5H), 2.13 (d, J = 12.0 Hz, 0.5H), 1.27 (dd, J = 7.4, 4.6 Hz, 7.5H), 1.20 (dd, J = 10.5, 6.6 Hz, 3H), 1.10 (d, J = 6.4 Hz, 1.5H), 1.03 (d, J = 6.2 Hz, 1.5H), 0.88 (d, J = 6.4 Hz, 1.5H) ppm. MS: M / e 491 (M+1) + .

[0446] Compound A25a (earlier peak): 1 1H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 6.86 - 6.78 (m, 3H), 5.51 (s, 1H), 4.04 (s, 2H), 3.91 (s, 2H), 3.61 (s, 3H), 3.47 (q, J = 6.4 Hz, 1H), 3.31 (m, 2H), 3.23 (dd, J = 9.4 Hz, 3.6 Hz, 1H), 2.84 (dd, J = 7.7 Hz, 3.9Hz, 2H), 2.73 (d, J = 10.5 Hz, 1H), 1.28 (s, 6H), 1.26 (d, J = 6.6 Hz, 3H), 1.19 (d, J = 6.3 Hz, 3H), 0.89 (d, J = 6.4 Hz, 3H) ppm. MS: M / e 491 (M+1) + .

[0447] Compound A25b (later peak): 1H NMR(400 MHz, DMSO-d6) δ 7.86(s, 1H), 6.84-6.76(m, 3H), 5.52(s, 1H), 4.04(s, 2H), 3.89(s, 2H), 3.61(s, 3H), 3.50-3.42(m, 2H), 3.35(m, 2H), 3.33 - 3.29(m, 1H), 2.58(dd, J = 8.9 Hz, 3.8 Hz, 1H), 2.14(d, J = 11.7 Hz, 1H), 1.27(d, J = 3.0 Hz, 6H), 1.22(d, J = 6.3 Hz, 3H), 1.10(d, J = 6.4 Hz, 3H), 1.02(d, J = 6.1 Hz, 3H) ppm. MS: M / e 491(M+1) + .

[0448] Compound A26: 2-(8-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-7-fluoro-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0449] Step A: tert-Butyl (2R,5S)-4-(2-(cyanomethyl)-7-fluoro-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0450] A solution of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (500 mg, 1.25 mmol) and select F (664 mg, 1.88 mmol) in CH3CN (10 mL) was stirred at room temperature for 4 h. The solution was diluted with EA (20 mL) and then washed with brine (10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (60-80% EA / PE) to give the title compound (270 mg, 51%). MS: M / e 419 (M+1). + .

[0451] Step B: 2-(8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-7-fluoro-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0452] A solution of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-7-fluoro-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (270 mg, 0.65 mmol) and TFA (2 ml) in DCM (10 ml) was stirred at room temperature for 30 min. The solution was diluted with DCM (10 ml) and then washed with aqueous NaHCO3 (10 ml × 2). The organic layer was washed with brine (10 ml), dried over Na2SO4, and evaporated to dryness to give the title compound (160 mg, 78%). MS: M / e 319 (M+1). + .

[0453] Step C: 2-(8-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-7-fluoro-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0454] A solution of 2-(8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-7-fluoro-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (160 mg, 0.50 mmol), 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethan-1-ol (209 mg, 1.00 mmol), (cyanomethyl)trimethylphosphonium iodide (367 mg, 1.50 mmol) and DIEA (649 mg, 5 mmol) in MeCN (4 ml) is stirred at 100° C. overnight. The reaction is diluted with EA (20 ml) and washed with brine (10 ml). The organic layer is concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (0-5% MeOH / DCM) to give the title compound A26, which was separated into compound A26a (24 mg) and compound A26b (24 mg) by chiral preparative HPLC. The chiral separation conditions were as follows: [Table 8]

[0455] Compound A26: 11H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 0.17H), 7.87 (s, 1H), 6.86 - 6.78 (m, 3H), 4.56 (s, 0.5H), 4.39 (s, 0.5H), 4.04 (s, 2H), 3.90 (d, J = 5.8 Hz, 2H), 3.78 (d, J = 11.8 Hz, 0.5H), 3.70 (s, 0.5H), 3.67 (s, 3H), 3.60 (dd, J = 15.3, 9.3 Hz, 1H), 3.48 (q, J = 6.5 Hz, 0.5H), 3.38 (s, 0.5H), 2.94 (d, J = 8.2 Hz, 0.5H), 2.65 (d, J = 12.3 Hz, 1H), 2.54 (s, 1H), 2.10 (d, J = 11.1 Hz, 0.5H), 1.29 - 1.24 (m, 7.5H), 1.22 (t, J = 7.2 Hz, 3H), 1.13 (d, J = 6.5 Hz, 1.5H), 1.04 (d, J = 6.3 Hz, 1.5H), 0.94 (d, J = 6.3 Hz, 1.5H) ppm. MS: M / e 509 (M+1) + .

[0456] Compound A26a (earlier peak): 1 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 6.87 - 6.82 (m, 1H), 6.81 - 6.77 (m, 2H), 4.57 (s, 1H), 4.05 (s, 2H), 3.91 (s, 2H), 3.67 (s, 3H), 3.64 - 3.55 (m, 2H), 3.40 - 3.34 (m, 1H), 3.31 (s, 1H), 2.94 (dd, J = 8.3 Hz, 3.6 Hz, 1H), 2.68 (s, 1H), 1.28 (s, 6H), 1.26 (d, J = 6.6 Hz, 3H), 1.22 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H) ppm. MS: M / e 509 (M+1) + .

[0457] Compound A26b (later peak):1 H NMR(400 MHz, DMSO-d6) δ 7.87(s, 1H), 6.81(d, J = 4.5 Hz, 3H), 4.40(s, 1H), 4.04(s, 2H), 3.89(s, 2H), 3.77(d, J = 6.7 Hz, 1H), 3.70(s, 1H), 3.67(s, 3H), 3.48(q, J = 6.7 Hz, 1H), 3.31(s, 1H), 2.64(dd, J = 12 Hz, 4 Hz, 1H), 2.09(dd, J = 11.9 Hz, 3.8 Hz, 1H), 1.27(d, J = 3.8 Hz, 6H), 1.20(d, J = 6.5 Hz, 3H), 1.13(d, J = 6.4 Hz, 3H), 1.03(d, J = 6.3 Hz, 3H) ppm. MS: M / e 509(M+1) + .

[0458] Compound A27: 2-(cyanomethyl)-8-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-7-carbonitrile [ka]

[0459] Step A: tert-Butyl (2R,5S)-4-(7-bromo-2-(cyanomethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0460] A solution of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (500 mg, 1.25 mmol) and NBS (245 mg, 1.38 mmol) in CH3CN (10 mL) was stirred at room temperature for 0.5 h. The solution was diluted with EA (20 mL) and then washed with brine (10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (50-80% EA / PE) to give the title compound (598 mg, 100%). MS: M / e 479, 481 (M+1). + .

[0461] Step B: tert-Butyl (2R,5S)-4-(7-cyano-2-(cyanomethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0462] A solution of tert-butyl (2R,5S)-4-(7-bromo-2-(cyanomethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (598 mg, 1.25 mmol), Zn(CN) (439 mg, 3.75 mmol), and Pd(PPh) (144 mg, 0.12 mmol) in DMF (10 ml) was stirred at 100 °C under N for 2 days. The mixture was poured into water (20 ml) and then extracted with EA (15 ml × 2). The organic layer was washed with brine (10 ml), dried over NaSO, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (60–100% EA / PE) to give the title compound (531 mg, crude). MS: M / e 426(M+1) + .

[0463] Step C: 2-(cyanomethyl)-8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-7-carbonitrile [ka]

[0464] A solution of tert-butyl (2R,5S)-4-(7-cyano-2-(cyanomethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-dimethylpiperazine-1-carboxylate (531 mg, crude) and TFA (4 ml) in DCM (16 ml) is stirred at room temperature for 30 min. The solution is diluted with DCM (15 ml) and then washed with aqueous NaHCO3 (10 ml × 2). The organic layer is washed with brine (10 ml), dried over Na2SO4, and evaporated to dryness to give the title compound (406 mg, crude). MS: M / e 326 (M+1) + .

[0465] Step D: 2-(cyanomethyl)-8-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-7-carbonitrile [ka]

[0466] A solution of 2-(cyanomethyl)-8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazine-7-carbonitrile (200 mg, 0.61 mmol), 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethan-1-ol (192 mg, 0.92 mmol), (cyanomethyl)trimethylphosphonium iodide (447 mg, 1.84 mmol), and DIEA (791 mg, 6.13 mmol) in MeCN (6 ml) is stirred at 100° C. overnight. The reaction is diluted with EA (20 ml) and washed with brine (10 ml). The organic layer is concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (0-5% MeOH / DCM) to give the title compound A27, which was separated into compound A27a (19 mg) and compound A27b (24 mg) by chiral preparative HPLC. The chiral separation conditions were as follows: [Table 9]

[0467] Compound A27: 11H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 6.86 - 6.78 (m, 3H), 4.09 (s, 2H), 3.92 (s, 0.5H), 3.90 (d, J = 3.2 Hz, 2H), 3.73 (d, J = 11.5 Hz, 0.5H), 3.63 (s, 3H), 3.56 - 3.44 (m, 1H), 3.36 (q, J = 6.5 Hz, 0.5H), 2.94 (d, J = 9.2 Hz, 0.5H), 2.88 - 2.79 (m, 1H), 2.73 (d, J = 9.8 Hz, 0.5H), 2.54 (s, 2H), 2.17 (d, J = 11.8 Hz, 0.5H), 1.47 (d, J = 6.6 Hz, 1.5H), 1.33 - 1.26 (m, 7.5H), 1.21 (t, J = 6.2 Hz, 3H), 0.97 (d, J = 6.2 Hz, 1.5H), 0.84 (d, J = 6.3 Hz, 1.5H) ppm. MS: M / e 516 (M+1)+.

