Pyrazolopyridone compounds

Abstract

Disclosed herein are compounds of Formula (I) for activating T cells, promoting T cell proliferation, and / or exhibiting anti-tumor activity, methods of treating cancer using the compounds disclosed herein, and pharmaceutical compositions comprising the compounds.

Description

[0001] This application is a divisional application of Chinese patent application No. 202280053906.2, entitled "Pyrazolopyridone Compound", filed on August 2, 2022 (PCT application No. PCT / CN2022 / 109663). Technical Field

[0002] This document discloses compounds of formula (I) for activating T cells, promoting T cell proliferation and / or exhibiting antitumor activity, methods for treating cancer using the compounds disclosed herein, and pharmaceutical compositions comprising the compounds. Background Technology

[0003] Diacylglycerol kinase (DGK) is a family of lipid kinases that phosphorylate diacylglycerol (DAG) and convert it to phosphatidic acid (PA). As substrates for DGK, DAG is produced at the plasma membrane from inositol phospholipids and other phospholipids via the hydrolysis of phospholipase C (PLC) in response to activation of various cell surface receptors, including G protein-coupled receptors (GPCRs) and receptors containing immune receptor tyrosine activation motifs (ITAMs) (Rhee, Sue Goo. Annual review of biochemistry. 2001, 70.1: 281-312). DAG is a key intracellular second messenger that recruits and activates numerous downstream effectors, including the protein kinase C (PKC), protein kinase D (PKD) family, and Ras guanylate-releasing protein (RasGRP), thereby activating NF-κB and the extracellular regulated kinase (ERK) pathway (Mérida, Isabel et al., Biochemical Journal. 2008, 409.1:1-18; Joshi, Rohan P. et al., International Journal of Molecular Sciences. 2013, 14.4:6649-6673). By consuming DAG, DGK controls and modulates the threshold and duration of DAG-mediated signal transduction. The mammalian DGK family comprises 10 distinct members, among which DGKα, DGKζ, and DGKδ are three major isotypes that are abundantly expressed in lymphoid tissues (Joshi, Rohan P. et al., International Journal of Molecular Sciences, 2013, 14.4: 6649-6673).

[0004] Cancer immunotherapy is a treatment approach that manipulates and enhances the host's immune system to recognize and attack cancer cells. The vast majority of research focuses on targeting immune checkpoint inhibitors, such as CTLA-4 and PD-1 / PD-L1, to revitalize depleted CD8+ cells within the tumor site. +T cells. It has been found that peripheral T cell tolerance, which normally protects against harmful autoimmune diseases, can be hijacked by tumors to suppress antitumor immune responses during carcinogenesis (Nüssing, Simone et al., Frontiers in Immunology. 2020, 11:2461). T cell anergy is one of the most important mechanisms of T cell tolerance and has been reported to occur 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 anergic-associated transcription factor Egr2 directly binds to the promoters of Dgka and Dgkz and increases their expression (Zheng, Yan et al., Journal of Experimental Medicine, 2012, 209.12:2157-2163; Zheng, Yan et al., Molecular Immunology, 2013, 55.3-4:283-291). In anergic T cells, both DGKα and DGKζ play key roles in negatively regulating DAG signaling downstream of the TCR and reducing the intensity of TCR activation (Chen, Shelley S. et al., Frontiers in Cell and Developmental Biology, 2016, 4:130). Therefore, we investigated immune cells expressing DGKα and DGKζ as potential targets for reversing the low responsiveness of tumor-infiltrating T cells. Genetic deletion of DGKα or DGKζ has been shown to enhance cytokine production and T cell proliferation (Olenchock, Benjamin A. et al., Nature Immunology. 2006, 7.11: 1174-1181; Zhong, Xiao-Ping et al., Nature Immunology. 2003, 4.9: 882-890). Single knockout of DGKα or DGKζ in either mouse or human chimeric antigen receptor (CAR) T cells has shown superior effector functions, as determined by enhanced in vitro cytotoxicity and cytokine secretion when co-cultured with title cells expressing the antigen (Riese, Matthew J. et al., Cancer Research. 2013, 73.12: 3566-3577; Jung, In-Young et al., Cancer Research. 2018, 78.16: 4692-4703).MesoCAR-transduced DGKα or DGKζ deficient T cells also showed significantly enhanced in vivo anti-mesothelioma activity (Riese, Matthew J. et al., Cancer Research. 2013, 73.12:3566-3577). DGKζ. - / - In mice, DGKα and DGKζ showed enhanced tumor suppression in both orthotopic and subcutaneous implantation models (Wesley, Erin M. et al., Immunohorizons, 2018, 2.4: 107-118; Wee, Susan et al., AACR; Cancer Research, 2019; 79(13 Supplement): Abstract nr 936). In addition to T cell regulation, DGKα and DGKζ also participate in regulating NK cell activation at the tumor site (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 was found to play a crucial role in controlling the activation threshold of mature B cells (Wheeler, Matthew L. et al., Science Signaling. 2013, 6.297:ra91-ra91). In summary, all these preclinical data suggest that the title "Inhibition of DGKα and DGKζ" may be therapeutically beneficial in promoting anticancer immunity.

[0005] While existing anti-CTLA-4 and anti-PD-1 therapies have demonstrated significant clinical benefits in subgroups of patients with various tumor types, unmet medical needs remain for developing novel immunotherapies to achieve robust and durable clinical anti-tumor efficacy. Preclinical data strongly suggest the great potential for developing DGKα and DGKζ targeted therapies to enhance anti-tumor immunity. Summary of the Invention

[0006] The above requirements have been met by providing compounds disclosed herein that have a novel core structure and exhibit the desired inhibition of both DGKα and DGKζ. In some embodiments, the compounds disclosed herein exhibit dual inhibitory activity against both DGKα and DGKζ. In some embodiments, the compounds disclosed herein exhibit selective inhibitory activity against DGKα in addition to DGKζ. In some embodiments, the compounds disclosed herein exhibit selective inhibitory activity against DGKζ in addition to DGKα.

[0007] This article discloses and provides compounds of formula (I).

[0008]

[0009] Or its stereoisomers or pharmaceutically acceptable salts

[0010] in

[0011] X 1 For C or N,

[0012] X 2 and X 3 Each of them is independently selected from -N- or -CH-;

[0013] symbol It can be a single bond or a double bond.

[0014] R 1 It is hydrogen, or an alkyl group optionally substituted with deuterium, halogen, hydroxyl, alkoxy or cycloalkyl;

[0015] R 2 It is hydrogen, halogen, alkyl or cyano, or when X 1 N and attached to X 1 The key When it is a double bond, R 2 It does not exist;

[0016] R 4 It is hydrogen, halogen, or alkyl, wherein the alkyl group is optionally halogenated or -OR 4a Replace, where R 4a It is hydrogen, alkyl, alkenyl, ynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, or heterocycloalkyl is optionally prefixed with -C. 1-6 Alkyl, -C 1-6 alkoxy or -C 3-8 Cycloalkyl substitution;

[0017] R 5 Hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, R 5a -C(O)-、R 5a -C(O)O-、R 5a -OC(O)-、R 5a -C(O)NR 5b -、R 5a -NR 5b -C(O)-、R 5a -SO2- or heterocyclic group, wherein the alkyl or alkenyl group is not substituted or is replaced by halogen, cyano, -C(O)OR 5c -C(O)R 5c -C(O)NR 5c R 5dheterocyclic, alkoxy, hydroxy, cycloalkyl, or NR 5c R 5d Substitution; and wherein each of the cycloalkyl and heterocyclic groups is not substituted or is substituted by an alkyl, cyano, or halogen-substituted alkyl, cyano, -C(O)OR 5c -C(O)R 5c -C(O)NR 5c R 5d Heterocyclic groups, alkoxy groups, hydroxyl groups, cycloalkyl groups, NR 5c R 5d 、or R 5c -SO2- substitution, where R 5a and R 5b Each is independently hydrogen, alkyl, or cycloalkyl; and wherein R 5c and R 5d It is hydrogen or alkyl;

[0018] R 6 It is hydrogen, halogen, unsubstituted or halogenated or cyano-substituted alkyl, or when attached to R 6 The bond attached to nitrogen When it is a double bond, R 6 It does not exist;

[0019] R 7 R 9 R 8 and R 10 Each of them is independently hydrogen, alkyl, alkoxy, or -C(O)R 7a The alkyl group is not substituted or is substituted with halogen, cyano, hydroxyl, or alkoxy groups, and R is... 7a It is hydrogen, alkyl, or alkoxy, provided that R 7 and R 9 At least one of them is not hydrogen;

[0020] Or R 7 and R 9 Each is hydrogen and R 8 and R 10 Together they form a bridge containing at least one -CH2- motif in addition to the two bridgehead atoms; or R 8 and R 10 Each is hydrogen and R 7 and R 9 Together they form a bridge containing at least one -CH2- moiety in addition to the two bridgehead atoms;

[0021] L 1 For direct bonds, -O-, -N(R) L -, -alkylene- or -C(O)-, wherein the -alkylene- is not substituted or is replaced by -C(O)NR L1Replace, and R L It is hydrogen or alkyl, wherein R L1 It is hydrogen, alkyl, or alkoxyalkyl;

[0022] Cy 1 It is an aryl, heterocyclic, heteroaryl, or cycloalkyl group, each of which is unsubstituted or substituented by one, two, or three substituents R. 3a Replace, where R 3a Selected from deuterium, hydroxyl, 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)-, cycloalkyl, heterocyclic, or heterocyclic oxy, wherein the alkyl group or alkoxy group is not substituted or is substituted by deuterium, halogen, alkoxy, hydroxyl, cyano, or heterocyclic group; wherein the cycloalkyl or heterocyclic group is not substituted or is substituted by alkoxy, alkyl, halogen, or hydroxyl, wherein R 3b and R 3c Each is independently hydrogen or alkyl.

[0023] In some embodiments, the compound of formula (I) is any of the following subgenera:

[0024]

[0025] These variables are as defined in this article.

[0026] R 1 Definition

[0027] In some embodiments, R 1 It is hydrogen, or an alkyl group optionally substituted with deuterium, halogen, hydroxyl, alkoxy, or cycloalkyl. In some embodiments, R 1 C is hydrogen, or optionally substituted with deuterium, halogen, hydroxyl, alkoxy or cycloalkyl. 1-4 Alkyl group. In some embodiments, R 1 C is hydrogen, or optionally replaced by deuterium or halogen. 1-3 Alkyl group. In some embodiments, R 1 C is hydrogen, or optionally replaced by deuterium. 1-3 alkyl.

[0028] In some embodiments, R 1It is hydrogen, methyl, methyl-d3, ethyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, or cyclopropylmethyl. In some embodiments, R 1 It is hydrogen, methyl, ethyl, or methyl-d3. In some embodiments, R 1 It is methyl or methyl-d3. In some embodiments, R 1 It is methyl.

[0029] R 2 Definition

[0030] In some embodiments, R 2 It is hydrogen, halogen, alkyl or cyano, or when X 1 N and attached to X 1 The key When it is a double bond, R 2 It does not exist. In some embodiments, R 2 For hydrogen, halogen, C 1-4 Alkyl or cyano. In some embodiments, R 2 It can be hydrogen, F, Br, Cl, or CN.

[0031] R 4 Definition

[0032] In some embodiments, R 4 It is hydrogen, halogen, or alkyl, wherein the alkyl group is optionally halogenated or -OR 4a Replace, where R 4a It is hydrogen, alkyl, alkenyl, ynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, or heterocycloalkyl is optionally prefixed with -C. 1-6 Alkyl, -C 1-6 alkoxy or -C 3-8 Cycloalkyl substitution. In some embodiments, R 4 It is hydrogen, halogen or C 1-4 Alkyl groups, wherein the alkyl group is optionally halogenated or -OR 4a Replacement. In some embodiments, R 4 It is hydrogen, halogen or C 1-4 Alkyl groups, wherein the alkyl groups are optionally substituted with halogens.

[0033] In some embodiments, R 4 It can be hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, ethyl, or 2,2,2-trifluoroethyl. In some embodiments, R 4 It is hydrogen.

[0034] R 5 Definition

[0035] In some embodiments, R 5Hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, R 5a -C(O)-、R 5a -C(O)O-、R 5a -OC(O)-、R 5a -C(O)NR 5b -、R 5a -NR 5b -C(O)-、R 5a -SO2- or heterocyclic group, wherein the alkyl or alkenyl group is not substituted or is replaced by halogen, cyano, -C(O)OR 5c -C(O)R 5c -C(O)NR 5c R 5d heterocyclic, alkoxy, hydroxy, cycloalkyl, or NR 5c R 5d Substitution; and wherein each of the cycloalkyl and heterocyclic groups is not substituted or is substituted by an alkyl, cyano, or halogen-substituted alkyl, cyano, -C(O)OR 5c -C(O)R 5c -C(O)NR 5c R 5d Heterocyclic groups, alkoxy groups, hydroxyl groups, cycloalkyl groups, NR 5c R 5d 、or R 5c -SO2- substitution, where R 5a and R 5b Each is independently hydrogen, alkyl, or cycloalkyl; and wherein R 5c and R 5d It is hydrogen or alkyl.

[0036] In some embodiments, R 5 It is hydrogen, alkyl, alkenyl, or alkynyl, wherein the alkyl group is unsubstituted or substituted with a cyano group. In some embodiments, R 5 C 1-4 Alkyl, C 2-4 alkenyl or C 2-4 Alkyne group, wherein the alkyl group is replaced by a cyano group.

[0037] In some embodiments, R 5It is hydrogen, CN-CH2-, -CH2C(O)-OMe, -CH(CH3)CN, ethylene oxide-2-ylmethyl-, prop-2-yn-1-yl, but-2-yn-1-yl, prop-1-en-2-yl, but-2-en-1-yl, but-3-en-1-yl, methyl, isopropyl, -CH2CH2-O-Me, -CH2C(O)NH2, -CH2CH2-OH, cyclopropyl-CH2-, -CH2CH2N(CH3)2, CH3-SO2-, cyclopropyl, cyclobutyl, cyclopropyl-C(O)-, 1-cyanocyclopropyl, 2-cyanocyclopropyl, 2-cyanocyclobutyl, 3-(cyanomethyl)-1-(ethylsulfonyl)azacyclobutane-3-yl, or 1-cyano-2-cyclopentylethyl-2-yl. Preferably, R 5 It is hydrogen, CN-CH2-, -CH2C(O)-OMe, -CH(CH3)CN, ethylene oxide-2-ylmethyl-, prop-2-yn-1-yl, but-2-yn-1-yl, or prop-1-en-2-yl. More preferably, R 5 It is CN-CH2-, prop-2-yn-1-yl, but-2-yn-1-yl, or prop-1-en-2-yl.

[0038] In some embodiments, R 5 It is CN-CH2-, -CH(CH3)CN, prop-2-yn-1-yl, but-2-yn-1-yl, or prop-1-en-2-yl. In some embodiments, R 5 It is CN-CH2-. In some embodiments, R 5 For -CH(CH3)CN. In some embodiments, R 5 It is prop-2-yn-1-yl. In some embodiments, R 5 It is but-2-yn-1-yl. In some embodiments, R 5 It is prop-1-en-2-yl.

[0039] R 6 Definition

[0040] In some embodiments, R 6 The alkyl group that is absent, or is hydrogen, halogenated, unsubstituted, or substituted with halogen or cyano, is provided that it is attached to R. 6 The bond attached to nitrogen When it is a double bond, R 6 It does not exist. In some embodiments, R 6 It does not exist. In some embodiments, R 6 It is hydrogen, F, Br, Cl, or C that is unsubstituted or substituted with a cyano group. 1-4 alkyl.

[0041] R 7 / R 9 R 8 / R 10 Definition

[0042] In some embodiments, R 7 R 9 R 8 and R 10 Each of them is independently hydrogen, alkyl, or -C(O)R 7a The alkyl group is not substituted or is substituted with halogen, cyano, hydroxyl, or alkoxy groups, and R is... 7a It is hydrogen, alkyl, or alkoxy, provided that R 7 and R 9 At least one of them is not hydrogen.

[0043] In some embodiments, R 7 and R 9 Each of them is independently hydrogen, alkyl, or -C(O)R 7a The alkyl group is not substituted or is substituted with halogen, cyano, hydroxyl, or alkoxy groups, and R is... 7a It is hydrogen, alkyl, or alkoxy. In some embodiments, R 7 and R 9 Each of them is independently C 1-4 Alkyl group. In some embodiments, R 7 and R 9 Each of them is independently C 1-2 alkyl.

[0044] In some embodiments, R 7 and R 9 Each of these can be 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.

[0045] In some embodiments, R 8 and R 10 Each is hydrogen.

[0046] In some embodiments, R 7 It is methyl, and R 9 It is methyl; or R 7 It is ethyl, and R 9 It is ethyl; or R 7 It is methyl, and R 9 It is ethyl; or R 7 It is methyl, and R 9 It is a methoxycarbonyl group; or R 7 It is hydrogen, and R 9 It is methyl; or R 7 It is hydrogen, and R 9 It is an ethyl group.

[0047] In some embodiments, R 7 and R 9 Each is hydrogen and R 8 and R 10 Together, they form a bridge containing at least one -CH2- motif in addition to the two bridgehead atoms. In some embodiments, R 7 and R 9 Each is hydrogen and R 8 and R 10 Together they form a bridge containing a -CH2- portion in addition to the two bridgehead atoms. In some embodiments, R 7 and R 9 Each is hydrogen and R 8 and R 10 Together they form a bridge containing two -CH2- portions in addition to the two bridgehead atoms.

[0048] In some embodiments, R 8 and R 10 Each is hydrogen and R 7 and R 9 Together, they form a bridge containing at least one -CH2- motif in addition to the two bridgehead atoms. In some embodiments, R 8 and R 10 Each is hydrogen and R 7 and R 9 Together they form a bridge containing a -CH2- portion in addition to the two bridgehead atoms. In some embodiments, R 8 and R 10 Each is hydrogen and R 7 and R 9 Together they form a bridge containing two -CH2- portions in addition to the two bridgehead atoms.

[0049] L 1 Definition

[0050] In some embodiments, L 1 For direct bonds, -O-, -N(R) L )-, -alkylene- or -C(O)-, where R L It is hydrogen or alkyl. In some embodiments, L 1 C 1-4 Alkylene, preferably C 1-2 Alkylene. In some embodiments, L 1 For direct bonds, -CH2-, -CH(CH3)-, -CH(CH2CH3)-, -CH(CHF2)-, -N(H)-, -N(CH3)-, -O-, -CH(C(O)-NHCH2CH2OCH3)-, or -C(CH3)2-. In some embodiments, L1 It is -CH2- or -CH(CH3)-.

[0051] X 2 and X 3 Definition

[0052] In some embodiments, X 2 and X 3 For N or CH. In some embodiments, X 2 Let N be the number of elements, and X be the number of elements. 3 For N; or X 2 Let N be the number of elements, and X be the number of elements. 3 For CH; or X 2 For CH, and X 3 For N; or X 2 For CH, and X 3 Let N be the number of elements in the array.

[0053] Cy 1 Definition

[0054] In some embodiments, Cy 1 It is an aryl, heterocyclic, heteroaryl, or cycloalkyl group, each of which is unsubstituted or substituented by one, two, or three substituents R. 3a Replace, where R 3a Selected from 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)-, heterocyclic group, or heterocyclic oxy group, wherein the alkyl portion of the alkyl or alkoxy group is not substituted or is substituted by deuterium, halogen, alkoxy, hydroxyl, cyano, or heterocyclic group; the cycloalkyl or heterocyclic group is not substituted or is substituted by alkoxy, alkyl, halogen, or hydroxyl group, wherein R 3b and R 3c Each is independently hydrogen or alkyl.

[0055] In some embodiments, Cy 1 R is either unsubstituted or substituted with one, two, or three substituents. 3a Substituted aryl, wherein R 3a Selected from 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 R3c ), R 3b -OC(O)-, heterocyclic group, or heterocyclic oxy group, wherein the alkyl portion of the alkyl or alkoxy group is not substituted or is substituted by deuterium, halogen, alkoxy, hydroxyl, cyano, or heterocyclic group; the cycloalkyl or heterocyclic group is not substituted or is substituted by alkoxy, alkyl, halogen, or hydroxyl group, wherein R 3b and R 3c Each is independently hydrogen or alkyl.

[0056] In some embodiments, Cy 1 R is either unsubstituted or substituted with one, two, or three substituents. 3a Substituted aryl, wherein R 3a Selected from alkoxy, halogen-substituted alkoxy, alkoxyalkyl-, alkyl, halogen-substituted alkyl, deuterium-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)-, heterocyclic group, or heterocyclic-substituted alkyl group, wherein the cycloalkyl, heterocyclic group, or heterocyclic oxy group is unsubstituted or substituted with an alkoxy group, alkyl group, halogen, or hydroxyl group, wherein R 3b and R 3c Each is independently hydrogen or alkyl.

[0057] In some embodiments, Cy 1 R is either unsubstituted or substituted with one, two, or three substituents. 3a Substituted aryl, wherein R 3a Selected from deuterium, fluorine, bromine, chlorine, methyl, methyl-d3, difluoromethyl, trifluoromethoxy, methoxy, methoxymethyl, trifluoromethyl, methanesulfonyl, 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, aziridine-1-yl, 2-methoxypropyl-2-yl, 1-methoxycyclopropyl, oxacyclobutane-3-yl, (oxacyclobutane-3-yl)methoxy, oxacyclobutane-3-yloxy, (tetrahydrofuran-3-yl)methoxy, (tetrahydro-2H-pyran-4-yl)oxy, 1-methylaziridine-3-yl, or 1-hydroxyaziridine-3-yl.

[0058] In some embodiments, Cy 1It is phenyl. In some embodiments, Cy 1 For the fourth position as disclosed in this article, an R 3a Replace and optionally in another R 3a Substituted phenyl groups.

[0059] In some embodiments, Cy 1 It is naphthyl. In some embodiments, Cy 1 It is naphth-1-yl, naphth-2-yl, naphth-3-yl, or naphth-4-yl.

[0060] In some embodiments, Cy 1 It is 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, or

[0061] In some embodiments, Cy 1 For not being replaced or by one, two or three R 3a The substituted monocyclic 5- to 9-membered heterocyclic group or bicyclic 7- to 10-membered heterocyclic group, wherein R 3a Selected from 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 a heterocyclic group, wherein the alkyl portion of the alkyl or alkoxy group is not substituted or is substituted with deuterium, halogen, alkoxy, hydroxyl, or cyano; the cycloalkyl or heterocyclic group is not substituted or is substituted with alkoxy, alkyl, halogen, or hydroxyl, wherein R 3b and R 3c Each is independently hydrogen or alkyl; preferably R 3a Selected from 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 a heterocyclic group, wherein the cycloalkyl or heterocyclic group is unsubstituted or substituted with an alkoxy, alkyl, halogen, or hydroxyl group, wherein R 3b and R 3c Each is independently hydrogen or alkyl. In some embodiments, the monocyclic 5- to 9-membered heterocyclic group is tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxane, piperidinyl, piperazinyl, or dihydropyridinyl, each of which is not substituted or is modified by one, two, or three R groups as disclosed herein. 3a Replacement. In some embodiments, Cy 1 It is tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, 1,4-dioxane-2-yl, 1,4-dioxane-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazine-1-yl, piperazine-2-yl, piperazine-3-yl, piperazine-4-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl, or 1,2-dihydropyridin-6-yl.

[0062] In some embodiments, Cy 1 For the fourth position as disclosed in this article, an R 3a Replace and optionally in another R 3a Substituted piperidinyl (e.g., piperidin-1-yl) or piperazineyl (e.g., piperazine-4-yl).

[0063] In some embodiments, the bicyclic 7- to 10-membered heterocyclic group is a chromanyl group, preferably chroman-2-yl, chroman-3-yl, chroman-4-yl, or chroman-6-yl; 2,3-dihydrofurano[2,3-b]pyridin-6-yl; 5,6,7,8-tetrahydroquinoxalin-2-yl; or benzo[d][1,3]dioxacyclopenten-5-yl.

[0064] In some embodiments, Cy 1 For not being replaced or by one, two or three R 3a Substituted monocyclic 5- to 9-membered heteroaryl or bicyclic 7- to 10-membered heteroaryl, wherein R 3a Selected from 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 a heterocyclic group, wherein the alkyl portion of the alkyl or alkoxy group is not substituted or is substituted with deuterium, halogen, alkoxy, hydroxyl, or cyano; the cycloalkyl or heterocyclic group is not substituted or is substituted with alkoxy, alkyl, halogen, or hydroxyl, wherein R 3b and R 3c Each is independently hydrogen or alkyl; preferably R 3a Selected from 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 a heterocyclic group, wherein the cycloalkyl or heterocyclic group is unsubstituted or substituted with an alkoxy, alkyl, halogen, or hydroxyl group, wherein R 3b and R 3c Each is independently hydrogen or alkyl; more preferably R 3a Selected from deuterium, fluorine, bromine, chlorine, methyl, methyl-d3, 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, aziridine-1-yl, 2-methoxypropyl-2-yl, 1-methoxycyclopropyl, oxacyclobutane-3-yl, 1-methylaziridine-3-yl, or 1-hydroxyaziridine-3-yl.

[0065] In some embodiments, the monocyclic 5- to 9-membered heteroaryl group is pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is not substituted or is modified by one, two, or three R groups as disclosed herein. 3aSubstitution. In some embodiments, the monocyclic 5- to 9-membered heteroaryl group is 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, pyrazin-2-yl, or pyridazin-4-yl, each of which is unsubstituted or replaced by one, two, or three R groups as disclosed herein. 3a replace.

[0066] In some embodiments, the bicyclic 7- to 10-membered heteroaryl group is indolyl, benzo[d]imidazolyl, triazolopyridyl, imidazopyridyl, benzoxazolyl, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, naphridyl, dioxin[pyridyl], quinoxalinyl, benzo[d]imidazolyl, or imidazo[4,5-b]pyridyl, each of which is not substituted or is modified by one, two, or three R groups as disclosed herein. 3aSubstitution. In some embodiments, the bicyclic 7- to 10-membered heteroaryl group is 1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-4-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-benzo[d]imidazol-7-yl, [1,2,4]triazolo[1,5-a]pyridin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-7-yl, [1,2,4]triazolo[1,5-a]pyridin-8-yl, 3H-imidazol[4,5-b]pyridin-2-yl, 3H- Imidazolo[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]thiazolyl-2-yl, benzo[d]thiazolyl-4-yl, benzo[d]thiazolyl-5-yl, benzo[d]thiazolyl Azol-6-yl, benzo[d]thiazol-7-yl, quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, quinoline-5-yl, quinoline-6-yl, quinoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, isoquinoline-5-yl, isoquinoline-6-yl, isoquinoline-7-yl, isoquinoline-8-yl, quinoxaline-2-yl, quinoxaline-3-yl, quinoxaline-4-yl, quinoxaline-5-yl, quinoxaline-6-yl, quinoxaline-7-yl, quinoxaline-8-yl, 1,8-naphthidin-2-yl, 1,8-naphthidin-3-yl, 1,8-naphthidin-4-yl, 2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-6-yl, 2,3- Dihydro-[1,4]dioxin[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-8-yl, quinoxalin-6-yl-2,3-d2, 1H-indol-2-yl, 1H-benzo[d]imidazol-2-yl, 1-methyl-1H-benzo[d]imidazol-6-yl, 3H-imidazol[4,5-b]pyridin-2-yl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl, 2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-6-yl, or pyrazolo[1,5-a]pyridin-2-yl, each of which is not substituted or is modified by one, two or three R as disclosed herein. 3a replace.

[0067] In some embodiments, Cy 1 The group is quinoxalinyl, such as quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl, preferably unsubstituted or with one, two, or three R groups. 3a Substituted quinoxaline-6-yl, where R 3a Selected from 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 a heterocyclic group, wherein the alkyl portion of the alkyl or alkoxy group is not substituted or is substituted with deuterium, halogen, alkoxy, hydroxyl, or cyano; the cycloalkyl or heterocyclic group is not substituted or is substituted with alkoxy, alkyl, halogen, or hydroxyl, wherein R 3b and R 3c Each is independently hydrogen or alkyl; preferably R 3a Selected from 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 a heterocyclic group, wherein the cycloalkyl or heterocyclic group is unsubstituted or substituted with an alkoxy, alkyl, halogen, or hydroxyl group, wherein R 3b and R 3c Each is independently hydrogen or alkyl; more preferably R 3aSelected from deuterium, fluorine, bromine, chlorine, methyl, methyl-d3, difluoromethyl, trifluoromethoxy, methoxy, methoxymethyl, trifluoromethyl, methanesulfonyl, 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, aziridine-1-yl, 2-methoxypropyl-2-yl, 1-methoxycyclopropyl, oxacyclobutane-3-yl, 1-methylaziridine-3-yl, 1-hydroxyaziridine-3-yl, (2,2-dimethylmorpholino)methyl, 4-((2S,6R)-2,6-dimethylmorpholino)methyl, or (4,4-difluoropiperidin-1-yl)methyl.

[0068] In some embodiments, Cy 1 For not being replaced or by one, two or three R 3a Substituted quinoxaline-6-yl, where R 3a It can be deuterium, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, fluorine, chlorine, cyano, amino, or cyclopropyl.

[0069] In some embodiments, Cy 1 for

[0070] a) Phenyl, 2-(trifluoromethoxy)phenyl, 2-methoxyphenyl, 2-(methoxymethyl)phenyl, 2-(trifluoromethyl)phenyl, 4-fluoro-2-(methoxymethyl)phenyl, 4-fluoro-2-methoxyphenyl, 4-fluoro-2-methylphenyl, 2-bromo-4-fluorophenyl, 4-fluoro-2-(methylsulfonyl)phenyl, 4-methyl-2-(trifluoromethyl)phenyl, 2-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2-ethoxy-4-fluorophenyl, 4-fluoro-2-isopropoxyphenyl, 4-fluoro-2-(trifluoromethoxy)phenyl, 2-(difluoromethoxy)-4-fluorophenyl, 2-(difluoromethyl)-4-fluorophenyl, 2-cyclopropyl-4-fluorophenyl, 4-fluoro-2-(1-hydroxyethyl) )phenyl, 4-cyclopropyl-2-methoxyphenyl, 2-ethyl-4-fluorophenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 2-methoxy-4-fluorophenyl, 2-(1,1-difluoroethyl)-4-fluorophenyl, 2-cyano-4-fluorophenyl, 4-fluoro-3-(methoxymethyl)phenyl, 3-methyl-2-(trifluoromethyl)phenyl, 4-fluoro-2,6-dimethoxyphenyl, 2,4-difluoro-6-methoxyphenyl, 2,6-dichloro-4-fluorophenyl, 4-cyclopropylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-cyclopropyl-phenyl, 4-(trifluoromethyl)phenyl, 4-methylphenyl, 4-(difluoromethyl)phenyl, 4-isopropoxyphenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 4 -Cyclopropyl-2-fluorophenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 3-methoxy-4-(trifluoromethyl)phenyl, 4-fluoro-3-methoxyphenyl, 2,6-difluorophenyl, 4-(trifluoromethoxy)phenyl, 4-acetamidophenyl, 4-fluoro-2-(1-methoxyethyl)phenyl, 2-(cyanomethyl)-4-fluorophenyl, 3,4-difluoro-2-(trifluoromethyl)phenyl, 2-carbamoyl-4-fluorophenyl, 2-methoxycarbonyl-4-fluorophenyl, 2-(dimethylcarbamoyl)-4-fluorophenyl, 2-((difluoromethoxy)methyl)-4-fluorophenyl, 2-(1-(difluoromethoxy)ethyl)-4-fluorophenyl, 2-(azacyclobutane-1-yl)-4-fluorophenyl, 4-Fluoro-2-(2-methoxypropyl-2-yl)phenyl, 4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-fluoro-2-(1-methoxycyclopropyl)phenyl, 4-fluoro-2-(oxetane-2-yl)phenyl, 4-fluoro-2-(1-methylazacyclobutane-3-yl)phenyl, 4-fluoro-2-(1-hydroxyazacyclobutane-3-yl)phenyl, 4-cyclopropyl-2-methoxyphenyl; 2-ethyl-4-fluorophenyl; 4-fluoro-2-(trifluoromethyl)phenyl; 2-methoxy-4-fluorophenyl; 2,6-difluoro-4-methoxyphenyl; 2,5-difluoro-4-methoxyphenyl; 3-methoxy-4-(trifluoromethyl)phenyl; naphth-2-yl; 2-fluoro-4-methylphenyl;4-((2,2-dimethylmorpholino)methyl)phenyl; 4-(((2S,6R)-2,6-dimethylmorpholino)methyl)phenyl; or 4-((4,4-difluoropiperidin-1-yl)methyl)phenyl; or;

[0071] b) 2,3-Dihydrobenzo[b][1,4]dioxin-6-yl, 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, or or

[0072] c) Tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, 1,4-dioxane-2-yl, 1,4-dioxane-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazine-2-yl, piperazine-3-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl, 1,2- Dihydropyridin-6-yl, 2,3-dihydrofurano[2,3-b]pyridin-6-yl, 2,3-dihydrofurano[3,2-b]pyridin-5-yl, 3,3-dimethyl-2,3-dihydrofurano[3,2-b]pyridin-5-yl, 5,6,7,8-tetrahydroquinoxalin-2-yl, 2,2-dimethylbenzo[d][1,3]dioxacyclopenten-5-yl, or 2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl; or

[0073] d) Chromated 2-base, chromated 3-base, chromated 4-base, chromated 6-base; or

[0074] e) 1H-pyrazole-3-yl, 1H-pyrazole-4-yl, 1H-pyrazole-5-yl, 1-ethyl-5-(trifluoromethyl)-1H-pyrazole-4-yl; 5-ethyl-1-methyl-1H-pyrazole-4-yl; 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, 1H-indole-2-yl, 1H-indole-3-yl, 1H-indole-4-yl, 1H-indole-5-yl, 1H-indole-6-yl, 1H-indole-7-yl, 3-methoxypyrazole Pyridine-2-yl, 3-fluoro-5-(trifluoromethyl)pyridin-2-yl, 3-fluoro-5-methylpyridin-2-yl, 5-chloropyridin-2-yl, (5-(trifluoromethoxy)pyridin-2-yl, 3-fluoro-5-(trifluoromethoxy)pyridin-2-yl, 5,6-dimethylpyridin-2-yl, 6-methoxy-5-methylpyridin-2-yl, 4-fluoro-6-isopropoxypyridin-3-yl, 6-isopropoxypyridin-3-yl, 2-methoxypyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 6-(difluoromethoxy)pyridin-3-yl, 6-methylpyridin-3-yl, 6-cyclopropylpyridin-3-yl, 6 -(difluoromethyl)pyridin-3-yl, 6-fluoropyridin-3-yl, 3-methoxypyridin-4-yl, 3-(trifluoromethyl)pyridin-4-yl, 5-fluoro-3-(trifluoromethyl)pyridin-2-yl, 5-chloro-1-ethyl-1H-imidazol-2-yl, 1-ethyl-2-(trifluoromethyl)-1H-imidazol-5-yl, -ethyl-5-(trifluoromethyl)-1H-pyridol-4-yl, -ethyl-1-methyl-1H-pyridol-4-yl, 1-methyl-5-(trifluoromethyl)-1H-pyridol-4-yl, 5-(difluoromethyl)-1-methyl-1H-pyridol-4-yl, 1-ethyl-3-(trifluoromethyl)pyridin-3-yl, 1H-pyrazole-5-yl, 3-chloro-1-ethyl-1H-pyrazole-5-yl, 1-ethyl-4-methyl-1H-pyrazole-5-yl, 5-isopropoxypyridin-2-yl, 6-(trifluoromethyl)pyridin-3-yl, 3,5-difluoropyridin-2-yl, 3,5-difluoropyridin-4-yl, 1-ethyl-4-cyano-1H-pyrazole-3-yl, 5-fluoropyridin-2-yl, 5-(difluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, pyrazin-2-yl, 5,6-dimethylpyrazin-2-yl, 5-methylpyrazin-2-yl or 3-(trifluoromethyl)pyridazin-4-yl; or

[0075] f) 1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-4-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-benzo[d]imidazol-7-yl, [1,2,4]triazolo[1,5-a]pyridin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-7-yl, [1,2,4]triazolo[1,5-a]pyridin-8-yl, 2-methyl-[1,2,4] Triazolo[1,5-a]pyridin-6-yl, 3H-imidazo[4,5-b]pyridin-2-yl, 3H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl, 3H-imidazo[4,5-b]pyridin-7-yl, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-7-yl, benzo[d]oxazol-2-yl, benzo[d]oxazol-4-yl, benzo[d]oxazol -5-yl, benzo[d]oxazol-6-yl, benzo[d]oxazol-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, 2-methylbenzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, quinoline-5-yl, quinoline-6-yl, quinoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, isoquinoline-5-yl, isoquinoline-6-yl, isoquinoline-7-yl, isoquinoline-8-yl, quinoxaline-2 -yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl, 1,8-naphthid-2-yl, 1,8-naphthid-3-yl, 1,8-naphthid-4-yl, 2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-8-yl, 3-methylquinoxalin-6-yl, 3-methoxyquinoxalin-6-yl, quinoxalin-6-yl-2,3-d2, 1-ethyl-1H-indol-2-yl, 1-methyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-1H-benzo[d]imidazol-2-yl, 1-propyl-1H-benzo[d]imidazol-2-yl, 1-ethyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl, 1-ethyl-7-(trifluoromethyl)-1H-benzo[ [d]imidazol-2-yl, 1-methyl-1H-benzo[d]imidazol-6-yl, 3-ethyl-3H-imidazo[4,5-b]pyridin-2-yl, 1-ethyl-1H-imidazo[4,5-b]pyridin-2-yl, 3-cyclopropylquinoxalin-6-yl, 3-aminoquinoxalin-6-yl, 3-trifluoromethylquinoxalin-6-yl, 2-trifluoromethylquinoxalin-6-yl, 3-difluoromethylquinoxalin-6-yl, 3-(1,1-difluoroethyl)quinoxalin Oxalin-6-yl, 2-deuter-3-methylquinoxalin-6-yl, 2-deuter-3-methoxyquinoxalin-6-yl, 3-methyl-5-methoxyquinoxalin-6-yl, 3-methyl-7-methoxyquinoxalin-6-yl, 3-methyl-5-trifluoromethylquinoxalin-6-yl, 3-methyl-7-trifluoromethylquinoxalin-6-yl, 1-ethyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl, 2,3-dihydro-[1,4]di Oxadiazine [2,3-b]pyridin-6-yl, 2,3-dimethyl-quinoxalin-6-yl, 3-ethyl-quinoxalin-6-yl, 3-chloro-quinoxalin-6-yl, 4-methoxy-quinoxalin-6-yl, 3-(difluoromethyl)quinoxalin-6-yl, 3-(1,1-difluoroethyl)quinoxalin-6-yl, 3-cyclopropyl-quinoxalin-6-yl, 2-hydroxy-3-methylquinoxalin-6-yl, or 3-(methyl-d3)quinoxalin-6-yl; or,

[0076] g) Cyclobutyl, cyclopentyl, cyclohexyl, 2,3-dihydro-1H-indene-1-yl, 2,3-dihydro-1H-indene-2-yl, 1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl, or 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl.

