Fused heterocyclic compounds as inhibitors of diacylglycerol kinase.

Abstract

Disclosed herein are compounds of Formula (I) that are DGK inhibitors for activating T cells, promoting T cell proliferation, and / or exhibiting anti-tumor activity, methods of using the compounds disclosed herein to treat cancer, and pharmaceutical compositions comprising the compounds. In some embodiments, the compounds disclosed herein exhibit selective inhibitory activity of DGKα over DGKζ. In some embodiments, the compounds disclosed herein exhibit selective inhibitory activity of DGKζ over DGKα. TIFF2026505790000901.tif57165

Description

[Technical Field]

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

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

[0003] Cancer immunotherapy is a type of cancer treatment that manipulates and strengthens the host immune system to recognize and attack cancer cells. The majority of research has focused on targeting depleted CD8 +The focus has been on targeted immune checkpoint inhibitors, such as CTLA-4 and PD-1 / PD-L1, which reactivate T cells. It has become clear that peripheral T cell tolerance, which normally prevents harmful autoimmune diseases, can be hijacked by tumors during carcinogenesis, hindering antitumor immune responses (Nussing, Simone, et al. Frontiers in Immunology. 2020, 11:2461). T cell anergy, one of the most important mechanisms of T cell tolerance, 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 anergy-associated transcription factor early growth response gene 2 (Egr2) directly binds to the Dgka and Dgkz promoters and increases their expression (Zheng, Yan, et al. Journal of Experimental Medicine 2012, 209.12:2157-2163; Zheng, Yan, et al. Molecular Immunology 2013, 55.3-4:283-291). In anergic T cells, DGKα and DGKζ both negatively regulate DAG signaling downstream of the TCR, playing an important role in reducing the intensity of TCR activation (Chen, Shelley S., et al. Frontiers in Cell and Developmental Biology 2016, 4:130). Therefore, we investigated immune cells expressing DGKα and DGKζ as potential targets for reversing the hyporesponsiveness of tumor-infiltrating T cells. It has been demonstrated that genetic deletion of DGKα or DGKζ enhances cytokine production and proliferation of T cells (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 both mouse and human chimeric antigen receptor (CAR)-T cells demonstrated superior effector function as determined by enhanced in vitro cytotoxicity and cytokine secretion when cocultured with the indicated antigen-expressing cells (Riese, Matthew J., et al. Cancer Research. 2013, 73.12:3566-3577; Jung, In-Young, et al. Cancer Research. 2018, 78.16:4692-4703). MesoCAR-transduced DGKα- or DGKζ-deficient T cells also demonstrated significantly increased in vivo activity against mesothelioma (Riese, Matthew J., et al. Cancer Research. 2013, 73.12:3566-3577). - / - Mice 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 Res 2019;79(13 Suppl):Abstract nr 936). In addition to their T cell regulatory functions, both DGKα and DGKζ are also involved in regulating NK cell activation at tumor sites (Prinz, Petra U., et al. International Journal of Cancer. 2014, 135.8:1832-1841; Yang, Enjun, et al. The Journal of Immunology. 2016, 197.3:934-941). Furthermore, DGKΚ has been found to play an important 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 of these preclinical data suggest that inhibition of DGKα and DGKΚ may be therapeutically beneficial in promoting immunity against cancer. Although existing anti-CTLA-4 and anti-PD-1 therapies have demonstrated clear clinical benefits in subsets of patients with various tumor types, there remains an unmet medical need to develop novel immunotherapies to achieve robust and durable clinical antitumor responses. Preclinical data strongly suggest great potential for the development of DGKα- and DGKζ-targeted therapies to improve antitumor immunity. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Rhee, Sue Goo.Annual review of biochemistry.2001,70.1:281-312 [Non-patent document 2] Merida, Isabel, et al.Biochemical Journal.2008,409.1:1-18 [Non-patent document 3] Joshi,Rohan P.,et al.International Journal of Molecular Sciences.2013,14.4:6649-6673 [Non-patent document 4] Nussing,Simone,et al.Frontiers in Immunology.2020,11:2461 [Non-patent document 5] Abe, Brian T., and Fernando Macian. Oncoimmunology.2013,2.2:e22679 [Non-patent document 6] Zheng,Yan,et al.Journal of Experimental Medicine 2012,209.12:2157-2163 [Non-Patent Document 7] Zheng,Yan,et al.Molecular Immunology.2013,55.3-4:283-291 [Non-patent document 8] Chen,Shelley S.,et al.Frontiers in Cell and Developmental Biology.2016,4:130 [Non-Patent Document 9] Olenchock,Benjamin A.,et al.Nature immunology.2006,7.11:1174-1181 [Non-Patent Document 10] Zhong,Xiao-Ping,et al.Nature immunology.2003,4.9:882-890 [Non-Patent Document 11] Riese, Matthew J., et al.Cancer Research.2013,73.12:3566-3577 [Non-Patent Document 12] Jung,In-Young,et al.Cancer Research.2018,78.16:4692-4703 [Non-Patent Document 13] Wesley,Erin M.,et al.Immunohorizons.2018,2.4:107-118 [Non-Patent Document 14] Wee,Susan,et al.AACR;Cancer Res 2019;79(13 Suppl):Abstract nr 936 [Non-Patent Document 15] Prinz,Petra U.,et al.International Journal of Cancer.2014.135.8:1832-1841 [Non-Patent Document 16] Yang,Enjun,et al.The Journal of Immunology.2016,197.3:934-941 [Non-Patent Document 17] Wheeler, Matthew L., et al.Science Signaling.2013,6.297:ra91-ra91 Summary of the Invention [Means for solving the problem]

[0005] The above needs have been met by providing compounds disclosed herein that have novel core structures and exhibit desirable inhibition of DGKα and DGKζ. In some embodiments, the compounds disclosed herein exhibit selective inhibitory activity of DGKα over DGKζ. In some embodiments, the compounds disclosed herein exhibit selective inhibitory activity of DGKζ over DGKα. In some embodiments, the compounds disclosed herein exhibit dual inhibitory activity of both DGKα and DGKζ. In some embodiments, the compounds disclosed herein exhibit close inhibitory activity against DGKα and DGKζ.