[0468] Compound A27a (earlier peak): 1 1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 6.87 - 6.79 (m, 3H), 4.09 (s, 2H), 3.91 (s, 2H), 3.73 (d, J = 11.8 Hz, 1H), 3.63 (s, 3H), 3.49 (q, J = 8.1 Hz, 1H), 3.33 - 3.30 (m, 1H), 2.95 (d, J = 8.5 Hz, 1H), 2.89 - 2.79 (m, 2H), 2.55 - 2.51 (m, 1H), 1.48 (d, J = 6.3 Hz, 3H), 1.28 (d, J = 2.4 Hz, 6H), 1.20 (d, J = 6.3 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H) ppm. MS: M / e 516 (M+1) + .

[0469] Compound A27b (later peak): 1H NMR(400 MHz, DMSO-d6) δ 8.00(s, 1H), 6.80(d, J = 8.0 Hz, 3H), 4.09(s, 2H), 3.99-3.91(m, 1H), 3.90(s, 2H), 3.63(s, 3H), 3.55-3.49(m, 1H), 3.37(q, J = 6.1 Hz, 1H), 3.31(s, 1H), 2.72(d, J =8.3 Hz, 1H), 2.53(m, 1H), 2.18(d, J = 12.5 Hz, 1H), 1.30(d, J = 6.3 Hz, 3H), 1.27(d, J = 3.6 Hz, 6H), 1.22(d, J = 6.4 Hz, 3H), 0.97(d, J = 6.5 Hz, 3H) ppm. MS: M / e 516(M+1) + .

[0470] Compound A28: 2-(8-((2S,5R)-4-(1-(8-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0471] Step A: 8-Fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxane-6-carbonitrile [ka]

[0472] To a solution of 3,4-difluoro-5-hydroxybenzonitrile (1.7 g, 10.9 mmol) and Cs2CO3 (14.3 g, 43.9 mmol) in DMA (50 mL) was added 2,2-dimethyloxetane (6.3 g, 87.2 mol) at room temperature. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was filtered. To the filtrate was added H2O (50 mL). The mixture was extracted with PE (100 mL × 3). The combined organic layers were washed to give the crude product. The crude product was purified by flash column chromatography (PE:EA = 5:1) to give the title compound (1.3 g, 57%). MS: M / e 208 (M+1) + .

[0473] Step B: 8-Fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxane-6-carbaldehyde [ka]

[0474] To a solution of 8-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxane-6-carbonitrile (1.3 g, 6.3 mmol) in THF (20 mL) was added DIABL-H (9.4 mL, 9.4 mmol, 1 M in n-hexane) portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched with 2 N HCl (30 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was extracted with EtOAc (50 mL × 3). The organic layer was concentrated and purified by flash column chromatography to give the title compound (0.9 g, 70%). MS: M / e 211 (M+1) + .

[0475] Step C: 1-(8-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethan-1-ol [ka]

[0476] To a solution of 8-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxane-6-carbaldehyde (0.9 g, 4.3 mmol) in THF (10 mL) was added MeMgBr (2.2 mL, 6.4 mmol, 3 M in EtO) portionwise at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with HO (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were concentrated and purified by flash column chromatography to give the title compound (0.55 g, 57% yield).

[0477] Step D: 2-(8-((2S,5R)-4-(1-(8-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0478] A solution of 2-(8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (60 mg, 0.2 mmol), 1-(8-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethan-1-ol (90 mg, 0.4 mmol), (cyanomethyl)trimethylphosphonium iodide (95 mg, 0.4 mmol), and DIPEA (130 mg, 1.0 mmol) in CHCN (2 mL) was stirred at 100 °C overnight. After completion, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Method B) to give the title compound (27 mg, 26%). 1H NMR(400 MHz, CD3OD) δ 7.78(s, 1H), 6.74 - 6.66(m, 2H), 5.62(s, 1H), 3.97 - 3.93(m, 4H), 3.74(s, 3H), 3.59 - 3.42(m, 3H), 2.97 - 2.80(m, 2H), 1.39 - 1.23(m, 14H), 1.13 - 1.01(m, 3H) ppm. MS: M / e 509(M+1) +

[0479] Compound A29: 2-(8-((2S,5R)-4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0480] A solution of 2-(8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (50 mg, 0.11 mmol), 1-(benzo[d][1,3]dioxol-5-yl)ethan-1-ol (21 mg, 0.13 mmol), (cyanomethyl)trimethylphosphonium iodide (122 mg, 0.5 mmol), and DIPEA (108 mg, 0.83 mmol) in MeCN (10 ml) is stirred at 100° C. overnight. After completion, the solution is concentrated under reduced pressure. The resulting residue is purified by preparative HPLC (Method A) to give the title compound (20 mg, 42%). 1H NMR(400 MHz, CD3OD) δ 7.78(s, 1H), 6.93(s, 1H), 6.82(t, J = 7.0 Hz, 1H), 6.78 - 6.71(m, 1H), 5.92(dd, J = 4.4, 3.4 Hz, 2H), 5.61(d, J = 1.4 Hz, 1H), 5.12 - 4.89(m, 1H), 4.88 - 4.38(m, 2H), 3.94(s, 2H), 3.73(s, 3H), 3.60(d, J = 10.1 Hz, 1H), 3.51 - 3.38(m, 1H), 2.99(s, 1H), 2.81(dd, J = 29.9, 12.2 Hz, 1H), 1.40 - 1.21(m, 6H), 1.16 - 0.99(m, 3H). MS: M / e 449(M+1) +

[0481] Compound A30: 2-(8-((2S,5R)-4-(1-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0482] A solution of 2-(8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (50 mg, 0.11 mmol), 1-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethan-1-ol (24 mg, 0.13 mmol), (cyanomethyl)trimethylphosphonium iodide (122 mg, 0.5 mmol), and DIPEA (108 mg, 0.83 mmol) in MeCN (10 ml) is stirred at 100° C. overnight. After completion, the solution is concentrated under reduced pressure. The resulting residue is purified by preparative HPLC (Method A) to give the title compound (15 mg, 30%). 1H NMR(400 MHz, CD3OD) δ 7.78(s, 1H), 6.81(s, 1H), 6.75(d, J = 7.8 Hz, 1H), 6.68 - 6.59(m, 1H), 5.61(d, J = 2.0 Hz, 1H), 4.80 - 4.48(m, 1H), 3.94(s, 2H), 3.73(s, 3H), 3.64 - 3.37(m, 3H), 3.02 - 2.92(m, 1H), 2.89 - 2.64(m, 2H), 1.66 - 1.61(m, 6H), 1.41 - 1.30(m, 3H), 1.29 - 1.21(m, 3H), 1.14 - 0.97(m, 3H). MS: M / e 477(M+1) +

[0483] Compound A31: 2-(8-((2S,5R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0484] A solution of 2-(8-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (50 mg, 0.11 mmol), 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-ol (25 mg, 0.13 mmol), (cyanomethyl)trimethylphosphonium iodide (122 mg, 0.5 mmol), and DIPEA (108 mg, 0.83 mmol) in MeCN (10 ml) is stirred at 100° C. overnight. After completion, the solution is concentrated under reduced pressure. The resulting residue is purified by preparative HPLC (Method A) to give the title compound (22 mg, 43%). 1H NMR(400 MHz, CD3OD) δ 7.78(s, 1H), 7.30(s, 1H), 7.20 - 7.10(m, 2H), 5.62(d, J = 1.8 Hz, 1H), 4.88 - 4.24(m, 2H), 3.94(s, 2H), 3.73(s, 3H), 3.72 - 3.38(m, 3H), 3.05 - 2.79(m, 2H), 1.41 - 1.33(m, 3H), 1.32 - 1.21(m, 3H), 1.16 - 1.00(m, 3H). MS: M / e 485(M+1) +

[0485] Compound A32: 2-(8-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0486] To a mixture of 2-(8-((2S,5R)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (65 mg, 0.2 mmol) in acetonitrile (3 mL) is added trimethyl(prop-2-yn-1-yl)phosphonium (97 mg, 0.4 mmol), 1-(4-fluoro-2-methoxyphenyl)ethan-1-ol (68 mg, 0.4 mmol), and DIEA (129 mg, 1 mmol). The reaction mixture is sealed and stirred overnight at 105 °C under a nitrogen atmosphere. The mixture is added HO and extracted with ethyl acetate. The organic phase is washed with brine, dried over NaSO, filtered, and concentrated. The crude product was purified by preparative TLC (DCM:MeOH=13:1) to give the title compound (10 mg). 1H NMR(400 MHz, DMSO-d6) δ 7.92(d, J = 3.2 Hz, 1H), 7.65-7.47(m, 1H), 6.94(t, J = 10.7 Hz, 1H), 6.84(q, J = 8.2 Hz, 1H), 5.57(s, 1H), 4.23(d, J = 6.6 Hz, 0.5H), 4.09(s, 2H), 4.05(d, J = 6.3 Hz, 0.5H), 3.86(s, 3H), 3.67(s, 3H), 3.20 - 3.05(m, 1H), 2.88-2.78(m, 1H), 2.40 - 2.27(m, 1H), 2.05-1.70(m, 2H), 1.68-1.35(m, 3H), 1.30(s, 1H), 1.24(dd, J = 21.1, 6.5 Hz, 3H), 1.2-0.81(m, 4H), 0.69(d, J = 19.6 Hz, 3H) ppm. MS: M / e 481(M+1) + .

[0487] Compound A33: 2-(8-((2S,5R)-4-(1-(2-(difluoromethoxy)-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0488] Step A: 1-(2-(difluoromethoxy)-4-fluorophenyl)ethan-1-one [ka]

[0489] A mixture of 1-bromo-2-(difluoromethoxy)-4-fluorobenzene (2.4 g, 10 mmol), tributyl(1-ethoxyvinyl)stannane (4.3 g, 12 mmol), and Pd(PPh3)2Cl2 (701 mg, 1 mmol) in toluene (20 mL) is stirred overnight at 100 °C under N2. HCl (1 N, 50 mL) is added dropwise to the resulting solution, and the mixture is stirred at room temperature for 1 h. The mixture is diluted with EtOAc, treated with saturated aqueous NaHCO3 to a pH of about 8, washed with brine, dried, and concentrated to dryness. The resulting residue is purified by flash column chromatography to give the title compound (1.6 g, 78%). MS: M / e 205 (M+1). + .