[0077] In some embodiments, Cy 12-(trifluoromethoxy)phenyl; 2-methoxyphenyl; 2-(methoxymethyl)phenyl; 2-(trifluoromethyl)phenyl; 4-fluoro-2-(methoxymethyl)phenyl; 4-fluoro-2-methoxyphenyl; 4-fluoro-2-(methoxymethyl)phenyl; 4-fluoro-2-methylphenyl; 2-bromo-4-fluorophenyl; 4-fluoro-2-(methylsulfonyl)phenyl; 4-methyl-2-(trifluoromethyl)phenyl; 2-chloro-4-fluorophenyl; 2,4-difluorophenyl; 2-ethoxy-4-fluorophenyl; 4-fluoro-2-isopropoxyphenyl; 4-fluoro-2-(trifluoromethoxy)phenyl; 2-(difluoromethoxy)-4-fluorophenyl; 2-(difluoromethyl)-4-fluorophenyl; 2-cyclopropyl-4-fluorophenyl; 4-fluoro- 2-(1-Hydroxyethyl)phenyl; 4-Cyclopropyl-2-methoxyphenyl; 2-Ethyl-4-fluorophenyl; 4-Fluoro-2-(trifluoromethyl)phenyl; 2-Methoxy-4-fluorophenyl; 2-(1,1-Difluoroethyl)-4-fluorophenyl; 4-Fluoro-3-(Methoxymethyl)phenyl; 3-Methyl-2-(trifluoromethyl)phenyl; 4-Fluoro-2,6-Dimethoxyphenyl; 2,4-Difluoro-6-methoxyphenyl; 2,6-Dichloro-4-fluorophenyl; 2,3-Dihydrobenzo[b][1,4]dioxin-6-yl; 3,3-Dimethyl-2,3-Dihydrobenzo[b][1,4]dioxin-6-yl; 2,2-Difluorobenzo[d][1,3]dioxacyclopenten-4-yl; 3-Methoxypyr 2-Pyridin-2-yl; 2-methoxypyridin-3-yl; 2-(trifluoromethyl)pyridin-3-yl; 6-(difluoromethoxy)pyridin-3-yl; 3-methoxypyridin-4-yl; 5-fluoro-3-(trifluoromethyl)pyridin-2-yl; 5-chloro-1-ethyl-1H-imidazol-2-yl; 1-ethyl-2-(trifluoromethyl)-1H-imidazol-5-yl; 1-ethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl; 5-ethyl-1-methyl-1H-pyrazol-4-yl; 1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl; 5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl; 1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl; 3-chloro-1-ethyl- 1H-pyrazol-5-yl; 1-ethyl-4-methyl-1H-pyrazol-5-yl; quinoline-3-yl; quinoline-2-yl; quinoxaline-6-yl; 3-methylquinoxaline-6-yl; 3-methylquinoxaline-6-yl; 3-methylquinoxaline-6-yl; 3-cyclopropylquinoxaline-6-yl; 3-aminoquinoxaline-6-yl; 3-trifluoromethylquinoxaline-6-yl; 3-difluoromethylquinoxaline-6-yl; 3-(1,1-difluoroethyl)quinoxaline-6-yl; 2-deuter-3-methylquinoxaline-6-yl; 2-deuter-3-methoxyquinoxaline-6-yl; 3-methyl-5-methoxyquinoxaline-6-yl; 3-methyl-7-methoxyquinoxaline-6-yl; 3-methyl-5-trifluoromethylquinoxaline-6-yl;3-Methyl-7-trifluoromethylquinoxalin-6-yl; quinoxalin-6-yl-2,3-d2; 1-ethyl-1H-indol-2-yl; 1-methyl-1H-benzo[d]imidazol-2-yl; 1-ethyl-1H-benzo[d]imidazol-2-yl; 1-propyl-1H-benzo[d]imidazol-2-yl; 1-ethyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl; 1-ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl; 1-ethyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl; 1-methyl-1H-benzo[d]imidazol-6-yl; 3-ethyl-3H-imidazo[4,5-b]pyridin-2-yl; 1-ethyl- 1H-Imidazolo[4,5-b]pyridin-2-yl; 1-Ethyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl; 3-Methoxyquinoxalin-6-yl; 3-(trifluoromethyl)pyridin-4-yl; 4-cyclopropylphenyl; 4-methoxyphenyl; 4-fluorophenyl; 4-cyclopropyl-phenyl; 4-(trifluoromethyl)phenyl; 4-methylphenyl; 4-(difluoromethyl)phenyl; 4-isopropoxyphenyl; 2-fluoro-4-(trifluoromethyl)phenyl; 4-cyclopropyl-2-fluorophenyl; 2,4-difluorophenyl; 4-cyclopropyl-2-fluorophenyl; 4-fluoro-2-(trifluoromethyl)phenyl; 3-methoxy-4-(trifluoromethyl)phenyl; 4-fluoro-3-methoxyphenyl; 2,6-difluorophenyl 2,6-Difluoro-4-methoxyphenyl; 2,5-Difluoro-4-methoxyphenyl; Naphth-2-yl; 3,4-Dihydro-2H-benzo[b][1,4]oxazin-6-yl; Scherman-4-yl; Scherman-6-yl; 4,4-Difluoro-Scherman-6-yl; 1,2,3,4-Tetrahydronaphth-1-yl; 2,3-Dihydro-1H-inden-1-yl; 5-Isopropoxypyridin-2-yl; 6-Isopropoxypyridin-3-yl; 6-(trifluoromethyl)pyridin-3-yl; 3,5-Difluoropyridin-2-yl; 3,5-Difluoropyridin-4-yl; 1-Ethyl-4-cyano-1H-pyrazol-3-yl; Quinoline-2-yl; Isoquinoline-3-yl; Isoquinoline-6-yl; Isoquinoline-7-yl; 1,8-Naphthyl 2-pyridinyl; quinoxalin-6-yl; quinoxalin-2-yl; [1,2,4]triazolo[1,5-a]pyridin-7-yl; benzo[d]thiazolyl; 2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-6-yl; 3,3-dimethyl-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-6-yl; 4-(trifluoromethoxy)phenyl; 4-fluorophenyl; 4-acetamidophenyl; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 5-fluoropyridinyl; 2-pyrazinyl; 2-pyrimidinyl; 2-pyrimidinyl; 7-yl; 3-methylisoquinoline-7-yl; 6-pyridinyl; 6-pyrimidinyl; 7-yl; or 4-pyrimidinyl.

[0078] In some embodiments, the compound of formula (I) is the compound of formula (If).

[0079]

[0080] Where R 1 R 2 R 4 R 5 R 7 R 8 R 9 R 10 X 2 X 3 L 1 Cy 1 As defined in equation (I). Detailed Implementation

[0081] definition

[0082] The following terms have indicative meanings throughout the specification:

[0083] As used herein, including the appended claims, unless the context clearly indicates otherwise, the singular forms of “a,” “an,” and “the” include their respective plural references.

[0084] Unless the context clearly indicates otherwise, the term “or” means the term “and / or” and is used interchangeably with the term “and / or”.

[0085] The term "alkyl" refers to a alkyl group selected from straight-chain and branched saturated hydrocarbon groups derived from alkanes by removing a hydrogen atom from the same carbon atom, containing 1 to 18, such as 1 to 12, further such as 1 to 10, even further such as 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 groups include, but are not limited to: methyl, ethyl, 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or sec-butyl (“s-Bu”), 1,1-dimethylethyl or tert-butyl (“t-Bu”), 1-pentyl, 2- The alkyl group may be enriched with deuterium, for example, -CD3, -CD2CD3, etc. The term "alkylene" refers to a alkyl group selected from straight-chain and branched saturated hydrocarbon groups derived from alkanes by removing two hydrogen atoms from the same carbon atom, containing 1 to 6, such as 1 to 4 carbon atoms, further such as 1 to 3, and even further such as 1, 2 or 3 carbon atoms, including but not limited to methylene (-CH2-), ethylene (-CH2CH2-), 1-methylmethylene (-CH(CH3)-) or trimethylene (-CH2CH2CH2-).

[0086] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0087] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, and iodine). Examples of haloalkyl groups include halogenated C-type alkyl groups. 1-8 Alkyl, Halogenated C 1-6 Alkyl or halogenated C 1-4 Alkyl groups, but not limited to -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0088] The term "alkyloxy" or "alkoxy" refers to an alkyl group, as defined above, attached to a portion of the parent molecule via an oxygen atom. Alkyloxy groups (e.g., C1646) 1-6 Alkyloxy or C 1-4 Examples of alkyloxy groups include, but are not limited to: methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, and hexoxy.

[0089] The term "amino" refers to –NH2.

[0090] The term "alkenyl" as used herein refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups comprising at least one C=C double bond and 2 to 18 (e.g., 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: vinyl or vinyl, propenyl, propenyl, 2-propenyl, 2-methylpropenyl, butenyl, butenyl, butenyl, 3-alkenyl, butane-1,3-dienyl, 2-methylbutenyl, hexenyl, hexenyl, 2-alkenyl, hexenyl, 3-alkenyl, hexenyl, and 1,3-dienyl groups.

[0091] The term "alkynyl" as used herein refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups comprising at least one C≡C triple bond and 2 to 18 (e.g., 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 (propynyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0092] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cycloalkyl groups that contain monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyl groups.

[0093] 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, or 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., C16, C26 ... 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embodiment, the cycloalkyl group is a monocyclic ring (abbreviated as C16) containing 3 to 6 carbon atoms. 3-6Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms, having a fused bicyclic arrangement (selected from the [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems) or having a bridged bicyclic arrangement (selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane). Further examples of dicyclic cycloalkyl groups include those having a bicyclic arrangement (selected from the [5,6] and [6,6] ring systems).

[0094] This document uses the term "deuteration" to modify a chemical structure or organic group (group or radical) in which one or more carbon-bonded hydrogen atoms are replaced by one or more deuterium atoms, such as "deuterated alkyl", "deuterated cycloalkyl", "deuterated heterocycloalkyl", "deuterated aryl", "deuterated morpholino", etc. 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 is replaced by deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to deuterium; and the carbon atom may be bonded to at most one deuterium atom; more than one carbon atom in an alkyl group may also be bonded to deuterium.

[0095] The term "aryl" used alone or in combination with other terms refers to a group selected from the following:

[0096] 5- and 6-membered carbon-ring aromatic rings, such as phenyl;

[0097] Bicyclic systems (such as 7- to 12-membered bicyclic systems), wherein at least one ring is a carbocyclic and aromatic, such as naphthyl and indanyl; and,

[0098] Tricyclic systems (such as decacyclic to 15-membered tricyclic systems) in which at least one ring is a carbocyclic and aromatic, such as fluorene.

[0099] The terms "aromatic ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic ring has 5 to 10 cyclic carbon atoms (i.e., C64, C16, C26 ... 5-10 Aryl). Examples of monocyclic or bicyclic aromatic rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthraceneyl, phenanthrene, etc. In some embodiments, the aromatic ring is a naphthyl ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic ring is a phenyl ring.

[0100] The term "heteroaryl" in this article refers to groups selected from the following:

[0101] - A 5-, 6-, or 7-membered aromatic monocyclic ring comprising at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O) (e.g., from 1 to 4, or in some embodiments from 1 to 3, or in some embodiments from 1 to 2 heteroatoms), wherein the remaining ring atoms are carbon;

[0102] -7 to 12-membered bicyclic rings comprising at least one heteroatom (e.g., from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2 heteroatoms) selected from nitrogen, oxygen, or optionally oxidized sulfur as a ring member, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0103] -11 to 14-membered tricyclic rings comprising at least one heteroatom (e.g., from 1 to 4, or from 1 to 3 in some embodiments, or 1 or 2 heteroatoms in other embodiments) selected from nitrogen, oxygen, or optionally oxidized sulfur as a ring member, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0104] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle does not exceed 1. When a heteroaryl group contains more than one heteroatom ring member, these heteroatoms can be the same or different. The nitrogen atom in one or more rings of a heteroaryl group can be oxidized to form N-oxides.

[0105] The term “optionally oxidized sulfur” as used in this article refers to -S-, SO, or SO2.

[0106] 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 cyclic members, wherein 1, 2, 3, or 4 heteroatomic ring members are independently selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring members are carbon. In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatomic 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 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic aromatic heterocycle is an 8- to 10-membered heteroaryl ring, which is bicyclic and has 1 or 2 heteroatomic ring members independently selected from nitrogen, sulfur, and oxygen.

[0107] Examples of heteroaryl groups or monocyclic or bicyclic aromatic heterocycles, but not limited to (as numbered starting from the connection position specified as priority 1), include: 1H-pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, or 1H-pyrazol-5-yl), pyridyl (or pyridinyl) (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cyclolinyl, pyrazinyl, pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, or 2,4-pyrimidinyl, 3,5-pyrimidinyl), imidazoleyl (e.g., 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, or 2,4-imidazolyl), imidazopyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl. (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), tetrazolyl, thiophene (e.g., thiophene-2-yl, thiophene-3-yl), triazinyl, benzothiophene, furanyl (furyl or furanyl), benzofuranyl, benzimidazolyl, indoleyl (e.g., 1H-indole-2-yl, 1H-indole-3-yl, 1H-indole-4-yl, 1H-indole-5-yl, 1H-indole-6-yl or 1H-indole-7-yl), isoindoleyl, dihydroindoleyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl (e.g., pyrazin-2-yl), pyridazinyl, pyrroleyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl), quinolinyl (such as quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, or quinolin-7-yl), isoquinolinyl (such as isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl), , isoquinoline-7-yl, or isoquinoline-8-yl), pyrazolyl, pyrrolopyridyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), pteridinyl, purineyl, 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 (e.g., furazan-2-yl, furazan-3-yl), benzofurazanyl, benzobenzylthio, benzothiazolyl, benzoxazolyl (e.g., benzo[d]oxazol-2-yl) Benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl or benzo[d]oxazol-7-yl), quinazolinyl, quinoxolinyl (such as quinoxolin-2-yl, quinoxolin-3-yl, quinoxolin-4-yl, quinoxolin-5-yl, quinoxolin-6-yl, quinoxolin-7-yl or quinoxolin-8-yl), naphthidyl (such as 1,8-Naphthidin-2-yl, 1,8-Naphthidin-3-yl, or 1,8-Naphthidin-4-yl), 2,3-dihydro-[1,4]dioxin[2,3-b]pyridyl (e.g., 2,3-dihydro-[1,4]dioxin[2,3-b]pyridyl-6-yl, 2,3-dihydro-[1,4]dioxin[2,3-b]pyridyl-7-yl, or 2,3-dihydro-[1,4]dioxin[2,3-b]pyridyl-8-yl), furanopyridyl, benzothiazolyl (e.g., benzo[d]thiazolyl-2-yl, benzo[d]thiazolyl-4-yl, benzo[d]thiazolyl-5-yl, benzo[d]thiazolyl, benzo[d]thiazolyl-5-yl, benzo[d]thiazolyl-6-yl, benzo[d]thiazolyl-7-yl, or benzo[d]thiazolyl-8-yl), furanopyridyl, benzothiazolyl (e.g., benzo[d]thiazolyl-2-yl, benzo[d]thiazolyl-4-yl, benzo[d]thiazolyl-5-yl, benzo[d]thiazolyl-5-yl, benzo[d]thiazolyl-6-yl, benzo[d]thiazolyl-7-yl, or benzo[d]thiazolyl-8-yl), furanopyridyl, benzo[d]thiazolyl, furanopyridyl, furanothiazolyl, furanothiazolyl, furanothiazolyl, furanothiazolyl, furanothiazolyl, furanothiazolyl, furanothiazolyl, fur [1,2,4]triazol[1,5-a]pyridyl (e.g., [1,2,4]triazol[1,5-a]pyridyl, [1,2,4]triazol[1,5-a]pyridyl, [1,2,4]triazol[1,5-a]pyridyl, [1,2,4]triazol[1,5-a]pyridyl, [1,2,4]triazol[1,5-a]pyridyl-2-yl, [1,2,4]triazol[1,5-a]pyridyl-5-yl, [1,2,4]triazol[1,5-a]pyridyl-6 ... Triazolo[1,5-a]pyridin-7-yl, or [1,2,4]triazolo[1,5-a]pyridin-8-yl), 3H-imidazo[4,5-b]pyridinyl (such as 3H-imidazo[4,5-b]pyridin-2-yl, 3H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl or 3H-imidazo[4,5-b]pyridin-7-yl), 1H-imidazo[4,5-b]pyridinyl (such as 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-7-yl), [4,5-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-7-yl), [1,2,4]triazolo[1,5-a]pyridyl (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), indazole (such as 1H-indazole-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0108] In addition, "heteroaryl" fused with "heterocyclic group" is defined as "heteroaryl".

[0109] "Heterocyclic group", "heterocyclic" or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclic group (which contains one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, wherein the remaining ring members are carbon), including monocyclic, fused, bridged and spirocyclic, i.e. containing monocyclic heterocyclic groups, bridged heterocyclic groups, spirocyclic groups and fused heterocyclic groups.

[0110] The term "monocyclic heterocyclic group" refers to a monocyclic group in which at least one ring member is selected from a heteroatom of nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle may be saturated or partially saturated.

[0111] Exemplary monocyclic 4- to 9-membered heterocyclic groups include, but are not limited to: (numbered starting from the connection position designated as priority 1) pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, imidazolidine-2-yl, imidazolidine-4-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, ethylene oxide, acridine-1-yl, acridine-2-yl, azircyclic octyl-1-yl, azircyclic octyl-2-yl, azircyclic octyl-3-yl, azircyclic octyl-4-yl, azircyclic octyl-5-yl, thiiranyl, azircyclic butane-1-yl, azircyclic butane -2-yl, azacyclobutane-3-yl, oxacyclobutane, thiocyclobutane, 1,2-thiocyclobutane, 1,3-thiocyclobutane, dihydropyridyl, tetrahydropyridyl, thiomorpholinyl, oxothiocyclohexyl, piperazinyl, homopiperazinyl, homopiperidinyl, azacycloheptane-1-yl, azacycloheptane-2-yl, azacycloheptane-3-yl, azacycloheptane-4-yl, oxacycloheptane, thiocycloheptyl, 1,4-oxothiocyclohexyl, 1,4-dioxacycloheptane, 1,4-oxothiocycloheptane, 1,4-oxazazacycloheptane, 1,4-dithiocycloheptane, 1,4-thiazepanyl and 1,4-diazacycloheptane, 1,4-dithiazyl, 1,4-azathiazyl, oxacycloheptane basalt, diazoxide Basic, sulfur-nitrogen The following are listed: 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxane, 1,3-dioxolane, pyrazolinyl, pyrazolaneyl, dithianeyl, dithiopentaneyl, pyrazolaneyl, imidazolinyl, pyrimidinoneyl, or 1,1-dioxo-thiomorpholinyl.

[0112] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group having rings linked by a shared carbon atom (called a spiro atom), comprising one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the remaining ring members being carbon. One or more rings of the spiroheterocyclic group may contain one or more double bonds, but none of the rings has a fully coupled π-electron system. Preferably, the spiroheterocyclic group is 6- to 14-membered, and more preferably 7- to 12-membered. Depending on the number of shared spiro atoms, spiroheterocyclic groups are classified as monospirocyclic, dispirocyclic, or polyspirocyclic, and preferably refer to monospirocyclic or dispirocyclic groups, and 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 monospirocyclic groups.

[0113] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group (where each ring in the system shares adjacent atom pairs (carbon and carbon atoms, or carbon and nitrogen atoms)) containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the remaining ring members being carbon. One or more rings of a fused heterocyclic group may contain one or more double bonds, but none of the rings has a fully coupled π-electron system. Preferably, the fused heterocyclic group is 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of member rings, fused heterocyclic groups are classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, and more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Representative examples of fused heterocycles include, but are not limited to, the following groups: octahydrocyclopenta[c]pyrrole (e.g., octahydrocyclopenta[c]pyrrole-2-yl), octahydropyrrolo[3,4-c]pyrroleyl, octahydroisoindolyl, isoindololinyl (e.g., isoindololin-2-yl), and octahydro-benzo[b][1,4]dioxin.

[0114] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic alkyl group (where each pair of rings in the system shares two discontinuous atoms), containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, wherein the remaining ring members are carbon. One or more rings of the bridged heterocyclic group may contain one or more double bonds, but none of the rings has a fully coupled π-electron system. Preferably, the bridged heterocyclic group is 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of member rings, bridged heterocyclic groups are classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, and preferably refer to bicyclic, tricyclic, or tetracyclic bridged heterocyclic groups, and more preferably bicyclic or tricyclic bridged heterocyclic groups. Representative examples of bridging heterocyclic groups include, but are not limited to, the following groups: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3.3.2]decyl.

[0115] 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-overlapping mirror images of each other. When the compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader category of stereoisomers. This is intended to include all possible stereoisomers, such as substantially pure, resolved enantiomers, their racemic mixtures, and mixtures of diastereomers. This is intended to include all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specified, reference to one isomer applies to any possible isomer. Whenever the composition of an isomer is not specified, all possible isomers are included.

[0116] As used herein, the term "substantially pure" means that the title stereoisomer contains no more than 35% by weight, such as no more than 30%, further such as no more than 25%, or even further such as no more than 20% of any one or more other stereoisomers. In some embodiments, the term "substantially pure" means that the title stereoisomer contains no more than 10% by weight, for example no more than 5%, such as no more than 1% of any one or more other stereoisomers.

[0117] When the compounds disclosed herein contain alkene double bonds, such double bonds are intended to include E and Z geometric isomers unless otherwise stated.

[0118] When the compounds disclosed herein contain a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring can be formed in cis and trans arrangements. Cis formation means that both substituents are located above the two substituent positions on the carbon atom, while trans formation means that they are located on opposite sides.

[0119] It may be advantageous to separate the reaction products from each other and / or from the starting material. The desired products of each step or series of steps are separated and / or purified (hereinafter referred to as separations) to the desired homogeneity using techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or rapid column chromatography. Rapid column chromatography can involve a variety of methods, including, for example: reversed-phase and normal-phase; size exclusion; ion exchange; high, medium, and low-pressure liquid chromatography rapid column chromatography methods and apparatus; small-scale analysis; simulated moving bed (“SMB”) and preparative thin-layer or thick-layer rapid column chromatography, as well as techniques for small-scale thin-layer and rapid column chromatography. Those skilled in the art will apply the techniques most likely to achieve the desired separations.

[0120] "Diarrhetinic isomers" refer to stereoisomers of compounds having two or more chiral centers that are not mirror images of each other. Mixtures of diastereomers can be separated into their individual diastereomers based on their physicochemical differences using methods well known to those skilled in the art (such as rapid column chromatography and / or stepwise crystallization). Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into their corresponding pure enantiomers. Enantiomers can also be separated using chiral HPLC columns.

[0121] A single stereoisomer (e.g., a substantially pure enantiomer) can be obtained by resolving a racemic mixture using an optically active resolving agent to form diastereomers (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH et al., “Flashcolumn chromatographyic resolution of enantiomers: Selective review.” J. Chromatogr., 113(3)(1975): 283-302). Racemic mixtures of the chiral compounds of the present invention can be separated and isolated by any suitable method comprising: (1) forming ionic diastereomeric salts with the chiral compounds and separating them by stepwise crystallization or other methods; (2) forming diastereomeric compounds with chiral derivatizing agents, separating these diastereomeric compounds and converting them into pure stereoisomers; and (3) directly separating substantially pure or enriched stereoisomers under chiral conditions. See: Wainer, Irving W. ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993. The absolute configuration of the chiral center in the compound can be determined using methods known to those skilled in the art, such as single-crystal X-ray crystallography or cocrystallization of the target compound with the targeted protein, sometimes coupled with spectroscopic techniques (e.g., NMR spectroscopy). In some embodiments, the absolute configuration of the chiral center in the compound can be elucidated from the X-ray single-crystal structure of the compound. In some embodiments, the absolute configuration of the chiral center elucidated by the X-ray crystal structure of a compound can be used to infer the absolute configuration of the corresponding chiral center in another compound or intermediate obtained by the same or similar synthetic methods.

[0122] The term "pharmaceutically acceptable salt" refers to salts that, to the extent of reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately prepared by reacting the free base functional group with a suitable organic acid, or separately prepared by reacting the acidic group with a suitable base.

[0123] "Selective inhibitory activity" or "selectivity" refers to the difference in the degree of inhibition against DGKα and DGKζ; the greater the degree of inhibition achieved against a particular isoform relative to another isoform, the greater the selectivity of the inhibitor for that particular isoform. In some embodiments, "a compound exhibiting selective inhibitory activity against DGKα exceeding that against DGKζ" refers to a compound exhibiting an IC50 against DGKα no greater than about 2000 nM and an IC50 ratio against DGKζ to that against DGKα greater than or equal to about 20; "a compound exhibiting selective inhibitory activity against DGKζ exceeding that against DGKα" refers to a compound exhibiting an IC50 against DGKζ no greater than about 2000 nM and an IC50 ratio against DGKα to that against DGKζ greater than or equal to about 20; "a compound exhibiting dual inhibitory activity" refers to a compound exhibiting inhibitory activity against both DGKα and DGKζ, wherein the IC50 is no greater than 500 nM and the ratio of the two IC50 values ​​is no greater than 20.

[0124] Furthermore, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by alkalizing the solution of the acid salt. Conversely, if the product is a free base, the addition salt (such as a pharmaceutically acceptable addition salt) can be produced by following the conventional procedure for preparing acid addition salts from base compounds, by dissolving the free base in a suitable organic solvent and treating the solution with acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts without excessive experimentation.

[0125] As defined herein, a “pharmaceutically acceptable salt” includes a salt of at least one compound of formula (I), and a salt of a stereoisomer of a compound of formula (I), such as an enantiomer salt, and / or a diastereomer salt.

[0126] The terms “administration” and “treatment” as used herein, when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, mean contact between an exogenous drug, therapeutic agent, diagnostic agent, or composition and the animal, human, subject, cell, tissue, organ, or biological fluid. Cell treatment encompasses contact between a reagent and a cell, as well as contact between a reagent and a fluid, wherein the fluid contacts the cell. The terms “administration” and “treatment” also mean, for example, in vitro and ex vivo treatment of cells by means of a reagent, diagnostic agent, conjugated compound, or another cell. The term “subject” as used herein includes any biological entity, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit), and most preferably a human.

[0127] The term "effective amount" or "therapeutic effective amount" refers to the 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 the treatment of such disease, disorder, or symptom. "Therapeutic effective amount" can vary depending on the compound, the disease, disorder, and / or the symptom of the disease or disorder, the severity of the disease, disorder, and / or the age of the subject being treated, and / or the weight of the subject being treated. An appropriate amount in any given situation may be obvious to those skilled in the art or may be determined by routine experiments. In some embodiments, "therapeutic effective amount" is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, as defined above, that is effective in treating a subject's disease or disorder. In the case of combination therapies, "therapeutic effective amount" refers to the total amount of the combination of substances used to effectively treat a disease, disorder, or symptom.

[0128] Pharmaceutical compositions containing the compounds disclosed herein may be administered to subjects in need via oral, inhalation, rectal, parenteral, or topical administration. For oral administration, the pharmaceutical composition may be a conventional solid formulation, such as tablets, powders, granules, capsules, etc.; a liquid formulation, such as an aqueous or oil suspension; or other liquid formulations, such as syrups, solutions, suspensions, etc. For parenteral administration, the pharmaceutical composition may be a solution, aqueous solution, oil suspension concentrate, lyophilized powder, etc. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably tablets or capsules. The pharmaceutical composition may be administered as a single unit with a precise dosage. In addition, the pharmaceutical composition may further contain other active ingredients.

[0129] All formulations of the pharmaceutical compositions disclosed herein can be produced using conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients to form the desired formulation. "Pharmaceutically acceptable excipients" refer to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as: diluents, transport carriers (e.g., water, various organic solvents), fillers (e.g., starch, sucrose), binders (e.g., cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone (PVP)); wetting agents, such as glycerin; disintegrants, such as agar, calcium carbonate, and sodium bicarbonate; absorption enhancers, such as quaternary ammonium compounds; surfactants, such as hexadecyl alcohol; absorbent carriers, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, and polyethylene glycol. In addition, the pharmaceutical compositions may also contain other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, aromatic compounds, sweeteners, and dyes.

[0130] The term “disease” refers to any illness, discomfort, ailment, symptom, or indication and is interchangeable with the terms “disorder” or “symptom”.

[0131] Throughout this specification and the appended claims, unless the context otherwise requires, the term "comprising" and variations such as "including" and "containing" are intended to specify the presence of the following feature but do not exclude the presence or addition of one or more other features. When used herein, the term "comprising" may be replaced by the terms "containing" or "including," or sometimes by "having."

[0132] Throughout this specification and the appended claims, the term "Cn-m" indicates a range including the endpoints, where n and m are integers and indicate the number of carbon atoms. Examples include C 1-8 C 1-6 wait.

[0133] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0134] abbreviation:

[0135]

[0136]

[0137]

[0138] General synthesis scheme

[0139] The compounds disclosed herein (including their salts) can be prepared using known organic synthesis techniques and can be synthesized according to any of the many possible synthetic pathways.

[0140] The reactions for preparing the compounds disclosed herein can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents are substantially non-reactive with the starting materials, intermediates, or products at the temperature at which the reaction takes place (e.g., at temperatures ranging from room temperature to the boiling point of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent.

[0141] The selection of appropriate protective groups can be readily determined by those skilled in the art.

[0142] The reaction can be monitored using any suitable method known in the art (e.g., NMR, UV, HPLC, LC-MS, and TLC). The compound can be purified using a variety of methods, including HPLC and normal-phase silica gel rapid column chromatography.

[0143] Chiral analytical HPLC was used for retention time analysis of different chiral examples, and the conditions were categorized as follows based on the column, mobile phase, and solvent ratio used. The preparation of pure chiral examples can be performed using techniques known to those skilled in the art. Absolute stereochemistry was not specified at the newly formed carbon-nitrogen bonds.

[0144] The compounds disclosed in this article can be prepared by the following schemes I to V.

[0145] Option I

[0146]

[0147] From R 1 To R 9 and R 8L (corresponding to L) 1 -Cy 1 The substitution of ) is defined as mentioned in equation (I).

[0148] In Scheme I, commercially available compound 1 is protected with THP or SEM to obtain compound 2. Compound 2 is reduced under reducing conditions (e.g., Pd-C / H2 or Fe powder / NH4Cl) to form compound 3, which is an amine. Compound 3 is acetylated with acetyl chloride or acetic anhydride to give compound 4, which is then reacted with a suitable R... 1 -X / R 1-OTf reacts under basic conditions (e.g., Cs₂CO₃, NaH, or t-BuOK) to give compound 5. Compound 5 is further cyclized under basic conditions (e.g., LiHMDS, NaHMDS, or KHMDS) to give compound 6. Compound 6 is reacted with a trifluoromethanesulfonate reagent (e.g., Tf₂O or PhNTf₂) or phosphoryl chloride to give compound 7. Compound 7 is reacted with a suitable chiral secondary amine via a nucleophilic aromatic substitution reaction to give compound 8. The protected group on the amine of compound 8 is removed under acidic conditions (e.g., TFA, or a 1,4-dioxane solution of 4M HCl) to give compound 9. The most common procedure is to N-alkylate secondary amine 9 to prepare tertiary amine 10 via phosphonium salt-mediated alkylation of the amine with the corresponding alcohol, either by treatment with an alkylating agent (such as an alkyl halide or sulfonate) or by reductive alkylation with an aldehyde or ketone (Florencio Zaragoza and Henrik Stephensen, J. Org. Chem. [Journal of Organic Chemistry] 2001, 66, 2518-2521). Deprotection of compound 10 under acidic conditions (such as TFA, or a 1,4-dioxane solution of 4M HCl) yields compound 11. Conventional reaction methods, such as copper-catalyzed Chan-Lam reaction of compound 11 with the corresponding alkenylboronic ester, or alkylation, alkenylation, acylation, or sulfonation under alkaline conditions (such as Cs₂CO₃, NaH, or t-BuOK) with the corresponding alkyl halide, or with the corresponding alkylsulfonyl chloride / aliphatic acyl chloride, under condensation conditions (such as Et₃N / HATU), yield compound 12 (where R...). 2 (where R is H), and compounds of formula 12 (where R is H). 2 The halogenation reaction of H with an electrophilic halogenating agent (such as NBS, NCS, or selectfluor) yields a compound of formula 12 (where R is H). 2 (where R is F, Cl or Br), then a compound of formula I (where R is F, Cl or Br) 2 (Br) can also be used to prepare compounds of formula 12 (where R is Br) by coupling with Zn(CN)2 and 2,4,6-trimethylcyclotriboroxane via a Pd-catalyst. 2 (For CN or Me).

[0149] Compound 10 disclosed herein can also be prepared via scheme II.