[0006] As used herein, a compound of formula (I): [ka] or a stereoisomer or a pharmaceutically acceptable salt thereof is disclosed, During the ceremony, X1 is C or N; R1 is hydrogen or alkyl optionally substituted with deuterium, halogen, hydroxy, alkoxy, or cycloalkyl; R2 is hydrogen, halogen, alkyl, or cyano, with the proviso that when X1 is N, R2 is absent; R4 is hydrogen, halogen, or alkyl, wherein alkyl is optionally substituted with deuterium or halogen; R5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cyano, or heterocyclyl, wherein said alkyl or said alkenyl is unsubstituted or substituted with halogen, cyano, heterocyclyl, alkoxy, hydroxy, or cycloalkyl; R7, R9, R8, and R 10each is independently hydrogen, alkyl, or alkoxy, wherein the alkyl is unsubstituted or substituted with halogen, provided that at least one of R7 and R9 is not hydrogen; L1 is a direct bond or -C(R L1 )(R L2 ) in which R L1 , the R L2 each independently is hydrogen or C optionally substituted with deuterium, halogen, alkyl, alkylene, alkynyl, cyano 1-4 is alkyl, Cy1 is aryl, heterocyclyl, heteroaryl, or cycloalkyl, each of which is unsubstituted or contains one, two, or three substituents R 3a and each R 3a are independently hydroxy, alkoxy, alkyl, halogen, aminoalkyl, 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, each of which alkyl portions is unsubstituted or substituted with deuterium, halogen, alkoxy, hydroxy, cyano, or heterocyclyl, and said cycloalkyl or said heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl, or R 3b and R 3c together form a bridge containing at least one -CH2- moiety, However, when the compound is 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2,4-Dimethyl-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(2,2,2-trifluoroethyl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-(2-methoxyethyl)-4-methyl-2, 4-Dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetamide, methyl 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetate 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)propanenitrile, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-(2-hydroxyethyl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(cyclopropylmethyl)-7-((2S,5R)-2,5-Dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-(2-(dimethylamino)ethyl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazine- 1-yl)-4-methyl-2-(oxiran-2-ylmethyl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(methylsulfonyl)-2H-pyrazolo[4,3-b]pyridin-5(4H)-one, 2-cyclobutyl-7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro 2-(cyclopropanecarbonyl)-7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 1-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)cyclopropane Isopropylpropane-1-carbonitrile, 2-cyclopropyl-7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-isopropyl-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(3-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile, 3-cyclopentyl-3-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)propanenitrile, 7-((2S,5R)- 2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(prop-2-yn-1-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethyl-4-( 1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-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, 7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(prop-1-en-2-yl)- 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, 7-((2S,5R)-2,5-diethyl-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,3-b]pyridin-5-one, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 2-(7- ((2S,5R)-4-(1-(4-fluoro-3-(methoxymethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-(methoxymethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-( 2,6-difluoro-4-methoxyphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(5-fluoropyridin-2-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-([1,2,4]triazolo[1,5- a]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,5-difluoro-4-methoxyphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-cyclopropylphenyl)propyl)-2,5-Dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-phenylethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-methoxyphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro 2-(7-((2S,5R)-4-(1-(quinolin-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinolin-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, tolyl, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(2-methylbenzo[d]oxazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(2-methylbenzo[d]oxazol-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2- (7-((2S,5R)-4-(1-(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, 2-(7-((2S,5R)-2,5-dimethyl-4-(quinoxalin-6-ylmethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(quinoxalin-6-ylmethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile5-dimethyl-4-(1-(2-methylbenzo[d]oxazol-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-di, A mixture of 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 and 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile. )ethyl)piperazin-1-yl)-4-ethyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(isoquinolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-([1,2,4]triazolo[1,5-a]pyridin-7-yl)ethyl)-2,5-diethylpiperazine-1- 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-(methyl-d3)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(benzo[d]thiazol-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-((4-fluoro-2-methoxyphenyl)(4-fluorophenyl)methyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(quinoxalin-6-ylmethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S, 5R)-2,5-diethyl-4-(1-(quinolin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinolin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinolin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinolin-6-yl)ethyl)piperazin-1-yl)- 4-Methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinolin-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(isoquinolin-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(1,8-naphthyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-methyl-1H-benzo[d]imidazol-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalin-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-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile a mixture of 2-(7-((2S,5R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2 -(7-((2S,5R)-2,5-diethyl-4-(1-(pyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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,5-Diethyl-4-(4-fluorobenzyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 2-(7-((2S,5R)-4-(1-(4-cyclopropyl-2-fluorophenyl)ethyl)- 2,5-Diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-fluoropyridin-2-yl)ethyl)piperazin-1-yl) 2-(7-((2S,5R)-4-(2,4-difluorobenzyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-cyclopropyl-2-fluorophenyl)propyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile -dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methoxy-4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-(trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-isopropoxypyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-3-methoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-( (2S,5R)-4-(1-(2,6-difluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 2-(7-((2S,5R)-2,5-diethyl-4-(1- (4-fluoro-2-(2-methoxyethoxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3,5-difluoropyridin-4-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyrazin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo, [4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-phenylethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2- (7-((2S,5R)-2,5-diethyl-4-(1-(3-methoxypyridin-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methoxypyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, R)-2,5-diethyl-4-(1-(3-(methoxymethyl)pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2,6-dimethoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S, 5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-(2-hydroxyethyl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-Ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2-ethyl-5-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5S)-5-(hydroxymethyl)-2-methyl- 4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5S)-5-(methoxymethyl)-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2R,5R)-2-(hydroxymethyl)-5-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl) 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methoxypyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-Dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-(methoxymethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile lysin-2-yl)acetonitrile, 3-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)benzamide, N-(3-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)phenyl)acetamide, 2-(7-((2S,5R )-2,5-diethyl-4-(1-(3-methyl-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 2-(7-((2S,5R)-2,5-diethyl-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 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-fluoro-4-(trifluoromethyl)pyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-fluoro-4-(trifluoromethyl)pyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile,5-diethyl-4-(1-(5-methyl-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 2-(7-((2S, 5R)-4-(1-(2-chloro-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methyl-6-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5 R)-2,5-diethyl-4-(1-(3-(trifluoromethyl)pyridin-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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 tolyl, 4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)benzamide, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-(hydroxymethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-Diethyl-4-(1-(4-(trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(4-methyl-5-oxo-7-(5-( 1-(quinoxalin-6-yl)ethyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 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, 2-(7-((2S,5R)-4-(1-(4-(difluoromethyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazine-1- 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyrimidin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyrimidin-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyrimidin-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,4-difluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(6-chloro-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2, -(cyanomethyl)-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridine-6-carbonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2 S,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, 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, S,5R)-4-(1-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-(2,2-difluoroethyl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2- (7-((2S,5R)-2,5-diethyl-4-(1-(5-isopropoxypyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-ethoxy-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile,5-Diethyl-4-(1-(4-fluoro-2-isopropoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2R,5R)-2-(methoxymethyl)-5-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl 2-(7-((2S,5R)-2-(2-hydroxyethyl)-5-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2-(2-hydroxyethyl)-5-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 5R)-2,5-diethyl-4-(1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3,5-difluoropyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(2, 3-Dihydro-1H-inden-1-yl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(chroman-4-yl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-((dimethylamino)methyl)phenyl)ethyl)-2,5-Diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(hydroxymethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)piperazin-1-yl) 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo- so-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(cyanomethyl)-7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridine-6-carbonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methoxy-4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-di Hydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-((2S,5R)-1-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-5-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-Dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-isopropoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((3R)-3-ethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile Acetonitrile, 2-(6-chloro-7-((3R)-3-ethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(methylamino)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, )-2-(2-methoxyethyl)-5-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, N-(2-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)phenyl)acetamide, 2-(7-((2S,5R)-2,5-diethyl-4-(1- (1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(4-(cyclopropylmethyl)-7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-Dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-6-fluoro-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(cyanomethyl)-7-((2S,5R)-3-ethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridine-6-carbonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2 -(trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-(difluoromethoxy)-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-(difluoromethoxy)-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, methyl 4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-1-(1-(quinoxalin-6-yl)ethyl)piperazine-2-carboxylate, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-1H-imidazol-2-yl)ethyl)piperazin-1-yl)- 4-Methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-cyclopropyl-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-1H-indol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-Dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(4-methyl-7-((3S)-3-methyl-4-(1-, (quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(6-bromo-7-((2S,5R)-3-ethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6-(difluoromethoxy)pyridin-3-yl)ethyl)-2,5- Diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-5-methyl-1H-imidazol-2-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-(1-ethyl-4-methyl-1H-imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-4-(1-(1-ethyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-(3-(hydroxymethyl)-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-ethyl-3H-imidazo[4,5-b]pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-4-(1-(5-chloro-1-ethyl) 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(1-hydroxyethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(1-hydroxyethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2,2'-(6-cyano-7-((2S, 5R)-5-Ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-2H-pyrazolo[4,3-b]pyridine-2,4(5H)-diyl)diacetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-isopropyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-chloro-1-ethyl)piperazin-1-yl)- 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-propyl-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-propyl-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile,5-Diethyl-4-(1-(1-isopropyl-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-6-fluoro-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-fluoro 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-( 1-(2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-1-(1-(quinoxalin-6-yl)ethyl)piperazine-2-carboxamide, 2-(7-((2S,5R)-4-(1-(4-cyclopropyl-2-methoxyphenyl)ethyl)-2,5-diethylpiperazine-1 -yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(cyanomethyl)-7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridine-6-carbonitrile, 2-(7-((2S,5R)-4-(1-(2,4-difluoro-6-methoxyphenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-Dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-4-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-ethyl-4-fluorophenyl)ethyl)piperazin-1-yl) 