[0490] Step B: 1-(2-(difluoromethoxy)-4-fluorophenyl)ethan-1-ol [ka]

[0491] To a solution of 1-(2-(difluoromethoxy)-4-fluorophenyl)ethan-1-one (1.6 g, 7.8 mmol) in MeOH (10 mL) is added NaBH (300 mg, 7.8 mmol) at room temperature, and the mixture is stirred at room temperature for 30 minutes. The mixture is quenched with water and extracted with DCM. The combined organic layers are washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue is purified by flash column chromatography to give the title compound (1.2 g, 75%). MS: M / e 207 (M+1) + .

[0492] Step C: 2-(8-((2S,5R)-4-(1-(2-(difluoromethoxy)-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0493] To a solution of 1-(2-(difluoromethoxy)-4-fluorophenyl)ethan-1-ol (82 mg, 0.4 mmol), 2-(8-((2S,5R)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (65 mg, 0.2 mmol), and (cyanomethyl)trimethylphosphonium iodide (97 mg, 0.4 mmol) in CHCN (3 mL) is added DIPEA (129 mg, 1 mmol). The mixture is sealed in a vial and heated at 100 °C overnight. The mixture is then cooled to room temperature, diluted with water, extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated. The resulting residue was purified by flash column chromatography (DCM:MeOH = 13:1) to give the title compound (21 mg, 20%). 1 H NMR(400 MHz, DMSO-d6) δ 7.86(d, J = 2.5 Hz, 1H), 7.71 - 7.57(m, 1H), 7.52 - 7.16(m, 1H), 7.17 - 7.06(m, 2H), 5.52(s, 1H), 4.16 - 3.93(m, 3H), 3.60(s, 3H), 3.33(s, 3H), 3.16 - 3.00(m, 1H), 2.90-2.75(m, 1H), 2.29 - 2.14(m, 1H), 2.02 - 1.80(m, 1H), 1.71 - 1.37(m, 3H), 1.22(dd, J = 18.6, 6.4 Hz, 3H), 0.99-0.82(m, 3H), 0.70-0.52(m, 3H) ppm. MS: M / e 517(M+1) + .

[0494] Compound A34: 2-(8-((2S,5R)-4-(1-(2-(difluoromethyl)-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0495] Step A: 1-(2-(difluoromethyl)-4-fluorophenyl)ethan-1-one [ka]

[0496] A mixture of 1-bromo-2-(difluoromethyl)-4-fluorobenzene (1.12 g, 5 mmol), tributyl(1-ethoxyvinyl)stannane (2.17 g, 6 mmol), and Pd(PPh3)2Cl2 (350 mg, 0.5 mmol) in toluene (10 mL) was stirred overnight at 100 °C under N2. HCl (1 N, 30 mL) was added dropwise to the resulting solution, and the mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc, treated with saturated aqueous NaHCO3 to a pH of approximately 8, washed with brine, dried, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (800 mg, 85%). 1 H NMR(400 MHz, CD3OD) δ 8.10(dd, J = 8.2, 5.9 Hz, 1H), 7.52(d, J = 9.5 Hz, 1H), 7.49 - 7.19(m, 2H), 2.66 - 2.53(m, 3H). MS: M / e 189(M+1) + .

[0497] Step B: 1-(2-(difluoromethyl)-4-fluorophenyl)ethan-1-ol [ka]

[0498] To a solution of 1-(2-(difluoromethyl)-4-fluorophenyl)ethan-1-ol (400 mg, 2.13 mmol) in MeOH (5 mL) was added NaBH (65 mg, 1.7 mmol) at room temperature and the mixture was stirred at room temperature for 30 minutes. The mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (190 mg, 48%). MS: M / e 191 (M+1) + .

[0499] Step C: 2-(8-((2S,5R)-4-(1-(2-(difluoromethyl)-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0500] To a solution of 1-(2-(difluoromethyl)-4-fluorophenyl)ethan-1-ol (57 mg, 0.3 mmol), 2-(8-((2S,5R)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (65 mg, 0.2 mmol), and (cyanomethyl)trimethylphosphonium iodide (97 mg, 0.4 mmol) in CHCN (2 mL) is added DIPEA (103 mg, 0.8 mmol). The mixture is sealed in a vial and heated at 100 °C overnight. The mixture is then cooled to room temperature, diluted with water, extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated. The resulting residue was purified by flash column chromatography (DCM:MeOH = 13:1) to give the title compound (17 mg, 17%). 1H NMR(400 MHz, CD3OD) δ 7.86 - 7.62(m, 2H), 7.58-7.17(m, 3H), 5.61(d, J = 9.5 Hz, 1H), 4.14 - 3.90(m, 3H), 3.73(s, 3H), 3.48(d, J = 13.5 Hz, 1H), 3.27(s, 2H), 3.21-3.04(m, 1H), 2.90 - 2.66(m, 1H), 2.40 - 2.21(m, 1H), 2.09(s, 1H), 1.87 - 1.47(m, 3H), 1.33(dd, J = 14.1, 6.5 Hz, 3H), 1.09-0.93(m, 3H), 0.73-0.55(m, 3H) ppm. MS: M / e 501(M+1) + .

[0501] Compound A35: 2-(8-((2S,5R)-2,5-diethyl-4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0502] Step A: 1-(pyridin-4-yl)ethan-1-ol [ka]

[0503] To a solution of 1-(pyridin-4-yl)ethan-1-one (1.2 g, 10 mmol) in EtOH (10 mL) was added NaBH (190 mg, 5 mmol) at 0 °C, and the mixture was stirred at room temperature for 30 min. The mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (900 mg, 75%). MS: M / e 124 (M+1) + .

[0504] Step B: 2-(8-((2S,5R)-2,5-diethyl-4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0505] To a solution of 1-(pyridin-4-yl)ethan-1-ol (37 mg, 0.3 mmol), 2-(8-((2S,5R)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (65 mg, 0.2 mmol), and (cyanomethyl)trimethylphosphonium iodide (97 mg, 0.4 mmol) in CHCN (3 mL) was added DIPEA (129 mg, 1 mmol). The mixture was sealed in a vial and heated at 100 °C overnight. The mixture was then cooled to room temperature, diluted with water, extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated. The resulting residue was purified by flash column chromatography (DCM:MeOH = 13:1) to give the title compound (5 mg, 6%). 1 H NMR(400 MHz, CDCl3) δ 8.58(s, 2H), 7.35(s, 3H), 5.60(s, 1H), 3.78(d, J = 2.5 Hz, 2H), 3.75-3.55(m, 4H), 3.46-3.20(m, 1H), 3.10-2.90(m, 1H), 2.88-2.61(m, 1H), 2.40 - 2.22(m, 1H), 2.16-1.83(m, 2H), 1.82-1.53(m, 3H), 1.46(s, 1H), 1.35 - 1.27(m, 3H), 0.94(dd, J = 20.8, 13.6 Hz, 3H), 0.67(dt, J = 34.0, 7.3 Hz, 3H) ppm. MS: M / e 434(M+1) + .

[0506] Compound A36: 2-(8-((2S,5R)-2,5-diethyl-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0507] To a solution of 2-(8-((2S,5R)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (65 mg, 0.2 mmol) and 1-(bromomethyl)-4-(trifluoromethoxy)benzene (76 mg, 0.3 mmol) in CHCN (2 mL) was added DIPEA (77 mg, 0.6 mmol). The reaction mixture was sealed in a vial and heated at 90 °C for 2 h, then cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM:MeOH = 15:1) to give the title compound (29 mg, 29%). 1 H(400 MHz, DMSO-d6) δ 7.93(s, 1H), 7.55(d, J = 8.5 Hz, 2H), 7.39(d, J = 8.0 Hz, 2H), 5.60(s, 1H), 4.10(s, 2H), 3.78(d, J = 14.0 Hz, 1H), 3.66(d, J = 11.3 Hz, 4H), 3.41(d, J = 10.7 Hz, 3H), 2.86 - 2.67(m, 2H), 2.46(d, J = 11.3 Hz, 1H), 1.94(dt, J = 15.4, 7.6 Hz, 1H), 1.70(dd, J = 13.3, 6.8 Hz, 1H), 1.59(d, J = 7.4 Hz, 2H), 0.93(t, J = 7.2 Hz, 3H), 0.74(t, J = 7.3 Hz, 3H) ppm. MS: M / e 503(M+1) + .

[0508] Compound A37: 2-(8-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0509] Step A: 1-(6-cyclopropylpyridin-3-yl)ethan-1-one [ka]

[0510] A mixture of 1-(6-bromopyridin-3-yl)ethan-1-one (1 g, 5 mmol), cyclopropylboronic acid (473 mg, 5.5 mmol), tricyclohexylphosphine (140 mg, 0.5 mmol), potassium phosphate (1.6 g, 7.5 mmol), and Pd(OAc) (112 mg, 0.5 mmol) in toluene (15 mL) and water (1.5 mL) was stirred overnight at 100 °C under N. The mixture was treated with water (50 mL), extracted with EtOAc (20 mL × 3), washed with brine (50 mL), dried, and concentrated to dryness. The resulting residue was purified by flash column chromatography (0–50% EtOAc / PE within 25 min) to give the title compound (620 mg, 77%). MS: M / e 162 (M+1). + .

[0511] Step B: 1-(6-cyclopropylpyridin-3-yl)ethan-1-ol [ka]

[0512] To a solution of 1-(6-cyclopropylpyridin-3-yl)ethan-1-one (620 mg, 3.8 mmol) in MeOH (10 mL) was added NaBH (117 mg, 3.1 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 min. The mixture was treated with water (100 mL) and extracted with DCM (20 mL × 2). The combined organic layers were dried over NaSO and concentrated to dryness. The resulting residue was purified by flash column chromatography (0–100% EtOAc / PE in 25 min) to give the title compound (420 mg, 68%). MS: M / e 164 (M+1). + .