[0150] Option II

[0151]

[0152] In Scheme II, compound 2b is prepared by N-alkylation of secondary amine compound 1b via treatment with an alkylating agent (such as an alkyl halide or sulfonate) or by reductive alkylation with an aldehyde or ketone. The most common procedure is N-alkylation of the amine with the corresponding alcohol via phosphonium salt-mediated alkylation of the amine and the corresponding alcohol. Compound 2b is deprotected under acidic conditions (such as TFA, or a 1,4-dioxane solution of 4M HCl) to give compound 3b. Compound 3b reacts with compound 7 via a nucleophilic aromatic substitution reaction to give compound 10.

[0153] The compound of formula 12 disclosed herein can also be prepared by the following scheme III.

[0154] Option III

[0155]

[0156] In Scheme III, the protected group on the amine of compound 8 is removed under acidic conditions (such as TFA, or a 1,4-dioxane solution of 4M HCl) to obtain compound 1c. Compound 1c is selectively protected on the nitrogen atom of piperazine with Boc2O to obtain compound 2c. Compound 2c is alkylated with the corresponding alkyl halide under alkaline conditions (such as Cs2CO3, NaH, or t-BuOK) to obtain compound 3c. Compound 3c is deprotected under acidic conditions (such as TFA, or a 1,4-dioxane solution of 4M HCl) to obtain compound 4c. Compound 4b is prepared by N-alkylation of the secondary amine compound 4b by treatment with an alkylating agent (such as an alkyl halide, sulfonate, etc.) or by reductive alkylation with an aldehyde or ketone. The most common procedure is N-alkylation of the secondary amine compound 4b via phosphonium salt-mediated alkylation of the amine with the corresponding alcohol.

[0157] Compound 10d disclosed in this article can also be prepared by the following IV method.

[0158] Option IV

[0159]

[0160] In Scheme IV, PG 2 Installation via compound 4 with appropriate R 1Alkylation of X (such as PMB-Cl or DMB-Cl) under alkaline conditions (such as Cs2CO3 or NaH) yields compound 5d; cyclization under alkaline conditions (such as lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, etc.) yields compound 6d, which is subsequently reacted with a trifluoromethanesulfonate reagent (such as trifluoromethanesulfonic anhydride, N-phenylbis(trifluoromethanesulfonyl)imide) or phosphoryl chloride to yield compound 7d, which reacts with the corresponding secondary amine 3b via a nucleophilic aromatic substitution reaction to yield compound 8d. Removal of the protecting group of compound 8d under strong acid conditions (such as TfOH or TFA) yields compound 9d; selective N-alkylation of the pyrazole of compound 9d by treatment with the corresponding alkyl halide yields compound 10d.

[0161] The compound of formula 10A disclosed in this article can also be prepared by the following scheme V.

[0162] Option V

[0163]

[0164] In scheme V, commercially available compound 1A is ammonolyzed to give compound 2A, which is then reduced under suitable reducing conditions (e.g., Pd-C / H2 or Fe powder / NH4Cl) to give compound 3A. Compound 3A then reacts with the corresponding sulfonyl chloride under alkaline conditions (e.g., Et3N or pyridine) to give compound 4A, which reacts with a suitable R... 1 X / R 1 OTf reacts under alkaline conditions (e.g., K₂CO₃, Cs₂CO₃, or NaH) to give compound 5A. The protected group on the amine of compound 5A is removed with 2-mercaptoacetic acid to give compound 6A. Compound 6A is treated with 1,1'-carbonyldiimidazole under alkaline conditions (e.g., NaH) to give cyclized compound 7A. The amine moiety 3b is assembled by chlorination with phosphoryl chloride to give a chlorinated intermediate, which is reacted with 3b to prevent hydrolysis, giving compound 8A. This intermediate is deprotected under acidic conditions (e.g., TFA, or a 1,4-dioxane solution of 4M HCl) to give compound 9A. Compound 9A is then alkylated with the corresponding alkyl halide under alkaline conditions (e.g., Cs₂CO₃ or NaH) to give compound 10A.

[0165] Example

[0166] The following examples are intended to be purely illustrative and should not be construed as limiting in any way. Unless otherwise stated, the experimental methods used in the examples below are conventional methods. Unless otherwise stated, reagents and materials are commercially available. All solvents and chemicals used are analytical grade or chemically pure. All solvents were redistilled before use. Anhydrous solvents were prepared according to standard or reference methods. Silica gel (100-200 mesh) for rapid column chromatography and silica gel (GF254) for thin-layer rapid column chromatography (TLC) are commercially available from Qingdao Haiyang Chemical Co., Ltd. or Yantai Chemical Co., Ltd., China; unless otherwise stated, all were eluted with petroleum ether (60°C-90°C) / ethyl acetate (v / v) and developed with a solution of iodine or phosphomolybdic acid in ethanol. Unless otherwise stated, all extraction solvents were dried over anhydrous Na₂SO₄.

[0167] Recorded on a Bruck-400 nuclear magnetic resonance spectrometer using TMS (tetramethylsilane) as an internal standard. 1 1H NMR spectra. LC / MS data were recorded using an Agilent 1100 high-performance liquid chromatography-rapid column chromatography-ion trap mass spectrometry (LC-MSD trap) equipped with a diode array detector (DAD) for detection at 214 nm and 254 nm and an ion trap (ESI source). All compound names except reagents are provided by [the relevant authority / organization]. Generation. Single-crystal X-ray crystallography is used to elucidate the absolute configuration of chiral centers in compounds. For example, single-crystal X-ray crystallography determines that the compounds disclosed herein, such as compounds A2a, A2b, A22a, A22b, A133, A134, A269c, A269d, A274, A301, A302, A303, A317, A318, A319, or A336, have the desired configuration.

[0168] synthesis

[0169] Preparative HPLC conditions (Method A)

[0170]

[0171]

[0172] Preparative HPLC conditions (Method B)

[0173] column Waters XSelect CSH C18, 150×19mm, 5μm Column temperature RT Detection wavelength DAD, UVλ = 214 / 254nm Runtime 17.0min Flow rate 17 mL / min Mobile phase A <![CDATA[0.03%NH3.H2O-H2O(v / v)]]> Mobile phase B <![CDATA[CH3CN]]>

[0174] Intermediate 1: 6-(1-((2R,5S)-2,5-dimethylpiperazin-1-yl)ethyl)quinoxaline

[0175] Step A: Quinoxalo-6-carboxylic acid methoxy-methyl-amide

[0176] HATU (136.8 g, 0.3 mmol), DIPEA (155 g, 1.2 mol), and N,N-dimethylhydroxylamine hydrochloride (35 g, 0.36 mol) were added to a solution of quinoxaloline-6-carboxylic acid (52.2 g, 0.3 mol) in DCM (1 L). The mixture was stirred at RT for 4 hours. The reaction mixture was diluted with DCM and washed with water. The organic layer was separated, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (67 g, 99%). 1 H NMR (400MHz, DMSO): δ9.05 (s, 2H), 8.31 (d, J = 1.8 Hz, 1H), 8.18 (d, J = 8.6 Hz, 1H), 8.03 (dd, J = 8.7, 1.8 Hz, 1H), 3.59 (s, 3H), 3.36 (s, 3H) ppm. MS:M / e 218(M+1) + .

[0177] Step B: 1-(quinoxalo-6-yl)ethyl-1-one

[0178] Magnesium methyl bromide (133 mL, 3 M, 0.39 mol) was added to a solution of quinoxaloline-6-carboxylic acid methoxy-methyl-amide (67 g, 0.3 mol) in THF (500 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, then at room temperature for 2 h. The reaction was quenched by adding an aqueous solution of NH4Cl. The resulting mixture was extracted with EA and then concentrated using a rotary evaporator to give a residue. The residue was purified by rapid column chromatography (PE:EA = 1:3) to give the title compound (41 g, 77%). MS: M / e 173 (M+1) + .

[0179] Step C: 1-(quinoxalo-6-yl)ethanol-1-ol

[0180] NaBH4 (6.7 g, 0.17 mol) was added to a solution of 1-(quinoxalo-6-yl)ethyl-1-one (40 g, 0.23 mol) in 200 mL of EtOH at 0 °C for 1 hour. The reaction was quenched by adding water. The mixture was extracted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (29 g, 62%). 1H NMR (400MHz, DMSO) δ8.93 (d, J = 9.0 Hz, 2H), 8.11-8.00 (m, 2H), 7.86 (t, J = 12. 6Hz, 1H), 5.52 (d, J = 4.2Hz, 1H), 5.07-4.92 (m, 1H), 1.44 (d, J = 6.4Hz, 3H) ppm. MS:M / e 175(M+1) + .

[0181] Step D: (2S,5R)-2,5-dimethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester

[0182] A solution of 1-(quinoxalo-6-yl)ethane-1-ol (22 g, 0.13 mol), (2S,5R)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (32 g, 0.15 mol), (cyanomethyl)trimethylphosphonium iodide (46 g, 0.19 mol), and DIPEA (65 g, 0.5 mol) in CH3CN (200 mL). The mixture was stirred overnight at 105 °C and cooled to room temperature, followed by removal of the solvent under reduced pressure. The resulting residue was diluted with water, extracted with EA, and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (32 g, 68%). 1 H NMR (400MHz, DMSO): δ8.92(dq,J=5.4,1.8Hz,2H),8.09(d,J=9.0Hz,1H),8.01(dd,J=6.0,1.3Hz,1H),7.95-7.89(m,1H),4.19-4.01(m,1H),3.98- 3.84(m,1H),3.74-3.63(m,1H),3.41(d,J=12.3Hz,1H),3.33-3.05(m,1H ),2.74-2.65(m,1H),1.98(d,J=14.2Hz,1H),1.39(d,J=2.4Hz,9H),1.33

[0183] -1.23(m,4H),1.20-1.03(m,2H),1.00-0.83(m,3H)ppm. MS:M / e 371(M+1) + .

[0184] Step E: 6-(1-((2R,5S)-2,5-dimethylpiperazin-1-yl)ethyl)quinoxaline (intermediate 1)

[0185] TFA (90 mL) was added to a solution of (2S,5R)-2,5-dimethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester (32 g) in DCM (300 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure. The resulting residue was diluted with water and extracted with EA. The aqueous layer was adjusted to pH 12-13 with saturated Na2CO3 solution, followed by extraction with DCM. The combined organic layers were washed with brine, then separated, dried over Na2SO4, filtered, and concentrated to give intermediate 1.

[0186] The residual intermediate 1 (18 g) obtained from the diastereomer mixture was chirally resolved by passing it through a C18 column (mobile phase B: MeOH; mobile phase A: H2O (0.5% NH3H2O)) to obtain intermediate 1a (first elution peak, 8 g, 34%) and intermediate 1b (later elution peak, 8 g, 34%).

[0187] Intermediate 1a: 1 H NMR (400MHz, DMSO-d6) δ8.93 (dd, J=6.8, 1.7Hz, 2H), 8.14-8.02 (m, 1H), 7.91 (s, 1H ),7.82(dd,J=8.7,1.7Hz,1H),4.46(q,J=7.0Hz,1H),2.97(dd,J=10.7,2.3Hz,1H), 2.72-2.59(m,2H),2.37-2.29(m,1H),2.05-2.01(m,1H),1.83(s,1H),1.51(d,J=7 .1Hz, 3H), 1.42 (t, J = 10.3Hz, 1H), 1.08 (d, J = 6.0Hz, 3H), 0.86 (d, J = 6.3Hz, 3H) ppm. MS:M / e 271(M+1) + .

[0188] Intermediate 1b: 1 H NMR (400MHz, CD3OD) δ8.90(dd,J=5.5,1.7Hz,2H),8.15(s,1H),8.12-8.05(m,2H),4.82(s,1H),3.50-3.40(m,1H),3.23(s ,2H),3.10-3.00(m,1H),2.67-2.50(m,2H),1.58(t,J=6.0Hz,3H),1.44(t,J=5.6Hz,3H),1.16(dd,J=6.5,2.6Hz,3H)ppm. MS:M / e 271(M+1) + .

[0189] Intermediate 2: 4-Methyl-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate

[0190] Step A: Methyl 4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate

[0191] DHP (84 g, 1 mol) was added in several portions to a solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (85.5 g, 0.5 mol) and TsOH·H₂O (9.5 g, 0.05 mol) in THF (0.6 L). The reaction was stirred at 80 °C for 16 h. The mixture was then cooled to room temperature and concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (121 g, 94%). 1 HNMR (400MHz, CDCl3): δ8.38 (s, 1H), 5.43 (dd, J = 2.4, 8.8Hz, 1H), 4.15-4.05 (m, 1H), 3.9 9(s,3H),3.78-3.68(m,1H),2.26-2.17(m,1H),2.01-1.85(m,2H),1.76-1.60(m,3H)ppm. MS:M / e 278(M+23) + .

[0192] Step B: Methyl 4-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate

[0193] Add (6 g) to a solution of methyl 4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (64 g and 57 g, two batches) in MeOH (300 mL). Stir the mixture at room temperature under a H2 atmosphere, filter, and wash with MeOH. Concentrate the combined filtrates to give the title compound (96 g, 90%). 1 HNMR (400MHz, CDCl3): δ7.21 (s, 1H), 5.33 (dd, J = 2.4, 9.6Hz, 1H), 4.11-4.02 (m, 1H ),3.92(s,3H),3.71-3.62(m,1H),2.12-1.90(m,3H),1.76-1.52(m,3H)ppm.MS:M / e 226(M+1) + .

[0194] Step C: Methyl 4-acetamido-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate

[0195] Ac₂O (60 mL) was added dropwise to a solution of methyl 4-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (96 g, 426 mmol) in pyridine (0.4 L) while maintaining the temperature below 20 °C. The resulting mixture was stirred at RT for 3 h and concentrated to dryness. The residue was recrystallized from PE / EA to give the title compound (84 g, 74%). 1 HNMR (400MHz, CDCl3): δ8.99(s,1H),8.43(s,1H),5.46-5.36(m,1H),4.12-4.03(m,1H) ,3.96(s,3H),3.74-3.60(m,1H),2.20(s,3H),2.14-1.96(m,3H),1.75-1.54(m,3H)ppm. MS:M / e 268(M+1) + .

[0196] Step D: Methyl 4-(N-methylacetamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate

[0197] Cs₂CO₃ (306 g, 943 mmol) was added to a solution of methyl 4-acetamido-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (84 g, 314.6 mmol) in DMF (0.5 L), followed by the addition of CH₃I (134 g, 943 mmol). The reaction mixture was stirred at room temperature (RT) for 16 h. The reaction mixture was filtered through diatomaceous earth and washed with DCM. The filtrate was concentrated, and the resulting residue was diluted with water, extracted with DCM (400 mL x 2), washed with brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (92 g, crude). 1 HNMR (400MHz, CDCl3): δ7.67(s,1H),5.47-5.36(m,1H),4.16-4.03(m,1H),3.92(s,3H),3.77-3.65(m,1H),3.18(s,3H),2.23-2.12(m,1H),2.09 -1.90(m,2H),1.87(s,3H),1.80-1.56(m,3H)ppm MS:M / e 282(M+1) + .

[0198] Step E: 7-hydroxy-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridine 5-Pyridoxine

[0199] A solution of LiHMDS (approximately 500 mL, 1 mol / L, approximately 1.6 equivalents) was added dropwise to a solution of methyl 4-(N-methylacetamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (88 g, 313 mmol) in THF (0.8 L) at -70 °C (forming a suspension). The reaction was stirred for 0.5 h, quenched with water, and slowly heated to RT. The resulting mixture was extracted with EA. The aqueous phase was collected, treated with citric acid to pH 3–4, and stirred at RT for 0.5 h to obtain a suspension. The suspension was filtered and dried to give the title compound (45.5 g). 1 HNMR (400MHz, DMSO-d6) δ11.24(s,1H),8.07(s,1H),5.65(s,1H),5.51(dd,J=2.4Hz,10.0Hz,1H),4.00-3.88(m,1H ),3.72-3.61(m,1H),3.31(s,3H),2.19-2.05(m,1H),2.03-1.89(m,2H),1.80-1.64(m,1H),1.61-1.50(m,2H)ppm. MS:M / e 250(M+1) + .

[0200] Step F: 4-Methyl-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridine Pyridine-7-yltrifluoromethanesulfonate (Intermediate 2)

[0201] A solution of 7-hydroxy-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (49.8 g, 200 mmol) in THF (0.5 L) was reacted with K₂CO₃ (55 g, 400 mmol), followed by 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (100 g, 943 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through diatomaceous earth and washed with EA. The filtrate was concentrated under reduced pressure. The resulting residue was diluted with water, washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography and further prepared into a slurry with EA / PE to give the title compound (70 g, 90%). 1 HNMR (400MHz, CDCl3) δ7.65 (s, 1H), 6.58 (s, 1H), 5.58 (dd, J = 2.8Hz, 8.0Hz, 1H), 4.11- 4.00(m,1H),3.82-3.70(m,1H),3.52(s,3H),2.26-1.96(m,3H),1.81-1.61(m,3H)ppm. MS:M / e 382(M+1) + .

[0202] Intermediate 3: 7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0203] Step A: (R)-2-(benzylamino)butyrate methyl ester

[0204] Benzyl bromide (146.1 g, 0.85 mol) was added to a solution of (R)-2-aminobutyrate methyl ester (100.0 g, 0.85 mol) in CH3CN (1000 mL) at 0 °C under a N2 atmosphere. The reaction was stirred overnight at room temperature and concentrated under reduced pressure. The resulting residue was dissolved in EA (1000 mL) and washed with water (1000 mL x 3). The organic layer was concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography (PE:EA = 10:1) to give the title compound (106 g, 60%). MS: M / e 208 (M+1) + .

[0205] Step B: (R)-2-((S)-N-benzyl-2-((tert-butoxycarbonyl)amino)butyrylamino)methyl butyrate

[0206] HATU (319.0 g, 0.84 mmol) was added to a solution of (R)-2-(benzylamino)butyrate (117.0 g, 0.56 mol), (S)-2-((tert-butoxycarbonyl)amino)butyric acid (170.5 g, 0.84 mmol), and 4-methylmorpholine (113.1 g, 1.12 mmol) in DCM (2000 mL) at 0 °C. The reaction was stirred overnight at room temperature, quenched with water, and washed with water (1500 mL x 2). The organic layer was concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography (PE:EA = 10:1) to give the title compound product (178 g, 80%). MS: M / e 393 (M+1) + .

[0207] Step C: Methyl (R)-2-((S)-2-amino-N-benzylbutyrylamino)butyrate

[0208] HCl (400 mL, 4 M, 1,4-dioxane solution) was added to a solution of (R)-2-((S)-N-benzyl-2-((tert-butoxycarbonyl)amino)butyrylamino)methyl butyrate (178 g, 0.45 mol) in 1,4-dioxane (100 mL) at room temperature. The resulting mixture was stirred at room temperature for another 2 hours and concentrated under vacuum to give a crude product (200 g, crude product). MS: M / e 293 (M+1) + .

[0209] Step D: (3S,6R)-1-benzyl-3,6-diethylpiperazine-2,5-dione

[0210] A solution of (R)-2-((S)-2-amino-N-benzylbutyrylamino)butyrate (200 g, crude) in EA (1000 mL) was added to an aqueous solution of 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 prepared with MTBE to give the title compound (61 g, 52% for both steps, ee: 97%). MS: M / e 261 (M+1) + .

[0211] Step E: (2R,5S)-1-benzyl-2,5-diethylpiperazine

[0212] A solution of (3S,6R)-1-benzyl-3,6-diethylpiperazine-2,5-dione (61.0 g, 0.23 mol) in THF (500 mL) was slowly added to a solution of LiAlH4 (26.5 g, 0.69 mol) in THF (1000 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 hours, and then stirred overnight at 80 °C. The reaction was slowly quenched at 0 °C with water (27 mL). Then, 1 N aqueous NaOH solution (54 mL) and water (81 mL) were added sequentially. The resulting mixture was stirred for 2 hours. The white precipitate formed was removed by filtration. The filter cake was washed with EA (500 mL). The combined filtrates were evaporated. The resulting residue was dissolved in toluene. The solvent was removed to dryness under vacuum to give the title compound (51 g, 95%). MS: M / e 233 (M+1) + .

[0213] Step F: 7-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran- 2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0214] A mixture of intermediate 2 (3.8 g, 10 mmol), (2R,5S)-1-benzyl-2,5-diethylpiperazine (3.6 g, 15 mmol), and DIPEA (6.4 g, 50 mmol) in CH3CN (50 mL) was heated to 105 °C overnight under N2 atmosphere. The solvent was removed under vacuum. The crude product was purified by rapid column chromatography (DCM:MeOH = 15:1) to give the title compound (4.2 g, 90%). MS: M / e 464 (M+1) + .

[0215] Step G: 7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2, 4-Dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (Intermediate 3)

[0216] A mixture of 7-((2S,5R)-4-benzyl-2,5-diethylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (4.2 g, 9.1 mmol) and Pd / C (420 mg, 10% soluble in water) in MeOH (50 mL) was shaken overnight at room temperature under a nitrogen atmosphere (50 psi). The reaction mixture was filtered through diatomaceous earth. The filter cake was washed with EA (50 mL). The combined filtrates were concentrated to dryness to give the title compound (3.2 g, 94%). MS: M / e 374 (M+1) + .

[0217] Intermediate 4: 7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0218] Step A: (2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester.

[0219] DIPEA (3.71 g, 28.75 mmol) was added to a solution of 1-(quinoxalo-6-yl)ethanol-1-ol (1.0 g, 5.75 mmol), (2S,5R)-2,5-diethylpiperazine-1-carboxylic acid tert-butyl ester (1.68 g, 6.90 mmol), and (cyanomethyl)trimethylphosphonium iodide (2.1 g, 8.62 mmol) in CH3CN (12 mL). The mixture was degassed three times under a nitrogen atmosphere. The mixture was then stirred at 105 °C for 24 h. The reaction was quenched with saturated NH4Cl (20 mL) at room temperature. The resulting mixture was extracted with EA (35 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography to give the title compound (1.1 g, 48%). MS: M / e 399 (M+1) + .

[0220] Step B: 6-(1-((2R,5S)-2,5-diethylpiperazine-1-yl)ethyl)quinoxaline .

[0221] TFA (2 mL) was added to a solution of (2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.26 mmol) in DCM (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure to give the crude product (TFA salt). The crude product was alkalized to pH about 10 with Na2CO3 (4 M) and extracted with EA (35 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, and concentrated under reduced pressure to give the title compound (300 mg, 80%). 1 H NMR (400MHz, CDCl3) δ8.83(s,2H),8.06(s,2H),7.98-7.69(m,1H),4.50(s,1H),3.10-2.73(m,2H),2.62-2.39(m,2H),2.33-2.04(m,3H),1. 95-1.67(m,2H),1.66-1.57(m,1H),1.46-1.34(m,2H),1.32-1.14(m, 2H),1.05-0.96(m,1.5H),0.94-0.86(m,3H),0.76-0.71(m,1.5H)ppm. MS:M / e 299(M+1) + .

[0222] Step C: 7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl- 2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0223] DIPEA (206 mg, 1.6 mmol) was added to a solution of 6-(1-((2R,5S)-2,5-diethylpiperazin-1-yl)ethyl)quinoxaline (286 mg, 0.96 mmol) and intermediate 2 (305 mg, 0.8 mmol) in CH3CN (15 mL). The resulting mixture was heated at 90 °C and N2 for 96 hours, cooled to room temperature, diluted with water (50 mL), and extracted with EA (60 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by rapid column chromatography (DCM / MeOH = 15 / 1) to give the title compound (280 mg, 66%). MS: M / e 530 (M+1) + .

[0224] Step D: 7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl- 2,4-Dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (Intermediate 4)

[0225] TFA (4 mL) was added to a solution of 7-((2S,5R)-2,5-diethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (280 mg, 0.53 mmol) in DCM (4 mL). The resulting mixture was stirred overnight at room temperature. Another portion of TFA (2 mL) was added to the reaction mixture and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with a water / DCM mixture, alkalized to pH 7-8 with saturated NaHCO3 solution, and extracted with DCM (60 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and the resulting residue was purified by rapid column chromatography (DCM / MeOH = 10 / 1) to give the title compound (100 mg, 42%). MS:M / e 446(M+1) + .

[0226] Intermediate 5: 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0227] Step A: (2R,5S)-2,5-diethyl-4-(4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyrazol) tert-butyl pyridinium-7-yl)piperazine-1-carboxylate

[0228] HCl (5 mL, 4.0 M 1,4-dioxane solution) was added to a stirred solution of intermediate 3 (3 g, 8.04 mmol) in MeOH (20 mL). The reaction mixture was stirred over the weekend, concentrated to obtain a residue, which was treated with THF / H₂O (50 mL / 20 mL, v / v), followed by the addition of K₂CO₃ (3.3 g, 24.1 mmol), and then Boc₂O (1.75 g, 8.04 mmol). The mixture was then stirred for 1 hour, acidified with citric acid to pH 4–5, and extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (1.4 g, 45%). MS: M / e 390 (M+1) + .

[0229] Step B: (2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]) tert-butyl pyridin-7-yl)-2,5-diethylpiperazine-1-carboxylate

[0230] To a stirred solution of (2R,5S)-2,5-diethyl-4-(4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 3.6 mmol) in DMF / H2O (10 mL / 2 mL), K2CO3 (1.49 g, 10.8 mmol) was added, followed by 2-iodoacetonitrile (482.4 mg, 7.2 mmol). The reaction mixture was stirred overnight, poured into H2O (30 mL), and extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (1 g, 65%). MS: M / e 429 (M+1) + .

[0231] Step C: 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyridine Azo[4,3-b]pyridin-2-yl)acetonitrile (intermediate 5)

[0232] TFA (3 mL) was added to a stirred solution of (2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazine-1-carboxylic acid tert-butyl ester (1 g, 2.34 mmol) in CH2Cl2 (15 mL). The reaction mixture was then stirred for 5 hours, concentrated to obtain a residue, alkalized to pH 10-11 with saturated NaHCO3 aqueous solution, and extracted with CH2Cl2 / IPA (3 / 1, 30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the title compound (752 mg, 98%). 1 H NMR (400MHz, DMSO-d6) δ7.94(s,1H),5.59(s,2H),5.35(s,1H),4.31(s,1H),4.08(d,J=13.2Hz,1H),3.23(s,3H),3.04(d d,J=12.8,4.4Hz,1H),2.80-2.72(m,1H),2.65-2.59(m,1H),1.83-1.72(m,1H),1.64-1.41(m,3H),0.87-0.75(m,8H)ppm. MS:M / e 329(M+1) + .

[0233] Intermediate 6: 7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0234] Step A: (R)-2-(benzylamino)butyrate methyl ester.

[0235] (Bromomethyl)benzene (122.5 g, 716 mmol) was added dropwise to a solution of (R)-2-aminobutyric acid methyl chloride (100 g, 651 mmol) and K₂CO₃ (225 g, 1.628 mol) in CH₃CN (700 mL) 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 rapid column chromatography to give the title compound (70 g, 52%). MS: M / e 208 (M+1) + .

[0236] Step B: (R)-2-((S)-N-benzyl-2-((tert-butoxycarbonyl)amino)propionamido)methyl butyrate.

[0237] NMM (43 g, 422 mmol) was added to a solution of (R)-2-(benzylamino)butyrate (35 g, 169 mmol), (tert-butoxycarbonyl)-L-alanine (48 g, 254 mmol), and HATU (116 g, 304 mmol) in DCM (400 mL). 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 Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography to give the title compound (45 g, 70%). MS: M / e 379 (M+1) + .

[0238] Step C: (R)-2-((S)-2-amino-N-benzylpropamido)methyl butyrate hydrogen chloride.

[0239] HCl (119 mL, 4 M, 1 oxane solution) was added to a solution of (R)-2-((S)-N-benzyl-2-((tert-butoxycarbonyl)amino)propamido)butyrate (45 g, 119 mmol) in DCM (250 mL) 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) + .

[0240] Step D: (3S,6R)-1-benzyl-6-ethyl-3-methylpiperazine-2,5-dione.

[0241] Add EA (150 mL) to a solution of (R)-2-((S)-2-amino-N-benzylpropamido)butyrate methyl chloride (32 g, 102 mmol) in NaHCO3 (150 mL, 4 M). Stir the reaction mixture at room temperature for 2 hours. Dry the combined organic layers over Na2SO4 and concentrate under reduced pressure to give the title compound (22 g, 87%). MS: M / e 247 (M+1) +.

[0242] Step E: (2R,5S)-1-benzyl-2-ethyl-5-methylpiperazine.

[0243] LiAlH4 (6.2 g, 163 mmol) was added fractionally to a solution of (3S,6R)-1-benzyl-6-ethyl-3-methylpiperazin-2,5-dione (20 g, 81.3 mmol) in THF (300 mL) at 0 °C. The reaction mixture was stirred at 70 °C for 36 h and H2O (6.2 mL) was added, followed by the addition of NaOH (6.2 mL, 20%) and H2O (12.4 mL) at 0 °C to quench the reaction solution. After filtration, the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the title compound (11 g, 61%). MS: M / e 219 (M+1) + .

[0244] Step F: (2S,5R)-4-benzyl-5-ethyl-2-methylpiperazine-1-carboxylic acid tert-butyl ester .

[0245] Et3N (7.6 g, 75 mmol) was added to a solution of (2R,5S)-1-benzyl-2-ethyl-5-methylpiperazine (11 g, 50 mmol) and Boc2O (12 g, 55 mmol) in DCM (200 mL). 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 Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography to give the title compound (14 g, 69%). MS: M / e 319 (M+1) + .

[0246] Step G: (2S,5R)-5-ethyl-2-methylpiperazine-1-carboxylic acid tert-butyl ester .

[0247] AcOH (2 mL) was added to a solution of (2S,5R)-4-benzyl-5-ethyl-2-methylpiperazine-1-carboxylic acid tert-butyl ester (10 g, 31.4 mmol) and Pd / C (2.5 g, 10% soluble in water) in MeOH (60 mL) at room temperature. The resulting mixture was degassed three times under H2 atmosphere and stirred for 12 hours at room temperature and under H2 atmosphere. After filtration, the combined organic layers were concentrated under reduced pressure to give a crude product (AcOH salt). The crude product was alkalized to pH about 10 with Na2CO3 (4 M) and extracted with EA (80 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, and concentrated under reduced pressure to give the title compound (5.5 g, 77%). 1HNMR (400MHz, CDCl3) δ4.21-4.09(m,1H),3.72-3.69(d,J=12.9Hz,1H),3.24-3.19(dd,J=13.7,4.0Hz,1H),3.14-3.10(dd,J=12.8,4.7Hz,1H),2.86-2 .75(m,1H),2.53-2.49(dd,J=12.8,2.7Hz,1H),2.33-2.12(m,1H),1.65-1. 54(m,2H),1.46(s,9H),1.25-1.24(d,J=4.0Hz,3H),0.98-0.91(m,3H)ppm. MS:M / e 229(M+1) + .

[0248] Step H: (2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester

[0249] A sealed tube was loaded with 1-(quinoxalo-6-yl)ethanol-1-ol (5 g, 28.7 mmol), (2S,5R)-5-ethyl-2-methylpiperazine-1-carboxylic acid tert-butyl ester (6.5 g, 28.7 mmol), (cyanomethyl)trimethylphosphonium iodide (8.3 g, 34.4 mmol), DIPEA (7.4 g, 57.4 mmol), and acetonitrile (100 mL). The reaction mixture was stirred overnight at 105 °C and cooled to room temperature. The solvent was removed. Water was added, and the aqueous solution was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by rapid column chromatography (EA / PE) to give the title compound (10.5 g, crude). MS: M / e 385 (M+1) + .

[0250] Step I: 6-(1-((2R,5S)-2-ethyl-5-methylpiperazin-1-yl)ethyl)quinoxaline

[0251] TFA (30 mL) was added to a solution of (2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester (10.5 g) in DCM (100 mL). The reaction mixture was stirred at RT for 4 hours and concentrated to dryness. The resulting residue was dissolved in water. The resulting mixture was extracted with EA. The aqueous layer was adjusted to pH 12–13 with saturated Na₂CO₃ aqueous solution and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated to dryness. The resulting residue (4.6 g) was used for the next step without further purification. MS: M / e 285 (M+1) + .

[0252] Step G: 7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl 2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0253] Triethylamine hydrochloride, intermediate 2 (914 mg, 2.4 mmol), and DIPEA (774 mg, 6 mmol) were added to a solution of 6-(1-((2R,5S)-2-ethyl-5-methylpiperazin-1-yl)ethyl)quinoxaline (568 mg, 2 mmol) in dioxane (5 mL). The reaction mixture was stirred at 100 °C over a weekend and concentrated to dryness. The reaction mixture was quenched with water. The resulting mixture was extracted with EA (100 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography (MeOH / DCM) to give the title compound (1 g, 95%). 1 H NMR(400MHz,CD3OD)δ8.87(dd,J=6.0,4.0Hz,2H),8.16-8.01(m,3H),7.99-7.93(m,1H),5.65-5.52( m,2H),5.49(s,1H),4.09-3.91(m,2.5H),3.75(dd,J=15.1,10.3Hz,1H),3.56(s,1.5H),3.44(s,3H) ,3.25-3.01(m,1H),2.95-2.80(m,1H),2.26-2.12(m,2H),2.07-1.98(m,2H),1.77(d,J=20.1Hz,2H) ,1.64(dd,J=13.3,5.9Hz,3H),1.48-1.42(m,4.5H),1.22(d,J=6.5Hz,1.5H),0.91-0.85(m,3H)ppm. MS:M / e 516(M+1) + .

[0254] Step K: 7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl 2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (intermediate 6)

[0255] To a solution of 300 mg of 7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one in MeOH (4 mL), HCl (2 mL, 4 M dioxane solution) was added. The reaction mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The resulting residue (350 mg, crude) was used directly for the next step without further purification. MS: M / e432 (M+1) + .

[0256] Intermediate 7: 4-(4-methoxybenzyl)-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyran Azo[4,3-b]pyridin-7-yltrifluoromethanesulfonate

[0257] Step A: Ethyl 4-((4-methoxybenzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate

[0258] Ethyl 4-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (5 g, 20.92 mmol), 4-methoxybenzaldehyde (2.85 g, 20.92 mmol), and sodium triacetoxyborohydride (6.65 g, 31.38 mmol) in DCM (100 mL) were stirred at RT for 3 hours. The reaction mixture was extracted with DCM (500 mL). The organic layer was washed with water, dried, and concentrated to dryness. The resulting residue was purified by rapid column chromatography (PE:EA = 1:1) to give the title compound (7.23 g, 96%). MS: M / e 360(M+1)+

[0259] Step B: Ethyl 4-(N-(4-methoxybenzyl)acetamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate

[0260] A mixture of ethyl 4-((4-methoxybenzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (1 g, 2.785 mmol), acetic anhydride (5 mL), and pyridine (20 mL) was stirred overnight at RT. The reaction mixture was concentrated to give a crude product, which was dissolved in water. The resulting solution was extracted with DCM (100 mL x 2). The organic layer was dried and concentrated to dryness. The resulting residue was purified by rapid column chromatography (PE:EA = 1:1) to give the title compound (1.1 g, 98%). MS: M / e 402(M+1)+

[0261] Step C: 7-Hydroxy-4-(4-methoxybenzyl)-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazole [4,3-b]pyridin-5-one

[0262] LiHMDS (4.1 mL, 4.1 mmol) was added dropwise to a solution of ethyl 4-(N-(cyclopropylmethyl)acetamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (1.1 g, 2.743 mmol) in THF at -78 °C and stirred for 2 hours. The reaction mixture was quenched with AcOH / water and extracted with DCM (100 mL x 2). The organic layer was dried and concentrated to dryness. The resulting residue was purified by rapid column chromatography (DCM:MeOH = 10:1) to give the title compound (800 mg, 82%). MS: M / e 356 (M+1) + .