2-(7-((2S,5R)-2,5-diethyl-4-(3-(trifluoromethyl)benzoyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-6-oxo-1,6-dihydropyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-2-methyl-1H-imidazol-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-2-methyl-1H-imidazol-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-Dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)ethyl) Piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-chloro-1-ethyl-1H-pyrazol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-ethyl-1-methyl-1H-pyrazole 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-(2-hydroxyethyl)-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-( 1-ethyl-1H-imidazo[4,5-b]pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-4-methyl-1H-pyrazol-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-(trifluoromethyl)pyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(, 1-ethyl-2-methyl-1H-imidazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, or 2-(7-((2S,5R)-2,5-dimethyl-4-((R)-1- (quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-ethyl-7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(2,2-difluoroethyl)-7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl) )piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-4-(1-cyclohexylethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazine-1- 2-(7-((2R,5R)-5-ethyl-2-(methoxymethyl)-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6-chloro-4-(trifluoromethyl)pyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-4-methyl-1H-pyrazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 7-((2S,5R)-4-(1-(1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile Lysin-5-one, 2-(7-((2R,5R)-5-ethyl-2-(hydroxymethyl)-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b ]pyridin-2-yl)acetonitrile, 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, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-methyl-3-(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, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-methyl-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, 2-(7-((2S,5R)-4-(1-(5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-methyl-4-(trifluoromethyl)pyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[ 4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(1-(2,2-difluoroethyl)-1H-imidazol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-2,4- Dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-2-(trifluoromethyl)-1H-imidazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 3-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazine 2-(7-((2S,5R)-2,5-diethyl-4-(4-fluoro-2-(trifluoromethyl)benzyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(tetrahydro-2H-pyran-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile or 2-(7-((2S,5R)-2,5-dimethyl-4-((R)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile -pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-b]pyridin-1-yl)acetonitrile or 2-(7-((2S,5R)-2,5-dimethyl-4-((R)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-3-(trifluoromethyl)-4,5 -dihydro-1H-pyrazolo[4,3-b]pyridin-1-yl)acetonitrile, 2-(3-chloro-7-((2S,5R)-2,5-dimethyl-4-((R)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, or 2-(3-chloro-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro- 2H-Pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(4-fluoro-2-(trifluoromethyl)benzyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-(difluoromethoxy)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-omethoxy(omethoxy)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethoxy)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile -pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-chloro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo -4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-(difluoromethyl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile Pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-(1,1-difluoroethyl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)propyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)propyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4, ... -(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-(methyl-d3)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((R)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-3-fluoro-4-methyl-5-oxo-4,5-dihydro-1H-pyrazolo[4,3-b]pyridin-1-yl)acetonitrile , or 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-3-fluoro-4-methyl-5-oxo-4,5-dihydro-1H-pyrazolo[4,3-b]pyridin-1-yl)acetonitrile, 2-(7-((2R,5R)-5-ethyl-2-((R)-1-hydroxyethyl)-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)acetonitrile 2-(7-((2S,5R)-2,5-dimethyl-4-((R)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((R)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, or 2-(7 -((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2R,5R)-2-(difluoromethyl)-5-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo- 4,5-Dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(2,2-difluoro-1-(quinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(3-chloro-7-((2S,5R)-2,5-dimethyl-4-((R)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, or 2-(3-chloro-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5- Ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-3-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl-2,3-d2)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-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-dimethyl-4-(1-(2-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(2-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, -((R)-1-(2-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-((2S,5R)-4-(1-(3-methoxyquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(3-hydroxyoxetan-3-yl)ethyl)fluoro)fluoro)fluoro)fluoro)fluoro)fluoro)fluoro)fluoro)fluoro)fluoro)fluoro)fluoro)fluoro)fluoro)fluoro)fluoro)fluoro)fluoro) 2-(7-((2S,5R)-4-(1-(2,6-dichloro-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3,4-difluoro-2-methoxyphenyl)ethyl)-2,5-Dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-6-methoxy-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl) piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-(methyl-d3)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-chloro-2-(trifluoromethyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl) -4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-ethylquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-hydroxyquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4, 5-Dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-chloroquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methoxyquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-hydroxyquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-methoxyquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile Acetonitrile, 2-(7-((2S,5R)-4-(1-(2-hydroxyquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-(dimethylphosphoryl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile , 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(1-methoxyethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-(cyanomethyl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 7-((2S,5R)-4-(1-(3,4-difluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-5-fluorobenzamide, methyl 2-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-5-fluorobenzoate, 2-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-5-fluoro-N-methylbenzamide, 2-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-, 5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-5-fluoro-N,N-dimethylbenzamide, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,3-dimethylquinoxaline-6 -yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((3R,4R)-3-ethoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3 -b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)-N-(2-methoxyethyl)-2-(4-(trifluoromethyl)phenyl)acetamide, 2-(7-((2S,5R)-4-(2-(4-fluorophenyl)propan-2-yl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-(2,5-dimethyl-4-(methyl(3-methylquinoxalin-6-yl)amino)piperidin-1-yl)-4 -methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-allyl-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, or 2-allyl-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, 2-(but-3-en-1-yl)-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, or 2-(but-3-en-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, 2- Allyl-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-en-1-yl)-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(3,3-difluoroallyl)-7-((2 S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-methylisoquinolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(isoquinolin-3-yl)ethyl) )-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(2-methylquinolin-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 7-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-dimethylpiperazin-1-yl)ethyl)-2-naphthonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-(hydroxymethyl)quinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile Hydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-cyclopropylquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-(difluoromethyl)quinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile Pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-(1,1-difluoroethyl)quinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-(methyl-d3)quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo [4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-(trifluoromethyl)quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(2-(trifluoromethyl)quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-hydroxy-3-methylquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-6-fluoro-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo [4,3-b]pyridin-2-yl)acetonitrile, 2-(cyanomethyl)-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridine-6-carbonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4, 3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(2-methylbenzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile -pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(benzo[d]thiazol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3H-spiro[benzo[b][1,4]dioxin-2,1'-cyclopropane]-7-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile5-Dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl) 2-(7-((2S,5R)-4-(1-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(1- 2-(7-((2S,5R)-4-(1-(2-(1-(difluoromethoxy)ethyl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-(1-(difluoromethoxy)ethyl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(1-methoxycyclohexyl) 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4,4-difluorochroman-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-4-((4-fluorophenyl)(5-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4, ,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(di-p-tolylmethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(but-2-yn-1-yl)-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, 2-(but-2-yn-1-yl)-7-((2S,5R)-4-(1-(3-(difluoromethyl)quinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one 2-(4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)phenyl)-2-methylpropanedione, 2-(7-((2S,5R)-4-(1-(2,3-dihydrofuro[2,3-b]pyridin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)phenyl)-2-methylpropanedione tolyl, 2-(4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)propyl)phenyl)-2-methylpropanenitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-methylphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-((2,2-dimethylmorpholino)methyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-((2,2-dimethylmorpholino)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S, 5R)-4-(1-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-((4,4-difluoropiperidin-1-yl)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile tolyl, 2-(4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-3-fluorophenyl)-2-methylpropanenitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-methylpyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-( (2S,5R)-4-(1-(5-(difluoromethyl)pyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-Diethyl-4-(1-(6-methylpyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6-(difluoromethyl)pyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrofuro[3,2-b]pyridin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrofuro[3,2-b]pyridin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-di Ethyl-4-(1-(6-fluoropyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-( 5,6-dimethylpyrazin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-methylpyrazin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5,6,7,8-tetrahydroquinoxalin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-6-isopropoxypyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-6-isopropoxypyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile -(1-(3-fluoro-5-methylpyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(5-chloropyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1- (5-(trifluoromethoxy)pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro-5-(trifluoromethoxy)pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)- 4-(1-(5,6-dimethylpyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-methoxy-5-methylpyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-Diethyl-4-(1-(6-methylpyridazin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methylisoquinolin-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-methylisoquinolin-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-((2S,5R)-4-(1-(2,6-naphthyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,6-naphthyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(4-cyclopropylbenzoyl)-2,5-diethylpiperazin-1-yl )-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(5-methylpicolinoyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(2,6-naphthyridine-3-carbonyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3 -b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(isoquinoline-3-carbonyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(quinoline-7-carbonyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(quinoline-7-carbonyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile,5-diethyl-4-(quinoxaline-2-carbonyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-((tetrahydrofuran-3-yl)oxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonite, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-((tetrahydrofuran-3-yl)methoxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-methoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5 R)-2,5-diethyl-4-(1-(4-(oxetan-3-yloxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(oxetan-3-ylmethoxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(oxetan-3-ylmethoxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6-((4,4-difluoropiperidin-1-yl)methyl)pyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6-((4,4-difluoropiperidin-1-yl)methyl)pyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, -((2S,5R)-4-(1-(4-(4,4-difluoropiperidine-1-carbonyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(morpholinomethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3,4-dimethylphenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4,5-dimethylpyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(6-(1-((2R,5S)-4-(2-(cyanomethyl)-4 -methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)pyridin-3-yl)-2-methylpropanenitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro-5-isopropoxypyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(imidazo [1,2-a]pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyrazolo[1,5-a]pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(but-2-yn-1-yl)-7-((2S,5R)-4-(1-(2,2-dimethylbenzo[4,3-b]pyridin-2-yl)acetonitrile [d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-4-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-5-ethyl-4-(1-(isoquinolin-3-yl)ethyl)-2-methylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-5-ethyl-4-(1-(isoquinolin-3-yl)ethyl)-2-methylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinolin-2-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, or 2-(but-2-yn-1-yl)-7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinolin-7-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, The variables are as defined herein.