[0513] Step C: 2-(8-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0514] A mixture of 2-(8-((2S,5R)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (32.8 mg, 0.1 mmol), 1-(6-cyclopropylpyridin-3-yl)ethan-1-ol (32.6 mg, 0.2 mmol), (cyanomethyl)trimethylphosphonium iodide (72.9 mg, 0.3 mmol), and DIPEA (129 mg, 1 mmol) in CHCN (4 mL) is stirred in a sealed tube at 100 °C overnight. The reaction mixture is diluted with EtOAc (15 mL), washed with HO, brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by preparative TLC (CH2Cl2 / MeOH=10 / 1) to give the title compound A37, which was further separated into compound A37a (5 mg) and compound A37b (5 mg) by preparative HPLC (Method A).

[0515] Compound A37a (early peak):1 1H NMR (500 MHz, CD3OD) δ 8.30 (d, J = 2.0 Hz, 1H), 7.78 (s, 1H), 7.70 (dd, J = 8.0, 2.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 5.60 (s, 1H), 3.92 (s, 2H), 3.82 - 3.76 (m, 1H), 3.73 (s, 3H), 3.30 - 3.25 (m, 3H), 3.00 - 2.86 (m, 2H), 2.41 - 2.34 (m, 1H), 2.13 - 2.02 (m, 2H), 1.86 - 1.78 (m, 1H), 1.57 - 1.48 (m, 2H), 1.35 (d, J = 6.4 Hz, 3H), 1.05 - 0.92 (m, 7H), 0.72 (t, J = 7.2 Hz, 3H) ppm. MS: M / e 474 (M+1) + .

[0516] Compound A37b (slower peak): 1 1H NMR (500 MHz, CD3OD) δ 8.33 (d, J = 2.0 Hz, 1H), 7.78 (s, 1H), 7.72 (dd, J = 8.0, 2.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 5.59 (s, 1H), 3.93 (s, 2H), 3.73 (s, 3H), 3.67 - 3.60 (m, 1H), 3.52 - 3.46 (m, 1H), 3.35 - 3.30 (m, 2H), 3.17 - 3.11 (m, 1H), 2.71 - 2.65 (m, 1H), 2.36 - 2.29 (m, 1H), 2.11 - 2.05 (m, 1H), 1.95 - 1.86 (m, 1H), 1.72 - 1.50 (m, 3H), 1.32 (d, J = 6.4 Hz, 3H), 1.07 - 0.89 (m, 7H), 0.63 (t, J = 7.2 Hz, 3H) ppm. MS: M / e 474 (M+1) + .

[0517] Compound A38: 2-(8-((2S,5R)-2,5-diethyl-4-(1-(6-isopropylpyridin-3-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0518] Step A: 1-(6-Isopropylpyridin-3-yl)ethan-1-one [ka]

[0519] To a stirred solution of 1-(6-bromopyridin-3-yl)ethan-1-one (2 g, 10 mmol) in anhydrous THF (30 mL) under N2, XantphosPdG3 (190 mg, 0.2 mmol) was added, followed by isopropylzinc(II) bromide (0.5 M, 30 mL, 15 mmol). After the addition, the reaction mixture was stirred overnight at 30 °C in a sealed tube. The reaction mixture was added dropwise to MeOH to quench the reaction. Most of the solvent was removed to give a residue, which was then treated with EtOAc (200 mL), washed with brine, dried over Na2SO4, concentrated, and purified by flash column chromatography to give the title compound (1.17 g, 71.8%). MS: M / e 164 (M+1). + .

[0520] Step B: 1-(6-Isopropylpyridin-3-yl)ethan-1-ol [ka]

[0521] To a stirred solution of 1-(6-isopropylpyridin-3-yl)ethan-1-one (660 mg, 4 mmol) in MeOH (25 mL) was added NaBH (153 mg, 4 mmol). The reaction mixture was then stirred for 30 minutes. The reaction mixture was quenched with H O, and most of the MeOH was then removed to obtain the aqueous layer, which was then extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over Na SO and concentrated to give the title compound (580 mg, 87.8%). MS: M / e 166 (M+1). + .

[0522] Step C: 2-(8-((2S,5R)-2,5-diethyl-4-(1-(6-isopropylpyridin-3-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0523] A mixture of 1-(6-isopropylpyridin-3-yl)ethan-1-ol (201 mg, 1.22 mmol), 2-(8-((2S,5R)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (200 mg, 0.61 mmol), (cyanomethyl)trimethylphosphonium iodide (590 mg, 2.44 mmol), and DIPEA (314 mg, 2.44 mmol) in MeCN (5 mL) is stirred at 100 °C overnight. The reaction mixture is diluted with water (50 mL), extracted with water (10 mL × 2), dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography (0 to 10% MeOH / DCM within 30 min) to give the title compound A38 (200 mg), which was further separated into compound A38a (46 mg) and compound A38b (68 mg) by preparative HPLC (Method A).

[0524] Compound A38a (early peak):1 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.83 (s, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 5.49 (s, 1H), 4.00 (s, 2H), 3.72 (q, J = 6.1 Hz, 1H), 3.58 (s, 3H), 3.12 (d, J = 12.1 Hz, 1H), 2.98 (dt, J = 13.7, 6.8 Hz, 1H), 2.86 (d, J = 11.9 Hz, 1H), 2.75 (d, J = 8.7 Hz, 1H), 2.52 (s, 2H), 2.25 (s, 1H), 2.03 - 1.88 (m, 1H), 1.70 - 1.56 (m, 1H), 1.50 - 1.35 (m, 2H), 1.27 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.9 Hz, 6H), 0.83 (t, J = 7.1 Hz, 3H), 0.61 (t, J = 7.0 Hz, 3H) ppm. MS: M / e 476 (M+1) + .

[0525] Compound A38b (the slower peak): 1 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.84 (s, 1H), 7.71 - 7.61 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 5.48 (s, 1H), 4.01 (s, 2H), 3.58 (s, 4H), 3.33 (d, J = 11.5 Hz, 2H), 2.99 (dt, J = 13.7, 8.2 Hz, 2H), 2.52 (s, 2H), 2.16 (d, J = 11.9 Hz, 1H), 1.78 (d, J = 6.9 Hz, 1H), 1.47 (dd, J = 20.0, 7.8 Hz, 3H), 1.22 (dd, J = 16.8, 6.3 Hz, 9H), 0.94 (t, J = 7.0 Hz, 3H), 0.49 (s, 3H) ppm. MS: M / e 476 (M+1) + .

[0526] Compound A39: 5-(1-((2R,5S)-4-(2-(cyanomethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-diethylpiperazin-1-yl)ethyl)picolinonitrile [ka]

[0527] Step A: 5-Acetylpicolinonitrile [ka]

[0528] A mixture of 1-(6-bromopyridin-3-yl)ethan-1-one (2.0 g, 10 mmol) and CuCN (1.79 g, 20 mmol) in DMF (20 mL) was stirred at 110 °C for 16 h. The mixture was diluted with EtOAc (50 mL) and filtered through a pad of diatomaceous earth. The filtrate was washed with brine (20 mL × 3), dried over NaSO, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title compound (700 mg, 48%). 1 H NMR (400 MHz, CDCl3) δ 9.22(s, 1H), 8.36(d, J = 8.0 Hz, 1H), 7.83(d, J = 8.0 Hz, 1H), 2.69(s, 3H) ppm.

[0529] Step B: 5-(1-hydroxyethyl)picolinonitrile [ka]

[0530] To a solution of 5-acetylpicolinonitrile (350 mg, 2.4 mmol) in MeOH (5 mL) at 0 °C, NaBH (91 mg, 2.4 mmol) was added portionwise and the mixture was stirred at room temperature for 1 h. The mixture was treated with NaHCO (20 mL) and extracted with EtOAc (15 mL × 3). The combined extracts were washed with brine (15 mL × 2), dried over NaSO, filtered, and concentrated to dryness to give the title compound (340 mg, 95%). 1 H NMR(400 MHz, DMSO-d6) δ 8.71(s, 1H), 8.09 - 7.89(m, 2H), 5.56(d, J = 4.4 Hz, 1H), 4.95 - 4.79(m, 1H), 1.35(d, J = 6.4 Hz, 3H) ppm.

[0531] Step C: 5-(1-((2R,5S)-4-(2-(cyanomethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-diethylpiperazin-1-yl)ethyl)picolinonitrile [ka]

[0532] To a solution of 2-(8-((2S,5R)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (33 mg, 0.1 mmol), 5-(1-hydroxyethyl)picolinonitrile (30 mg, 0.2 mmol), and (cyanomethyl)trimethylphosphonium iodide (73 mg, 0.30 mmol) in CHCN (1 mL) is added DIPEA (77 mg, 0.60 mmol). The stirred mixture is stirred in a sealed tube at 105° C. for 16 h. Additional (cyanomethyl)trimethylphosphonium iodide (73 mg, 0.30 mmol) and DIPEA (77 mg, 0.60 mmol) are added. The resulting mixture is continued to stir at 105° C. for 20 h. The mixture was cooled, diluted with EtOAc (10 mL), washed with brine (5 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (16 mg, 35%). 1 H NMR(400 MHz, CD3OD) δ 8.83 - 8.66(m, 1H), 8.14 - 7.98(m, 1H), 7.90 - 7.82(m, 1H), 7.79(s, 1H), 5.70 - 5.53(m, 1H), 4.03 - 3.77(m, 3H), 3.73(s, 3H), 3.60 - 3.36(m, 1H), 3.25 - 3.08(m, 1H), 3.06 - 2.86(m, 1H), 2.85 - 2.18(m, 2H), 2.15 - 1.48(m, 5H), 1.43 - 1.33(m, 3H), 1.08 - 0.88(m, 3H), 0.82 - 0.57(m, 3H) ppm. MS: M / e 459(M+1) + .

[0533] Compound A40: 2-(5-(1-((2R,5S)-4-(2-(cyanomethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-diethylpiperazin-1-yl)ethyl)pyridin-2-yl)-2-methylpropanenitrile [ka]

[0534] Step A: 2-(5-bromopyridin-2-yl)-2-methylpropanenitrile [ka]

[0535] To a mixture of 2-(5-bromopyridin-2-yl)acetonitrile (2.0 g, 10 mmol) and t-BuOK (2.8 g, 25 mmol) in THF (30 mL) was added dropwise MeI (3.6 g, 25 mmol) at 0 °C, and the mixture was stirred at room temperature for 16 h. The resulting suspension was diluted with EtOAc (50 mL) and filtered. The filtrate was washed with brine (20 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the title compound (2.05 g, 91%). 1 H NMR (400 MHz, CDCl3) δ 8.65(s, 1H), 7.85(d, J = 8.4 Hz, 1H), 7.50(d, J = 8.4 Hz, 1H), 1.74(s, 6H) ppm.