[0263] Step D: 4-(4-methoxybenzyl)-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyrazole [4,3-b]pyridin-7-yl trifluoromethanesulfonate (intermediate 7)

[0264] A mixture of 7-hydroxy-4-(4-methoxybenzyl)-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (800 mg, 2.253 mmol), 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.2 g, 3.380 mmol), and K₂CO₃ (933 mg, 6.761 mmol) in DMF (15 mL) was stirred overnight at room temperature under N₂. The reaction mixture was quenched with water and extracted with DCM (50 mL x 2). The organic layer was dried and concentrated to dryness. The resulting residue was purified by rapid column chromatography (DCM:MeOH = 20:1) to give the title compound (520 mg, 47%). MS: M / e488 (M+1) + .

[0265] Intermediate 8: 4-(3,4-dimethoxybenzyl)-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate.

[0266] Step A: 4-((3,4-dimethoxybenzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-carboxylic acid Ethyl acetate

[0267] Ethyl 4-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (5 g, 20.92 mmol), 3,4-dimethoxybenzaldehyde (3.47 g, 20.92 mmol), and sodium triacetoxyborohydride (6.65 g, 31.38 mmol) in DCM (100 mL) were stirred at room temperature for 3 hours. The reaction mixture was quenched with water and extracted with DCM (250 mL x 2). The organic layer was dried and concentrated to dryness. The resulting residue was purified by rapid column chromatography (PE:EA = 1:1) to give the title compound (7.33 g, 90%). MS: M / e 390 (M+1) + .

[0268] Step B: 4-(N-(3,4-dimethoxybenzyl)acetamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole- Ethyl 3-formate

[0269] A mixture of ethyl 4-((3,4-dimethoxybenzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (1 g, 2.571 mmol), acetic anhydride (5 mL), and pyridine (20 mL) was stirred overnight at RT. The reaction mixture was concentrated to give a crude product, which was dissolved in water. The resulting solution was extracted with DCM (100 mL x 2). The organic layer was dried and concentrated to dryness. The resulting residue was purified by rapid column chromatography (PE:EA = 1:1) to give the title compound (0.95 g, 86%). MS: M / e 432 (M+1) + .

[0270] Step C: 4-(3,4-dimethoxybenzyl)-7-hydroxy-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H- Pyrazolo[4,3-b]pyridin-5-one

[0271] LiHMDS (3.3 mL, 3.3 mmol) was added dropwise to a solution of ethyl 4-(N-(3,4-dimethoxybenzyl)acetamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (0.95 g, 2.205 mmol) in THF at -78 °C and stirred for 2 hours. The reaction mixture was quenched with AcOH. The resulting mixture was extracted with DCM (200 mL) and washed with water. The organic layer was dried and concentrated to dryness. The residue was purified by rapid column chromatography (DCM:MeOH = 10:1) to give the title compound (720 mg, 85%). MS: M / e 386 (M+1) + .

[0272] Step D: 4-(3,4-dimethoxybenzyl)-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H- Pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate (intermediate 8)

[0273] A mixture of 4-(3,4-dimethoxybenzyl)-7-hydroxy-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (720 mg, 1.87 mmol), 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1 g, 2.805 mmol), and K₂CO₃ (516 mg, 3.740 mmol) in DMF (15 mL) was stirred overnight at N₂ and room temperature. The reaction mixture was extracted with DCM (100 mL) and washed with water. The organic layer was dried and concentrated to dryness. The resulting residue was purified by rapid column chromatography (DCM:MeOH = 20:1) to give the title compound (720 mg, 75%). MS: M / e 518 (M+1) + .

[0274] Intermediate 9: 4-Methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-d]pyrimidine-5,7(6H)-dione

[0275] Step A: 4-Nitro-1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide

[0276] A solution of NH3 (7M) in MeOH (80 mL) was added to ethyl 4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (8 g, 29.7 mmol). The reaction mixture was stirred at 80 °C for 16 hours, cooled to room temperature, and concentrated to dryness. The resulting residue was treated with PE / EA to form a slurry, giving the title compound (6.8 g, 95%). MS: M / e 241(M+1) + .

[0277] Step B: 4-Amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide

[0278] Pd / C (0.6 g, 10% soluble in water) was added to a solution of 4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide (6.2 g, 25.8 mmol) in MeOH (100 mL). The resulting mixture was stirred at room temperature under a H2 atmosphere. The reaction mixture was filtered and washed with MeOH. The combined filtrates were concentrated to give the title compound (5.1 g, 94%). MS: M / e 211(M+1) + .

[0279] Step C: 4-((2,4-dinitrophenyl)sulfonamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-methyl amide 2,4-Dinitrobenzenesulfonyl chloride (6.11 g, 23 mmol) was added dropwise to a solution of 4-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide (4.6 g, 21.9 mmol) and TEA (3.33 g, 33 mmol) in THF (0.2 L). The reaction mixture was stirred at room temperature for 6 hours and concentrated to dryness. The resulting residue was diluted with water and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (5.3 g, 55%). MS: M / e 441 (M+1) + .

[0280] Step D: 4-((N-methyl-2,4-dinitrophenyl)sulfonamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyran azole-3-carboxamide

[0281] K₂CO₃ (3.3 g, 24 mmol) was added to a solution of 4-((2,4-dinitrophenyl)sulfonamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide (5.3 g, 12 mmol) in DMF (60 mL), followed by CH₃I (3.4 g, 24 mmol). The reaction mixture was stirred at RT for 16 hours. The reaction solvent was concentrated to dryness. The resulting residue was diluted with water and extracted with DCM (100 mL x 2). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (4.8 g, 88%). MS: M / e 455 (M+1) + .

[0282] Step E: 4-(methylamino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide

[0283] 2-Mercaptoacetic acid (1.36 g, 14.8 mmol) was added to a solution of 4-((N-methyl-2,4-dinitrophenyl)sulfonamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide (4.8 g, 10.57 mmol) and TEA (2.13 g, 21.14 mmol) in DCM (40 mL). The reaction mixture was stirred for 6 hours. The reaction was quenched with water. The resulting mixture was extracted with DCM:IPA (3:1, 100 mL x 5). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (DCM:MeOH = 10:1) to give the title compound (1.8 g, 75%). MS: M / e 225 (M+1) + .

[0284] Step F: 4-Methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-d]pyrimidine-5,7 (6H)-Diketone (Intermediate 9)

[0285] NaH (240 mg, 6 mmol) was added to a solution of 4-(methylamino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide (680 mg, 3 mmol) in 15 mL of DMF at 0 °C. After 1 hour, CDI (972 mg, 6 mmol) was added to the reaction mixture and the resulting mixture was heated to 80 °C overnight. The reaction mixture was cooled to room temperature, quenched with H2O, and concentrated to dryness. The resulting residue was purified by rapid column chromatography (DCM:MeOH = 10:1) to give the title compound (0.6 g, 80%). 1HNMR(400MHz,DMSO-d6)δ11.19(s,1H),8.15(s,1H),5.55(dd,J=2.4,9.2Hz,1H),3.98-3.89(m,1 H),3.74-3.63(m,1H),3.27(s,3H),2.15-1.85(m,3H),1.78-1.63(m,1H),1.62-1.50(m,2H)ppm. MS:M / e251(M+1) + .

[0286] Intermediate 10: 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0287] Step A: (2R,5S)-2,5-dimethyl-4-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5- Dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 10A)

[0288] DIPEA (3.87 g, 30 mmol) was added to a solution of (2R,5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (2.56 g, 12 mmol) and intermediate 2 (3.81 mg, 10 mmol) in CH3CN (15 mL). The mixture was then heated at 90 °C and N2 for 16 hours. The mixture was cooled to room temperature, diluted with water (150 mL), and extracted with EA (80 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography (DCM:MeOH = 15:1) to give the title compound (4.9 g, crude). MS: M / e 446 (M+1) + .

[0289] Step B: 7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2, 4-Dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (intermediate 10B)

[0290] TFA (5 mL) was added to a solution of intermediate 10A (4.9 g, crude) in DCM (20 mL). The resulting mixture was stirred overnight at room temperature. The mixture was diluted with water, alkalized with saturated NaHCO3 solution, extracted with DCM:IPA (3:1, 80 mL x 3), dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography (DCM:MeOH = 5:1, MeOH solution in 1 mol / L NH3) to give the title compound (2.9 g, 84% for both steps). 1HNMR(400MHz,CD3OD)δ8.03(d,J=2.8Hz,1H),5.65(s,1H),5.60-5.32(m,1H),4.85-4.76(m,1H),4.53-4.42(m,1H),4.11-3.96(m,1H),3.82-3 .70(m,1H),3.69-3.57(m,2H),3.56-3.49(m,1H),3.46(s,3H),3.04-2. 92(m,1H),2.30-2.00(m,3H),1.85-1.60(m,3H),1.42-1.30(m,6H)ppm. MS:M / e 346(M+1) + .

[0291] Step C: (2R,5S)-2,5-dimethyl-4-(4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyrazol) tert-butyl pyridinium-7-yl)piperazine-1-carboxylate

[0292] Dioxane / HCl (g) (4.0 M, 5 mL) was added to a stirred solution of intermediate 10B (3 g, 8.70 mmol) in MeOH (20 mL). After addition, the reaction was stirred over the weekend. The reaction mixture was concentrated to obtain a residue, which was treated with THF / H2O (50 mL / 20 mL), followed by the addition of K2CO3 (3.60 g, 26.08 mmol) and then Boc2O (1.90 g, 8.70 mmol). The mixture was then stirred for 1 hour. The mixture was acidified to pH 4–5 with citric acid and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The resulting residue was purified by rapid column chromatography to give the title compound (1.7 g, 54%). MS: M / e 362 (M+1) + .

[0293] Step D: (2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]) tert-butyl pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate

[0294] K₂CO₃ (1.95 g, 14.1 mmol) was added to a stirred solution of the compound from step C (1.7 g, 4.71 mmol) in DMF / H₂O (10 mL / 2 mL), followed by the addition of 2-iodoacetonitrile (1.18 g, 7.06 mmol). After the addition, the reaction mixture was stirred overnight at RT. The reaction mixture was poured into H₂O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated. The resulting residue was purified by rapid column chromatography to give the title compound (1.3 g, 69%). MS: M / e 401 (M+1) + .

[0295] Step E: 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyridine Azo[4,3-b]pyridin-2-yl)acetonitrile

[0296] TFA (3 mL) was added to a stirred solution of (2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.3 g, 3.25 mmol) in CH2Cl2 (15 mL). The mixture was then stirred for 5 hours. The reaction mixture was concentrated to give a residue, which was alkalized to pH 10-11 with aqueous NaHCO3 solution and extracted with CH2Cl2 / IPA (3 / 1, 30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and dried to give the title compound (870 mg, 89%). MS: M / e 301 (M+1) + .

[0297] Intermediate 11: 2-(but-2-yn-1-yl)-7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0298] Step A: (2R,5S)-2-ethyl-5-methyl-4-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4, 5-Dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 11A)

[0299] A mixture of intermediate 2 (19 g, 50 mmol), (2R,5S)-2-ethyl-5-methylpiperazine-1-carboxylic acid tert-butyl ester (12.54 g, 55 mmol), and DIPEA (12.9 g, 0.1 mol) in CH3CN (200 mL) was stirred overnight at 100 °C in a sealed tube. The reaction mixture was concentrated to dryness. The resulting residue was dissolved in CH2Cl2 (200 mL) and washed with H2O and brine, dried over Na2SO4, and concentrated. The resulting residue was purified by rapid column chromatography to give the title compound (20 g, 83.5%). MS: M / e 460 (M+1) + .

[0300] Step B: 7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4, [3-b]pyridin-5-one

[0301] Dioxane / HCl (g) (4.0 M, 50 mL) was added to a stirred solution of intermediate 11A (6 g, 12.5 mmol) in MeOH (50 mL). The mixture was then stirred at 50 °C for 3 days. The reaction mixture was concentrated to give the title compound (crude), which was used directly for the next step. MS: M / e 276 (M+1) + .

[0302] Step C: (2R,5S)-2-ethyl-5-methyl-4-(4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3- b]Pyridin-7-yl)piperazine-1-carboxylic acid tert-butyl ester

[0303] 7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (12.5 mmol) was dissolved in THF / H₂O (80 mL / 80 mL) and then alkalized to pH 7-8 with NaHCO₃. NaHCO₃ (2.1 g, 25 mmol) was added to the reaction mixture, followed by Boc₂O (3.28 g, 15 mmol). After addition, the reaction mixture was stirred for 4 hours. The reaction mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated. The resulting residue was purified by rapid column chromatography to give the title compound (3.8 g, 81%). MS: M / e 376 (M+1) + .

[0304] Step D: (2R,5S)-4-(2-(but-2-yn-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4, 3-b]pyridin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylic acid tert-butyl ester

[0305] K₂CO₃ (2.78 g, 20.2 mmol) was added to a stirred solution of (2R,5S)-2-ethyl-5-methyl-4-(4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylic acid tert-butyl ester (3.8 g, 10.1 mmol) in DMF / H₂O (30 mL / 10 mL), followed by the addition of 1-bromobut-2-yne (2.02 g, 15.2 mmol). After the addition, the reaction mixture was stirred overnight at RT. The reaction mixture was poured into H₂O (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated. The resulting residue was purified by rapid column chromatography to give the title compound (2.2 g, 51%). MS: M / e 428 (M+1) + .

[0306] Step E: 2-(but-2-yn-1-yl)-7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-2,4- Dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0307] TMSOTf (2.3 g, 10.3 mmol) was added to a stirred solution of (2R,5S)-4-(2-(but-2-yn-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2-ethyl-5-methylpiperazin-1-carboxylic acid tert-butyl ester (2.2 g, 5.15 mmol) in CH2Cl2 (50 mL). The mixture was then stirred for 2 hours. The mixture was quenched with aqueous Na2CO3 solution and extracted with CH2Cl2 / IPA (3 / 1, 50 mL x 4). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the title compound (1.8 g, 99%). MS: M / e 328 (M+1) + .

[0308] Intermediate 12: 5-Bromo-4-fluoro-2-isopropoxypyridine

[0309] To a solution of 5-bromo-4-fluoropyridin-2-ol (764 mg, 4 mmol) in chloroform (15 mL), 2-iodopropane (743 mg, 4.4 mmol) and silver carbonate (1.32 g, 4.8 mmol) were added, and the reaction solution was stirred overnight at room temperature. The reaction mixture was concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (700 mg, 75%). MS: M / e 234 (M+1) + .

[0310] Intermediate 13: 1-(5-chloropyridin-2-yl)ethanol-1-ol

[0311] At -78 °C, methyl magnesium bromide (0.9 mL, 1.42 mmol) was added to a solution of 5-chloropyridinecarboxaldehyde (200 mg, 1.42 mmol) in THF (20 mL) and stirred for 1 h. The mixture was extracted with DCM (100 mL) and washed with water. The organic layer was dried over Na₂SO₄ and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM:MeOH = 20:1) to give the title compound (150 mg, 67%). MS: M / e 158 (M+1) + .

[0312] Intermediate 14: 3-bromo-1-methylisoquinoline

[0313] Tetramethylstanane (787 mg, 4.4 mmol) and Pd(PPh3)2Cl2 (280 mg, 0.4 mmol) were added to a mixture of 1,3-dibromoisoquinoline (1.15 g, 4 mmol) and LiCl (185 mg, 4.4 mmol) in DMF (10 mL). The reaction solution was stirred overnight at 100 °C. The reaction mixture was concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (630 mg, 71%). MS: M / e 222(M+1) + .

[0314] Intermediate 15: Tetrahydro-2H-pyran-4-yl-4-methylbenzenesulfonate

[0315] TsCl (2.28 g, 12 mmol) was added to a solution of tetrahydro-2H-pyran-4-ol (1.02 g, 10 mmol) and TEA (2 g, 20 mmol) in DCM (20 mL) at 0 °C. The reaction mixture was stirred overnight at 25 °C. The mixture was diluted with H2O, extracted with DCM (80 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (1.4 g, 55%). 1 H NMR(400MHz, CDCl3) δ7.80(d,J=8.4Hz,2H),7.34(d,J=8.0Hz,2H),4.73-4.65(m ,1H),3.92-3.82(m,2H),3.52-3.42(m,2H),2.45(s,3H),1.91-1.69(m,4H),ppm.

[0316] Intermediate 16: 7-bromo-3-methylisoquinoline

[0317] Step A: N-(3-bromobenzyl)-1,1-dimethoxypropyl-2-amine

[0318] A mixture of (3-bromophenyl)methylamine (744 mg, 4 mmol) and 1,1-dimethoxyprop-2-one (472 mg, 4 mmol) in DCM (10 mL) was then added in a single batch, and the reaction mixture was stirred overnight at RT. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The aqueous layer was then extracted with EtOAc. The combined organic layers were washed with an aqueous solution of NaCl. The organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue (1 g, crude product) was used directly for the next step without purification. MS: M / e 288 (M+1) + .

[0319] Step B: 7-Bromo-3-methylisoquinoline (Intermediate 16)

[0320] Chlorosulfonic acid (3 mL) was added dropwise to N-(3-bromobenzyl)-1,1-dimethoxypropyl-2-amine (1 g, crude). The reaction mixture was heated to 100 °C for 20 min, then cooled and poured into K₂CO₃ (aqueous solution). The aqueous suspension was extracted with EtOAc. The organic fraction was washed with brine, dried (Na₂SO₄), filtered, and concentrated. The residue was purified by rapid column chromatography to give the title compound (260 mg, 34% yield). MS: M / e 222 (M+1) + .

[0321] Intermediate 17: (4-bromophenyl)(4,4-difluoropiperidin-1-yl)methyl ketone

[0322] A solution of 4-bromobenzoic acid (500 mg, 2.5 mmol), 4,4-difluoropiperidine (333 mg, 2.75 mmol), HATU (1.15 g, 3 mmol), and DIPEA (645 mg, 5 mmol) in CH₂Cl₂ (10 mL) was stirred overnight. The reaction mixture was diluted with CH₂Cl₂ (20 mL), washed with H₂O and brine, dried over Na₂SO₄, and concentrated to dryness. The residue was purified by rapid column chromatography to give the title compound (705 mg, 92.7%). MS: M / e 304 / 306 (M+1) + .

[0323] Intermediate 18: 2-(6-bromopyridin-3-yl)-2-methylpropionitrile

[0324] At 0 °C, a solution of 2-(6-bromopyridin-3-yl)acetonitrile (591 mg, 3.0 mmol) in THF (5 mL) was added to a suspension of NaH (60%, 360 mg, 9 mmol) in THF (5 mL), and the resulting reaction mixture was stirred at room temperature for 1 hour. At the end of this stage, methyl iodine (1.06 g, 7.5 mmol) was added, followed by stirring for another 16 hours. After this time, the reaction mixture was quenched by adding a saturated ammonium chloride solution, followed by extraction into ethyl acetate. The combined organic fractions were concentrated under reduced pressure, and the resulting residue was purified by rapid column chromatography (EtOAc:PE = 0%–50% over 25 min) to give the title compound (130 mg, 19%). MS: M / e 225 (M+1) + .

[0325] Intermediate 19: 2-Bromo-3-fluoro-5-isopropoxypyridine

[0326] At 0 °C, a solution of propan-2-ol (270 mg, 4.5 mmol) in DMF (5 mL) was added to a suspension of NaH (60%, 300 mg, 7.5 mmol) in DMF (5 mL), and the resulting reaction mixture was stirred at room temperature for 1 hour. At the end of this stage, 2-bromo-3,5-difluoropyridine (582 mg, 3 mmol) was added, followed by stirring for another 16 hours. After this time, the reaction mixture was quenched by adding a saturated ammonium chloride solution, followed by extraction into ethyl acetate. The combined organic fractions were concentrated under reduced pressure, and the resulting residue was purified by rapid column chromatography (EtOAc:PE = 0%–50% over 20 minutes) to give the title compound (460 mg, 66%). 1 H NMR (400MHz, CDCl3) δ7.95-7.82 (m, 1H), 6.92 (dd, J = 9.7, 1.9Hz, 1H), 4.54 (heptane, J = 5.9Hz, 1H), 1.43 (d, J = 6.1Hz, 6H) ppm. MS:M / e 234(M+1) + .

[0327] Intermediate 20: 1-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl) ethanol-1-ol

[0328] Step A: 1-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)ethyl-1-one

[0329] A mixture of 5-bromo-2,2-difluorobenzo[d][1,3]dioxane (9.5 g, 40.1 mmol), tributyl(1-ethoxyvinyl)stanane (17.5 g, 48.5 mmol), and Pd(PPh3)2Cl2 (1.4 g, 2.0 mmol) in toluene (100 mL) was stirred at 100 °C and N2 for 16 hours. The mixture was cooled and a solution of HCl / dioxane (4 M, 30 mL) was added, followed by stirring for 10 minutes. The resulting mixture was washed with brine (50 mL x 2) and NaHCO3 (50 mL), dried over Na2SO4, filtered, and concentrated to dryness to give the title compound (12.5 g, crude), which was used directly for the next step without any further purification. 1 H NMR (400MHz, DMSO-d6) δ7.95 (s, 1H), 7.91 (d, J = 8.4Hz, 1H), 7.56 (d, J = 8.4Hz, 1H), 2.59 (s, 3H).

[0330] Step B: 1-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)ethanol-1-ol (Intermediate 20)

[0331] NaBH4 (1.2 g, 35.3 mmol) was added in portions to a solution of 1-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)ethyl-1-one (12.5 g, crude) in MeOH (100 mL) at 0 °C, and the mixture was stirred at rt for 1 h. Brine (200 mL) was added to the mixture, and it was extracted with EtOAc (100 mL x 3). The extracts were combined and washed with brine (100 mL x 2), dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title compound (5.9 g, 73% for both steps). 1 H NMR (400MHz, DMSO-d6) δ7.36 (s, 1H), 7.32 (d, J = 8.4Hz, 1H), 7.17 (d, J = 8.0Hz, 1H), 5.31 (d, J = 4.4Hz, 1H), 4.81-4.69 (m, 1H), 1.31 (d, J = 6.4Hz, 3H).

[0332] Compound A1: 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0333] Step A: 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl- 2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0334] DIPEA (0.77 g, 6 mmol) was added to a solution of intermediate 2 (1.15 g, 3 mmol) and intermediate 1 (0.9 g, 3.32 mmol) in CH3CN (20 mL). The resulting mixture was heated at 90 °C and N2 for 60 h and then cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with DCM (80 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and the resulting residue was purified by rapid column chromatography to give the title compound (1.34 g, 89%). MS: M / e 502 (M+1) + .

[0335] Step B: 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl- 2,4-Dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0336] TFA (20 mL) was added to a solution of 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (1.34 g, 2.67 mmol) in DCM (10 mL). The resulting mixture was stirred overnight at room temperature. Another portion of TFA (10 mL) was added and the reaction was stirred for 6 hours. The reaction mixture was concentrated under reduced pressure, diluted with a water / DCM mixture, alkalized to pH 7-8 with a saturated aqueous NaHCO3 solution, and extracted with DCM:IPA (6:1, 60 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by rapid column chromatography to give the title compound A1 (0.75 g, 67%). 1 HNMR(400MHz,CD3OD)δ8.93-8.82(m,2H),8.20-7.96(m,3H),7.80(s,1H),5.56(s,1H), 5.12-4.92(m,0.5H),4.82-4.50(m,1H),4.40-4.25(m,0.5H),4.05-3.90(m,0.5H),3.86 -3.77(m,0.5H),3.75-3.62(m,1H),3.52-3.42(m,0.5H),3.46(s,3H),3.02-2.65(m,2H) ,2.30-2.15(m,0.5H),1.55-1.35(m,4.5H),1.27-1.16(m,3H),1.12-0.96(m,1.5H)ppm. MS:M / e 418(M+1) + .

[0337] Compound A2: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0338] 2-Iodoacetonitrile (250 mg, 1.5 mmol) was added to a solution of 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (417 mg, 1 mmol) and K₂CO₃ (276 mg, 2 mmol) in DMF (10 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with EA (80 mL x 2). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound A2 (350 mg, 76%), which was then separated into compounds A2a (60 mg) and A2b (90 mg) by chiral preparative HPLC. The chiral separation conditions are shown below.

[0339]

[0340] Compound A2: 1 HNMR(400MHz,CD3OD)δ8.90-8.84(m,2H),8.15-8.01(m,3H),7.95-7.90(m,1H),5.57(s,1H),5.49-5 .44(m,2H),4.96-4.88(m,0.5H),4.65-4.50(m,1H),4.35-4.20(m,0.5H),4.04-3.93(m,0.5H),3.88- 3.78(m,0.5H),3.73-3.64(m,1H),3.51-3.43(m,0.5H),3.43(s,3H),3.12-3.03(m,0.5H),2.98-2.80 (m,1.5H),2.25-2.16(m,0.5H),1.51-1.38(m,4.5H),1.26-1.17(m,3H),1.06(d,J=6.4Hz,1.5H)ppm. MS:M / e 457(M+1) + .

[0341] Compound A2a (first peak, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile): 1HNMR(400MHz,CD3OD)δ8.88(d,J=2.0Hz,1H),8.87(d,J=1.6Hz,1H),8.15-8 .01(m,3H),7.92(s,1H),5.57(s,1H),5.46(s,2H),5.02-4.86(m,1H),4.36- 4.20(m,1H),4.02-3.91(m,1H),3.51-3.42(m,1H),3.43(s,3H),3.12-3.04 (m,1H),2.98-2.85(m,2H),1.44(t,J=5.6Hz,6H),1.06(d,J=6.4Hz,3H)ppm. MS:M / e 457(M+1) + .

[0342] Compound A2b (later peak, 2-(7-((2S,5R)-2,5-dimethyl-4-((R)-1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile): 1 HNMR (400MHz, CD3OD) δ8.87(d,J=2.0Hz,1H),8.86(d,J=1.6Hz,1H),8.14-8.01(m,3H),7.93(s,1H),5.57(s,1H),5.47(s,2H),4.75-4.46(m ,2H),3.90-3.78(m,1H),3.74-3.64(m,2H),3.44(s,3H),2.91-2.82(m ,1H),2.26-2.18(m,1H),1.47(d,J=6.8Hz,3H),1.17-1.18(m,6H)ppm. MS:M / e 457(M+1) + .

[0343] Compound A16: 1-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)cyclopropane-1-nitrile

[0344] 1,2-Dibromoethane (28 mg, 0.15 mmol) was added to a solution of 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile (23 mg, 0.05 mmol) and NaH (8 mg, 0.2 mmol) in DMSO (1 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with EA (20 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM:MeOH = 15:1) and further purified by preparative HPLC to give the title compound A16 (3 mg, 12%). 1 HNMR(400MHz,CD3OD)δ8.90-8.80(m,2H),8.00-7.92(m,4H),5.59(s,1H),4.75-4.23(m,2H),4.09-3.64(m,2H),3. 51-3.44(m,0.5H),3.45(s,3H),3.19-2.76(m,2H),2.28-2.16(m,0.5H),2.05-1.88(m,4H),1.72-1.05(m,9H)ppm. MS:M / e 483(M+1) +

[0345] Compound A17: 2-Cyclopropyl-7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0346] To a solution of 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (13 mg, 0.03 mmol), cyclopropylboronic acid (3 mg, 0.045 mmol), and Na₂CO₃ (6 mg, 0.06 mmol) in toluene (2 mL), Cu(OAc)₂ (6 mg, 0.03 mmol) and 2,2'-bipyridine (4 mg, 0.03 mmol) were added. The reaction mixture was stirred overnight at 80 °C and O₂. The reaction mixture was diluted with water and extracted with EA (25 mL x 2). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to give the title compound A17 (3 mg, 21%).1 HNMR(400MHz,CD3OD)δ8.90-8.84(m,2H),8.15-8.05(m,3H),7.88(s,1H),5.52(s,1H),4.77-4.35(m,1.5H),4.00-3.79(m,2H),3.72-3.60(m, 1.5H),3.51-3.42(m,0.5H),3.42(s,3H),3.16-2.79(m,2H),2.26-2.14 (m,0.5H),1.55-1.40(m,4H),1.24-1.15(m,6H),1.13-1.02(m,3H)ppm. MS:M / e 458(M+1) + .

[0347] Compound A19: 2-(3-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-(ethylsulfonyl)azacyclobutane-3-yl)acetonitrile

[0348] To a solution of 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (13 mg, 0.03 mmol) in CH3CN (1 mL), 2-(1-(ethylsulfonyl)azacyclobutane-3-ylidene)acetonitrile (8 mg, 0.045 mmol) and DBU (9 mg, 0.06 mmol) were added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with EA (20 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give title compound 19 (6 mg, 33%). 1HNMR(400MHz,CD3OD)δ8.90-8.84(m,2H),8.19-8.16(m,1H),8.14-8.01(m,3H),5.58(s,1H),4.90-4.87(m,0. 5H),4.75-4.50(m,3H),4.45-4.32(m,0.5H),4.29-4.20(m,2H),4.02-3.92(m,0.5H),3.86-3.78(m,0.5H),3. 73-3.64(m,1H),3.61-3.54(m,2H),3.50-3.44(m,0.5H),3.46(s,3H),3.18-3.04(m,2.5H),2.97-2.80(m,1.5 H),2.24-2.17(m,0.5H),1.51-1.37(m,4.5H),1.36-1.27(m,3H),1.26-1.18(m,3H),1.09-1.03(m,1.5H)ppm. MS:M / e 604(M+1) + .

[0349] Compound A20: 3-Cyclopentyl-3-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)propionitrile

[0350] To a solution of 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (13 mg, 0.03 mmol) in CH3CN (1 mL), 3-cyclopentylacrylonitrile (8 mg, 0.045 mmol) and DBU (9 mg, 0.06 mmol) were added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with EA (20 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give the title compound A20 (6 mg, 33%). 1HNMR (400MHz, CD3OD) δ8.90-8.84(m,2H),8.16-7.98(m,3H),7.94(t,J=3.2Hz,1H),5.58-5.52(m,1H) ,4.75-4.32(m,2H),4.02-3.92(m,0.5H),3.88-3.76(m,0.5H),3.74-3.60(m,1H),3.50-3.45(m,0.5H ),3.45(s,3H),3.25-3.00(m,2.5H),2.97-2.80(m,1.5H),2.68-2.42(m,1H),2.26-2.17(m,0.5H),1. 96-1.83(m,1H),1.78-1.50(m,4H),1.49-1.41(m,4.5H),1.40-1.17(m,7H),1.09-1.01(m,1.5H)ppm. MS:M / e 539(M+1) + .

[0351] Compound A22: 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0352] To a solution of 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (252 mg, 0.6 mmol) and K₂CO₃ (166 mg, 1.2 mmol) in DMF (5 mL), 1-bromobut-2-yne (120 mg, 0.9 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with EA (60 mL x 2). The combined organic layers were 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 title compound A22 (140 mg, 50%), which was then separated by chiral preparative HPLC to produce compounds A22a (50 mg) and A22b (50 mg). The chiral separation conditions are shown below.

[0353]

[0354]

[0355] Compound A22a (earlier isomer, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-dimethyl-4-((R)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one): 1 HNMR(400MHz,CD3OD)δ8.91 -8.80(m,2H),8.15-7.98(m,3H),7.90(s,1H),5.53(s,1H),5.04(s,2H),4.80-4.45(m,2H),3.86-3.74(m,1H),3.71-3 .59(m,2H),3.44(s,3H),2.86-2.74(m,1H),2.22-2.14(m,1H),1.86(s,3H),1.52-1.38(m,3H),1.24-1.12(m,6H)ppm. MS:M / e 470(M+1) + .

[0356] Compound A22b (later isomer, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one): 1 HNMR(400MHz,CD3OD)δ8.91 -8.80(m,2H),8.16-8.00(m,3H),7.90(s,1H),5.53(s,1H),5.03(s,2H),5.02-4.86(m,1H),4.40-4.15(m,1H),4.01-3.91( m,1H),3.51-3.38(m,4H),3.12-3.04(m,1H),2.95-2.81(m,2H),1.85(s,3H),1.48-1.36(m,6H),1.04(d,J=4.8Hz,3H)ppm. MS:M / e 470(M+1) + .

[0357] Compound A23: 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0358] 1-Bromobut-2-yne (6 mg, 0.045 mmol) was added to a solution of intermediate 4 (14 mg, 0.03 mmol) and K₂CO₃ (8 mg, 0.06 mmol) in DMF (5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with EA (20 mL x 2). The combined organic layers were 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 A23 (2 mg, 13%). 1 HNMR(400MHz,CD3OD)δ8.91-8.86(m,2H),8.16-7.95(m,3H),7.89(s,1H),5.52(s,1H),5.04(s,2H),4.11-4 .00(m,0.5H),3.95-3.84(m,0.5H),3.58-3.49(m,0.5H),3.44(s,3H),3.31-3.28(2H),3.24-3.14(m,0.5H), 3.12-3.02(m,0.5H),2.98-2.87(m,0.5H),2.77-2.62(m,1H),2.46-2.29(m,1H),2.21-2.10(m,0.5H),2.06- 1.91(m,0.5H),1.84(s,3H),1.76-1.50(m,3H),1.50-1.36(m,3H),1.10-0.90(m,3H),0.72-0.49(m,3H)ppm. MS:M / e 498(M+1) + .

[0359] Compound A24: 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(prop-1-en-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0360] To a solution of 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (13 mg, 0.03 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxane (10 mg, 0.06 mmol), and Na₂CO₃ (6 mg, 0.06 mmol) in toluene (2 mL), Cu(OAc)₂ (6 mg, 0.03 mmol) and 2,2'-bipyridine (4 mg, 0.03 mmol) were added. The reaction mixture was stirred overnight at 80 °C and O₂. The reaction mixture was diluted with water and extracted with EA (25 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to give the title compound A24 (1 mg, 7%). 1 HNMR(400MHz,CD3OD)δ8.95-8.80(m,2H),8.35-7.95(m,4H),5.65-5.45(m,2H),4.75-4.23(m,2H),4.03-3.62(m,2H),3. 54-3.40(m,4.5H),3.17-2.73(m,2H),2.50-2.16(m,3.5H),1.55-1.39(m,4H),1.55-1.39(m,4H),1.14-1.02(m,1H)ppm. MS:M / e458(M+1) + .

[0361] Compound A25: 7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(prop-1-en-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0362] Cu(OAc)₂ (5 mg, 0.03 mmol) and 2,2'-bipyridine (5 mg, 0.03 mmol) were added to a solution of intermediate 4 (14 mg, 0.03 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxane (10 mg, 0.06 mmol), and Na₂CO₃ (6 mg, 0.06 mmol) in toluene (3 mL). The reaction mixture was stirred overnight at 80 °C and O₂. The reaction mixture was diluted with water and extracted with EA (60 mL x 2). The combined organic layers were 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 A25 (1 mg, 6%). 1 HNMR(400MHz,CD3OD)δ8.91-8.84(m,2H),8.19(s,1H),8.16-8.00(m,3H),5.58-5.47(m,2H),4.61(s,1H), 4.12-4.02(m,0.5H),3.95-3.82(m,0.5H),3.62-3.52(m,0.5H),3.45(s,3H),3.31-3.28(2H),3.26-3.20( m,0.5H),3.16-3.04(m,0.5H),2.98-2.86(m,0.5H),2.80-2.69(m,1H),2.46-2.29(m,4H),2.26-2.14(m,0 .5H),2.08-1.94(m,0.5H),1.80-1.55(m,3H),1.49-1.40(m,3H),1.10-0.94(m,3H),0.71-0.49(m,3H)ppm. MS:M / e 486(M+1) + .