[0007] Definition of R1

[0008] In some embodiments, R 1 is hydrogen or alkyl optionally substituted with deuterium, halogen, hydroxy, alkoxy, or cycloalkyl.

[0009] In some embodiments, R1 is hydrogen or C1-4 alkyl optionally substituted with deuterium, halogen, hydroxy, alkoxy, or cycloalkyl, and in some embodiments, R1 is hydrogen or C1-3 alkyl optionally substituted with deuterium or halogen.

[0010] In some embodiments, R1 is hydrogen, methyl, ethyl, isopropyl, n-propyl, methyl-d3, and in some embodiments, R1 is hydrogen, methyl, ethyl, methyl-d3, and more preferably, R1 is methyl.

[0011] Definition of R2 and X1

[0012] In some embodiments, X 1 is N; in some embodiments, X 1 is C.

[0013] In some embodiments, R2 is hydrogen, halogen, alkyl, or cyano, with the proviso that when X1 is N, then R2 is absent.

[0014] In some embodiments, R2 is hydrogen, halogen, C 1-4 alkyl or cyano, provided that X is C; preferably, R is hydrogen, F, Br, Cl, methyl, ethyl, or —CN, more preferably, R is F, Br, methyl, or —CN.

[0015] Definition of R4

[0016] In some embodiments, R4 is hydrogen, halogen, or alkyl, wherein alkyl is optionally substituted with halogen or deuterium; in some embodiments, R4 is hydrogen, deuterium, halogen, or alkyl optionally substituted with halogen or deuterium; in some embodiments, R4 is hydrogen, methyl, or methyl-d3; in some embodiments, R4 is hydrogen.

[0017] Definition of R5

[0018] In some embodiments, R5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cyano, or heterocyclyl, wherein the alkyl or alkenyl is unsubstituted or substituted with halogen, cyano, heterocyclyl, alkoxy, hydroxy, or cycloalkyl.

[0019] In some embodiments, R5 is hydrogen, alkyl, alkenyl, or alkynyl, wherein the alkyl is unsubstituted or substituted with cyano, cycloalkyl, or cycloalkoxy; in some embodiments, R5 is C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 alkynyl, wherein the alkyl is cyano, C 3-6 Cycloalkyl, or C 2-6 It is substituted with cycloalkoxy.

[0020] In some embodiments, R5 is hydrogen, -CH2-CN, -CH(CH3)CN, -CH2-CH2-CN, -CH2-CH2-CH2-CN, -CH(CH3)-CH2-CN, -CH2-CH(CH3)-CN, -CH(CH2CH3)-CN, oxiran-2-ylmethyl, oxiran-2-yl, oxetan-3-ylmethyl, oxetan-2-methyl, oxetan-3-yl, oxetan-2-yl, prop-2-yn-1-yl, but-2-yn-1-yl. , but-3-yn-1-yl, pent-2-yn-1-yl, pent-3-yn-1-yl, pent-4-yn-1-yl, prop-2-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, pent-2-en-1-yl, pent-3-en-1-yl, pent-4-en-1-yl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, azetidin-2-yl, azetidin-3-yl, azetidin-3-ylmethyl, azetidin- In some embodiments, R5 is hydrogen, —CH2—CN, —CH(CH3)CN, —CH2—CH2—CN, CH2—CH2—CH2—CN, —CH(CH3)—CH2—CN, —CH2—CH(CH3)—CN, —CH2—CH(CH3)—CN, —CH2—CH(CH3)—CN, —CH2—CH(CH3)—CN, —CH2—CH(CH3)—CN, —CH2— (CH2CH3)-CN, oxetan-3-ylmethyl, oxetan-2-methyl, oxetan-3-yl, oxetan-2-yl, prop-2-yn-1-yl, but-2-yn-1-yl, but-3-yn-1-yl, or pent-3-yn-1-yl, and in some embodiments, R5 is CN-CH2-, -CH2-CH2-CN, but-2-yn-1-yl, but-2-yn-1-yl, or oxetan-3-ylmethyl, oxetan-3-yl.

[0021] R7 / R 9、 R8 / R 10 Definition of

[0022] In some embodiments, R7, R9, R8, and R10 are each independently hydrogen, alkyl, or alkoxy, wherein the alkyl is unsubstituted or substituted with halogen, provided that at least one of R7 and R9 is not hydrogen.

[0023] In some embodiments, each of R7 and R9 is independently hydrogen, alkyl, wherein the alkyl is unsubstituted or substituted with halogen; in some embodiments, each of R7 and R9 is independently C 1-4 alkyl, and in some embodiments, each of R7 and R9 is independently C 1-2 In some embodiments, R7 and R9 are each independently hydrogen, methyl, ethyl, isopropyl, or n-propyl.

[0024] In some embodiments, R7 is methyl and R9 is methyl, in some embodiments, R7 is ethyl and R9 is ethyl, in some embodiments, R7 is methyl and R9 is ethyl.

[0025] In some embodiments, R and R 10 are each hydrogen.

[0026] In some embodiments, the carbon at position 2 on the piperazine ring is in the S configuration and the carbon at position 5 on the piperazine ring is in the R configuration.

[0027] Definition of L1

[0028] In some embodiments, L is a direct bond or -C(R L1 )(R L2 ) in which R L1 , the R L2 each independently is hydrogen or C optionally substituted with deuterium, halogen, alkyl, alkylene, alkynyl, cyano 1-4 It is alkyl.

[0029] In some embodiments, L is a direct bond, —C(R L1 )(R L2 ) and the R L1 , the R L2 each independently is hydrogen or optionally substituted with deuterium, halogen, 1-4 In some embodiments, L1 is alkyl, and in some embodiments, L1 is a direct bond, -CH2-, -CH(CH3)-, -CH(CD3)-, -CH(CH2CH3)-, -CH(C3H7)-, -CH(CHF2)-, or -C(CH3)2-, and in some embodiments, L1 is -CH(CH2CH3)-, -CH(CH3)-, or -CH(CD3)-.

[0030] In some embodiments, the compound of formula (I) is a compound of formula (II): [ka] or a stereoisomer or a pharmaceutically acceptable salt thereof; In the formula, R 11 is methyl, methyl-d3, or ethyl, and X1, R2, R7, R9, and Cy1 are as defined above.

[0031] In some embodiments, R 11 and the carbon attached to Cy1 is in the R configuration.

[0032] In some embodiments, R 11 and the carbon attached to Cy1 is in the S configuration.

[0033] In some embodiments, the compound of Formula (II) is a compound of Formula (IIa): [ka] or a stereoisomer or a pharmaceutically acceptable salt thereof; In the formula, R 11 Each of R is methyl or ethyl, and X, R, R, R, and Cy are as defined above.

[0034] In some embodiments, the compound of Formula (II) is a compound of Formula (IIb): [ka] or a stereoisomer or a pharmaceutically acceptable salt thereof; In the formula, R 11 Each of R is methyl or ethyl, and X, R, R, R, and Cy are as defined above.

[0035] Definition of Cy1

[0036] In some embodiments, Cy1 is aryl, heterocyclyl, heteroaryl, or cycloalkyl, each of which is unsubstituted or contains 1, 2, or 3 substituents R 3a and each R 3a are independently hydroxy, alkoxy, alkyl, halogen, aminoalkyl, 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, each of which alkyl portions is unsubstituted or substituted with deuterium, halogen, alkoxy, hydroxy, cyano, or heterocyclyl, and said cycloalkyl or said heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy; R 3b and R 3c are each independently hydrogen or alkyl, or R 3b and R 3c together form a bridge containing at least one -CH2- moiety.

[0037] In some embodiments, R 3ais fluoro, bromo, chloro, methyl, ethyl, isopropyl, trifluoromethyl, hydroxyl, 1-methylpyrrolyl, 1-methylazetidinyl, 1-methylpiperidinyl, dimethylaminomethyl, 1,1-difluoroethyl, 3,3-difluoro-1-methylazetidinyl, dimethylaminyl, 1,1-dimethylmethyl, methoxy, cyclopropyl, cyclobutane, 2-fluoro-2-methylethyl, oxetan-3-ylmethyloxy, oxolan-3-ylmethyloxy, oxan-4-ylmethyloxy, oxetan-3-yloxy, oxolan-3-yloxy, oxan-3-yloxy, oxetan-3-methyl-3-yloxy, difluoromethoxy, 2-methoxyethoxy, (2-methoxyethoxy)methyl, 1,1-dioxidethiomorpholine- and selected from 4-methyl, isopropoxy, dimethylcarbamoyl, (3-hydroxyazetidin-1-yl)methanone, formylamino, acetamido, propionamino, cyclopropoxy or amino, 4,4-difluoropiperidin-1-yl)methyl, oxetan-3-ylmethyl, (4-methoxypiperidin-1-yl)methyl, cyanomethyl, cyano, 1,1-dioxidethiomorpholino)methyl, methylcarbamoyl, 4-methoxypiperidine-1-carbonyl, (3-methoxypropyl)(methyl)carbamoyl), (methylsulfonyl)methyl, 5-cyclopropoxy, 3-methoxypyrrolidine-1-carbonyl, 4-(3-methoxypyrrolidine-1-carbonyl)phenyl, 3-methoxypyrrolidine-1-carbonyl, or 4-(methoxymethyl).

[0038] In some embodiments, R 3aare fluoro, bromo, chloro, methyl, ethyl, isopropyl, trifluoromethyl, hydroxyl, 1-methylpyrrolyl, 1-methylazetidinyl, 1-methylpiperidinyl, dimethylaminomethyl, 1,1-difluoroethyl, 3,3-difluoro-1-methylazetidinyl, dimethylaminyl, 1,1-dimethylmethyl, methoxy, cyclopropyl, cyclobutane, 2-fluoro-2-methylethyl, oxetan-3-ylmethyloxy, oxolan-3-ylmethyloxy, oxane 4-ylmethyloxy, oxetan-3-yloxy, oxolan-3-yloxy, oxan-3-yloxy, oxetan-3-methyl-3-yloxy, difluoromethoxy, 2-methoxyethoxy, (2-methoxyethoxy)methyl, 1,1-dioxidethiomorpholin-4-methyl, isopropoxy, dimethylcarbamoyl, (3-hydroxyazetidin-1-yl)methanone, formylamino, acetamido, propionamino, cyclopropoxy, or amino.