[0536] Step B: 2-(5-acetylpyridin-2-yl)-2-methylpropanenitrile [ka]

[0537] A mixture of 2-(5-bromopyridin-2-yl)acetonitrile (1.0 g, 4.4 mmol), tributyl(1-ethoxyvinyl)stannane (2.0 g, 5.5 mmol), and Pd(PPh3)2Cl2 (160 mg, 0.23 mmol) in toluene (12 mL) is stirred at 100 °C under N2 for 16 h. The mixture is cooled and diluted with EtOAc (30 mL). The suspension is filtered through a pad of diatomaceous earth, and the filtrate is washed with brine (20 mL × 2), dried over Na2SO4, filtered, and concentrated. The resulting residue is diluted with EtOAc (20 mL), and a 4 M HCl / dioxane solution (3 mL) is added and stirred for 20 min. The resulting mixture is basified with aqueous NaHCO3, and the mixture is extracted with EtOAc (20 mL × 3). The combined extracts were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title compound (710 mg, 86%). 1 H NMR (400 MHz, CDCl3) δ 9.14(s, 1H), 8.27(d, J = 8.4 Hz, 1H), 7.71(d, J = 8.4 Hz, 1H), 2.64(s, 3H), 1.78(s, 6H) ppm.

[0538] Step C: 2-(5-(1-hydroxyethyl)pyridin-2-yl)-2-methylpropanenitrile [ka]

[0539] To a solution of 2-(5-acetylpyridin-2-yl)-2-methylpropanenitrile (700 mg, 3.7 mmol) in MeOH (10 mL) was added NaBH (140 mg, 3.7 mmol) portionwise at room temperature, and the mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc (20 mL) and treated with NaHCO (20 mL). The aqueous layer was extracted with EtOAc (10 mL × 2). The combined organics were washed with brine (20 mL × 2), dried over NaSO, filtered, and concentrated to dryness to give the title compound (660 mg, 94%).1 H NMR(400 MHz, DMSO-d6) δ 8.54(s, 1H), 7.81(d, J = 8.0 Hz, 1H), 7.53(d, J = 8.0 Hz, 1H), 5.33(d, J = 4.4 Hz, 1H), 4.87 - 4.68(m, 1H), 1.67(s, 6H), 1.34(d, J = 6.4 Hz, 3H) ppm.

[0540] Step D: 2-(5-(1-((2R,5S)-4-(2-(cyanomethyl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-8-yl)-2,5-diethylpiperazin-1-yl)ethyl)pyridin-2-yl)-2-methylpropanenitrile [ka]

[0541] To a solution of 2-(8-((2S,5R)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (33 mg, 0.1 mmol), 2-(5-(1-hydroxyethyl)pyridin-2-yl)-2-methylpropanenitrile (38 mg, 0.2 mmol), and (cyanomethyl)trimethylphosphonium iodide (150 mg, 0.6 mmol) in CHCN (0.5 mL) is added DIPEA (77 mg, 0.60 mmol). The stirred mixture is stirred in a sealed tube at 105 °C for 16 h. The mixture is cooled, diluted with EtOAc (10 mL), washed with brine (5 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the title compound (42 mg, 84%). 1H NMR(400 MHz, CD3OD) δ 8.64 - 8.51(m, 1H), 7.96 - 7.85(m, 1H), 7.78(s, 1H), 7.66 - 7.56(m, 1H), 5.67 - 5.54(m, 1H), 4.00 - 3.91(m, 2H), 3.90 - 3.62(m, 4H), 3.58 - 3.32(m, 2H), 3.29 - 3.12(m, 1H), 3.04 - 2.85(m, 1H), 2.79 - 2.34(m, 1H), 2.32 - 1.99(m, 1H), 1.94 - 1.52(m, 10H), 1.42 - 1.32(m, 3H), 1.10 - 0.88(m, 3H), 0.81 - 0.51(m, 3H) ppm. MS: M / e 501(M+1) + .

[0542] Compound A41: 2-(8-((2S,5R)-2,5-diethyl-4-(1-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0543] Step A: 2-(5-bromopyridin-2-yl)prop-2-ol [ka]

[0544] To a solution of 1-(5-bromopyridin-2-yl)ethan-1-one (5.0 g, 25 mmol) in THF (100 mL) at 0 °C under N2, MeMgBr (3.0 M, 10 mL, 30 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. Aqueous NH4Cl (100 mL) was added, and the mixture was extracted with EtOAc (50 mL × 2). The organics were combined, washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography to give the title compound (1.1 g, 20%). 1 H NMR (400 MHz, DMSO-d6) δ 8.57(s, 1H), 7.98(d, J = 8.4 Hz, 1H), 7.60(d, J = 8.4 Hz, 1H), 5.29(s, 1H), 1.40(s, 6H).

[0545] Step B: 1-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethan-1-one [ka]

[0546] A mixture of 2-(5-bromopyridin-2-yl)prop-2-ol (540 mg, 2.5 mmol), tributyl(1-ethoxyvinyl)stannane (1.2 g, 3.3 mmol), and Pd(PPh3)2Cl2 (90 mg, 0.13 mmol) in toluene (6 mL) was stirred at 100 °C under N2 for 16 h. The mixture was cooled and diluted with EtOAc (20 mL). The suspension was filtered through a pad of diatomaceous earth, and the filtrate was washed with brine (20 mL × 3), dried over Na2SO4, filtered, and concentrated. The resulting residue was diluted with EtOAc (10 mL), and a 4 M HCl / dioxane solution (2 mL) was added and stirred for 20 min. The resulting mixture was basified with aqueous NaHCO3, and the mixture was extracted with EtOAc (10 mL × 3). The combined extracts were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title compound (265 mg, 59%).1 H NMR (400 MHz, DMSO-d6) δ 9.04(s, 1H), 8.26(d, J = 8.4 Hz, 1H), 7.80(d, J = 8.4 Hz, 1H), 5.39(s, 1H), 2.61(s, 3H), 1.45(s, 6H).

[0547] Step C: 2-(5-(1-hydroxyethyl)pyridin-2-yl)prop-2-ol [ka]

[0548] To a solution of 1-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethan-1-one (260 mg, 1.45 mmol) in MeOH (4 mL) at room temperature, NaBH (55 mg, 1.45 mmol) is added portionwise, and the mixture is stirred at room temperature for 1 h. The mixture is diluted with EtOAc (20 mL) and treated with NaHCO (20 mL). The aqueous layer is extracted with EtOAc (10 mL × 2). The combined organics are washed with brine (20 mL × 2), dried over NaSO, filtered, and concentrated to dryness to give the title compound (220 mg, 84%). 1 H NMR(400 MHz, DMSO-d6) δ 8.41(s, 1H), 7.68(d, J = 8.0 Hz, 1H), 7.57(d, J = 8.0 Hz, 1H), 5.22(d, J = 4.0 Hz, 1H), 5.14(s, 1H), 4.80 - 4.62(m, 1H), 1.40(s, 6H), 1.33(d, J = 6.4 Hz, 3H).

[0549] Step D: 2-(8-((2S,5R)-2,5-diethyl-4-(1-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0550] To a solution of 2-(8-((2S,5R)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (33 mg, 0.1 mmol), 2-(5-(1-hydroxyethyl)pyridin-2-yl)prop-2-ol (36 mg, 0.2 mmol), and (cyanomethyl)trimethylphosphonium iodide (150 mg, 0.6 mmol) in CHCN (0.5 mL) is added DIPEA (129 mg, 1.0 mmol). The stirred mixture is stirred in a sealed tube at 105 °C for 16 h. The mixture is cooled, diluted with EtOAc (10 mL), washed with brine (5 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the title compound (32 mg, 76%). 1 H NMR(400 MHz, CD3OD) δ 8.54 - 8.40(m, 1H), 7.90 - 7.73(m, 2H), 7.71 - 7.59(m, 1H), 5.67 - 5.54(m, 1H), 4.00 - 3.89(m, 2H), 3.88 - 3.60(m, 4H), 3.55 - 3.42(m, 1H), 3.35 - 3.10(m, 2H), 3.07 - 2.83(m, 1H), 2.75 - 2.35(m, 1H), 2.34 - 2.00(m, 1H), 1.98 - 1.49(m, 10H), 1.42 - 1.33(m, 3H), 1.08 - 0.89(m, 3H), 0.76 - 0.55(m, 3H). MS: M / e 492(M+1) + .

[0551] Compound A42: 2-(8-((2S,5R)-4-(1-(6-cyclopropyl-2-fluoropyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0552] Step A: 6-Cyclopropyl-2-fluoronicotinaldehyde [ka]

[0553] To a solution of 6-chloro-2-fluoronicotinaldehyde (0.32 g, 2 mmol) and cyclopropylboronic acid (258 mg, 3 mmol) in toluene / HO (10 mL / 1 mL) was added dichlorobis(tricyclohexylphosphine)palladium(II) (147 mg, 0.2 mmol) and KPO (842 mg, 4 mmol). The reaction mixture was stirred overnight at 100 °C under N. The mixture was cooled to room temperature, diluted with water (40 mL), extracted with EA (60 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (130 mg, 39%). MS: M / e 166 (M+1). + .

[0554] Step B: 1-(6-cyclopropyl-2-fluoropyridin-3-yl)ethan-1-ol [ka]

[0555] To a solution of 6-cyclopropyl-2-fluoronicotinaldehyde (1.3 g, 7.8 mmol) in THF (50 mL) was added a solution of CHMgBr in ether (3 mL, 9 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NHCl (30 mL) and HO (100 mL), extracted with EtOAc (100 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (900 mg, 63%). 1H NMR(400 MHz, DMSO-d6) δ 7.84 - 7.76(m, 1H), 7.10(d, J = 7.2 Hz, 1H), 5.31(d, J = 4.0 Hz, 1H), 4.85 - 4.74(m, 1H), 2.08 - 1.98(m, 1H), 1.27(d, J = 6.4 Hz, 3H), 0.96 - 0.87(m, 2H), 0.84 - 0.75(m, 2H) ppm.

