Heterocyclic Compounds

Abstract

Disclosed herein are compounds of formula (I) that are DGK inhibitors, which activate T cells, promote T cell proliferation, and / or exhibit anti-tumor activity; methods of using the compounds disclosed herein to treat cancer; and pharmaceutical compositions containing the compounds. In one aspect, provided herein are methods for 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, provided herein are methods for treating diseases, particularly hyperproliferative disorders, e.g., cancer, in mammals, including humans. TIFF2026504408000737.tif58165

Description

[Technical Field]

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

[0002] Diacylglycerol kinases (DGKs) are a family of lipid kinases that phosphorylate diacylglycerol (DAG) to convert it to phosphatidic acid (PA). As a substrate for DGKs, DAG is generated from inositol phospholipids and other phospholipids in the plasma membrane by hydrolysis of phospholipase C (PLC) in response to activation of various cell surface receptors, such as 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 recruit and activate many downstream effectors, including protein kinase C (PKC), protein kinase D (PKD) family members, and Ras guanyl nucleotide-releasing protein (RasGRP), which activates 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 regulates and modulates the threshold and duration of DAG-mediated signaling. The mammalian DGK family contains 10 different members, of which DGKα, DGKζ, and DGKδ are three major isoforms 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 aims to manipulate and stimulate the host immune system to recognize and attack cancer cells. Much of the research has focused on targeted immune checkpoint inhibitors, such as CTLA-4 and PD-1 / PD-L1, to reactivate exhausted CD8+ T cells within the tumor site. It has become clear that peripheral T cell tolerance, which normally prevents harmful autoimmune diseases, can be hijacked by tumors to block antitumor immune responses during carcinogenesis (Nussing, Simone, et al. Frontiers in Immunology. 2020, 11:2461). T cell anergy is one of the most important mechanisms of T cell tolerance, and it has been reported that this anergy occurs in tumor-infiltrating T cells, contributing to the immunosuppressive nature 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 and Zheng, Yan, et al. Molecular Immunology 2013, 55.3-4:283-291). In anergic T cells, DGKα and DGKζ both negatively regulate DAG signaling downstream of the TCR, playing an important role in reducing the intensity of TCR activation (Chen, Shelley S., et al. Frontiers in Cell and Developmental Biology 2016, 4:130). Therefore, we investigated immune cells expressing DGKα and DGKζ as potential targets for reversing the hyporesponsiveness of tumor-infiltrating T cells. It has been demonstrated that genetic deletion of DGKα or DGKζ enhances cytokine production and proliferation of T cells (Olenchk, Benjamin A., et al. Nature immunology. 2006, 7.11:1174-1181 and Zhong, Xiao-Ping, et al. Nature immunology. 2003, 4.9:882-890).Single knockout of DGKα or DGKζ in both mouse and human chimeric antigen receptor (CAR)-T cells demonstrated superior effector function as determined by enhanced in vitro cytotoxicity and cytokine secretion when cocultured with antigen-expressing cells (Riese, Matthew J., et al. Cancer Research. 2013, 73.12:3566-3577 and Jung, In-Young, et al. Cancer Research. 2018, 78.16:4692-4703). MesoCAR-transduced T cells lacking DGKα or DGKζ also demonstrated significantly enhanced in vivo activity against mesothelioma (Riese, Matthew J., et al. Cancer Research. 2013, 73.12:3566-3577). - / - Mice have demonstrated enhanced tumor suppression efficacy in both orthotopic and subcutaneous tumor models (Wesley, Erin M., et al. Immunohorizons. 2018, 2.4:107-118; Wee, Susan, et al. AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 936). In addition to their T cell regulatory functions, both DGKα and DGKζ are also 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 an important role in regulating the activation threshold of mature B cells (Wheeler, Matthew L., et al. Science Signaling. 2013, 6.297:ra91-ra91). Collectively, these preclinical data suggest that inhibition of the subject DGKα and DGKζ may be therapeutically beneficial in promoting immunity against cancer. Although existing anti-CTLA-4 and anti-PD-1 therapies have demonstrated clear clinical benefits in patient subsets with various tumor types, there remains an unmet medical need to develop novel immunotherapies to achieve robust and durable clinical antitumor responses. Preclinical data suggest that the development of targeted therapies against DGKα and DGKζ holds great potential for improving antitumor immunity. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Rhee, Sue Goo.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

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

[0006] As used herein, compounds of formula (I) [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopic substitution, or prodrug thereof, wherein the variables are as defined herein.

[0007] In some embodiments, the compound of Formula (I) is a compound of Formula (IA1), a compound of Formula (IA2), a compound of Formula (IA3), or a compound of Formula (IA4): [ka] and wherein the variables are as defined herein.

[0008] In some embodiments, the compound of Formula (I) is a compound of Formula (IB1), a compound of Formula (IB2), a compound of Formula (IB3), or a compound of Formula (IB4): [ka] and wherein the variables are as defined herein.

[0009] In some embodiments, the compound of Formula (I) is a compound of Formula (IC1), a compound of Formula (IC2), a compound of Formula (IC3), or a compound of Formula (IC4): [ka] and wherein the variables are as defined herein.

[0010] In some embodiments, the compound of formula (I) has formula (II): [ka] is a compound of wherein m is 0, 1, 2, or 3, n is 0 or 1, and other variables are as defined herein.

[0011] In one aspect, provided herein is a method for 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, provided herein is a method for treating a disease, particularly a hyperproliferative disorder, e.g., cancer, in a mammal, including a human.

[0012] In another aspect, provided herein are methods for preparing the compounds described herein.

[0013] The present embodiments 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

[0014] definition The following terms have the indicated meanings throughout this specification.

[0015] As used in this specification, including the appended claims, singular terms such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0016] The term "or" is used to mean, and is used interchangeably with, the term "and / or," unless the context clearly dictates otherwise.

[0017] The term "alkyl" refers to a hydrocarbon group selected from straight and branched chain saturated hydrocarbon groups derived from an alkane by removing one hydrogen atom from the same carbon atom, and containing 1 to 18, for example 1 to 12, further for example 1 to 10, even further for example 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. Alkyl groups 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 s-butyl ("s-Bu"), 1,1-dimethylethyl or t-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 groups. The alkyl group can be optionally deuterium enriched, e.g., -CD3, -CD2CD3, etc. The term "alkylene" refers to a hydrocarbon group selected from straight and branched chain saturated hydrocarbon groups derived from an alkane by the removal of two hydrogen atoms from the same carbon atom and containing 1 to 6, e.g., 1 to 4 carbon atoms, further e.g., 1 to 3, and even further 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 said to be "substituted," they can be substituted with any of the substituent(s) found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro), alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, nitro, cyano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonato, phosphine, thiocarbonyl, sulfonyl, sulfone, sulfonamide, ketone, aldehyde, ester, urea, urethane, oxime, hydroxylamine, alkoxyamine, aralkoxyamine, N-oxide, hydrazine, hydrazide, hydrazone, azide, isocyanate, isothiocyanato, cyanate, thiocyanato, B(OH), O(alkyl)aminocarbonyl, aryl, heterocyclyl, or heteroaryl.

[0018] The term "halogen" refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I).

[0019] 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 Examples include alkyl, including but not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, and the like.

[0020] The terms "alkyloxy" or "alkoxy" refer to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Alkyloxy, e.g., C 1-6 Alkyloxy or C 1-4Examples of alkyloxy include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0021] The term "amino" refers to -NH2.

[0022] The term "alkenyl," as used herein, refers to a hydrocarbon group selected from straight- and branched-chain hydrocarbon groups containing at least one C=C double bond and 2 to 18, such as 2 to 8, further such as 2 to 6, carbon atoms. Examples of alkenyl groups, e.g., C2-6 alkenyl, include, but are not limited to, 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.

[0023] The term "alkynyl," as used herein, refers to a hydrocarbon group selected from straight- and branched-chain hydrocarbon groups containing at least one C≡C triple bond and 2 to 18, such as 2 to 8, further such as 2 to 6, carbon atoms. Examples of alkynyl groups, e.g., C2-6 alkynyl, include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0024] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, such as fused, bridged, or spirocycloalkyls. For example, the cycloalkyl group can contain 3 to 12, such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Even further, for example, the cycloalkyl group can be selected from monocyclic groups containing 3 to 12, such as 3 to 10, further such as 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 groups. 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 groups. In preferred embodiments, cycloalkyl is a monocyclic ring containing 3 to 6 carbon atoms (C), including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3~6 (Abbreviated as cycloalkyl). Examples of bicyclic cycloalkyl groups 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 as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.

[0025] The term "deuterated compound" refers to a compound in which one or more carbon-bonded hydrogen(s) have been replaced with one or more deuterium(s). The term "deuterated" is used herein to modify a chemical structure or organic group or radical in which one or more carbon-bonded hydrogen(s) have been replaced with one or more deuterium(s), such as "deuterated alkyl," "deuterated cycloalkyl," "deuterated heterocycloalkyl," "deuterated aryl," "deuterated morpholinyl," and the like. For example, the term "deuterated alkyl," as defined above, refers to an alkyl group, as defined herein, in which at least one carbon-bonded hydrogen atom has been replaced with deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to deuterium, and a carbon atom can be bonded to multiple deuteriums, and multiple carbon atoms of an alkyl group can be bonded to deuterium.

[0026] The term "aryl," used alone or in combination with other terms, refers to an aromatic carbocyclic group of 6 to 14 carbon atoms, having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl). In some embodiments, aryl groups contain 6 to 14 carbons, and in other cases 6 to 12 or 6 to 10 carbon atoms, in the ring portion of the group. Specific aryl groups include phenyl, biphenyl, naphthyl, and the like. Aryl groups can be substituted or unsubstituted. The term "aryl group" also includes groups containing fused rings, such as aromatic-aliphatic fused ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). In some embodiments, aryl groups refer to groups selected from 5- and 6-membered aromatic carbocyclic rings, e.g., phenyl; bicyclic ring systems, such as 7-12 membered bicyclic ring systems, in which at least one ring is carbocyclic and aromatic, e.g., naphthyl and indanyl; and tricyclic ring systems, such as 10-15 membered tricyclic ring systems, in which at least one ring is carbocyclic and aromatic, e.g., fluorenyl.

[0027] 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 5-10 (aryl). 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.

[0028] As used herein, the term "heteroaryl" means 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, and in some embodiments, 1 to 2 heteroatoms, with the remaining ring atoms being carbon; - 7-12 membered bicyclic rings containing, as ring member(s), at least one heteroatom, for example 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, selected from nitrogen, oxygen, or optionally oxidized sulfur, with 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 a group selected from 11-14 membered tricyclic rings containing as ring member(s) at least one heteroatom, e.g., 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, selected from nitrogen, oxygen, or optionally oxidized sulfur, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being present in the aromatic ring.

[0029] When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is 1 or less. When a heteroaryl group contains two or more heteroatom ring members, the heteroatoms can be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group can be oxidized to form N-oxides.

[0030] As used herein, the term "optionally oxidized sulfur" refers to -S-, SO, or SO2.

[0031] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 ring members, including 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring members being carbon. In some embodiments, a monocyclic or bicyclic aromatic heterocycle 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 aromatic heterocycle is a 5- to 6-membered heteroaryl ring, which is monocyclic and has 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 an 8-10 membered heteroaryl ring that is bicyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0032] Examples of heteroaryl groups or monocyclic or bicyclic aromatic heterocycles include (numbered from the attachment position assigned priority 1) 1H-pyrazolyl (such as 1H-pyrazol-3-yl, 1H-pyrazol-4-yl or 1H-pyrazol-5-yl), pyridyl or pyridinyl (such as 2-pyridyl, 3-pyridyl or 4-pyridyl), cinnolinyl, pyrazinyl, pyrimidinyl (such as pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl or 2,4-pyrimidinyl, 3,5-pyrimidinyl), imidazolyl (1H-imidazole), 1H-imidazol-4-yl, 1H-imidazol-5-yl, or 2,4-imidazolyl, etc.), imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl, etc.), tetrazolyl, thienyl (thien-2-yl, thien-3-yl, etc.), triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzimidazolyl, indolyl (1H-indol-2-yl, 1H-indol-3-yl, etc.), Indolyl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, etc.), isoindolyl, indolinyl, oxadiazolyl (1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, etc.), phthalazinyl, pyrazinyl (pyrazin-2-yl, etc.), pyridazinyl, pyrrolyl, triazolyl (1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, etc.), quinolinyl (quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, or quinolin-7-yl, etc.), isoquinolinyl (isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, or isoquinolin-8-yl, etc.), pyrazolyl, pyrrolopyridinyl (1H-pyrrolo[2,3-b]pyridin-5-yl, etc.), pyrazolopyridinyl (1H-pyrazolo[3,4-b]pyridin-5-yl, etc.), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl (furazan-2-yl, furazan-3-yl, etc.), benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl (benzo[d]oxazol-2-yl, benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, benzo[d]oxazole- 6-yl or benzo[d]oxazol-7-yl, etc.), quinazolinyl, quinoxalinyl (quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl or quinoxalin-8-yl, etc.), naphthyridinyl (1,8-naphthyridin-2-yl, 1,8-naphthyridin-3-yl or 1,8-naphthyridin-4-yl, etc.), 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl (2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, etc. lysin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, etc.), furopyridinyl, benzothiazolyl (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, etc.), benzo[d]imidazolyl (1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-4-yl, 1H-benzo[d]imidazol- -benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, or 1H-benzo[d]imidazol-7-yl, etc.), [1,2,4]triazolo[1,5-a]pyridinyl (such as [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, etc.), 3H-imidazo[4,5-b]pyridinyl (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, etc.), 1H-imidazo[4,5-b]pyridinyl (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, etc.), [ 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), indazolyl (e.g., 1H-indazol-5-yl), 5,6,7,8-tetrahydroisoquinoline, thiazolo[5,4-b] pyridinyl (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, etc.), thiazolo[4,5-b]pyridinyl (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, etc.), thieno[2,3-b]pyridinyl (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, etc.), thieno[3,2-b]pyridinyl (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, etc.).

[0033] Additionally, a "heteroaryl" fused to a "heterocyclyl" is also defined as a "heteroaryl."

[0034] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to non-aromatic heterocyclyl groups, including monocyclic, fused, bridged, and spirocyclic rings, that contain one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, i.e., monocyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclic groups.

[0035] 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.

[0036] Exemplary 4- to 9-membered monocyclic heterocyclyl groups include (numbered from the attachment 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, morpholin-2-yl, molybdenum-2-yl, methylpyrrolidin-1-yl, methylpyrrolidin-2-yl, methylpyrrolidin-3 ... 3-thithietanyl, oxiranyl, 1-aziridinyl, 2-aziridinyl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thiiranyl, 1-azetidin-1, azetidin-2-yl, azetidin-3-yl, oxetanyl, 3-oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl yl, homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azatianyl, 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.

[0037] The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl having rings connected via a 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 in a spiroheterocyclyl group may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably, the spiroheterocyclyl has 6 to 14 members, more preferably 7 to 12 members. According to the number of common spiro atoms, spiroheterocyclyl is divided into monospiroheterocyclyl, dispiroheterocyclyl, or polyspiroheterocyclyl, preferably monospiroheterocyclyl or dispiroheterocyclyl, more preferably 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. Examples of spiroheterocyclyl groups include spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.4]octanyl, spiro[2.6]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[2.7]decanyl, spiro[3.6]decanyl, spiro[4.5]decanyl, spiro[3.7]undecanyl, spiro[4.6]undecanyl, spiro[5.5]undecanyl, spiro[4.7]dodecanyl, and spiro[5.6]dodecanyl, which are substituted or unsubstituted by one or two carbon atoms. Examples of groups in which an atom is replaced by oxygen or nitrogen include, but are not limited to, 2-oxa-6-azaspiro[3.3]heptanyl (e.g., 2-oxa-6-azaspiro[3.3]heptan-6-yl), 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-aza-spiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, and 5-oxa-spiro[2.4]heptyl, and spiro[benzo[d][1,3]dioxole-2,1′-cyclobutan]-yl (e.g., spiro[benzo[d][1,3]dioxole-2,1′-cyclobutan]-5-yl).

[0038] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclyl group, in which each ring shares an adjacent atom pair (carbon atom-carbon atom or carbon atom-nitrogen atom) with another ring and contains 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 the fused heterocyclic group may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably, the fused heterocyclyl has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of membered rings, the fused heterocyclyl is divided into 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 examples of fused heterocycles include, but are not limited to, octahydrocyclopenta[c]pyrrole (e.g., octahydrocyclopenta[c]pyrrol-2-yl), octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindolinyl (e.g., isoindolin-2-yl), and octahydro-benzo[b][1,4]dioxine groups.

[0039] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic alkyl group, in which any two rings in the system share two non-linking atoms and contain 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 in a bridged heterocyclyl group may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably, the bridged heterocyclyl has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of ring members, the bridged heterocyclyl is divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, and preferably refers to bicyclic, tricyclic, or tetracyclic bridged heterocyclyl, more preferably bicyclic or tricyclic bridged heterocyclyl. Representative examples of bridged heterocyclyls 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 groups.

[0040] A "cycloalkylalkyl" group is a radical of the formula: -alkyl-cycloalkyl, where alkyl and cycloalkyl are as defined above. Substituted cycloalkylalkyl groups can 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.

[0041] An "aralkyl" group is a radical of the formula: -alkyl-aryl, where alkyl and aryl are defined above. Substituted aralkyl groups can 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 groups and fused (cycloalkylaryl)alkyl groups, such as 4-ethyl-indanyl.

[0042] A "heterocyclylalkyl" group is a radical of the formula: -alkyl-heterocyclyl, where alkyl and heterocyclyl are as defined above. Substituted heterocyclylalkyl groups can be substituted on the alkyl, the heterocyclyl, or both the alkyl and the 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.

[0043] "Halogen" means fluorine, chlorine, bromine, or iodine.

[0044] A "hydroxyalkyl" group is an alkyl group as defined above that is substituted with one or more hydroxy groups.

[0045] An "alkoxy" group is an --O-(alkyl), where alkyl is defined above.

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

[0047] An "amino" group is a radical of the formula: --NH.sub.2.

[0048] An "alkylamino" group is a radical of the formula: --NH-alkyl or --N(alkyl)2, where each alkyl is independently as defined above.

[0049] A "carboxy" group is a radical of the formula: --C(O)OH.

[0050] An “aminocarbonyl” group is a group of the formula: —C(O)N(R # )2, -C(O)NH(R # ), or a radical of —C(O)NH2, where each R # is independently a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclyl group as defined herein.

[0051] An “acylamino” group refers to a group of the formula: —NHC(O)(R # ) or -N(alkyl)C(O)(R # ) radical, where each alkyl and R # are independently as defined above.

[0052] A “sulfonylamino” group refers to a group of the formula: —NHSO(R # ) or -N(alkyl)SO2(R # ) radical, where each alkyl and R # is as defined above.

[0053] A "urea" group refers to 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.

[0054] With the exception of alkyl groups, when groups described herein are said to be "substituted," they can be substituted with any suitable substituent(s). Illustrative examples of substituents include those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro), alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, nitro, cyano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonato, phosphine, thiocarbonyl, sulfonyl, sulfone, sulfonamide, ketone, aldehyde, ester, urea, urethane, oxime, hydroxylamine, alkoxyamine, aralkoxyamine, N-oxide, hydrazine, hydrazide, hydrazone, azide, isocyanate, isothiocyanate, cyanate, thiocyanate, oxygen (=O), B(OH), O(alkyl)aminocarbonyl, cycloalkyl (which may be simply and heterocyclyl (which may be a single ring or a fused or non-fused polycyclic ring) (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocyclyl (which may be a single ring or a fused or non-fused polycyclic ring) (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl), single ring or a fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl), aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclylalkoxy.

[0055] 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 the compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All possible stereoisomers, such as substantially pure resolved enantiomers, racemic mixtures thereof, and diastereomeric mixtures, are intended to be encompassed. All stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts are intended to be included. Unless otherwise specifically stated, a reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is not specified, all possible isomers are included.

[0056] As used herein, the term "substantially pure" means that the title stereoisomer contains 35% by weight or less, such as 30% by weight or less, further such as 25% by weight or less, even further such as 20% by weight or less of any other stereoisomer(s). In some embodiments, the term "substantially pure" means that the title stereoisomer contains 10% by weight or less, such as 5% by weight or less, such as 1% by weight or less of any other stereoisomer(s).

[0057] When compounds disclosed herein contain olefinic double bonds, unless otherwise specified, it is intended that such double bond include both E and Z geometric isomers.

[0058] When the compounds disclosed herein contain a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring may adopt cis and trans configurations, where cis means that both substituents are found on the upper side of the two arrangements of substituents on the carbon, while trans means that they are on opposite sides.

[0059] "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 based on their physical chemical differences by methods well known to those skilled in the art, such as flash column chromatography and / or fractional crystallization. Enantiomers can be resolved by converting the enantiomeric mixture into 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), resolving the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be resolved using a chiral HPLC column.

[0060] "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., 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 they can be prepared separately by reacting a free base function with a suitable organic acid, or by reacting an acidic group with a suitable base.

[0061] "Selective inhibitory activity" or "selectivity" refers to the difference in the degree of inhibition against DGKα and DGKζ, and in some embodiments, "a compound that exhibits selective inhibitory activity against DGKα over DGKζ" refers to a compound that exhibits a ratio of IC50 for DGKζ to IC50 for DGKα of about 20 or more. In some embodiments, "a compound that exhibits selective inhibitory activity against DGKζ over DGKα" refers to a compound that exhibits a ratio of IC50 for DGKα to IC50 for DGKζ of about 20 or more. In some embodiments, a "compound that exhibits selective inhibitory activity of DGKα against DGKζ" refers to a compound that has an IC50 against DGKα of about 2000 nM or less and a ratio of the IC50 against DGKζ to the IC50 against DGKα of about 20 or more; a "compound that exhibits selective inhibitory activity of DGKζ against DGKα" refers to a compound that has an IC50 against DGKζ of about 2000 nM or less and a ratio of the IC50 against DGKα to the IC50 against DGKζ of about 20 or more; and a "compound that exhibits dual inhibitory activity" refers to a compound that exhibits inhibitory activity with an IC50 against both DGKα and DGKζ 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 with an IC50 against both DGKα and DGKζ of 1000 nM or less and a ratio of the two IC50 values ​​of 20 or less. In some embodiments, a "compound exhibiting 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.

[0062] As defined herein, "pharmaceutically acceptable salts thereof" includes salts of at least one compound of formula (I), (IA1), (IA2), (IA3), (IA4), (IB1), (IB2), (IB3), (IB4), (IC1), (IC2), (IC3), (IC4) and (II) (collectively Formulas (I) through (II)), as well as salts of stereoisomers, e.g., enantiomeric and / or diastereomeric salts, of compounds of formula (I) through formula (II).

[0063] 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 pharmaceutical, therapeutic, diagnostic, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent with the cell, as well as contact of a reagent with a fluid when the fluid is in contact with the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatments (e.g., of a cell) with a reagent, diagnostic, binding compound, or with another cell. As used herein, the term "subject" includes any organism, preferably an animal, more preferably a mammal (e.g., a rat, mouse, dog, cat, rabbit), and most preferably a human.

[0064] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient, such as a compound, that, when administered to a subject to treat a disease or at least one clinical symptom of a disease or disorder, is sufficient to affect such treatment for 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 of the subject being treated, and / or the weight of the subject being treated. The appropriate amount in any given case will be apparent to one of ordinary skill in the art or can 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, that is effective in "treating" a disease or disorder in a subject, as defined above. In the case of a combination therapy, a "therapeutically effective amount" refers to the total amount of the combined components for effective treatment of a disease, disorder, or condition.

[0065] All formulations of the pharmaceutical compositions disclosed herein can be prepared by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients to prepare the desired formulation. "Pharmaceutically acceptable excipients" refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as diluents, vehicles (water, various organic solvents, etc.), excipients (starch, sucrose, etc.), binders (cellulose derivatives, alginates, gelatin, polyvinylpyrrolidone (PVP), etc.), humectants (glycerol, etc.), disintegrants (agar, calcium carbonate, sodium bicarbonate, etc.), absorption enhancers (quaternary ammonium compounds, etc.), surfactants (hexadecanol, etc.), absorption carriers (kaolin, soap clay, etc.), lubricants (talc, calcium stearate, magnesium stearate, polyethylene glycol, etc.). In addition, the pharmaceutical composition may further comprise other pharmaceutically acceptable excipients, such as dispersing agents, stabilizers, thickening agents, complexing agents, buffers, penetration enhancers, polymers, flavoring agents, sweetening agents, and dyes.

[0066] The term "disease" refers to any disease, ailment, illness, symptom, or indication, and may be used interchangeably with the terms "disorder" or "condition."

[0067] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," are intended to specify the presence of the subsequent feature but do not exclude the presence or addition of one or more other features. As used herein, the word "comprising" may be substituted with the words "containing," "including," or, in some cases, "having."

[0068] Throughout this specification and the claims that follow, 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.

[0069] The term "tautomer" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of isomeric forms may vary depending on the environment in which the compound is found, for example, whether the compound is a solid or in an organic or aqueous solution. For example, pyrazole may exhibit the following isomeric forms in aqueous solution, which are called tautomers of each other: [ka]

[0070] As would be readily understood by one of ordinary skill in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of a compound of any one of Formula (I) through Formula (II) are within the scope of the present invention.

[0071] Unless specifically defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0072] It should also be noted that the compounds provided herein may contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), sulfur 35( 35 S), or carbon-14 ( 14 They may be radiolabeled with radioisotopes such as C, or with deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen-15( 15The compound 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, 134, 140, 141, 150, 162, 170, 181, 191, 192, 193, 194, 195, 196, 197, 198, 199, 20

[0073] 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 the phosphate source. In unstimulated cells, DGK activity is low, allowing DAG to be used for glycerophospholipid biosynthesis. However, upon receptor activation of the phosphoinositide pathway, DGK activity increases, promoting the conversion of DAG to PA. Because both lipids are thought to function as bioactive lipid signaling molecules with distinct intracellular targets, DGK occupies a critical position, effectively functioning as a switch by terminating signaling from one lipid while simultaneously activating signaling from another. 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 classified into five groups according to the presence of additional functional domains and substrate specificity. See van Blitterswijk WJ, Houssa B (October 2000), "Properties and functions of diacylglycerol kinases," Cellular Signalling, 12(9-10):595-605. These are as follows: a) Type 1 (DGK-α, DGK-β, DGK-γ) contains an EF-hand motif and a recoverin homology domain b) Type 2 (DGK-δ, DGK-η, DGK-κ) contains a pleckstrin homology domain c) Type 3 (DGK-ε) has specificity for arachidonic acid-containing DAG d) Type 4 (DGK-ζ, DGK-ι) contains a MARCKS homology domain, ankyrin repeats, a C-terminal nuclear localization signal, and a PDZ-binding motif. e) Type 5 (DGK-theta) contains a third cysteine-rich domain, a pleckstrin homology domain, and a proline-rich region.

[0074] As used herein, the term "treating" refers to the total or partial alleviation of a disorder, disease, or condition, or one or more symptoms associated with a disorder, disease, or condition, or the slowing or halting of further progression or worsening of those symptoms, or the alleviation or elimination of the cause(s) of the disorder, disease, or condition itself. In one embodiment, "treating" refers to the total or partial alleviation of a disorder, disease, or condition, or symptoms associated with a condition, that is treatable or preventable by inhibition of the DGK pathway. In another embodiment, "treating" refers to the total or partial alleviation of a disorder, disease, or condition, or symptoms associated with a condition, that is treatable or preventable by inhibition of the DGK-α pathway. In another embodiment, "treating" refers to the total or partial alleviation of a disorder, disease, or condition, or symptoms associated with a condition, that is treatable or preventable by inhibition of the DGK-ζ pathway. In one embodiment, the disorder is cancer.

[0075] As used herein, "preventing" refers to a method of delaying and / or preventing, in whole or in part, the onset, recurrence, or spread of a disorder, disease, or condition, a method of preventing a subject from acquiring a disorder, disease, or condition, or a method of reducing a subject's risk of acquiring a disorder, disease, or condition. In another embodiment, the disorder is a condition treatable or preventable by inhibition of the DGK pathway. In another embodiment, the disorder is a condition treatable or preventable by inhibition of the DGK-α pathway. In another embodiment, the disorder is a condition treatable or preventable by inhibition of the DGK-ζ pathway. In one embodiment, the disorder is cancer.

[0076] The term "subject" includes animals, including, but not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, and in one embodiment, mammals, and in another embodiment, humans. In one embodiment, the subject is a human having or at risk of having liver fibrosis or diabetes or metabolic syndrome, or a condition or symptom thereof that leads to liver fibrosis, treatable or preventable by inhibition of the JNK pathway.

[0077] As used herein, the term "compound" refers to compounds of Formula (I), (IA1), (IA2), (IA3), (IA4), (IB1), (IB2), (IB3), (IB4), (IC1), (IC2), (IC3), (IC4), (II), and salts of stereoisomers of compounds of Formula (I), (IA1), (IA2), (IA3), (IA4), (IB1), (IB2), (IB3), (IB4), (IC1), (IC2), (IC3), (IC4), and (II) (collectively Formulas (I) through (II)), as well as further embodiments provided herein. In one embodiment, a "compound" is a compound exemplified herein. The term "compound" includes pharmaceutically acceptable salts, tautomers, isotopic substitutions, stereoisomers, deuterated compounds, and prodrugs of the compounds provided herein.

[0078] As used herein, unless otherwise indicated, the term "prodrug" refers to a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to yield an active compound, particularly a compound of any one of Formulas (I) to (II). Examples of prodrugs include, but are not limited to, derivatives and metabolites of a compound that contains a biohydrolyzable moiety, such as a biohydrolyzable amide, a biohydrolyzable ester, a biohydrolyzable carbamate, a biohydrolyzable carbonate, a biohydrolyzable ureide, and a biohydrolyzable phosphate analog. In certain embodiments, a prodrug of a compound with a carboxyl functional group is a lower alkyl ester of the carboxylic acid. Conveniently, the carboxylic acid ester is formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs are typically prepared by well-known methods, for example, as described in Burger's Medicinal Chemistry and Drug Discovery 6. th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

[0079] As used herein, unless otherwise indicated, the terms "stereoisomer" or "stereoisomerically pure" refer to one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound will contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of that compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of that compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of that 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 that compound. The compounds may contain chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof, and all such isomeric forms, including mixtures thereof, are included in the embodiments disclosed herein.

[0080] compound

[0081] The compounds provided 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 of both DGKα and DGKζ. In some embodiments, the compounds disclosed herein exhibit selective inhibitory activity of DGKα over DGKζ. In some embodiments, the compounds disclosed herein exhibit selective inhibitory activity of DGKζ over DGKα.

[0082] As used herein, compounds of formula (I) [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopic substitution, 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-; X 4 is N, O or S, R 1 is hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, 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 alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, with the proviso that X 1 If N, then R 2 Provided that there is no R 4 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, with the proviso that X 4 If is O or S, then R 4 Provided that there is no R 5 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, 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-, 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 7 , R 9 , R 8 , and R 10 each independently represents hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted cycloalkyl, —C(O)R 7a , or -alkyl-C(O)R 7a where R 7a is hydrogen, alkyl, or alkoxy, with the proviso that R 7 and R 9 at least one of which is not hydrogen; or R 7 and R 9 are each hydrogen, and R 8 and R 10 together form a bridge containing at least one -CH2- moiety in addition to the two bridgehead atoms, or R 8 and R 10 are each hydrogen, and R 7 and R 9 together form a bridge which contains at least one -CH2- moiety in addition to the two bridgehead atoms, L 1 is a direct bond, -O-, -N(R L )-, substituted or unsubstituted alkyl, -alkylene, or -C(O)-, and 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, 1 to 5 substituents R 3ais replaced by R 3a is deuterium, alkoxy, alkyl, halogen, oxo, 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)-, cycloalkyl or heterocyclyl; Optionally, two R 3a are attached to the same carbon and together form a spirocyclic ring, Optionally, 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.

[0083] X 1 and X 4 Definition of

[0084] In some embodiments, X 1 is C. In some embodiments, X 1 is N. In some embodiments, X 4 is N. In some embodiments, X 4 is S. In some embodiments, X 4 is O. In some embodiments, X 1 is C and X 4 is N. In some embodiments, X 1 is N and X 4 is N. In some embodiments, X 1 is C and X 4 is S.

[0085] In some embodiments, the compound of Formula (I) has the formula (IA1), (IB1), or (IC1): [ka] and wherein the variables are as defined herein.

[0086] In some embodiments, the compound of Formula (I) has formula (IA2), (IB2), or (IC2): [ka] and wherein the variables are as defined herein.

[0087] In some embodiments, the compound of Formula (I) has formula (IA3), (IB3), or (IC3): [ka] and wherein the variables are as defined herein.

[0088] In some embodiments, the compound of Formula (I) has formula (IA4), (IB4), or (IC4): [ka] and wherein the variables are as defined herein.

[0089] In some embodiments, the compound of formula (I) has formula (II): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopically substituted derivative, or prodrug thereof, During the ceremony, X 1 is C or N, X 4 is N, O or S, R 1 is hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, 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 alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, with the proviso that X 1 If N, then R 2 Provided that there is no R 4 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, with the proviso that X 4 If is O or S, then R 4 Provided that there is no R 5 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, 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 -OC(O)-, R 5a -C(O)NR 5b -, R 5a -NR 5b -C(O)- or R 5a -SO2- and R 5a and R 5bare each independently hydrogen, alkyl, or cycloalkyl; R 7 , and R 9 each independently represents hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted cycloalkyl, —C(O)R 7a , or -alkyl-C(O)R 7a where R 7a is hydrogen, alkyl, or alkoxy, with the proviso that R 7 and R 9 at least one of which is not hydrogen; or R 7 and R 9 together form a bridge which contains at least one -CH2- moiety in addition to the two bridgehead atoms, L 1 is a direct bond, -O-, -N(R L )-, substituted or unsubstituted alkyl, -alkylene, or -C(O)-, and R L is hydrogen or alkyl, m is 0, 1, 2 or 3; n is 0 or 1, R 3a is deuterium, alkoxy, alkyl, halogen, oxo, 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)-, cycloalkyl or heterocyclyl; Optionally, two R 3a are attached to the same carbon and together form a spirocyclic ring, Optionally, 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.

[0090] Unless specifically indicated otherwise, "an embodiment" or "embodiments" hereinafter refers to an embodiment with respect to a compound of any one of Formula (I) through Formula (II).

[0091] R 1 Definition of

[0092] In some embodiments, R 1 is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 1 is hydrogen or a substituted or unsubstituted C 1-4 It is alkyl.

[0093] 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 1-3 In some embodiments, R is alkyl or halogen. 1 is hydrogen or C optionally substituted with deuterium 1-3 It is alkyl.

[0094] 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. 1is hydrogen, methyl, ethyl, or methyl-d3. In some embodiments, R 1 is methyl or methyl-d3. In some embodiments, R 1 is methyl.

[0095] R 2 Definition of

[0096] In some embodiments, R 2 is hydrogen, halogen, alkyl, alkoxyl, or cyano, with the proviso that X 1 If N, then R 2 In some embodiments, R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 In some embodiments, R 2 is hydrogen, F, Br, Cl, or CN. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is F, Br, or Cl.