[0039] In some embodiments, Cy1 is phenyl. In some embodiments, Cy1 is substituted with one R as disclosed herein at the 4-position. 3a and optionally substituted at other positions by R3a.

[0040] In some embodiments, Cy1 is unsubstituted or contains 1, 2, or 3 R 3a and a monocyclic 5- to 9-membered heterocyclyl or a bicyclic 7- to 10-membered heterocyclyl substituted with

[0041] In some embodiments, the monocyclic 5-9 membered heterocyclyl is unsubstituted or contains 1, 2, or 3 R 3a is replaced by [ka] wherein each of X4, X5, X6, X7, and X8 is independently selected from N or C, and X9 is C, N, S, or O, with the proviso that when X4, X5, X6, X7, and X8 are N, then X4, X5, X6, X7, and X8 are each independently unsubstituted.

[0042] In some embodiments, the monocyclic 5-9 membered heterocyclyl is thiazole, isothiazole, triazole, pyridine, pyrazine, pyrimidine, each of which is unsubstituted or contains 1, 2, or 3 R 3a is replaced by .

[0043] In some embodiments, the monocyclic 5-9 membered heterocyclyl is thiazole, isothiazole, triazole, pyridine, pyrazine, pyrimidine, each of which is unsubstituted or contains 1, 2, or 3 R 3a is replaced by .

[0044] In some embodiments, monocyclic 5- to 9-membered heterocyclyl is 4-(3-methoxyazetidine-1-carbonyl)phenyl, 4-(N,N-dimethylcarbamoyl)phenyl, 4-(N,N-dimethylcarbamoyl)-2-fluoro-phenyl, 4-((1,1-dioxidothiomorpholino)methyl)-3,5-difluorophenyl, 2,4-dimethylphenyl, 4-ethylphenyl, 3-methyl-4-(trifluoromethyl)phenyl, 4-methoxy-3-methylphenyl, 4-(1,1-difluoroethyl)phenyl, 4-(1,1-difluoroethyl)phenyl, 4-(2-methoxyethoxy)phenyl, 2-fluoro-4-methoxyphenyl, 2-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl, 4-methoxy-2-methylphenyl, 4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl, 4-((oxetan-3-yl)oxy)methyl)phenyl, 4- ... 4-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl, 4-((2-methoxyethoxy)methyl)phenyl, 4-(difluoromethoxy)phenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 2-fluoro-4-(oxetan-3-yloxy)phenyl, 4-((3-methyloxetan-3-yl)oxy)phenyl, 4-((dimethylamino)methyl)-3,5-difluorophenyl, 4-(pyrrolidin-1-ylmethyl)phenyl, 4-((3,3-difluoroazetidin-1-yl)methyl)phenyl, 4-((dimethylamino)methyl)phenyl, 4-((methylamino)methyl)phenyl, 1-methyl-1H-1,2,3-triazol-4-yl)phenyl, 4-isopropylphenyl, 4-cyclopropoxyphenyl, 4-isopropoxyphenyl, 4-methoxyphenyl, 4,5-Dimethylthiazol-2-yl, 6-cyclopropoxypyridin-3-yl, 6-cyclopropylpyridin-3-yl, 6-cyclopropyl-5-fluoropyridin-3-yl, 6-methoxypyridin-3-yl, 6-(methoxymethyl)pyridin-3-yl, 6-isopropylpyridin-3-yl, 6-ethylpyridin-3-yl, 6-cyclopropyl-2-fluoropyridin-3-yl, 2-fluoropropan-2-yl)pyridin-3-yl, 6-cyclopropyl-4-fluoropyridine -3-yl, 2-cyclopropylpyrimidin-5-yl, 6-methyl-5-(trifluoromethyl)pyridin-2-yl, 5-isopropoxypyridin-2-yl, 3,5-dimethylpyridin-2-yl, 5,6-dimethylpyridin-2-yl, 5-methoxy-6-methylpyridin-2-yl, 6-(methoxymethyl)-5-methylpyridin-2-yl, 5-cyclopropyl-3-methylpyridin-2-yl, 5-cyclopropyl-6-methylpyridin-2-yl, 5-methoxypyridin-2-yl, 5 -Methoxy-3-methylpyridin-2-yl, 1-(5-(methoxymethyl)pyridin-2-yl, 5-cyclopropyl-6-fluoropyridin-2-yl, 5-cyclopropyl-4-fluoropyridin-2-yl, ((4,4-difluoropiperidin-1-yl)methyl)pyridin-2-yl, 4-(oxetan-3-ylmethyl)phenyl, 6-aminopyridin-3-yl, 4-((4-methoxypiperidin-1-yl)methyl)phenyl, 4-(cyanomethyl)-phenyl, 4-cyano-phenyl , 4-((1,1-dioxidothiomorpholino)methyl)phenyl, 4-(methylcarbamoyl)phenyl, (4-methoxypiperidine-1-carbonyl)phenyl, 4-((3-methoxypropyl)(methyl)carbamoyl)phenyl, 4-((methylsulfonyl)methyl)phenyl, 6-(1,1-difluoroethyl)pyridin-3-yl, 5-cyclopropoxypyridin-2-yl, 4-(3-methoxypyrrolidine-1-carbonyl)phenyl, or 4-(methoxymethyl)phenyl.

[0045] In some embodiments, monocyclic 5- to 9-membered heterocyclyl is 4-(3-methoxyazetidine-1-carbonyl)phenyl, 4-(N,N-dimethylcarbamoyl)phenyl, 4-(N,N-dimethylcarbamoyl)-2-fluoro-phenyl, 4-((1,1-dioxidothiomorpholino)methyl)-3,5-difluorophenyl, 2,4-dimethylphenyl, 4-ethylphenyl, 3-methyl-4-(trifluoromethyl)phenyl, 4-methoxy-3-methylphenyl, 4-(1,1-difluoroethyl)phenyl, 4-(1,1-difluoroethyl)phenyl, 4-(2-methoxyethoxy)phenyl, 2-fluoro-4-methoxyphenyl, 2-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl, 4-methoxy-2-methylphenyl, 4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl, 4-((oxetan-3-yl)oxy)methyl)phenyl, 4- ... 4-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl, 4-((2-methoxyethoxy)methyl)phenyl, 4-(difluoromethoxy)phenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 2-fluoro-4-(oxetan-3-yloxy)phenyl, 4-((3-methyloxetan-3-yl)oxy)phenyl, 4-((dimethylamino)methyl)-3,5-difluorophenyl, 4-(pyrrolidin-1-ylmethyl)phenyl, 4-((3,3-difluoroazetidin-1-yl)methyl)phenyl, 4-((dimethylamino)methyl)phenyl, 4-((methylamino)methyl)phenyl, 1-methyl-1H-1,2,3-triazol-4-yl)phenyl, 4-isopropylphenyl, 4-cyclopropoxyphenyl, 4-isopropoxyphenyl, 4-methoxyphenyl, 4,5-dimethylthiazol-2-yl, 6-cyclopropoxypyridin-3-yl, 6-cyclopropylpyridin-3-yl, 6-cyclopropyl-5-fluoropyridin-3-yl, 6-methoxypyridin-3-yl), 6-(methoxymethyl)pyridin-3-yl, 6-isopropylpyridin-3-yl, 6-ethylpyridin-3-yl, 6-cyclopropyl-2-fluoropyridin-3-yl, 2-fluoropropan-2-yl)pyridin-3-yl, 6-cyclopropyl-4-fluoropyridin-3-yl, 2-cyclopropylpyrimidin-5-yl, 6-methyl-5-(trifluoromethyl)pyridin-2- yl, 5-isopropoxypyridin-2-yl, 3,5-dimethylpyridin-2-yl, 5,6-dimethylpyridin-2-yl, 5-methoxy-6-methylpyridin-2-yl, 6-(methoxymethyl)-5-methylpyridin-2-yl, 5-cyclopropyl-3-methylpyridin-2-yl, 5-cyclopropyl-6-methylpyridin-2-yl, 5-methoxypyridin-2-yl, 5-methoxy-3-methylpyridin-2-yl, 1-(5-(methoxymethyl)pyridin-2-yl, 5-cyclopropyl-6-fluoropyridin-2-yl, or 5-cyclopropyl-4-fluoropyridin-2-yl.