[0363] Compound A26: 7-((2S,5R)-2,5-dimethyl-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-4-methyl-2-(prop-1-en-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0364] Step A: (2S,5R)-2,5-dimethyl-4-(4-(trifluoromethoxy)benzyl)piperazine-1-carboxylic acid tert-butyl ester

[0365] DIPEA (774 mg, 6 mmol) was added to a solution of (2S,5R)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (214 mg, 1 mmol), (4-(trifluoromethoxy)phenyl)methanol (576 mg, 3 mmol), and (cyanomethyl)trimethylphosphonium iodide (729 mg, 3 mmol) in CH3CN (10 mL). The reaction mixture was sealed in a flask and heated at 90 °C for 16 h, then cooled to room temperature, diluted with water, and extracted with EA (60 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography (EA:PE = 1:4) to give the title compound (380 mg, 94%). 1 H NMR (400MHz, CD3OD) δ7.38(d,J=7.2Hz,2H),7.16(d,J=6.4Hz,2H),4.28-4.16(m,1H),3.72-3.56(m,2H),3.50-3.40(m,1H),3.3 6-3.24(m,1H),3.05-2.85(m,1H),2.78-2.64(m,1H),2.20-2.12(m,1H),1.46(s,9H),1.28-1.18(m,3H),1.04-0.92(m,3H)ppm. MS:M / e 389(M+1) + .

[0366] Step B: (2R,5S)-2,5-dimethyl-1-(4-(trifluoromethoxy)benzyl)piperazine

[0367] TFA (4 mL) was added to a solution of (2S,5R)-2,5-dimethyl-4-(4-(trifluoromethoxy)benzyl)piperazine-1-carboxylic acid tert-butyl ester (380 mg, 1 mmol) in DCM (10 mL). The reaction mixture was stirred overnight at room temperature and concentrated to dryness. The resulting residue was dissolved in saturated NaHCO3 solution and extracted with DCM (60 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography (EA:PE = 1:1) to give the title compound (200 mg, 70%). MS: M / e 289 (M+1) + .

[0368] Step C: 7-((2S,5R)-2,5-dimethyl-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-4-methyl- 2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0369] DIPEA (78 mg, 0.6 mmol) was added to a solution of (2R,5S)-2,5-dimethyl-1-(4-(trifluoromethoxy)benzyl)piperazine (86 mg, 0.3 mmol) and intermediate 2 (76 mg, 0.2 mmol) in CH3CN (6 mL). The mixture was then heated at 90 °C and N2 for 60 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EA (80 mL). The combined organic layers were 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 (50 mg, 32%). MS: M / e 520 (M+1) + .

[0370] Step D: 7-((2S,5R)-2,5-dimethyl-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-4-methyl- 2,4-Dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0371] TFA (4 mL) was added to a solution of 7-((2S,5R)-2,5-dimethyl-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (50 mg, 0.096 mmol) in DCM (4 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with water / DCM, alkalized to pH 7-8 with saturated NaHCO3 solution, and extracted with DCM (60 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound (22 mg, 50%). MS: M / e 436 (M+1) + .

[0372] Step E: 7-((2S,5R)-2,5-dimethyl-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-4-methyl- 2-(prop-1-en-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0373] To a solution of 7-((2S,5R)-2,5-dimethyl-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (22 mg, 0.046 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxane (16 mg, 0.092 mmol), and Na₂CO₃ (10 mg, 0.092 mmol) in toluene (3 mL), Cu(OAc)₂ (8 mg, 0.046 mmol) and 2,2'-bipyridine (7 mg, 0.046 mmol) were added. The reaction mixture was stirred overnight at 80 °C and O₂ (balloon). The reaction mixture was diluted with water, extracted with EA (50 mL), 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 A26 (3 mg, 13%). 1 HNMR(400MHz,CD3OD)δ8.18(s,1H),7.50(d,J=7.6Hz,2H),7.23(d,J=6.4Hz ,2H),5.60-5.50(m,2H),4.92(s,1H),4.76-4.55(m,2H),3.76-3.66(m,1H), 3.65-2.54(m,2H),3.45(s,3H),3.02-3.08(m,1H),2.99-2.90(m,1H),2.41 -2.37(m,1H),2.35(s,3H),1.33(d,J=3.6Hz,3H),1.14(d,J=3.2Hz,3H)ppm. MS:M / e 476(M+1) + .

[0374] Compound A28: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0375] 2-Iodoacetonitrile (66 mg, 0.3 mmol) was added to a solution of intermediate 4 (90 mg, 0.2 mmol) and K₂CO₃ (55 mg, 0.4 mmol) in DMF (5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, extracted with EA (60 mL x 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 title compound A28 (90 mg), a mixture of diastereomers, which was further separated by chiral preparative HPLC to yield compounds A28a (26 mg) and A28b (20 mg). The chiral separation conditions are shown below.

[0376]

[0377] Compound A28a (first eluting peak): 1 HNMR(400MHz,CD3OD)δ8.93-8.84(m,2H),8.12-8.01(m,3H),7.92(s,1H),5.56(s ,1H),5.45(s,2H),4.12-4.00(m,1H),3.43(s,3H),3.39-3.26(m,3H),3.14-3.04( m,1H),3.00-2.89(m,1H),2.48-2.36(m,1H),2.26-2.10(m,1H),1.96-1.79(m,1H ),1.70-1.54(m,2H),1.51-1.42(m,3H),1.06-0.85(m,3H),0.74-0.65(m,3H)ppm. MS:M / e 485(M+1) + .

[0378] Compound A28b (later peak): 1 HNMR(400MHz,CD3OD)δ8.92-8.84(m,2H),8.15-7.98(m,3H),7.93(s,1H),5.55(s ,1H),5.47(s,2H),3.96-3.85(m,1H),3.62-3.50(m,1H),3.43(s,3H),3.35-3.28( m,2H),3.27-3.18(m,1H),2.80-2.68(m,1H),2.38-2.30(m,1H),2.06-1.90(m,1H ),1.80-1.55(m,3H),1.48-1.37(m,3H),1.12-1.00(m,3H),0.65-0.48(m,3H)ppm. MS:M / e 485(M+1)+ .

[0379] Compound A29: 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0380] Step A: (2S,5R)-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)-2,5-dimethylpiperazine-1-methyl tert-butyl ester.

[0381] DIPEA (2103 mg, 16.3 mmol) was added to a solution of 1-(4-fluoro-2-(methoxymethyl)phenyl)ethane-1-ol (600 mg, 3.26 mmol), (2S,5R)-2,5-dimethylpiperazin-1-carboxylic acid tert-butyl tert-butyl ester (1050 mg, 4.9 mmol), and (cyanomethyl)trimethylphosphonium iodide (1584 mg, 6.52 mmol) in CH3CN (4 mL). The mixture was degassed three times under a nitrogen atmosphere. The mixture was then stirred at 105 °C for 24 h. The reaction mixture was quenched with saturated NH4Cl (20 mL) at room temperature and extracted with EA (35 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography to give the title compound (800 mg, 65%). MS: M / e 381 (M+1) + .

[0382] Step B: (2R,5S)-1-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)-2,5-dimethylpiperazine.

[0383] To a solution of (2S,5R)-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (800 mg, 2.105 mmol) in DCM (25 mL), HCl (6 mL, 4 M, 1,4-dioxane solution) was added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure to give the crude product (HCl salt). The crude product was alkalized to pH about 10 with Na₂CO₃ (4 M) and extracted with EA (35 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na₂SO₄, and concentrated under reduced pressure to give the title compound (400 mg, 68%), which was used directly for the next step without purification. MS: M / e 281 (M+1) + .

[0384] Step C: 7-((2S,5R)-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)-2,5-dimethylpiperazine- 1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one.

[0385] DIPEA (921 mg, 7.14 mmol) was added to a solution of (2R,5S)-1-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)-2,5-dimethylpiperazine (400 mg, 1.428 mmol) and intermediate 2 (597 mg, 1.57 mmol) in CH3CN (5 mL) at room temperature. The mixture was stirred at 105 °C for 24 hours. The reaction mixture was then concentrated under reduced pressure to give a crude product. The crude product was purified by rapid column chromatography to give the title compound (450 mg, 74%). MS: M / e 512 (M+1) + .

[0386] Step D: 7-((2S,5R)-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)-2,5-dimethylpiperazine- 1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one.

[0387] HCl (6 mL, 4 M 1,4-dioxane solution) was added to a solution of 7-((2S,5R)-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (450 mg, 1.054 mmol) in MeOH (15 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure to give a crude product (HCl salt). The crude product was alkalized to pH about 10 with Na2CO3 (4 M) and extracted with EA (40 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, and concentrated under reduced pressure to give the title compound (380 mg, 84%). MS: M / e 428 (M+1) + .

[0388] Step E: 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)-2,5-dimethylpiperazine (1-azinyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile.

[0389] 2-Iodoacetonitrile (223 mg, 1.334 mmol) was added to a solution of 7-((2S,5R)-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (380 mg, 0.889 mmol) and K₂CO₃ (246 mg, 1.779 mmol) in DMF (10 mL) at room temperature. The mixture was stirred at room temperature for 12 hours. The reaction mixture was then quenched with saturated NaCl (20 mL) at room temperature and extracted with EA (45 mL x 2). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH = 20:1) to obtain the title compound, compound A29 (200 mg), which was further separated into compound A29a (86 mg) and compound A29b (88 mg) by preparative HPLC (method A).

[0390] Compound A29: 1 H NMR (400MHz, DMSO-d6) δ7.99(s,1H),7.57(d,J=7.2Hz,1H),7.14(dd,J=16.3,9.8Hz,2H),5.62(d,J=3.3Hz,2H),5.41(d,J=5.5Hz,1H),4 .58(s,1H),4.50(s,1H),3.93-3.64(m,1H),3.28(s,3H),2.93-2.61(m,7H),1.30-1.16(m,6H),1.12-0.97(m,3H),0.90(d,J=6.6Hz,2H). MS:M / e 467(M+1) +

[0391] Compound A29a (first eluting peak): 1 H NMR (400MHz, CD3OD) δ7.93(s,1H),7.69(s,1H),7.08-7.05(m,2H),5.56(s,1H),5.48(s,2H),4.61-4.56(m,1H),4.53(s,3H),3.86(s, 1H),3.63-3.59(m,2H),3.43(s,3H),3.39(s,3H),2.82-2.79(d,J=12Hz,1H),2.17-2.14(d,J=12Hz,1H),1.33(s,3H),1.18(s,6H)ppm. MS:M / e 467(M+1) + .

[0392] Compound A29b (later peak): 1 H NMR (400MHz, CD3OD) δ7.92(s,1H),7.62(s,1H),7.13-7.11(d,J=8Hz,1H),7.06-7.04(m,1H),5.56(s,1H),5.47(s,2H),4.66-4.59(m,4H ),3.94(s,1H),3.43-3.42(m,7H),3.01-2.89(m,3H),1.40-1.39(d,J=4Hz,3H),1.30-1.29(d,J=4Hz,3H),1.00-0.99(d,J=4Hz,3H)ppm. MS:M / e 467(M+1) + .

[0393] Compound A46: A mixture of 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile and 2-(7-((2S,5R)-4-(1-(2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0394] Step A: 5-bromo-2-((2-methylallyl)oxy)phenol and 4-bromo-2-((2-methylallyl)oxy)phenol mixture.

[0395] A solution of 3-bromo-2-methylprop-1-ene (8.6 g, 63.7 mmol) in DMF (50 mL) was added to a solution of 4-bromophenyl-1,2-diol (10.0 g, 52.9 mmol) and Li₂CO₃ (5.8 g, 79.4 mmol) in DMF (50 mL), and the mixture was stirred at 60 °C for 2 days. The mixture was cooled, and the resulting suspension was filtered. The filtrate was treated with EA (200 mL) and H₂O (200 mL), and then acidified to pH 5 with an aqueous solution of HCl (1 M). The organic layers were separated, and the aqueous layer was extracted with EA (50 mL x 2). The combined organic layers were washed with brine (100 mL x 3), dried over Na₂SO₄, and concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (4.7 g, 37%) of the positional isomers, as a mixture. MS: M / e 243, 245 (M+1) + .

[0396] Step B: 7-Bromo-2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin and 6-Bromo-2,2-dimethyl-2, A mixture of 3-dihydrobenzo[b][1,4]dioxins.

[0397] A solution of a mixture of 5-bromo-2-((2-methylallyl)oxy)phenol and 4-bromo-2-((2-methylallyl)oxy)phenol was refluxed in 50 mL of HCOOH for 5 hours. The mixture was concentrated to dryness. The resulting residue was diluted with EA (100 mL), washed with saturated NH4Cl (50 mL x 2), saturated NaHCO3 aqueous solution (50 mL), and brine (50 mL x 2), dried, and concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (1.5 g, 33%) as a mixture. MS: M / e 243, 245 (M+1) + .

[0398] Step C: 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl-1-one and 1-(2,2- A mixture of dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl-1-one.

[0399] A mixture of 7-bromo-2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin and 6-bromo-2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin (1.4 g, 5.76 mmol), tributyl(1-ethoxyvinyl)stanane (4.1 g, 11.3 mmol), and Pd(PPh3)2Cl2 (200 mg, 0.286 mmol) in toluene (20 mL) was stirred at 100 °C and N2 for 16 hours. The mixture was diluted with EA (20 mL) and H2O (20 mL). The suspension was filtered through a diatomaceous earth mat. The aqueous layer was extracted with EA (10 mL x 2). The combined organic layers were treated with HCl (5 mL, 4 M 1,4-dioxane solution) and stirred for 5 minutes. The resulting mixture was washed with brine (20 mL), saturated NaHCO3 aqueous solution (20 mL x 2), and brine (20 mL), dried, and concentrated to dryness. The resulting oil was purified by rapid column chromatography to give the title compound (630 mg, 53%) as a mixture. MS: M / e 207 (M+1) + .

[0400] Step D: 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanol-1-ol and 1-(2,2- A mixture of dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanol-1-ol.

[0401] To a solution of 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl-1-one and 1-(2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl-1-one (630 mg, 3.06 mmol) in MeOH (10 mL), NaBH4 (232 mg, 6.12 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was treated with a saturated aqueous solution of NaHCO3 and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (620 mg, 97%) as a mixture. MS: M / e 209 (M+1) + .

[0402] Step E: 7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl (1-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-) b]Pyridin-5-one and 7-((2S,5R)-4-(1-(2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl (1-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-) b] A mixture of pyridin-5-ones.

[0403] A mixture of 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanol-1-ol and 1-(2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanol-1-ol (180 mg, 0.86 mmol), intermediate 10B (130 mg, 0.38 mmol), and DIPEA (350 mg, 2.7 mmol) in MeCN (2 mL) was stirred at 100 °C for 16 h. The mixture was diluted with EA (20 mL), washed with brine (10 mL x 3), dried, and concentrated. The resulting residue was purified by preparative TLC (CH2Cl2 / MeOH = 15 / 1) to give the title compound (180 mg, 88%) as a mixture. MS: M / e 536 (M+1) + .

[0404] Step F: 7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl 1-(2S, 1-yl)-2,5-dimethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one and 7-((2S, 5R)-4-(1-(2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazine-1- A mixture of (4,3-b)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one.

[0405] Add HCl (3 mL, 4 M 1,4-dioxane solution) to a stirred mixture of [7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one and 7-((2S,5R)-4-(1-(2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one] (160 mg, 0.3 mmol) in MeOH (3 mL). Stir the resulting mixture at room temperature for 16 hours. The reaction mixture was concentrated to dryness to give the title compound (180 mg, crude product) as a mixture. MS: M / e 452 (M+1) + .

[0406] Step G: 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl) (Ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl) Acetonitrile and 2-(7-((2S,5R)-4-(1-(2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2, A mixture of 5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile Compound.

[0407] To [7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one and 7-((2S,5R)-4-(1-(2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin- A mixture of 6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (170 mg, 0.37 mmol), K₂CO₃ (200 mg, 1.45 mmol), and H₂O (0.5 mL) in MeCN (3 mL) was mixed with 2-iodoacetonitrile (100 mg, 0.60 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with 5 mL of brine and extracted with EA (5 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over Na₂SO₄, and concentrated to dryness. The resulting residue was purified by preparative TLC (CH₂Cl₂:MeOH = 15:1) to give two fractions, named compound A46a (1.5 mg) and compound A46b (24 mg).

[0408] Compound A46a (first eluting peak): 1H NMR(400MHz,CD3OD)δ7.92(s,1H),7.00-6.86(m,2H),6.82-6.70(m,1H),6.24(s, 1H),5.93-5.69(m,1H),5.50(d,J=18.0Hz,1H),3.95-3.83(m,2H),3.60(s,3H),3 .48-3.35(m,1H),3.28-3.03(m,2H),2.95-2.74(m,1H),2.74-2.54(m,2H),2.39- 2.25(m,1H),1.34-1.30(m,9H),1.21(d,J=6.0Hz,3H),0.96(d,J=6.0Hz,3H)ppm. MS:M / e 491(M+1) + .

[0409] Compound A46b (later peak): 1 H NMR (400MHz, CD3OD) δ7.92(d,J=1.2Hz,1H),6.96-6.66(m,3H),5.55(d,J=1.6Hz,1H),5.47(d,J=2.0Hz,2H),4.87-4.18(m,2H),3.88(d,J=6.0H z,2H),3.63-3.52(m,1H),3.46-3.37(m,4H),3.03-2.90(m,1H),2.87-2 .23(m,2H),1.42-1.30(m,9H),1.29-1.18(m,3H),1.15-0.93(m,3H)ppm. MS:M / e491(M+1) + .

[0410] Another batch of 150 mg of compound A46, as a mixture of 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile and 2-(7-((2S,5R)-4-(1-(2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, was prepared according to the procedure described for compound A46 as would be known to those skilled in the art.

[0411] The mixture of compound A46 (150 mg) was further separated into four isomers by two separate chiral preparative HPLC tests: compound A46c (9 mg), compound A46d (9 mg), compound A46e (14 mg), and compound A46f (10 mg). The chiral separation conditions are shown below.

[0412] First preparative HPLC conditions

[0413]

[0414]

[0415] Second preparative HPLC conditions

[0416]

[0417] Compound A46c (first peak): 1 HNMR(400MHz,CD3OD)δ7.91(s,1H),6.88(d,J=1.6Hz,1H),6.87-6.80(m,1H),6.74 (d,J=8.0Hz,1H),5.55(s,1H),5.47(s,2H),4.30(s,1H),3.89(s,2H),3.60-3.49( m,1H),3.46-3.37(m,4H),3.37-3.31(m,1H),3.04-2.91(m,2H),2.86-2.74(m,1H) ,1.38(d,J=6.4Hz,3H),1.32(s,6H),1.29-1.26(m,3H),0.98(d,J=6.4Hz,3H)ppm. MS:M / e 491(M+1) + .

[0418] Compound A46d (second peak): 1 HNMR(400MHz,CD3OD)δ7.92(s,1H),6.88-6.76(m,3H),5.55(s,1H),5.47(s,2H),4.57(s,1H),4.27(s,1H),3.88(s,2H),3.57-3.46(m,1H),3 .45-3.36(m,4H),3.02-2.89(m,2H),2.88-2.74(m,1H),1.38(d,J=6.8Hz,3H),1.33(s,6H),1.27(d,J=6.8Hz,3H),0.97(d,J=6.4Hz,3H)ppm. MS:M / e 491(M+1) + .

[0419] Compound A46e (third peak): 1 HNMR(400MHz,CD3OD)δ7.93(s,1H),7.00-6.79(m,2H),6.79-6.65(m,1H),5.57(s,1H),5.48(s,2H),4.71-4.42(m,2H),3.89(s,2H),3 .70-3.52(m,2H),3.43(s,3H),3.04-2.52(m,2H),2.47-2.22(m,1H),1.33-1.28(m,9H),1.22(d,J=6.0Hz,3H),1.19-1.06(m,3H)ppm. MS:M / e 491(M+1) + .

[0420] Compound A46f (fourth peak): 1 HNMR(400MHz,CD3OD)δ7.92(s,1H),6.88-6.72(m,3H),5.56(s,1H),5.47(s,2H),4.65-4.85(m,1H),4.57(s,1H),3.87(s,2H),3.69-3.51(m,2H ),3.49-3.34(m,4H),2.71(dd,J=12.0,3.6Hz,1H),2.27(d,J=12.8Hz,1H),1.32-1.28(m,9H),1.21(d,J=6.4Hz,3H),1.11(d,J=6.4Hz,3H)ppm. MS:M / e 491(M+1) + .

[0421] Compounds A46d and A46f can also be synthesized by the following alternative method:

[0422] A mixture of compounds A46d and A46f: 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile.

[0423] Step A: 1-(4-bromo-2-((4-methoxybenzyl)oxy)phenyl)ethyl-1-one.

[0424] 1-(chloromethyl)-4-methoxybenzene (7.3 g, 46.7 mmol) was added to a mixture of 1-(4-bromo-2-hydroxyphenyl)ethyl-1-one (10.0 g, 46.7 mmol), K₂CO₃ (12.9 g, 93.6 mmol), and DMF (80 mL) at room temperature, and the mixture was stirred for 16 hours. H₂O (200 mL) was added to the mixture, and it was extracted with EtOAc (100 mL x 3). The combined extracts were washed with brine (100 mL x 3), dried over Na₂SO₄, filtered, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title compound (13.8 g, 88%). 1 H NMR (400MHz, DMSO-d6) δ7.58-7.48(m,2H),7.44(d,J=8.4Hz,2H),7.23(dd,J=8. 4,1.6Hz,1H),6.97(d,J=8.8Hz,2H),5.19(s,2H),3.77(s,3H),2.45(s,3H)ppm.

[0425] Step B: 4-bromo-2-((4-methoxybenzyl)oxy)phenylacetate.

[0426] 3-Chloroperoxybenzoic acid (22.0 g, 95.6 mmol) was added in portions to a stirred solution of 1-(4-bromo-2-((4-methoxybenzyl)oxy)phenyl)ethyl-1-one (12.8 g, 38.3 mmol) in CH2Cl2 (150 mL), and the resulting mixture was stirred at room temperature for 64 hours. The suspension was filtered, and the filtrate was washed with NaHCO3 (50 mL x 3) and brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated to dryness to give the title compound (13.5 g, crude product).

[0427] Step C: 4-bromo-2-((4-methoxybenzyl)oxy)phenol.

[0428] To a solution of 4-bromo-2-((4-methoxybenzyl)oxy)phenylacetate (13.0 g, 37 mmol) in THF (100 mL), an aqueous solution of NaOH (4 M, 50 mL) was added and the mixture was stirred for 2 hours. The mixture was acidified to pH 3 with HCl (2 M). The mixture was extracted with EtOAc (100 mL x 2). The combined extracts were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by rapid column chromatography to give the title compound (6.8 g, 60% for both steps). 1H NMR (400MHz, DMSO-d6) δ9.29 (s, 1H), 7.39 (d, J = 8.4Hz, 2H), 7.13 (d, J = 2.0Hz ,1H),7.00-6.85(m,3H),6.74(d,J=8.4Hz,1H),5.02(s,2H),3.76(s,3H)ppm.

[0429] Step D: 4-bromo-2-((4-methoxybenzyl)oxy)-1-((2-methylallyl)oxy)benzene.

[0430] 3-Bromo-2-methylprop-1-ene (8.6 g, 63.7 mmol) was added to a mixture of 4-bromo-2-((4-methoxybenzyl)oxy)phenol (6.8 g, 22.1 mmol), K₂CO₃ (9.1 g, 66.3 mmol), and DMF (50 mL) at room temperature, and the mixture was stirred for 5 hours. The mixture was diluted with EtOAc (100 mL), washed with brine (50 mL x 3), dried over Na₂SO₄, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (6.71 g, 84%). 1 H NMR (400MHz, DMSO-d6) δ7.37(d,J=8.4Hz,2H),7.22(d,J=2.4Hz,1H),7.04(dd,J=8.4,2.0Hz,1H),6 .99-6.89(m,3H),5.04(s,2H),5.02(s,1H),4.92(s,1H),4.46(s,2H),3.76(s,3H),1.74(s,3H)ppm.

[0431] Step E: 5-bromo-2-((2-methylallyl)oxy)phenol.

[0432] A solution of 4-bromo-2-((4-methoxybenzyl)oxy)-1-((2-methylallyl)oxy)benzene (5.7 g, 15.7 mmol) in acetic acid (50 mL) was stirred at 100 °C for 6 hours. The mixture was concentrated to dryness, and the residue was diluted with EtOAc (100 mL), washed with NaHCO3 (aqueous solution, 20 mL x 2) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography (120 g silica gel column) to give the title compound (3.4 g, 89%). 1 HNMR (400MHz, DMSO-d6) δ9.47(s,1H),6.96-6.92(m,1H),6.89-6.80(m,2H),5.05(s,1H),4.93(s,1H),4.44(s,2H),1.76(s,3H)ppm. MS:M / e 243(M+1)+

[0433] Step F: 7-bromo-2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin.

[0434] A solution of 5-bromo-2-((2-methylallyl)oxy)phenol (3.36 g, 13.9 mmol) in HCOOH (60 mL) was stirred at 100 °C for 2 hours. The mixture was concentrated to dryness, and the resulting residue was diluted with EA (50 mL), washed with H2O (20 mL x 3), NaHCO3 (20 mL x 2), and brine (20 mL x 2), dried, concentrated, and purified by rapid column chromatography to give the title compound (980 mg, 29%). 1 H NMR (400MHz, CDCl3) δ6.97 (d, J = 2.0 Hz, 1H), 6.95-6.89 (m, 1H), 6.75 (d, J = 8.4 Hz, 1H), 3.86 (s, 2H), 1.33 (s, 6H) ppm.

[0435] Step G: 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl-1-one.

[0436] A mixture of 7-bromo-2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin (980 mg, 4.05 mmol), tributyl(1-ethoxyvinyl)stanane (2.17 g, 6.01 mmol), and Pd(PPh3)2Cl2 (140 mg, 0.20 mmol) in toluene (20 mL) was stirred at 100 °C and N2 for 16 h. The mixture was cooled and diluted with EA (40 mL) and 20 mL H2O. The suspension was filtered through a diatomaceous earth mat. The organic layer was treated with HCl / dioxane (4 M, 3 mL) and stirred for 2 min. The resulting mixture was washed with brine (20 mL x 2), NaHCO3 (20 mL x 2), and brine (20 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography to give the title compound (530 mg, 64%). 1 H NMR (400MHz, CDCl3) δ7.54-7.44(m,2H),6.92(d,J=8.0Hz,1H),3.94(s,2H),2.53(s,3H),1.36(s,6H)ppm.

[0437] Step H: 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanol-1-ol.

[0438] NaBH4 (98 mg, 2.57 mmol) was added to a solution of 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl-1-one (530 mg, 2.57 mmol) in MeOH (5 mL) at 0 °C, and the mixture was stirred at RT for 30 min. The mixture was treated with NaHCO3 (20 mL) and extracted with EA (10 mL x 3). The combined extracts were washed with brine (10 mL x 2), dried over Na2SO4, and concentrated to dryness to give the title compound (515 mg, 96%). 1 H NMR (400MHz, DMSO-d6) δ6.83-6.71 (m, 3H), 4.99 (d, J = 4.4Hz, 1H), 4.66-4.49 (m, 1H), 3.88 (s, 2H), 1.28-1.24 (m, 9H).

[0439] Step I: 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl) (Ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl) Acetonitrile

[0440] DIPEA (540 mg, 4.2 mmol) was added to a solution of 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanol-1-ol (208 mg, 1.0 mmol), intermediate 10 (210 mg, 0.7 mmol), and (cyanomethyl)trimethylphosphonium iodide (510 mg, 2.1 mmol) in CH3CN (2 mL). The mixture was diluted with EA (20 mL), washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography and further purified by preparative HPLC to give the title compound (60 mg, 17%, mixture), which was further separated by chiral preparative HPLC into compounds A46d (14 mg) and A46f (16 mg). The chiral separation conditions are shown below.

[0441]

[0442] Compound A46d (first eluting peak): 1HNMR(400MHz,CD3OD)δ7.92(s,1H),6.88-6.76(m,3H),5.55(s,1H),5.47(s,2H),4.57(s,1H),4.27(s,1H),3.88(s,2H),3.57-3.46(m,1H),3 .45-3.36(m,4H),3.02-2.89(m,2H),2.88-2.74(m,1H),1.38(d,J=6.8Hz,3H),1.33(s,6H),1.27(d,J=6.8Hz,3H),0.97(d,J=6.4Hz,3H)ppm. MS:M / e 491(M+1) + .

[0443] Compound A46f: (Later elution peak): 1 HNMR(400MHz,CD3OD)δ7.92(s,1H),6.88-6.72(m,3H),5.56(s,1H),5.47(s,2H),4.65-4.85(m,1H),4.57(s,1H),3.87(s,2H),3.69-3.51(m,2H ),3.49-3.34(m,4H),2.71(dd,J=12.0,3.6Hz,1H),2.27(d,J=12.8Hz,1H),1.32-1.28(m,9H),1.21(d,J=6.4Hz,3H),1.11(d,J=6.4Hz,3H)ppm. MS:M / e 491(M+1) + .

[0444] Compound A47: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-ethyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0445] Step A: Ethyl 4-acetamido-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate

[0446] A mixture of ethyl 4-((cyclopropylmethyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (200 mg, 0.8368 mmol), acetic anhydride (2 mL), and pyridine (5 mL) was stirred overnight at RT. The mixture was concentrated, extracted with DCM (100 mL), and washed with water. The organic layer was dried and concentrated to dryness. The resulting residue was purified by rapid column chromatography (PE:EA = 1:1) to give the title compound (200 mg, 85.05%). MS: M / e 282 (M+1) +

[0447] Step B: Ethyl 4-(N-ethylacetamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate

[0448] Ethyl 4-acetamido-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (200 mg, 0.7117 mmol), iodoethane (167 mg, 1.068 mmol), and Cs₂CO₃ (464 mg, 1.423 mmol) in DMF (5 mL) were stirred overnight at 60 °C. The mixture was concentrated, extracted with DCM (100 mL), and washed with water. The organic layer was dried and concentrated to dryness. The resulting residue was purified by rapid column chromatography (PE:EA = 1:1) to give the title compound (200 mg, 90.94%). MS: M / e 310 (M+1) +

[0449] Step C: 4-Ethyl-7-hydroxy-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridine 5-Pyridoxine

[0450] LiHMDS (1 mL, 1 mmol) was added dropwise to a solution of ethyl 4-(N-ethylacetamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (200 mg, 0.6473 mmol) in THF at -78 °C and stirred for 2 hours. The mixture was quenched with AcOH, extracted with DCM (80 mL), and washed with water. The organic layer was dried and concentrated to dryness. The resulting residue was purified by rapid column chromatography (DCM:MeOH = 10:1) to give the title compound (130 mg, 49.43%). MS: M / e264 (M+1) +

[0451] Step D: 4-Ethyl-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridine pyridine-7-yltrifluoromethanesulfonate

[0452] A mixture of 4-ethyl-7-hydroxy-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (130 mg, 0.4943 mmol), 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (265 mg, 0.7414 mmol), and K₂CO₃ (134 mg, 0.9886 mmol) in DMF (5 mL) was stirred overnight at N₂ and RT. The mixture was extracted with DCM (50 mL) and washed with water. The organic layer was dried and concentrated to dryness. The resulting residue was purified by rapid column chromatography (DCM:MeOH = 20:1) to give the title compound (150 mg, 76.83%). MS: M / e 396(M+1)+

[0453] Step E: 7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-ethyl- 2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0454] A mixture of 4-ethyl-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate (150 mg, 0.3796 mmol), 6-(1-((2R,5S)-2,5-diethylpiperazin-1-yl)ethyl)quinoxaline (170 mg, 0.5696 mmol), and DIPEA (245 mg, 1.899 mmol) in CH3CN (5 mL) was stirred overnight at 100 °C under N2. The mixture was extracted with DCM (50 mL) and washed with water. The organic layer was dried and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM:MeOH = 20:1) to give the title compound (60 mg, 29.10%). MS: M / e 544(M+1)+

[0455] Step F: 7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-ethyl- 2,4-Dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0456] A mixture of 7-((2S,5R)-2,5-diethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-ethyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (60 mg, 0.1105 mmol) in TFA (2 mL) and DCM (2 mL) was stirred overnight at RT. The solution was concentrated and purified by preparative TLC (DCM:MeOH = 20:1) to give the title compound (50 mg, 98.58%). MS: M / e 460(M+1)+

[0457] Step G: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-ethyl 5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0458] A mixture of 7-((2S,5R)-2,5-diethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-ethyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (50 mg, 0.1089 mmol), 2-iodoacetonitrile (36 mg, 0.2179 mmol), and K₂CO₃ (45 mg, 0.3268 mmol) in DMF (3 mL) was stirred at RT for 5 hours. The mixture was extracted with DCM (50 mL) and washed with water. The organic layer was dried and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM:MeOH = 20:1) to give the title compound (18 mg, 33.18%). 1H NMR(400MHz,DMSO-d6)δ8.94(s,2H),8.14-8.01(m,3H),7.96(s,1H),5.60(s,2H),5.38(s,1H),4.05(s,1H),3.94-3.77(m,3H),3 .21-2.93(m,3H),2.88-2.61(m,2H),1.66-1.48(m,3H),1.41-1.33(m,3H),1.12(s,3H),1.06-0.78(m,4H),0.68-0.40(m,3H)ppm. MS:M / e 499(M+1)+

[0459] Compound A52: 2-(7-((2S,5R)-4-(1-(benzo[d]thiazo-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0460] Step A: 1-(benzo[d]thiazolyl-2-yl)ethanol-1-ol

[0461] A mixture of 2-aminobenzylthiol (1.25 g, 10 mmol) and 2-hydroxypropionic acid (1.08 g, 12 mmol) in HCl (30 mL, 4 M) was heated to reflux overnight. After cooling to room temperature, the reaction mixture was poured into water. The pH was then adjusted to 10–11 with ammonia. The mixture was filtered, and the resulting residue was recrystallized from water to give the title compound (450 mg, 25%). MS: M / e 180 (M+1) + .

[0462] Step B: (2S,5R)-4-(1-(benzo[d]thiazolyl-2-yl)ethyl)-2,5-diethylpiperazine-1-carboxylic acid tert-butyl ester

[0463] A mixture of (2S,5R)-2,5-diethylpiperazine-1-carboxylic acid tert-butyl ester (170 mg, 0.7 mmol), 1-(benzo[d]thiazol-2-yl)ethanol-1-ol (200 mg, 1.1 mmol), (cyanomethyl)trimethylphosphonium iodide (97 mg, 1.4 mmol), and DIPEA (450 mg, 3.5 mmol) in CH3CN (2 mL) was heated to 105 °C overnight under N2 atmosphere. The solvent was removed under vacuum. The crude product was purified by silica gel rapid column chromatography (DCM:MeOH = 100:1) to give the title compound (280 mg, 79%, 80% purity). MS: M / e 403 (M+1) + .

[0464] Step C: 2-(1-((2R,5S)-2,5-diethylpiperazine-1-yl)ethyl)benzo[d]thiazole

[0465] TFA (2 mL) was added to a solution of (2S,5R)-4-(1-(benzo[d]thiazol-2-yl)ethyl)-2,5-diethylpiperazine-1-carboxylic acid tert-butyl ester (280 mg, 80% purity) in DCM (5 mL) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction solvent was removed under vacuum. The crude product was dissolved in DCM (mL) and neutralized to pH 8 with aqueous NaOH solution. The organic layer was concentrated to give the title compound (160 mg, crude), which was used directly for the next step without further purification. MS: M / e 295 (M+1) + .

[0466] Step D: 7-((2S,5R)-4-(1-(benzo[d]thiazolyl-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4- Methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0467] A mixture of intermediate 2 (77 mg, 0.2 mmol), 2-(1-((2R,5S)-2,5-diethylpiperazin-1-yl)ethyl)benzo[d]thiazole (60 mg, 0.2 mmol), and DIPEA (128 mg, 1 mmol) in CH3CN was heated to 105 °C overnight under N2 atmosphere. The solvent was removed under vacuum. The crude product was purified by preparative TLC (DCM:MeOH = 15:1) to give the title compound (50 mg, 47%). MS: M / e 535 (M+1) + .