[0097] In some embodiments, R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 alkoxyl 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, and alkyl is deuterium, halogen or -OR 4a optionally replaced by R 4ais hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl, and alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is -C 1-6 Alkyl, -C 1-6 Alkoxy or -C 3-8 In some embodiments, R 4 is hydrogen, halogen or C 1-4 alkyl, wherein the alkyl is a halogen or -OR 4a In some embodiments, R 4 is hydrogen, halogen or C 1-4 In some embodiments, R is an alkyl, optionally substituted with deuterium or halogen. 4 is hydrogen or C optionally substituted with deuterium 1-3 In some embodiments, R is alkyl or halogen. 4 is hydrogen or C optionally substituted with deuterium 1-3 It is alkyl.

[0100] In some embodiments, R 4 is hydrogen, fluoro, chloro, bromo, methyl, methyl-d3, trifluoromethyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, propyl, cyclopropyl. In some embodiments, R 4 is hydrogen, methyl, methyl-d3, ethyl, 2,2-difluoroethyl, propyl, or cyclopropyl.

[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 -, R5a -NR 5b -C(O)-, R 5a -SO2- or heterocyclyl, wherein the alkyl is unsubstituted or is selected from the group consisting of 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 the cycloalkyl and heterocyclyl is unsubstituted or alkyl, cyano, or halogen-substituted alkyl, 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 -SO2- and R 5a and R 5b are each independently substituted with hydrogen, alkyl, or cycloalkyl; 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 group, wherein the alkyl is substituted with cyano. 5 is C 1-4 alkyl, which is substituted with cyano.

[0104] In some embodiments, R 5 is C 1-4 alkyl, wherein the alkyl is selected from the group consisting of cyano, alkoxy, hydroxy, NR 5c R5d , -NO-CH3, -S(=O)-CH3, -S(=O)2-CH3, or -S(=O)(=NH)-CH3.

[0105] In some embodiments, R 5 is 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-cyclopentyleth-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 5is 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 5 is but-2-yn-1-yl, 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- or but-2-yn-1-yl.

[0106] R 7 / R 9 、 R 8 / R 10 Definition of

[0107] In some embodiments, R 7 , R 9 , R 8 , and R 10 are each independently hydrogen, alkyl, alkoxy, 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, provided that R 7 and R 9 At least one of them is not hydrogen.

[0108] In some embodiments, R 7 and R 9 are each independently hydrogen, alkyl, or —C(O)R 7a wherein the alkyl is unsubstituted or substituted with halogen, cyano, hydroxy, or alkoxy; R7a is hydrogen, alkyl, or alkoxy. In some embodiments, R 7 and R 9 are each independently 1-4 In some embodiments, R 7 and R 9 are each independently 1-2 It is alkyl.

[0109] 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, provided that R 7 and R 9 At least one of them is not hydrogen.

[0110] In some embodiments, R 8 and R 10 are hydrogen atoms.

[0111] 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 is 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 R 9 is ethyl.

[0112] In some embodiments, R 7 and R 9 are hydrogen, and R 8 and R 10together 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.

[0113] 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 containing two bridgehead atoms plus one -CH- 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.

[0114] In some embodiments, R 8 and R 10 are hydrogen atoms.

[0115] 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 10are 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. In some embodiments, R 8 and R 10 are hydrogen, and R 7 is methoxymethyl, and R 9 is methyl, ethyl or methoxymethyl.

[0116] L 1 Definition of

[0117] In some embodiments, L 1 is a direct bond, -O-, -N(R L )-, -alkylene-, or -C(O)-, and R L is hydrogen or alkyl, and the -alkylene- is unsubstituted or substituted with deuterium, halogen, alkoxy, alkynyl, or heterocyclyl. In some embodiments, L 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(CD)—, —CH(CHCH)—, —CH(CHF)—, —CH(prop-1-ynyl)-, —N(H)—, —N(CH)—, —O—, —CH(C(O)—NHCHCHOCH)—, or —C(CH)—. In some embodiments, L1 is -CH2-, -CH(CH3)-, or -CH(CD3)-. In some embodiments, L 1 is -CH(CH3)- or -CH(CD3)-.

[0118] X 2 and X 3 Definition of

[0119] 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.

[0120] Cy 1 Definition of

[0121] In some embodiments, Cy 1 is aryl, heterocyclyl, heterocyclyl, heteroaryl, or cycloalkyl, each of which is unsubstituted or contains one, two, three, or four substituents R 3a is replaced by 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 within the alkyl or alkoxy group 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.

[0122] 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 may contain one, two or three substituents R 3a optionally replaced by R 3a is deuterium, fluoro, bromo, chloro, 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, cyano and selected from anomethyl, 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, 1-hydroxyazetidin-3-yl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, or 2-fluoropropan-2-yl.

[0123] In some embodiments, Cy 1is aryl, which is unsubstituted or contains one, two or three substituents R 3a is replaced by 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 within the alkyl or alkoxy group 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.

[0124] In some embodiments, Cy 1 is aryl, which is unsubstituted or contains one, two or three substituents R 3a is replaced by R 3a is alkoxy, halogen-substituted alkoxy, alkoxyalkyl-, alkyl, alkenyl, 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)-, heterocyclylalkyl- or heterocyclyl, wherein 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 phenyl, which can be one or two R 3a is replaced by R 3a is fluoro, chloro, bromo; methyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, methoxymethyl, 1-methoxyethyl, ethyl, propyl, isopropyl, tert-butyl, 2-hydroxypropan-2-yl, 1-hydroxy-2-methylpropan-2-yl, 2-cyanopropan-2-yl, morpholinomethyl; prop-1-en-2-yl; cyclopropyl, 1-methylcyclopropyl; methoxy, difluoromethoxy, trifluoromethoxy, 1,1-difluoroethoxy, isopropoxy; oxetan-3-yl, morpholino, 2-oxa-6-azaspiro[3.3]heptan-6-yl; or methylcarbamoyl.

[0126] In some embodiments, Cy 1 is an aryl having 6 to 14 carbon atoms, having a single ring or multiple fused 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, indenyl, dihydroindenyl, or tetrahydronaphthyl, which is unsubstituted or substituted with one, two, or three R 3a is replaced by

[0127] In some embodiments, Cy 1 is phenyl. In some embodiments, Cy 1 is one R disclosed herein at position 4 3a and optionally substituted with R at other positions 3a is phenyl substituted with

[0128] In some embodiments, Cy 1 is naphthalenyl. In some embodiments, Cy 1 are naphthalen-1-yl, naphthalen-2-yl, naphthalen-3-yl, and naphthalen-4-yl.

[0129] In some embodiments, Cy 1 is unsubstituted or contains one, two, three or four R 3a 5-9 membered monocyclic heterocyclyl or 7-10 membered bicyclic heterocyclyl, substituted by (provided that valence theory is satisfied), and 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)-, oxo, or heterocyclyl, wherein the alkyl portion within an alkyl or alkoxy group 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 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 the 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 5- to 9-membered monocyclic 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-dioxan-2-yl, 1,4-dioxan-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.

[0130] In some embodiments, Cy 1 is piperidinyl (e.g., piperidin-1-yl) or piperazinyl (e.g., piperazin-4-yl), which is substituted with one R as disclosed herein at the 4-position. 3a and in other positions R 3a is optionally replaced by

[0131] In some embodiments, Cy 1 is unsubstituted or contains one, two, three or four R 3a In some embodiments, Cy is a 7- to 10-membered bicyclic heterocyclyl substituted with (provided that valence theory is satisfied). 1 is dihydrobenzodioxinyl, benzodioxolyl, chromanyl, or chromenyl, which is unsubstituted or substituted with one, two, three, or three R 3a is replaced by R 3ais selected from alkoxy, alkyl, halogen, and oxo. In some embodiments, Cy 1 is 2,3-dihydrobenzo[b][1,4]dioxin-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, benzo[d][1,3]dioxol-4-yl, benzo[d][1,3]dioxol-5-yl, chroman-2-yl, chroman-3-yl, chroman-4-yl, chroman-5-yl, chroman-6-yl, chroman-7-yl, chromen-2-yl, chromen-3-yl, chromen-4-yl, chromen-5-yl, chromen-6-yl, chromen-7-yl, each of which is unsubstituted or substituted by one, two, three or three R 3a is replaced by R 3a is selected from alkoxy, alkyl, halogen, and oxo. In some embodiments, R 3a is methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, or oxo. In some embodiments, two R 3a are linked to the same carbon and together form a spirocyclic ring, e.g. [ka] Form.

[0132] In some embodiments, Cy 1 is unsubstituted or contains one, two or three R 3a and R is a 5- to 9-membered monocyclic heteroaryl or a 7- to 10-membered bicyclic heteroaryl substituted with 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)-, oxo, phenyl, or heterocyclyl, wherein the alkyl portion within an alkyl or alkoxy group 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, oxo, hydroxyalkyl-, cyano, cyano-substituted alkyl, N(R 3b R 3c )-C(O)-, N(R 3b R 3c )-, R 3b -OC(O)-, oxo, phenyl, or heterocyclyl, wherein 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 more preferably R 3a is selected from deuterium, fluoro, bromo, chloro, methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, methoxy, methoxymethyl, methylsulfonyl, ethoxy, isopropoxy, isopropyl, tert-butyl, cyclopropyl, 1-hydroxyethyl, ethyl, 1,1-difluoroethyl, cyano, cyclopropyl-, acetamido, 1-methoxyethyl, cyanomethyl, carbamoyl, methoxycarbonyl, methylcarbamoyl, dimethylcarbamoyl, (difluoromethoxy)methyl, amino, isopropylamino, (difluoromethoxy)ethyl, azetidin-1-yl, 2-methoxypropan-2-yl, 1-methoxycyclopropyl, oxetan-3-yl, 1-methylazetidin-3-yl, 1-hydroxyazetidin-3-yl, phenyl, or oxo.

[0133] In some embodiments, the 5-9 membered monocyclic heteroaryl is pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is unsubstituted or contains one, two, or three R as disclosed herein. 3a In some embodiments, the 5- to 9-membered monocyclic heteroaryl is substituted with 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, thiazol-4-yl, thiazol-5-yl, 1H-pyrazol-5-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-6-yl, pyridin-7-yl, pyridin-8-yl, pyridin-9-yl, pyridin-10-yl, pyridin-11-yl, pyridin-12-yl, pyridin-13-yl, pyridin-14-yl, pyridin-15-yl, pyridin-16-yl, pyridin-17-yl, pyridin-18-yl, pyridin-19-yl, pyridin-20-yl, pyridin-21-yl, pyridin-22-yl, pyridin-23-yl, pyridin-24-yl, pyridin-25-yl, pyridin-26-yl, pyridin-27-yl, pyridin-28-yl, pyridin-29-yl, pyridin-31-yl, pyridin-29-yl, pyridin-29-yl, pyridin-21-yl, pyridin-22-yl, pyridin-23-yl, pyridin-24-yl, pyridin-25-yl, pyridin-26-yl, pyridin-27-yl, pyridin-28-yl, pyridin-29-yl, pyridin-29-yl, pyridin-31-yl, pyridin-29-yl rimidin-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 contains one, two, or three R as disclosed herein. 3a In some embodiments, R 3a is selected from deuterium, fluoro, bromo, chloro, methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, isopropoxy, isopropyl, tert-butyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, isopropylamino, azetidin-1-yl, phenyl, or oxo.

[0134] In some embodiments, the 7-10 membered bicyclic heteroaryl is selected from the group consisting of indolyl, triazolopyridinyl, imidazopyridinyl, benzoxazolyl, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, dioxinopyridinyl, quinoxalinyl, benzo[d]imidazolyl, benzofuranyl, benzoxazinyl, imidazo[4,5-b]pyridinyl, thiazolo[5,4 ... and thieno[4,5-b]pyridinyl, thieno[2,3-b]pyridinyl, dihydrodioxinopyridinyl, dioxinopyridinyl, dihydro-2H-pyranopyridinyl, 2H-pyranopyridinyl, dihydrofuropyridinyl, furopyridinyl, benzo[d]thiazolyl, isoindolinyl, or thieno[3,2-b]pyridinyl, each of which is unsubstituted or contains one, two, or three R as disclosed herein. 3aIn some embodiments, the 7- to 10-membered bicyclic heteroaryl is quinoxalin-6-yl, quinoxalin-2-yl, isoquinolin-3-yl, isoquinolin-7-yl, quinolin-6-yl, 1H-benzo[d]imidazol-5-yl, benzofuran-6-yl, benzofuran-5-yl, benzo[e][1,3]oxazin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyrid ... -[1,4]dioxino[2,3-b]pyridin-7-yl, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl, 2,3-dihydrofuro[2,3-b]pyridin-6-yl, 2,3-dihydrofuro[3,2-b]pyridin-5-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, isoindolin-5-yl, 1H-benzo[ d]imidazol-2-yl, 1H-benzo[d]imidazol-4-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 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-7-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-7-yl, isoquinolin-1-yl, isoquinolin-4-yl, isoquinolin-5- yl, isoquinolin-6-yl, isoquinolin-8-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-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, 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, 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. 3a is replaced by

[0135] In some embodiments, Cy 1 is quinoxalinyl, 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 by one, two or three R 3a is replaced by R 3a is deuterium, alkoxy, alkyl, halogen, oxo, 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 within the alkyl or alkoxy group 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 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 more preferably R 3a is selected from deuterium, fluoro, bromo, chloro, 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.

[0136] In some embodiments, Cy 1 is quinoxalin-2-yl or quinoxalin-6-yl, which is unsubstituted or contains one, two or three R 3a is replaced by 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, 2,2,2-trifluoroethyl, 2-fluoropropan-2-yl, methoxy, isopropoxy, difluoromethoxy, fluoro, chloro, oxo, cyano, amino, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl, or cyclobutyl, preferably deuterium, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, fluoro, chloro, cyano, amino, or cyclopropyl. In some embodiments, Cy 1 is quinoxalin-6-yl, 3-methylquinoxalin-6-yl, 3-(trifluoromethyl)quinoxalin-6-yl, or quinoxalin-2-yl.

[0137] In some embodiments, Cy 1 is benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, isoindolin-4-yl, indolin-5-yl, 1H-benzo[d]imidazol-5-yl, benzofuran-6-yl, benzofuran-5-yl, or benzo[e][1,3]oxazin-6-yl, isoquinolin-3-yl, isoquinolin-7-yl, quinolin-6-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, 3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl, 2,3-dihydrofuro[2,3-b]pyridin-6-yl, 2,3-dihydrofuro[3,2-b]pyridin-5-yl, each of which is unsubstituted or substituted with one, two or three R 3a is replaced by 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, 2,2,2-trifluoroethyl, 2-fluoropropan-2-yl, methoxy, isopropoxy, difluoromethoxy, fluoro, chloro, bromo, oxo, cyano, amino, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl, or cyclobutyl, and is preferably deuterium, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, fluoro, chloro, cyano, amino, or cyclopropyl.

[0138] In some embodiments, Cy 1 teeth, - 4-fluoro-2-methoxyphenyl, p-tolyl, 4-fluoro-2-(trifluoromethyl)phenyl, 2-(difluoromethoxy)-4-fluorophenyl, 4-fluoro-2-(trifluoromethoxy)phenyl, 4-fluoro-2-(methoxymethyl)phenyl, 4-fluoro-2-(1-methoxyethyl)phenyl, 1-(difluoromethoxy-4-fluorophenyl, 2-(difluoromethyl)-4-fluorophenyl, 2-(1,1-difluoroethoxy)-4-fluorophenyl, 3- (trifluoromethyl)phenyl, 3-isopropoxyphenyl, 3-(trifluoromethoxy)phenyl, 3-isopropylphenyl, 3-(tert-butyl)phenyl, 3-(2-hydroxypropan-2-yl)phenyl, 3-(difluoromethyl)-4-fluorophenyl, 4-fluoro-3-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 4-methyl-3-(trifluoromethyl)phenyl, 4-methyl-2-(trifluoromethyl)phenyl, 3- Cyclopropylphenyl, 3-(1-methylcyclopropyl)phenyl, 3-(oxetan-3-yl)phenyl, 4-fluoro-3-(methylcarbamoyl)phenyl, 3-(1-hydroxy-2-methylpropan-2-yl)phenyl, 3-(2-cyanopropan-2-yl)phenyl, 4-fluoro-3-(prop-1-en-2-yl)phenyl, 4-fluoro-3-(1-methylcyclopropyl)phenyl, 3-methyl-4-(trifluoromethyl)phenyl, 4-(morpholinomethyl)phenyl , 3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl, 3-morpholinophenyl, 3-(morpholinomethyl)phenyl, 4-morpholinophenyl, 4-(trifluoromethyl)phenyl, 4-fluorophenyl, 3-methyl-2-(trifluoromethyl)phenyl, 3-(difluoromethyl)-5-fluorophenyl, 3-(1,1-difluoroethyl)-4-methoxyphenyl, m-tolyl, 3-methoxyphenyl, or 3-(difluoromethyl)phenyl; or 3,3-dimethyl-2,3-dihydro-1H-inden-5-yl, or - 4,4-difluorochroman-6-yl, 2,2-dimethyl-4-oxochroman-7-yl, 3-methyl-4-oxo-4H-chromen-6-yl, 2,2-dimethylchroman-7-yl or 2-methyl-4-oxo-4H-chromen-7-yl, or - 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 8-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 7-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 5-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 8-chloro-3,3-dimethyl fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-difluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 7-fluoro-2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, or 7-chloro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl; - 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2-difluorobenzo[d][1,3]dioxol-5-yl, 2-ethyl-2-methylbenzo[d][1,3]dioxol-5-yl, spiro[benzo[d][1,3]dioxole-2,1'-cyclobutan]-5-yl, 6-chloro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 7-chloro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 4-chloro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 7-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 4-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 4,6-difluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2,7-trimethylbenzo[d][1,3]dioxol-5-yl, 7-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-4-yl, 2,2-dimethylbenzo[d][1,3]dioxol-4-yl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 4-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, or 2,2-dimethylbenzo[d][1,3]dioxol-5-yl; - 2-(trifluoromethyl)pyridin-3-yl, 6-isopropoxypyridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl, 2-(trifluoromethyl)pyridin-4-yl, 4-(trifluoromethyl)pyridin-2-yl, 2-(azetidin-1-yl)pyridin-4-yl, 2-(isopropylamino)pyridin-4-yl, 6-isopropylpyridin-2-yl, 2-isopropoxypyridin-4-yl, 6-(trifluoromethoxy)pyridin-2-yl, 2-(tert-butyl)pyridin-4-yl, 2-(methylcarbamoyl)pyridin-4-yl, 2 -(2,2-dimethylcarbamoyl)pyridin-4-yl, 5,6-dimethylpyridin-2-yl, 2-phenylpyridin-4-yl, 5-(difluoromethyl)pyridin-2-yl, 5-methylpyridin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, 2-methoxypyridin-4-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 1-methyl-2-oxo-1,2-dihydropyridin-4-yl, 2-(trifluoromethyl)thiazol-4-yl, or 1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, or quinoxalin-6-yl, 3-methylquinoxalin-6-yl, 3-(trifluoromethyl)quinoxalin-6-yl, or quinoxalin-2-yl, or isoquinolin-3-yl, 2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl, 2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl, 1,2-dimethyl-4-oxo-1,4-dihydroquinolin-7-yl, 1,3-dimethyl-4-oxo-1,4-dihydroquinolin-6-yl or 2-methylquinolin-7-yl, or 2-methyl-1H-benzo[d]imidazol-5-yl, 2,2-dimethyl-2,3-dihydrobenzofuran-6-yl, 2,2-dimethyl-3-oxo-2,3-dihydrobenzofuran-6-yl, 3,3-dimethyl-2,3-dihydrobenzofuran-5-yl or 3-methyl-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl, - 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 4,4-difluoro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl, 4,4-difluoro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl, - 7-chloro-3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 7-fluoro-3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 8-fluoro-3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridin-6-yl, 3,3-dimethyl-2,3-dihydrofuro[3,2-b]pyridin-5-yl 2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl, 2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 3-methyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, or 3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl; - 2-methylbenzo[d]thiazol-5-yl, 2-methylbenzo[d]thiazol-6-yl, 2-ethylbenzo[d]thiazol-5-yl, 2-isopropylbenzo[d]thiazol-5-yl or 2-(trifluoromethyl)thiazol-5-yl, 2-methyl-1,3-dioxoisoindolin-5-yl, 2-isopropyl-1,3-dioxoisoindolin-5-yl, 1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl, 2,3,3-trimethyl-1-oxoisoindolin-5-yl, 2-methyl-3-oxoisoindolin-5-yl or 2-methyl-1-oxoisoindolin-5-yl.

[0139] In some embodiments, the moiety [ka] teeth, [ka] wherein m is 0, 1, 2, or 3; R 3a is alkoxy, alkyl, halogen, and oxo.

[0140] In some embodiments, the moiety [ka] is 2,2-dimethylbenzo[d][1,3]dioxol-5-yl or 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, where m is 0, 1, 2, or 3; R 3a is alkoxy, alkyl, halogen, and oxo. In some embodiments, the moiety [ka] are 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2-difluorobenzo[d][1,3]dioxol-5-yl, 2-ethyl-2-methylbenzo[d][1,3]dioxol-5-yl, spiro[benzo[d][1,3]dioxole-2,1'-cyclobutan]-5-yl, 6-chloro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 7-chloro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 4-chloro-2,2-dimethylbenzo[d][ 1,3]dioxol-5-yl, 7-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 4-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 4,6-difluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2,7-trimethylbenzo[d][1,3]dioxol-5-yl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 4-fluoro-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, 8-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 7-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 5-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin benzo[b][1,4]dioxin-6-yl, 8-chloro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-difluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 7-fluoro-2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, or 7-chloro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl.

[0141] General synthetic scheme

[0142] The compounds disclosed herein, including their salts, can be prepared using known organic synthesis techniques, or can be synthesized according to any of a number of possible synthetic routes.

[0143] The reaction 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.Suitable solvents can be substantially non-reactive with starting materials, intermediates, or products at the temperature at which the reaction is carried out, for example, a temperature that can vary from room temperature to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of solvents.

[0144] The selection of an appropriate protecting group can be readily determined by one of ordinary skill in the art.

[0145] Reactions can be monitored according to any suitable method known in the art, such as NMR, UV, HPLC, LC-MS, and TLC. Compounds can be purified by a variety of methods, including HPLC and normal phase silica flash column chromatography.

[0146] Chiral analytical HPLC was used to analyze the retention times of different chiral examples, and the conditions were divided into the following methods according to the column, mobile phase, and solvent ratio used. The preparation of homochiral examples can be carried out by techniques known to those skilled in the art. Absolute stereochemistry was not assigned to the newly formed carbon-nitrogen bond.

[0147] [Table 1A-1] [Table 1A-2] [Table 1A-3] [Table 1A-4] [Table 1A-5]

[0148] General synthetic scheme

[0149] The compounds disclosed herein, including their salts, can be prepared using known organic synthesis techniques, or can be synthesized according to any of a number of possible synthetic routes.

[0150] The reaction 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.Suitable solvents can be substantially non-reactive with starting materials, intermediates, or products at the temperature at which the reaction is carried out, for example, a temperature that can vary from room temperature to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of solvents.

[0151] The selection of an appropriate protecting group can be readily determined by one of ordinary skill in the art.

[0152] Reactions can be monitored according to any suitable method known in the art, such as NMR, UV, HPLC, LC-MS, and TLC. Compounds can be purified by a variety of methods, including HPLC and normal phase silica flash column chromatography.

[0153] Chiral analytical HPLC was used to analyze the retention times of different chiral examples, and the conditions were divided into the following methods according to the column, mobile phase, and solvent ratio used. The preparation of homochiral examples can be carried out by techniques known to those skilled in the art. Absolute stereochemistry was not assigned to the newly formed carbon-nitrogen bond.

[0154] The compounds disclosed herein can be prepared according to Schemes IV.

[0155] Scheme I [ka]

[0156] In the formula, R 1 ~R 9 and R 8L (L 1 -Cy 1 The substitution of (corresponding to) is as defined in formula (I).

[0157] In Scheme I, commercially available compound 1 (X1 is CH or N) is reacted with an appropriate chiral secondary amine via nucleophilic aromatic substitution to give compound 2. Compound 2 is reacted with an appropriate R4-X under basic conditions (e.g., K2CO3, Cs2CO3, etc.) to give compound 3. Compound 3 can be used to generate compound 4 via a standard Pd-catalyzed CO coupling reaction using an appropriate Pd catalyst and ligand under basic conditions (e.g., KOH). Compound 4 is reacted with an appropriate R1-X under basic conditions (e.g., K2CO3, Cs2CO3, etc.) to give compound 5. Compound 5 is reacted with a formylating reagent (e.g., DMF) under basic conditions (e.g., n-BuLi or LDA) to give compound 6. Reduction of compound 6 using a reducing agent (e.g., NaBH4) gives compound 7 as an alcohol. Compound 7, which contains a hydroxyl group, can be chlorinated by treatment with a chlorinating agent such as (SOCl2) to give compound 8. Compound 8, as a benzyl halide, can be converted to the corresponding compound 9 by treatment with a cyanating agent (e.g., TMSCN) under basic conditions (e.g., CsCO or n-BuNF). Compound 9 is deprotected using acidic conditions (e.g., TFA or 4 M HCl in 1,4-dioxane) to give compound 10. Tertiary amine compound 11 is prepared by N-alkylation of secondary amine compound 10 by treatment with reductive alkylation with an aldehyde or ketone, the most frequently used procedure being via phosphonium salt-mediated alkylation of the amine with the corresponding alcohol (Florencio Zaragoza and Henrik Stephensen, J. Org. Chem. 2001, 66, 2518-2521).

[0158] Compound 7 disclosed herein can also be prepared according to Scheme II below.

[0159] Scheme II [ka]

[0160] In Scheme II, compound 3 can be converted to the corresponding compound 1a by treatment with a strong base (e.g., n-BuLi) and methyl chloroformate. The chlorine atom-containing compound 1a can be converted to the corresponding hydroxyl group-containing compound by a standard Pd-catalyzed CO coupling reaction using an appropriate Pd catalyst and ligand under basic conditions (e.g., KOH), while the ester group of compound 1a is hydrolyzed to the carboxylic acid of compound 2a. Compound 2a is reacted with an appropriate R1-X under basic conditions (e.g., K2CO3, Cs2CO3), to give compound 3a. Reduction of compound 3a using a reducing agent (e.g., NaBH4) gives compound 7 as an alcohol.

[0161] Compound 7 disclosed herein can also be prepared according to Scheme III below.

[0162] Scheme III [ka]

[0163] In Scheme III, reduction of compound 1a using a reducing agent (e.g., NaBH4) affords compound 1b as an alcohol. Compound 1b can be converted to the corresponding compound 2b by treatment with an organic base (e.g., imidazole) and TBSCl. Compound 2b, which contains a chlorine atom, can be converted to the corresponding hydroxyl group-containing compound 3b by a standard Pd-catalyzed CO coupling reaction using an appropriate Pd catalyst and ligand under basic conditions (e.g., KOH). Compound 3b is reacted with an appropriate R1-X under basic conditions (e.g., K2CO3, Cs2CO3) to afford compound 4b. Deprotection of compound 4b using a fluorine-containing reagent (e.g., tetrabutylammonium fluoride) affords compound 7.

[0164] Compounds of formula 12c disclosed herein can be prepared according to Scheme IV.

[0165] Scheme IV [ka]

[0166] Halogenation of compound 6c with an electrophilic halogenating reagent (such as NBS, NCS, or Selectfluor) gives compound 7c. Reduction of compound 7c using a reducing agent (such as NaBH) gives compound 8c as an alcohol. Compound 8c, containing a hydroxyl group, can be chlorinated by treatment with a chlorinating agent such as SOCl or MsCl to give compound 9c. Compound 9c as a benzyl halide can be converted to the corresponding compound 10c by treatment with a cyanating agent (such as TMSCN) under basic conditions (such as CsCO or n-BuNF). Deprotection of compound 10c using acidic conditions (such as TFA or 4 M HCl in 1,4-dioxane) gives compound 11c. Tertiary amine compounds 12c are prepared by N-alkylation of secondary amine compounds 11c by treatment with aldehydes or ketones in a reductive alkylation, the most frequently used procedure being via phosphonium salt-mediated alkylation of the amine with the corresponding alcohol (Florencio Zaragoza and Henrik Stephensen, J. Org. Chem. 2001, 66, 2518-2521).

[0167] Compounds of formula 11d disclosed herein can also be prepared according to Scheme V.

[0168] Scheme V [ka]

[0169] In Scheme V, compound 2d' is prepared by N-alkylation of secondary amine compound 1d' by treatment with an alkylating agent (such as an alkyl halide or alkyl sulfonate) or by reductive alkylation with an aldehyde or ketone, the most frequently used procedure being phosphonium salt-mediated alkylation of the amine with the corresponding alcohol. Compound 2d' is deprotected using acid conditions (such as TFA or 4 M HCl in 1,4-dioxane) to give compound 3d'. Compound 1d was synthesized according to a literature method (Shaker Youssef and Wolfgang Pfleiderer, J. Heterocyclic Chem. 35, 949-954, 1998). Compound 1d is reacted with an appropriate acid via a cyclization reaction to give compound 2d. Compound 2d is then phosphonium-mediated S-alkylation with an appropriate chiral secondary amine (corresponding to compound 3d') in the presence of a phosphonium reagent (such as BOP) under basic conditions (such as DBU or DIPEA). N The reaction is carried out by Ar reaction to give compound 3d. Compound 3d is deprotected using acid conditions (such as TFA) to give compound 4d. Compound 4d containing a hydroxyl group can be chlorinated by treatment with a chlorinating agent such as (SOCl) to give compound 5d. Compound 5d as a benzyl halide can be converted to the corresponding compound 11d by treatment with a cyanating agent (such as TMSCN) under basic conditions (such as CsCO or n-BuNF). [Example]

[0170] Example

[0171] The following examples are intended to be illustrative only and should not be construed as limiting in any way. Unless otherwise specified, experimental methods in the following examples are conventional. Unless otherwise specified, all reagents and materials are commercially available. All solvents and chemicals used are of analytical grade or chemical purity. All solvents are redistilled before use. All anhydrous solvents are 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) are commercially available from Tsingdao Haiyang Chemical Co., Ltd. or Yantai Chemical Co., Ltd., China. All are eluted with petroleum ether (60-90°C) / ethyl acetate (v / v) and visualized with iodine or molybdophosphoric acid ethanol solution unless otherwise specified. All extraction solvents are dried over anhydrous Na2SO4 unless otherwise specified. 1 H NMR spectra were recorded on a Bruck-400 nuclear magnetic resonance spectrometer using 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) and an ion trap (ESI source) detecting at 214 nm and 254 nm. All compound names, except for reagent names, were generated by ChemDraw®.

[0172] synthesis

[0173] [Table 2]

[0174] [Table 3]

[0175] Intermediate 1: (2S,5R)-2,5-diethylpiperazine-1-carboxylate tert-butyl [ka]

[0176] Step A: (R)-2-(benzylamino)butanoic acid methyl ester [ka]

[0177] To a solution of (R)-methyl 2-aminobutanoate (100.0 g, 0.85 mol) in CHCN (1000 mL) was added benzyl bromide (146.1 g, 0.85 mol) at 0 °C under a N atmosphere. The reaction was stirred at room temperature overnight and concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (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: EtOAc = 10:1) to give the title compound (106 g, 60%). MS: M / e 208 (M+1) + .

[0178] Step B: (R)-2-((S)-N-benzyl-2-((tert-butoxycarbonyl)amino)butanamido)methyl butanoate [ka]

[0179] To a solution of (R)-methyl 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) was added HATU (319.0 g, 0.84 mmol) at 0° C. 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: EtOAc = 10:1) to give the title compound (178 g, 80%). MS: M / e 393 (M+1) + .

[0180] Step C: (R)-2-((S)-2-amino-N-benzylbutanamido)butanoate methyl [ka]

[0181] To a solution of (R)-2-((S)-N-benzyl-2-((tert-butoxycarbonyl)amino)butanamido)methyl 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 hours and concentrated in vacuo to give the title compound (200 g, crude). MS: M / e 293 (M+1). + .

[0182] Step D: (3S,6R)-1-benzyl-3,6-diethylpiperazine-2,5-dione [ka]

[0183] To a solution of methyl (R)-2-((S)-2-amino-N-benzylbutanamido)butanoate (200 g, crude) in 1000 mL of EtOAc was added aqueous NaHCO3 (300 mL) at room temperature. The reaction mixture was stirred at room temperature for an additional 2 hours. The organic layer was concentrated under reduced pressure. The resulting residue was triturated with MTBE to give the title compound (61 g, 52% for two steps, ee: 97%). MS: M / e 261 (M+1) + .

[0184] Step E: (2R,5S)-1-benzyl-2,5-diethylpiperazine [ka]

[0185] To a THF solution (1000 mL) of LiAlH4 (26.5 g, 0.69 mol), a THF solution (500 mL) of (3S,6R)-1-benzyl-3,6-diethylpiperazine-2,5-dione (61.0 g, 0.23 mol) was slowly added at 0°C. The resulting mixture was stirred at room temperature for 2 hours and then at 80°C overnight. The reaction was slowly quenched with water (27 mL) at 0°C. Then, 1N aqueous NaOH solution (54 mL) and water (81 mL) were added sequentially. The resulting mixture was stirred for 2 hours. The formed white precipitate was removed by filtration. The filter cake was washed with EtOAc (500 mL). The combined filtrate was evaporated. The resulting residue was dissolved in toluene. The solvent was removed in vacuo to dryness to give the title compound (51 g, 95%). MS: M / e 233 (M+1) + .

[0186] Step F: (2S,5R)-4-benzyl-2,5-diethylpiperazine-1-carboxylate tert-butyl. [ka]

[0187] To a solution of (2R,5S)-1-benzyl-2,5-diethylpiperazine (46.4 g, 200 mmol) and BocO (48 g, 220 mmol) in DCM (800 mL) was added EtN (30.3 g, 300 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction was quenched with saturated NaCl (400 mL) at room temperature. The resulting mixture was extracted with DCM (800 mL x 2). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound (43.2 g, 65%). MS: M / e 333 (M+1) + .

[0188] Step G: (2S,5R)-tert-Butyl 2,5-diethylpiperazine-1-carboxylate. [ka]

[0189] To a solution of tert-butyl (2S,5R)-4-benzyl-2,5-diethylpiperazine-1-carboxylate (43.2 g, 130 mmol) and Pd / C (6.6 g, 10% in water) in MeOH (240 mL) was added AcOH (5 mL) at room temperature. The resulting mixture was degassed three times under H atmosphere and stirred at room temperature for 12 hours under H atmosphere. After filtration, the combined organic layers were concentrated under reduced pressure to give the crude product. The crude product was basified to pH 10 with NaCO (4 M) and extracted with EA (200 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over NaSO, and concentrated under reduced pressure to give the title compound (22 g, 70%). 1H NMR (400 MHz, CDCl3) δ 3.96 - 3.84 (m, 1H), 3.74 (d, J = 13.2 Hz, 1H), 3.12 - 3.00 (m, 2H), 2.72 - 2.60 (m, 1H), 2.52 (dd, J = 1.2 Hz, MS: M / e 243 (M+1) + .