[0046] In some embodiments, Cy 1 teeth [ka] and wherein ring A and ring B are each independently a fused aryl, a fused 5- to 6-membered heteroaryl, or a fused 5- to 6-membered heterocyclyl; Each of p and q is independently 0, 1, 2, or 3, provided that the sum of p and q is 3 or less.

[0047] In some embodiments, ring A is a fused 6-membered heterocyclyl, a fused 6-membered aryl, or a fused 6-membered cycloalkyl, preferably pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or phenyl, more preferably pyridinyl, pyrimidinyl, or pyridazinyl.

[0048] In some embodiments, Ring B is a fused 5-membered heterocyclyl or a fused 5-membered heteroaryl, preferably imidazole, thiazolyl, [1,2,4]triazolyl, tetrahydroimidazolyl, thiazolyl, pyrazolyl, thiazolyl, thienyl, oxazolyl, thiadiazolyl, thienyl, 1,2-dihydrothiazolyl, oxadiazolyl, [1,2,3]triazolyl, dioxolyl, or furanyl, more preferably thiazolyl, pyrazolyl, thiophenyl, or imidazole.

[0049] In some embodiments, [ka] teeth, [ka] is.

[0050] In some embodiments, [ka] teeth, [ka] is.

[0051] In some embodiments, the bicyclic 7-10 membered heteroaryl is selected from the group consisting of 6,7-dihydro-5H-cyclopenta[b]pyridine, 6,7-dihydro-5H-cyclopenta[c]pyridine, 2,3-dihydro-1H-indene, 2,3-dihydrobenzofuran, benzo[d][1,3]dioxole, 2,3-dihydrobenzo[b][1,4]dioxine, 4,5,6,7-tetrahydrobenzo[d]thiazole, 4,5,6,7-tetrahydrobenzo[d]isothiazole, quinoxaline, benzo[d]oxazole, benzo[d]thiazole, thiazolo[5,4-b]pyridine, thiazolo[4,5-b]pyridine, benzo[b]thiophene, benzofuran, benzo[c][1,2,5]thiadiazole, 1H-imidazo[4,5-b]pyridine, [1, 2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,5-a]pyridine, benzo[c]isothiazole, thiazolo[4,5-c]pyridine, thiazolo[4,5-b]pyridine, thieno[2,3-b]pyridine, imidazo[1,2-b]pyridazine, pyrazolo[1 ,5-a]pyrimidine, thieno[3,2-b]pyridine, pyrazolo[1,5-a]pyridine, [1,2,4]triazolo[4,3-a]pyridine, phthalazine, isoquinoline, 2,3-dihydrofuro[2,3-c]pyridine, or 2,3-dihydrofuro[2,3-b]pyridine, each of which is unsubstituted or substituted by one, two, or three R3a.In some embodiments, the bicyclic 7-10 membered heteroaryl is selected from the group consisting of 6,7-dihydro-5H-cyclopenta[b]pyridine, 6,7-dihydro-5H-cyclopenta[c]pyridine, 2,3-dihydro-1H-indene, 2,3-dihydrobenzofuran, benzo[d][1,3]dioxole, 2,3-dihydrobenzo[b][1,4]dioxine, 4,5,6,7-tetrahydrobenzo[d]thiazole, 4,5,6,7-tetrahydrobenzo[d]isothiazole, quinoxaline, benzo[d]oxazole, benzo[d]thiazole, thiazolo[5,4-b]pyridine, thiazolo[4 ,5-b]pyridine, benzo[b]thiophene, benzofuran, benzo[c][1,2,5]thiadiazole, 1H-imidazo[4,5-b]pyridine, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,5-a]pyridine, benzo[c]isothiazole, thiazolo[4,5-c]pyridine, thiazolo[4,5-b]pyridine, or thieno[2,3-b]pyridine, each of which is unsubstituted or substituted by one, two, or three R.

[0052] In some embodiments, the bicyclic 7-10 membered heteroaryl is selected from the group consisting of 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, 6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl, 6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl, 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, benzo[d][1,3]dioxol-5-yl, 2,3-dihydrobenzofuran-6-yl, benzo[d][1,3]dioxol-5-yl, benzo[d][1,3]dioxol-5-yl, benzo[d]pyridin-2-yl, benzo[d]pyridin-2-yl, 6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl, 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, benzo[d][1,3]dioxol-5-yl, benzo[d]pyridin-2-yl, benzo[d]pyridin-2-yl, benzo[d]pyridin-3 ... benzo[b][1,4]dioxin-6-yl, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl, 4,5,6,7-tetrahydrobenzo[d]isothiazol-3-yl, quinolin-2-yl, quinolin-6-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, thiazolo[5,4-b]pyridin-5-yl, thiazolo[5,4-b]pyridin-6-yl, thiazolo[4,5-b]pyridin-5-yl, thiazolo[ 4,5-b]pyridin-6-yl, benzo[b]thiophen-6-yl, benzofuran-6-yl, benzo[c][1,2,5]thiadiazol-5-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, pyrazolo[1,5-a]pyridin,5-yl, pyrazolo[1,5-a]pyridin-6-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1 ,2-a]pyridin-6-yl, pyrazolo[1,5-a]pyridin-5-yl, pyrazolo[1,5-a]pyridin-6-yl, imidazo[1,5-a]pyridin-5-yl, imidazo[1,5-a]pyridin-6-yl, benzo[c]isothiazol-5-yl, benzo[c]isothiazol-6-yl, thiazolo[4,5-c]pyridin-5-yl, thiazolo[4,5-c]pyridin-6-yl, thiazolo[4,5-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-6-yl, thieno[2,3-b]pyridin-6-yl, thieno[2,3-b]pyridin-5-yl, 4-fluoro-2-methylbenzo[d]thiazol-5-yl, 2-(methoxymethyl)thiazolo[5,4-b]pyridin-5-yl, 2-(difluoromethyl)thieno[2,3-b]pyridin-6-yl, 2-(methoxymethyl)benzo[d]thiazol-6-yl, 2-cyclopropoxythiazolo[5,4-b]pyridin-5-yl, 2-(2-fluoroethoxy)thiazolo[5,4-b]pyridin-5-yl, 2-(difluoromethyl)thieno[2,3-b]pyridin-6-yl, 2-methylimidazo[1, 2-b]pyridazin-6-yl, 3-methylpyrazolo[1,5-a]pyrimidin-5-yl, 2-methylpyrazolo[1,5-a]pyrimidin-5-yl, 2-ethylimidazo[1,2-b]pyridazin-6-yl, pyrazolo[1,5-a]pyrimidin-5-yl, 2-methylthieno[3,2-b]pyridin-5-yl, 2,3-dimethylpyrazolo[1,5-a]pyrimidin-5-yl, 2-fluoropyrazolo[1,5-a]pyrimidin-5-yl, pyrazolo[1,5-a]pyridin-5-yl, 3-fluoro-2-methylpyrazolo[1,5-a]pyridin-6-yl pyrimidin-5-yl, 3-fluoropyrazolo[1,5-a]pyrimidin-5-yl, 2-methylpyrazolo[1,5-a]pyridin-5-yl, pyrazolo[1,5-a]pyrimidin-5-yl, 3-fluoropyrazolo[1,5-a]pyridin-5-yl, 3-chloroimidazo[1,2-b]pyridazin-6-yl, 3-fluoroimidazo[1,2-b]pyridazin-6-yl, 3-fluoro-2-methylpyrazolo[1,5-a]pyridin-5-yl, 2-chloropyrazolo[1,5-a]pyrimidin-5-yl, 2-chloro-3-fluoropyrazolo[ 1,5-a]pyrimidin-5-yl, 7-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, imidazo[1,2-b]pyridazin-2-yl, thiazolo[5,4-b]pyridin-2-yl, [1,2,4]triazolo[4,3-a]pyridin-7-yl, phthalazin-6-yl, phthalazin-5-yl, 1-methylisoquinolin-6-yl, 2,3-dihydrofuro[2,3-c]pyridin-5-yl, 2,2-difluorobenzo[d][1,3]dioxol-5-yl, 2,3-dihydrofuro[2,3-b]pyridin-6-yl, 4-((3-methoxypyrrolidin-1-yl)methyl)phenyl, 3-methylpyrazolo[1,5-a]pyridin-6-yl, or quinoxalin-2-yl, each of which is unsubstituted or contains one, two, or three R, 3aIn some embodiments, the bicyclic 7-10 membered heteroaryl is substituted with 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, 6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl, 6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl, 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, benzo[d][1,3]dioxol-5-yl, 2,3-dihydro- benzo[b][1,4]dioxin-6-yl, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl, 4,5,6,7-tetrahydrobenzo[d]isothiazol-3-yl, quinolin-2-yl, quinolin-6-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, thiazolo[5,4-b]pyridin-5-yl, thiazolo[5,4-b]pyridin-6-yl, thiazolo[4,5-b]pyridin-5-yl, thiazolo[4, 5-b]pyridin-6-yl, benzo[b]thiophen-6-yl, benzofuran-6-yl, benzo[c][1,2,5]thiadiazol-5-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, pyrazolo[1,5-a]pyridin,5-yl, pyrazolo[1,5-a]pyridin-6-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1,2- a]pyridin-6-yl, pyrazolo[1,5-a]pyridin-5-yl, pyrazolo[1,5-a]pyridin-6-yl, imidazo[1,5-a]pyridin-5-yl, imidazo[1,5-a]pyridin-6-yl, benzo[c]isothiazol-5-yl, benzo[c]isothiazol-6-yl, thiazolo[4,5-c]pyridin-5-yl, thiazolo[4,5-c]pyridin-6-yl, thiazolo[4,5-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-6-yl, thieno[2,3-b]pyridin-6-yl, or thieno[2,3-b]pyridin-5-yl, each of which is unsubstituted or contains one, two, or three R, 3a is replaced by .