[0468] Step E: 7-((2S,5R)-4-(1-(benzo[d]thiazolyl-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4- Methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0469] A solution of dioxane in HCl (0.5 mL, 2 mmol, 4 M) was added to a solution of 7-((2S,5R)-4-(1-(benzo[d]thiazolyl-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (50 mg, 0.09 mmol) in MeOH (2 mL). The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction solvent was removed under vacuum. The crude product was dissolved in DCM (10 mL) and neutralized to pH 8 with aqueous NaOH. The organic layer was concentrated to give the crude product, which was further purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound (15 mg, 37%). MS: M / e 451 (M+1) + .

[0470] Step F: 7-2-(7-((2S,5R)-4-(1-(benzo[d]thiazolyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0471] Add 2-iodoacetonitrile (8.5 mg, 0.05 mmol) to a solution of the compound from step E (15 mg, 0.03 mmol) and K₂CO₃ (4.6 mg, 0.06 mmol) in DMF (2 mL). Stir the resulting mixture overnight at room temperature. Dilute the reaction mixture with EA (10 mL) and wash with brine (10 mL x 3). Concentrate the organic layer under reduced pressure. Purify the resulting residue by preparative TLC (DCM:MeOH = 15:1) to give the title compound (8 mg, 48%). 1 H NMR (400MHz, CD3OD) δ7.95-7.90(m,3H),7.49-7.41(m,2H),5.61-5.58(m,1H),5.48(s,2H),4.37(br s,1H),3.48-3.46(m,1H),3.45(s,3H),3.15-3.10(m,2H),2.94-2.68(m,3H),2 .20-2.16(m,1H),1.98-1.90(m,3H),1.65-1.54(m,3H),1.05-0.78(m,6H)ppm. MS:M / e 490(M+1) + .

[0472] Compound A62: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(isoquinoline-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0473] Step A: 1-(isoquinoline-7-yl)ethyl-1-one

[0474] Pd(PPH3)2Cl2 (1.61 g, 2.35 mmol) was added to a solution of 7-bromoisoquinoline (4.9 g, 23.55 mmol) and tributyl(1-ethoxyvinyl)stanane (11 g, 30.6 mmol) in toluene (60 mL). The mixture was heated at 100 °C and N2 for 16 h. The reaction mixture was cooled to room temperature, diluted with H2O / EA, filtered through a diatomaceous earth mat, and washed with EA. The filtrate was collected, washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was dissolved in THF (80 mL) and 3N HCl (20 mL) was added. The mixture was then stirred at room temperature for 5 h. The reaction mixture was diluted with water, extracted with EA (60 mL x 3), washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography (DCM:MeOH = 20:1) to give the title compound (2.3 g, 57%). MS:M / e 172(M+1) + .

[0475] Step B: 1-(isoquinoline-7-yl)ethanol-1-ol

[0476] NaBH4 (516 mg, 13.6 mmol) was added in several portions to a solution of 1-(isoquinolin-7-yl)ethyl-1-one (2.33 g, 13.6 mmol) in MeOH (60 mL) in an ice bath. The mixture was stirred at room temperature for 2 h. The reaction was quenched with cold water, extracted with DCM (80 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (DCM:MeOH = 10:1) to give the title compound (1.2 g, 51%). 1 HNMR(400MHz,DMSO-d6)δ9.25(s,1H),8.42(d,J=5.6Hz,1H),8.00(s,1H),7.91-7.85(m,1 H),7.80-7.70(m,2H),5.39(d,J=4.0Hz,1H),4.94-4.81(m,1H),1.37(d,J=6.4Hz,3H)ppm. MS:M / e 174(M+1) + .

[0477] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(isoquinoline-7-yl)ethyl)piperazin-1-yl)-4-methyl 5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0478] DIPEA (103 mg, 0.8 mmol) was added to a solution of 1-(isoquinoline-7-yl)ethanol-1-ol (70 mg, 0.4 mmol), intermediate 5 (65 mg, 0.2 mmol), and (cyanomethyl)trimethylphosphonium iodide (97 mg, 0.4 mmol) in CH3CN (2 mL). The mixture was sealed in a flask and heated at 100 °C for 16 hours. Another portion of (cyanomethyl)trimethylphosphonium iodide (97 mg, 0.4 mmol) was added and the mixture was heated at 100 °C for 26 hours. The mixture was then cooled to room temperature, diluted with water, extracted with EA (50 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography (DCM:MeOH = 15:1) and preparative HPLC to give the title compound (8 mg, 8%). 1 HNMR(400MHz,CD3OD)δ9.21(d,J=8.8Hz,1H),8.41(t,J=5.2Hz,1H),8.11-8.02(m,1H),8.00-7.88(m,3H),7.86-7.78(m,1H),5.59-5.51(m,1H) ,5.49-5.43(m,2H),4.04-3.96(m,0.5H),3.91-3.81(m,0.5H),3.59-3. 50(m,0.5H),3.43(s,3H),3.32-3.28(m,2.5H),3.26-3.17(m,0.5H),3.1 1-3.03(m,0.5H),2.97-2.86(m,0.5H),2.75-2.64(m,0.5H),2.55-2.30 (m,1H),2.21-2.09(m,0.5H),2.06-1.92(m,0.5H),1.91-1.78(m,0.5H), 1.76-1.51(m,2.5H),1.49-1.36(m,3H),1.05(t,J=7.6Hz,1.5H),0.97( t,J=7.2Hz,1.5H),0.65(t,J=7.6Hz,1.5H),0.54(t,J=7.6Hz,1.5H)ppm. MS:M / e 484(M+1) + .

[0479] Compound A63: 2-(7-((2S,5R)-4-(1-(1,8-naphthid-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile.

[0480] Step A: 1-(1,8-naphthid-2-yl)ethanol-1-ol.

[0481] A solution of 1,8-naphthyl-2-carboxaldehyde (600 mg, 3.794 mmol) in THF (30 mL) was degassed three times under a nitrogen atmosphere. Then, CH3MgBr (1.6 mL, 3 M Et2O solution) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 4 hours. The reaction mixture was quenched with saturated NH4Cl (20 mL) at room temperature and extracted with EA (45 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography to give the title compound (400 mg, 61%). MS: M / e 175 (M+1) + .

[0482] Step B: (2S,5R)-4-(1-(1,8-naphthid-2-yl)ethyl)-2,5-diethylpiperazine-1-carboxylic acid tert-butyl ester.

[0483] DIPEA (747 mg, 5.780 mmol) was added to a solution of 1-(1,8-naphthid-2-yl)ethanol-1-ol (200 mg, 1.156 mmol), (2S,5R)-2,5-diethylpiperazine-1-carboxylic acid tert-butyl ester (281 mg, 1.156 mmol), and (cyanomethyl)trimethylphosphonium iodide (562 mg, 2.312 mmol) in CH3CN (2 mL). The mixture was degassed three times under a nitrogen 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 rapid column chromatography to give the title compound (120 mg, 26%). MS: M / e 399 (M+1) + .

[0484] Step C: 2-(1-((2R,5S)-2,5-diethylpiperazine-1-yl)ethyl)-1,8-naphthidine.

[0485] HCl (2 mL, 4 M 1,4-dioxane solution) was added to a solution of (2S,5R)-4-(1-(1,8-naphthid-2-yl)ethyl)-2,5-diethylpiperazine-1-carboxylic acid tert-butyl ester (120 mg, 0.300 mmol) in DCM (6 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure to give the crude product (HCl salt). The crude product was alkalized to pH about 10 with Na2CO3 (4 M) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, and concentrated under reduced pressure to give the title compound (60 mg, 66%). MS: M / e 299 (M+1) + .

[0486] Step D: 7-((2S,5R)-4-(1-(1,8-naphthid-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl 2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one.

[0487] DIPEA (130 mg, 1.005 mmol) was added to a solution of 2-(1-((2R,5S)-2,5-diethylpiperazin-1-yl)ethyl)-1,8-naphthidine (60 mg, 0.201 mmol) and intermediate 2 (92 mg, 0.242 mmol) in CH3CN (2 mL) at room temperature. The mixture was stirred at 105 °C for 24 hours. The mixture was then concentrated under reduced pressure to give the crude product. The crude product was purified by rapid column chromatography to give the title compound (80 mg, 75%). MS: M / e 530 (M+1) + .

[0488] Step E: 7-((2S,5R)-4-(1-(1,8-naphthid-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl 2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one.

[0489] HCl (3 mL, 4 M 1,4-dioxane solution) was added to a solution of 7-((2S,5R)-4-(1-(1,8-naphthid-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (80 mg, 0.151 mmol) in DCM (6 mL). The mixture was stirred at room temperature for 3 hours. The mixture was then concentrated under reduced pressure to give a crude product (HCl salt). The crude product was alkalized to pH about 10 with Na2CO3 (4 M) and extracted with EA (35 mL x 2). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, and concentrated under reduced pressure to give the title compound (50 mg, 75%). MS: M / e 446 (M+1) + .

[0490] Step F: 2-(7-((2S,5R)-4-(1-(1,8-naphthid-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4- Methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile.

[0491] 2-Iodoacetonitrile (28 mg, 0.169 mmol) was added to a solution of 7-((2S,5R)-4-(1-(1,8-naphthid-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (50 mg, 0.112 mmol) and K₂CO₃ (46 mg, 0.336 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 12 hours. The reaction mixture was then quenched with saturated NaCl (10 mL) at room temperature and extracted with EA (30 mL x 2). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give the title compound (6 mg, 11%). 1H NMR(400MHz,CD3OD)δ9.21-9.19(t,J=4.7Hz,1H),8.69-8.59(m,2H),8.01(s,1H),7.86-7 .76(m,2H),5.70-5.78(d,J=8Hz,1H),5.50(s,2H),5.15-5.11(m,1H),3.91-3.78(m,3H), 3.72-3.58(m,1H),3.47(s,3H),2.83-2.69(m,1H),2.13-1.95(m,3H),1.93-1.91(d,J=6. 8Hz,2H),1.85-1.75(m,3H),1.24-1.15(m,1H),1.05-1.01(m,2H),0.93-0.80(m,3H)ppm. MS:M / e 485(M+1) + .

[0492] Compound A65: a mixture of 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile and 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylquinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile.

[0494] Step A: A mixture of 3-methylquinoxaloline-6-carboxylic acid and 2-methylquinoxaloline-6-carboxylic acid

[0495] A solution of 3,4-diaminobenzoic acid (10 g, 65.72 mmol) and 2-oxopropanal (14.21 g, 40% soluble in water) in MeOH (100 mL) was stirred at room temperature for 4 hours. The mixture was then concentrated under reduced pressure to give a crude product (90% purity), which was used directly in the next step without purification. MS: M / e 189 (M+1) + .

[0496] Step B: N-methoxy-N,3-dimethylquinoxaline-6-carboxamide and N-methoxy-N,2-dimethylquinoxaline- Mixture of 6-formamide

[0497] To a solution of 3-methylquinoxaloline-6-carboxylic acid (12 g, 64.2 mmol), N,O-dimethylhydroxylamine (9.2 g, 96.26 mmol), and HATU (36.6 g, 96.26 mmol) in DMF (150 mL), NaHCO3 (16.2 g, 192.6 mmol) was added. The mixture was stirred at room temperature for 12 hours. The mixture was then quenched with saturated NH4Cl (60 mL) and extracted with EA (300 mL x 2). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography to give the title compound (11 g, 74%). MS: M / e 232 (M+1) + .

[0498] Step C: A mixture of 1-(3-methylquinoxalin-6-yl)ethyl-1-one and 1-(2-methylquinoxalin-6-yl)ethyl-1-one Compound.

[0499] A solution of N-methoxy-N,3-dimethylquinoxaloline-6-carboxamide (8.6 g, 37.2 mmol) in anhydrous THF (100 mL) was degassed three times under a nitrogen atmosphere. CH3MgBr (18.6 mL, 55.8 mmol, 3 M) was added dropwise at 0 °C. The mixture was stirred at room temperature for 4 hours. The mixture was then quenched with saturated NH4Cl (60 mL) and extracted with EA (150 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography to give the title compound (4.0 g, 57%). MS: M / e 187 (M+1) + .

[0500] Step D: A mixture of 1-(3-methylquinoxalo-6-yl)ethanol-1-ol and 1-(2-methylquinoxalo-6-yl)ethanol-1-ol Compound.

[0501] NaBH4 (188 mg, 4.94 mmol) was added to a solution of 1-(3-methylquinoxalo-6-yl)ethyl-1-one (1.15 g, 6.18 mmol) in MeOH (30 mL) at 0 °C. The mixture was stirred at 0 °C for 2 hours. The mixture was then quenched with saturated NH4Cl (20 mL) and extracted with EA (45 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography to give the title compound (600 mg, 52%). MS: M / e 189 (M+1) + .

[0502] Step E: 7-((2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalo-6-yl)ethyl)piperazin-1-yl)- 4-Methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one and 7-((2S,5R)- 2,5-Diethyl-4-(1-(2-methylquinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-) A mixture of (2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one).

[0503] DIPEA (279 mg, 2.16 mmol) was added to a solution of 1-(3-methylquinoxalo-6-yl)ethanol-1-ol (98 mg, 0.519 mmol), intermediate 3 (150 mg, 0.432 mmol), and (cyanomethyl)trimethylphosphonium iodide (210 mg, 0.864 mmol) in CH3CN (2 mL). The mixture was degassed three times under a nitrogen atmosphere. The mixture was then stirred at 105 °C for 24 h. The reaction mixture was quenched with saturated NH4Cl (20 mL) at room temperature and extracted with EA (30 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography to give the title compound (110 mg, 47%). MS: M / e 544 (M+1) + .

[0504] Step F: 7-((2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalo-6-yl)ethyl)piperazin-1-yl)- 4-Methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one and 7-((2S,5R)-2,5-diethyl-4-(1-(2-methyl) Quinoxaline-6-yl)

[0505] A mixture of (ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one.

[0506] HCl (3 mL, 4 M 1,4-dioxane solution) was added to a solution of 7-((2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (100 mg, 0.184 mmol) in MeOH (5 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure to give a crude product (HCl salt). The crude product was alkalized to pH about 10 with Na2CO3 (4 M) and extracted with EA (35 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, and concentrated under reduced pressure to give the title compound (80 mg, 94%). MS: M / e 460 (M+1) + .

[0507] Step G: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalo-6-yl)ethyl)piperazine-1- )-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile and 2-(7-((2S,5R)-2,5- Diethyl-4-(1-(2-methylquinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazole A mixture of [4,3-b]pyridin-2-yl)acetonitrile.

[0508] 2-Iodoacetonitrile (44 mg, 0.261 mmol) was added to a solution of 7-((2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (80 mg, 0.174 mmol) and K₂CO₃ (72 mg, 0.522 mmol) in DMF (3 mL) at room temperature. The mixture was stirred at room temperature for 12 hours. The reaction mixture was then quenched with saturated NaCl (20 mL) at room temperature and extracted with EA (30 mL x 2). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The resulting residue was purified by preparative TLC to give the title compound (13 mg, 15%) as a mixture. 1 H NMR(400MHz,CD3OD)δ8.81(s,1H),8.07-7.93(m,4H),5.56(s,1H),5.47(s, 2H),4.04-3.88(m,1H),3.63-3.58(m,1H),3.31(s,3H),3.10-2.77(m,2H), 2.76-2.63(m,4H),2.61-2.38(m,1H),2.17-1.88(m,2H),1.88-1.61(m,2H) ,1.45-1.41(m,3H),1.60(m,1H),1.43-0.98(m,3H),0.56-0.42(m,3H)ppm. MS:M / e 499(M+1) + .

[0509] Compound A69: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0510] Step A: 1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl-1-ol

[0511] NaBH4 (243 mg, 6.40 mmol) was added to a solution of 1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl-1-one (1.1 g, 5.3 mmol) in MeOH (20 mL) at 0 °C. The mixture was stirred for 30 min. The mixture was then quenched with saturated NH4Cl (20 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography to give the title compound (900 mg, 82%). MS: M / e191 (M-17)+ .

[0512] Step B: (2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)piperazine-1-carboxylic acid tert-butyl ester

[0513] DIPEA (3.1 g, 24.05 mmol) was added to a solution of 1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl-1-ol (1.0 g, 4.81 mmol), (2S,5R)-2,5-diethylpiperazine-1-carboxylic acid tert-butyl ester (1.17 g, 4.81 mmol), and (cyanomethyl)trimethylphosphonium iodide (1.17 g, 9.62 mmol) in CH3CN (5 mL). The mixture was degassed three times under a nitrogen atmosphere. The mixture was then stirred at 105 °C for 24 h. The reaction mixture was quenched with saturated NH4Cl (20 mL) at room temperature and extracted with EA (30 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography to give the title compound (1.1 g, 53%). MS: M / e 433 (M+1) + .

[0514] Step C: (2R,5S)-2,5-diethyl-1-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)piperazine

[0515] HCl / dioxane (6 mL, 4 M) was added to a solution of (2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 2.3 mmol) in DCM (20 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure to give a crude product (HCl salt). The crude product was alkalized to pH 10 with Na₂CO₃ (4 M) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na₂SO₄ and concentrated under reduced pressure to give the title compound (700 mg, 91%), which was used directly for the next step without purification. MS: M / e 333 (M+1) + .

[0516] Step D: 7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)piperazine-1- )-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0517] DIPEA (1354 mg, 10.5 mmol) was added to a solution of (2R,5S)-2,5-diethyl-1-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)piperazine (700 mg, 2.1 mmol) and intermediate 2 (953 mg, 2.5 mmol) in CH3CN (2 mL) at room temperature. The mixture was stirred at 105 °C for 24 hours. The mixture was then concentrated under reduced pressure to give the crude product. The crude product was purified by rapid column chromatography to give the title compound (1.0 g, 85%). MS: M / e 564 (M+1) + .

[0518] Step E: 7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)piperazine-1- 4-Methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (compound A231)

[0519] HCl / dioxane (10 mL, 4 M) was added to a solution of 7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (1.0 g, 1.77 mmol) in MeOH (20 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure to give the crude product (HCl salt). The crude product was alkalized to pH 10 with Na2CO3 (4 M) and extracted with EA (35 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4 and concentrated under reduced pressure to give the title compound (700 mg, 82%), a mixture of diastereomers, some of which were further separated into compound A231a (10 mg) and compound A231b (10 mg) by preparative HPLC (method A).

[0520] Compound A231a: 1 H NMR (400MHz, CDCl3) δ7.76(s,1H),7.45(s,1H),7.41(s,1H),7.27(s,1H),5.65(s,1H),4.05(s,1H),3.48-3.42(m,4H),3.09-2.99(m,1 H),2.75-2.65(m,1H),2.32-2.22(m,1H),1.87-1.55(m,5H),1.50-1.46(m,1H),1.29-1.25(m,3H),0.93(s,3H),0.61-0.56(m,3H)ppm. MS:M / e 480(M+1) + .

[0521] Compound A231b: 1H NMR (400MHz, CDCl3) δ10.62 (s, 1H), 7.68-7.66 (t, J = 8Hz, 1H), 7.43 (s, 2H), 7.32-7. 29(m,1H),5.62(s,1H),4.22-4.21(m,1H),3.45(s,3H),3.22(m,1H),2.91(m,2H),2. 36-2.34(m,1H),2.05-2.00(m,1H),1.78-1.72(m,1H),1.62-1.56(m,3H),1.37-1.3 1(m,1H),1.29-1.23(m,3H),0.90-0.86(t,J=8Hz,3H),0.71-0.67(t,J=8Hz,3H)ppm. MS:M / e 480(M+1) + .

[0522] Step F: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)piperazine- 1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile (compound A69)

[0523] 2-Iodoacetonitrile (366 mg, 2.19 mmol) was added to a solution of 7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (700 mg, 1.46 mmol) and K₂CO₃ (403 mg, 2.92 mmol) in DMF (20 mL) at room temperature. The mixture was stirred at room temperature for 12 hours. The reaction mixture was then quenched with saturated NaCl (20 mL) at room temperature and extracted with EA (50 mL x 2). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to give crude compound A69 (600 mg), a mixture of diastereomers, which was further separated into compound A69a (106 mg) and compound A69b (150 mg) by preparative HPLC (Method A).

[0524] Compound A69a (first eluting peak): 1H NMR (400MHz, CD3OD) δ7.92-7.91(m,1H),7.80(t,J=7.2Hz,1H),7.53(d,J=8Hz,1H),7.44 (d,J=10Hz,1H),5.56(s,1H),5.47(s,2H),4.28-4.23(m,1H),3.43(s,3H),3.32-3.30(m ,3H),2.92-2.88(m,2H),2.40-2.38(m,1H),2.11-2.07(m,1H),1.80-1.76(m,1H),1.56- 1.52(m,2H),1.36-1.32(m,3H),0.95-0.91(t,J=8Hz,3H),0.78-0.74(t,J=8Hz,3H)ppm. MS:M / e 519(M+1) + .

[0525] Compound A69b (later peak): 1 H NMR (400MHz, CD3OD) δ7.95-7.91(m,1H),7.87(t,J=7.2Hz,1H),7.51(d,J=8Hz,1H),7.41(d,J=10 .4Hz,1H),5.56(s,1H),5.48(s,2H),4.10-4.07(m,1H),3.52-3.51(m,1H),3.43(s,3H),3.31(s, 2H),3.18-3.14(m,1H),2.76-2.65(m,1H),2.39-2.29(m,1H),1.95-1.91(m,1H),1.70-1.66(m,2 H), 1.55-1.51 (m, 1H), 1.36-1.32 (m, 3H), 1.03-0.99 (t, J = 8Hz, 3H), 0.67-0.63 (t, J = 8Hz, 3H) ppm. MS:M / e519(M+1) + .

[0526] Compound A71: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0527] Step A: (2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)piperazine-1-carboxylic acid tert-butyl ester

[0528] A mixture of (2S,5R)-2,5-diethylpiperazine-1-carboxylic acid tert-butyl ester (1.5 g, 6.2 mmol), 1-(4-fluoro-2-methoxyphenyl)ethanol-1-ol (1.58 g, 9.3 mmol), (cyanomethyl)trimethylphosphonium iodide (3.0 g, 12.4 mmol), and DIPEA (3.96 g, 31 mmol) in CH3CN (10 mL) was heated to 105 °C overnight under N2 atmosphere. The solvent was removed under vacuum. The crude product was purified by silica gel rapid column chromatography (DCM:MeOH = 100:1) to give the title compound (2.1 g, 86%). MS: M / e 395 (M+1) + .

[0529] Step B: (2R,5S)-2,5-diethyl-1-(1-(4-fluoro-2-methoxyphenyl)ethyl)piperazine

[0530] TFA (4 mL) was added to a solution of (2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)piperazine-1-carboxylic acid tert-butyl ester (2.1 g, 5.3 mmol) in DCM (20 mL) at room temperature. The resulting mixture was stirred at room temperature for an additional 3 hours. The reaction solvent was removed under vacuum. The crude product was dissolved in DCM (mL) and neutralized to pH 8 with aqueous NaOH solution. The organic layer was concentrated to give a crude product (1.6 g), which was used directly for the next step without further purification. MS: M / e 295 (M+1) + .

[0531] Step C: 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)piperazin-1-yl)- 4-Methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0532] A mixture of intermediate 2 (773 mg, 2.03 mmol), (2R,5S)-2,5-diethyl-1-(1-(4-fluoro-2-methoxyphenyl)ethyl)piperazine (600 mg, 2.03 mmol), and DIPEA (mg, mmol) in CH3CN was heated to 105 °C overnight under N2 atmosphere. The solvent was removed under vacuum. The crude product was purified by rapid column chromatography (DCM:MeOH = 20:1) to give the title compound (750 mg, 71%). MS: M / e 526 (M+1) + .

[0533] Step D: 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)piperazin-1-yl)- 4-Methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0534] A solution of dioxane in HCl (1.9 mL, 7.6 mmol, 4 M) was added to a solution of 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (400 mg, 0.76 mmol) in MeOH (5 mL) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction solvent was removed under vacuum. The crude product was dissolved in DCM (20 mL) and neutralized to pH 8 with aqueous NaOH. The organic layer was concentrated to give the crude product, which was further purified by rapid column chromatography (DCM:MeOH = 10:1) to give the title compound (280 mg, 84%). MS: M / e 442 (M+1) + .

[0535] Step E: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)piperazine-1- (4,3-b)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0536] 2-Iodoacetonitrile (160 mg, 0.96 mmol) was added to a solution of 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (280 mg, 0.64 mmol) and K₂CO₃ (178 mg, 12.8 mmol) in DMF (5 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with EA (20 mL) and washed with brine (20 mL x 3). The organic layer was concentrated under reduced pressure to give compound A71. The resulting residue containing compound A71 was purified by preparative TLC (DCM:MeOH = 15:1) to give two compounds, compound A71a (38 mg, 12%) and compound A71b (crude). Compound A71b (crude product) was further purified by preparative HPLC (method A) to obtain compound A71b (19 mg, 6%).

[0537] Compound A71a: 1H NMR (400MHz, CD3OD) δ7.92(s,1H),7.55(s,1H),6.74-6.66(m,2H),5.54(s,1H),5.47(s,2H),4.10(br s,1H),3.82(s,3H),3.43(s,3H),3.12-3.01(m,2H),2.68-2.55(m,2H),2.39-2.5(m,1H),2.01(br s,1H),1.65-1.48(m,4H),1.35-1.21(m,3H),1.05-0.98(m,3H),0.72-0.68(m,3H)ppm. MS:M / e 481(M+1) + .

[0538] Compound A71b: 1 H NMR (400MHz, CD3OD) δ7.90(s,1H),7.45(s,1H),6.76-6.69(m,2H),5.52(s,1H),5.44(s,2H),4.31(br s,1H),3.81(s,3H),3.41(s,3H),3.35-3.23(m,1H),2.93-2.63(m,4H),2.45(br s,1H),2.02(br s,1H),1.78(br s,1H),1.52-1.48(m,2H),1.30-1.25(m,3H),0.99-0.92(m,3H),0.75-0.68(m,3H)ppm. MS:M / e 481(M+1) + .

[0539] Compound A79: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0540] Step A: (2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)piperazine-1-methyl tert-butyl ester

[0541] To a solution of 1-(4-fluoro-2-(methoxymethyl)phenyl)ethane-1-ol (200 mg, 1.1 mmol) in MeCN (10 mL), tert-butyl (2S,5R)-2,5-diethylpiperazine-1-carboxylate (290 mg, 1.2 mmol), (cyanomethyl)trimethylphosphonium iodide (550 mg, 2.3 mmol), and DIPEA (700 mg, 5.4 mmol) were added. The resulting mixture was stirred overnight at 100 °C. The reaction mixture was concentrated and purified by reverse-phase C18 column (water, 0.05% TFA / MeCN) to give the title compound (140 mg, 32%). MS: M / e 409 (M+1) + .

[0542] Step B: (2R,5S)-2,5-diethyl-1-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)piperazine

[0543] TFA (2 mL) was added to a solution of (2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)tert-butylpiperazine (140 mg, 0.34 mmol) in DCM (5 mL). The resulting mixture was stirred at RT for an additional 3 hours. The reaction solvent was removed under vacuum. The crude product was dissolved in water and adjusted to pH 9 with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EA (25 mL x 2). The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 50:1) to give the title compound (80 mg, 76%). MS: M / e 309 (M+1) + .

[0544] Step C: 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)piperazine- 1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0545] Intermediate 2 (148 mg, 0.39 mmol) and DIPEA (100 mg, 0.78 mmol) were added to a solution of (2R,5S)-2,5-diethyl-1-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)piperazine (80 mg, 0.26 mmol) in MeCN (5 mL). The resulting mixture was stirred overnight at 100 °C. The reaction solvent was removed under reduced pressure to give the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 40:1) to give the title compound (130 mg, 93%). MS: M / e 540(M+1)+.

[0546] Step D: 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)piperazine- 1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0547] TFA (2 mL) was added to a solution of 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (130 mg, 0.24 mmol) in DCM (5 mL). The resulting mixture was stirred at RT for 2 hours. The reaction solvent was removed under vacuum. The crude product was dissolved in water and adjusted to pH 9 with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with (DCM:i-PrOH = 4:1, 25 mL x 2). The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 30:1) to give the title compound (65 mg, 59%). MS:M / e 456(M+1) + .

[0548] Step E: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)piperidine (1-azinyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0549] To a solution of 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(methoxymethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (20 mg, 0.044 mmol) in DMF (2 mL), K₂CO₃ (18 mg, 0.13 mmol) and 2-iodoacetonitrile (11 mg, 0.065 mmol) were added. The resulting mixture was stirred overnight at RT. The reaction mixture was diluted with EA (20 mL) and washed with water. The organic layer was dried over Na₂SO₄ and concentrated to give a crude product. The crude product was purified by preparative TLC (DCM:MeOH = 20:1) to give the title compound (7.8 mg, 36%). 1 HNMR(400MHz,CD3OD)δ7.92(s,1H),7.75-7.51(m,1H),7.23-6.95(m,2H),5.56(s, 1H),5.47(s,2H),4.68-4.48(m,2H),4.15-3.80(m,1H),3.55-3.30(m,7H),3.25-3. 01(m,1H),2.95-2.70(m,1H),2.65-2.30(m,1H),2.29-2.02(m,1H),2.00-1.75(m,1 H),1.74-1.33(m,3H),1.32-1.20(m,4H),1.15-0.80(m,3H),0.75-0.51(m,3H)ppm. MS:M / e 495(M+1) + .

[0550] Compound A84: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methylphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0551] Step A: 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methylphenyl)ethyl)piperazin-1-yl)-4- Methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0552] A mixture of intermediate 3 (100 mg, 0.27 mmol), 1-(4-fluoro-2-methylphenyl)ethanol-1-ol (83 mg, 0.54 mmol), (cyanomethyl)trimethylphosphonium iodide (131 mg, 0.54 mmol), and DIPEA (350 mg, 2.7 mmol) in CH3CN (2 mL) was heated to 105 °C overnight under N2 atmosphere. The solvent was removed under vacuum. The crude product was purified by preparative TLC (DCM:MeOH = 15:1) to give the title compound (80 mg, 59%). MS: M / e 510 (M+1) + .

[0553] Step B: 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methylphenyl)ethyl)piperazin-1-yl)-4- Methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0554] A solution of dioxane in HCl (1 mL, 4 mmol, 4 M) was added to a solution of 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methylphenyl)ethyl)piperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (80 mg, 0.16 mmol) in MeOH (2 mL) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction solvent was removed under vacuum. The crude product was dissolved in DCM (10 mL) and neutralized to pH 8 with aqueous NaOH. The organic layer was concentrated to give the crude product, which was further purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound (20 mg, 29%). MS: M / e 426 (M+1) + .

[0555] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methylphenyl)ethyl)piperazin-1-yl)- 4-Methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0556] To a solution of 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methylphenyl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (20 mg, 0.05 mmol) and K₂CO₃ (13 mg, 0.09 mmol) in DMF (2 mL), 2-iodoacetonitrile (12 mg, 0.07 mmol) was added. The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with EA (10 mL) and washed with brine (10 mL x 3). The organic layer was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (DCM:MeOH = 15:1) to give the title compound (2.2 mg, 10%). 1 H NMR(400MHz,CD3OD)δ7.92(s,1H),7.58-7.45(m,1H),6.91-6.81(m,2H),5.55-5.47(m,3H),3.97-3.87(m,1H),3.51-3.42(m,4H),3.1 9-3.02(m,1H),2.82-2.62(m,3H),2.47-2.29(m,4H),1.75-1.61(m,3H),1.35-1.24(m,5H),1.55-0.88(m,3H),0.69-0.63(m,2H)ppm. MS:M / e 465(M+1) + .

[0557] Compound A95: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-(2-hydroxyethyl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0558] Step A: 4-(N-(2-((tert-butyldimethylsilyl)oxy)ethyl)acetamido)-1-(tetrahydro-2H- Ethyl pyran-2-yl)-1H-pyrazole-3-carboxylate

[0559] Ethyl 4-acetamido-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (1 g, 3.56 mmol), tert-butyl(2-iodoethoxy)dimethylsilane (1.53 g, 5.35 mmol), and Cs₂CO₃ (2.32 g, 7.12 mmol) in DMF (10 mL) were stirred overnight at RT, followed by stirring at 60 °C for 2 days. Afterward, the mixture was poured into water (15 mL) and extracted with EA (20 mL x 2). The organic layer was washed with brine (10 mL), dried, and concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography with 0%–50% EA in PE to give the title compound (0.37 g, 24%). MS: M / e 440 (M+1)+ .

[0560] Step B: 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-hydroxy-2-(tetrahydro-2H-pyran- 2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0561] LiHMDS (1M, 1.6ml, 1.6mmol) was added dropwise to a stirred solution of ethyl 4-(N-(2-((tert-butyldimethylsilyl)oxy)ethyl)acetamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-carboxylate (0.37 g, 0.84 mmol) in THF (10 ml) at -60 °C and N2. The solution was stirred at -60 °C for 1.5 h. After completion, the solution was quenched with H2O (1 ml) and heated to RT. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography with 0%–10% MeOH in DCM to give the title compound (250 mg, 75%) as a pale yellow solid. MS: M / e 394 (M+1) + .

[0562] Step C: 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-oxo-2-(tetrahydro-2H-pyran- 2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yltrifluoromethanesulfonate

[0563] A mixture of 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-hydroxy-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (250 mg, 0.63 mmol), 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (340 mg, 0.95 mmol), and K₂CO₃ (175 mg, 1.27 mmol) in THF (10 mL) was stirred overnight at RT. Afterward, the solution was diluted with EA (15 mL), washed with brine (10 mL), dried, and concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography with 0%–30% EA in PE to give the title compound (290 mg, 87%). MS: M / e 526 (M+1) + .

[0564] Step D: 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-((2S,5R)-2,5-diethyl-4- (1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-] b] Pyridin-5-one

[0565] A mixture of 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate (290 mg, 0.55 mmol), 6-(1-((2R,5S)-2,5-diethylpiperazin-1-yl)ethyl)quinoxaline (165 mg, 0.55 mmol), and DIPEA (214 mg, 1.66 mmol) in MeCN (6 mL) was stirred at 110 °C for 4 days. After completion, the solution was concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography using 30%–100% EA in PE to give the title compound (140 mg, 38%). MS: M / e 674 (M+1) + .

[0566] Step E: 7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-(2-hydroxy) (2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one)

[0567] To a solution of 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-((2S,5R)-2,5-diethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (140 mg, 0.21 mmol) in MeOH (2 mL), HCl / dioxane (4 M, 2 mL, 8 mmol) was added dropwise, followed by stirring at RT for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure to give the title compound (98 mg, 100%), which was used directly for the next step without further purification. MS: M / e 476 (M+1) + .

[0568] Step F: 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-((2S,5R)-2,5-diethyl-4- (1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0569] TBSCl (55 mg, 0.36 mmol) was added to a solution of 7-((2S,5R)-2,5-diethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-(2-hydroxyethyl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (98 mg, 0.21 mmol), DIPEA (81 mg, 0.63 mmol), and DMAP (catalyst) in DCM (5 mL), followed by stirring overnight at RT. After completion, the reaction mixture was diluted with DCM (10 mL), washed with brine (10 mL), dried, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC using DCM:MeOH (20:1) to give a crude product (120 mg, 100%), which was used directly for the next step without further purification. MS: M / e 590 (M+1) + .

[0570] Step G: 2-(4-(2-(tert-butyldimethylsilyloxy)ethyl)-7-((2S,5R)-2,5-diethyl- 4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl) Acetonitrile The mixture of the compound from step F (60 mg, 0.10 mmol), 2-iodoacetonitrile (25.5 mg, 0.15 mol), and K₂CO₃ (28 mg, 0.20 mmol) in DMF (2 mL) was stirred at RT for 5 hours. After completion, the mixture was poured into water (15 mL) and subsequently extracted with EA (20 mL x 2). The organic layer was washed with brine (10 mL), dried, and concentrated under reduced pressure to give a crude product (63 mg), which was used directly for the next step without further purification. MS: M / e 629 (M+1) + .