[0190] Intermediate 2: (2R,5S)-tert-butyl 2,5-diethylpiperazine-1-carboxylate [ka]

[0191] Step A: (S)-2-(benzylamino)butanoic acid methyl ester [ka]

[0192] To a solution of compound 1 (250 g, 1.6 mol) in DCE (3500 mL) were added TEA (164 g, 1.6 mol), PhCHO (172 g, 1.6 mol), and NaBH(OAc) (516 g, 2.4 mol) in an ice bath. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with NaCO (1000 mL) and extracted with DCM (1500 mL x 2). The combined organic layers were washed with brine (1000 mL) and concentrated. The residue was purified by silica gel chromatography (PE:EA = 20:1) to give the title compound (315 g, 93.8%) as a colorless oil. MS: M / e 208 (M+1) +

[0193] Step B: (S)-2-((R)-N-benzyl-2-((tert-butoxycarbonyl)amino)butanamido)methyl butanoate [ka]

[0194] To a solution of (S)-methyl 2-(benzylamino)butanoate (244 g, 1.2 mol) in DCM (7000 mL), (R)-2-((tert-butoxycarbonyl)amino)butanoic acid (285 g, 1.4 mol) and EDCI (113 g, 0.16 mol) were added in an ice bath. The reaction mixture was stirred at room temperature for 30 minutes. EDCI (113 g, 0.16 mol) was added. The reaction mixture was stirred for another hour, and additional EDCI (113 g, 0.16 mol) was added. Afterwards, the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was poured into HO (2500 mL) and extracted with DCM (1500 mL × 2). The combined organic layers were washed with brine (1000 mL) and concentrated. The residue was purified by silica gel chromatography (PE:EA = 10:1) to give the title compound (152 g, 33%) as a colorless oil. MS: M / e 393 (M+1) +

[0195] Step C: (3R,6S)-1-benzyl-3,6-diethylpiperazine-2,5-dione [ka]

[0196] A reaction mixture of (S)-2-((R)-N-benzyl-2-((tert-butoxycarbonyl)amino)butanamido)methyl butanoate (143 g, 0.36 mol) in 4N HCl / dioxane (1500 mL) was stirred at room temperature for 5 hours. The reaction mixture was then basified with saturated NaHCO3 to pH 9.0 and stirred for 2 hours. The mixture was extracted with DCM (1500 mL × 2). The combined organic layers were washed with brine (2 L) and concentrated. The residue was purified by silica gel chromatography (PE:EA = 2:1) to give the title compound (80 g, 85%) as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.23 ​​(s, 1H), 7.36-7.23 (m, 5H), 5.10 (d, J = 15.2 Hz, 1H), 4.15-4.13 (m, 1H), 4.08 (d, J =14.8 Hz 1H), 3.65-3.63 (m, 1H), 1.93-1.82 (m, 4H), 0.84-0.79 (m, 6H) ppm. MS: M / e 261 (M+1 )+ .

[0197] Step D: (2S,5R)-1-benzyl-2,5-diethylpiperazine [ka]

[0198] To a solution of (3R,6S)-1-benzyl-3,6-diethylpiperazine-2,5-dione (70 g, 0.27 mol) in THF (1000 mL) was added a solution of LiAlH4 (51 g, 1.35 mol) in an ice bath. The reaction mixture was stirred at 70 °C for 4 hours. The reaction mixture was cooled, and water (51.15 mL), 10% NaOH (51.15 mL), and water (153.45 mL) were added. The mixture was stirred for 4 hours. The mixture was filtered. The filtrate was concentrated to give the title compound (62 g, 99.9%), which was used in the next step without further purification. MS: M / e 233 (M+1) + .

[0199] Step E: (2R,5S)-tert-butyl 4-benzyl-2,5-diethylpiperazine-1-carboxylate [ka]

[0200] To a solution of (2S,5R)-1-benzyl-2,5-diethylpiperazine (62 g, 0.27 mol) in THF (1000 mL), BocO (64 g, 0.29 mol) and DIEA (50 g, 0.39 mol) were added in an ice bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into HO (300 mL) and extracted with DCM (1000 mL × 2). The combined organic layers were washed with brine (1 L) and concentrated. The residue was purified by silica gel chromatography (PE:EA = 25:1) to give the title compound (74 g, 88.7%) as a colorless oil. 1 H NMR (DMSO-d6, 400 MHz): δ 7.34-7.23 (m, 5H), 3.88-3.84 (m, 2H), 3.67 (d, J =18.4 Hz, 1H), 3.50 (d, J = 18.0 Hz, 1H), 3.06-3.04 (m, 1H), 2.58-2.50 (m, 1H), 2.27 (d, J = 17.2 Hz, 1H), 1.82-1.75 (m, 1H), 1.59-1.45 (m, 13H), 0.88 (t, J = 9.6 Hz, 3H), 0.74 (t, J = 9.6 Hz, 3H) ppm. MS: M / e 333 (M+1) + .

[0201] Step F: (2R,5S)-tert-Butyl 2,5-diethylpiperazine-1-carboxylate [ka]

[0202] To a solution of tert-butyl (2R,5S)-4-benzyl-2,5-diethylpiperazine-1-carboxylate (70 g, 0.1 mol) in MeOH (500 mL) was added Pd / C (14 g) at room temperature. The reaction mixture was stirred under H (1 atm) at 30° C. overnight. The resulting mixture was filtered and concentrated to give the title compound (50 g, 98%) as a colorless oil. 1H NMR (DMSO-d6, 400 MHz): δ 3.76-3.74 (m, 1H), 3.63 (d, J = 17.6 Hz, 1H), 3.00 (dd, J = 5.2, 17.6 Hz, 1H), 2.89 (dd, J = 6.0, 17.2 Hz, 1H), 2.57-2.56 (m, 1H), 2.41-2.24 (m, 1H), 1.79-1.72 (m, 1H), 1.57-1.46 (m, 3H), 1.38 (s, 9H), 0.88-0.77 (m, 6H) ppm. LCMS [Column: Xbridge C18; Column size: 4.6 * 50 mm, 3.5 μm; Mobile phase: 95% water (0.1% TFA) and 5% CH3CN to 5% water (0.1% TFA) and 95% CH3CN over 6.5 min, followed by 0.5 min under these conditions. Purity was >95%, Rt=3.131 min; MS: M / e 243 (M+1). + .

[0203] Intermediate 3: (2R,5S)-2-ethyl-5-methylpiperazine-1-carboxylate tert-butyl [ka]

[0204] Step A: Methylbenzyl-L-alaninate [ka]

[0205] To a suspension of methyl L-alaninate 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 hours. The mixture was filtered. The filter cake was washed with EtOAc (200 mL x 3). The organics were combined and concentrated. The resulting residue was diluted with EtOAc (500 mL), washed with a saturated aqueous solution of NaHCO3 (200 mL), brine (200 mL x 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) + .

[0206] Step B: Methyl N-benzyl-N-((R)-2-((tert-butoxycarbonyl)amino)butanoyl)-L-alaninate [ka]

[0207] To a mixture of methyl benzyl-L-alaninate (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 a saturated aqueous solution of NaHCO (100 mL × 2), brine (100 mL × 2), dried over NaSO, and concentrated. The residue was purified by flash column chromatography to give the title compound (45 g, 85%). MS: M / e 379 (M+1) + .

[0208] Step C: Methyl N-((R)-2-aminobutanoyl)-N-benzyl-L-alaninate [ka]

[0209] To a solution of methyl N-benzyl-N-((R)-2-((tert-butoxycarbonyl)amino)butanoyl)-L-alaninate (41.0 g, 108.5 mmol) in 300 mL of EtOAc was added HCl (100 mL, 4 M in dioxane) at room temperature, and the mixture was stirred at room temperature for 3 days. The mixture was concentrated to dryness to give the title compound (38.0 g, crude), which was used directly in the next step. MS: M / e 279 (M+1) + .

[0210] Step D: (3R,6S)-1-benzyl-3-ethyl-6-methylpiperazine-2,5-dione [ka]

[0211] To a mixture of methyl N-((R)-2-aminobutanoyl)-N-benzyl-L-alaninate hydrochloride (38.0 g, crude) in EA / HO (200 mL / 50 mL) solvent mixture was added NaHCO (55 g, 650 mmol) portionwise at room temperature. The resulting mixture was stirred at room temperature for 5 hours. The layers were separated. The aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over NaSO, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound (24 g, 88% for two steps). MS: M / e 247 (M+1) + .

[0212] Step E: (2S,5R)-1-benzyl-5-ethyl-2-methylpiperazine [ka]

[0213] To (3R,6S)-1-benzyl-3-ethyl-6-methylpiperazine-2,5-dione (23.6 g, 95.9 mmol) was slowly added a solution of borane in THF (1 M, 480 mL) over 15 minutes. The resulting mixture was stirred at 70° C. for 72 hours. The mixture was cooled to 0° C. and MeOH (100 mL) was slowly added, followed by HCl (5 M, 40 mL). A large amount of bubbles was observed. After stirring for 30 minutes, the mixture was heated at 70° C. for 2 hours. The mixture was concentrated to dryness and purified by flash column chromatography to give the title compound (21.5 g, crude), which was used directly in the next step. MS: M / e 219 (M+1) + .

[0214] Step F: tert-Butyl (2R,5S)-4-benzyl-2-ethyl-5-methylpiperazine-1-carboxylate [ka]

[0215] 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 dropwise addition of di-tert-butyl decarbonate (20.0 g, 91.7 mmol). The resulting mixture was stirred at room temperature for 16 hours. 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). + .

[0216] Step G: tert-Butyl (2R,5S)-2-ethyl-5-methylpiperazine-1-carboxylate [ka]

[0217] 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 hours. The mixture was filtered, and the filtrate was concentrated. The resulting oil was treated with an aqueous solution of 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, MS: M / e 229 (M+1) + .

[0218] Intermediate 4: (2S,5R)-tert-butyl 5-ethyl-2-methylpiperazine-1-carboxylate [ka]

[0219] Step A: (R)-2-(benzylamino)butanoic acid methyl ester. [ka]

[0220] To a solution of (R)-methyl 2-aminobutanoate hydrochloride (100 g, 651 mmol) and K2CO3 (225 g, 1.628 mol) in CH3CN (700 mL) was added (bromomethyl)benzene (122.5 g, 716 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. After filtration, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound (70 g, 52%). MS: M / e 208 (M+1) + .

[0221] Step B: (R)-2-((S)-N-benzyl-2-((tert-butoxycarbonyl)amino)propanamido)methyl butanoate [ka]

[0222] To a solution of (R)-methyl 2-(benzylamino)butanoate (35 g, 169 mmol), (tert-butoxycarbonyl)-L-alanine (48 g, 254 mmol), and HATU (116 g, 304 mmol) in DCM (400 mL) was added NMM (43 g, 422 mmol). The reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched with saturated NaCl (100 mL) at room temperature. The resulting mixture was extracted with DCM (300 mL x 2). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound (45 g, 70%). MS: M / e 379 (M+1) + .

[0223] Step C: (R)-2-((S)-2-amino-N-benzylpropanamido)methylbutanoate hydrochloride [ka]

[0224] To a solution of (R)-2-((S)-N-benzyl-2-((tert-butoxycarbonyl)amino)propanamido)methyl butanoate (45 g, 119 mmol) in DCM (250 mL) was added HCl (119 mL, 4 M in 1,4-dioxane) at room temperature. The reaction mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure to give the title compound (32 g, 86%). MS: M / e 279 (M+1) + .

[0225] Step D: (3S,6R)-1-benzyl-6-ethyl-3-methylpiperazine-2,5-dione [ka]

[0226] To a solution of (R)-2-((S)-2-amino-N-benzylpropanamido)methyl butanoate hydrochloride (32 g, 102 mmol) in NaHCO3 (150 mL, 4 M) was added EA (150 mL). The reaction mixture was stirred at room temperature for 2 h. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the title compound (22 g, 87%). MS: M / e 247 (M+1) + .

[0227] Step E: (2R,5S)-1-benzyl-2-ethyl-5-methylpiperazine. [ka]

[0228] To a solution of (3S,6R)-1-benzyl-6-ethyl-3-methylpiperazine-2,5-dione (20 g, 81.3 mmol) in THF (300 mL) at 0° C., LiAlH (6.2 g, 163 mmol) was added portionwise. The reaction mixture was stirred at 70° C. for 36 h, and HO (6.2 mL) was added. The reaction solution was then quenched by the addition of NaOH (6.2 mL, 20%) and HO (12.4 mL) at 0° C. After filtration, the combined organic layer was dried over NaSO and concentrated under reduced pressure to give the title compound (11 g, 61%). MS: M / e 219 (M+1). + .

[0229] Step F: tert-Butyl (2S,5R)-4-benzyl-5-ethyl-2-methylpiperazine-1-carboxylate [ka]

[0230] To a solution of (2R,5S)-1-benzyl-2-ethyl-5-methylpiperazine (11 g, 50 mmol) and BOC-2O (12 g, 55 mmol) in DCM (200 mL) was added EtN (7.6 g, 75 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction was quenched with saturated NaCl (100 mL) at room temperature. The resulting mixture was extracted with DCM (200 mL x 2). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound (14 g, 69%). MS: M / e 319 (M+1) + .

[0231] Step G: tert-Butyl (2S,5R)-5-ethyl-2-methylpiperazine-1-carboxylate [ka]

[0232] To a solution of tert-butyl (2S,5R)-4-benzyl-5-ethyl-2-methylpiperazine-1-carboxylate (10 g, 31.4 mmol) and Pd / C (2.5 g, 10% in water) in MeOH (60 mL) was added AcOH (2 mL) at room temperature. The resulting mixture was degassed three times under H atmosphere and stirred at room temperature for 12 hours under H atmosphere. After filtration, the combined organic layer was concentrated under reduced pressure to give the crude product (AcOH salt). The crude product was basified to pH 10 with NaCO (4 M) and extracted with EA (80 mL × 3). The combined organic layer was washed with brine (20 mL × 3), dried over NaSO, and concentrated under reduced pressure to give the title compound (5.5 g, 77%). 1 H NMR (400 MHz, CDCl3) δ 4.21-4.09 (m, 1H), 3.72-3.69 (d, J = 12.9 Hz, 1H), 3.24-3.19 (dd, J = 13.7, 4.0 Hz, 1H), 3.14-3.10 (dd, J = 12.8, 4.7 Hz, 1H), 2.86-2.75 (m, 1H), 2.53-2.49 (dd, J = 12.8, 2.7 Hz, 1H), 2.33-2.12 (m, 1H), 1.65-1.54 (m, 2H), 1.46 (s, 9H), 1.25-1.24 (d, J = 4.0 Hz, 3H), 0.98-0.91 (m, 3H) ppm. MS: M / e 229 (M+1) + .

[0233] Intermediate 5: 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0234] Step A: tert-butyl (2R,5S)-4-(2-chloro-9H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0235] To a solution of 2,6-dichloro-9H-purine (200 g, 529 mmol) in EtOH (2400 mL) was added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (238 g, 555 mmol) and DIPEA (204.6 g, 794 mmol). The reaction was stirred at 80 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was taken up in DCM and washed with H2O. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (387 g, 99%). 1 H NMR (400 MHz,CD3OD) δ 7.97 (s, 1H), 6.17 - 5.05 (m, 2H), 4.43 (d, J = 20.5 Hz, 1H), 3.83 (d, J = 13.6 Hz, 1H), 3.80 - 3.35 (m, 2H), 1.50 (d, J = 3.6 Hz, 9H), 1.30 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H) ppm. MS: M / e 367 (M+1) + .

[0236] Step B: tert-Butyl (2R,5S)-4-(2-chloro-9-methyl-9H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0237] To a solution of tert-butyl (2R,5S)-4-(2-chloro-9H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (387 g, 1.06 mol) in acetone (2500 mL) was added K2CO3 (295 g, 2.12 mol) and CHCl (181 g, 1.27 mol). The reaction was stirred at room temperature overnight. The mixture was filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was dissolved in DCM and washed with H2O. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. A solution of PE / EtOAc (2 / 1) was added to the residue and stirred for 15 minutes. The mixture was filtered. The filter cake was dried under vacuum to give the title compound (350 g, 87%). 1 H NMR (400 MHz, CD3OD) δ 7.95 (s, 1H), 6.19 - 4.92 (m, 2H), 4.43 (d, J = 19.6 Hz, 1H), 3.82 (d, J = 13.8 Hz, 1H), 3.75 (s, 3H), 3.70 - 3.34 (m, 2H), 1.49 (s, 9H), 1.30 (d, J = 6.7 Hz, 3H), 1.17 (d, J = 6.8 Hz, 3H) ppm. MS: M / e 381 (M+1) + .

[0238] Step C: tert-Butyl (2R,5S)-2,5-dimethyl-4-(9-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)piperazine-1-carboxylate [ka]

[0239] To a solution of tert-butyl (2R,5S)-4-(2-chloro-9-methyl-9H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (100 g, 263 mmol) in dioxane / HO (1400 mL / 170 mL) was added 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (11.2 g, 26.3 mmol), KOH (44 g, 789 mmol), and Pd(dba) (2.41 g, 2.63 mmol). The reaction was stirred at 90 °C overnight. The mixture was cooled to room temperature, and EtOAc (1.5 L) was added and separated. The HO phase was filtered. The filtrate was adjusted to pH 6-7 and extracted with DCM. The organic phase was dried over NaSO and concentrated under reduced pressure to give the title compound (100.8 g). 1 H NMR (400 MHz, CD3OD) δ 7.56 (s, 1H), 5.67 - 4.90 (m, 2H), 4.36 (d, J = 22.3 Hz, 1H), 3.76 (d, J = 13.5 Hz, 1H), 3.62 (s, 3H), 3.57 - 3.33 (m, 2H), 1.49 (d, J = 4.2 Hz, 9H), 1.24 (d, J = 7.0 Hz, 3H), 1.15 (d, J = 6.8 Hz, 3H) ppm. MS: M / e 363 (M+1) + .

[0240] Step D: tert-Butyl (2R,5S)-4-(3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0241] To a mixture of tert-butyl (2R,5S)-2,5-dimethyl-4-(9-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)piperazine-1-carboxylate (96 g, 265 mmol) in dioxane (2000 mL) was added CsCO (432 g, 1.33 mol) and CHCl (376 g, 2.65 mol). The reaction was stirred at room temperature overnight and at 70 °C for 2 hours. The reaction mixture was filtered. The filtrate was removed to dryness under reduced pressure. The crude product was dissolved in DCM and washed with H0. The organic phase was dried over NaSO and concentrated under reduced pressure. PE / EtOAc (500 mL / 500 mL) was added to the residue and stirred for 0.5 hours. The mixture was filtered. The filter cake was dried to give the title compound (52 g, 53%). 1 H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 5.71 (s, 0.5H), 5.52 (s, 0.5H), 4.51 (s, 0.5H), 4.30 (s, 0.5H), 3.96 (d, J = 6.9 Hz, 3H), 3.91 - 3.55 (m, 5H), 3.31 (m, 2H), 1.47 (s, 9H), 1.35 - 1.23 (m, 3H), 1.15 (d, J = 6.5 Hz, 3H) ppm. MS: M / e 376 (M+1) + .

[0242] Step E: tert-butyl (2R,5S)-4-(8-formyl-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0243] To a solution of tert-butyl (2R,5S)-4-(3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (20 g, 53.2 mmol) in THF (1.2 L) was added LDA (106 mL, 2 M, 212 mmol) at temperatures below −60° C. The reaction was stirred at −65° C. for 1 hour, after which DMF (19.4 g, 266 mmol) was added at −78° C. The reaction was stirred at −60° C. for an additional 1 hour. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (23.1 g). 1 H NMR (400 MHz, CD3OD) δ 9.68 (s, 1H), 6.35 - 5.72(m, 1H), 5.40 - 4.65 (m, 1H), 4.39 (s, 1H), 4.07 (s, 3H), 3.80 (s, 3H), 3.78 - 3.35 (m, 3H), 1.49 (s, 9H), 1.33 - 1.24 (m, 3H), 1.18 - 1.07 (m, 3H) ppm. MS: M / e 405 (M+1) + .

[0244] Step F: tert-Butyl (2R,5S)-4-(8-(hydroxymethyl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0245] NaBH4 (1.5 g, 40 mol) was added to a solution of tert-butyl (2R,5S)-4-(8-formyl-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (23.1 g, 57 mmol) in MeOH (10 mL) at 0 °C for 5 minutes. The reaction mixture was quenched with water and extracted with DCM. The organic layer was purified by flash column chromatography (DCM / MeOH) to give the title compound (15.6 g, 68%). MS: M / e 406 (M+1) + .

[0246] Step G: tert-Butyl (2R,5S)-4-(8-(chloromethyl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0247] To a solution of tert-butyl (2R,5S)-4-(8-(hydroxymethyl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (12 g, 29.6 mmol) in DCM (150 mL) was added SOCl (4.2 g, 35.5 mmol) at 0 °C. The reaction was stirred at room temperature for 5 minutes. The reaction mixture was quenched with water and washed with water, saturated NaHCO, and saturated NaCl. The organic layer was dried over NaSO and concentrated under reduced pressure. The crude product was used directly in the next step.

[0248] Step H: tert-Butyl (2R,5S)-4-(8-(cyanomethyl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0249] To a solution of tert-butyl (2R,5S)-4-(8-(chloromethyl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate from the previous step (14.6 g, 148 mmol) and CS2CO3 (28.9 g, 88.8 mmol) in MeCN (400 mL). The resulting mixture was stirred at 60 °C for 1 h. HO was added to the mixture and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH) to give the title compound (5.8 g, 47% for two steps). 1 H NMR (400 MHz, CD3OD) δ 6.25 - 5.64 (m, 1H), 5.36 - 4.66 (m, 1H), 4.38 (s, 1H), 4.23 (s, 2H), 3.94 (s, 3H), 3.80 (s, 3H), 3.75 - 3.33 (m, 3H), 1.48 (s, 9H), 1.28 (dd, J = 19.6, 6.3 Hz, 3H), 1.15 (d, J = 6.7 Hz, 3H) ppm. MS: M / e 416 (M+1) + .

[0250] Step I: 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0251] To a stirred solution of tert-butyl (2R,5S)-4-(8-(cyanomethyl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (1.3 g, 3 mmol) in CHCl (15 mL) was added TFA (4 mL). After stirring for 3 h, the reaction mixture was concentrated to give a residue, which was basified with aqueous KCO to pH = 10-12 and extracted with CHCl / IPA (3 / 1, 50 mL × 6). The combined organic layers were dried over NaSO and concentrated to give the title compound (700 mg, 71%). MS: M / e 316 (M+1). + .

[0252] Intermediate 6: 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0253] Step A: tert-butyl (2R,5S)-4-(2-chloro-9-ethyl-9H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0254] To a solution of tert-butyl (2R,5S)-4-(2-chloro-9H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (6.97 g, 19 mmol) in acetone (100 mL) was added KCO (5.2 g, 38 mmol), followed by EtI (5.9 g, 38 mmol). After the addition, the reaction mixture was stirred overnight. The reaction mixture was filtered, and the filtrate was concentrated to give a residue which was treated with CHCl (100 mL), washed with brine, dried over NaSO, and concentrated to give the title compound (6.5 g, 87%). MS: M / e 395 (M+1) + .

[0255] Step B: tert-Butyl (2R,5S)-4-(9-ethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0256] To a solution of tert-butyl (2R,5S)-4-(2-chloro-9-ethyl-9H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (6.5 g, 16.4 mmol) in dioxane (80 mL) was added aqueous KOH (3.68 g, 65.8 mmol in 15 mL of HO), Pd(dba) (751 mg, 0.82 mmol), and t-BuXphOS (695 mg, 16.4 mmol). After the addition, the reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was diluted with HO (80 mL) and extracted with EtOAc (60 mL × 3). The organic layer was discarded, and the aqueous layer was acidified with aqueous citric acid to pH = 6–7 and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound (5.3 g, 86%). MS: M / e 377 (M+1) + .

[0257] Step C: tert-Butyl (2R,5S)-4-(9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0258] To a stirred solution of tert-butyl (2R,5S)-4-(9-ethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (5.3 g, 14.1 mmol) in dioxane (500 mL) was added CsCO (13.7 g, 42 mmol), followed by MeI (20 g, 0.14 mmol). After the addition, the reaction mixture was stirred at room temperature for 3 days and at 80 °C for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated to give a residue that was purified by flash column chromatography to give the title compound (3.32 g, 60%). MS: M / e 391 (M+1) + .

[0259] Step D: tert-Butyl (2R,5S)-4-(9-ethyl-8-formyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0260] To a stirred solution of tert-butyl (2R,5S)-4-(9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (3.32 g, 8.51 mmol) in THF (300 mL) was added dropwise LDA (2.0 M, 17 mL, 34 mmol) at −78° C. After stirring at that temperature for 1 h, DMF (3.06 g, 42.6 mmol) was added dropwise, and then the mixture was allowed to warm to room temperature. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the title compound (crude, 100%), which was used directly in the next step.

[0261] Step E: tert-Butyl (2R,5S)-4-(9-ethyl-8-(hydroxymethyl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0262] To a stirred solution of tert-butyl (2R,5S)-4-(9-ethyl-8-formyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (crude, 8.51 mmol) in MeOH (20 mL) was added NaBH (224 mg, 6 mmol). After stirring for 10 min, the reaction was quenched with HO and extracted with CHCl (50 mL × 3). The combined organic layers were washed with brine, dried over NaSO, concentrated, and purified by flash column chromatography to give the title compound (2.9 g, 81%).

[0263] Step F: tert-Butyl (2R,5S)-4-(9-ethyl-3-methyl-8-(((methylsulfonyl)oxy)methyl)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0264] To a stirred solution of tert-butyl (2R,5S)-4-(9-ethyl-8-(hydroxymethyl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (2.9 g, 6.9 mmol) in CHCl (30 mL) was added EtN (1.4 g, 13.8 mmol), followed by MsCl (1.2 g, 10.4 mmol). After the addition, the reaction mixture was stirred for 2 h. The reaction mixture was washed with HO (20 mL) and extracted with CHCl (30 mL × 2). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound (2.4 g, 70%).

[0265] Step G: tert-Butyl (2R,5S)-4-(8-(cyanomethyl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0266] To a stirred solution of tert-butyl (2R,5S)-4-(9-ethyl-3-methyl-8-(((methylsulfonyl)oxy)methyl)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (2.4 g, 4.8 mmol) in CHCN (30 mL) was added CsCO (3.2 g, 9.6 mmol), followed by TMSCN (0.95 g, 9.6 mmol). After the addition, the reaction mixture was stirred at 70 °C for 2 h. 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, concentrated, and purified by flash column chromatography to give the title compound (1.3 g, 63%).

[0267] Step H: 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0268] To a stirred solution of tert-butyl (2R,5S)-4-(8-(cyanomethyl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (1.3 g, 3 mmol) in CHCl (15 mL) was added TFA (4 mL). After stirring for 3 h, the reaction mixture was concentrated to give a residue, which was basified with aqueous KCO to pH = 10-12 and extracted with CHCl / IPA (3 / 1, 50 mL × 6). The combined organic layers were dried over NaSO and concentrated to give the title compound (700 mg, 71%). MS: M / e 330 (M+1). + .

[0269] Compound A1: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0270] Step A: (2R,5S)-tert-butyl 4-(5-chloro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0271] To a solution of 5,7-dichloro-3H-imidazo[4,5-b]pyridine (2 g, 10.6 mmol) in DMSO (20 mL) were added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (11.4 g, 53.2 mmol) and DIPEA (6.8 g, 53.2 mmol). The resulting mixture was stirred in a sealed tube at 160° C. for 30 hours. The mixture was diluted with EtOAc and then washed with water. The reaction solvent was concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (3.2 g, 82%). MS: M / e 366 (M+1) + .

[0272] Step B: tert-Butyl (2R,5S)-4-(5-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0273] To a solution of tert-butyl (2R,5S)-4-(5-chloro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (3.2 g, 8.22 mmol) in acetone (50 mL) was added KCO (2.3 g, 16.4 mmol) and CHI (2.3 g, 16.4 mmol). The resulting mixture was stirred at room temperature overnight. The organic layer was concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (2.5 g, 76%). MS: M / e 380 (M+1)+.

[0274] Step C: 7-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-5-chloro-3-methyl-3H-imidazo[4,5-b]pyridine-2-carboxylate methyl ester [ka]

[0275] To a solution of tert-butyl (2R,5S)-4-(5-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (1 g, 2.63 mmol) in THF (15 mL) was added n-BuLi (2.5 mL, 1.6 M, 3.95 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 1 hour and warmed to −40° C. for an additional 1 hour, after which methyl carbonochloridate (1.98 g, 21.1 mmol) was added at −78° C. The reaction mixture was stirred at −78° C. for an additional 10 minutes. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The crude product was concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (700 mg, 61%). MS: M / e 438 (M+1) + .

[0276] Step D: 7-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridine-2-carboxylic acid [ka]

[0277] To a solution of methyl 7-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-5-chloro-3-methyl-3H-imidazo[4,5-b]pyridine-2-carboxylate (0.9 g, 2.01 mmol) in dioxane (15 mL) was added t-BuXphos (88 mg, 0.2 mmol), KOH (346 mg, 6.2 mmol in 1.8 mL of water), and Pd2(dba)3 (94 mg, 0.1 mmol). The resulting mixture was stirred at 90°C for 4 hours. The reaction solvent was poured into water and extracted with EtOAc (discarded). The aqueous layer was adjusted to pH = 3 with citric acid. The aqueous layer was extracted with EtOAc to give the title compound (900 mg, crude). MS: M / e 406 (M+1) + .

[0278] Step E: 7-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridine-2-carboxylate methyl ester [ka]

[0279] To a solution of 7-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridine-2-carboxylic acid (700 mg, 1.73 mmol) in dioxane (20 mL) was added CsCO (1.69 g, 5.19 mmol) and CHI (736 mg, 5.19 mmol). The resulting mixture was stirred at 90 °C overnight. The reaction solvent was removed to dryness under reduced pressure. The crude product was purified by flash column chromatography to give the title compound (163 mg, 22%). MS: M / e 434 (M+1) + .

[0280] Step F: (2R,5S)-tert-butyl 4-(2-(hydroxymethyl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0281] To a solution of methyl 7-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridine-2-carboxylate (190 mg, 0.44 mmol) in THF (10 mL) was added NaBH (34 mg, 0.88 mmol). The resulting mixture was stirred at 50 °C overnight. Then, NaBH (34 mg, 0.88 mmol) was added, and the resulting mixture was stirred at 60 °C overnight. The reaction mixture was quenched with water and extracted with (DCM / IPA = 4 / 1). The residue was purified by preparative TLC (DCM:MeOH = 20:1) to give the title compound (130 mg, 73%) as a white solid. MS: M / e 406 (M+1) + .

[0282] Step G: (2R,5S)-tert-butyl 4-(2-(chloromethyl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0283] To a solution of tert-butyl (2R,5S)-4-(2-(hydroxymethyl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (80 mg, 0.197 mmol) in DCM (20 mL) was added SOCl (90 mg). The resulting mixture was stirred at room temperature for 5 minutes. The reaction solvent was washed with water, saturated NaHCO, and saturated NaCl. The organic layer was concentrated to give the title compound, which was used directly in the next step without further purification.

[0284] Step H: (2R,5S)-tert-butyl 4-(2-(cyanomethyl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0285] To a solution of crude (2R,5S)-tert-butyl 4-(2-(chloromethyl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate in CHCN (3 mL) was added TMSCN (80 mg, 0.79 mmol) and CsCO (192 mg, 0.58 mmol). The resulting mixture was stirred at 70 °C for 30 min. The reaction solvent was removed in vacuo. The crude product was purified by preparative TLC (DCM:MeOH = 30:1) to give the title compound (50 mg, 61% yield for two steps). MS: M / e 415 (M+1). + .

[0286] Step I: 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0287] To a solution of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (50 mg, 0.12 mmol) in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction solvent was removed under vacuum. The crude product was dissolved in water and adjusted to pH=9 with saturated NaHCO3. The aqueous layer was extracted with (DCM / IPA=4 / 1) and purified by preparative TLC (DCM:MeOH=30:1) to give the title compound (20 mg, 52%). MS: M / e 315 (M+1) + .

[0288] Step J: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0289] To a solution of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (10 mg, 0.032 mmol) in CHCN (10 mL) was added 1-(quinoxalin-6-yl)ethan-1-ol (11 mg, 0.064 mmol), (cyanomethyl)trimethylphosphonium iodide (31 mg, 0.127 mmol), and DIPEA (41 mg, 0.32 mmol). The resulting mixture was stirred at 105° C. for 15 hours. The reaction solvent was removed under reduced pressure to dryness. The crude product was purified by preparative TLC (DCM:MeOH=20:1) and further purified by preparative HPLC (Method A) to give the title compound (1 mg, 18%). 1 H NMR (400 MHz, CD3OD) δ 8.90-8.80 (m, 2H), 8.15 - 7.95 (m, 3H), 5.52 (s, 1H), 4.20 (s, 2H), 3.97 (s, 3H), 3.83 (s, 3H),3.75 - 3.55 (m, 2H), 3.50 - 3.33 (m, 2H), 3.20 - 3.02 (m, 1H), 2.98 - 2.63 (m, 2H), 2.25 - 2.15 (m, 1H), 1.49 - 1.30 (m, 4H), 1.25 - 1.18 (m, 3H), 1.08 - 1.01 (m, 1H) ppm. MS: M / e 471 (M+1) + .

[0290] Compound A1 can also be synthesized according to the following synthesis method.

[0291] Compound A1: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0292] Step A: tert-butyl (2R,5S)-4-(5-chloro-2-(hydroxymethyl)-3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0293] To a solution of methyl 7-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-5-chloro-3-methyl-3H-imidazo[4,5-b]pyridine-2-carboxylate (1.6 g, 3.66 mmol) in THF (10 mL) was added NaBH (278 mg, 7.32 mmol). The resulting mixture was stirred at 70 °C for 24 hours. The reaction mixture was quenched with water and extracted with EtOAc. The residue was purified by flash column chromatography (DCM:MeOH = 20:1) to give the title compound (1.2 g, 80% yield) as a white solid. MS: M / e 410 (M+1) + .

[0294] Step B: tert-butyl (2R,5S)-4-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0295] To a mixture of tert-butyl (2R,5S)-4-(5-chloro-2-(hydroxymethyl)-3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (1.1 g, 2.6 mmol) in DCM (15 mL) was added TBSCl (0.58 g, 3.9 mmol) and imidazole (0.53 g, 7.78 mmol). The resulting mixture was stirred at room temperature overnight. The reaction solvent was washed with water and purified by flash column chromatography (PE / EtOAc) to give the title compound (1.2 g, 85% yield) as a colorless oil. MS: M / e 524 (M+1) + .

[0296] Step C: tert-butyl (2R,5S)-4-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0297] To a solution of tert-butyl (2R,5S)-4-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (1.2 g, 2.3 mmol) in 1,4-dioxane (20 mL), t-BuXphos (98 mg, 0.11 mmol), KOH (385 mg, 6.9 mmol in 2.5 mL of water), and Pd2(dba)3 (107 mg, 0.11 mmol) were added. The resulting mixture was stirred at 80 °C for 3 h. The reaction solvent was poured into water and extracted with EtOAc (discarded). The aqueous layer was adjusted to pH = 3 with citric acid. The aqueous layer was extracted with EtOAc and purified by flash column chromatography (PE / EtOAc) to give the title compound (900 mg, crude) as a white solid. MS: M / e 506 (M+1) + .