[0556] Step C: 2-(8-((2S,5R)-4-(1-(6-cyclopropyl-2-fluoropyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0557] To a solution of 1-(6-cyclopropyl-2-fluoropyridi...

Claims

1. A compound of formula (I), 【Chemistry 477】 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, During the ceremony, X １ is C or N, X ２ and X ３ are each independently selected from —N— or —CH—; sign 【Chemistry 478】 is a single or double bond, R １ is hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; R ２ is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, provided that X １ is N and X １ Bonds connected to 【Chemistry 479】 is a double bond, R ２ does not exist, R ４ is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; R ５ is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; R ５ａ -C(O)-, R ５ａ -C(O)O-, R ５ａ -O-C(O)-, R ５ａ -C(O)NR ５ｂ -, R ５ａ -NR ５ｂ -C(O)-, R ５ａ -SO ２ - or R ５ａ -O-N=CH-, and R ５ａ and R ５ｂ each independently being hydrogen, alkyl, or cycloalkyl; R ６ is absent, hydrogen, halogen, or alkyl unsubstituted or substituted with halogen or cyano, with the proviso that R ６ The bond connecting the nitrogen to which 【Chemical 480】 is a double bond, R ６ does not exist, R ７ , R ９ , R ８ and R １０ each independently represents hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, —C(O)R ７ａ or -alkyl-C(O)R ７ａ and R ７ａ is hydrogen, alkyl, or alkoxy, provided that R ７ and R ９ At least one of them is not hydrogen, or R ７ and R ９ are each hydrogen, and R ８ and R １０ together form two bridgehead atoms plus at least one -CH ２ - moiety, or R ８ and R １０ are each hydrogen, and R ７ and R ９ together form two bridgehead atoms plus at least one -CH ２ - forming a bridge containing a moiety, L １ is a direct bond, -O-, -N(R Ｌ )-, substituted or unsubstituted alkyl, -alkylene, or -C(O)-, wherein R Ｌ is hydrogen or alkyl, Cy １ is unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted heteroaryl; Cy １ optionally one, two, or three substituents R ３ａ is replaced by R ３ａ is deuterium, alkoxy, alkyl, halogen, R ３ｂ -SO ２ -, cycloalkyl, cyano, R ３ｂ -C(O)-N(R ３ｃ ) -, N(R ３ｂ R ３ｃ )-C(O)-, N(R ３ｂ R ３ｃ ), R ３ｂ selected from —O—C(O)—, cycloalkyl or heterocyclyl; Any two R ３ａ are attached to the same carbon and together form a spiro ring, Any two R ３ａ is Cy １ forms a condensed ring with R ３ａ is unsubstituted or substituted with cyano, alkoxy, alkyl, halogen or hydroxy; R ３ｂ and R ３ｃ are each independently hydrogen or alkyl.

2. 2. The method of claim 1, wherein the compound of formula (I) is a compound of formula (II). 【Chemistry 481】

3. 3. The method of claim 2, wherein the compound of formula (II) is a compound of formula (III). 【Chemistry 482】

4. 2. The method of claim 1, wherein the compound of formula (I) is a compound of formula (IV). 【Chemistry 483】

5. 2. The method of claim 1, wherein the compound of formula (I) is a compound of formula (V). 【Chem.484】

6. 2. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (VI): 【Chemistry 485】

7. R １ The compound of claim 1 , wherein is hydrogen or substituted or unsubstituted alkyl.

8. R １ is hydrogen or C optionally substituted with deuterium, halogen, hydroxy, alkoxy or cycloalkyl １－４ alkyl, preferably R １ is hydrogen or C optionally substituted with deuterium or halogen １－３ alkyl, and more preferably, R １ is hydrogen or C optionally substituted with deuterium １－３ The compound of claim 1 , wherein the aryl group is alkyl.

9. R １ is hydrogen, methyl, methyl-d3, ethyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl or cyclopropylmethyl, preferably R １ is hydrogen, methyl, ethyl or methyl-d3, more preferably R １ The compound of claim 1 , wherein is methyl.

10. R ２ is hydrogen, halogen, C １－４ Alkyl, C １－４ alkoxy or cyano, preferably R ２ is hydrogen, F, Br, Cl or CN, more preferably R ２ is hydrogen, F or CN, and even more preferably, R ２ The compound of claim 1 , wherein is hydrogen.

11. R ４ is hydrogen, halogen or alkyl, said alkyl optionally being halogen or -OR ４ａ and R ４ａ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl, and said alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally —C １－６ Alkyl, —C １－６ Alkoxy or -C ３－８ substituted with cycloalkyl, preferably R ４ is hydrogen, halogen or C １－４ alkyl, said alkyl optionally being halogen or -OR ４ａ and more preferably, R ４ is hydrogen, halogen or C １－４ alkyl, said alkyl being optionally substituted with halogen, more preferably R ４ The compound of claim 1 , wherein is hydrogen.

12. R ４ is hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, ethyl or 2,2,2-trifluoroethyl, preferably R ４ The compound of claim 1 , wherein is hydrogen.

13. R ５ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, R ５ａ -C(O)-, R ５ａ -C(O)O-, R ５ａ -O-C(O)-, R ５ａ -C(O)NR ５ｂ -, R ５ａ -NR ５ｂ -C(O)-, R ５ａ -SO ２ -, R ５ａ -O-N=CH- or heterocyclyl, The alkyl may be unsubstituted or may be substituted with cyano, —C(O)OR ５ｃ , -C(O)R ５ｃ , -S(=O)-R ５ｃ , -S(=O) ２ -R ５ｃ , -S(=O)(=NH)-R ５ｃ , —C(O)NR ５ｃ R ５ｄ , heterocyclyl, alkoxy, hydroxy, cycloalkyl or NR ５ｃ R ５ｄ is replaced by, and Each of the cycloalkyl and heterocyclyl groups is unsubstituted or substituted with alkyl, cyano, or halogen, cyano, —C(O)OR ５ｃ , -C(O)R ５ｃ , —C(O)NR ５ｃ R ５ｄ , heterocyclyl, alkoxy, hydroxy, cycloalkyl, NR ５ｃ R ５ｄ or R ５ｃ -SO ２ - is substituted with R ５ａ and R ５ｂ are each independently hydrogen, alkyl, or cycloalkyl, and R ５ｃ and R ５ｄ is hydrogen or alkyl.

14. R ５ is hydrogen, alkyl, alkenyl or alkynyl, wherein the alkyl is unsubstituted or substituted with cyano, preferably R ５ is C １－４ Alkyl, C ２－４ Alkenyl or C ２－４ The compound of claim 1 , wherein the alkyl is substituted with cyano.

15. R ５ is hydrogen, -CH ２ -CN, -CH ２ C(O)-OMe, -CH(CH ３ )CN, oxiran-2-ylmethyl-, prop-2-yn-1-yl, but-2-yn-1-yl, prop-1-en-2-yl, methyl, isopropyl, —CH ２ CH ２ -O-CH ３ , -CH ２ -O-CH ３ , -CH(CH ３ )-O-CH ３ , -CH ２ C(O)NH ２ , -CH ２ CH ２ —OH, —CH ２ —OH, cyclopropyl-CH ２ -, -CH ２ CH ２ N (CH ３ ) ２ , C.H. ３ -SO ２ -, cyclopropyl, cyclobutyl, cyclopropyl-C(O)-, 1-cyanocyclopropyl, 2-cyanocyclopropyl, 2-cyanocyclobutyl, 3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl, 1-cyano-2-cyclopentylethan-2-yl, -CH ２ -N(CH ３ ) ２ , -CH=N-O-CH ３ , -CH ２ -S(=O)-CH ３ , -CH ２ -S(=O) ２ -CH ３ or -CH ２ -S(=O)(=NH)-CH ３ and preferably, R ５ is hydrogen, CN-CH ２ -, -CH ２ C(O)-OMe, -CH(CH ３ )CN, oxiran-2-ylmethyl-, prop-2-yn-1-yl, but-2-yn-1-yl, prop-1-en-2-yl, —CH ２ -OH, -CH(CH ３ )CN, -CH ２ -O-CH ３ , -CH(CH ３ )-O-CH ３ , -CH ２ -N(CH ３ ) ２ , -CH=N-O-CH ３ , -CH ２ -S(=O)-CH ３ , -CH ２ -S(=O) ２ -CH ３ or -CH ２ -S(=O)(=NH)-CH ３ and more preferably, R ５ is CN-CH ２ -, prop-2-yn-1-yl, but-2-yn-1-yl or prop-1-en-2-yl, -CH ２ -OH, -CH(CH ３ )CN, -CH ２ -O-CH ３ , -CH(CH ３ )-O-CH ３ , -CH ２ -N(CH ３ ) ２ , -CH=N-O-CH ３ , -CH ２ -S(=O)-CH ３ , -CH ２ -S(=O) ２ -CH ３ or -CH ２ -S(=O)(=NH)-CH ３ and more preferably, R ５ is CN-CH ２ -, -CH ２ -OH, -CH(CH ３ )CN, -CH ２ -O-CH ３ , -CH(CH ３ )-O-CH ３ , -CH ２ -N(CH ３ ) ２ , -CH=N-O-CH ３ , -CH ２ -S(=O)-CH ３ , -CH ２ -S(=O) ２ -CH ３ or -CH ２ -S(=O)(=NH)-CH ３ and more preferably, R ５ is CN-CH ２ The compound of claim 1, wherein

16. R ７ and R ９ each independently represents hydrogen, alkyl, or —C(O)R ７ａ wherein the alkyl is unsubstituted or substituted with halogen, cyano, hydroxy or alkoxy; R ７ａ is hydrogen, alkyl or alkoxy, preferably R ７ and R ９ Each of the groups independently represents C １－４ alkyl, and more preferably, R ７ and R ９ Each of the groups independently represents C １－２ The compound of claim 1 , wherein the aryl group is alkyl.