[0571] Step H: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4- (2-Hydroxyethyl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0572] The mixture of the compound from step G (63 mg, 0.1 mmol) and TBAF (1 M, 0.15 mL, 0.15 mmol) in THF (5 mL) was stirred at RT for 0.5 h. After completion, the solution was concentrated under reduced pressure. The resulting residue was purified by preparative TLC with DCM:MeOH (15:1) and subsequently by preparative HPLC to give the title compound (5 mg). 1H NMR (400MHz, DMSO-d6) δ8.98-8.89(m,2H),8.15-8.02(m,2H),8.00-7.92(m,2H),5.61(s,2H),5.39(s,1H),4.82(t,J=5.3Hz,1H),4.0 5(d,J=6.3Hz,0.5H),3.90(d,J=6.4Hz,0.5H),3.85(s,2H),3.58(dd,J=14.0,4.0Hz,2H),3.49-3.35(m,1H),3.33-3.28(m,1H),3.14( s,1H),2.99(d,J=11.3Hz,1H),2.83(d,J=9.9Hz,0.5H),2.62(d,J=10.7Hz,0.5H),2.32(d,J=7.3Hz,0.5H),2.25(d,J=12.0Hz,0.5H), 2.16-1.86(m,1H),1.73-1.46(m,3H),1.37(dd,J=14.1,6.2Hz,3H),0.97(dd,J=26.9,20.2Hz,3H),0.57(dd,J=33.3,26.6Hz,3H)ppm. MS:M / e 515(M+1)+.

[0573] Compound A96: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0574] A mixture of 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-(2-hydroxyethyl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile (8 mg, 0.016 mmol), CH3I (2.4 mg, 0.017 mmol), and K2CO3 (3.2 mg, 0.023 mmol) in DMF (0.5 mL) was stirred overnight at RT. After completion, the mixture was poured into water (10 mL) and then extracted with EA (10 mL x 2). The organic layer was washed with brine (10 mL), dried, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give the title compound (0.57 mg, FA salt). 1H NMR (400MHz, CD3OD) δ8.91-8.86(m,2H),8.65-8.41(m,1H),8.14-7.98(m,4H),5.83-5.70(m,1H),5.57(d,J=6.3Hz,1 H),4.08(d,J=7.8Hz,0.5H),4.04(d,J=5.6Hz,2H),3.92(d,J=6.3Hz,0.5H),3.82(t,J=5.7Hz,2H),3.58(d,J=12.7Hz ,0.5H),3.40-3.33(m,0.5H),3.29-3.19(m,3H),3.11(d,J=13.7Hz,1H),2.86-2.65(m,3H),2.46-2.35(m,1H),2.25- 1.98(m,1H),1.62(s,2H),1.45(dd,J=10.8,6.5Hz,3H),1.38-1.25(m,2H),1.11-0.96(m,3H),0.72-0.53(m,3H)ppm. MS:M / e 529(M+1) + .

[0575] Compound A97: 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0576] 2-Iodoacetonitrile (300 mg, 1.8 mmol) was added to a solution of intermediate 6 (510 mg, 1.2 mmol) and K₂CO₃ (330 mg, 2.4 mmol) in DMF (10 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with EA (40 mL) and washed with brine (20 mL x 3). The organic layer was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (DCM:MeOH = 15:1) to give the crude product compound A97. The crude product was purified by chiral separation to give compounds A97a (24 mg) and A97b (34 mg). The chiral separation conditions are shown below.

[0577] Compound A97a (first eluting peak): 1 H NMR (400MHz, CD3OD) δ8.88 (d, J=3.2Hz, 2H), 8.13

[0578] -8.02(m,3H),7.92(s,1H),5.59(s,1H),5.44(s,2H),4.09-4.05(m,1H),3.43(s,3H),3.32

[0579] -3.31(m,2H),3.08-2.95(m,2H),2.93(br s,1H),2.44(br s,1H),1.65-1.61(m,2H),1.46

[0580] -1.44(m,6H),0.72(t,J=7.4Hz,3H)ppm. MS:M / e 471.3(M+1) + .

[0581] Compound A97b (later peak): 1 H NMR (400MHz, CD3OD) δ8.87(d,J=4.4Hz,2H),8.09-8.03(m,3H),7.93(s,1H),5.57(s,1H),5.47(s,2H),4.42(br s,1H),3.94-3.92(m1H),3.61-3.58(m,1H),3.44(s,3H),3.24-3.21(m,1H),2.85-2.81(m,2H),2.27-2 .21(m,1H),1.78-1.56(m,2H),1.45(d,J=6.6Hz,3H),1.24(d,J=6.5Hz,3H),1.09(t,J=7.4Hz,3H)ppm. MS:M / e 471.3(M+1) + .

[0582] Compound A98: 2-(7-((2S,5R)-2-ethyl-5-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0583] Step A: Benzyl-D-alanine methyl ester

[0584] Benzyl bromide (32.5 g, 0.19 mol) was added to a solution of D-alanine methyl ester (20.0 g, 0.19 mol) in CH3CN (200 mL) at 0 °C under a N2 atmosphere. The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the resulting residue was dissolved in EA (500 mL) and washed with water (500 mL x 3). The organic layer was concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography (PE:EA = 10:1) to give the title compound (17 g, 46%). MS: M / e 194 (M+1) + .

[0585] Step B: N-Benzyl-N-((S)-2-((tert-Butoxycarbonyl)amino)butyryl)-D-alanine methyl ester

[0586] HATU (49.4 g, 0.13 mmol) was added to a solution of (R)-2-(benzylamino)butyrate (17.0 g, 0.09 mol), (S)-2-((tert-butoxycarbonyl)amino)butyric acid (26.8 g, 0.13 mol), and 4-methylmorpholine (18.2 g, 0.18 mol) in DCM (500 mL) at 0 °C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with water and washed with water (1500 mL x 2). The organic layer was concentrated under reduced pressure and purified by rapid column chromatography (PE:EA = 10:1) to give the title compound (25 g, 75%). MS: M / e 379 (M+1) + .

[0587] Step C: (3S,6R)-1-benzyl-3-ethyl-6-methylpiperazine-2,5-dione

[0588] A solution of dioxane in HCl (100 mL, 4 M) was added to a solution of (R)-2-((S)-N-benzyl-2-((tert-butoxycarbonyl)amino)butyrylamino)butyrate (25 g, 66 mmol) in 1,4-dioxane (20 mL) at room temperature. The resulting mixture was stirred at room temperature for another 2 hours. The solvent was removed under vacuum. The resulting residue was dissolved in H₂O and adjusted to pH 9 by neutralization with aqueous NaHCO₃ solution. The resulting mixture was stirred at room temperature for 2 hours and then extracted with EA (500 mL x 2). The organic layer was concentrated under reduced pressure and purified by rapid column chromatography (PE:EA = 10:1) to give the title compound (15 g, 92%). MS: M / e 247 (M+1) + .

[0589] Step D: (2R,5S)-1-benzyl-5-ethyl-2-methylpiperazine

[0590] (3S,6R)-1-benzyl-3-ethyl-6-methylpiperazine-2,5-dione (15.0 g, 0.06 mol) was slowly added to a solution of LiAlH4 (6.9 g, 0.18 mol) in THF (200 mL), and dissolved in THF (100 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 hours, and then stirred overnight at 80 °C. The reaction was slowly quenched at 0 °C with water (7 mL). Then, 1N aqueous NaOH solution (14 mL) and water (28 mL) were added sequentially. The resulting mixture was stirred for 2 hours. The white precipitate formed was removed by filtration through diatomaceous earth. The filter cake was washed with EA (500 mL). The combined filtrates were evaporated. The resulting residue was dissolved in toluene and dried to give the title compound (12 g, 91%). MS: M / e 219 (M+1) + .

[0591] Step E: 7-((2S,5R)-4-benzyl-2-ethyl-5-methylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyridine) (2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0592] A mixture of intermediate 2 (2.3 g, 6 mmol), (2R,5S)-1-benzyl-2,5-diethylpiperazine (2 g, 9 mmol), and DIPEA (3.9 g, 30 mmol) in CH3CN (50 mL) was heated to 105 °C overnight under N2 atmosphere. The solvent was removed under vacuum. The crude product was purified by rapid column chromatography (DCM:MeOH = 15:1) to give the title compound (2.2 g, 82%). MS: M / e 450 (M+1) + .

[0593] Step F: 7-((2S,5R)-2-ethyl-5-methylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-) 2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0594] A mixture of 7-((2S,5R)-4-benzyl-2-ethyl-5-methylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (2.2 g, 4.9 mmol) and Pd / C (220 mg, 10% soluble in water) in MeOH (30 mL) was shaken overnight at room temperature under N2 atmosphere (50 psi). The mixture was filtered through diatomaceous earth. The filter cake was washed with EA (50 mL). The combined filtrates were concentrated and purified by rapid column chromatography (DCM:MeOH = 10:1) to give the title compound (1.3 g, 74%). MS: M / e 360 ​​(M+1) + .

[0595] Step G: 7-((2S,5R)-2-ethyl-5-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl 2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0596] A mixture of 7-((2S,5R)-2-ethyl-5-methylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (1.3 g, 3.6 mmol), 1-(quinoxalo-6-yl)ethanol-1-ol (940 mg, 5.4 mmol), (cyanomethyl)trimethylphosphonium iodide (1.4 g, 5.4 mmol), and DIPEA (4.7 mg, 36 mmol) in CH3CN (10 mL) was heated to 105 °C overnight in a sealed tube under N2 atmosphere. The solvent was removed under vacuum. The crude product was purified by rapid column chromatography (DCM:MeOH = 15:1) to give the title compound (320 mg, 17%). MS: M / e 516 (M+1) + .

[0597] Step H: 7-((2S,5R)-2-ethyl-5-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl 2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0598] Dioxane HCl solution (10 mL, 40 mmol, 4 M) was added to a solution of 7-((2S,5R)-2-ethyl-5-methyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (320 mg, 0.62 mmol) in MeOH (5 mL) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction solvent was removed under vacuum. The crude product was dissolved in DCM (10 mL) and neutralized with aqueous NaOH to adjust the pH to 8. The organic layer was concentrated and purified by rapid column chromatography (DCM:MeOH = 15:1) to give the title compound (150 mg, 56%). MS: M / e 432 (M+1) + .

[0599] Step I: 2-(7-((2S,5R)-2-ethyl-5-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)- 4-Methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0600] 2-Iodoacetonitrile (85 mg, 0.51 mmol) was added to a solution of 7-((2S,5R)-2-ethyl-5-methyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (150 mg, 0.34 mmol) and K₂CO₃ (97 mg, 0.68 mmol) in DMF (2 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with EA (10 mL) and washed with brine (10 mL x 3). The organic layer was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (DCM:MeOH = 15:1) to give the crude product compound A98. The crude product was purified by chiral separation to give compounds A98a (27 mg) and A98b (41 mg). The chiral separation conditions are shown below.

[0601] Compound A98a (first eluting peak): 1 H NMR (400MHz, CD3OD): δ8.88(d,J=3.6Hz,2H),8.12-8.02(m,3H),7.92(s,1H),5.55(s,1H),5.47(s,2H),3.99-3.97(m,1H),3.47(br s,1H),3.43(s,3H),3.33-3.31(m,2H),3.09-2.89(m,3H),2.17-2.15(m,1H),1.92- 1.90 (m, 1H), 1.44 (d, J = 6.4Hz, 3H), 1.03 (d, J = 6.5Hz, 3H), 0.96 (t, J = 7.4Hz, 3H) ppm. MS:M / e 471(M+1) + .

[0602] Compound A98b (later peak): 1 H NMR (400MHz, CD3OD): δ8.87 (d, J=4.6Hz, 2H), 8.10-8.01 (m, 3H), 7.92 (s, 1H), 5. 56(s,1H),5.46(s,2H),3.83-3.81(m,1H),3.68-3.65(m,2H),3.43(s,3H),3.33- 3.31(m,2H),2.79-2.77(m,1H),2.35-2.32(m,1H),1.98-1.96(m,1H),1.72-1.7 0 (m, 1H), 1.45 (d, J = 6.4Hz, 3H), 1.19 (d, J = 6.5Hz, 3H), 0.58 (t, J = 7.5Hz, 3H) ppm. MS:M / e 471(M+1) + .

[0603] Compound A99: 2-(7-((2S,5S)-5-(hydroxymethyl)-2-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0604] Step A: ((benzyloxy)carbonyl)-D-serine-L-alanine methyl ester

[0605] HATU (22.9 g, 60 mmol) was added to a stirred mixture of ((benzyloxy)carbonyl)-D-serine (11.95 g, 50 mmol) and D-alanine methyl ester hydrochloride (7 g, 50 mmol) in CH₂Cl₂ (200 mL), followed by DIPEA (19 g, 0.15 mol). The reaction mixture was stirred overnight after the addition. The reaction mixture was washed with H₂O (200 mL). The organic layer was separated, washed with brine, dried over Na₂SO₄, and concentrated. The resulting residue was further washed with H₂O (200 mL) and filtered. The filter cake was collected, dried, and gave the title compound (28 g, 86%). MS: M / e 325 (M+1) + .

[0606] Step B: (3R,6S)-3-(hydroxymethyl)-6-methylpiperazine-2,5-dione

[0607] Pd / C (2 g, 10% soluble in water) was added to a solution of ((benzyloxy)carbonyl)-D-serine-L-alanine methyl ester (16.2 g, 50 mmol) in MeOH (200 mL). The mixture was then stirred overnight in H2 (1 atm). The reaction mixture was filtered and the filtrate was concentrated to approximately 100 mL. The resulting mixture was stirred in a sealed tube at 100 °C for 2 days. The reaction mixture was cooled to room temperature and MTBE (200 mL) was added, followed by filtration. The filter cake was collected, dried, and the title compound (3.5 g, 44.3%) was obtained. MS: M / e 159 (M+1) + .

[0608] Step C: ((2S,5S)-5-methylpiperazin-2-yl)methanol hydrochloride

[0609] A mixture of (3R,6S)-3-(hydroxymethyl)-6-methylpiperazine-2,5-dione (3.5 g, 22.2 mmol) in THF-BH3 (1.0 M, 140 mL) was stirred overnight at 70 °C. The reaction was quenched by gradually adding MeOH (20 mL) at 0 °C, followed by the addition of concentrated HCl (10 mL). The resulting solid was filtered, the filter cake was collected, and dried to give the title compound (4.5 g, 100%). MS: M / e 131 (M+1) + .

[0610] Step D: (2S,5S)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[0611] A solution of Boc₂O (14.5 g, 66.6 mmol) in MeOH (10 mL) was added dropwise to a stirred solution of ((2S,5S)-5-methylpiperazin-2-yl)methanol hydrochloride (4.5 g, 22.2 mmol) and Et₃N (8.9 g, 88.8 mmol) in MeOH (100 mL) at 0 °C–5 °C. The reaction mixture was then stirred overnight at 50 °C. The reaction mixture was concentrated to obtain a residue, which was treated with EA / H₂O (100 mL / 100 mL). The organic layer was separated, washed with brine, dried over Na₂SO₄, and purified by rapid column chromatography (petroleum ether / EA = 100 / 1-1 / 1) to give di-tert-butyl (2S,5S)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate (7.5 g, 100%), which was dissolved in an EtOH / NaOH aqueous solution (50 mL / 50 mL) and the mixture was stirred at 80 °C for 2 days. Most of the EtOH was removed, yielding an aqueous layer, which was acidified to pH 9-10 with HCl aqueous solution (3 M) and then extracted with EA (40 mL x 10). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give the title compound (4.6 g, 91%). MS: M / e 231 (M+1) + .

[0612] Step E: (2S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[0613] Et3N (1.86 g, 18.4 mmol) was added to a stirred solution of (2S,5S)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (2.12 g, 9.2 mmol) in CH2Cl2 (50 mL), followed by DMAP (114 mg, 0.92 mmol) and then TBSCl (2.08 g, 13.8 mmol). After the additions, the reaction mixture was stirred overnight at room temperature. The reaction mixture was treated with H2O and extracted with CH2Cl2 (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by rapid column chromatography (PE:EA = 2:1) to give the title compound (2.72 g, 86%). MS: M / e 345 (M+1) + .

[0614] Step F: (2S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-4-(1-(quinoxal) tert-butyl lin-6-yl)ethyl)piperazine-1-carboxylate

[0615] A mixture of (2S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylpiperazin-1-carboxylate tert-butyl ester (172 mg, 0.5 mmol), 1-(quinoxalo-6-yl)ethanol-1-ol (174 mg, 1 mmol), (cyanomethyl)trimethylphosphonium iodide (364.5 mg, 1.5 mmol), and DIPEA (645 mg, 5 mmol) in CH3CN (10 mL) was stirred overnight at 100 °C in a sealed tube. The reaction mixture was poured into H2O (50 mL) and extracted with EA (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by preparative TLC (EA) to give the title compound (130 mg, 52%). MS: M / e501 (M+1) + .

[0616] Step G: ((2S,5S)-5-methyl-1-(1-(quinoxalo-6-yl)ethyl)piperazin-2-yl)methanol

[0617] To a stirred solution of (2S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester (130 mg, 0.26 mmol) in CH₂Cl₂ (5 mL), HCl (2 mL, 4.0 M, 1,4-dioxane solution) was added and the mixture was stirred for 3 hours. The reaction mixture was concentrated to obtain a residue, which was used directly for the next step without further purification. MS: M / e 287 (M+1) + .

[0618] Step H: 7-((2S,5S)-5-(hydroxymethyl)-2-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazine-1- )-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0619] A mixture of intermediate 2 (33 mg, 0.26 mmol), ((2S,5S)-5-methyl-1-(1-(quinoxalo-6-yl)ethyl)piperazin-2-yl)methanol (0.26 mmol), and DIPEA (100.6 mg, 0.78 mmol) in CH3CN (5 mL) was stirred at 75 °C for 3 days. The reaction mixture was poured into H2O (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by preparative TLC (CH2Cl2 / MeOH = 10 / 1) to give the title compound (13 mg). MS: M / e 518 (M+1) + .

[0620] Step I: 7-((2S,5S)-5-(hydroxymethyl)-2-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazine-1- 4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0621] To a stirred solution of 7-((2S,5S)-5-(hydroxymethyl)-2-methyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (87 mg, 0.168 mmol) in MeOH / CH2Cl2 (5 mL / 3 mL), HCl (2 mL, 4.0 M, 1,4-dioxane solution) was added and the mixture was stirred overnight. The reaction mixture was concentrated to obtain a residue, which was treated with a saturated aqueous solution of NaHCO3 and then extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by preparative TLC (CH2Cl2 / MeOH = 10 / 1) to give the title compound (54 mg, 74%). MS:M / e 434(M+1) + .

[0622] Step J: 2-(7-((2S,5S)-5-(hydroxymethyl)-2-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazine- 1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0623] A mixture of 7-((2S,5S)-5-(hydroxymethyl)-2-methyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (54 mg, 0.124 mmol), 2-iodoacetonitrile (42 mg, 0.25 mmol), and K₂CO₃ (34.5 g, 0.25 mmol) in DMF (4 mL) was stirred overnight. The reaction mixture was poured into H₂O (15 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to dryness. The resulting residue was purified by preparative TLC (CH₂Cl₂ / MeOH = 10 / 1) to give the title compound (30 mg, 51%). 1 H NMR (400MHz, DMSO-d6) δ8.93 (s, 2H), 8.19-7.90 (m, 4H), 5.62 (d, J = 16.8Hz, 2H), 5.45(d,J=18Hz,1H),5.08-4.53(m,1H),4.48-4.05(m,2H),3.82-3.38(m,3H),3 .28(s,3H),3.19(d,J=11.6Hz,0.5H),2.98(d,J=10.8Hz,1H),2.89-2.62(m,2H) ,2.24(d,J=11.2Hz,0.5H),1.52-1.35(m,3H),1.23(s,1.5H),1.06(s,1.5H)ppm. MS:M / e 473(M+1) +.

[0624] Compound A100: 2-(7-((2S,5S)-5-(methoxymethyl)-2-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0625] Step A: 2-(7-((2S,5S)-5-(chloromethyl)-2-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazine-1- (4,3-b)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0626] Et3N (10 mg, 0.1 mmol) was added to a stirred solution of 2-(7-((2S,5S)-5-(hydroxymethyl)-2-methyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile (23 mg, 0.05 mmol) in CH2Cl2 (5 mL), followed by the addition of MeSO2Cl (6.7 mg, 0.06 mmol). The reaction mixture was stirred overnight. The reaction mixture was diluted with CH2Cl2 (10 mL), washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, and concentrated to give the title compound, which was used directly in the next step without further purification. MS: M / e 491 (M+1) + .

[0627] Step B: 2-(7-((2S,5S)-5-(methoxymethyl)-2-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazine (1-azinyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0628] A mixture of 2-(7-((2S,5S)-5-(chloromethyl)-2-methyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile (10 mg, 0.02 mmol) in MeOH (3 mL) was stirred at 50 °C for 3 days. The reaction mixture was concentrated to obtain a residue, which was purified by preparative TLC (CH2Cl2 / MeOH = 10 / 1) to give the title compound (3 mg). 1H NMR(400MHz,DMSO-d6)δ8.90-8.85(m,2H),8.14-7.99(m,3H),7.94(s,1H),5.62-5.57 (m,1H),5.48(s,2H),4.40-4.20(m,1H),4.15-4.01(m,1H),3.85-3.67(m,2H),3.66-3. 47(m,2H),3.44(s,3H),2.97-2.74(m,2H),2.39(d,J=10.0Hz,1H),2.27-2.01(m,1H), 1.54(d,J=6.4Hz,2H),1.52-1.46(m,3H),1.38(d,J=6.4Hz,1H),1.26-1.18(m,3H)ppm. MS:M / e 487(M+1) + .

[0629] Compound A101: 2-(7-((2R,5R)-2-(hydroxymethyl)-5-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0630] Step A: (2R,5R)-5-(hydroxymethyl)-2-methyl-4-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-2-) 4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylic acid tert-butyl ester

[0631] A mixture of intermediate 2 (1.143 g, 3 mmol), (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (0.83 g, 3.6 mmol), and DIPEA (774 mg, 6 mmol) in CH3CN (15 mL) was stirred over a weekend at 100 °C in a sealed tube. The reaction mixture was poured into H2O (50 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (930 mg, 67%). MS: M / e 462 (M+1) + .

[0632] Step B: 7-((2R,5R)-2-(hydroxymethyl)-5-methylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyridine) (2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0633] TFA (2 mL) was added to a stirred solution of (2R,5R)-5-(hydroxymethyl)-2-methyl-4-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylic acid tert-butyl ester (400 mg, 0.87 mmol) in CH2Cl2 (10 mL). After addition, the reaction mixture was stirred for 4 hours. The reaction mixture was concentrated to obtain a residue, which was treated with aqueous NaHCO3 and extracted with EA (10 mL). The organic layer was discarded, and the aqueous layer was extracted with CH2Cl2 / IPA (2 / 1, 10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the title compound (130 mg, 41%). MS: M / e 362 (M+1) + .

[0634] Step C: 7-((2R,5R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpiperazine-1- )-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0635] Et3N (73 mg, 0.72 mmol) was added to a stirred solution of 7-((2R,5R)-2-(hydroxymethyl)-5-methylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (130 mg, 0.36 mmol) in CH2Cl2 (10 mL), followed by DMAP (4.5 mg, 0.036 mmol). Then TBSCl (84.6 mg, 0.54 mmol) was added. After the additions, the reaction mixture was stirred overnight. The reaction mixture was washed with H2O (10 mL) and brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by preparative TLC (CH2Cl2 / MeOH = 10 / 1) to give the title compound (70 mg, 41%). MS: M / e 476 (M+1) + .

[0636] Step D: 7-((2R,5R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-4-(1-(quinoline) (Oxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4, [3-b]pyridin-5-one

[0637] A mixture of 7-((2R,5R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (70 mg, 0.66 yridine66neuinoxalin-6-yl) ethanol-1-ol (76.7 mg, 0.44 mmol), (cyanomethyl)trimethylphosphonium iodide (107 mg, 0.44 mmol), and DIPEA (189 mg, 1.47 mmol) in CH3CN (3 mL) was stirred overnight at 100 °C in a sealed tube. The reaction mixture was diluted with EA (10 mL), washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by preparative TLC (EA) to give the title compound (50 mg, 54%). MS:M / e 632(M+1) + .

[0638] Step E: 2-(7-((2R,5R)-2-(hydroxymethyl)-5-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazine- 1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0639] To a stirred solution of 7-((2R,5R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (50 mg, 0.079 mmol) in MeOH (5 mL), HCl (2 mL, 4.0 M 1,4-dioxane solution) was added and the mixture was stirred overnight. The reaction mixture was concentrated to obtain a residue, which was dissolved in DMF / H2O (3 mL / 2 mL) and K2CO3 (21.8 mg, 0.158 mmol) was added, followed by 2-iodoacetonitrile (26.4 mg, 0.158 mmol), and the mixture was stirred for 2 hours. The reaction mixture was poured into H2O (10 mL) and extracted with EA (20 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by preparative TLC (CH2Cl2 / MeOH = 10 / 1) to give the title compound (21 mg). 1H NMR (400MHz, CD3OD) δ8.91-8.85(m,2H),8.14-7.97(m,3H),7.96-7.91(m,1H),5.68-5.59(m,1H),5.50-5.43(m,2H),4.17-4.09(m,0.5H) ,4.03-3.64(m,4.5H),3.50-3.39(m,4H),3.06-2.46(m,3H),1.46(d,J=6.4Hz,3H),1.20(d,J=6.0Hz,1.5H),1.05(d,J=6.4Hz,1.5H)ppm. MS:M / e 473(M+1) + .

[0640] Compound A102: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0641] Step A: 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-(4-methyl) (Oxybenzyl)-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0642] DIPEA (93 mg, 0.72 mmol) was added to a solution of intermediate 7 (177 mg, 0.36 mmol) and intermediate 1 (108 mg, 0.4 mmol) in CH3CN (5 mL). The mixture was then heated at 90 °C and N2 for 56 hours. The mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EA (60 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (150 mg, 68%). MS: M / e 608 (M+1) + .

[0643] Step B: 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-2,4-di Hydrogen-5H-pyrazolo[4,3-b]pyridin-5-one

[0644] Trifluoromethanesulfonic acid (4 mL) was added to a solution of 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-(4-methoxybenzyl)-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (150 mg, 0.247 mmol) in TFA (4 mL). The resulting mixture was stirred overnight at room temperature. The mixture was quenched with ice water, alkalized to pH 7-8 with saturated Na₂CO₃ solution, and extracted with DCM / IPA (6 / 1, 60 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The resulting residue was purified by preparative TLC to give the title compound (15 mg, 15%). MS: M / e 404 (M+1) + .

[0645] Step C: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-5-oxo 4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0646] 2-Iodoacetonitrile (7 mg, 0.041 mmol) was added to a solution of 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (15 mg, 0.037 mmol) and K₂CO₃ (10 mg, 0.074 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water, extracted with EA (60 mL), washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography to give the title compound (1 mg, 6%). 1 HNMR(400MHz,DMSO-d6)δ10.43(s,1H),8.98-8.87(m,2H),8.16-7.90(m,3H),7.7 1(s,1H),5.56(s,2H),5.29-5.24(m,1H),4.02-3.86(m,1H),3.81-3.75(m,0.5H), 3.62-3.48(m,1.5H),3.30-3.23(m,0.5H),2.99-2.92(m,1H),2.90-2.66(m,2H), 2.15-1.95(m,0.5H),1.42-1.28(m,5H),1.16-1.08(m,2H),1.00-0.94(m,2H)ppm. MS:M / e443(M+1) + .

[0647] Compound A103: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0648] Step A: 7-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4- Methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0649] DIPEA (155 mg, 0.8 mmol) was added to a solution of intermediate 3 (150 mg, 0.4 mmol), 1-(4-(trifluoromethyl)phenyl)ethyl-1-ol (114 mg, 0.6 mmol), and (cyanomethyl)trimethylphosphonium iodide (194 mg, 0.8 mmol) in CH3CN (5 mL). The mixture was sealed in a flask and heated at 100 °C for 16 hours. The mixture was then cooled to room temperature, diluted with water, extracted with EA (60 mL x 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 (100 mg, 45%). MS: M / e 546 (M+1) + .

[0650] Step B: 7-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4- Methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0651] TFA (8 mL) was added to a solution of 7-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (100 mg, 0.183 mmol) in DCM (3 mL). The mixture was stirred at room temperature for 16 h. The mixture was concentrated to dryness. The resulting residue was alkalized with saturated NaHCO3 solution, extracted with DCM / IPA (3 / 1, 60 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give the title compound (50 mg, 59%). MS: M / e 462 (M+1) + .

[0652] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazine-1- (4,3-b)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0653] To a solution of 7-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (50 mg, 0.11 mmol) and K₂CO₃ (30 mg, 0.22 mmol) in DMF (4 mL), 2-iodoacetonitrile (28 mg, 0.165 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, extracted with EA (60 mL x 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 (20 mg, 40%). 1 HNMR(400MHz,CD3OD)δ7.94-7.91(m,1H),7.69-7.54(m,4H),5.54(s,1H),5.49-5.44(m,2H),3.89-3.81(m,0.5H),3.74- 3.66(m,0.5H),3.55-3.46(m,0.5H),3.43(s,3H),3.31-3.26(m,2.5H),3.20-3.10(m,0.5H),3.06-2.98(m,0.5H),2.92- 2.83(m,0.5H),2.72-2.63(m,0.5H),2.41-2.25(m,1H),2.19-2.06(m,0.5H),2.00-1.75(m,1H),1.75-1.49(m,2.5H),1. 39-1.28(m,3H),1.03(t,J=7.6Hz,1.5H),0.96(t,J=7.2Hz,1.5H),0.70(t,J=7.6Hz,1.5H),0.62(t,J=7.6Hz,1.5H)ppm. MS:M / e 501(M+1) + .

[0654] Another batch of compound A103 (575 mg) was prepared according to the procedure described above, as would be known to those skilled in the art. Compound A103 (575 mg, a mixture) was then further separated into compound A103a (145 mg) and compound A103b (195 mg) by chiral preparative HPLC. The chiral separation conditions are shown below.

[0655]

[0656] Compound A103a (first eluting peak): 1H NMR (400MHz, CD3OD) δ7.92(s,1H),7.65(d,J=7.6Hz,2H),7.58(d,J=7.6Hz,2H),5.56(s, 1H),5.46(s,2H),4.83-4.20(m,1H),3.91-3.80(m,1H),3.43(s,3H),3.28(s,2H),3.02(d ,J=11.6Hz,1H),2.88(d,J=11.6Hz,1H),2.38(s,1H),2.21-2.05(m,1H),1.91-1.76(m,1H ), 1.62-1.47 (m, 2H), 1.35 (d, J = 6.0Hz, 3H), 0.96 (t, J = 6.8Hz, 3H), 0.70 (t, J = 6.8Hz, 3H). MS:M / e 501(M+1) + .

[0657] Compound A103b (later peak): 1 H NMR(400MHz,CD3OD)δ7.93(s,1H),7.68-7.55(m,4H),5.55(s,1H),5.47(s,2H),4.75-3 .85(m,1H),3.75-3.64(m,1H),3.51(d,J=12.8Hz,1H),3.43(s,3H),3.30-3.29(m,1H),3 .16(d,J=10.4Hz,1H),2.67(d,J=11.6Hz,1H),2.30(d,J=12.0Hz,1H),2.05-1.85(m,1H) ,1.80-1.45(m,3H),1.33(d,J=6.0Hz,3H),1.03(t,J=7.2Hz,3H),0.62(t,J=6.8Hz,3H). MS:M / e 501(M+1) + .

[0658] Compound A111: 2-(7-((2S,5R)-4-(1-(2-bromo-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0659] Step A: (2R,5S)-1-(1-(2-bromo-4-fluorophenyl)ethyl)-2,5-diethylpiperazine

[0660] (2S,5R)-4-(1-(2-bromo-4-fluorophenyl)ethyl)-2,5-diethylpiperazine-1-carboxylic acid tert-butyl ester (150 mg) was dissolved in DCM (3 mL), and TFA (2 mL) was added. The mixture was stirred at RT for 4 hours. The mixture was concentrated to dryness to give the title compound (200 mg, crude), which was used directly for the next step without purification. MS: M / e343(M+1) + .

[0661] Step B: 7-((2S,5R)-4-(1-(2-bromo-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl 2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0662] Intermediate 2 (76 mg, 0.2 mmol) and DIPEA (65 mg, 0.5 mmol) were added to a solution of (2R,5S)-1-(1-(2-bromo-4-fluorophenyl)ethyl)-2,5-diethylpiperazine (34 mg, 0.1 mmol) in acetonitrile (2 mL). The mixture was stirred over a period of time in a sealed tube at 100 °C. The reaction was quenched with water, extracted with EA, washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (MeOH:DCM = 0%–10% within 20 min) to give the product (60 mg, crude). MS: M / e 574 (M+1) + .

[0663] Step C: 7-((2S,5R)-4-(1-(2-bromo-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl 2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0664] To a solution of 7-((2S,5R)-4-(1-(2-bromo-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (60 mg) in MeOH (1.5 mL), HCl (g) (4 M dioxane solution, 2 mL) was added. The reaction was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure. The resulting residue (50 mg, crude) was used directly for the next step without further purification. MS: M / e 490 (M+1) + .

[0665] Step D: 2-(7-((2S,5R)-4-(1-(2-bromo-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0666] Potassium carbonate (55 mg, 0.4 mmol) and 2-iodoacetonitrile (25 mg, 0.15 mmol) were added to a solution of 7-((2S,5R)-4-(1-(2-bromo-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (50 mg, crude) in DMF (2 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, extracted with EA, washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by preparative TLC (DCM:MeOH = 13:1) to give the title compound (3 mg, 5%). 1 H NMR (400MHz, CD3OD) δ7.93 (d, J=2.4Hz, 1H), 7.78-7.64 (m, 1H), 7.40-7.32 (m, 1H), 7.16 (dd, J=1 5.9,7.3Hz,1H),5.56(s,1H),5.47(d,J=3.5Hz,2H),4.23-4.18(m,1H),3.49(d,J=14.5Hz,1H), 3.43(s,3H),3.18-2.99(m,1H),2.90-2.69(m,2H),2.42-2.23(m,1H),2.03-1.80(m,1H),1.88- 1.63(m,2H),1.56(d,J=7.9Hz,2H),1.28-1.23(m,3H),0.94-0.76(m,3H),0.74-0.63(m,3H)ppm. MS:M / e529(M+1) + .

[0667] Compound A115: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-methyl-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0668] Step A: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-methyl-2-(trifluoromethyl)phenyl)ethyl)piperidine (1-azinyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0669] To a solution of intermediate 5 (30 mg, 0.09 mmol) in CH3CN (3 mL), 1-(4-methyl-2-(trifluoromethyl)phenyl)ethyl-1-ol (56 mg, 0.27 mmol), (cyanomethyl)trimethylphosphonium iodide (111 mg, 0.46 mmol), and DIPEA (118 mg, 0.9 mmol) were added. The resulting mixture was stirred overnight at 105 °C. The reaction solvent was removed under reduced pressure to give the crude product compound A115. Compound A115 was purified by preparative TLC (DCM:MeOH = 20:1) and further separated by preparative HPLC (Method A) into compounds A115a (1.23 mg) and A115b (0.53 mg).

[0670] Compound A115a (first eluting peak): 1 H NMR (400MHz, CD3OD) δ7.93 (s, 1H), 7.87 (d, J = 8.0Hz, 1H), 7.46-7.41 (m, 2H), 5. 58-5.50(m,1H),5.47(s,2H),4.05-4.01(m,1H),3.49-3.44(m,1H),3.43(s,3H ),3.22-3.15(m,1H),2.80-2.57(m,2H),2.39(s,3H),2.19(d,J=11.0Hz,1H),1 .93-1.47(m,4H),1.33-1.18(m,4H),1.15-0.97(m,3H),0.78-0.48(m,3H)ppm. MS:M / e515(M+1) + .