[0298] Step D: tert-Butyl (2R,5S)-4-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0299] To a mixture of tert-butyl (2R,5S)-4-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (600 mg, 1.19 mmol) in dioxane (80 mL) was added CsCO (2.3 g, 7.1 mmol) and CHI (1 g, 7.1 mmol). The resulting mixture was stirred at room temperature overnight. The reaction solvent was removed to dryness under reduced pressure. The crude product was purified by flash column chromatography (PE / EtOAc and DCM / MeOH) to give the title compound (380 mg). MS: M / e 520 (M+1) + .

[0300] Step E: (2R,5S)-tert-butyl 4-(2-(hydroxymethyl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0301] To a solution of tert-butyl (2R,5S)-4-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (380 mg, 0.73 mmol) in THF (10 mL) was added TBAF (1.1 mL, 1.1 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction solvent was concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM / MeOH) to give the title compound (300 mg, crude) as a yellow solid. MS: M / e 406 (M+1) + .

[0302] Step F: (2R,5S)-tert-butyl 4-(2-(chloromethyl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0303] To a solution of tert-butyl (2R,5S)-4-(2-(hydroxymethyl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (150 mg, 0.37 mmol) in DCM (150 mL) was added SOCl (220 mg, 1.85 mmol). The resulting mixture was stirred at room temperature for 5 minutes. The reaction solvent was washed with water, aqueous NaHCO, and aqueous NaCl. The organic layer was concentrated to give the title compound, which was used directly in the next step without further purification.

[0304] Step G: (2R,5S)-tert-butyl 4-(2-(cyanomethyl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0305] To a solution of crude (2R,5S)-tert-butyl 4-(2-(chloromethyl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate in CH3CN (20 mL) was added TMSCN (183 mg, 1.85 mmol) and TBAF (1.8 mL, 1.85 mmol). The resulting mixture was stirred at 0 °C for 30 minutes. The reaction solvent was removed in vacuo. The crude product was purified by preparative TLC (DCM:MeOH = 30:1) to give the title compound (60 mg). MS: M / e 415 (M+1) + .

[0306] Step H: 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0307] To a solution of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (120 mg, 0.29 mmol) in DCM (10 mL) was added TFA (3 mL). The resulting mixture was stirred at room temperature for 1.5 hours. The reaction solvent was removed in vacuo. The crude product was dissolved in water and adjusted to pH=9 with aqueous NaHCO3. The aqueous layer was extracted with (DCM:IPA=3:1) to give the title compound (100 mg, crude) as a yellow solid. MS: M / e 315 (M+1) + .

[0308] Step I: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0309] To a mixture of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (100 mg, 0.32 mmol) in CHCN (10 mL) was added 1-(quinoxalin-6-yl)ethan-1-ol (83 mg, 0.48 mmol), (cyanomethyl)trimethylphosphonium iodide (387 mg, 1.6 mmol), and DIPEA (410 mg, 3.2 mmol). The resulting mixture was stirred at 105 °C overnight. The reaction solvent was removed under reduced pressure to dryness. The crude product was purified by preparative TLC (DCM:MeOH=50:1) to give the title compound A1, which was further separated into compound A1a (1 mg) and compound A1b (1 mg) by preparative HPLC (Method B).

[0310] Compound A1a (early peak): 1 H NMR (400 MHz, CD3OD) δ 8.90-8.8. (m, 2H), 8.20 - 7.98 (m, 3H), 5.52 (s, 1H), 5.09 - 4.95 (m, 1H), 4.55 - 4.30 (m, 1H), 4.00 - 3.90 (m, 4H), 3.83 (s, 3H), 3.50 - 3.34 (m, 1H), 3.10 - 3.02 (m, 1H), 2.98 - 2.63 (m, 4H), 1.49 - 1.30 (m, 6H), 1.08 - 1.01 (m, 3H) ppm. MS: M / e 471 (M+1) +

[0311] Compound A1b (slow peak)1 H NMR (400 MHz, CD3OD) δ 8.90-8.8. (m, 2H), 8.15 - 7.95 (m, 3H), 5.52 (s, 2H), 4.87 - 4.55 (m, 2H), 3.97 (s, 3H), 3.83 - 3.75 (m, 4H), 3.70 - 3.55 (m, 2H), 2.95 - 2.63 (m, 2H), 2.25 - 2.15 (m, 1H), 1.49 - 1.30 (m, 3H), 1.25 - 1.13 (m, 6H) ppm. MS: M / e 471 (M+1) +

[0312] Compound A4: 2-(7-((2S,5R)-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0313] To a solution of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (30 mg, 0.096 mmol) in CHCN (3 mL) was added 1-(4-fluoro-2-methoxyphenyl)ethan-1-ol (33 mg, 1.91 mmol), (cyanomethyl)trimethylphosphonium iodide (116 mg, 0.48 mmol), and DIPEA (123 mg, 0.96 mmol). The resulting mixture was stirred at 105° C. overnight. The reaction solvent was removed under reduced pressure to dryness. The crude product was purified by preparative TLC (DCM:MeOH=20:1) to give the title compound A4, which was further separated into compound A4a (0.7 mg) and compound A4b (0.91 mg) by preparative HPLC (Method A).

[0314] Compound A4a (early peak): 1H NMR (400 MHz, CD3OD) δ 7.58 - 7.50 (m, 1H), 6.78 - 6.59 (m, 2H), 5.51 (s, 1H), 4.80 - 4.55 (m, 1H), 4.55 - 3.98 (m, 2H), 3.97 (s, MS: M / e 467 (M+1) + .

[0315] Compound A4b (late peak): 1 H NMR (400 MHz, CD3OD) δ 7.55 - 7.45 (m, 1H), 6.68 - 6.56 (m, 2H), 5.51 (s, 1H), 4.57 - 4.10 (m, 2H), 4.05 - 3.85 (m, 4H), 3.85 - 3.55 MS: M / e 467 (M+1) + .

[0316] Compound A5: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(p-tolyl)ethyl)piperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0317] To a mixture of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (30 mg, 0.1 mmol) in CHCN (3 mL) was added 1-(p-tolyl)ethan-1-ol (39 mg, 0.29 mmol), (cyanomethyl)trimethylphosphonium iodide (116 mg, 0.5 mmol), and DIPEA (123 mg, 1 mmol). The resulting mixture was stirred at 105 °C overnight. The reaction solvent was removed under reduced pressure to dryness. The crude product was purified by preparative TLC (DCM:MeOH=20:1) to give the title compound A5, which was further separated into compound A5a (0.65 mg) and compound A5b (0.48 mg) by preparative HPLC (Method A).

[0318] Compound A5a (early peak): 1 H NMR (400 MHz, CD3OD) δ 7.25 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 5.51 (s, 1H), 4.78 - 4.65 (m, 1H), 4.21 (s, 1H), 3.97 (s, 3H), 3.97 (s, 3H), 3.66 - 3.41 (m, 2H), 2.80 - 2.61 (m, 4H), 2.31 (s, 3H), 2.26 - 2.19 (m, 1H), 1.34 (d, J = 10.5 Hz, 3H), 1.18 (d, J = 6.6 Hz, 3H), 1.13 (d, J = 6.1 Hz, 3H) ppm. MS: M / e 433 (M+1) + .

[0319] Compound A5b (late peak): 1H NMR (400 MHz, CD3OD) δ 7.26 (d, J = 7.9 Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 5.50 (s, 1H), 4.56 - 4.45 (m, 1H), 4.20 (s, 1H), 3.97 (s, 3H), 3.83 (s, 3H), 3.62 (s, 1H), 3.40- 3.33 (m, 1H),2.98- 2.75 (m, 5H), 2.32 (s, 3H), 1.36 (d, J = 6.5 Hz, 3H), 1.31 (d, J = 6.5 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H) ppm. MS: M / e 433 (M+1) + .

[0320] Compound A6: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)ethyl)piperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0321] Step A: 1-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)ethan-1-ol [ka]

[0322] To a solution of 1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (200 mg, 1.12 mmol) in THF (8 mL) at −60° C. under N was added MeMgBr (3 M, 0.41 mL, 1.23 mmol) dropwise. The solution was allowed to warm to room temperature and stirred overnight at room temperature. Upon completion, the solution was quenched with HO (10 mL) and then extracted with EtOAc (10 mL × 2). The organic layer was washed with aqueous NaHCO (10 mL), brine (10 mL), dried over anhydrous NaSO, and then concentrated under reduced pressure to give the title compound (217 mg, 100%), which was used directly in the next step without further purification. MS: M / e 195 (M+1) + .

[0323] Step B: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)ethyl)piperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0324] To a mixture of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (30 mg, 0.1 mmol) in CHCN (3 mL) was added 1-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)ethan-1-ol (56 mg, 0.29 mmol), (cyanomethyl)trimethylphosphonium iodide (116 mg, 0.5 mmol), and DIPEA (123 mg, 1 mmol). The resulting mixture was stirred at 105° C. overnight. The reaction solvent was removed under reduced pressure to dryness. The crude product was purified by preparative TLC (DCM:MeOH=15:1) to give the title compound A6, which was further separated into compound A6a (0.77 mg) and compound A6b (0.64 mg) by preparative HPLC (Method A).

[0325] Compound A6a (early peak): 1 H NMR (400 MHz, CD3OD) δ 7.62 (s, 1H), 5.51 (s, 1H), 4.77 - 4.63 (m, 1H), 4.21 (s, 1H), 3.97 (s, 6H), 3.83 (s, 3H), 3.81- 3.70 (m, 1H), 3.57- 3.45 (m, 2H), 2.86- 2.70 (m, 3H), 2.31 (d, J = 12.5 Hz, 1H), 1.35 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 6.6 Hz, 3H), 1.09 (d, J = 6.5 Hz, 3H) ppm. MS: M / e 491 (M+1) + .

[0326] Compound A6b (late peak): 1 H NMR (400 MHz, CD3OD) δ 7.61 (s, 1H), 5.51 (s, 1H), 4.75 - 4.63 (m, 1H), 4.23 - 4.17 (m, 1H), 3.98 (s, 3H), 3.97 (s, 3H), 3.83 (s, 3H), 3.39 - 3.33 (m, 2H), 3.04 - 2.90 (m, 2H), 2.85 - 2.61 (m, 3H), 1.33 (d, J = 6.7 Hz, 3H), 1.29 (d, J = 6.5 Hz, 3H), 1.00 (d, J = 6.5 Hz, 3H) ppm. MS: M / e 491 (M+1) + .

[0327] Compound A7: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(2-(trifluoromethyl)pyridin-3-yl)ethyl)piperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0328] Step A: 1-(2-(trifluoromethyl)pyridin-3-yl)ethan-1-ol [ka]

[0329] To a solution of 2-(trifluoromethyl)nicotinaldehyde (200 mg, 1.1 mmol) in THF (10 mL) was added methylmagnesium bromide (0.7 mL, 2.2 mmol, 3 M in EtO) at 0 °C under a N atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water (5 mL) and extracted with EtOAc (15 mL × 3). The organic phase was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (PE: EtOAc = 2:1) to give the target compound (120 mg, 55% yield) as a clear oil. MS: M / e 192 (M+1) + .

[0330] Step B: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(2-(trifluoromethyl)pyridin-3-yl)ethyl)piperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0331] To a mixture of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (30 mg, 0.1 mmol) in CH3CN (3 mL) was added 1-(2-(trifluoromethyl)pyridin-3-yl)ethan-1-ol (56 mg, 0.29 mmol), (cyanomethyl)trimethylphosphonium iodide (116 mg, 0.5 mmol), and DIPEA (123 mg, 1 mmol). The resulting mixture was stirred at 105 °C overnight. The reaction solvent was removed under reduced pressure. The resulting residue was purified by preparative TLC (DCM:MeOH=20:1) to give the title compound A7, which was further separated into compound A7a (1.21 mg) and compound A7b (0.81 mg) by preparative HPLC (Method A).

[0332] Compound A7a (early peak): 1 H NMR (400 MHz, CD3OD) δ 8.55 (d, J = 4.6 Hz, 1H), 8.48 (d, J = 8.4 Hz, 1H), 7.68 (dd, J = 7.9, 4.7 Hz, 1H), 5.51 (s, 1H), 4.20 (d, J = 4.9 Hz, 1H), 3.99 - 3.91 (m, 4H), 3.83 (s, 3H), 3.72 - 3.53 (m, 3H), 2.85 - 2.55 (m, 3H), 1.93 (d, J = 12.1 Hz, 1H), 1.36 (d, J = 6.4 Hz, 3H), 1.21 - 1.11 (m, 6H) ppm. MS: M / e 488 (M+1) + .

[0333] Compound A7b (late peak): 1H NMR (400 MHz, CD3OD) δ 8.56 (d, J = 4.2 Hz, 1H), 8.51 (d, J = 7.9 Hz, 1H), 7.70 (dd, J = 8.2, 4.4 Hz, 1H), 5.51 (s, 1H), 4.25 - 4.16 (m, 2H), 3.97 (s, 3H), 3.83 (s, 3H), 3.42 - 3.33 (m, 2H), 3.08 - 2.60 (m, 5H),1.43 (d, J = 6.6 Hz, 3H), 1.29 (d, J = 6.4 Hz, 3H), 1.02 (d, J = 6.5 Hz, 3H) ppm. MS: M / e 488 (M+1) + .

[0334] Compound A9: 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0335] Step A: tert-Butyl (tert-butoxycarbonyl)(4,6-dichloro-3-nitropyridin-2-yl)carbamate [ka]

[0336] To a solution of 4,6-dichloro-3-nitropyridin-2-amine (2 g, 9.66 mmol) in THF (20 ml) at 0° C. was added NaH (60%, 1.16 g, 29 mmol). Then, (Boc)2O (6.3 g, 28.90 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc (30 ml) and then washed with water (20 ml). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 0-60% EtOAc in PE to give the title compound (3.63 g, 92%). MS: M / e 408 (M+1) + .

[0337] Step B: tert-Butyl (tert-butoxycarbonyl)(6-chloro-4-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-nitropyridin-2-yl)carbamate [ka]

[0338] A solution of tert-butyl (tert-butoxycarbonyl)(4,6-dichloro-3-nitropyridin-2-yl)carbamate (1.9 g, 4.67 mmol), (2R,5S)-1-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazine (1.5 g, 4.93 mmol), and DIPEA (3 g, 23.26 mmol) in DCM (30 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using 0-15% EtOAc in PE to give the title compound (1.8 g, 57%). MS: M / e 676 (M+1). + .

[0339] Step C: tert-Butyl (tert-butoxycarbonyl)(4-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-nitro-6-oxo-1,6-dihydropyridin-2-yl)carbamate [ka]

[0340] A solution of tert-butyl (tert-butoxycarbonyl)(6-chloro-4-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-nitropyridin-2-yl)carbamate (0.6 g, 0.89 mmol), Pd(dba) (81.4 mg, 0.089 mmol), t-BuXPhos (75.6 mg, 0.18 mmol), and KOH (100 mg, 1.79 mmol) in dioxane (15 mL) and water (3 mL) was stirred at 80 °C in a sealed tube under N for 3 h. The mixture was concentrated. The residue was diluted with EtOAc (20 mL) and washed with brine (10 mL). The organic layer was concentrated to dryness. The resulting residue was purified by flash column chromatography using 0-60% EtOAc in PE to give the title compound (0.4 g, 68%). MS: M / e 658 (M+1) + .

[0341] Step D: tert-Butyl (tert-butoxycarbonyl)(4-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-3-nitro-6-oxo-1,6-dihydropyridin-2-yl)carbamate [ka]

[0342] A solution of tert-butyl (tert-butoxycarbonyl)(4-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-nitro-6-oxo-1,6-dihydropyridin-2-yl)carbamate (1.2 g, 1.83 mmol), MeI (0.52 g, 3.66 mmol), and Cs2CO3 (1.8 g, 5.52 mmol) in dioxane (20 mL) was stirred at 80 °C overnight. The mixture was concentrated. The residue was diluted with EtOAc (30 mL) and washed with brine (15 mL). The organic layer was concentrated to dryness. The resulting residue was purified by flash column chromatography using 0-50% EtOAc in PE to give the title compound (0.66 g, 54%). MS: M / e 672 (M+1) + .

[0343] Step E: tert-butyl (3-amino-4-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)(tert-butoxycarbonyl)carbamate [ka]

[0344] A solution of tert-butyl (tert-butoxycarbonyl)(4-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-3-nitro-6-oxo-1,6-dihydropyridin-2-yl)carbamate (0.66 g, 0.98 mmol) and Pd / C (0.1 g) in MeOH (15 ml) was stirred overnight at room temperature under H2. The mixture was filtered. The filtrate was concentrated to dryness to give the title compound (0.62 g, 98%). MS: M / e 642 (M+1). + .

[0345] Step F: 5,6-Diamino-4-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methylpyridin-2(1H)-one [ka]

[0346] A solution of tert-butyl (3-amino-4-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)(tert-butoxycarbonyl)carbamate (310 mg, 0.48 mmol) and TFA (3 ml) in DCM (15 ml) was stirred at room temperature for 2 hours. The mixture was washed with NaHCO3 (aq, 10 ml), brine (10 ml), dried over Na2SO4, and then concentrated to dryness to give the title compound (200 mg, 93%). MS: M / e 442 (M+1). + .

[0347] Step G: N-(3-amino-4-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-2-cyanoacetamide [ka]

[0348] A solution of 5,6-diamino-4-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methylpyridin-2(1H)-one (200 mg, 0.45 mmol), 2-cyanoacetic acid (46 mg, 0.54 mmol), HATU (259 mg, 0.68 mmol), and DIPEA (176 mg, 1.36 mmol) in THF (10 mL) was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc (20 mL) and washed with brine (15 mL). The organic layer was concentrated. The residue was purified by flash column chromatography using 0-10% MeOH in DCM to give the title compound (130 mg, 56%). MS: M / e 509 (M+1). + .

[0349] Step H: 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0350] A solution of N-(3-amino-4-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-2-cyanoacetamide (65 mg, 0.13 mmol) in AcOH (1 ml) was stirred at 80° C. overnight. The mixture was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (DCM:MeOH=15:1) to give the title compound A9 (18 mg), which was further separated into compound A9a (4 mg) and compound A9b (7 mg) by preparative HPLC (Method A).

[0351] Compound A9: 11H NMR (400 MHz, DMSO-d6) δ 13.10 - 12.50 (m, 1H), 8.09 - 7.95 (m, 1H), 7.67 - 7.49 (m, 2H), 5.44 - 5.17 (m, 1H), 4.27 (s, 0.5H), 4.23 (s, 0.5H), 4.22 - 4.11 (m, 1H), 4.01 (s, 0.5H), 3.92 - 3.72 (m, 1H), 3.57 (s, 0.5H), 3.48 - 3.35 (m, 4H), 3.26 - 3.14 (m, 0.5H), 3.13 - 2.96 (m, 1H), 2.90 (s, 0.5H), 2.85 (d, J = 11.4 Hz, 1H), 2.67 (s, 0.5H), 1.87 (d, J = 11.5 Hz, 0.5H), 1.28 (d, J = 6.2 Hz, 2H), 1.21 (dd, J = 11.4, 6.5 Hz, 2.5H), 1.11 - 1.00 (m, 2H), 0.96 - 0.85 (m, 2.5H) ppm. MS: M / e 491 (M+1) + .

[0352] Compound A9a (earlier peak): 1 1H NMR (400 MHz, DMSO-d6)) δ 13.21 - 12.27 (m, 1H), 8.04 - 7.95 (m, 1H), 7.63 - 7.50 (m, 2H), 5.32 (s, 1H), 4.19 (s, 2H), 3.82 (s, 1H), 3.58 (s, 1H), 3.47 - 3.43 (m, 1H), 3.41 (s, 3H), 3.31 - 3.25 (m, 1H), 3.10 - 2.90 (m, 1H), 2.81 (s, 1H), 1.87 (d, J = 11.2 Hz, 1H), 1.28 (d, J = 6.4 Hz, 3H), 1.07 (d, J = 6.4 Hz, 3H), 0.94 (s, 3H) ppm. MS: M / e 491 (M+1) + .

[0353] Compound A9b (later peak): 1H NMR (400 MHz, DMSO-d6)) δ 12.76 (s, 1H), 8.11 - 8.01 (m, 1H), 7.67 - 7.52 (m, 2H), 5.26 (s, 1H), 4.22 (s, 2H), 4.00 (s, 1H), 3.41 (s, 3H), 3.31 - 3.28 (m, 2H), 3.20 (d, J = 9.2 Hz, 1H), 3.00 (s, 1H), 2.85 (d, J = 11.0 Hz, 1H), 2.69 (s, 1H), 1.22 (t, J = 7.6 Hz, 6H), 0.93 (d, J = 6.4 Hz, 3H) ppm. MS: M / e 491 (M+1) + .

[0354] Compound A10: 2-(6-((2R,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0355] Step A: 2,6-Dichloro-9-methyl-9H-purine [ka]

[0356] To a solution of 2,6-dichloro-9H-purine (20 g, 106 mmol) and KCO (29.3 g, 212 mmol) in DMF (120 mL) was added CHI (22.5 g, 158 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with water, extracted with EtOAc (300 mL x 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (EtOAc:PE = 1:1) to give the title compound (14 g, 65%). MS: M / e 203 (M+1)+ .

[0357] Step B: (2R,5R)-4-(2-chloro-9-methyl-9H-purin-6-yl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate tert-Butyl. [ka]

[0358] To a solution of 2,6-dichloro-9-methyl-9H-purine (2.0 g, 9.9 mmol) and tert-butyl (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (2.28 g, 9.9 mmol) in n-BuOH (40 mL) was added DIPEA (3.83 g, 29.7 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the title compound (3.3 g, 84% yield). MS: M / e 397 (M+1). + .

[0359] Step C: (2R,5R)-4-(2-chloro-9-methyl-9H-purin-6-yl)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate tert-Butyl. [ka]

[0360] To a solution of tert-butyl (2R,5R)-4-(2-chloro-9-methyl-9H-purin-6-yl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (3.3 g, 8.329 mmol) in DMF (50 mL) at 0° C. was added NaH (1.33 g, 60% content, 33.3 mmol). The mixture was stirred at 0° C. for 0.5 hours. Then, CHCl was added. The reaction was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with EtOAc (120 mL×2). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH=10:1) to give the title compound (2.4 g, 70%). MS: M / e 411 (M+1) + .

[0361] Step D: (2R,5R)-4-(2-hydroxy-9-methyl-9H-purin-6-yl)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate tert-Butyl. [ka]

[0362] A solution of (2R,5R)-tert-butyl 4-(2-chloro-9-methyl-9H-purin-6-yl)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate (2.4 g, 5.85 mmol), Pd2(dba)3 (536 mg, 0.585 mmol), t-BuXphos (498 mg, 1.17 mmol), and KOH (5.85 mL, 3 M, 17.55 mmol) in dioxane (30 mL) was degassed three times under N2 atmosphere. The mixture was then stirred at 90 °C for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (60 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH = 10:1) to give the title compound (1.7 g, 74%). MS: M / e 393(M+1) + .

[0363] Step E: tert-butyl (2R,5R)-4-(3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate [ka]

[0364] To a solution of tert-butyl (2R,5R)-4-(2-hydroxy-9-methyl-9H-purin-6-yl)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate (1.7 g, 4.33 mmol) and CsCO (2.82 g, 8.66 mmol) in dioxane (40 mL) was added CHCl (923 mg, 6.50 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with water, extracted with EtOAc (80 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH = 10:1) to give the title compound (960 mg, 54%). MS: M / e 407 (M+1). + .

[0365] Step F: tert-butyl (2R,5R)-4-(8-bromo-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate [ka]

[0366] To a solution of tert-butyl (2R,5R)-4-(3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate (300 mg, 0.739 mmol) in CHCN (10 mL) was added NBS (197 mg, 1.108 mmol). The reaction was stirred at room temperature for 4 hours. The reaction mixture was diluted with saturated NHCl, extracted with EtOAc (50 mL x 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH = 10:1) to give the title compound (350 mg, 98%). MS: M / e 485 (M+1) + .

[0367] Step G: Methyl 6-((2R,5R)-4-(tert-butoxycarbonyl)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purine-8-carboxylate [ka]

[0368] A solution of (2R,5R)-4-(8-bromo-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate (350 mg, 0.723 mmol), Pd(dppf)Cl, and EtN (146 mg, 1.446 mmol) in MeOH (10 mL) was degassed three times under a CO atmosphere. The mixture was then stirred at 90 °C under a CO atmosphere for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (35 mL × 2). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH = 8:1) to give the title compound (280 mg, 83%). MS: M / e 465 (M+1). + .

[0369] Step H: tert-butyl (2R,5R)-4-(8-(hydroxymethyl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate [ka]

[0370] To a solution of methyl 6-((2R,5R)-4-(tert-butoxycarbonyl)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purine-8-carboxylate (280 mg, 0.603 mmol) in MeOH (10 mL) was added NaBH (92 mg, 2.414 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NH Cl, extracted with EtOAc (30 mL × 2), washed with brine, dried over Na SO , filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH=8:1) to give the title compound (200 mg, 76%). MS: M / e 437 (M+1) + .

[0371] Step I: tert-butyl (2R,5R)-4-(8-(chloromethyl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate [ka]

[0372] To a solution of tert-butyl (2R,5R)-4-(8-(hydroxymethyl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate (200 mg, 0.459 mmol) in DCM (8 mL) was added SOCl2 (218 mg, 1.835 mmol). The reaction was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to give the title compound (190 mg, 91%). MS: M / e 455 (M+1) + .

[0373] Step J: tert-butyl (2R,5R)-4-(8-(cyanomethyl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate [ka]

[0374] To a solution of tert-butyl (2R,5R)-4-(8-(chloromethyl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate (190 mg, 0.419 mmol) in DCM (15 mL) was added TBAF (1.67 mL, 1 M, 1.674 mmol), followed by TMSCN (166 mg, 1.674 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with water, extracted with DCM (40 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH = 8:1) to give the title compound (150 mg, 81%). MS: M / e 446 (M+1) + .

[0375] Step K: 2-(6-((2R,5R)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0376] To a stirred solution of tert-butyl (2R,5R)-4-(8-(cyanomethyl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate (150 mg, 0.337 mmol) in CHCl (15 mL) was added TFA (3 mL). The reaction mixture was then stirred at room temperature for 4 h and concentrated to give a residue, which was basified with saturated aqueous NaHCO to pH = 10-11 and extracted with CHCl / IPA (3 / 1, 30 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound (40 mg, 34%). MS: M / e 346 (M+1). + .

[0377] Step L: 2-(6-((2R,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0378] 2-(6-((2R,5R)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (40 mg, 0.116 mol), 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol (36 mg, 0.174 mol), (cyanomethyl)trimethylphosphonium iodide (56 mg, 0.232 mol), and DIPEA (45 mg, 0.348 mol) were dissolved in a CH3CN solution (2 mL). The mixture was degassed three times under a N2 atmosphere. The mixture was then stirred at 105 °C for 24 hours. 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 A10 (6 mg), which was further separated by preparative HPLC (Method A) into compound A10a (2 mg) and compound A10b (1.5 mg).

[0379] Compound A10: 1 H NMR (400 MHz, CD3OD) δ 8.07-7.94 (m, 1H), 7.43-7.39 (m, 2H), 6.32-6.05 (m, 0.5H), 5.95-5.66 (m, 0.5H), 5.37-5.12 (m, 0.5H), 4.81-4.57 (m, 0.5H), 4.21 (dd, J = 24.3, 4.1 Hz, 2H), 3.93 (t, J = 5.6 Hz, 3H), 3.79 (s, 3H), 3.76-3.59 (m, 3H), 3.43 (d, J = 4.0 Hz, 1H), 3.26-3.18 (m, 3H), 2.94-2.53 (m, 2H), 2.35-1.98 (m, 1H), 1.39-1.34 (m, 3H), 1.04-0.89 (m, 3H) ppm. MS: M / e 536 (M+1) +

[0380] Compound A10a (early peak): 11H NMR (400 MHz, CD3OD) δ 8.06 - 7.91 (m, 1H), 7.45 - 7.36 (m, 2H), 6.06 - 6.02 (m, 0.5H), 5.95 - 5.91 (m, 0.5H), 5.16 - 5.12 (m, 0.5H), 4.94 - 4.90 (m, 0.5H), 4.21 (d, J = 19.3 Hz, 1H), 3.94 (s, 3H), 3.92 - 3.88 (m, 1H), 3.79 (d, J = 2.7 Hz, 3H), 3.69 - 3.60 (m, 3H), 3.40 - 3.33 (m, 1H), 3.22 (d, J = 10.8 Hz, 3H), 2.94 - 2.51 (m, 2H), 2.27 (d, J = 12.3 Hz, 1H), 1.31 (d, J = 6.2 Hz, 3H), 1.11 - 0.98 (m, 3H) ppm. MS: M / e 536 (M+1) +

[0381] Compound A10b (slow peak): 1 1H NMR (400 MHz, CD3OD) δ 8.08 - 7.98 (m, 1H), 7.44 - 7.39 (m, 2H), 6.31 (s, 0.5H), 5.67 (d, J = 13.6 Hz, 0.5H), 5.39 (s, 0.5H), 4.64 - 4.57 (m, 0.5H), 4.11 - 3.98 (m, 2H), 3.93 (d, J = 11.3 Hz, 3H), 3.85 - 3.73 (m, 4H), 3.50 - 3.45 (m, 0.5H), 3.43 (d, J = 3.9 Hz, 3H), 3.35 - 3.31 (m, 0.5H), 3.27 - 3.06 (m, 1.5H), 3.01 - 2.59 (m, 3.5H), 1.29 - 1.21 (m, 3H), 0.90 (d, J = 6.5 Hz, 3H) ppm. MS: M / e 536 (M+1) +

[0382] Compound A11: 2-(6-((2R,5R)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0383] Step A: 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-ol [ka]

[0384] To a solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one (720 mg, 4.1 mmol) in MeOH (20 mL) was added NaBH (228 mg, 6.0 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness. The resulting residue was treated with saturated aqueous NaHCO and extracted with EtOAc (20 mL × 3). The combined layers were washed with brine (20 mL × 3), dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (360 mg, 50%). MS: M / e 181 (M+1) + .

[0385] Step B: 2-(6-((2R,5R)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0386] 2-(6-((2R,5R)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (50 mg, 0.145 mol), 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-ol (52 mg, 0.290 mol), (cyanomethyl)trimethylphosphonium iodide (70 mg, 0.290 mol), and DIPEA (56 mg, 0.435 mol) were dissolved in a CH3CN solution (1 mL). The mixture was degassed three times under a N2 atmosphere. The mixture was then stirred at 105 °C for 24 hours. 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 A11, which was further separated into compound A11a (3 mg) and compound A11b (4 mg) by preparative HPLC (Method A).

[0387] Compound A11a (early peak): 1 H NMR (400 MHz, CD3OD) δ 6.85 (s, 1H), 6.81-6.74 (m, 2H), 5.98 (d, J = 53.1 Hz, 1H), 5.16 (s, 0.5H), 4.89-4.84 (m, 0.5H), 4.30-4.19 (m, 4.5H), 3.94 (s, 3H), 3.79 (s, 3H), 3.76-3.65 (m, 1.5H), 3.63-3.58 (m, 2H), 3.49-3.40 (m, 1H), 3.36-3.32 (m, 1H), 3.26 (s, 3H), 2.83-2.58 (m, 3H), 1.31 (d, J = 6.3 Hz, 3H), 1.04 (d, J = 6.3 Hz, 3H) ppm. MS: M / e 508 (M+1) +

[0388] Compound A11b (late peak): 1H NMR (400 MHz, CD3OD) δ 6.84 (s, 1H), 6.83-6.75 (m, 2H), 6.24 (s, 0.5H), 5.69 (s, 0.5H), 5.32 (s, 0.5H), 4.59 (s, 0.5H), 4.30-4.21 (m, 4.5H), 3.96-3.82 (m, 4H), 3.80-3.75 (m, 4H), 3.70-3.48 (m, 2H), 3.39 (s, 3H), 3.19-3.06 (m, 1.5H), 2.95 (s, 1H), 2.88-2.64 (m, 2H), 1.29 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H) ppm. MS: M / e 508 (M+1) +

[0389] Compound A12: 2-(6-((2R,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0390] Step A: 3,3-Dimethyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carbonitrile [ka]

[0391] To a solution of 4-fluoro-3-hydroxybenzonitrile (100 g, 0.73 mol) and CsCO (951 g, 2.92 mol) in DMAc (1000 mL) was added 2,2-dimethyloxirane (210 g, 2.92 mol) at room temperature. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was filtered. The filtrate was diluted with EtOAc (1000 mL) and washed with H2O (1000 mL). The aqueous layer was extracted with EtOAc (1000 mL × 2). The combined organic layer was concentrated. The residue was triturated with H2O (500 mL) to give the crude product (120 g), which was recrystallized with n-hexane to give the title compound (71 g).

[0392] Step B: 3,3-Dimethyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde [ka]

[0393] To a solution of 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carbonitrile (71 g, 0.37 mol) in THF (700 mL) was slowly added DIBAL-H (550 mL, 0.55 mol, 1 M in n-hexane) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. The reaction was monitored by HPLC (quenched with 3 N HCl). After complete disappearance of 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carbonitrile, the reaction was slowly quenched with 2 N HCl at 0° C. The resulting mixture was filtered. The filtrate was concentrated. The residue was dissolved in EtOAc (1000 mL) and washed with 1 N HCl (1000 mL × 2). The organic phase was concentrated to dryness. The crude product was purified by flash column chromatography to give the title compound (64 g).

[0394] Step C: 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-ol [ka]

[0395] To a solution of 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (31 g, 0.16 mol) in THF (300 mL) was slowly added MeMgBr (106 mL, 0.32 mmol, 3 M in EtO) at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was slowly quenched with HO at 0 °C and then filtered. The filtrate was extracted with EtOAc (500 mL × 2). The combined organic phase was concentrated to give the crude product (30 g, containing 1.9% BP1). The crude product was dissolved in DCM (300 mL), and TEA (29.1 g, 2 equiv.) and TrtCl (16 g, 0.4 equiv.) were added successively. The reaction was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After complete disappearance of BP1, the reaction mixture was diluted with DCM (300 mL) and washed with HO (300 mL). The organic phase was concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (26 g).