17. R ７ and R ９ are each independently hydrogen, methyl, ethyl, methoxymethyl, 2-methoxyethyl, cyanomethyl, hydroxyethyl, hydroxymethyl, methoxycarbonyl, or difluoromethyl, with the proviso that R ７ and R ９ The compound of claim 1 , wherein at least one of is not hydrogen.

18. R ７ is methyl, and R ９ is methyl, or R ７ is ethyl, and R ９ is ethyl, or R ７ is methyl, and R ９ is ethyl, or R ７ is ethyl, and R ９ is methyl, or R ７ is methyl, and R ９ is methoxycarbonyl, or R ７ is hydrogen, and R ９ is methyl, or R ７ is hydrogen, and R ９ The compound of claim 1 , wherein is ethyl.

19. X ２ is N and X ３ is N, or X ２ is N and X ３ is CH, or X ２ is CH and X ３ is N, or X ２ is CH and X ３ is CH, and preferably X ２ is N and X ３ The compound of claim 1 , wherein is N.

20. X ２ and X ３ The compound of claim 1, wherein is nitrogen, the 2-position carbon of the piperazine ring is in the S configuration, and the 5-position carbon of the piperazine ring is in the R configuration.

21. R ８ and R １０ and n is 0 or 1. The compound of claim 1, wherein each is hydrogen.

22. L １ represents a direct bond, —O—, —N(R Ｌ )-, -alkylene-, or -C(O)-, and R Ｌ is hydrogen or alkyl, said -alkylene- being unsubstituted or substituted with halogen, alkoxy or heterocyclyl, preferably L １ is C １－４ alkylene, preferably C １－２ alkylene, and more preferably, L １ is a direct bond, -CH ２ -, -CH(CH ３ ) -, -CH(CH ２ CH ３ )-,-CH(CHF ２ )-, -N(H)-, -N(CH ３ )-, -O-, -CH(C(O)-NHCH ２ CH ２ OCH ３ ) - or -C(CH ３ ) ２ -, and more preferably, L １ is -CH ２ -, -CH(CH2CH3)- or CH(CH ３ )-, and more preferably, L １ is CH(CH ３ 2. The compound of claim 1, wherein:

23. Cy １ is aryl, heterocyclyl, heteroaryl, or cycloalkyl, each of which is unsubstituted or contains one, two, or three substituents R ３ａ and R ３ａ is deuterium, alkoxy, halogen-substituted alkoxy, alkoxyalkyl-, alkyl, halogen-substituted alkyl, halogen, R ３ｂ -SO ２ -, cycloalkyl, hydroxyalkyl-, cyano, R ３ｂ -C(O)-N(R ３ｃ )-, cyano-substituted alkyl, N(R ３ｂ R ３ｃ )-C(O)-, R ３ｂ -O-C(O)- or heterocyclyl, wherein said cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R ３ｂ and R ３ｃ are each independently hydrogen or alkyl, preferably R ３ａ is deuterium, fluorine, bromine, chlorine, methyl, difluoromethyl, trifluoromethoxy, methoxy, methoxymethyl, trifluoromethyl, methylsulfonyl, difluoro, ethoxy, isopropyl, isopropoxy, difluoromethoxy, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl, cyclobutyl, 1-hydroxyethyl, 2-hydroxyethyl, ethyl, 1,1-difluoroethyl, cyano, dimethoxy, dichloro, acetamido, 1-methoxyethyl, cyanomethyl, carboxy ...

2. The compound of claim 1, selected from rubamoyl, methoxycarbonyl, dimethylcarbamoyl, (difluoromethoxy)methyl, amino, 1-(difluoromethoxy)ethyl, azetidin-1-yl, 2-methoxypropan-2-yl, 1-methoxycyclopropyl, oxetan-3-yl, 1-methylazetidin-3-yl, 1-hydroxyazetidin-3-yl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, or 2-fluoropropan-2-yl.

24. Cy １ is an aryl of 6 to 14 carbon atoms having a single ring or multiple condensed rings, unsubstituted or containing one, two, or three R ３ａ 2. The compound of claim 1 , substituted with:

25. The aryl is phenyl, naphthyl or anthryl, indanyl or tetrahydronaphthyl, and is unsubstituted or has one, two or three R ３ａ 25. The compound of claim 24 substituted with:

26. Cy １ is a monocyclic 5- to 9-membered heterocyclyl or a bicyclic 7- to 10-membered heterocyclyl, which is unsubstituted or contains one, two, or three R ３ａ 2. The compound of claim 1 , substituted with:

27. The monocyclic 5- to 9-membered heterocyclyl is tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, piperidinyl, piperazinyl, or dihydropyridinyl, each of which is unsubstituted or contains one, two, or three R ３ａ 27. The compound of claim 26 substituted with:

28. Cy １ is a monocyclic 5- to 9-membered heterocyclyl or a bicyclic 7- to 10-membered heterocyclyl, which is unsubstituted or contains one, two, or three R ３ａ 2. The compound of claim 1 , substituted with:

29. The monocyclic 5- to 9-membered heteroaryl is pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is unsubstituted or contains one, two, or three R ３ａ 29. The compound of claim 28 substituted with:

30. The monocyclic 5- to 9-membered heteroaryl is 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, pyrazin-2-yl, or pyridazin-4-yl, each of which is unsubstituted or substituted by one, two, or three R ３ 30. The compound of claim 29 substituted with:

31. The bicyclic 7- to 10-membered heteroaryl is indolyl, benzo[d]imidazolyl, triazolopyridinyl, imidazopyridinyl, benzoxazolyl, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, dioxinopyridinyl, quinoxalinyl, benzo[d]imidazolyl, imidazo[4,5-b]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyridyl, thieno[2,3-b]pyridyl, or thieno[3,2-b]pyridyl, each of which is unsubstituted or substituted by one, two, or three R ３ 29. The compound of claim 28 substituted with:

32. The bicyclic 7-10 membered heteroaryl may be 1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-4-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-benzo[d]imidazol-7-yl, [1,2,4]triazolo[1,5-a]pyridin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-7-yl, [1,2,4]triazolo[1,5-a]pyridin- azolo[1,5-a]pyridin-8-yl, 3H-imidazo[4,5-b]pyridin-2-yl, 3H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl, 3H-imidazo[4,5-b]pyridin-7-yl, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-7-yl, benzo[d]oxazol-2-yl, benzo[d]oxazol-4-yl, Benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]oxazol-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin quinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl, 1,8-naphthyridin-2-yl, 1,8-naphthyridin-3-yl, 1,8-naphthyridin-4-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, quinoxalin-6-yl-2,3-d2, 1H-indol-2-yl, 1H-benzo[d]imidazol-2-yl, 1-methyl-1H-benzo[d]imidazol-6-yl, 3H-imidazo[4,5-b]pyridin-2-yl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-b]pyridin-5-yl, thiazolo[5,4-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-7-yl, thiazolo[4,5-b]pyridin-2-yl thiazolo[4,5-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-6-yl, thiazolo[4,5-b]pyridin-7-yl, thieno[2,3-b]pyridin-2-yl, thieno[2,3-b]pyridin-3-yl, thieno[2,3-b]pyridin-4-yl, thieno[2,3-b]pyridin-5-yl, thieno[2,3 -b]pyridin-6-yl, thieno[3,2-b]pyridin-2-yl, thieno[3,2-b]pyridin-3-yl, thieno[3,2-b]pyridin-5-yl, thieno[3,2-b]pyridin-6-yl, thieno[3,2-b]pyridin-7-yl, each of which is unsubstituted or contains one, two, or three R, as disclosed herein. ３ 29. The compound of claim 28 substituted with:

33. Cy １ is quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl, preferably quinoxalin-6-yl, and is unsubstituted or substituted with one, two, or three R ３ａ and R ３ａ is deuterium, alkoxy, alkyl, halogen, R ３ｂ -SO ２ -, cycloalkyl, cyano group, R ３ｂ -C(O)-N(R ３ｃ ) -, N(R ３ｂ R ３ｃ )-C(O)-, N(R ３ｂ R ３ｃ ), R ３ｂ -O-C(O)- or heterocyclyl, wherein the alkyl moiety in the alkyl or alkoxy is unsubstituted or substituted with halogen, alkoxy, hydroxy or cyano, and the cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R ３ｂ and R ３ｃ are each independently hydrogen or alkyl, preferably R ３ａ is deuterium, alkoxy, halogen-substituted alkoxy, alkoxyalkyl-, alkyl, halogen-substituted alkyl, halogen, R ３ｂ -SO ２ -, cycloalkyl, hydroxyalkyl-, cyano group, R ３ｂ -C(O)-N(R ３ｃ )-, cyano-substituted alkyl, N(R ３ｂ R ３ｃ )-C(O)-, N(R ３ｂ R ３ｃ ) -, R ３ｂ -O-C(O)- or heterocyclyl, wherein said cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; R ３ｂ and R ３ｃ are each independently hydrogen or alkyl, and more preferably, R ３ａ is selected from deuterium, fluorine, bromine, chlorine, methyl, difluoromethyl, trifluoromethoxy, methoxy, methoxymethyl, trifluoromethyl, methylsulfonyl, difluoro, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl, 1-hydroxyethyl, ethyl, 1,1-difluoroethyl, cyano, dimethoxy, dichloro, cyclopropyl-, acetamido, 1-methoxyethyl, cyanomethyl, carbamoyl, methoxycarbonyl, dimethylcarbamoyl, (difluoromethoxy)methyl, amino, 1-(difluoromethoxy)ethyl, azetidin-1-yl, 2-methoxypropan-2-yl, 1-methoxycyclopropyl, oxetan-3-yl, 1-methylazetidin-3-yl, or 1-hydroxyazetidin-3-yl.