[0053] In some embodiments, the bicyclic 7-10 membered heteroaryl is thiazolo[5,4-b]pyridin-5-yl, thieno[2,3-b]pyridin-6-yl, pyrazolo[1,5-a]pyrimidin-5-yl, pyrazolo[1,5-a]pyridin-5-yl, or imidazo[1,2-b]pyridazin-6-yl.

[0054] In some embodiments, Cy1 is 4-(3-methoxyazetidine-1-carbonyl)phenyl, N,N-dimethylbenzamido-4-yl, 2,6-difluoro-N,N-dimethylbenzamido-4-yl, 2-fluoro-N,N-dimethylbenzamido-4-yl, 4-((1,1-dioxidethiomorpholino)methyl)-2,6-difluorophenyl, 2,4-dimethylphenyl, 4-ethylphenyl, 3-methyl-4-(trifluoromethyl)phenyl. nyl, 4-(1,1-difluoroethyl)phenyl, 4-(2-methoxyethoxy)phenyl, 2-fluoro-4-methoxyphenyl, 2-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl, 4-methoxy-2-methylphenyl, 4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl, 4-((oxetan-3-yloxy)methyl)phenyl, 4-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl phenyl, 4-((2-methoxyethoxy)methyl)phenyl, 4-(difluoromethoxy)phenyl, 3-fluoro-4-methoxyphenyl, 3-methyl-4-(oxetan-3-yloxy)phenyl, 2-fluoro-4-(oxetan-3-yloxy)phenyl, 3-fluoro-4-(oxetan-3-yloxy)phenyl, 4-((3-methyloxetan-3-yl)oxy)phenyl, 4-((dimethylamino)methyl)-3,5-difluorophenyl, 4-(pyrrolidin-1-ylmethyl)phenyl, 4-((3,3-difluoroazetidin-1-yl)methyl)phenyl, 4-((dimethylamino)methyl)phenyl, 4-((methylamino)methyl)phenyl, 4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl, 4-isopropylphenyl, 4-cyclopropoxyphenyl, 4-isopropoxyphenyl, 4-methoxyphenyl, 4,5-dimethylthiazol-2-yl, 4,5,6,7-Tetrahydrobenzo[d]thiazol-2-yl, 6-cyclopropoxypyridin-3-yl, 6-cyclopropylpyridin-3-yl, 6-cyclopropyl-5-fluoropyridin-3-yl, 6-methoxypyridin-3-yl, 6-(methoxymethyl)pyridin-3-yl, 6-isopropylpyridin-3-yl, 6-ethylpyridin-3-yl, 6-cyclopropyl-2-fluoropyridin-3-yl, 6-(2-fluoropropan-2-yl)pyridin-3-yl, 6-cyclopropyl-4-fluoropyridin-3-yl, 2-cyclopropyl Pyrimidin-5-yl, 6-methyl-5-(trifluoromethyl)pyridin-2-yl, 5-isopropoxypyridin-2-yl, 5-cyclopropylpyridin-2-yl, 3,5-dimethylpyridin-2-yl, 5,6-dimethylpyridin-2-yl, 5-methoxy-6-methylpyridin-2-yl, 6-(methoxymethyl)-5-methylpyridin-2-yl, 5-cyclopropyl-3-methylpyridin-2-yl, 5-cyclopropyl-6-methylpyridin-2-yl, 5-methoxypyridin-2-yl, 5-methoxy-3-methylpyridin-2 -yl, 1-(5-(methoxymethyl)pyridin-2-yl, 5-cyclopropyl-6-fluoropyridin-2-yl, 5-cyclopropyl-4-fluoropyridin-2-yl, 2,3-dihydro-1H-inden-5-yl, 1,1-dimethyl-2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-5-yl, benzo[d][1,3]dioxol-5-yl, 4-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 6,7 -dihydro-5H-cyclopenta[b]pyridin-2-yl, 2,3-dihydrofuro[3,2-b]pyridin-5-yl, 2,3-dihydrofuro[2,3-b]pyridin-5-yl, [1,3]dioxolo[4,5-b]pyridin-5-yl, 3-fluoropyrazolo[1,5-a]pyridin-6-yl, pyrazolo[1,5-a]pyridin-6-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 3-methylimidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-7-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,5-a]pyridin-6-yl, benzo[d]oxazol-6-yl, 7-fluoro-2-methylbenzo[d]oxazol-6-yl, 4-acetamido-2-fluoro-3-hydroxyphenyl, benzo[c]isothiazol-5-yl, benzo[b]thiophen-6-yl, benzo[d]thiazol-6-yl, 2-methylbenzo[d]thiazol-6-yl, 2-ethylbenzo[d]thiazol-6-yl, thiazolo[5,4-b]pyridin-5 -yl, thiazolo[4,5-b]pyridin-6-yl, 4-fluorobenzo[d]thiazol-6-yl, 7-fluorobenzo[d]thiazol-6-yl, 5-fluorobenzo[d]thiazol-6-yl, 7-fluoro-2-methylbenzo[d]thiazol-6-yl, benzo[d]oxazol-5-yl, benzo[c][1,2,5]thiadiazol-5-yl, benzo[d]thiazol-5-yl, 2-methylbenzo[d]thiazol-5-yl, 2-ethylbenzo[d]thiazol-5-yl, 4-fluorobenzo[d]thiazol- 5-yl, 3-methylquinoxalin-2-yl, 5-fluoro-2-methylbenzo[d]thiazol-6-yl, 2-methylthiazolo[5,4-b]pyridin-5-yl, 2-(difluoromethyl)thieno[2,3-b]pyridin-6-yl, thieno[2,3-b]pyridin-6-yl, 2-methylthieno[2,3-b]pyridin-6-yl, 2-fluorothieno[2,3-b]pyridin-6-yl, 6-(1,1-difluoroethyl)pyridin-3-yl, 4-trifluoromethyl-phenyl, 3-methylquinoxalin-6-yl, 3-(methyl -d3) quinoxalin-6-yl, 4-fluoro-2-methylbenzo[d]thiazol-5-yl, 2-(methoxymethyl)thiazolo[5,4-b]pyridin-5-yl, 2-(difluoromethyl)thieno[2,3-b]pyridin-6-yl, 2-(methoxymethyl)benzo[d]thiazol-6-yl, 2-cyclopropoxythiazolo[5,4-b]pyridin-5-yl, 2-(2-fluoroethoxy)thiazolo[5,4-b]pyridin-5-yl, 2-(difluoromethyl)thieno[2,3-b]pyridin-6-yl, 2-methylimidazo[1,2-b]pyridazin-6-yl, 3-methylpyrazolo[1,5-a]pyrimidin-5-yl, 2-methylpyrazolo[1,5-a]pyrimidin-5-yl, 2-ethylimidazo[1,2-b]pyridazin-6-yl, pyrazolo[1,5-a]pyrimidin-5-yl, 2-methylthieno[3,2-b]pyridin-5-yl, 2,3-dimethylpyrazolo[1,5-a]pyrimidin-5-yl, 2-fluoropyrazolo[1,5-a]pyrimidin-5-yl, pyrazolo [1,5-a]pyridin-5-yl, 3-fluoro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl, 3-fluoropyrazolo[1,5-a]pyrimidin-5-yl, 2-methylpyrazolo[1,5-a]pyridin-5-yl, pyrazolo[1,5-a]pyrimidin-5-yl, 3-fluoropyrazolo[1,5-a]pyridin-5-yl, 3-chloroimidazo[1,2-b]pyridazin-6-yl, 3-fluoroimidazo[1,2-b]pyridazin-6-yl yl, 3-fluoro-2-methylpyrazolo[1,5-a]pyridin-5-yl, 2-chloropyrazolo[1,5-a]pyrimidin-5-yl, 2-chloro-3-fluoropyrazolo[1,5-a]pyrimidin-5-yl, 7-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, imidazo[1,2-b]pyridazin-2-yl, thiazolo[5,4-b]pyridin-2-yl, [1,2,4]triazolo[4,3-a] Pyridin-7-yl, phthalazin-6-yl, phthalazin-5-yl, 1-methylisoquinolin-6-yl, 2,3-dihydrofuro[2,3-c]pyridin-5-yl, 2,2-difluorobenzo[d][1,3]dioxol-5-yl, 2,3-dihydrofuro[2,3-b]pyridin-6-yl, 4-((3-methoxypyrrolidin-1-yl)methyl)phenyl, 3-methylpyrazolo[1,5-a]pyridin-6-yl, quinoxalin-2-yl.