[0396] Step D: 2-(6-((2R,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0397] 2-(6-((2R,5R)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (250 mg, 0.725 mol), 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-ol (302 mg, 1.449 mol), (cyanomethyl)trimethylphosphonium iodide (352 mg, 1.449 mol), and DIPEA (281 mg, 2.175 mol) were dissolved in a CH3CN solution (3 mL). The mixture was degassed three times under a N2 atmosphere. The mixture was then stirred at 105 °C for 24 hours. 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 A12 (240 mg), which was further separated into compound A12a (70 mg) and compound A12b (68 mg) by chiral preparative HPLC. The chiral separation conditions are shown below. [Table 4]

[0398] Compound A12a (early peak): 1 H NMR (400 MHz, CD3OD) δ 6.84-6.73 (m, 3H), 6.24 (s, 0.5H), 5.67-5.63 (m, 0.5H), 5.35-5.31 (m, 0.5H), 4.63-4.59 (m, 0.5H), 3.93 (s, 3H), 3.88 (s, 3H), 3.80-3.75 (m, 4H), 3.50-3.43 (m, 1H), 3.39 (s, 3H), 3.30 (s, 2H), 3.15-3.07 (m, 2H), 2.90 (s, 1H), 2.83-2.75 (m, 1H), 1.32 (s, 6H), 1.25 (d, J = 6.4 Hz,3H), 0.85 (d, J = 6.5 Hz, 3H) ppm. MS: M / e 536 (M+1) +

[0399] Compound A12b (late peak): 1H NMR (400 MHz, CD3OD) δ 6.81-6.72 (m, 3H), 6.03 (s, 0.5H), 5.89 (d, J = 13.2 Hz, 0.5H), 5.13 (s, 0.5H), 4.84-4.79 (m, 0.5H), 3.93 (s, 3H), 3.87 (s, 2H), 3.78 (s, 3H), 3.75-3.68 (m, 1H), 3.66-3.56 (m, 2H), 3.54-3.49 (m, 1H), 3.40-3.30 (m, 4H), 3.29-3.18 (m, 3H), 2.60-2.40 (m, 1H), 1.31 (s, 6H), 1.27 (d, J = 6.4 Hz, 3H), 0.99 (d, J = 6.2 Hz, 3H) ppm. MS: M / e 536 (M+1) +

[0400] Compound A13: 2-(6-((2R,5R)-2-(methoxymethyl)-5-methyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0401] Step A: 7-Bromo-2-methylquinoxaline [ka]

[0402] 7-Bromo-2-chloroquinoxaline (243 g, 1 mol) and ferric acetylacetonate (17.63 g, 50 mmol) were dissolved in dry THF (1.5 L). Methylmagnesium bromide (3 M in ethyl ether) solution (370 ml, 1.1 mol) was added dropwise at 0°C. After stirring for 1 h, the reaction mixture was quenched with 1 M aqueous HCl (1 L). The organics were removed under reduced pressure. DCM (1 L) was added to dilute the solid and filtered to separate the undissolved material. The organic layer was washed with brine, dried over MgSO4, filtered, and the solvent was removed under vacuum. The residue (230 g) was slurried in ethanol (920 ml) for 2 h and filtered. The solid (150 g) was dissolved in EtOAc (2 L) and decolorized with activated carbon (70 g). The mixture was filtered and concentrated to give the title compound (120 g, 54%). 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.91 (dd, J = 8.9, 2.0 Hz, 1H), 2.72 (s, 3H) ppm. MS: M / e 223 (M+1) + .

[0403] Step B: 1-(3-methylquinoxalin-6-yl)ethan-1-one [ka]

[0404] To a solution of 7-bromo-2-methylquinoxaline (66 g, 0.3 mol) and CsCO (147 g, 0.45 mol) in DMF / HO (8 / 1, 1.3 L) was added 1-(vinyloxy)butane (240 g, 2.4 mol), Pd(OAc) (5.4 g, 0.024 mol), and DPPP (29.6 g, 0.072 mol). The mixture was stirred at 116 °C under N for 16 h. The reaction was cooled to 0-10 °C and treated dropwise with 2 N HCl (600 mL) and stirred at 0-10 °C for 1 h. The mixture was diluted with water (500 mL), forming a suspension. The mixture was filtered through a pad of Celtic and washed with water (500 mL). The filtrate was extracted with EtOAc (2 L), washed with brine, dried over NaSO, filtered, and concentrated. The aqueous and brine layers were combined, extracted with DCM (1 L x 2), washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The combined residue was purified by flash column chromatography to give the title compound (35 g, 62%). 1 HNMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.28 (dd, J = 1.6 Hz, 8.8 Hz, 1H), 8.13 (d, J = 9.2 Hz, 1H), 2.82 (s, 3H), 2.76 (s, 3H) ppm. MS: M / e 187 (M+1) + .

[0405] Step C: 1-(3-methylquinoxalin-6-yl)ethan-1-ol [ka]

[0406] To a solution of 1-(3-methylquinoxalin-6-yl)ethan-1-one (55.4 g, 298 mmol) in EtOH (500 mL) at 0 °C, NaBH (6.8 g, 179 mmol) was added portionwise. After the addition, the reaction was stirred at 0 °C for 1 h. Water was added to quench the reaction, and most of the EtOH was concentrated under reduced pressure. The residue was diluted with water, extracted with DCM (500 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 (47.6 g, 85%). 1 H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 0.8 Hz, 1H), 7.75 (dd, J = 1.6 Hz, 8.4 Hz, 1H), 5.17 - 5.09 (m, 1H), 2.77 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H) ppm. MS: M / e 189(M+1) + .

[0407] Step D: 2-(6-((2R,5R)-2-(methoxymethyl)-5-methyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0408] 2-(6-((2R,5R)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (43 mg, 0.125 mol), 1-(3-methylquinoxalin-6-yl)ethan-1-ol (47 mg, 0.249 mol), (cyanomethyl)trimethylphosphonium iodide (61 mg, 0.249 mol), and DIPEA (48 mg, 0.375 mol) were dissolved in CHCN (1 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 to give the title compound A13 (crude), which was further separated into compound A13a (6 mg) and compound A13b (4 mg) by preparative HPLC (Method A).

[0409] Compound A13a (early peak): 1 H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.94 (s, 1H), 7.89 (dd, J = 8.7, 1.5 Hz, 1H), 6.16-5.85 (m, 1H), 5.13 (s, 0.5H), 4.96-4.91 (m, 0.5H), 4.19 (d, J = 25.6 Hz, 1H), 3.94 (s, 3H), 3.79 (s, 3H), 3.76 (d, J = 6.6 Hz, 1H), 3.72-3.63 (m, 3.5H), 3.45-3.39 (m, 0.5H), 3.19 (s, 3H), 2.83-2.77 (m, 0.5H), 2.76 (s, 3H), 2.66-2.59 (m, 1.5H), 2.45 (d, J = 12.1 Hz, 1H), 1.43 (d, J = 6.5 Hz, 3H), 1.09 (d, J = 6.5 Hz, 3H) ppm. MS: M / e 516(M+1) + .

[0410] Compound A13b (late peak): 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.96 (s, 1H), 7.90 (dd, J = 8.7, 1.6 Hz, 1H), 6.31 (s, 0.5H), 5.68-5.62 (m, 0.5H), 5.40 (s, 0.5H), 4.63-4.59 (m, 0.5H), 4.19 (d, J = 33.4 Hz, 1H), 4.08-3.86 (m, 5H), 3.89-3.78 (m, 1H), 3.82 (s, 3H), 3.56-3.48 (m, 0.5H), 3.41 MS: M / e 516(M+1) + .

[0411] Compound A14: 2-(6-fluoro-7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0412] Step A: tert-butyl (2R,5S)-4-(6-fluoro-2-formyl-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0413] To a solution of tert-butyl (2R,5S)-4-(2-formyl-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (5.5 g, 13.7 mmol) in THF (30 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (7.2 g, 20.5 mmol). The resulting mixture was stirred at 40° C. overnight. The reaction solvent was collected by filtration and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound (2.5 g, 43%). MS: M / e 422 (M+1) + .

[0414] Step B: tert-butyl (2R,5S)-4-(6-fluoro-2-(hydroxymethyl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0415] To a solution of tert-butyl (2R,5S)-4-(6-fluoro-2-formyl-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (3 g, 7.1 mmol) in MeOH (10 mL) was added NaBH (270 mg, 7.1 mmol). The resulting mixture was stirred at 0° C. for 5 minutes. The reaction mixture was diluted with DCM and washed with water, and the organic layer was concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (2.4 g, 73%). MS: M / e 424 (M+1) + .

[0416] Step C: tert-butyl (2R,5S)-4-(2-(chloromethyl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0417] To a solution of SOCl (1.4 g, 11.8 mmol) in DCM (600 mL) was added tert-butyl (2R,5S)-4-(6-fluoro-2-(hydroxymethyl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (1 g, 2.36 mmol). The resulting mixture was stirred at room temperature for 10 minutes. The reaction medium was washed with water, aqueous NaHCO, and brine. The organic layer was concentrated to give the title compound, which was used directly in the next step without further purification.

[0418] Step D: tert-butyl (2R,5S)-4-(2-(cyanomethyl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0419] To a solution of crude tert-butyl (2R,5S)-4-(2-(chloromethyl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate in CHCN (30 mL) was added TMSCN (1.17 g, 11.8 mmol) and CsCO (3.8 g, 11.8 mmol). The resulting mixture was stirred at 60 °C for 30 minutes. The reaction solvent was removed in vacuo. The crude product was purified by flash column chromatography to give the title compound (400 mg). MS: M / e 433 (M+1) + .

[0420] Step E: 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0421] To a solution of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (400 mg, 0.93 mmol) in DCM (10 mL) was added TFA (3 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction solvent was removed under vacuum. The crude product was dissolved in water and adjusted to pH=9 with aqueous NaHCO3 solution. The aqueous layer was extracted with (DCM / IPA=3 / 1) to give the title compound (400 mg, crude). MS: M / e 333 (M+1) + .

[0422] Step F: 2-(6-fluoro-7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0423] To a solution of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (30 mg, 0.09 mmol) in CH3CN (3 mL) were added 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol (57 mg, 0.27 mmol), (cyanomethyl)trimethylphosphonium iodide (110 mg, 0.45 mmol), and DIPEA (117 mg, 0.9 mmol). The resulting mixture was stirred at 105 °C overnight. The reaction solvent was removed under reduced pressure. The resulting residue was purified by preparative TLC (DCM:MeOH=20:1) to give the title compound 14, which was further separated into compound A14a (2 mg) and compound A14b (1 mg) by preparative HPLC (Method A).

[0424] Compound A14a (early peak): 1 H NMR (400 MHz, CD3OD) δ 8.10 - 8.02 (m, 1H), 7.39 (t, J = 8.2 Hz, 2H), 4.66 (br s, 1H), 4.23 - 4.09 (m, 2H), 4.02 - 3.93 (m, 5H), 3.89 (s, 3H), 3.56 (s, 1H), 2.95 - 2.65 (m,2H), 1.95 (d, J = 12.2 Hz, 1H), 1.31 (d, J = 6.4 Hz, 3H), 1.26 (d, J = 6.7 Hz, 3H), 1.15 (d, J = 6.5 Hz, 3H) ppm. MS: M / e 523 (M+1) + .

[0425] Compound A14b (late peak): 1H NMR (400 MHz, CD3OD) δ 8.17 - 8.06 (m, 1H), 7.47 - 7.35 (m, 2H), 4.95 (br s, 1H), 4.24 - 3.95 (m, 2H), 3.98 (s, 3H), 3.89 (s, 3H), 3.80 (q, J = 13.1 Hz, 2H), 3.17 - 3.07 (m, 1H), 2.89 (d, J = 10.9 Hz, 1H), 2.75 - 2.66 (m, 2H), 1.52 (d, J = 6.6 Hz, 3H), 1.25 (d, J = 6.4 Hz, 3H), 1.00 (d, J = 6.5 Hz, 3H) ppm. MS: M / e 523 (M+1) + .

[0426] Compound A16: 2-(6-fluoro-7-((2S,5R)-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0427] To a solution of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (30 mg, 0.09 mmol) in CHCN (3 mL) was added 1-(4-fluoro-2-methoxyphenyl)ethan-1-ol (46 mg, 0.27 mmol), (cyanomethyl)trimethylphosphonium iodide (110 mg, 0.45 mmol), and DIPEA (117 mg, 0.9 mmol). The resulting mixture was stirred at 105 °C overnight. The reaction solvent was removed under reduced pressure. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (4 mg, 8%). 1H NMR (400 MHz, DMSO-d6) 7.56 - 7.42 (m, 1H), 6.95 - 6.67 (m, 2H), 4.68- 4.42 (m, 1H), 4.37 (d, J = 3.8 Hz, 2H), 4.11 - 3.90 (m, 1H), 3.80 (s, 3H), 3.80 (d, J = 2.9 Hz, 3H), 3.76 (s, 3H), 3.68 - 3.51 (m, 1H), 3.36 - 3.34 (m, 1H), 2.96 - 2.55 (m, 2H),, 2.07 (d, J = 11.4 Hz, 1H), 1.30 (d, J = 6.4 MS: M / e 485 (M+1) + .

[0428] Compound A18: 2-(7-((2S,5R)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0429] To a solution of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (30 mg, 0.09 mmol) in CHCN (3 mL) was added 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-ol (49 mg, 0.27 mmol), (cyanomethyl)trimethylphosphonium iodide (110 mg, 0.45 mmol), and DIPEA (117 mg, 0.9 mmol). The resulting mixture was stirred at 105 °C overnight. The reaction solvent was removed under reduced pressure to give the title compound A18, which was further separated by preparative HPLC (Method A) into compound A18a (1 mg) and compound A18b (2 mg).

[0430] Compound A18a (early peak): 1 H NMR (400 MHz, DMSO-d6) δ 6.82 (d, J = 7.1 Hz, 1H), 6.81 (s, 2H), 4.56 (s, 1H), 4.38 (s, 2H), 4.23 (s, 4H), 3.88 (s, 3H), 3.76 (s, 3H), 3.64 - 3.42 (m, 3H), 2.91 (d, J = 8.6 Hz, 1H), 2.68 (s, 1H), 2.58-2.56 (m, 1H),1.26 (d, J = 6.4 Hz, 3H), 1.21 (d, J = 6.5 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H) ppm. MS: M / e 495 (M+1) + .

[0431] Compound A18b (slow peak): 1H NMR (400 MHz, DMSO-d6) δ 6.84 (s, 1H), 6.79 (t, J = 8.3 Hz, 2H), 4.40 (s, 1H), 4.37 (s, 2H), 4.21 (s, 4H), 3.87 (s, 3H), 3.76 (s, 5H), 3.44 (d, J = 6.6 Hz, 1H), 3.33-3.31 (m, 1H), 2.64 (d, J = 8.0 Hz, 1H), 2.10 (d, J = 9.1 Hz, 1H), 1.20 (d, J = 6.3 Hz, 3H), 1.13 (d, J = 6.4 Hz, 3H), 1.03 (d, J = 6.4 Hz, 3H) ppm. MS: M / e 495 (M+1) + .

[0432] Compound A19: 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0433] 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (250 mg, 0.753 mol), 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-ol (313 mg, 1.506 mol), (cyanomethyl)trimethylphosphonium iodide (366 mg, 1.506 mol), and DIPEA (292 mg, 2.259 mol) were dissolved in a CH3CN solution (3 mL). The mixture was degassed three times under a N2 atmosphere. The mixture was then stirred at 105 °C for 24 hours. 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 A19 (60 mg), which was further separated into compound A19a (18 mg) and compound A19b (18 mg) by chiral preparative HPLC. The chiral separation conditions are shown below.

[0434] [Table 5]

[0435]

[0436] Compound A19a (early peak): 1 H NMR (400 MHz, CD3OD) δ 6.83-6.77 (m, 3H), 4.67 (s, 1H), 4.58 (s, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.89 (s, 2H), 3.72-3.61 (m, 3H), 3.04 (dd, J = 11.5, 3.3 Hz, 1H), 2.85-2.75 (m, 1H), 2.62 (dd, J = 11.5, 3.7 Hz, 1H), 1.36 (d, J = 6.4 Hz, 3H), 1.33 (s, 6H), 1.30 (d, J = 6.5 Hz, 4H), 1.01 (d, J = 6.4 Hz, 3H) ppm. MS: M / e 523(M+1) + .

[0437] Compound A19b (slow peak): 1 H NMR (400 MHz, CD3OD) δ 6.82 (d, J = 6.6 Hz, 2H), 6.77 (d, J = 8.8 Hz, 1H), 4.60-4.53 (m, 2H), 4.06-3.95 (m, 1H), 3.98 (s, 3H), 3.93-3.89 (m, 1H), 3.90 (s, 3H), 3.87 (s, 2H), 3.5-3.39 (m, 2H), 2.76 (dd, J = 11.7, 3.2 Hz, 1H), 2.21 (d, J = 11.3 Hz, 1H), 1.31 (d, J = 2.7 Hz, 6H), 1.28 (d, J = 6.5 1.24 (d, J = 6.5 Hz, 3H), 1.11 (d, J = 6.4 Hz, 3H) ppm. MS: M / e 523(M+1) + .

[0438] Compound A20: 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-ethyl-6-fluoro-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0439] Step A: tert-butyl (2R,5S)-4-(5-chloro-3-ethyl-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0440] To a solution of tert-butyl (2R,5S)-4-(5-chloro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (49 g, 134.2 mmol) and KCO (55.6 g, 403 mmol) in acetone (300 mL) was added CHCHI (41.9 g, 268.4 mmol). The reaction was stirred at room temperature for 16 hours. After filtration, the reaction mixture was diluted with water, extracted with EtOAc (300 mL x 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (PE:EtOAc = 1:1) to give the title compound (23.5 g, 45%). MS: M / e 394 (M+1). + .

[0441] Step B: tert-Butyl (2R,5S)-4-(3-ethyl-5-hydroxy-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0442] A solution of (2R,5S)-tert-butyl 4-(5-chloro-3-ethyl-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (23.5 g, 60 mmol), Pd(dba) (5.47 g, 6 mmol), t-BuXphos (5.11 g, 12 mmol), and KOH (60 mL, 3 M, 180 mmol) in dioxane (120 mL) was degassed three times under N. The mixture was then stirred at 90 °C for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH = 10:1) to give the title compound (15.6 g, 69%). MS: M / e 376 (M+1) + .

[0443] Step C: (2R,5S)-tert-butyl 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0444] To a solution of tert-butyl (2R,5S)-4-(3-ethyl-5-hydroxy-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (7.5 g, 20 mmol) and CsCO (22.8 g, 60 mmol) in dioxane (210 mL) was added CHCl (28.4 g, 200 mmol). The reaction was stirred at room temperature for 16 hours. After filtration, the reaction mixture was diluted with water, extracted with EtOAc (150 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH = 20:1) to give the title compound (5 g, 64%). MS: M / e 390 (M+1). + .

[0445] Step D: tert-Butyl (2R,5S)-4-(3-ethyl-2-formyl-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0446] A solution of tert-butyl (2R,5S)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (5.0 g, 12.853 mmol) in THF (150 mL) was degassed three times under N2 atmosphere. LDA (19.3 mL, 2 M, 38.560 mmol) was then added dropwise at -78 °C. The mixture was stirred at -78 °C for 1 h. DMF (9.39 g, 128.53 mmol) was added to quench the reaction. The reaction mixture was stirred for 1 h, diluted with saturated NH4Cl, extracted with EtOAc (150 mL × 2), washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH=20:1) to give the title compound (5.0 g, 93%). MS: M / e 418 (M+1) + .

[0447] Step E: tert-butyl (2R,5S)-4-(3-ethyl-6-fluoro-2-formyl-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0448] To a solution of tert-butyl (2R,5S)-4-(3-ethyl-2-formyl-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (1.0 g, 2.40 mmol) in THF (60 mL) was added Selectfluor (2.55 g, 7.20 mmol). The reaction was stirred at 60° C. for 6 hours. After filtration, the reaction mixture was concentrated to dryness. The resulting residue was purified by flash column chromatography (PE:EtOAc=1:1) to give the title compound (450 mg, 43%). MS: M / e 436 (M+1) + .

[0449] Step F: tert-butyl (2R,5S)-4-(3-ethyl-6-fluoro-2-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0450] To a solution of tert-butyl (2R,5S)-4-(3-ethyl-6-fluoro-2-formyl-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (450 mg, 1.034 mmol) in MeOH (10 mL) was added NaBH (39 mg, 1.034 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NH Cl, extracted with EtOAc (30 mL x 2), washed with brine, dried over Na SO , filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH=10:1) to give the title compound (350 mg, 77%). MS: M / e 438 (M+1) + .

[0451] Step G: tert-butyl (2R,5S)-4-(2-(chloromethyl)-3-ethyl-6-fluoro-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0452] To a solution of tert-butyl (2R,5S)-4-(3-ethyl-6-fluoro-2-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (350 mg, 0.801 mmol) in DCM (20 mL) was added SOCl (100 mg, 0.841 mmol). The reaction was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated to give the title compound (350 mg, 96%). MS: M / e 456 (M+1) + .

[0453] Step H: tert-butyl (2R,5S)-4-(2-(cyanomethyl)-3-ethyl-6-fluoro-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0454] To a solution of tert-butyl (2R,5S)-4-(2-(chloromethyl)-3-ethyl-6-fluoro-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (350 mg, 0.769 mmol) in DCM (20 mL) was added TBAF (1.54 mL, 1 M, 1.538 mmol), followed by TMSCN (153 mg, 1.538 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with water, extracted with DCM (40 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (PE: EtOAc = 1:5) to give the title compound (300 mg, 87%). MS: M / e 447 (M+1) + .

[0455] Step I: 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-ethyl-6-fluoro-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0456] To a stirred solution of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-3-ethyl-6-fluoro-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (300 mg, 0.673 mmol) in CHCl (20 mL) was added TFA (5 mL). The reaction mixture was then stirred at room temperature for 4 h and concentrated to give a residue, which was basified with saturated aqueous NaHCO to pH 10-11 and extracted with CHCl / IPA (3 / 1, 50 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound (180 mg, 78%). MS: M / e 347 (M+1). + .

[0457] Step J: 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-ethyl-6-fluoro-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0458] A solution of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-ethyl-6-fluoro-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (180 mg, 0.520 mmol), 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-ol (216 mg, 1.040 mmol), (cyanomethyl)trimethylphosphonium iodide (253 mg, 1.040 mmol), and DIPEA (201 mg, 1.560 mol) in CH3CN (2 mL) was prepared. The mixture was degassed three times under N2 atmosphere. The mixture was then stirred at 105 °C for 24 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH=15:1) and preparative HPLC (Method A) to give the title compound (16 mg, 6%). 1 H NMR (400 MHz, CD3OD) δ 6.88-6.84 (m, 3H), 4.59 (s, 1H), 4.42 (d, J = 7.2 Hz, 2H), 4.26-4.21 (m, 0.5H), 4.08-3.99 (m, 0.5H), 3.89 (d, J=11.0 Hz, 6H), 3.76-3.49 (m, 2H), 3.13-3.04 (m, 2H), 3.03-2.31 (m, 2H), 1.44 (dd, J = 17.7, 10.6 Hz, 6H), 1.33 (d, J = 5.8 Hz, 8H), 1.21 (t, J = 17.9 Hz, 4H) ppm. MS: M / e 537 (M+1) +

[0459] Compound A21: 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-ethyl-6-fluoro-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0460] Step A: 2-chloro-6-(hydroxymethyl)pyridin-3-ol [ka]

[0461] A solution of 2-chloropyridin-3-ol (2 g, 15.50 mmol), formaldehyde (37%, 12.6 g, 155 mmol), and NaHCO (3.9 g, 46.5 mmol) in water (50 mL) was stirred at 90 °C overnight. The reaction mixture was quenched with concentrated HCl and extracted with CHCl / IPA (3 / 1, 10 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound (2.1 g, 85%) as a colorless oil. MS: M / e 160 (M+1) + .

[0462] Step B: 1-((2-chloro-6-(hydroxymethyl)pyridin-3-yl)oxy)propan-2-one [ka]

[0463] A solution of 2-chloro-6-(hydroxymethyl)pyridin-3-ol (2.1 g, 13.21 mmol), 1-chloropropan-2-one (1.46 g, 15.85 mmol), KI (219 mg, 1.32 mmol), and KCO (3.65 g, 26.42 mmol) in ACN (100 mL) was stirred at 60 °C for 1 h. The mixture was diluted with CHCl (20 mL), then washed with H0, brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (2.7 g, 95%) as a colorless oil. MS: M / e 216 (M+1) + .

[0464] Step C: 6-chloro-5-(2-oxopropoxy)picolinaldehyde [ka]

[0465] A mixture of 1-((2-chloro-6-(hydroxymethyl)pyridin-3-yl)oxy)propan-2-one (2.7 g, 12.56 mmol) and Dess-Martin periodinane (6.4 g, 15.07 mmol) in DCM (30 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM, washed with water, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (2.6 g, 97%). MS: M / e 214 (M+1) + .

[0466] Step D: 1-((2-chloro-6-(1-hydroxyethyl)pyridin-3-yl)oxy)-2-methylpropan-2-ol [ka]

[0467] To a stirred solution of 6-chloro-5-(2-oxopropoxy)picolinaldehyde (2.6 g, 12.21 mmol) in dry THF (200 mL) was added MeMgBr (1.0 M, 30.5 mL, 30.5 mmol) dropwise at 0 °C. The mixture was then stirred for half an hour. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (2.6 g, 87%) as a colorless oil. MS: M / e 246 (M+1) + .

[0468] Step E: 1-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethan-1-ol [ka]

[0469] A mixture of 1-((2-chloro-6-(1-hydroxyethyl)pyridin-3-yl)oxy)-2-methylpropan-2-ol (1 g, 4.08 mmol), Pd(OAc) (91 mg, 0.41 mmol), BINAP (254 mg, 0.41 mmol), and CsCO (2.66 g, 8.16 mmol) dissolved in toluene (30 mL) was stirred at 100 °C under N overnight. The reaction mixture was extracted with EtOAc (100 mL × 3). 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 (550 mg, 64%) as a colorless oil. MS: M / e 210 (M+1) + .

[0470] Step F: 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-ethyl-6-fluoro-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0471] 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-ethyl-6-fluoro-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (120 mg, 0.347 mmol), 1-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethan-1-ol (218 mg, 1.040 mmol), (cyanomethyl)trimethylphosphonium iodide (337 mg, 1.388 mmol), and DIPEA (224 mg, 1.735 mol) were dissolved in a CH3CN solution (2 mL). The mixture was degassed three times under a N2 atmosphere. The mixture was then stirred at 105 °C for 24 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH=15:1) and preparative HPLC (Method A) to give the title compound (11 mg, 6%). 1 H NMR (400 MHz, CD3OD) δ 7.33 (t, J = 6.1 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 4.65 (d, J = 34.1 Hz, 1H), 4.43 (dd, J = 13.1, 6.0 Hz, 2H), 4.26-4.05 (m, 2H), 4.03-3.97 (m, 0.5H), 3.98 (s, 2H), 3.89 (s, 3H), 3.79-3.62 (m, 2H), 3.38-3.34 (m, 1.5H), 3.23-3.00 (m, 1H), 2.88-2.50 (m, 1H), 1.46 (t, J MS: M / e 538 (M+1) +

[0472] Compound A22: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0473] To a solution of 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (20 mg, 0.0.04 mmol) in CHCN (0.2 mL) and THF (2 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (23 mg, 0.06 mmol). The resulting mixture was stirred at room temperature for 10 minutes. The reaction solvent was removed under reduced pressure. The resulting residue was purified by preparative TLC to give the title compound A22, which was further separated by preparative HPLC (Method A) into compound A22a (0.63 mg) and compound A22b (0.3 mg, crude).

[0474] Compound A22a (early peak): 1 H NMR (400 MHz, DMSO-d6) δ 8.93 (t, J = 4.2 Hz, 2H), 8.18 - 7.90 (m, 3H), 4.37 (s, 2H), 4.01 (d, J = 6.5 Hz, 1H), 3.93 - 3.83 (m, 4H), 3.76 (s, 3H), 3.69 - 3.61 (m, 1H), 3.51 (d, J = 13.5 Hz, 1H), 3.06 - 2.93 (m, 2H), 2.68 (d, J = 7.9 Hz, 1H), 1.42 - 1.29 (m, 5H), 1.20 - 1.08 (m, 2H), 0.97 (t, J = 11.8 Hz, 2H) ppm. MS: M / e 489 (M+1) + .

[0475] Compound A23: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ka]

[0476] 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (40 mg, 0.093 mol), 1-(3-methylquinoxalin-6-yl)ethan-1-ol (35 mg, 0.185 mol), (cyanomethyl)trimethylphosphonium iodide (45 mg, 0.185 mol), and DIPEA (36 mg, 0.279 mol) were dissolved in a CH3CN solution (1 mL). The mixture was degassed three times under a N2 atmosphere. The mixture was then stirred at 105 °C for 24 hours. 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 A23, which was further separated into compound A23a (7 mg) and compound A23b (4 mg) by preparative HPLC (Method A).

[0477] Compound A23a (early peak): 11H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 1.4 Hz, 1H), 7.93 (dd, J = 8.7, 1.7 Hz, 1H), 4.84 - 4.76 (m, 2H), 4.23 - 4.18 (m, 1H), 4.07 - 3.98 (m, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 3.85 - 3.75 (m, 2H), 3.17 (dd, J = 11.5, 3.7 Hz, 1H), 2.84 - 2.78 (m, 2H), 2.77 (s, 3H), 1.48 (dd, J = 6.5 Hz, 3H), 1.45 (dd, J = 6.5 Hz, 3H), 1.07 (d, J = 6.5 Hz, 3H) ppm. MS: M / e 503(M+1) + .

[0478] Compound A23b (slow peak): 1 1H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.98 (s, 1H), 7.95 (dd, J = 8.6, 1.7 Hz, 1H), 4.84 - 4.80 (m, 1H), 4.63 - 4.54 (m, 1H), 4.25 - 1.28 (m, 1H), 4.10 - 3.99 (m, 2H), 3.98 (s, 3H), 3.90 (s, 3H), 3.88 - 3.83 (m, 1H), 3.61 - 3.50 (m, 1H), 2.90 (dd, J = 11.9, 3.8 Hz, 1H), 2.76 (s, 3H), 2.16 (dd, J = 11.8, 2.5 Hz, 1H), 1.44 (d, J = 6.6 Hz, 3H), 1.27 (d, J = 6.5 Hz, 3H), 1.20 (d, J = 6.5 Hz, 3H) ppm. MS: M / e 503(M+1) + .

[0479] Compound A24: 2-(6-((2S,5R)-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0480] 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (50 mg, 0.159 mol), 1-(4-fluoro-2-methoxyphenyl)ethan-1-ol (40 mg, 0.238 mol), (cyanomethyl)trimethylphosphonium iodide (77 mg, 0.318 mol), and DIPEA (62 mg, 0.477 mol) were dissolved in a CH3CN solution (1 mL). The mixture was degassed three times under a N2 atmosphere. The mixture was then stirred at 105 °C for 24 hours. 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 A24, which was further separated into compound A24a (5 mg) and compound A24b (3 mg) by preparative HPLC (Method A).

[0481] Compound A24a (early peak): 1 H NMR (400 MHz, CD3OD) δ 7.56 (s, 1H), 6.90-6.64 (m, 2H), 5.99-5.94 (m, 0.5H), 5.08-5.04 (m, 0.5H), 4.85-4.41 (m, 1H), 4.29-4.03 (m, 2H), 3.93 (s, 3H), 3.83 (s, 3H), 3.79 (s, 3H), 3.70-3.58 (m, 2H), 2.95-2.64 (m, 2H), 2.56-2.20 (m, 1H), 1.43-1.35 (m, 3H), 1.30 (d, J = 5.7 Hz, 3H), 1.18-1.01 (m, 3H) ppm. MS: M / e 468(M+1) + .

[0482] Compound A24b (slow peak): 1 H NMR (400 MHz, CD3OD) δ 7.52 (dd, J = 8.4, 7.0 Hz, 1H), 6.80 (dd, J = 11.2, 2.2 Hz, 1H), 6.74 (td, J = 8.4, 2.3 Hz, 1H), 6.19-5.02 (m, 2H), 4.38-3.34 (m, 1H), 4.21 (s, 1H), 3.93 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.53-3.38 (m, 1.5H), 3.12-2.91 (m, 2H), 2.92-2.70 (m, 1.5H), 1.41 (d, J = MS: M / e 468(M+1) + .

[0483] Compound A25: 2-(6-((2S,5R)-4-(1-(2-(difluoromethoxy)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0484] A mixture of 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (50 mg, 0.158 mmol), 1-(2-(difluoromethoxy)-4-fluorophenyl)ethan-1-ol (65.4 mg, 0.317 mmol), (cyanomethyl)trimethylphosphonium iodide (115 mg, 0.474 mmol), and DIPEA (204 mg, 1.58 mmol) in CH3CN (4 mL) was stirred in a sealed tube at 100 °C overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with H2O, brine, dried over Na2SO4, and concentrated to give a residue, which was purified by Pre-TLC (CH2Cl2 / MeOH=10:1) to give the title compound (18 mg, 23%). 1 H NMR (400 MHz, CD3OD) δ 7.81 - 7.65 (m, 1H), 7.13 - 6.68 (m, 3H), 6.04 - 4.45 (m, 2H), 4.21 (s, 2H), 4.16 - 3.97 (m, 1H), 3.93 (s, 3H), 3.78 (s, 3H), 3.65 - 3.46 (m, 1H), 3.04 - 2.60 (m, 2.5H), 2.28 - 2.07 (m, 0.5H), 1.50 - 1.22 (m, 6H), 1.13 - 0.85 (m, 3H)ppm. MS: M / e 504 (M+1) + .

[0485] Compound A26: 2-(6-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethoxy)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0486] A mixture of 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (50 mg, 0.158 mmol), 1-(4-fluoro-2-(trifluoromethoxy)phenyl)ethan-1-ol (71 mg, 0.317 mmol), (cyanomethyl)trimethylphosphonium iodide (115 mg, 0.474 mmol), and DIPEA (204 mg, 1.58 mmol) in CHCN (4 mL) was stirred in a sealed tube at 100 °C overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with HO, brine, dried over NaSO, and concentrated to give a residue, which was purified by pre-TLC (CHCl / MeOH=10:1) to give the title compound (4 mg). 1 H NMR (400 MHz, CD3OD) δ 7.47 - 7.34 (m, 1H), 7.23 - 7.07 (m, 2H), 6.32 - 4.99 (m, 2H), 4.27 - 4.06 (m, 3H), 3.93 (s, 3H), 3.78 (s, MS: M / e 522 (M+1) + .

[0487] Compound A27: 2-(6-((2S,5R)-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0488] 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (50 mg, 0.159 mol), 1-(4-fluoro-2-(methoxymethyl)phenyl)ethan-1-ol (44 mg, 0.238 mol), (cyanomethyl)trimethylphosphonium iodide (77 mg, 0.318 mol), and DIPEA (62 mg, 0.477 mol) were dissolved in a CH3CN solution (1 mL). The mixture was degassed three times under a N2 atmosphere. The mixture was then stirred at 105 °C for 24 hours. 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 A27, which was further separated into compound A27a (2 mg) and compound A27b (1.5 mg) by preparative HPLC (Method A).

[0489] Compound A27a (early peak): 1 H NMR (400 MHz, CD3OD) δ 7.74-7.64 (m, 1H), 7.04 (dd, J = 13.8, 5.8 Hz, 2H), 6.00-5.89 (m, 1H), 5.02-4.96 (m, 0.5H), 4.83-4.71 (m, 0.5H), 4.68-4.38 (m, 2H), 4.21 (s, 1H), 3.95-3.91 (m, 3H), 3.82-3.75 (m, 4H), 3.67-3.62 (m, 2H), 3.37 (s, 3H), 2.96-2.56 (m, 2H), 2.12 (d, J = 11.6 Hz, 1H), 1.30 (d, J = 6.5 Hz, 3H), 1.24 (d, J = 6.3 Hz, 3H), 1.05 (d, J = 6.5 Hz, 3H) ppm. MS: M / e 482(M+1) + .

[0490] Compound A27b (late peak): 1H NMR (400 MHz, CD3OD) δ 7.61 (dd, J = 8.6, 5.9 Hz, 1H), 7.11 (dd, J = 9.9, 2.6 Hz, 1H), 7.04 (dd, J = 9.7, 7.1 Hz, 1H), 6.17-6.13 (m, 0.5H), 5.65 (d, J = 12.5 Hz, 0.5H), 5.25 (s, 0.5H), 4.63-4.51 (m, 2.5H), 4.22-4.17 (m, 1H), 4.06-3.91 (m, 4H), 3.78 (s, 3H), 3.55-3.49 (m, 1H), 3.40 (s, 3H), 3.15-3.10 (m, 1H), 2.92-2.75 (m, 3H), 1.45 (d, J = 17.2 Hz, 3H), 1.27 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H) ppm. MS: M / e 482(M+1) + .