34. Cy １ is quinoxalin-6-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, thiazolo[5,4-b]pyridin-5-yl, thiazolo[5,4-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-7-yl, thiazolo[4,5-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-6-yl, thiazolo[4,5-b]pyridin-7-yl, thieno[2,3-b]pyridin-6-yl or thieno[3,2-b]pyridin-5-yl, each group being unsubstituted or substituted by one, two or three R ３ａ and R ３ａ is deuterium, methyl, ethyl, isopropyl, cyanomethyl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, difluoromethyl, trifluoromethyl, 2-fluoropropan-2-yl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl, or cyclobutyl.

35. Cy １ is quinoxalin-6-yl and is unsubstituted or contains one, two, or three R ３ａ and R ３ａ is deuterium, methyl, ethyl, isopropyl, cyanomethyl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, difluoromethyl, trifluoromethyl, 2-fluoropropan-2-yl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl, or cyclobutyl.

36. Cy1 is -phenyl, 2-(trifluoromethoxy)phenyl, 2-methoxyphenyl, 2-(methoxymethyl)phenyl, 2-(trifluoromethyl)phenyl, 4-fluoro-2-(methoxymethyl)phenyl, 4-fluoro-2-methoxyphenyl, 4-fluoro-2-methylphenyl, 2-bromo-4-fluorophenyl, 4-fluoro-2-(methylsulfonyl)phenyl, 4-methyl-2-(trifluoromethyl)phenyl, 2 chloro-4-fluorophenyl, 2,4-difluorophenyl, 2-ethoxy-4-fluorophenyl, 4-fluoro-2-isopropoxyphenyl, 4-fluoro-2-(trifluoromethoxy)phenyl, 2-(difluoromethoxy)-4-fluorophenyl, 2-(difluoromethyl)-4-fluorophenyl, 2-cyclopropyl-4-fluorophenyl, 4-fluoro-2-(1-hydroxyethyl)phenyl, 4-cyclopropyl-2-methoxyphenyl, 2-ethyl-4-fluorophenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 2-methoxy-4-fluorophenyl fluorophenyl, 2-(1,1-difluoroethyl)-4-fluorophenyl, 2-cyano-4-fluorophenyl, 4-fluoro-3-(methoxymethyl)phenyl, 3-methyl-2-(trifluoromethyl)phenyl, 4-fluoro-2,6-dimethoxyphenyl, 2,4-difluoro-6-methoxyphenyl, 2,6-dichloro-4-fluorophenyl, 4-cyclopropylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-cyclopropylphenyl, 4-(trifluoromethyl)phenyl, 4-methylphenyl, 4-(difluoromethyl)phenyl, 4-isopropoxyphenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 4-cyclopropyl-2-fluorophenyl, 3-methoxy-4-(trifluoromethyl)phenyl, 4-fluoro-3-methoxyphenyl, 2,6-difluorophenyl, 4-(trifluoromethoxy)phenyl, 4-acetylaminophenyl, 4-fluoro-2-(1-methoxyethyl)phenyl, 2-(cyanomethyl)-4-fluorophenyl, 3,4-difluoro-2-(trifluoromethyl)phenyl, 2-carbamoyl-4-fluorophenyl, 2-methoxycarbonyl-4-fluorophenyl, 2-(dimethylcarbamoyl)-4-fluorophenyl, 2-((difluoromethoxy)methyl)-4-fluorophenyl, 2-(1-(difluoromethoxy)ethyl)-4-fluorophenyl, 2-(azetidin-1-yl)-4-fluorophenyl, 4-fluoro-2-(2-methoxypropan-2-yl)phenyl, 3-(trifluoromethyl) 4-fluoro-2-(1-methoxycyclopropyl)phenyl, 4-fluoro-2-(oxiran-2-yl)phenyl, 4-fluoro-2-(1-methylazetidin-3-yl)phenyl, 4-fluoro-2-(1-hydroxyazetidin-3-yl)phenyl, 4-cyclopropyl-2-methoxyphenyl, 2-ethyl-4-fluorophenyl, 2,6-difluoro-4-methoxyphenyl, 2,5-difluoro-4-methoxyphenyl, or naphthalen-2-yl, -benzo[d][1,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,3-dihydrobenzo[b][1,4]dioxan-6-yl, 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxan-6-yl, 3,3-difluoro-2,3-dihydrobenzo[b][1,4]dioxan-6-yl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 2,2-dimethylbenzo[d][1,3]dioxol-4-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl or 【Chemical 486】 or tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, 1,4-dioxan-2-yl, 1,4-dioxan-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-2-yl, piperazin-3-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl or 1,2-dihydropyridin-6-yl, or -chroman-2-yl, chroman-3-yl or chroman-4-yl, or -1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1-ethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, 5-ethyl-1-methyl-1H-pyrazol-4-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl , pyrimidin-5-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 3-methoxypyridin-2-yl, 6-isopropoxypyridin-3-yl, 2-methoxypyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 6-(difluoromethoxy)pyridin-3-yl, 3-methoxy Pyridin-4-yl, 3-(trifluoromethyl)pyridin-4-yl, 5-fluoro-3-(trifluoromethyl)pyridin-2-yl, 5-chloro-1-ethyl-1H-imidazol-2-yl, 1-ethyl-2-(trifluoromethyl)-1H-imidazol-5-yl, 1-ethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, 5-ethyl-1-methyl-1H-pyrazol-4-yl, 1-methyl-5-(trifluoro methyl)-1H-pyrazol-4-yl, 5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl, 1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl, 3-chloro-1-ethyl-1H-pyrazol-5-yl, 1-ethyl-4-methyl-1H-pyrazol-5-yl, 5-isopropoxypyridin-2-yl, 6-(trifluoromethyl)pyridin-3-yl, 3,5-difluoropyridin-2-yl, 3,5-difluoropyridin-4-yl, 1-ethyl-4-cyano-1H-pyrazol-3-yl, 5-fluoropyridin-2-yl, pyrazin-2-yl, 3-(trifluoromethyl)pyridazin-4-yl, 6-cyclopropylpyridin-3-yl, 6-cyclobutylpyridin-3-yl, 6-isopropylpyridin-3-yl, 6-cyanopyridin-3-yl, 6-(2-cyanopropan-2-yl)pyridin-3-yl, 6-(2-hydroxypropan-2-yl)pyridin-3-yl, 6-cyclopropyl-2-fluoropyridin- 3-yl, 6-methoxypyridin-3-yl, 6-(2-fluoropropan-2-yl)pyridin-3-yl, 5-methoxypyridin-2-yl, 5-cyclopropylpyridin-2-yl, 6-(2,2-difluorocyclopropyl)pyridin-3-yl, 5-(difluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, 6-(1-fluorocyclopropyl)pyridin-3-yl, 6-(2-fluorocyclopropyl)pyridin-3-yl or 2-cyclopropylpyrimidin-5-yl, or -1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-4-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-benzo[d]imidazol-7-yl, [1,2,4]triazolo[1,5-a]pyridin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin 3H-imidazo[4,5-b]pyridin-7-yl, [1,2,4]triazolo[1,5-a]pyridin-8-yl, 3H-imidazo[4,5-b]pyridin-2-yl, 3H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl, 3H-imidazo[4,5-b]pyridin-7-yl, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-7-yl, benzo[d]oxazol-2-yl, benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]oxazol-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, 2-methylbenzo[d] Thiazol-6-yl, 5-fluorobenzo[d]thiazol-6-yl, 5-fluoro-2-methylbenzo[d]thiazol-6-yl, 6-fluoro-2-methylbenzo[d]thiazol-5-yl, 7-fluorobenzo[d]thiazol-6-yl, 7-fluoro-2-methylbenzo[d]thiazol-6-yl, 4-fluorobenzo[d]thiazol-5-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl, 1,8-naphthalene Phthyridin-2-yl, 1,8-naphthyridin-3-yl, 1,8-naphthyridin-4-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, 3-methylquinoxalin-6-yl, 3-methoxyquinoxalin-6-yl, quinoxalin-6-yl-2,3-d2, 1-ethyl-1H-indol-2-yl, 1-methyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-ethyl-6-(trifluoromethyl)-1H -benzo[d]imidazol-2-yl, 1-ethyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-methyl-1H-benzo[d]imidazol-6-yl, 3-ethyl-3H-imidazo[4,5-b]pyridin-2-yl, 1-ethyl-1H-imidazo[4,5-b]pyridin-2-yl, 3-cyclopropylquinoxalin-6-yl, -3-aminoquinoxalin-6-yl, 3-trifluoromethylquinoxalin-6-yl, 3-bisfluoromethylquinoxalin-6-yl, 3-(1,1-bisfluoroethyl)quinoxalin-6-yl, 2-deuterated-3-methylquinoxalin-6-yl, 2-deuterated-3-methoxyquinoxalin-6-yl, 3-methyl-5-methoxyquinoxalin-6-yl, 3-methyl-7-methoxyquinoxalin-6-yl, 3-methyl-5-trifluoromethylquinoxalin-6-yl, 3-methyl-7-trifluoromethylquinoxalin-6-yl, 1-ethyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin quinoxalin-6-yl, 2,3-dimethyl-quinoxalin-6-yl, 3-ethyl-quinoxalin-6-yl, 3-chloro-quinoxalin-6-yl, 4-methoxy-quinoxalin-6-yl, 3-(difluoromethyl)quinoxalin-6-yl, 3-(1,1-difluoroethyl)quinoxalin-6-yl or 3-cyclopropyl-quinoxalin-6-yl, or cyclobutyl, cyclopentyl, cyclohexyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl or 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl, or 24. The compound of claim 23, wherein the compound is thiazolo[5,4-b]pyridin-5-yl, 2-methylthiazolo[5,4-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-5-yl, 2-methylthiazolo[4,5-b]pyridin-5-yl, thieno[2,3-b]pyridin-6-yl, 2-methylthieno[2,3-b]pyridin-6-yl, 2-methylthieno[3,2-b]pyridin-5-yl, 2-fluorothieno[3,2-b]pyridin-5-yl or 2-fluorothieno[2,3-b]pyridin-6-yl.

37. 2. The compound of claim 1 selected from the compounds in Table 1.

38. 10. A pharmaceutical composition comprising one or more compounds of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

39. A compound which is any one of the exemplified compounds or a stereoisomer or pharmaceutically acceptable salt thereof.

40. A composition for treating a disease, comprising the compound of claim 1 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the disease is cancer.

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