[0671] Compound A115b (later peak): 1 H NMR (400MHz, CD3OD) δ7.92(s,1H),7.89(d,J=8.4Hz,1H),7.46(s,2H),5.56(s,1H),5.46(s,2H),4.16(s,1H),3.43(s,3H),3.16-3.05(m ,1H),2.97-2.80(m,3H),2.40(s,3H),2.37-1.85(m,3H),1.60-1.41(m,2H),1.32-1.21(m,4H),1.05-0.90(m,3H),0.75-0.52(m,3H)ppm. MS:M / e 515(M+1) + .

[0672] Compound A119: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0673] Step A: N-methoxy-N-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0674] A mixture of 3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (1 g, 5.56 mmol), N,O-dimethylhydroxylamine hydrochloride (0.65 g, 6.63 mmol), HATU (2.53 g, 6.66 mmol), and DIPEA (2.15 g, 16.67 mmol) in THF (15 mL) was stirred overnight at RT. Afterward, the solution was concentrated under reduced pressure. The resulting residue was dissolved in EA (30 mL), washed with NaHCO3 aqueous solution (10 mL x 2) and brine (10 mL), dried over Na2SO4, and then concentrated to dryness. The resulting residue was purified by rapid column chromatography (MeOH / DCM) to give the title compound (1.2 g, 100%). MS: M / e 224 (M+1) + .

[0675] Step B: 1-Ethyl-N-methoxy-N-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0676] A mixture of N-methoxy-N-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (1.2 g, 5.38 mmol), iodoethane (0.97 g, 6.22 mmol), and K₂CO₃ (2.23 g, 16.16 mmol) in MeCN (15 mL) was stirred overnight at 80 °C. Afterward, the solution was concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography (PE / EA) to give the title compound (140 mg). MS: M / e 252 (M+1) + .

[0677] Step C: 1-(1-Ethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)ethyl-1-one

[0678] MeMgBr (3M, 0.37 mL, 1.11 mmol) was added dropwise to a solution of 1-ethyl-N-methoxy-N-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (140 mg, 0.56 mmol) in THF (6 mL) at -60 °C and N2. The solution was naturally heated to RT and stirred overnight at RT. After completion, the solution was quenched with water (2 mL) and concentrated under reduced pressure. The resulting residue was purified by preparative TLC with PE:EA (2:1) to give the title compound (55 mg, 48%). MS: M / e 207 (M+1)+ .

[0679] Step D: 1-(1-Ethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)ethanol-1-ol

[0680] A mixture of 1-(1-ethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)ethyl-1-one (55 mg, 0.27 mmol) and NaBH4 (11 mg, 0.29 mmol) in MeOH (6 mL) was stirred overnight at RT. After completion, the solution was concentrated under reduced pressure. The resulting residue was dissolved in EA (10 mL), washed with NH4Cl aqueous solution (6 mL) and brine (6 mL), dried, and then concentrated to give the crude product (55 mg, 100%), which was used directly for the next step without further purification. MS: M / e 209 (M+1) + .

[0681] Step E: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-5-(trifluoromethyl)-1H-pyrazole-4-) (1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0682] A solution of intermediate 5 (43 mg, 0.13 mmol), 1-(1-ethyl-5-(trifluoromethyl)-1H-pyrazole-4-yl)ethanol-1-ol (27 mg, 0.13 mmol), (cyanomethyl)trimethylphosphonium iodide (95 mg, 0.39 mmol), and DIPEA (84 mg, 0.65 mmol) in MeCN (2 mL) was stirred overnight at 100 °C. After completion, the solution was concentrated under reduced pressure to give compound A119. The residue containing compound A119 was purified by preparative HPLC to give title compound A119a (0.65 mg) and compound A119b (0.75 mg).

[0683] Compound A119a (first elution peak): 1 H NMR (400MHz, DMSO-d6) δ7.98(s,1H),7.71(s,1H),5.62(s,2H),5.37(s,1H),4.25(q,J=7.1Hz,2H ),3.98(q,J=6.7Hz,1H),3.32-3.31(m,1H),3.27(s,3H),3.16(d,J=10.8Hz,1H),2.98(s,1H),2. 81(dd,J=11.9,3.9Hz,1H),2.75-2.66(m,1H),2.40(d,J=10.8Hz,1H),1.91-1.78(m,1H),1.51-1 .47(m,2H),1.36(t,J=7.2Hz,4H),1.31(d,J=6.5Hz,3H),0.79(s,3H),0.71(t,J=7.3Hz,3H)ppm. MS:M / e 519(M+1)+ .

[0684] Compound A119b (later peak): 1 H NMR (400MHz, DMSO-d6) δ7.99(s,1H),7.66(s,1H),5.62(s,2H),5.39(s,1H),4.25(q,J= 7.2Hz,2H),3.78(q,J=6.5Hz,1H),3.28(s,2H),3.27(s,3H),2.98(d,J=10.2Hz,2H),2.5 5(d,J=9.5Hz,1H),2.35(d,J=11.9Hz,1H),1.89-1.78(m,1H),1.60-1.40(m,2H),1.35( t,J=7.2Hz,4H), 1.27(d,J=6.5Hz,3H), 0.91(t,J=7.3Hz,3H), 0.61(t,J=7.1Hz,3H)ppm. MS:M / e 519(M+1) + .

[0685] Compound A126: 2-(7-((2S,5R)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile.

[0686] Step A: (2S,5R)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-diethyl Piperazine-1-carboxylic acid tert-butyl ester.

[0687] A mixture of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanol-1-ol (670 mg, 3.7 mmol), (2S,5R)-2,5-diethylpiperazine-1-carboxylic acid tert-butyl ester (600 mg, 2.48 mmol), (cyanomethyl)trimethylphosphonium iodide (1.5 g, 6.2 mmol), and DIPEA (1.6 g, 12.4 mmol) in MeCN (10 mL) was stirred at 100 °C for 16 hours. The mixture was diluted with EA (20 mL), washed with brine (20 mL x 3), dried over Na2SO4, and concentrated to dryness. The residue was purified by rapid column chromatography to give the title compound (410 mg, 41%). MS: M / e 405 (M+1) + .

[0688] Step B: (2R,5S)-1-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-diethyl Piperazine.

[0689] To a stirred solution of (2S,5R)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-diethylpiperazine-1-carboxylic acid tert-butyl ester (360 mg, 0.89 mmol) in EA (5 mL), HCl (5 mL, 4 M, 1,4-dioxane solution) was added. The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated to dryness to give the title compound (380 mg, HCl salt). MS: M / e 305 (M+1) + .

[0690] Step C: 7-((2S,5R)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-diethyl pyrazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one.

[0691] A mixture of (2R,5S)-1-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-diethylpiperazine (160 mg, 0.52 mmol), intermediate 2 (200 mg, 0.52 mmol), and DIPEA (500 mg, 3.87 mmol) in MeCN (3 mL) was stirred at 100 °C for 16 hours. The mixture was diluted with EA (10 mL), washed with brine (10 mL x 3), dried over NaSO4, and concentrated to dryness. The residue was purified by rapid column chromatography to give the title compound (70 mg, 25%). MS: M / e 536 (M+1) + .

[0692] Step D: 7-((2S,5R)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-diethyl ypiperazine-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one.

[0693] HCl (2 mL, 4 M 1,4-dioxane solution) was added to a stirred solution of 7-((2S,5R)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (65 mg, 0.12 mmol) in MeOH (3 mL). The resulting mixture was stirred at room temperature for 20 hours. The mixture was concentrated to dryness to give the title compound as an HCl salt (55 mg, 94%). MS: M / e 452 (M+1) + .

[0694] Step E: 2-(7-((2S,5R)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5- (diethylpiperazine-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile.

[0695] 2-Iodoacetonitrile (38 mg, 0.22 mmol) was added to a solution of 7-((2S,5R)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (55 mg, 0.11 mmol) and an aqueous solution of K₂CO₃ (3 M, 0.5 mL) in MeCN (3 mL). The resulting mixture was stirred at room temperature for 20 hours. The mixture was diluted with EA (10 mL), washed with brine (5 mL x 3), dried over Na₂SO₄, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (12 mg, 22%). 1 H NMR(400MHz,CD3OD)δ7.92(s,1H),6.90-6.70(m,3H),5.54(s,1H),5.47(s,2H) ,4.22(d,J=6.8Hz,4H),3.68-3.55(m,1H),3.52-3.38(m,4H),3.30-3.21(m,2H ),3.15-2.93(m,1H),2.89-2.54(m,1H),2.53-2.39(m,1H),2.17-1.87(m,1H), 1.85-1.44(m,3H),1.34-1.21(m,3H),1.05-0.91(m,3H),0.75-0.61(m,3H)ppm. MS:M / e 491(M+1) + .

[0696] Compound A127: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(p-tolyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0697] Step A: (2S,5R)-2,5-diethyl-4-(1-(p-tolyl)ethyl)piperazine-1-carboxylic acid tert-butyl ester

[0698] A mixture of 1-(p-tolyl)ethanol-1-ol (1 g, 7.35 mmol), (2S,5R)-2,5-diethylpiperazine-1-carboxylic acid tert-butyl ester (1.8 g, 7.44 mmol), (cyanomethyl)trimethylphosphonium iodide (3.6 g, 14.81 mmol), and DIPEA (5.7 g, 44.19 mmol) in MeCN (10 mL) was stirred overnight at 100 °C. After completion, the solution was concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography using 0%–5% EA in PE to give the title compound (1.66 g, 63%). MS: M / e 361 (M+1) + .

[0699] Step B: (2R,5S)-2,5-diethyl-1-(1-(p-tolyl)ethyl)piperazine

[0700] A mixture of (2S,5R)-2,5-diethyl-4-(1-(p-tolyl)ethyl)piperazine-1-carboxylic acid tert-butyl ester (1.66 g, 4.61 mmol) and TFA (4 mL) in DCM (20 mL) was stirred at RT for 2 hours. After completion, the solution was concentrated under reduced pressure. The resulting residue was dissolved in EA (20 mL), washed with NaHCO3 aqueous solution (15 mL) and brine (15 mL), dried, and concentrated under reduced pressure to give the title compound (1.19 g, 100%), which was used directly in the next step without further purification. MS: M / e261 (M+1) + .

[0701] Step C: 7-((2S,5R)-2,5-diethyl-4-(1-(p-tolyl)ethyl)piperazin-1-yl)-4-methyl-2- (tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0702] A mixture of (2R,5S)-2,5-diethyl-1-(1-(p-tolyl)ethyl)piperazine (1.19 g, 4.58 mmol), intermediate 2 (1.5 g, 3.94 mmol), and DIPEA (1.52 g, 11.78 mmol) in MeCN (10 mL) was stirred overnight at 105 °C. After completion, the solution was concentrated under reduced pressure and then purified by rapid column chromatography (MeOH / DCM) to give the title compound (1.6 g, 83%). MS: M / e 492 (M+1) + .

[0703] Step D: 7-((2S,5R)-2,5-diethyl-4-(1-(p-tolyl)ethyl)piperazin-1-yl)-4-methyl-2, 4-Dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0704] A mixture of 7-((2S,5R)-2,5-diethyl-4-(1-(p-tolyl)ethyl)piperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (1.6 g, 3.26 mmol) and HCl / dioxane (4 M, 4 mL) in MeOH (16 mL) was stirred overnight at RT. After completion, the solution was concentrated under reduced pressure to give the title compound (1.3 g, 100%), which was used directly for the next step without further purification. MS: M / e 408 (M+1) + .

[0705] Step E: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(p-tolyl)ethyl)piperazin-1-yl)-4-methyl- 5-O-4,5-Dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0706] A mixture of 7-((2S,5R)-2,5-diethyl-4-(1-(p-tolyl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (1.3 g, 3.19 mmol), 2-iodoacetonitrile (0.67 g, 4.01 mmol), and K₂CO₃ (0.88 g, 6.38 mmol) in DMF (15 mL) was stirred overnight at RT, followed by stirring at 60 °C for 24 hours. After completion, the mixture was poured into water (50 mL) and then extracted with EA (20 mL x 2). The organic layer was washed with brine (15 mL), dried, and concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography (MeOH / DCM) and the fractions were concentrated under reduced pressure to obtain the title compound, compound A127. It was further separated into compound A127a (118 mg) and compound A127b (76 mg) by preparative HPLC (method B).

[0707] Compound A127: 1 H NMR (400MHz, CD3OD) δ7.92 (d, J = 2.4Hz, 1H), 7.24 (dd, J = 11.4, 8.0Hz, 2H), 7.14 (dd, J = 18. 0,7.7Hz,3H),5.54(s,1H),5.46(d,J=3.5Hz,2H),3.73-3.47(m,1H),3.43(s,3H),3.20-2. 97(m,1H),2.73(m,1H),2.40(d,J=11.6Hz,1H),2.32(d,J=5.6Hz,3H),2.15-1.77(m,2H), 1.71-1.46(m,3H),1.31(dd,J=15.6,6.4Hz,3H),0.96-0.86(m,4H),0.67-0.60(m,3H)ppm. MS:M / e 447(M+1) + .

[0708] Compound A127a (first eluting peak): 1H NMR(400MHz,DMSO-d6)δppm 7.98(s,1H),7.22(d,J=7.9Hz,2H),7.14(d,J=7.9Hz,2H),5.61(s,2H),5.39(s,1H),3. 64(q,J=6.4Hz,1H),3.34(s,2H),3.27(s,3H),3.07(d,J=11.7Hz,1H),2.90(d,J=11.6Hz ,1H),2.73(d,J=8.5Hz,1H),2.34-2.27(m,4H),2.07-1.93(m,1H),1.66-1.54(m,1H),1. 54-1.36(m,2H),1.25(d,J=6.3Hz,3H),0.86(t,J=7.3Hz,3H),0.59(t,J=7.3Hz,3H)ppm. MS:M / e 447(M+1) + .

[0709] Compound A127b (later peak): 1 ¹H NMR (400MHz, DMSO-d⁶) δppm 7.98(s,1H),7.24(d,J=7.9Hz,2H),7.12(d,J=7.8Hz,2H),5.61(s,2H),5.38( s,1H),3.52(q,J=6.4Hz,1H),3.36(s,1H),3.34(s,2H),3.27(s,3H),3.02(d, J=9.2Hz,1H),2.47(s,1H),2.30-2.23(m,4H),1.93-1.78(m,1H),1.61-1.39( m, 3H), 1.21 (d, J = 6.4Hz, 3H), 0.94 (t, J = 7.2Hz, 3H), 0.54 (t, J = 6.9Hz, 3H) ppm. MS:M / e 447(M+1) + .

[0710] Compound A129: 2-(7-((2S,5R)-2,5-diethyl-4-((S)-1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0711] Step A: 7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-(4-methyl) (Oxybenzyl)-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0712] DIPEA (258 mg, 2 mmol) was added to a solution of intermediate 7 (500 mg, 1 mmol) and 6-(1-((2R,5S)-2,5-diethylpiperazin-1-yl)ethyl)quinoxaline (360 mg, 1.2 mmol) in CH3CN (8 mL). The mixture was then heated at 90 °C and N2 for 56 hours. The mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EA (80 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by rapid column chromatography to give the title compound (410 mg, 64%). MS: M / e 636 (M+1) + .

[0713] Step B: 7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-2,4-di Hydrogen-5H-pyrazolo[4,3-b]pyridin-5-one

[0714] Trifluoromethanesulfonic acid (6 mL) was added to a solution of 7-((2S,5R)-2,5-diethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-(4-methoxybenzyl)-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (410 mg, 0.64 mmol) in TFA (4 mL). The resulting mixture was stirred overnight at room temperature. The mixture was quenched with ice water, alkalized to pH 7–8 with saturated Na₂CO₃ solution, and extracted with DCM:IPA (6:1, 60 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The resulting residue was purified by preparative TLC to give the title compound (71 mg, 25%). MS: M / e 432 (M+1) + .

[0715] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-((S)-1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)- 5-O-4,5-Dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0716] 2-Iodoacetonitrile (42 mg, 0.25 mmol) was added to a solution of 7-((2S,5R)-2,5-diethyl-4-(1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (71 mg, 0.16 mmol) and K₂CO₃ (47 mg, 0.34 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 56 hours. The reaction mixture was diluted with water, extracted with EA (60 mL), washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography to give the title compound (14 mg, 18%). 1HNMR(400MHz,CD3OD)δ8.94-8.84(m,2H),8.16-7.95(m,3H),7.77 -7.72(m,1H),5.52-5.40(m,3H),4.14-3.85(m,1H),3.64-3.53(m,0.5H),3.40-3.20(m,2.5H), 3.27-3.18(m,0.5H),3.14-3.04(m,0.5H),2.99-2.90(m,0.5H),2.80-2.70(m,0.5H),2.48-2.32 (m,1H),2.25-2.10(m,0.5H),2.05-1.83(m,1H),1.80-1.54(m,2.5H),1.50-1.38(m,3H),1.07(t ,J=7.6Hz,1.5H),0.99(t,J=7.6Hz,1.5H),0.69(t,J=7.6Hz,1.5H),0.57(t,J=7.6Hz,1.5H)ppm. MS:M / e 471(M+1) + .

[0717] Compound A133: 2-(6-chloro-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile.

[0718] NCS (10 mg, 0.08 mmol) was added to a solution of 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile (30 mg, 0.07 mmol) (compound A2a) in CH3CN (5 mL) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction mixture was diluted with EA (20 mL) and washed with water (10 mL x 2). The organic layer was concentrated and purified by preparative TLC (DCM:MeOH = 15:1) to give the title compound (12 mg, 38%) as a single diastereomer. 1HNMR(400MHz,CD3OD)δ8.89-8.87(m,2H),8.14-8.03(m,3H),7.98(s,1H),5.50(s,2H),4.62-4.58(m,1H),4.20-4.16(m,1H),3.87-3.80(m,1H) ,3.53(s,3H),3.32-3.31(m,1H),3.15-3.10(m,1H),2.74-2.59(m,2H), 1.51(d,J=6.7Hz,3H), 1.29(d,J=6.4Hz,3H), 1.07(d,J=6.4Hz,3H)ppm. MS:M / e491(M+1) + .

[0719] Compound A134: 2-(cyanomethyl)-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalo-6-yl) Ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridine-6-onitrile.

[0720] Step A: 2-(6-bromo-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalo-6-yl)ethyl)piperazine- 1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile.

[0721] NBS (35 mg, 0.20 mmol) was slowly added to a solution of 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile (80 mg, 0.18 mmol) (compound A2a) in CH3CN (5 mL). The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction mixture was diluted with EA (20 mL) and washed with water (10 mL x 2). The organic layer was concentrated and purified by preparative TLC (DCM:MeOH = 15:1) to give the title compound (40 mg, 43%). MS: M / e 535 (M+1) + .

[0722] Step B: 2-(cyanomethyl)-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalo-6-yl)ethyl) Piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridine-6-nitrile.

[0723] A mixture of 2-(6-bromo-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile (40 mg, 0.08 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and Zn(CN)2 (19 mg, 0.16 mmol) in DMF (2 mL) was heated to 100 °C overnight under N2 atmosphere. The reaction mixture was diluted with EA (10 mL) and washed with brine (5 mL x 2). The organic layer was concentrated and purified by preparative TLC (DCM:MeOH = 15:1) to give the title compound (13.8 mg, 38%). 1 H NMR (400MHz, CD3OD) δ8.88(d,J=3.4Hz,2H),8.14-8.05(m,3H),7.99(s,1H),5.50(s,2H),4.01-3.96(m,2H),3.43(s,3H),3.1 8-3.15(m,1H),3.02-2.97(m,2H),2.81-2.72(m,1H),1.66(d,J=6.7Hz,3H),1.44(d,J=6.4Hz,3H),1.01(d,J=6.6Hz,3H)ppm. MS:M / e 482(M+1) + .

[0724] Compound A136: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-fluoro-3-(trifluoromethyl)pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0725] Step A: 3-Bromo-5-fluoro-N-methoxy-N-methylpyridine amide

[0726] A mixture of 3-bromo-5-fluoropyridinecarboxylic acid (1 g, 4.57 mmol), N,O-dimethylhydroxylamine hydrochloride (0.54 g, 5.51 mmol), HATU (2.1 g, 5.53 mmol), and DIPEA (1.8 g, 13.95 mmol) in THF (10 mL) was stirred at RT for 5 hours. Afterward, the solution was diluted with EA (20 mL), washed with NaHCO3 aqueous solution (10 mL), brine (10 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography (EA / PE) to give the title compound (1.1 g, 92%). 1H NMR (400MHz, CDCl3) δ8.45 (d, J = 2.1Hz, 1H), 7.71 (dd, J = 7.6, 2.2Hz, 1H), 3.57 (s, 3H), 3.41 (s, 3H) ppm.

[0727] Step B: 5-Fluoro-N-methoxy-N-methyl-3-(trifluoromethyl)pyridine amide

[0728] A mixture of 3-bromo-5-fluoro-N-methoxy-N-methylpyridine amide (1 g, 3.80 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.8 g, 4.17 mmol), and CuI (220 mg, 1.16 mmol) in DMF (10 mL) was stirred overnight at 120 °C under N2. After extraction, the mixture was poured into water (20 mL) and extracted with EA (15 mL x 2). The organic layer was washed with brine (10 mL), dried, and concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography (PE / EA) to give the title compound (0.84 g, 88%). MS: M / e 253(M+1)+.

[0729] Step C: 1-(5-fluoro-3-(trifluoromethyl)pyridin-2-yl)ethyl-1-one

[0730] MeMgBr (3M, 1.22ml, 3.66mmol) was added dropwise to a solution of 5-fluoro-N-methoxy-N-methyl-3-(trifluoromethyl)pyridineamide (0.84g, 3.33mmol) in THF (10ml) at -60℃ and N2. The solution was naturally heated to RT and stirred overnight at RT. After completion, the solution was quenched with water (10ml) and extracted with EA (15ml x 2). The organic layer was washed with brine (10ml), dried, and concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography (PE / EA) to give the title compound (245mg, 36%). MS: M / e 208 (M+1) + . 1 H NMR (400MHz, CDCl3) δ8.64 (d, J = 2.5 Hz, 1H), 7.82 (dd, J = 8.4, 2.6 Hz, 1H), 2.69 (s, 3H) ppm.

[0731] Step D: 1-(5-fluoro-3-(trifluoromethyl)pyridin-2-yl)ethanol-1-ol

[0732] A mixture of 1-(5-fluoro-3-(trifluoromethyl)pyridin-2-yl)ethyl-1-one (245 mg, 1.18 mmol) and NaBH4 (45 mg, 1.18 mmol) in MeOH (4 mL) was stirred at RT for 1.5 h. After completion, the solution was quenched with water (1 mL) and then concentrated under reduced pressure. The resulting residue was dissolved in EA (15 mL), washed with NaHCO3 aqueous solution (10 mL) and brine (10 mL), dried and concentrated to give the title compound (210 mg, 85%), which was used directly in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ 8.64 (d, J = 2.4Hz, 1H), 7.70 (dd, J = 8.2, 2.6Hz, 1H), 5.18 (q, J = 6.5Hz, 1H), 1.47 (d, J = 6.4Hz, 3H) ppm.

[0733] Step E: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-fluoro-3-(trifluoromethyl)pyridin-2-yl)ethyl) Piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0734] A mixture of intermediate 5 (50 mg, 0.15 mmol), 1-(5-fluoro-3-(trifluoromethyl)pyridin-2-yl)ethanol-1-ol (48 mg, 0.23 mmol), (cyanomethyl)trimethylphosphonium iodide (111 mg, 0.46 mmol), and DIPEA (197 mg, 1.53 mmol) in MeCN (2 mL) was stirred at 100 °C for 3 days. After completion, the solution was diluted with EA (15 mL), washed with brine (10 mL), dried, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give the title compound (2.86 mg). 1H NMR (400MHz, DMSO-d6) δ8.93(d,J=6.3Hz,1H),8.34(s,0.48H,HCOOH),8.19(td,J=9.2,6.8Hz,1H),7.97(d,J=2.0Hz, 1H),5.61(s,2H),5.36(d,J=10.4Hz,1H),4.30(s,1H),4.15(s,1H),3.26(s,4H),3.21-3.09(m,1H),3.03(s,2H),2.80 (d,J=10.4Hz,0.5H),2.24(d,J=11.0Hz,0.5H),1.88-1.72(m,0.5H),1.58(s,1.5H),1.37(dd,J=31.7,6.4Hz,4.5H),1 .11(s,0.5H),0.86(t,J=7.2Hz,1.5H),0.77(t,J=7.2Hz,1.5H),0.69(t,J=7.8Hz,1.5H),0.54(t,J=7.8Hz,1.5H)ppm. MS:M / e 520(M+1) + .

[0735] Compound A137: 2-(7-((2S,5R)-5-ethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0736] Step A: 1-(4-fluoro-2-methoxyphenyl)ethanol-1-ol.

[0737] NaBH4 (497 mg, 13.08 mmol) was added to a solution of 1-(4-fluoro-2-methoxyphenyl)ethyl-1-one (2.0 g, 11.89 mmol) in MeOH (30 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The mixture was then quenched with saturated NH4Cl (20 mL) and extracted with EA (45 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography to give the title compound (1.3 mg, 64%). MS: M / e 171 (M+1) + .

[0738] Step B: (2S,5R)-5-ethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester.

[0739] DIPEA (1270 mg, 9.85 mmol) was added to a solution of 1-(4-fluoro-2-methoxyphenyl)ethanol-1-ol (335 mg, 1.97 mmol), (2S,5R)-5-ethyl-2-methylpiperazine-1-carboxylic acid tert-butyl ester (450 mg, 1.97 mmol), and (cyanomethyl)trimethylphosphonium iodide (955 mg, 3.93 mmol) in CH3CN (2 mL). The mixture was degassed three times under a nitrogen atmosphere. The mixture was then stirred at 105 °C for 24 h. The reaction mixture was quenched with saturated NH4Cl (20 mL) at room temperature and extracted with EA (35 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography to give the title compound (180 mg, 24%). MS: M / e 381 (M+1) + .

[0740] Step C: (2R,5S)-2-ethyl-1-(1-(4-fluoro-2-methoxyphenyl)ethyl)-5-methylpiperazine.

[0741] To a solution of (2S,5R)-5-ethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)-2-methylpiperazin-1-carboxylic acid tert-butyl ester (90 mg, 0.237 mmol) in DCM (10 mL), HCl (4 mL, 4 M, 1,4-dioxane solution) was added at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure to give the crude product (HCl salt). The crude product was alkalized to pH approximately 10 with Na₂CO₃ (4 M) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na₂SO₄, and concentrated under reduced pressure to give the title compound (50 mg, 76%), which was used directly for the next step without purification. MS: M / e 281 (M+1) + .

[0742] Step D: 7-((2S,5R)-5-ethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)-2-methylpiperazine-1- 4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one.

[0743] DIPEA (103 mg, 0.80 mmol) was added to a solution of (2R,5S)-2-ethyl-1-(1-(4-fluoro-2-methoxyphenyl)ethyl)-5-methylpiperazine (45 mg, 0.160 mmol) and intermediate 2 (73 mg, 0.192 mmol) in CH3CN (1 mL) at room temperature. The mixture was stirred at 105 °C for 24 hours. The mixture was then concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography to give the title compound (50 mg, 61%). MS: M / e 512 (M+1) + .

[0744] Step E: 7-((2S,5R)-5-ethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)-2-methylpiperazine-1- 4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one.

[0745] HCl (2 mL, 4 M 1,4-dioxane solution) was added to a solution of 7-((2S,5R)-5-ethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)-2-methylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (50 mg, 0.1 mmol) in MeOH (4 mL). The mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure to give a crude product (HCl salt). The crude product was dissolved in water and alkalized to pH about 10 with Na2CO3 (4 M). The resulting mixture was extracted with EA (30 mL x 2). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, and concentrated under reduced pressure to give the title compound (35 mg, 81%). MS: M / e 428 (M+1) + .

[0746] Step F: 2-(7-((2S,5R)-5-ethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)-2-methylpiperazine- 1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile.

[0747] 2-Iodoacetonitrile (24 mg, 0.146 mmol) was added to a solution of 7-((2S,5R)-5-ethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)-2-methylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (35 mg, 0.073 mmol) and K₂CO₃ (20 mg, 0.146 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 12 hours. The reaction mixture was then quenched with saturated NaCl (20 mL) at room temperature and extracted with EA (30 mL x 2). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Method A) to give compound A137 (9 mg). 1 H NMR(400MHz,CD3OD)δ7.92(s,1H),7.50-7.47(m,1H),6.78-6.69(m,2H),5.56(s,1H),5.47(s,2H),4.61-4.35(m,3H),3.84(s,3H),3.34(s,3 H),3.28-3.26(m,1H),3.05-2.95(m,1H),2.78-2.75(m,1H),2.51-2.4 6(m,1H),1.36-1.34(m,2H),1.30-1.24(m,6H),0.80-0.76(m,3H)ppm. MS:M / e 467(M+1)+ .

[0748] Compound A143: 2-(7-((2R,5R)-2-(methoxymethyl)-5-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile

[0749] Step A: (2R,5R)-5-(methoxymethyl)-2-methyl-4-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-) 2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylic acid tert-butyl ester

[0750] NaH (60%, 24 mg, 0.6 mmol) was added to a stirred solution of (2R,5R)-5-(hydroxymethyl)-2-methyl-4-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylic acid tert-butyl ester (92.2 mg, 0.2 mmol) in THF (5 mL). After addition, the reaction mixture was stirred for 2 days. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with EA (10 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by preparative TLC (CH2Cl2 / MeOH = 10 / 1) to give the title compound (76 mg, 80%). MS: M / e 476 (M+1) + .

[0751] Step B: 7-((2R,5R)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyridine) (2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0752] TFA (1 mL) was added to a stirred solution of (2R,5R)-5-(methoxymethyl)-2-methyl-4-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylic acid tert-butyl ester (76 mg, 0.165 mmol) in CH2Cl2 (5 mL). After addition, the reaction mixture was stirred for 4 hours. The reaction mixture was alkalized with saturated aqueous Na2CO3 solution and extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the title compound (crude, 100%). MS: M / e 376 (M+1) + .

[0753] Step C: 7-((2R,5R)-2-(methoxymethyl)-5-methyl-4-(1-(quinoxalo-6-yl)ethyl)piperazine-1- )-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

[0754] A mixture of 7-((2R,5R)-2-(methoxymethyl)-5-methylpiperazin-1-yl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (crude, 0.165 mmol), 1-(quinoxalo-6-yl)ethanol-1-ol (86.1 mg, 0.495 mmol), (cyanomethyl)trimethylphosphonium iodide (120 mg, 0.495 mmol), and DIPEA (213 mg, 1.65 mmol) in CH3CN (4 mL) was stirred overnight at 100 °C in a sealed tube. The reaction ...

Claims

1. A compound of formula (I), or its stereoisomers or pharmaceutically acceptable salts in X 1 is C or N, X 2 and X 3 Each of is independently selected from -N- or -CH-; symbol is a single bond or a double bond, R 1 is hydrogen, or alkyl optionally substituted by deuterium, halogen, hydroxy, alkoxy or cycloalkyl; R 2 is hydrogen, halogen, alkyl or cyano, or when X 1 is N and attached to X 1 Key When it is a double bond, R 2 does not exist; R 4 is hydrogen, halogen or alkyl, wherein the alkyl is optionally substituted with halogen or -OR 4a Substituted, wherein R 4a is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by -C 1-6 Alkyl, -C 1-6 Alkoxy or -C 3-8 Cycloalkyl substitution; R 5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, R 5a -C(O)-、R 5a -C(O)O-、R 5a -OC(O)-、R 5a -C(O)NR 5b -、R 5a -NR 5b -C(O)-、R 5a -SO2- or heterocyclic, wherein the alkyl or alkenyl is unsubstituted or substituted by halogen, cyano, -C(O)OR 5c 、-C(O)R 5c 、-C(O)NR 5c R 5d , heterocyclic, alkoxy, hydroxy, cycloalkyl, or NR 5c R 5d and wherein each of the cycloalkyl and heterocyclyl groups is unsubstituted or substituted with alkyl, cyano or halogen; alkyl, cyano, -C(O)OR 5c 、-C(O)R 5c 、-C(O)NR 5c R 5d , heterocyclic group, alkoxy group, hydroxyl group, cycloalkyl group, NR 5c R 5d , or R 5c -SO2-substituted, where R 5a and R 5b are each independently hydrogen, alkyl, or cycloalkyl; and wherein R 5c and R 5d is hydrogen or alkyl; R 6 is hydrogen, halogen, alkyl which is unsubstituted or substituted by halogen or cyano, or when attached to R 6 The bond on the attached nitrogen When it is a double bond, R 6 does not exist; R 7 , R 9 , R 8 and R 10 Each of the following is independently hydrogen, alkyl, alkoxy, or -C(O)R 7a wherein the alkyl group is unsubstituted or substituted by halogen, cyano, hydroxyl, alkoxy or -C(O)R 7a substituted, and wherein R 7a is hydrogen, alkyl, or alkoxy, provided that R 7 and R 9 At least one of is not hydrogen; or R 7 and R 9 Each is hydrogen and R 8 and R 10 together form a bridge which, in addition to the two bridgehead atoms, contains at least one -CH2- group; or R 8 and R 10 Each is hydrogen and R 7 and R 9 together form a bridge which, in addition to the two bridgehead atoms, contains at least one -CH2- group; L 1 For direct bonds, -O-, -N(R L )-, -alkylene- or -C(O)-, wherein the -alkylene- is unsubstituted or replaced by -C(O)NR L1 Replace, and R L is hydrogen or alkyl, wherein R L1 is hydrogen, alkyl, or alkoxyalkyl; Cy 1 is aryl, heterocyclyl, heteroaryl, or cycloalkyl, each of which is unsubstituted or substituted with one, two or three substituents R 3a Substitution, where R 3a is selected from deuterium, hydroxyl, 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)-, cycloalkyl, heterocyclyl, or heterocyclyloxy, wherein the alkyl group or the alkyl group in the alkoxy group is unsubstituted or substituted with deuterium, halogen, alkoxy, hydroxyl, cyano, or heterocyclyl; the cycloalkyl or heterocyclyl group is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxyl, wherein R 3b and R 3c Each is independently hydrogen or alkyl.

2. The compound according to claim 1, wherein the compound of formula (I) is any one of the following subgenera:

3. The compound according to claim 1, wherein R 1 is hydrogen, or C optionally substituted by deuterium, halogen, hydroxyl, alkoxy or cycloalkyl 1-4 Alkyl; preferably R 1 is hydrogen, or C optionally substituted by deuterium or halogen 1-3 Alkyl; more preferably R 1 is hydrogen, or C optionally substituted by deuterium 1-3 alkyl.

4. The compound according to claim 1, wherein R 1 is hydrogen, methyl, methyl-d3, ethyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, or cyclopropylmethyl; preferably R 1 is hydrogen, methyl, ethyl or methyl-d3; more preferably R 1 It is methyl or methyl-d3.

5. The compound according to any one of claims 1 to 4, wherein R 2 For hydrogen, halogen, C 1-4 Alkyl or cyano; preferably R 2 is hydrogen, F, Br, Cl or CN.

6. A compound according to any one of claims 1 to 5, wherein R 4 is hydrogen, halogen or alkyl, wherein the alkyl is optionally substituted with halogen or -OR 4a Substitution, where R 4a is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by -C 1-6 Alkyl, -C 1-6 Alkoxy or -C 3-8 Cycloalkyl substituted; preferably R 4 is hydrogen, halogen or C 1-4 Alkyl, wherein the alkyl is optionally substituted with halogen or -OR 4a Substituted; more preferably R 4 is hydrogen, halogen or C 1-4 Alkyl, wherein the alkyl is optionally substituted with halogen.

7. A compound according to any one of claims 1 to 6, wherein R 4 is hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, ethyl, or 2,2,2-trifluoroethyl; preferably R 4 For hydrogen.

8. A compound, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is any one of the exemplified compounds.

9. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 8 or stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.

10. Use of the compound according to any one of claims 1 to 8 in the preparation of a medicament for treating a disease, wherein the disease is cancer.

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