[0491] Compound A28: 2-(6-((2S,5R)-4-(1-(4-fluoro-2-(1-methoxyethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0492] A solution of 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (50 mg, 0.16 mmol), 1-(4-fluoro-2-(1-methoxyethyl)phenyl)ethan-1-ol (31 mg, 0.16 mmol), (cyanomethyl)trimethylphosphonium iodide (115 mg, 0.48 mmol), and DIPEA (102 mg, 0.79 mmol) in MeCN (3 ml) was stirred at 100° C. overnight. Upon completion, the solution was concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (12 mg, 15%). 1 H NMR (400 MHz, CD3OD) δ 7.74 - 7.59 (m, 1H), 7.16 - 6.96 (m, 2H), 6.00 - 4.80 (m, 3H), 4.57 (s, 3H), 3.93 (s, 3H), 3.78 (s, 3H), 3.60-3.22 (m, 2H), 2.96 - 2.70 (m, 4H), 2.23 - 1.99 (m, 1H), 1.60 - 1.41 (m, 6H), 1.26 - 1.03 (m, 3H), 0.90 (t, J = 7.5 Hz, 3H) ppm. MS: M / e 496 (M+1) +

[0493] Compound A29: 2-(6-((2S,5R)-4-(1-(2-(1-(difluoromethoxy)ethyl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0494] Step A: 1-Bromo-2-(1-(difluoromethoxy)ethyl)-4-fluorobenzene [ka]

[0495] To a solution of 1-(2-bromo-5-fluorophenyl)ethan-1-ol (657 mg, 3 mmol) in DCM (11.8 mL) and HO (1.8 mL) was added (bromodifluoromethyl)trimethylsilane (1.8 g, 9 mmol) and AcOK (1.79 g, 18 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was diluted with DCM and washed with water. The organic layer was separated, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (260 mg, 32%). MS: M / e 269 (M+1) + .

[0496] Step B: 1-(2-(1-(difluoromethoxy)ethyl)-4-fluorophenyl)ethan-1-one [ka]

[0497] To a solution of 1-bromo-2-(1-(difluoromethoxy)ethyl)-4-fluorobenzene (268 mg, 1 mol) in toluene (10 mL) were added tributyl(1-ethoxyvinyl)stannane (430 mg, 1.2 mol) and Pd(PPh3)4 (140 mg, 0.2 mmol). The reaction mixture was protected with a N2 atmosphere and stirred at 100 °C overnight. The mixture was cooled to room temperature, and HCl / dioxane (4 M, 10 mL) was added and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. H2O was added to the residue, and the pH was adjusted to 7-8 with aqueous NaHCO3. The resulting mixture was extracted with EtOAc and then concentrated using a rotary evaporator to give a residue. The resulting residue was purified by flash column chromatography to give the title compound (190 mg, 82%). MS: M / e 233 (M+1) + .

[0498] Step C: 1-(2-(1-(difluoromethoxy)ethyl)-4-fluorophenyl)ethan-1-ol [ka]

[0499] NaBH4 (38 mg, 1 mmol) was added to a solution of 1-(2-(1-(difluoromethoxy)ethyl)-4-fluorophenyl)ethan-1-one (190 mg, 0.8 mol) in EtOH (200 ml) at 0 °C for 1 h. Water was added to quench the reaction. The mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (50 mg, 26%). MS: M / e 235 (M+1) + .

[0500] Step D: 2-(6-((2S,5R)-4-(1-(2-(1-(difluoromethoxy)ethyl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0501] To a solution of 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (40 mg, 0.12 mmol) and (cyanomethyl)trimethylphosphonium iodide (120 mg, 1 mmol) in CHCN (5 mL) was added DIPEA (250 mg, 2 mmol). The mixture was degassed three times under N atmosphere. The mixture was then stirred at 105 °C for 24 h. The reaction was quenched with saturated NH Cl (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (35 mL × 2). The combined organic layers were dried over Na SO and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Method A) to give the title compound A29a (0.51 mg) and compound A29b (0.83 mg).

[0502] Compound A29a (early peak): 1 H NMR (400 MHz, CD3OD) δ 7.72 (dd, J = 8.8, 6.0 Hz, 1H), 7.14 (dd, J = 10.3, 2.7 Hz, 1H), 7.04 (dd, J = 8.5, 5.6 Hz, 1H), 6.55 - 6.17 (m, 1H), 5.66 (d, J = 6.4 Hz, 1H), 5.34 (s, 1H), 4.56 (s, 2H), 3.94 (s, 3H), 3.84 (d, J = 6.5 Hz, 1H), 3.78 (s, 3H), 3.59 (s, 1H), 2.77 (s, 1H), 2.68 (d, J = 12.3 Hz, 1H), 2.21-2.15 (m, 1H), 2.03 (m, 1H),1.50 (d, J = 6.5 Hz, 3H), 1.30 (s, 3H), 1.22 (d, J = 6.6 Hz, 3H), 1.07 (d, J = 6.6 Hz, 3H) ppm. MS: M / e 532 (M+1) + .

[0503] Compound A29b (late peak): 1 H NMR (400 MHz, CD3OD) δ 7.62 - 7.54 (m, 1H), 7.21 (dd, J = 10.4, 2.7 Hz, 1H), 7.04 (td, J = 8.4, 2.6 Hz, 1H), 6.58 - 6.20 (m, 1H), 5.90 (d, J = 6.6 Hz, 1H), 5.65 (d, J = 13.2 Hz, 1H), 5.26 (s, 1H), 4.56 (s, 2H), 3.90 (dd, J = 21.3, 5.6 Hz, 4H), 3.78 (s, 3H), 3.55-3.48 (m, 1H), 2.84 (s, 2H), 2.03 (m, 1H),1.51 (d, J = 6.3 Hz, 3H), 1.30 (d, J = 6.5 Hz, 6H), 0.91 (d, J = 6.5 Hz, 3H) ppm. MS: M / e 532 (M+1) +.

[0504] Compound A30: 2-(6-((2S,5R)-4-(1-(2-(difluoromethyl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0505] Step A: 1-(2-(difluoromethyl)-4-fluorophenyl)ethan-1-one [ka]

[0506] A toluene solution (10 mL) of 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(PPh)Cl (350 mg, 0.5 mmol) was stirred overnight at 100 °C under N. HCl (4 mL, 4 M in 1,4-dioxane) was then added dropwise to the solution, and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was diluted with EtOAc (50 mL), treated with saturated aqueous NaHCO to pH 8, washed with brine (20 mL × 3), dried over NaSO, 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), 7.54 - 7.18 (m, 3H), 2.61 (d, J = 6.9 Hz, 3H) ppm. MS: M / e 189 (M+1) + .

[0507] Step B: 1-(2-(difluoromethyl)-4-fluorophenyl)ethan-1-ol [ka]

[0508] To a solution of 1-(2-(difluoromethyl)-4-fluorophenyl)ethan-1-one (400 mg, 2.13 mmol) in MeOH (5 mL) was added NaBH (65 mg, 1.7 mmol) at °C, and the resulting mixture was stirred at room temperature for 1 h. The resulting residue was treated with water and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography (EtOAc:PE = 0 to 100% in 20 min) to give the title compound (190 mg, 47%). 1 H NMR (400 MHz, DMSO-d6) δ 7.70 - 7.62 (m, 1H), 7.51 - 7.19 (m, 3H), 5.44 (d, J = 4.0 Hz, 1H), 5.10 - 5.02 (m, 1H), 1.32 (d, J = 6.4 Hz, 3H) ppm. MS: M / e 191 (M+1) + .

[0509] Step C: 2-(6-((2S,5R)-4-(1-(2-(difluoromethyl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0510] A mixture of 1-(2-(difluoromethyl)-4-fluorophenyl)ethan-1-ol (57 mg, 0.3 mmol), 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (63 mg, 0.2 mmol), (cyanomethyl)trimethylphosphonium iodide (97 mg, 0.4 mmol), and DIPEA (103 mg, 0.8 mmol) in MeCN (2 mL) was stirred at 100 °C in a sealed tube overnight. The mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with brine (20 mL × 2), dried over NaSO, and concentrated to dryness. The resulting residue was purified by preparative TLC (CHCl:MeOH = 13:1) to give the title compound (5 mg, 5%). 1 H NMR (400 MHz, CD3OD) δ 7.81 - 7.10 (m, 4H), 6.29 - 5.22 (m, 2H), 4.22 (t, J = 13.1 Hz, 1H), 3.93 (d, J = 6.6 Hz, 3H), 3.86 - 3.76 (m, MS: M / e 488 (M+1) + .

[0511] Compound A31: 2-(6-((2S,5R)-4-(1-(2-(1,1-difluoroethoxy)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0512] A mixture of 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (50 mg, 0.158 mmol), 1-(2-(1,1-difluoroethoxy)-4-fluorophenyl)ethan-1-ol (64 mg, 0.317 mmol), (cyanomethyl)trimethylphosphonium iodide (115 mg, 0.474 mmol), and DIPEA (204 mg, 1.58 mmol) in CH3CN (4 mL) was stirred in a sealed tube at 100 °C overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with H2O, brine, dried over Na2SO4, and concentrated to give a residue, which was purified by pre-TLC (CH2Cl2 / MeOH=10:1) to give the desired compound, which was further purified by preparative HPLC (Method A) to give the title compound (0.5 mg). 1 H NMR (400 MHz, CD3OD) δ 8.06 - 7.95 (m, 1H), 7.28 - 7.16 (m, 2H), 6.21-5.21 (m, 2H), 4.28 - 4.14 (m, 1H), 4.03 - 3.97 (m, 1H), 3.96 - 3.90 (m, 3H), 3.78 (s, 3H), 3.63 (s, 1H), 2.98 - 2.66 (m, 4H), 2.08 - 1.91 (m, 3H), 1.56 - 1.28 (m, 3H), 1.28 - 1.18 (m, 3H), 1.08 - 0.88 (m, 3H) ppm. MS: M / e 518 (M+1) + .

[0513] Compound A33: 2-(6-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0514] 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (50 mg, 0.159 mol), 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol (66 mg, 0.317 mol), (cyanomethyl)trimethylphosphonium iodide (77 mg, 0.317 mol), and DIPEA (62 mg, 0.477 mol) were dissolved in a CH3CN solution (1 mL). The mixture was degassed three times under a N2 atmosphere. The mixture was then stirred at 105 °C for 24 hours. 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 A33, which was further separated into compound A33a (4 mg) and compound A33b (3 mg) by preparative HPLC (Method A).

[0515] Compound A33a (early peak): 1 H NMR (400 MHz, CD3OD) δ 8.10-8.00 (m, 1H), 7.40 (t, J = 8.6 Hz, 2H), 5.94-5.89 (m, 1H), 5.07-5.03 (m, 0.5H), 4.86-4.82 (m, 0.5H), 4.23-4.18 (m, 1.5H), 3.93 (s, 3H), 3.92-3.87 (m, 1H), 3.79-3.74 (m, 3.5H), 3.64 (s, 1H), 3.46-3.42 (m, 0.5H), 2.73-2.64 (m, 1.5H), 1.99 (d, J = 12.2 Hz, MS: M / e 506(M+1) + .

[0516] Compound A33b (late peak): 1H NMR (400 MHz, CD3OD) δ 8.18-8.05 (m, 1H), 7.44 (t, J = 8.8 Hz, 2H), 6.23-6.18 (m, 0.5H), 5.66 (d, J = 13.3 Hz, 0.5H), 5.29 (s, 0.5H), 4.60 (d, J = 13.1 Hz, 0.5H), 4.08-4.02 (m, 1H), 3.95 (d, J = 14.6 Hz, 3H), 3.83-3.76 (m, 3.5H), 3.57-3.52 (m, 0.5H), 3.35-3.31 (m, 1.5H), 3.25-3.20 (m, MS: M / e 506(M+1) + .

[0517] Compound A34: 2-(6-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0518] Step A: 2-chloro-6-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-9-methyl-9H-purine [ka]

[0519] To a solution of 2,6-dichloro-9-methyl-9H-purine (311 mg, 1.54 mmol) and (2R,5S)-2,5-diethyl-1-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazine (450 mg, 1.40 mmol) in n-BuOH (20 mL) was added DIPEA (542 mg, 4.20 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the title compound (650 mg, 84%). MS: M / e 499 (M+1) + .

[0520] Step B: 6-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-9-methyl-9H-purin-2-ol [ka]

[0521] A solution of 2-chloro-6-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-9-methyl-9H-purine (600 mg, 1.204 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), t-BuXphos (51 mg, 0.12 mmol), and KOH (1.2 mL, 3 M, 3.6 mmol) in dioxane (10 mL) was degassed three times under N2 atmosphere. The mixture was then stirred at 90 °C for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH=10:1) to give the title compound (470 mg, 82%). MS: M / e 481 (M+1) + .

[0522] Step C: 6-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one [ka]

[0523] To a solution of 6-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-9-methyl-9H-purin-2-ol (470 mg, 0.979 mmol) and CsCO (638 mg, 1.958 mmol) in dioxane (30 mL) was added CHCl (208 mg, 1.468 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with water, extracted with EtOAc (60 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH=10:1) to give the title compound (270 mg, 56%). MS: M / e 495 (M+1). + .

[0524] Step D: 6-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purine-8-carbaldehyde [ka]

[0525] A solution of 6-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one (240 mg, 0.485 mmol) in THF (15 mL) was degassed three times under N2 atmosphere. Then, LDA (0.97 mL, 2 M, 1.940 mmol) was added at -78 °C. The mixture was stirred at -78 °C for 1 h, and DMF (106 mg, 1.455 mmol) was added. The reaction solution was stirred to room temperature for 2 h. The reaction mixture was diluted with water, extracted with EtOAc (45 mL × 2), washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH=10:1) to give the title compound (180 mg, 71%). MS: M / e 523 (M+1) + .

[0526] Step E: 6-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-8-(hydroxymethyl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one [ka]

[0527] To a solution of 6-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purine-8-carbaldehyde (180 mg, 0.345 mmol) in MeOH (10 mL) was added NaBH (20 mg, 0.517 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NH Cl, extracted with EtOAc (30 mL × 2), washed with brine, dried over Na SO , filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH=8:1) to give the title compound (150 mg, 83%). MS: M / e 525 (M+1)+ .

[0528] Step F: 8-(chloromethyl)-6-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one [ka]

[0529] To a solution of 6-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-8-(hydroxymethyl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one (150 mg, 0.286 mmol) in DCM (5 mL) was added SOCl2 (136 mg, 1.145 mmol). The reaction was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to give the title compound (150 mg, 97%). MS: M / e 543 (M+1) + .

[0530] Step G: 2-(6-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0531] To a solution of 8-(chloromethyl)-6-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one (150 mg, 0.277 mmol) and CsCO (361 mg, 1.107 mmol) in CHCN (10 mL) was added TMSCN (110 mg, 1.107 mmol). The reaction was stirred at room temperature for 4 hours. The reaction mixture was diluted with water, extracted with DCM (30 mL × 2), 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 A34, which was further separated into compound A34a (19 mg) and compound A34b (10 mg) by preparative HPLC (Method A).

[0532] Compound A34a (early peak): 1 H NMR (400 MHz, CD3OD) 8.09-7.96 (m, 1H), 7.40 (t, J = 7.9 Hz, 2H), 6.14 (d, J = 13.7 Hz, 0.5H), 5.78-5.74 (m, 0.5H), 5.12 (d, J = 13.2 Hz, 0.5H), 4.91-4.87 (m, 0.5H), 4.21 (d, J = 24.8 Hz, 2H), 4.02-3.93 (m, 1H), 3.92 (d, J = 4.3 Hz, 3H), 3.79 (t, J = 3.9 Hz, 3H), 3.62 (d, J = 13.7 Hz, 0.5H), 3.25-3.19 (m, 1.5H), 2.68-2.51 (m, 1H), 2.11 (d, J = 12.2 Hz, 1H), 1.84-1.66 (m, 2H), 1.54-1.48 (m, 2H), 1.28 (d, J = 6.4 Hz, 3H), 1.04-0.99 (m, 3H), 0.66-0.61 (m, 3H) ppm. MS: M / e 534(M+1) + .

[0533] Compound A34b (slow peak):1 H NMR (400 MHz, CD3OD) δ 8.06 (dd, J = 8.2, 6.0 Hz, 1H), 7.46-7.40 (m, 2H), 6.05-6.01 (m, 0.5H), 5.88 (d, J = 13.5 Hz, 0.5H), 5.18-5.13 (m, 0.5H), 4.87-4.83 (m, 0.5H), 4.30-4.09 (m, 3H), 3.92 (d, J = 10.3 Hz, 3H), 3.78 (d, J = 2.1 Hz, 3H), 3.37 (d, J = 11.7 Hz, 0.5H), 3.08-2.96 (m, 1.5H), 2.88-2.71 (m, 1H), 2.28 (t, J = 10.4 Hz, 1H), 2.18-1.96 (m, 2H), 1.51-1.35 (m, 2H), 1.26 (dd, J = 6.2, 2.4 Hz, 3H), 0.99-0.93 (m, 3H), 0.79-0.64 (m, 3H) ppm. MS: M / e 534(M+1) + .

[0534] Compound A35: 2-(9-ethyl-6-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0535] A solution of 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (50 mg, 0.15 mmol), 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol (32 mg, 0.15 mmol), (cyanomethyl)trimethylphosphonium iodide (110 mg, 0.46 mmol), and DIPEA (98 mg, 0.76 mmol) in MeCN (3 mL) was stirred at 100° C. overnight. Upon completion, the solution was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Method A) to afford the title compound A35a (16 mg) and compound A35b (9 mg).

[0536] Compound A35a (early peak): 1 H NMR (400 MHz, CD3OD) δ 8.11 - 8.00 (m, 1H), 7.39 (t, J = 8.9 Hz, 2H), 5.92 (d, J = 13.2 Hz, 1H), 5.05 (s, 1H), 4.37 (q, J = 7.2 Hz, 2H), 4.26 - 4.20 (m, 1H), 3.88 (s, 1H), 3.76 (s, 3H), 3.65 (s, 1H), 3.48 (s, 1H), 2.84 - 2.56 (m, 2H), 1.99 (d, J = 12.5 Hz, 1H), 1.46 (t, J = 7.2 Hz, 3H), 1.32 (d, J MS: M / e 520 (M+1) +

[0537] Compound A35b (slow peak): 1H NMR (400 MHz, CD3OD) δ 8.16 - 8.05 (m, 1H), 7.42 (t, J = 9.0 Hz, 2H), 6.34 - 5.04 (m, 2H), 4.37 (dd, J = 15.2, 7.5 Hz, 2H), 4.05 (s, 1H), 3.76 (s, 3H), 3.61 - 3.36 (m, 1H), 3.26 - 3.10 (m, 1H), 2.99 - 2.88 (m, 2H), 2.78 (s, 2H), 1.57 - 1.41 (m, 6H), 1.25 (d, J = 5.8 Hz, 3H), 0.90 (t, J = 6.7 Hz, 3H) ppm. MS: M / e 520 (M+1) +

[0538] Compound A36: 2-(6-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-bis(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0539] Step A: 2,6-Dichloro-9-(methyl-d3)-9H-purine [ka]

[0540] To a stirred solution of 2,6-dichloro-9H-purine (3.78 g, 20 mmol) in DMF (30 mL) was added KCO (5.52 g, 40 mmol), followed by CDI (4.35 g, 30 mmol). After the addition, the reaction mixture was stirred overnight. The reaction mixture was treated with HO (50 mL) and extracted with CHCl (50 mL × 3). The combined organic layers were washed with brine, dried over NaSO, concentrated, and purified by flash column chromatography to give the title compound (2.52 g, 61%). MS: M / e 206 (M+1)+ .

[0541] Step B: tert-Butyl (2R,5S)-4-(2-chloro-9-(methyl-d3)-9H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0542] A mixture of 2,6-dichloro-9-(methyl-d3)-9H-purine (2.52 g, 12.2 mmol), (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (2.61 g, 12.2 mmol), and DIPEA (2.37 g, 18.3 mmol) in n-BuOH (25 mL) was stirred for 3 days. The reaction mixture was concentrated to give the title material (4.3 g, 92%). MS: M / e 384 (M+1). + .

[0543] Step C: tert-Butyl (2R,5S)-4-(2-hydroxy-9-(methyl-d3)-9H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0544] To a stirred solution of tert-butyl (2R,5S)-4-(2-chloro-9-(methyl-d3)-9H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (3.51 g, 9.2 mmol) in dioxane (50 mL), Pd2(dba)3 (390 mg, 0.92 mmol), t-BuXPhos (390 mg, 0.92 mmol), and aqueous KOH (1.55 g, 27.6 mmol in 5 mL of HO) were added. After the addition, the reaction mixture was stirred at 100 °C under N2 for 3 h. The mixture was poured into HO (100 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were discarded, and the aqueous layer was acidified with aqueous citric acid to pH = 3–4 and then extracted with CHCl2 (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the title compound (4.15 g, 100%). MS: M / e 366 (M+1) + .

[0545] Step D: tert-Butyl (2R,5S)-4-(3,9-bis(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0546] To a stirred mixture of tert-butyl (2R,5S)-4-(2-hydroxy-9-(methyl-d3)-9H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (2 g, 5.46 mmol) in dioxane (50 mL), Cs2CO3 (5.3 g, 16.38 mmol) was added, followed by CD3I (1.58 g, 10.9 mmol). The mixture was then stirred in a sealed tube at 80 °C overnight. The mixture was poured into H2O (150 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (1 g, 48%). MS: M / e 383 (M+1) + .

[0547] Step E: tert-butyl (2R,5S)-4-(8-formyl-3,9-bis(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0548] To a stirred solution of tert-butyl (2R,5S)-4-(3,9-bis(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (500 mg, 1.3 mmol) in THF (10 mL) was added dropwise at −78° C. After stirring for 1 h, DMF (379 mg, 5.2 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 1 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, concentrated, and used directly in the next step without further purification. MS: M / e 411 (M+1) + .

[0549] Step F: tert-Butyl (2R,5S)-4-(8-(hydroxymethyl)-3,9-bis(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0550] To a stirred solution of tert-butyl (2R,5S)-4-(8-formyl-3,9-bis(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (crude, 1.3 mmol) in MeOH (15 mL) was added NaBH4 (74.1 mg, 1.96 mmol), followed by stirring for 10 min. The reaction mixture was poured into HO (30 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by flash column chromatography to give the title compound (240 mg, 45%). MS: M / e 413 (M+1) + .

[0551] Step G: tert-butyl (2R,5S)-4-(8-(chloromethyl)-3,9-bis(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0552] To a stirred solution of tert-butyl (2R,5S)-4-(8-(hydroxymethyl)-3,9-bis(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (240 mg, 0.58 mmol) in CHCl (10 mL) was added SOCl (138 mg, 1.16 mmol). The reaction mixture was then stirred for 10 minutes. The reaction mixture was concentrated to give the title compound, which was used directly in the next step. MS: M / e 431 (M+1). +

[0553] Step H: tert-Butyl (2R,5S)-4-(8-(cyanomethyl)-3,9-bis(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0554] To a stirred solution of tert-butyl (2R,5S)-4-(8-(chloromethyl)-3,9-bis(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (crude, 0.58 mmol) in CHCl (10 mL) was added TBAF (1.0 M, 2.32 mL, 2.32 mmol), followed by TMSCN (232 mg, 2.32 mmol). After the addition, the reaction mixture was stirred for 5 h. The reaction mixture was poured into HO (30 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine, dried over NaSO, concentrated, and purified by flash column chromatography to give the title compound (crude, 100%). MS: M / e 422 (M+1) +

[0555] Step I: 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,9-bis(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0556] To a stirred solution of tert-butyl (2R,5S)-4-(8-(cyanomethyl)-3,9-bis(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (crude, 0.58 mmol) in CHCl (10 mL) was added TFA (2 mL). After the addition, the reaction mixture was stirred for 1 h. The reaction mixture was concentrated to give a residue, which was treated with EtOAc / H0 (20 mL / 20 mL) to extract most of the TBAF, and the organic layer was discarded. The aqueous layer was basified with aqueous NaCO to pH = 10-12 and extracted with CHCl / IPA (3 / 1, 10 mL × 4). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound (120 mg, 64%). MS: M / e 322 (M+1) +

[0557] Step J: 2-(6-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-bis(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0558] A mixture of 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,9-bis(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (32.1 mg, 0.1 mmol), 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol (41.6 mg, 0.2 mmol), (cyanomethyl)trimethylphosphonium iodide (73 mg, 0.3 mmol), and DIPEA (129 mg, 1 mmol) in CH3CN (4 mL) was stirred in a sealed tube at 100 °C overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with HO, brine, dried over Na2SO4, and concentrated to give a residue, which was purified by pre-TLC (CHCl2 / MeOH=10:1) to give the title compound (15 mg). 1 H NMR (400 MHz, CD3OD) δ 8.14 - 8.02 (m, 1H), 7.46 - 7.34 (m, 2H), 6.24 - 5.01 (m, 2H), 4.29 - 4.15 (m, 2H), 4.10 - 3.41 (m, 3H), 2.99 - 2.62 (m, 3H), 1.57 - 1.46 (m, 1.5H), 1.34 - 1.21 (m, 4.5H), 1.07-1.04 (m, 1.5H), 0.93 - 0.86 (m, 1.5H) ppm. MS: M / e 512 (M+1) + .

[0559] Compound A37: 2-(6-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-9-(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0560] Step A: tert-butyl (2R,5S)-2,5-dimethyl-4-(3-methyl-9-(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)piperazine-1-carboxylate [ka]

[0561] To a stirred mixture of tert-butyl (2R,5S)-4-(2-hydroxy-9-(methyl-d3)-9H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (2 g, 5.46 mmol) in dioxane (50 mL), Cs2CO3 (5.3 g, 16.38 mmol) was added, followed by MeI (1.54 g, 10.9 mmol). The mixture was then stirred in a sealed tube at 80 °C overnight. The mixture was poured into HO (150 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (860 mg, 41%). MS: M / e 380 (M+1) + .

[0562] Step B: tert-butyl (2R,5S)-4-(8-formyl-3-methyl-9-(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0563] To a stirred solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(3-methyl-9-(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)piperazine-1-carboxylate (860 mg, 2.25 mmol) in THF (15 mL) was added dropwise at −78° C. After stirring for 1 h, DMF (657 mg, 9 mmol) was added and the mixture was stirred for 1 h. The mixture was quenched with aqueous NH4Cl and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was used directly in the next step without further purification. MS: M / e 408 (M+1) + .

[0564] Step C: tert-butyl (2R,5S)-4-(8-(hydroxymethyl)-3-methyl-9-(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0565] To a stirred solution of tert-butyl (2R,5S)-4-(8-formyl-3-methyl-9-(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (crude, 2.25 mmol) in MeOH (15 mL) was added NaBH4 (128 mg, 3.37 mmol), followed by stirring for 10 min. The reaction mixture was poured into HO (30 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by flash column chromatography to give the title compound (420 mg, 45%) as a white solid. MS: M / e 410 (M+1) + .

[0566] Step D: tert-Butyl (2R,5S)-4-(8-(chloromethyl)-3-methyl-9-(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0567] To a stirred solution of tert-butyl (2R,5S)-4-(8-(hydroxymethyl)-3-methyl-9-(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (420 mg, 1.02 mmol) in CHCl (10 mL) was added SOCl (243 mg, 2.04 mmol). The reaction mixture was then stirred for 10 minutes. The reaction mixture was concentrated to give the title compound, which was used directly in the next step. MS: M / e 428 (M+1). +

[0568] Step E: tert-butyl (2R,5S)-4-(8-(cyanomethyl)-3-methyl-9-(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0569] To a stirred solution of tert-butyl (2R,5S)-4-(8-(chloromethyl)-3-methyl-9-(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (crude, 1.02 mmol) in CHCl (15 mL) was added TBAF (1.0 M, 4 mL, 4.08 mmol), followed by TMSCN (408 mg, 4.08 mmol). After the addition, the reaction mixture was stirred for 4 h. The reaction mixture was poured into H0 (30 mL) and extracted with EtOAc (15 mL × 3). 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 (240 mg, 56%). MS: M / e 419 (M+1) +

[0570] Step F: 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-methyl-9-(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0571] To a stirred solution of tert-butyl (2R,5S)-4-(8-(cyanomethyl)-3-methyl-9-(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (240 mg, 0.57 mmol) in CHCl (10 mL) was added TFA (2 mL). After the addition, the reaction mixture was stirred for 1 h. The reaction mixture was concentrated to give a residue, which was basified with aqueous NaCO to pH = 10-12 and extracted with CHCl / IPA (3 / 1, 30 mL × 4). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound (120 mg, 66%). MS: M / e 319 (M+1) +

[0572] Step G: 2-(6-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-9-(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0573] A mixture of 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-methyl-9-(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (31.8 mg, 0.1 mmol), 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol (41.6 mg, 0.2 mmol), (cyanomethyl)trimethylphosphonium iodide (73 mg, 0.3 mmol), and DIPEA (129 mg, 1 mmol) in CH3CN (4 mL) was stirred in a sealed tube at 100 °C overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with HO, brine, dried over Na2SO4, and concentrated to give a residue, which was purified by pre-TLC (EtOAc, then CHCl2 / MeOH = 10:1) to give the title compound (5 mg). 1 H NMR (400 MHz, CD3OD) δ 8.12 - 8.03 (m, 1H), 7.46 - 7.36 (m, 2H), 6.23 - 5.00 (m, 2H), 4.25 - 4.15 (m, 2H), 4.10 - 3.85 (m, 1H), 3.78 MS: M / e 509 (M+1) + .

[0574] Compound A41: 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0575] Step A: 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0576] To a solution of 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (100 mg, 0.31 mmol) in CHCN (2 mL) was added 1-(3-(trifluoromethyl)phenyl)ethan-1-ol (180 mg, 0.95 mmol), (cyanomethyl)trimethylphosphonium iodide (308 mg, 1.27 mmol), and DIPEA (0.4 g, 3.1 mmol). The resulting mixture was stirred at 105° C. overnight. The reaction solvent was removed under reduced pressure and purified by preparative TLC (DCM / MeOH=30 / 1) to give the title compound (crude), which was further purified by preparative HPLC (Method A) to give the title compound (20 mg). 1H NMR (400 MHz, CD3OD) δ 7.78 - 7.46 (m, 4H), 6.01 - 4.95 (m, 2H), 4.21 (s, 2H), 3.93 (s, 3H), 3.78 (s, 3H), 3.74 - 3.45 (m, 2H), 3.05 - 2.75 (m, 2H), 2.73 - 2.03 (m, 1H), 1.98 - 1.21 (m, 6H), 1.15 - 0.83 (m, 3H) ppm. MS: M / e 488 (M+1) + .

[0577] Compound A42: 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0578] To a solution of 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (300 mg, 0.9 mmol) in CH3CN (8 mL) was added 1-(3-(trifluoromethyl)phenyl)ethan-1-ol (520 mg, 2.7 mmol), (cyanomethyl)trimethylphosphonium iodide (875 mg, 3.6 mmol), and DIPEA (1.16 g, 9 mmol). The resulting mixture was stirred at 105 °C overnight. The reaction solvent was removed under reduced pressure and purified by preparative TLC (DCM / MeOH = 30 / 1) to give the title compound A42, which was further separated into compound A42a (68.23 mg) and compound A42b (76.15 mg) by chiral preparative HPLC. The chiral separation conditions are shown below.

[0579] [Table 6]

[0580]

[0581] Compound A42: 1 H NMR (400 MHz, CD3OD) δ 7.78 - 7.60 (m, 2H), 7.60 - 7.46 (m, 2H), 6.25 - 5.52 (m, 1H), 5.43 - 5.01 (m, 0.5H), 4.73 - 4.62 (m, 0.5H), 4.37 (q, J = 7.0 Hz, 2H), 4.23 (s, 2H), 3.85 - 3.72 (m, 4H), 3.67 - 3.40 (m, 1.5H), 2.94 - 2.54 (m, 2H), 2.13 (d, J = 12.2 Hz, 0.5H), 1.46 (t, J = 6.9 Hz, 4.5H), 1.39 - 1.31 (m, 3H), 1.26 (d, J = 5.2 Hz, 1.5H), 1.06 (d, J = 6.3 Hz, 1.5H), 0.92 (d, J = 6.4 Hz, 1.5H) ppm. MS: M / e 502 (M+1) +

[0582] Compound A42a (earlier peak): 1 H NMR (400 MHz, CD3OD) δ 7.73 - 7.63 (m, 2H), 7.60 - 7.49 (m, 2H), 6.35 - 4.51 (m, 2H), 4.37 (d, J = 7.1 Hz, 2H), 4.22 (s, 2H), 3.76 (s, 3H), 3.73 (s, 1H), 3.65 - 3.36 (m, 1H), 2.85 (d, J = 20.8 Hz, 3H), 1.52 - 1.40 (m, 6H), 1.33 (d, J = 6.5 Hz, 3H), 0.91 (d, J = 6.4 Hz, 3H) ppm. MS: M / e 502 (M+1) + .

[0583] Compound A42b (later peak): 1H NMR (400 MHz, CD3OD) δ 7.75 (s, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.60 - 7.47 (m, 2H), 6.05- 4.95 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 4.23 (s, 2H), 3.76 (s, 3H), 3.56 (dd, J = 30.0, 23.5 Hz, 3H), 2.68 (s, 1H), 2.13 (d, J = 12.1 Hz, 1H), 1.46 (t, J = 7.2 Hz, 3H), 1.35 (d, J = 6.5 Hz, 3H), 1.27 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H) ppm. MS: M / e 502 (M+1) + .

[0584] Compound A43: 2-(9-ethyl-6-((2S,5R)-4-(1-(3-isopropoxyphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile. [ka]

[0585] Step A: 1-(3-isopropoxyphenyl)ethan-1-ol [ka]

[0586] A solution of 3-isopropoxybenzaldehyde (500 mg, 3.045 mmol) in THF (30 mL) was degassed three times under N2 atmosphere. Then, CH3MgBr (2 mL, 3 M, 6.09 mmol) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 4 h, diluted with saturated NH4Cl, extracted with EtOAc (150 mL × 2), washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (PE:EtOAc = 4:1) to give the title compound (500 mg, 91%). 1 H NMR (400 MHz, CDCl3) δ 7.29-7.21 (m, 1H), 6.92 (d, J = 6.7 Hz, 2H), 6.85-6.73 (m, 1H), 4.86 (q, J = 6.4 Hz, 1H), 4.57 (dt, J = 12.1, 6.0 Hz, 1H), 1.79 (s, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.34 (d, J = 6.1 Hz, 6H) ppm.

[0587] Step B: 2-(9-ethyl-6-((2S,5R)-4-(1-(3-isopropoxyphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile. [ka]

[0588] 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (120 mg, 0.365 mmol), 1-(3-isopropoxyphenyl)ethan-1-ol (197 mg, 1.094 mmol), (cyanomethyl)trimethylphosphonium iodide (177 mg, 0.730 mmol), and DIPEA (141 mg, 1.094 mol) were dissolved in CH3CN (2 mL). The mixture was degassed three times under N2 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) and preparative HPLC (Method A) to give the title compound (58 mg, 32%). 1 H NMR (400 MHz, CD3OD) δ 7.26-7.14 (m, 1H), 6.93 (dd, J = 19.2, 6.1 Hz, 2H), 6.79 (t, J = 9.2 Hz, 1H), 6.23-5.53 (m, 1H), 5.26-5.01 (m, 0.5H), 4.85-4.71 (m, 0.5H), 4.59 (dd, J = 11.9, 6.0 Hz, 1H), 4.37 (q, J = 6.9 Hz, 2H), 4.22 (s, 1H), 3.76 (s, 3H), 3.61 (s, 1H), 3.48 (s, 2H), 3.10-2.58 (m, MS: M / e 492 (M+1) +

[0589] Compound A44: 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-(trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0590] To a solution of 1-(3-(trifluoromethoxy)phenyl)ethan-1-ol (60 mg, 0.29 mmol), 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (60 mg, 0.19 mmol), and (cyanomethyl)trimethylphosphonium iodide (68 mg, 0.28 mmol) in CH3CN (5 mL) was added DIPEA (116 mg, 0.9 mmol). The mixture was sealed in a bottle and heated at 100 °C for 16 h. The mixture was cooled to room temperature, diluted with water, extracted with EtOAc (10 mL × 2), washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM:MeOH=15:1) to give the title compound (19 mg, 19%). 1 H NMR (400 MHz, CD3OD) δ 7.45 - 7.34 (m, 3H), 7.17 - 7.12 (m, 1H), 5.97 - 5.91 (m, 1H), 5.31 - 5.24 (m, 1H), 4.38 - 4.34 (m, 2H), 4.22 (s, 2H), 3.76 (s, 3H), 3.59 - 3.48 (m, 2H), 2.88 - 2.84 (m, 2H), 2.70 - 2.66 (m, 0.5H), 2.18 - 2.15 (m, 0.5H), 1.49 - 1.44 (m, 4H), 1.35 - 1.29 (m, 4H), 1.06 - 1.02 (m, 2H), 0.92 - 0.90 (m, 2H) ppm. MS: M / e 518 (M+1) + .

[0591] Compound A48: 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0592] 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (50 mg, 0.117 mol), 1-(quinoxalin-6-yl)ethan-1-ol (41 mg, 0.233 mol), (cyanomethyl)trimethylphosphonium iodide (57 mg, 0.233 mol), and DIPEA (45 mg, 0.351 mol) were dissolved in CH3CN (2 mL). The mixture was degassed three times under N2 atmosphere. The mixture was then stirred at 105 °C for 24 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (7 mg, 13%). 1 H NMR (400 MHz, CD3OD) 8.87 (t, J = 3.3 Hz, 2H), 8.13-8.02 (m, 3H), 5.90-4.65 (m, 2H), 4.26-4.15 (m, 2H), 4.00-3.96 (m, 1H), 3.94 (s, 3H), 3.78 (s, 3H), 3.68-3.49 (m, 1H), 3.15-2.00 (m, 3H), 1.54-1.49 (m, 1.5H), 1.44 (dd, J = 12.1, 6.5 Hz, 3H), 1.31-1.27 (m, 1.5H), 1.11 (d, J = 6.5 Hz, 1.5H), 0.96 (d, J = 6.3 Hz, 1.5H) ppm. MS: M / e 472(M+1) + .

[0593] Compound A49: 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0594] 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (315 mg, 1 mol), 1-(3-methylquinoxalin-6-yl)ethan-1-ol (376 mg, 2 mol), (cyanomethyl)trimethylphosphonium iodide (486 mg, 2 mol), and DIPEA (387 mg, 3 mol) were dissolved in CH3CN (3 mL). The mixture was degassed three times under N2 atmosphere. The mixture was then stirred at 105 °C for 24 hours. 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 A49 (80 mg), which was further separated by preparative HPLC (Method A) into compound A49a (32 mg) and compound A49b (35 mg).

[0595] Compound A49: 1 H NMR (400 MHz, CD3OD) δ 8.79 (d, J = 4.7 Hz, 1H), 8.09-7.90 (m, 3H), 6.27-4.55 (m, 2H), 4.20 (s, 2H), 3.96-3.86 (m, 4H), 3.78 (s, 3H), 3.76-3.60 (m, 2H),, 2.97-2.87 (m, 1.5H), 2.77 (d, J = 1.6 Hz, 3H), 2.20 (d, J = 11.5 Hz, 0.5H), 1.45-1.39 (m, 3H), 1.36-1.22 (m, 3H), 1.10-0.94 (m, 3H) ppm. MS: M / e 486(M+1) + .

[0596] Compound A49a (early peak): 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.98 (s, 1H), 7.93 (dd, J = 8.7, 1.6 Hz, 1H), 6.29-5.16 (m, 2H), 4.58 (s, 1H), 4.30-4.16 (m, 2H), 3.96-3.89 (m, 4H), 3.79 (s, 3H), 3,00-2.85 (m, 3H), 2.77 (s, 3H), 1.50 (s, 3H), 1.41 (t, J = 8.9 Hz, 3H), 0.94 (t, J = 8.4 Hz, 3H) ppm. MS: M / e 486(M+1) + .

[0597] Compound A49b (slow peak): 1 H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.96 (s, 1H), 7.92 (dd, J = 8.7, 1.6 Hz, 1H), 5.96-5.68 (m, 1H), 5.08-4.92 (m, 1H), 4.58 (s, 1H), 4.20 (s, 2H), 3.94 (s, 3H), 3.80-3.73 (m, 4H), 3.67-3.61 (m, 1H), 2.79-2.73 (m, 4H), 2.20 (d, J = 11.5 Hz, 1H), 1.45 (d, J = 6.5 MS: M / e 486(M+1) + .

[0598] Compound A50: 2-(6-((2S,5R)-5-ethyl-2-methyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0599] Step A: tert-butyl (2S,5R)-5-ethyl-2-methyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazine-1-carboxylate [ka]

[0600] A solution of 1-(3-methylquinoxalin-6-yl)ethan-1-ol (500 mg, 2.66 mmol), tert-butyl (2S,5R)-5-ethyl-2-methylpiperazine-1-carboxylate (758 mg, 3.32 mmol), (cyanomethyl)trimethylphosphonium iodide (1.29 g, 5.31 mmol), and DIPEA (2.74 g, 21.24 mmol) in MeCN (6 mL) was stirred at 100 °C overnight. The reaction was diluted with EtOAc (20 mL) and washed with brine (10 mL). The organic layer was concentrated to dryness. The resulting residue was purified by flash column chromatography using 0-20% EtOAc in PE to give the title product (1 g, 94%). MS: M / e 399 (M+1). + .

[0601] Step B: 7-(1-((2R,5S)-2-ethyl-5-methylpiperazin-1-yl)ethyl)-2-methylquinoxaline [ka]

[0602] A solution of tert-butyl (2S,5R)-5-ethyl-2-methyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazine-1-carboxylate (1 g, 2.51 mmol) and TFA (4 mL) in DCM (16 mL) was stirred at room temperature for 60 minutes. The reaction was concentrated under reduced pressure. The residue was diluted with EtOAc (20 mL) and washed with aqueous NaHCO (10 mL x 2). The organic layer was dried over NaSO and concentrated to dryness. The resulting residue was purified by flash column chromatography using 0-5% MeOH in DCM to give the title compound product (745 mg, 100%). MS: M / e 299 (M+1)+.

[0603] Step C: 8-((benzyloxy)methyl)-6-((2S,5R)-5-ethyl-2-methyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one [ka]

[0604] A solution of 7-(1-((2R,5S)-2-ethyl-5-methylpiperazin-1-yl)ethyl)-2-methylquinoxaline (645 mg, 2.16 mmol), 8-((benzyloxy)methyl)-6-hydroxy-3,9-dimethyl-3,9-dihydro-2H-purin-2-one (649 mg, 2.16 mmol), BOP (1.44 g, 3.25 mmol), and DBU (993 mg, 6.49 mmol) in CHCN (15 mL) was stirred at room temperature for 24 h. The reaction was concentrated to dryness. The resulting residue was diluted with EtOAc (20 mL) and washed with brine (10 mL). The organic layer was dried over NaSO and concentrated. The residue was purified by flash column chromatography using 0 to 10% MeOH in DCM to give the title compound (crude), which was used directly in the next step without further purification. MS: M / e 581 (M+1) + .

[0605] Step D: 6-((2S,5R)-5-ethyl-2-methyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-8-(hydroxymethyl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one [ka]

[0606] A solution of 8-((benzyloxy)methyl)-6-((2S,5R)-5-ethyl-2-methyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one (crude) in TFA (20 ml) was stirred at 66 °C for 2 days. The solution was concentrated to dryness. The residue was diluted with EtOAc (20 ml), washed with aqueous NaHCO (10 ml × 2) and brine (10 ml), dried over NaSO, and concentrated. The resulting residue was purified by flash column chromatography using 0-15% MeOH in DCM to give the title compound (580 mg) as an off-white solid. MS: M / e 491 (M+1) + .

[0607] Step E: 8-(chloromethyl)-6-((2S,5R)-5-ethyl-2-methyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one [ka]

[0608] To a solution of 6-((2S,5R)-5-ethyl-2-methyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-8-(hydroxymethyl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one (580 mg, 1.18 mmol) in DCM (15 mL) at 0° C., SOCl (423 mg, 3.55 mmol) was added and stirred at 0° C. for 20 minutes. The reaction was washed with aqueous NaHCO (10 mL) and brine (10 mL), dried over NaSO, and concentrated to dryness to give the title compound (601 mg, 100%), which was used directly in the next step. MS: M / e 509 (M+1). + .

[0609] Step F: 2-(6-((2S,5R)-5-ethyl-2-methyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0610] A solution of 8-(chloromethyl)-6-((2S,5R)-5-ethyl-2-methyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one (601 mg, 1.18 mmol), TMSCN (351 mg, 3.55 mmol), and CsCO (1.15 g, 3.53 mmol) in MeCN (15 mL) was stirred at 66 °C for 60 min. The reaction mixture was poured into water (15 mL) and then extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (10 mL), dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography using 0-10% MeOH in DCM to give the title compound A50, which was separated into compound A50a (40 mg) and compound A50b (60 mg) by chiral preparative HPLC. The chiral separation conditions are shown below.

[0611]

Table 7

[0612]

[0613] Compound A50a (early peak): 1 H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.92 (s, 1H), 7.85 (d, J = 8.6 Hz, 1H), 5.97 (s, 0.5H), 5.70 (d, J = 14.0 Hz, 0.5H), 5.05 (s, 0.5H), 4.64 (d, J = 14.0 Hz, 0.5H), 4.36 (d, J = 33.8 Hz, 2H), 3.98 (q, J = 6.5 Hz, 1H), 3.82 (d, J = 23.8 Hz, 3H), 3.64 (s, 3H), 3.31 (s, 0.5H), 3.00 (s, 0.5H), 2.82 (d, J = 25.2 Hz, 2H), 2.70 (s, 3H), 2.34 (s, 1H), 1.56 - 1.47 (m, 1H), 1.45 - 1.39 (m, 1H), 1.38 - 1.30 (m, 6H), 0.63 (t, J = 7.2 Hz, 3H) ppm. MS: M / e 500 (M+1) + .

[0614] Compound A50b (late peak): 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.95 (s, 1H), 7.86 (d, J = 8.6 Hz, 1H), 5.97 (d, J = 13.2 Hz, 0.5H), 5.73 (s, 0.5H), 4.98-4.80 (m, 1H), 4.37 (d, J = 37.3 Hz, 2H), 3.83 (s, 4H), 3.64 (s, 3H), 3.59 (s, 0.5H), 3.32-3.19 (m, 0.5H), 3.11 (s, 1H), 2.70 (s, 3H), 2.55 (d, J = 9.0 Hz, 1H), 2.16 (d, J = 11.8 Hz, 1H), 1.51-1.41 (m, 2H), 1.34 (d, J = 6.2 Hz, 3H), 1.21-1.10 (m, 3H), 0.99 (t, J = 9.2 Hz, 3H) ppm. MS: M / e 500 (M+1) + .

[0615] Compound A51: 2-(6-((2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0616] Step A: tert-butyl (2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazine-1-carboxylate [ka]

[0617] A solution of 1-(3-methylquinoxalin-6-yl)ethan-1-ol (500 mg, 2.66 mmol), tert-butyl (2S,5R)-2,5-diethylpiperazine-1-carboxylate (805 mg, 3.33 mmol), (cyanomethyl)trimethylphosphonium iodide (1.29 g, 5.31 mmol), and DIPEA (2.74 g, 21.24 mmol) in MeCN (6 mL) was stirred at 100 °C overnight. The reaction was diluted with EtOAc (20 mL) and washed with brine (10 mL). The organic layer was concentrated to dryness. The resulting residue was purified by flash column chromatography using 0-20% EtOAc in PE to give the title compound (1 g, 91%). MS: M / e 413 (M+1). + .

[0618] Step B: 7-(1-((2R,5S)-2,5-diethylpiperazin-1-yl)ethyl)-2-methylquinoxaline [ka]

[0619] A solution of tert-butyl (2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazine-1-carboxylate (1 g, 2.43 mmol) and TFA (4 mL) in DCM (16 mL) was stirred at room temperature for 30 minutes. The reaction was concentrated under reduced pressure. The residue was diluted with EtOAc (20 mL) and washed with aqueous NaHCO (10 mL × 2). The organic layer was dried over NaSO and concentrated to dryness. The resulting residue was purified by flash column chromatography using 0-5% MeOH in DCM to give the title compound (757 mg, 100%). MS: M / e 313 (M+1)+.

[0620] Step C: 8-((benzyloxy)methyl)-6-((2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one [ka]

[0621] A solution of 7-(1-((2R,5S)-2,5-diethylpiperazin-1-yl)ethyl)-2-methylquinoxaline (400 mg, 1.28 mmol), 8-((benzyloxy)methyl)-6-hydroxy-3,9-dimethyl-3,9-dihydro-2H-purin-2-one (423 mg, 1.41 mmol), BOP (737 mg, 1.67 mmol), and DBU (392 mg, 2.56 mmol) in MeCN (12 mL) was stirred at room temperature for 24 h and then at 50 °C overnight. The reaction was concentrated to dryness. The resulting residue was diluted with EtOAc (20 mL) and washed with brine (10 mL). The organic layer was dried over NaSO and concentrated. The residue was purified by flash column chromatography using 0 to 10% MeOH in DCM to give the title compound (crude), which was used directly in the next step without further purification. MS: M / e 595 (M+1) + .

[0622] Step D: 6-((2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-8-(hydroxymethyl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one [ka]

[0623] A solution of 8-((benzyloxy)methyl)-6-((2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one (crude) in TFA (10 mL) was stirred at 66 °C for 3 days. The solution was concentrated to dryness. The residue was diluted with EtOAc (20 mL), washed with aqueous NaHCO (10 mL × 2) and brine (10 mL), dried over NaSO, and concentrated. The resulting residue was purified by flash column chromatography using 0-15% MeOH in EtOAc to give the title compound (250 mg). MS: M / e 505 (M+1) + .

[0624] Step E: 8-(chloromethyl)-6-((2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one [ka]

[0625] To a solution of 6-((2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-8-(hydroxymethyl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one (250 mg, 0.50 mmol) in DCM (15 mL) at 0° C., SOCl (177 mg, 1.49 mmol) was added and stirred at 0° C. for 25 minutes. The reaction was washed with aqueous NaHCO (10 mL) and brine (10 mL), dried over NaSO, and concentrated to dryness to give the title compound (259 mg, 100%), which was used directly in the next step. MS: M / e 523 (M+1). + .

[0626] Step F: 2-(6-((2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0627] A solution of 8-(chloromethyl)-6-((2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one (259 mg, 0.50 mmol), TMSCN (148 mg, 1.49 mmol), and CsCO (485 mg, 1.49 mmol) in MeCN (10 mL) was stirred at 70 °C for 60 min. The reaction mixture was poured into water (15 mL) and then extracted with EtOAc (15 mL × 2). The organic layer was washed with brine (10 mL), dried over NaSO, and concentrated to dryness. The resulting residue was purified by preparative TLC using EtOAc:MeOH (13:1) to give the title compound A51, which was separated into compound A51a (21 mg) and compound A51b (31 mg) by chiral preparative HPLC. The chiral separation conditions are shown below.

[0628] [Table 8]

[0629]

[0630] Compound A51a (early peak): 11H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.91 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 5.85 (s, 0.5H), 5.74 (d, J = 13.0 Hz, 0.5H), 4.98 (s, 0.5H), 4.72 (d, J = 13.1 Hz, 0.5H), 4.40 (s, 1H), 4.31 (s, 1H), 3.97 (q, J = 6.1 Hz, 1H), 3.81 (d, J = 17.1 Hz, 3H), 3.63 (s, 3H), 3.30 - 3.28 (m, 0.5H), 2.94 (q, J = 22.9, 1.5H), 2.78 (d, J = 12.4 Hz, 0.5H), 2.70 (s, 3H), 2.67 (s, 0.5H), 2.32 (dd, J = 23.0, 11.0 Hz, 1H), 2.02 - 1.87 (m, 2H), 1.50 (s, 1H), 1.36 (d, J = 5.2 Hz, 3H), 1.33 - 1.26 (m, 1H), 0.87 (dt, J = 14.7, 7.3 Hz, 3H), 0.65 - 0.5 (m, 3H) ppm. MS: M / e 514 (M+1) + .

[0631] Compound A51b (slow peak): 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.93 (s, 1H), 7.85 (d, J = 8.6 Hz, 1H), 6.01 (d, J = 13.8 Hz, 0.5H), 5.57 (s, 0.5H), 4.98 (d, J = 12.5 Hz, 0.5H), 4.74 (s, 0.5H), 4.41 (s, 1H), 4.31 (s, 1H), 3.82 (d, J = 13.9 Hz, 4H), 3.64 (s, 3H), 3.55 (d, J = 13.5 Hz, 0.5H), 3.12 (dd, J = 20.6, 10.0 Hz, 1.5H), 2.70 (s, 3H), 2.59 (d, J = 8.9 Hz, 0.5H), 2.47 (s, 0.5H), 2.23 (d, J = 12.4 Hz, 1H), 1.84 - 1.64 (m, 2H), 1.44 (s, 2H), 1.33 (d, J = 5.6 Hz, 3H), 0.97 (s, 3H), 0.54 (t, J = 7.3 Hz, 3H) ppm. MS: M / e 514 (M+1) + .

[0632] Compound A52: 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0633] To a mixture of 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (165 mg, 0.5 mmol), 1-(3-methylquinoxalin-6-yl)ethan-1-ol (122.2 mg, 0.65 mmol), and (cyanomethyl)trimethylphosphonium iodide (243 mg, 1 mmol) in CHCN (5 mL) was added DIPEA (645 mg, 5 mmol). The mixture was stirred in a sealed tube at 100 °C overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with brine, dried over NaSO, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound A52 (65 mg), which was separated into compound A52a (23 mg) and compound A52b (28 mg) by chiral preparative HPLC. The chiral separation conditions are shown below.

[0634] [Table 9]

[0635]

[0636] Compound A52a (early peak): 1 H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.00 - 7.90 (m, 2H), 6.33 - 5.16 (m, 2H), 4.43-4.29 (m, 2H), 4.20 (s, 2H), 3.96-3.89 (m, 1H), 3.76 (s, 3H), 3.67-3.42 (m, 1H), 3.04-2.85 (m, 3H), 2.77 (s, 3H), 1.62 - 1.37 (m, 9H), 0.95 (d, J = 6.4 Hz, 3H) ppm. MS: M / e 500 (M+1) + .

[0637] Compound A52b (late peak): 1H NMR (400 MHz, CD3OD) δ 8.77 (s, 1H), 8.07 - 7.85 (m, 3H), 6.11 - 4.94 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 4.22 (s, 1H), 3.76 (s, 4H), 3.71 - 3.42 (m, 2H), 3.30-3.10 (m, 1H), 2.76 (s, 4H), 2.20 (d, J = 12 Hz, 1H), 1.54 - 1.36 (m, 6H), 1.37-1.22 (m, 3H), 1.10 (d, J = 6.4 Hz, 3H) ppm. MS: M / e 500 (M+1) + .

[0638] Compound A53: 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3-ethyl-9-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0639] Step A: tert-butyl (2R,5S)-4-(3-ethyl-9-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0640] To a mixture of tert-butyl (2R,5S)-2,5-dimethyl-4-(9-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)piperazine-1-carboxylate (5 g, 13.8 mmol) in 1,4-dioxane (700 mL) was added CsCO (22.5 g, 69 mmol) and CHCHI (10.7 g, 69 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was filtered. The filtrate was removed to dryness under reduced pressure. The crude product was purified by flash column chromatography to give the title compound (1.7 g, 31%). MS: M / e 391 (M+1) + .

[0641] Step B: tert-Butyl (2R,5S)-4-(3-ethyl-8-formyl-9-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0642] To a solution of tert-butyl (2R,5S)-4-(3-ethyl-9-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (1.7 g, 4.4 mmol) in THF (100 mL) was added LDA (6.1 mL, 2 M, 13.2 mmol) at temperatures below −60° C. The reaction was stirred at −65° C. for 1 hour, and then DMF (1.56 g, 22 mmol) was added at −78° C. The reaction was stirred at −60° C. for an additional 1 hour. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The crude product was concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM / MeOH) to give the title compound (1.2 g, 66%). MS: M / e 419 (M+1) + .

[0643] Step C: tert-Butyl (2R,5S)-4-(3-ethyl-8-(hydroxymethyl)-9-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0644] NaBH4 (106 mg, 2.38 mol) was added to a solution of tert-butyl (2R,5S)-4-(3-ethyl-8-formyl-9-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (1.2 g, 2.8 mmol) in MeOH (15 mL) at 0 °C for 5 minutes. The reaction mixture was quenched with water and extracted with DCM. The organic layer was purified by flash column chromatography (DCM / MeOH) to give the title compound (800 mg, 66%). MS: M / e 421 (M+1) + .

[0645] Step D: tert-Butyl (2R,5S)-4-(8-(chloromethyl)-3-ethyl-9-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0646] To a solution of SOCl (340 mg, 2.8 mmol) in DCM (400 mL) was added tert-butyl (2R,5S)-4-(3-ethyl-8-(hydroxymethyl)-9-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (800 mg, 1.9 mmol) at −10° C. The reaction was stirred at room temperature for 5 minutes. The reaction mixture was quenched with water and washed with water, saturated NaHCO, and saturated NaCl. The organic layer was dried over NaSO and used directly in the next step.

[0647] Step E: tert-butyl (2R,5S)-4-(8-(cyanomethyl)-3-ethyl-9-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0648] To a solution of tert-butyl (2R,5S)-4-(8-(chloromethyl)-3-ethyl-9-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate in DCM (40 mL) was added TMSCN (564 mg, 5.7 mmol) and TBAF (1 M, 5.7 mL, 5.7 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction solvent was washed with water, dried over Na2SO4, and removed in vacuo. The crude product was purified by flash column chromatography (DCM / MeOH) to give the title compound (500 mg, 61% for two steps). MS: M / e 430 (M+1) + .

[0649] Step F: 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-ethyl-9-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0650] To a solution of tert-butyl (2R,5S)-4-(8-(cyanomethyl)-3-ethyl-9-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazine-1-carboxylate (500 mg, 1.17 mmol) in DCM (10 mL) was added TFA (3 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction solvent was removed under vacuum. The crude product was dissolved in water and adjusted to pH=9 with saturated NaHCO3. The aqueous layer was extracted with (DCM / IPA=4 / 1) and lyophilized to give the title compound (400 mg, crude). MS: M / e 330 (M+1)+ .

[0651] Step G: 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3-ethyl-9-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0652] To a solution of 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-ethyl-9-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (200 mg, 0.6 mmol) in CHCN (5 mL) was added 1-(3-methylquinoxalin-6-yl)ethan-1-ol (339 mg, 1.8 mmol), (cyanomethyl)trimethylphosphonium iodide (583 mg, 2.4 mmol), and DIPEA (0.74 g, 6 mmol). The resulting mixture was stirred at 105 °C overnight. The reaction solvent was removed under reduced pressure and purified by preparative TLC (DCM:MeOH=30:1) to give the title compound A53 (50 mg), which was further separated into compound A53a (20 mg) and compound A53b (16 mg) by chiral preparative SFC. The chiral separation conditions are shown below.

[0653] [Table 10]

[0654]

[0655] Compound A53a (early peak): 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H), 8.01 - 7.86 (m, 2H), 6.20 - 5.14 (m, 2H), 4.25 - 4.10 (m, 4H), 3.89 (s, 4H), 3.55 (d, J = 61.5 Hz, 1H), 2.90 (d, J = 27.4 Hz, 3H), 2.77 (s, 3H), 1.50 (s, 3H), 1.44 - 1.29 (m, 6H), 0.95 (d, J = 6.3 Hz, 3H) ppm. MS: M / e 500 (M+1) + .

[0656] Compound A53b (slow peak): 1 H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.99 - 7.87 (m, 2H), 6.01 - 4.98 (m, 2H), 4.32 - 4.26 (m, 2H), 4.21 (s, 1H), 3.97 - 3.82 (m, 3H), 3.82 - 3.47 (m, 3H), 2.76 (s, 3H), 2.71 - 2.66 (m, 2H), 2.19 (d, J = 11.9 Hz, 1H), 1.47 - 1.41 (m, 3H), 1.36 (t, J = 7.0 Hz, 3H), 1.29 (s, 3H), 1.10 (d, J = 6.4 Hz, 3H) ppm. MS: M / e 500 (M+1) + .

[0657] Compound A54: 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-(trifluoromethyl)quinoxalin-6-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0658] Step A: 7-Bromo-2-(trifluoromethyl)quinoxaline [ka]

[0659] A solution of 3,3-dibromo-1,1,1-trifluoropropan-2-one (5.77 g, 21.386 mmol) and AcONa (8.44 g, 106.9 mmol) in CHOH (60 mL) and HO (60 mL) was stirred at 90 °C for 30 min. Then, 4-bromobenzene-1,2-diamine (2.0 g, 10.7 mmol) was added. The mixture was stirred at room temperature for 12 h. After filtration, the mixture was extracted with EtOAc (35 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (PE: EtOAc = 5:1) to give the crude compound (3.2 g). The crude product (1.6 g) was further purified by chiral preparative SFC to give the title compound (680 mg, MS: M / e 277 (M+1)). + ) and another regioisomer (620 mg, MS: M / e 277 (M+1) + The chiral separation conditions are as follows:

[0660] [Table 11]

[0661]

[0662] Step B: 1-(3-(trifluoromethyl)quinoxalin-6-yl)ethan-1-one [ka]

[0663] A solution of 6-bromo-2-(trifluoromethyl)quinoxaline (360 mg, 1.304 mmol), tributyl(1-ethoxyvinyl)stannane (942 mg, 2.609 mmol), and Pd(PPh)Cl (183 mg, 0.261 mmol) in toluene (20 mL) was stirred at 90 °C for 12 h under N. The reaction mixture was quenched with saturated aqueous NaHCO (30 mL), extracted with EtOAc (50 mL × 2), combined, washed with brine (30 mL × 2), dried, and concentrated to dryness. The resulting oil was diluted with THF (30 mL). HCl (3 mL, 4 M in 1,4-dioxane) was then added dropwise to the solution, and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (30 mL), treated with saturated aqueous NaHCO to pH 8, washed with brine (30 mL x 3), dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography (PE: EtOAc = 6:1) to give the title compound (300 mg, 96%). MS: M / e 241 (M+1). +

[0664] Step C: 1-(3-(trifluoromethyl)quinoxalin-6-yl)ethan-1-ol [ka]

[0665] To a solution of 1-(3-(trifluoromethyl)quinoxalin-6-yl)ethan-1-one (300 mg, 1.25 mmol) in CHOH (15 mL) was added NaBH (48 mg, 1.25 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NH Cl, extracted with EtOAc (35 mL x 2), washed with brine, dried over Na SO , filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (PE: EtOAc = 5:1) to give the title compound (290 mg, 96%). MS: M / e 243 (M+1) +

[0666] Step D: 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-(trifluoromethyl)quinoxalin-6-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0667] 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (70 mg, 0.213 mmol), 1-(3-(trifluoromethyl)quinoxalin-6-yl)ethan-1-ol (77 mg, 0.319 mmol), (cyanomethyl)trimethylphosphonium iodide (104 mg, 0.426 mmol), and DIPEA (82 mg, 0.639 mol) were dissolved in a CH3CN solution (1 mL). The mixture was degassed three times under N2 atmosphere. The mixture was then stirred at 100 °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 (56 mg, 48%). 1H NMR (400 MHz, CD3OD) δ 9.23 (d, J = 4.1 Hz, 1H), 8.27-8.12 (m, 3H), 6.25-5.56 (m, 1H), 5.32-5.01 (m, 0.5H), 4.78-4.56 (m, 0.5H), 4.37 (q, J = 7.1 Hz, 2H), 4.21 (s, 1H), 3.99 (q, J = 6.3 Hz, 0.5H), 3.84 (q, J = 6.3 Hz, 0.5H), 3.76 (s, 3H), 3.72-3.47 (m, 1H), 3.30 -3.17 (m, 1H), 3.06-2.65 (m, 2.5H), 2.19 (d, J = 12.1 Hz, 0.5H), 1.45 (dd, J = 13.2, 6.5 Hz, 7H), 1.28 (s, 2H), 1.12 (d, J = 6.4 Hz, 1.5H), 0.97 (d, J = 6.3 Hz, 1.5H) ppm. MS: M / e 554 (M+1) +

[0668] Compound A55: 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methylbenzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0669] To a solution of 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (100 mg, 0.3 mmol) in CHCN (2 mL) was added 1-(2-methylbenzo[d]thiazol-5-yl)ethan-1-ol (64 mg, 0.33 mmol), (cyanomethyl)trimethylphosphonium iodide (111 mg, 0.46 mmol), and DIPEA (156 mg, 1.2 mmol). The resulting mixture was stirred at 100° C. overnight. The reaction solvent was removed under reduced pressure. The resulting residue was purified by preparative TLC (DCM:MeOH=13:1) to give the title compound (36 mg, 24%). 1 H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 17.7 Hz, 1H), 7.77 (t, J = 8.6 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 5.75-4.95 (m, 2H), 4.30 (d, J = 7.3 Hz, 2H), 3.96 - 3.67 (m, 6H), 3.55 (d, J = 6.1 Hz, 2H), 2.84 (d, J = 3.1 Hz, 4H), 2.21-2.05 (m, 1H), 1.51 (d, J = 6.4 Hz, 4H), 1.38 - 1.22 (m, 5H), 1.06 - 0.84 (m, 3H) ppm. MS: M / e 460 (M+1) + .

[0670] Compound A56: 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methylbenzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0671] Step A: 1-(2-methylbenzo[d]thiazol-6-yl)ethan-1-ol [ka]

[0672] To a solution of 1-(2-methylbenzo[d]thiazol-6-yl)ethan-1-one (150 mg, 0.79 mmol) in MeOH (15 mL) was added NaBH (30 mg, 0.79 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over NaSO, and concentrated to give the title compound (130 mg, 86%). MS: M / e 194 (M+1) + .

[0673] Step B: 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methylbenzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0674] To a solution of 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (50 mg, 0.15 mmol) in CHCN (3 mL) was added 1-(2-methylbenzo[d]thiazol-6-yl)ethan-1-ol (29 mg, 0.15 mmol), (cyanomethyl)trimethylphosphonium iodide (110 mg, 0.46 mmol), and DIPEA (98 mg, 0.76 mmol). The resulting mixture was stirred at 105 °C overnight. The reaction solvent was removed under reduced pressure to dryness. The resulting residue was purified by preparative HPLC (Method A) to give the title compound A56a (26 mg) and compound A56b (24 mg).

[0675] Compound A56a (early peak): 1H NMR (400 MHz, CD3OD) δ 7.92 (s, 2H), 7.62 (s, 1H), 6.38 - 4.98 (m, 2H), 4.37 (d, J = 7.2 Hz, 2H), 4.24 (s, 2H), 4.11 - 3.83 (m, 1H), 3.77 (s, 3H), 3.73 - 3.32 (m, 2H), 3.29 - 3.05 (m, 2H), 2.84 (s, 3H), 1.93 - 1.41 (m, 6H), 1.40 - 1.04 (m, 6H) ppm. MS: M / e 505 (M+1) +

[0676] Compound A56b (slow peak): 1 H NMR (400 MHz, CD3OD) δ 8.41 - 7.83 (m, 2H), 7.81 - 7.52 (m, 1H), 6.74 - 5.95 (m, 1H), 5.95 - 5.17 (m, 1H), 4.84 - 4.48 (m, 2H), 4.36 (s, 2H), 4.26 (s, 2H), 3.78 (s, 3H), 3.73 - 3.36 (m, 2H), 3.10 - 2.95 (m, 1H), 2.87 (s, 3H), 1.82 (s, 3H), 1.66 - 1.35 (m, 6H), 1.35 - 1.13 (m, 3H) ppm. MS: M / e 505 (M+1) +

[0677] Compound A57: 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methyl-1H-benzo[d]imidazol-5-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0678] Step A: Mixture of 6-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole and 5-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole [ka]

[0679] To a solution of 5-bromo-2-methyl-1H-benzo[d]imidazole (1.05 g, 5 mmol) in THF (20 mL) was added NaH (60%, 400 mg, 10 mmol) at 0 °C. After 30 min, a solution of (2-(chloromethoxy)ethyl)trimethylsilane (1 g, 6 mmol) in THF (5 mL) was added to the reaction, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with HO 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 flash column chromatography (DCM:MeOH=10:1) to give the title compound (1.5 g, 88%). MS: M / e 341 (M+1) + .

[0680] Step B: Mixture of 1-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)ethan-1-one and 1-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethan-1-one [ka]

[0681] A toluene solution (20 mL) of a mixture of 6-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole and 5-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (1.5 g, 4.4 mmol), tributyl(1-ethoxyvinyl)stannane (1.9 g, 5.3 mmol), and Pd(PPh)Cl (308 mg, 0.44 mmol) was stirred overnight at 100 °C under N. The reaction mixture was concentrated under reduced pressure. The residue was diluted with THF (20 mL), followed by the addition of TFA (1.5 mL) and stirring for 30 min. The resulting mixture was washed with saturated aqueous NaHCO, extracted with EtOAc, dried, and concentrated to dryness. The resulting oil was purified by flash column chromatography (DCM:MeOH=10:1) to give the title compounds (500 mg, 37%) as a mixture. MS: M / e 305 (M+1) + .

[0682] Step C: Mixture of 1-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)ethan-1-ol and 1-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethan-1-ol [ka]

[0683] To a mixture of 1-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)ethan-1-one and 1-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethan-1-one (200 mg, 0.67 mmol) in EtOH (4 mL) was added NaBH (25 mg, 0.67 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was treated with water and extracted with DCM. The combined organic layers were dried over MgSO and concentrated to dryness. The resulting residue (200 mg, crude) was used in the next step without further purification. MS: M / e 307 (M+1) + .

[0684] Step D: Mixture of 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile and 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0685] 1-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)ethan-1-ol and 1-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethan-1-ol (100 mg, 0.33 mmol), 2-(6-((2S,5R)-2,5-dimethyl A mixture of (2H-purin-8-yl)-3-(2 ... + .

[0686] Step E: 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methyl-1H-benzo[d]imidazol-5-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0687] 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile and 2-(6-((2S,5R)-2,5-di To a stirred mixture of methyl-4-(1-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (20 mg) in DCM (1 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (2 mg, 12%). 1 H NMR (400 MHz, CD3OD) δ 7.49-7.40 (m, 2H), 7.26 (t, J = 8.6 Hz, 1H), 5.90 (s, 2H), 4.37 (d, J = 7.0 Hz, 2H), 3.76 (s, 3H), 3.68-3.57 (m, 2H), 2.90 (s, 2H), 2.65 (s, 2H), 2.55 (d, J = 3.6 Hz, 3H), 2.25 (d, J = 12.0 Hz, 1H), 1.46 (t, J = 6.9 Hz, 4H), 1.37 (dd, J = 10.3, 6.5 Hz, 3H), 1.30-1.14 (m, 2H), 1.06-0.88 (m, 3H) ppm. MS: M / e 488 (M+1) + .

[0688] Compound A58: 2-(6-((2S,5R)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile [ka]

[0689] 2-(6-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-...

Claims

1. Formula (I) 【Chemical 651】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopically substituted or prodrug thereof. [In the formula, X １ is C or N, X ２ and X ３ are each independently selected from —N— or —CH—; X ４ is N, O or S, R １ is hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, 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 alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, with the proviso that X １ If N, then R ２ Provided that there is no R ４ is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, with the proviso that X ４ If is O or S, then R ４ Provided that there is no R ５ is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, 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)- or R ５ａ -SO ２ - and R ５ａ and R ５ｂ are each independently hydrogen, alkyl, or cycloalkyl; R ７ , R ９ , R ８ , and R １０ each independently represents hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted cycloalkyl, —C(O)R ７ａ or -alkyl-C(O)R ７ａ wherein R ７ａ is hydrogen, alkyl, or alkoxy, with the proviso that R ７ and R ９ at least one of which is not hydrogen; or R ７ and R ９ are each hydrogen, and R ８ and R １０ together form at least one -CH in addition to the two bridgehead atoms. ２ -forming a bridge containing a moiety, or R ８ and R １０ are each hydrogen, and R ７ and R ９ together form at least one -CH in addition to the two bridgehead atoms. ２ - provided that the bridge contains a moiety, L １ represents a direct bond, —O—, —N(R Ｌ )-, substituted or unsubstituted alkyl, -alkylene, or -C(O)-, and 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 1 to 5 substituents R ３ａ is replaced by R ３ａ is deuterium, alkoxy, alkyl, halogen, oxo, 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; Optionally, two R ３ａ are attached to the same carbon and together form a spirocyclic ring, Optionally, 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.

2. Formula (IA1), (IB1) or (IC1): 【Chemical 652】 and 2. The compound of claim 1, wherein the variables are as defined herein.

3. Formula (IA2), (IB2) or (IC2): 【Chemical 653】 and 2. The compound of claim 1, wherein the variables are as defined herein.

4. Formula (IA3), (IB3) or (IC3): 【Chemical 654】 and 2. The compound of claim 1, wherein the variables are as defined herein.

5. Formula (IA4), (IB4) or (IC4): 【Chemical Formula 655】 and 2. The compound of claim 1, wherein the variables are as defined herein.

6. Formula (II): 【Chemical 656】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopically substituted or prodrug thereof. [In the formula, X １ is C or N, X ４ is N, O or S, R １ is hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, 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 alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, with the proviso that X １ If N, then R ２ Provided that there is no R ４ is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, with the proviso that X ４ If is O or S, then R ４ Provided that there is no R ５ is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, 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)- or R ５ａ -SO ２ - and R ５ａ and R ５ｂ are each independently hydrogen, alkyl, or cycloalkyl; R ７ , and R ９ each independently represents hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted cycloalkyl, —C(O)R ７ａ or -alkyl-C(O)R ７ａ wherein R ７ａ is hydrogen, alkyl, or alkoxy, with the proviso that R ７ and R ９ at least one of which is not hydrogen; or R ７ and R ９ together form at least one -CH in addition to the two bridgehead atoms. ２ - provided that the bridge contains a moiety, L １ represents a direct bond, —O—, —N(R Ｌ )-, substituted or unsubstituted alkyl, -alkylene, or -C(O)-, and R Ｌ is hydrogen or alkyl, m is 0, 1, 2 or 3; n is 0 or 1; R ３ａ is deuterium, alkoxy, alkyl, halogen, oxo, 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; Optionally, two R ３ａ are attached to the same carbon and together form a spirocyclic ring, Optionally, 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 and each independently is hydrogen or alkyl.

7. R １ The compound of any one of claims 1 to 6, 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, halogen, hydroxy, alkoxy or cycloalkyl １－４ alkyl, and more preferably, R １ is hydrogen or C optionally substituted with deuterium １－３ alkyl or halogen, and even more preferably, R １ The compound of any one of claims 1 to 7, wherein is hydrogen, methyl, methyl-d3, ethyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, or cyclopropylmethyl.

9. R ２ But hydrogen, halogen, C １－４ Alkyl, C １－４ alkoxyl or cyano, preferably R ２ The compound of claim 8 , wherein is hydrogen, F, Br, Cl, or CN.

10. R ４ is hydrogen, halogen or alkyl, and the alkyl is deuterium, halogen or —OR ４ａ and optionally substituted with R ４ａ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl, and the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is -C １－６ Alkyl, -C １－６ Alkoxy or -C ３－８ Optionally substituted with cycloalkyl, preferably R ４ is hydrogen or C optionally substituted with deuterium １－３ alkyl or halogen, more preferably R ４ The compound according to any one of claims 1 to 9, wherein is hydrogen, fluoro, chloro, bromo, methyl, methyl-d3, trifluoromethyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, propyl, cyclopropyl.

11. R ５ is hydrogen, alkyl, alkenyl or alkynyl, said alkyl being unsubstituted or substituted with cyano, preferably R ５ But C １－４ Alkyl, C ２－４ alkenyl or C ２－４ Alkynyl, wherein the alkyl is substituted with cyano, more preferably R ５ But C １－４ The compound of any one of claims 1 to 10, wherein said alkyl is substituted with cyano.

12. 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 １－２ The compound of any one of claims 1 to 11, which is alkyl.

13. 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 and n is 0 or 1. The compound of claim 12, provided that at least one of is not hydrogen.

14. R ８ and R １０ are each hydrogen, and R ７ is methyl and R ９ is methyl or R ８ and R １０ are each hydrogen, and R ７ is ethyl and R ９ is ethyl or R ８ and R １０ are each hydrogen, and R ７ is methyl and R ９ is ethyl, or R ８ and R １０ are each hydrogen, and R ７ is ethyl and R ９ is methyl or R ８ and R １０ are each hydrogen, and R ７ is methoxymethyl, and R ９ The compound of any one of claims 1 to 13, wherein is methyl, ethyl or methoxymethyl.

15. L １ is a direct bond, —O—, —N(R Ｌ )-, -alkylene-, or -C(O)-, and R Ｌ is hydrogen or alkyl, and said -alkylene- is unsubstituted or substituted with deuterium, halogen, alkoxy, alkynyl or heterocyclyl, preferably L １ is a direct bond, —O—, —N(R Ｌ )-, -alkylene-, or -C(O)-, and R Ｌ is hydrogen or alkyl, preferably L １ But C １－４ Alkylene, preferably C １－２ alkylene, and more preferably, L １ is a direct bond, -CH ２ -, -CH(CH ３ ) -, -CH(CD ３ ) -, -CH(CH ２ CH ３ )-,-CH(CHF ２ )-, -CH(prop-1-ynyl)-, -N(H)-, -N(CH ３ )-, -O-, -CH(C(O)-NHCH ２ CH ２ OCH ３ ) - or -C(CH ３ ) ２ The compound according to any one of claims 1 to 14, wherein

16. Cy １ is aryl, heterocyclyl, heterocyclyl, heteroaryl, or cycloalkyl, each of which is unsubstituted or contains one, two, three, or four substituents R ３ａ is substituted with 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 -O-C(O)-, or heterocyclyl, wherein the alkyl group or the alkyl moiety within the alkoxy group is unsubstituted or substituted with halogen, alkoxy, hydroxy, or cyano, the cycloalkyl or the heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy, and R ３ｂ and R ３ｃ The compound according to any one of claims 1 to 5 and 7 to 15, wherein each is independently hydrogen or alkyl.

17. Cy １ is unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted heteroaryl, preferably Cy １ is one, two or three substituents R ３ａ and optionally substituted with R ３ａ deuterium, fluoro, bromo, chloro, 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, 17. The compound of claim 16, wherein the aryl group is 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.

18. Cy １ is aryl, which is unsubstituted or contains one, two or three substituents R ３ａ is substituted with R ３ａ is alkoxy, halogen-substituted alkoxy, alkoxyalkyl-, alkyl, alkenyl, 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 -OC(O)-, heterocyclylalkyl- or heterocyclyl, wherein said cycloalkyl or said heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy; R ３ｂ and R ３ｃ 17. The compound of claim 16, wherein each is independently hydrogen or alkyl.

19. Cy １ is phenyl, which is ３ａ is substituted with R ３ａ is fluoro, chloro, bromo; methyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, methoxymethyl, 1-methoxyethyl, ethyl, propyl, isopropyl, tert-butyl, 2-hydroxypropan-2-yl, 1-hydroxy-2-methylpropan-2-yl, 2-cyanopropan-2-yl, morpholinomethyl; prop-1-en-2-yl; cyclopropyl, 1-methylcyclopropyl; methoxy, difluoromethoxy, trifluoromethoxy, 1,1-difluoroethoxy, isopropoxy; oxetan-3-yl, morpholino, 2-oxa-6-azaspiro[3.3]heptan-6-yl; or methylcarbamoyl.

20. Cy １ is unsubstituted or contains one, two, three or four R ３ａ and R is a 5- to 9-membered monocyclic heterocyclyl or a 7- to 10-membered bicyclic heterocyclyl substituted with (provided that valence theory is satisfied), 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 -O-C(O)-, oxo, or heterocyclyl, wherein the alkyl group or the alkyl moiety within the alkoxy group is unsubstituted or substituted with halogen, alkoxy, hydroxy, or cyano, the cycloalkyl or the heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy, and R ３ｂ and R ３ｃ are each independently hydrogen or alkyl, preferably R ３ａ is 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 said heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy; R ３ｂ and R ３ｃ are each independently hydrogen or alkyl, and preferably said 5- to 9-membered monocyclic 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 and preferably Cy 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-dioxan-2-yl, 1,4-dioxan-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.

21. Cy １ is dihydrobenzodioxinyl, benzodioxolyl, chromanyl, or chromenyl, which is unsubstituted or substituted with one, two, three, or three R ３ａ is substituted with R ３ａ is selected from alkoxy, alkyl, halogen, and oxo, preferably Cy １ is 2,3-dihydrobenzo[b][1,4]dioxin-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, benzo[d][1,3]dioxol-4-yl, benzo[d][1,3]dioxol-5-yl, chroman-2-yl, chroman-3-yl, chroman-4-yl, chroman-5-yl, chroman-6-yl, chroman-7-yl, chromen-2-yl, chromen-3-yl, chromen-4-yl, chromen-5-yl, chromen-6-yl, chromen-7-yl, each of which is unsubstituted or substituted by one, two, three or three R ３ａ is substituted with R ３ａ is selected from alkoxy, alkyl, halogen, and oxo, preferably R ３ａ 17. The compound of claim 16, wherein is methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo or oxo.

22. Cy １ is a 5- to 9-membered monocyclic heteroaryl or a 7- to 10-membered bicyclic heteroaryl, which is unsubstituted or contains one, two, or three R ３ａ is substituted with 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 -O-C(O)-, oxo, phenyl, or heterocyclyl, wherein the alkyl group or the alkyl moiety within the alkoxy group is unsubstituted or substituted with halogen, alkoxy, hydroxy, or cyano, the cycloalkyl or the heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy, and 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, oxo, hydroxyalkyl-, cyano, cyano-substituted alkyl, N(R ３ｂ R ３ｃ )-C(O)-, N(R ３ｂ R ３ｃ ) -, R ３ｂ -O-C(O)-, oxo, phenyl or heterocyclyl, wherein said cycloalkyl or said 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, fluoro, bromo, chloro, methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, methoxy, methoxymethyl, methylsulfonyl, ethoxy, isopropoxy, isopropyl, tert-butyl, cyclopropyl, 1-hydroxyethyl, ethyl, 1,1-difluoroethyl, cyano, cyclopropyl-, acetamido, 1-methoxyethyl, cyanomethyl, carbamoyl, methoxycarbonyl, methylcarbamoyl, dimethylcarbamoyl, (difluoromethoxy)methyl, amino, isopropylamino, (difluoromethoxy)ethyl, azetidin-1-yl, 2-methoxypropan-2-yl, 1-methoxycyclopropyl, oxetan-3-yl, 1-methylazetidin-3-yl, 1-hydroxyazetidin-3-yl, phenyl, or oxo.

23. Cy １ is pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is unsubstituted or contains one, two, or three R ３ａ and preferably Cy １ is 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, thiazol-4-yl, thiazol-5-yl, 1H-pyrazol-5-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, pyrazin-2-yl, or pyridazin-4-yl, each of which is unsubstituted or contains one, two, or three R as disclosed herein. ３ａ and preferably R ３ａ is selected from deuterium, fluoro, bromo, chloro, methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, isopropoxy, isopropyl, tert-butyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, isopropylamino, azetidin-1-yl, phenyl, or oxo.

24. Cy １ is indolyl, triazolopyridinyl, imidazopyridinyl, benzoxazolyl, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, dioxinopyridinyl, quinoxalinyl, benzo[d]imidazolyl, benzofuranyl, benzoxazinyl, imidazo[4,5-b]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyridinyl, thieno[2,3-b]pyridinyl, dihydrodioxinopyridinyl, dioxinopyridinyl, dihydro-2H-pyranopyridinyl, 2H-pyranopyridinyl, dihydrofuropyridinyl, furopyridinyl, benzo[d]thiazolyl, isoindolinyl, or thieno[3,2-b]pyridinyl, each of which is unsubstituted or substituted with one, two, or three R ３ａ and preferably Cy １ quinoxalin-6-yl, quinoxalin-2-yl, isoquinolin-3-yl, isoquinolin-7-yl, quinolin-6-yl, 1H-benzo[d]imidazol-5-yl, benzofuran-6-yl, benzofuran-5-yl, benzo[e][1,3]oxazin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyrid ... benzo[d]thiazol-7-yl, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl, 2,3-dihydrofuro[2,3-b]pyridin-6-yl, 2,3-dihydrofuro[3,2-b]pyridin-5-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, isoindolin-5-yl, 1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-4-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-7-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-7-yl, isoquinolin-1-yl, isoquinolin-4-yl, isoquinolin-5- yl, isoquinolin-6-yl, isoquinolin-8-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-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, 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, 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. ３ａ 17. The compound of claim 16 substituted with:

25. Cy １ quinoxalin-6-yl, quinoxalin-2-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, isoindolin-4-yl, indolin-5-yl, 1H-benzo[d]imidazol-5-yl, benzofuran-6-yl, benzofuran-5-yl, or benzo[e][1,3]oxazin-6-yl, isoquinolin-3-yl, isoquinolin-7-yl, quinolin-6-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, 3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl, 2,3-dihydrofuro[2,3-b]pyridin-6-yl, 2,3-dihydrofuro[3,2-b]pyridin-5-yl, each of which is unsubstituted or substituted with 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, 2,2,2-trifluoroethyl, 2-fluoropropan-2-yl, methoxy, isopropoxy, difluoromethoxy, fluoro, chloro, bromo, oxo, cyano, amino, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl, or cyclobutyl, preferably deuterium, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, fluoro, chloro, cyano, amino, or cyclopropyl.

26. Cy １ but, - 4-fluoro-2-methoxyphenyl, p-tolyl, 4-fluoro-2-(trifluoromethyl)phenyl, 2-(difluoromethoxy)-4-fluorophenyl, 4-fluoro-2-(trifluoromethoxy)phenyl, 4-fluoro-2-(methoxymethyl)phenyl, 4-fluoro-2-(1-methoxyethyl)phenyl, 1-(difluoromethoxy-4-fluorophenyl, 2-(difluoromethyl)-4-fluorophenyl, 2-(1,1-difluoroethoxy)-4-fluorophenyl, 3- (trifluoromethyl)phenyl, 3-isopropoxyphenyl, 3-(trifluoromethoxy)phenyl, 3-isopropylphenyl, 3-(tert-butyl)phenyl, 3-(2-hydroxypropan-2-yl)phenyl, 3-(difluoromethyl)-4-fluorophenyl, 4-fluoro-3-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 4-methyl-3-(trifluoromethyl)phenyl, 4-methyl-2-(trifluoromethyl)phenyl, 3- Cyclopropylphenyl, 3-(1-methylcyclopropyl)phenyl, 3-(oxetan-3-yl)phenyl, 4-fluoro-3-(methylcarbamoyl)phenyl, 3-(1-hydroxy-2-methylpropan-2-yl)phenyl, 3-(2-cyanopropan-2-yl)phenyl, 4-fluoro-3-(prop-1-en-2-yl)phenyl, 4-fluoro-3-(1-methylcyclopropyl)phenyl, 3-methyl-4-(trifluoromethyl)phenyl, 4-(morpholinomethyl)phenyl , 3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl, 3-morpholinophenyl, 3-(morpholinomethyl)phenyl, 4-morpholinophenyl, 4-(trifluoromethyl)phenyl, 4-fluorophenyl, 3-methyl-2-(trifluoromethyl)phenyl, 3-(difluoromethyl)-5-fluorophenyl, 3-(1,1-difluoroethyl)-4-methoxyphenyl, m-tolyl, 3-methoxyphenyl, or 3-(difluoromethyl)phenyl; or 3,3-dimethyl-2,3-dihydro-1H-inden-5-yl, or 4,4-difluorochroman-6-yl, 2,2-dimethyl-4-oxochroman-7-yl, 3-methyl-4-oxo-4H-chromen-6-yl, 2,2-dimethylchroman-7-yl or 2-methyl-4-oxo-4H-chromen-7-yl, or - 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 8-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 7-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 5-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 8-chloro-3,3-dimethyl fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-difluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 7-fluoro-2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, or 7-chloro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl; - 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2-difluorobenzo[d][1,3]dioxol-5-yl, 2-ethyl-2-methylbenzo[d][1,3]dioxol-5-yl, spiro[benzo[d][1,3]dioxole-2,1'-cyclobutan]-5-yl, 6-chloro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 7-chloro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 4-chloro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 7-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 4-fluoro or 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 4,6-difluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2,7-trimethylbenzo[d][1,3]dioxol-5-yl, 7-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-4-yl, 2,2-dimethylbenzo[d][1,3]dioxol-4-yl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 4-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, or 2,2-dimethylbenzo[d][1,3]dioxol-5-yl; - 2-(trifluoromethyl)pyridin-3-yl, 6-isopropoxypyridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl, 2-(trifluoromethyl)pyridin-4-yl, 4-(trifluoromethyl)pyridin-2-yl, 2-(azetidin-1-yl)pyridin-4-yl, 2-(isopropylamino)pyridin-4-yl, 6-isopropylpyridin-2-yl, 2-isopropoxypyridin-4-yl, 6-(trifluoromethoxy)pyridin-2-yl, 2-(tert-butyl)pyridin-4-yl, 2-(methylcarbamoyl)pyridin-4-yl, 2 -(2,2-dimethylcarbamoyl)pyridin-4-yl, 5,6-dimethylpyridin-2-yl, 2-phenylpyridin-4-yl, 5-(difluoromethyl)pyridin-2-yl, 5-methylpyridin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, 2-methoxypyridin-4-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 1-methyl-2-oxo-1,2-dihydropyridin-4-yl, 2-(trifluoromethyl)thiazol-4-yl, or 1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl, or quinoxalin-6-yl, 3-methylquinoxalin-6-yl, 3-(trifluoromethyl)quinoxalin-6-yl, or quinoxalin-2-yl, or isoquinolin-3-yl, 2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl, 2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl, 1,2-dimethyl-4-oxo-1,4-dihydroquinolin-7-yl, 1,3-dimethyl-4-oxo-1,4-dihydroquinolin-6-yl or 2-methylquinolin-7-yl, or 2-methyl-1H-benzo[d]imidazol-5-yl, 2,2-dimethyl-2,3-dihydrobenzofuran-6-yl, 2,2-dimethyl-3-oxo-2,3-dihydrobenzofuran-6-yl, 3,3-dimethyl-2,3-dihydrobenzofuran-5-yl or 3-methyl-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl, - 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 4,4-difluoro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl, 4,4-difluoro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl, - 7-chloro-3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 7-fluoro-3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 8-fluoro-3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridin-6-yl, 3,3-dimethyl-2,3-dihydrofuro[3,2-b]pyridin-5-yl 2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl, 2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 3-methyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, or 3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl; 2-methylbenzo[d]thiazol-5-yl, 2-methylbenzo[d]thiazol-6-yl, 2-ethylbenzo[d]thiazol-5-yl, 2-isopropylbenzo[d]thiazol-5-yl or 2-(trifluoromethyl)thiazol-5-yl, or 17. The compound of claim 16, which is 2-methyl-1,3-dioxoisoindolin-5-yl, 2-isopropyl-1,3-dioxoisoindolin-5-yl, 1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl, 2,3,3-trimethyl-1-oxoisoindolin-5-yl, 2-methyl-3-oxoisoindolin-5-yl, or 2-methyl-1-oxoisoindolin-5-yl.

27. The part 【Chemical 657】 but, 【Chemical Formula 658】 wherein m is 0, 1, 2, or 3; R ３ａ The compound of claim 6 , wherein is alkoxy, alkyl, halogen, and oxo.

28. The part 【Chemistry 659】 is 2,2-dimethylbenzo[d][1,3]dioxol-5-yl or 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, where m is 0, 1, 2, or 3; R ３ａ 28. The compound of claim 27, wherein is alkoxy, alkyl, halogen, and oxo.

29. The part 【Chemical Formula 660】 However, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2-difluorobenzo[d][1,3]dioxol-5-yl, 2-ethyl-2-methylbenzo[d][1,3]dioxol-5-yl, spiro[benzo[d][1,3]dioxole-2,1'-cyclobutan]-5-yl, 6-chloro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 7-chloro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 4-chloro-2,2-dimethylbenzo[d][1,3 ]dioxol-5-yl, 7-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 4-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 4,6-difluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2,7-trimethylbenzo[d][1,3]dioxol-5-yl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 4-fluoro-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, 8-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 7-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 5-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 8-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, The compound of claim 27, which is tetrafluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-difluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 7-fluoro-2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, or 7-chloro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl.

30. The compound is 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A1), 2-(7-((2S,5R)-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A4), 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(p-tolyl)ethyl)piperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A5), 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)ethyl)piperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A6), 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(2-(trifluoromethyl)pyridin-3-yl)ethyl)piperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A7), 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A9), 2-(6-((2R,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A10), 2-(6-((2R,5R)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A11), 2-(6-((2R,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A12), 2-(6-((2R,5R)-2-(methoxymethyl)-5-methyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A13), 2-(6-fluoro-7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A14), 2-(6-fluoro-7-((2S,5R)-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A16), 2-(7-((2S,5R)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A18), 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A19), 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-ethyl-6-fluoro-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A20), 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-ethyl-6-fluoro-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A21), 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A22), 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A23), 2-(6-((2S,5R)-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A24), 2-(6-((2S,5R)-4-(1-(2-(difluoromethoxy)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A25), 2-(6-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethoxy)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A26), 2-(6-((2S,5R)-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A27), 2-(6-((2S,5R)-4-(1-(4-fluoro-2-(1-methoxyethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A28), 2-(6-((2S,5R)-4-(1-(2-(1-(difluoromethoxy)ethyl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A29), 2-(6-((2S,5R)-4-(1-(2-(difluoromethyl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A30), 2-(6-((2S,5R)-4-(1-(2-(1,1-difluoroethoxy)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A31), 2-(6-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A33), 2-(6-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A34), 2-(9-ethyl-6-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A35), 2-(6-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-bis(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A36), 2-(6-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-9-(methyl-d3)-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A37), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A41), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A42), 2-(9-ethyl-6-((2S,5R)-4-(1-(3-isopropoxyphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A43), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-(trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A44), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A48), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A49), 2-(6-((2S,5R)-5-ethyl-2-methyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A50), 2-(6-((2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A51), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A52), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-3-ethyl-9-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A53), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-(trifluoromethyl)quinoxalin-6-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A54), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methylbenzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A55), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methylbenzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A56), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methyl-1H-benzo[d]imidazol-5-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A57), 2-(6-((2S,5R)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A58), 2-(6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A59), 2-(6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A60), 2-(6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-ethyl-9-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A61), 2-(6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-diethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A62), 2-(6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A63), 2-(6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A64), 2-(6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A65), 2-(6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-3-ethyl-9-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A66), 2-(6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A67), 2-(6-((2S,5R)-4-(1-(8-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A68), 2-(6-((2S,5R)-4-(1-(7-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,4,5,9-tetrahydro-2H-purin-8-yl)acetonitrile (A69), 2-(6-((2S,5R)-4-(1-(5-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A70), 2-(9-ethyl-6-((2S,5R)-4-(1-(5-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A71), 2-(6-((2S,5R)-4-(1-(8-chloro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A72), 2-(6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A74), 2-(6-((2S,5R)-4-(1-(4,4-difluorochroman-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A77), 2-(6-((2S,5R)-4-(1-(4,4-difluorochroman-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A78), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A79), 2-(6-((2S,5R)-4-(1-(3,3-difluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A80), 2-(6-((2S,5R)-4-(1-(2,2-dimethyl-4-oxochroman-7-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A81), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methyl-1,3-dioxoisoindolin-5-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A83), 2-(6-((2S,5R)-4-(1-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A85), 2-(9-cyclopropyl-6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A86), 2-(9-(2,2-difluoroethyl)-6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A87), 2-(6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-9-propyl-3,9-dihydro-2H-purin-8-yl)acetonitrile (A88), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(;3-methyl-4-oxo-4H-chromen-6-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A91), 2-(6-((2S,5R)-4-(1-(2,2-dimethylchroman-7-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A94), 2-(9-ethyl-6-((2S,5R)-4-(1-(2-ethylbenzo[d]thiazol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A95), 2-(9-ethyl-6-((2S,5R)-4-(1-(2-isopropylbenzo[d]thiazol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A96), 2-(6-((2S,5R)-4-(1-(2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A97), 2-(6-((2S,5R)-4-(1-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A98), 2-(6-((2S,5R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A99), 2-(6-((2S,5R)-4-(1-(4,4-difluoro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A102), 2-(6-((2S,5R)-4-(1-(4,4-difluoro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A103), 2-(9-ethyl-6-((2S,5R)-4-(1-(3-isopropylphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A108), 2-(6-((2S,5R)-4-(1-(3-(tert-butyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A110), 2-(9-ethyl-6-((2S,5R)-4-(1-(3-(2-hydroxypropan-2-yl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A111), 2-(6-((2S,5R)-4-(1-(3-(difluoromethyl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A112), 2-(9-ethyl-6-((2S,5R)-4-(1-(4-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A113), 2-(9-ethyl-6-((2S,5R)-4-(1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A114), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(4-methyl-3-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A115), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(4-methyl-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A116), 2-(9-ethyl-6-((2S,5R)-4-(1-(6-isopropoxypyridin-2-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A117), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(6-(trifluoromethyl)pyridin-2-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A118), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-(trifluoromethyl)pyridin-4-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A119), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(4-(trifluoromethyl)pyridin-2-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A120), 2-(6-((2S,5R)-4-(1-(2-(azetidin-1-yl)pyridin-4-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A121), 2-(9-ethyl-6-((2S,5R)-4-(1-(2-(isopropylamino)pyridin-4-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A122), 2-(9-ethyl-6-((2S,5R)-4-(1-(6-isopropylpyridin-2-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A123), 2-(9-ethyl-6-((2S,5R)-4-(1-(2-isopropoxypyridin-4-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A124), 2-(6-((2S,5R)-4-(1-(3-cyclopropylphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A125), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-(1-methylcyclopropyl)phenyl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A126), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-(oxetan-3-yl)phenyl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A127), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(6-(trifluoromethoxy)pyridin-2-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A128), 2-(6-((2S,5R)-4-(1-(2-(tert-butyl)pyridin-4-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A129), 4-(1-((2R,5S)-4-(8-(cyanomethyl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazin-1-yl)ethyl)-N-methylpicolinamide (A130), 4-(1-((2R,5S)-4-(8-(cyanomethyl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazin-1-yl)ethyl)-N,N-dimethylpicolinamide (A131), 5-(1-((2R,5S)-4-(8-(cyanomethyl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazin-1-yl)ethyl)-2-fluoro-N-methylbenzamide (A132), 2-(9-ethyl-6-((2S,5R)-4-(1-(3-(1-hydroxy-2-methylpropan-2-yl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A133), 2-(3-(1-((2R,5S)-4-(8-(cyanomethyl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-6-yl)-2,5-dimethylpiperazin-1-yl)ethyl)phenyl)-2-methylpropanenitrile (A134), 2-(9-ethyl-6-((2S,5R)-4-(1-(4-fluoro-3-(prop-1-en-2-yl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A135), 2-(9-ethyl-6-((2S,5R)-4-(1-(4-fluoro-3-(1-methylcyclopropyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A136), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-methyl-4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A137), 2-(6-((2S,5R)-4-(1-(5,6-dimethylpyridin-2-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A138), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(4-(morpholinomethyl)phenyl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A139), 2-(6-((2S,5R)-4-(1-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A140), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-morpholinophenyl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A141), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-(morpholinomethyl)phenyl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A142), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(4-morpholinophenyl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A143), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-phenylpyridin-4-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A144), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(p-tolyl)but-2-yn-1-yl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A145), 2-(6-((2S,5R)-4-(1-(5-(difluoromethyl)pyridin-2-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A146), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(5-methylpyridin-2-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A147), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A148), 2-(6-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A149), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A150), 2-(6-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A151), 8-(but-2-yn-1-yl)-6-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3,9-dimethyl-3,9-dihydro-2H-purin-2-one (A152), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-2-yl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A153), 2-(6-((2S,5R)-4-(1-(isoquinolin-3-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A154), 2-(6-((2S,5R)-4-(1-(1,2-dimethyl-4-oxo-1,4-dihydroquinolin-7-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A155), 2-(9-ethyl-6-((2S,5R)-4-(1-(7-fluoro-2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A156), 2-(9-ethyl-6-((2S,5R)-4-(1-(7-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A157), 2-(6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A158), 2-(6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A159), 2-(6-((2S,5R)-4-(1-(7-chloro-3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A160), 2-(9-ethyl-6-((2S,5R)-4-(1-(7-fluoro-3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A161), 2-(6-((2S,5R)-4-(1-(7-fluoro-3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A162), 2-(9-ethyl-6-((2S,5R)-4-(1-(8-fluoro-3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A163), 2-(6-((2S,5R)-4-(1-(8-fluoro-3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A164), 2-(9-(2,2-difluoroethyl)-6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A165), 2-(9-(2,2-difluoroethyl)-6-((2S,5R)-4-(1-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A166), 2-(6-((2S,5R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A167), 2-(9-ethyl-6-((2S,5R)-4-(1-(2-ethyl-2-methylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A168), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(spiro[benzo[d][1,3]dioxole-2,1′-cyclobutan]-5-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A169), 2-(6-((2S,5R)-4-(1-(6-chloro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A170), 2-(6-((2S,5R)-4-(1-(7-chloro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A171), 2-(6-((2S,5R)-4-1-(4-chloro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A172), 2-(9-ethyl-6-((2S,5R)-4-(1-(7-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A173), 2-(9-ethyl-6-((2S,5R)-4-(1-(6-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A174), 2-(9-ethyl-6-((2S,5R)-4-(1-(4-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A175), 2-(6-((2S,5R)-4-(1-(4,6-difluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A176), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2,2,7-trimethylbenzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A177), 2-(9-ethyl-6-((2S,5R)-4-(1-(2-isopropyl-1,3-dioxoisoindolin-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A178), 2-(6-((2S,5R)-4-(1-(2,2-dimethyl-3-oxo-2,3-dihydrobenzofuran-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A179), 2-(6-((2S,5R)-4-(1-(2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A180), 2-(6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrofuro[3,2-b]pyridin-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A181), 2-(6-((2S,5R)-4-(3,3-dimethyl-2,3-dihydrofuro[3,2-b]pyridine-5-carbonyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A182), 2-(6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzofuran-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A183), 2-(6-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A184), 2-(9-ethyl-6-((2S,5R)-4-(1-(7-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-4-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A185), 2-(6-((2S,5R)-4-(1-(2,2-dimethylbenzo[d][1,3]dioxol-4-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A186), 2-(6-((2S,5R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A187), 2-(3-ethyl-6-fluoro-7-((2S,5R)-4-(1-(4-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A190), 2-(7-((2S,5R)-4-(1-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-ethyl-6-fluoro-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A188), 2-(3-ethyl-6-fluoro-7-((2S,5R)-4-(1-(7-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A189), 2-(3-ethyl-6-fluoro-7-((2S,5R)-4-(1-(4-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A190), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methyl-4-oxo-4H-chromen-7-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A191), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-methyl-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A192), 2-(6-((2S,5R)-4-(1-(1,3-dimethyl-4-oxo-1,4-dihydroquinolin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,4,5,9-tetrahydro-2H-purin-8-yl)acetonitrile (A193), 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A2), 2-(7-((2S,5R)-4-(1-(4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A3), 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(4-methyl-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A8), 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(4-methyl-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A15), 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-methyl-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-6-fluoro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile (A17), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(4-methyl-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-3,9-dimethyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A32), 2-(6-((2S,5R)-4-(1-(3-(difluoromethyl)-5-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A38), 2-(6-((2S,5R)-4-(1-(3-(1,1-difluoroethyl)-4-methoxyphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A39), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A40), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(m-tolyl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A45), 2-(9-ethyl-6-((2S,5R)-4-(1-(3-methoxyphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A46), 2-(9-ethyl-6-((2S,5R)-4-(1-(2-methoxypyridin-4-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A47), 2-(6-((2S,5R)-4-(1-(7-chloro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A73), 2-(6-((2S,5R)-4-(1-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A75), 2-(6-((2S,5R)-4-(1-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A76), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A82), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2,3,3-trimethyl-1-oxoisoindolin-5-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A84), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(3-methyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A89), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methylquinolin-7-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A90), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A92), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A93), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methyl-3-oxoisoindolin-5-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A100), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-methyl-1-oxoisoindolin-5-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A101), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-(trifluoromethyl)thiazol-4-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A104), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(2-(trifluoromethyl)thiazol-5-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A105), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A106), 2-(6-((2S,5R)-2,5-dimethyl-4-(1-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)piperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A107), 2-(6-((2S,5R)-4-(1-(3-(difluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-9-ethyl-3-methyl-2-oxo-3,9-dihydro-2H-purin-8-yl)acetonitrile (A109), 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydrothiazolo[5,4-b]pyridin-2-yl)acetonitrile (A194), 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydrothiazolo[5,4-b]pyridin-2-yl)acetonitrile (A195), or 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(4-methyl-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydrothiazolo[5,4-b]pyridin-2-yl)acetonitrile (A196).

31. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 30, or stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.

32. 31. A method of treating a disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 30, wherein the disease is cancer.

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