[0055] In some embodiments, Cy1 is 4-(3-methoxyazetidine-1-carbonyl)phenyl, N,N-dimethylbenzamido-4-yl, 2,6-difluoro-N,N-dimethylbenzamido-4-yl, 2-fluoro-N,N-dimethylbenzamido-4-yl, 4-((1,1-dioxidethiomorpholino)methyl)-2,6-difluorophenyl, 2,4-dimethylphenyl, 4-ethylphenyl, 3-methyl-4-(trifluoromethyl)phenyl. nyl, 4-(1,1-difluoroethyl)phenyl, 4-(2-methoxyethoxy)phenyl, 2-fluoro-4-methoxyphenyl, 2-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl, 4-methoxy-2-methylphenyl, 4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl, 4-((oxetan-3-yloxy)methyl)phenyl, 4-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl phenyl, 4-((2-methoxyethoxy)methyl)phenyl, 4-(difluoromethoxy)phenyl, 3-fluoro-4-methoxyphenyl, 3-methyl-4-(oxetan-3-yloxy)phenyl, 2-fluoro-4-(oxetan-3-yloxy)phenyl, 3-fluoro-4-(oxetan-3-yloxy)phenyl, 4-((3-methyloxetan-3-yl)oxy)phenyl, 4-((dimethylamino)methyl)-3,5-difluorophenyl, 4-(pyrrolidin-1-ylmethyl)phenyl, 4-((3,3-difluoroazetidin-1-yl)methyl)phenyl, 4-((dimethylamino)methyl)phenyl, 4-((methylamino)methyl)phenyl, 4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl, 4-isopropylphenyl, 4-cyclopropoxyphenyl, 4-isopropoxyphenyl, 4-methoxyphenyl, 4,5-dimethylthiazol-2-yl, 4,5,6,7-Tetrahydrobenzo[d]thiazol-2-yl, 6-cyclopropoxypyridin-3-yl, 6-cyclopropylpyridin-3-yl, 6-cyclopropyl-5-fluoropyridin-3-yl, 6-methoxypyridin-3-yl, 6-(methoxymethyl)pyridin-3-yl, 6-isopropylpyridin-3-yl, 6-ethylpyridin-3-yl, 6-cyclopropyl-2-fluoropyridin-3-yl, 6-(2-fluoropropan-2-yl)pyridin-3-yl, 6-cyclopropyl-4-fluoropyridin-3-yl, 2-cyclopropyl Pyrimidin-5-yl, 6-methyl-5-(trifluoromethyl)pyridin-2-yl, 5-isopropoxypyridin-2-yl, 5-cyclopropylpyridin-2-yl, 3,5-dimethylpyridin-2-yl, 5,6-dimethylpyridin-2-yl, 5-methoxy-6-methylpyridin-2-yl, 6-(methoxymethyl)-5-methylpyridin-2-yl, 5-cyclopropyl-3-methylpyridin-2-yl, 5-cyclopropyl-6-methylpyridin-2-yl, 5-methoxypyridin-2-yl, 5-methoxy-3-methylpyridin-2 -yl, 1-(5-(methoxymethyl)pyridin-2-yl, 5-cyclopropyl-6-fluoropyridin-2-yl, 5-cyclopropyl-4-fluoropyridin-2-yl, 2,3-dihydro-1H-inden-5-yl, 1,1-dimethyl-2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-5-yl, benzo[d][1,3]dioxol-5-yl, 4-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 6,7 -dihydro-5H-cyclopenta[b]pyridin-2-yl, 2,3-dihydrofuro[3,2-b]pyridin-5-yl, 2,3-dihydrofuro[2,3-b]pyridin-5-yl, [1,3]dioxolo[4,5-b]pyridin-5-yl, 3-fluoropyrazolo[1,5-a]pyridin-6-yl, pyrazolo[1,5-a]pyridin-6-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 3-methylimidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-7-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,5-a]pyridin-6-yl, benzo[d]oxazol-6-yl, 7-fluoro-2-methylbenzo[d]oxazol-6-yl, 4-acetamido-2-fluoro-3-hydroxyphenyl, benzo[c]isothiazol-5-yl, benzo[b]thiophen-6-yl, benzo[d]thiazol-6-yl, 2-methylbenzo[d]thiazol-6-yl, 2-ethylbenzo[d]thiazol-6-yl, thiazolo[5,4-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-6-yl, 4-fluorobenzo[d]thiazol-6-yl, 7-fluorobenzo[d]thiazol-6-yl, 5-fluorobenzo[d]thiazol-6-yl, 7-fluoro-2-methylbenzo[d]thiazol- 6-yl, benzo[d]oxazol-5-yl, benzo[c][1,2,5]thiadiazol-5-yl, benzo[d]thiazol-5-yl, 2-methylbenzo[d]thiazol-5-yl, 2-ethylbenzo[d]thiazol-5-yl, 4-fluorobenzo[d]thiazol-5-yl, 3-methylquinoxalin-2-yl, 5-fluoro-2-methylbenzo[d]thiazol-6-yl, 2-methylbenzo[d]thiazol-5-yl Thiazolo[5,4-b]pyridin-5-yl, thieno[2,3-b]pyridin-6-yl, 2-methylthieno[2,3-b]pyridin-6-yl, 2-fluorothieno[2,3-b]pyridin-6-yl, 6-(1,1-difluoroethyl)pyridin-3-yl, 4-trifluoromethyl-phenyl, 3-methylquinoxalin-6-yl, or 3-(methyl-d3)quinoxalin-6-yl.

[0056] In some embodiments, Cy1 is 2-methylthiazolo[5,4-b]pyridin-5-yl, 2-(difluoromethyl)thieno[2,3-b]pyridin-6-yl, 2-methylimidazo[1,2-b]pyridazin-6-yl, 2-methylpyrazolo[1,5-a]pyrimidin-5-yl, pyrazolo[1,5-a]pyridin-5-yl, 3-fluoro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl, 3-fluoropyrazolo[1,5-a]pyrimidin-5-yl, 3-fluoropyrazolo[1,5-a]pyridin-5-yl, 3-chloroimidazo[1,2-b]pyridazin-6-yl, or 3-fluoroimidazo[1,2-b]pyridazin-6-yl.

[0057] The disclosure herein provides a compound, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound is any one of the exemplified compounds.

[0058] The disclosure herein provides pharmaceutical compositions comprising one or more compounds herein, or stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.

[0059] Disclosed herein is a method of treating cancer, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound herein or a pharmaceutical composition herein. DETAILED DESCRIPTION OF THE INVENTION

[0060] definition The following terms have the meanings indicated throughout this specification.

[0061] As used in this specification, including the appended claims, singular words such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0062] The term "or" means, and is used interchangeably with, the term "and / or," unless context clearly dictates otherwise.

[0063] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched-chain saturated hydrocarbon groups derived from an alkane by removing one hydrogen atom from the same carbon atom, which contain 1 to 18 (e.g., 1 to 12, further 1 to 10, further 1 to 8, or 1 to 6, or 1 to 4) carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C 1-6 Examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups. Alkyl groups may optionally be deuterium-enriched (e.g., -CD3, -CD2CD3, etc.). The term "alkylene" refers to a hydrocarbon group selected from straight- and branched-chain saturated hydrocarbon groups derived from an alkane by removing two hydrogen atoms from the same carbon atom, containing 1 to 6 (e.g., 1 to 4, even 1 to 3 carbon atoms, even 1, 2, or 3) carbon atoms, including, but not limited to, methylene (-CH2-), ethylene (-CH2CH2-), 1-methylethylene (-CH(CH3)-), or trimethylene (-CH2CH2CH2-).

[0064] The term "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0065] The term "haloalkyl" refers to an alkyl group in which one or more hydrogens are replaced by one or more halogen atoms, such as fluoro, chloro, bromo, and iodo. Examples of haloalkyl include haloC 1-8 Alkyl, HaloC 1-6 Alkyl or haloC 1-4 Alkyl includes, but is not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, -CF3, and the like.

[0066] The terms "alkyloxy" or "alkoxy" refer to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Alkyloxy, e.g., C 1-6 Alkyloxy or C 1-4 Examples of alkyloxy include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0067] The term "amino" refers to -NH2.

[0068] The term "alkenyl," as used herein, refers to a hydrocarbon group selected from straight-chain and branched-chain hydrocarbon groups containing at least one C=C double bond and 2 to 18, such as 2 to 8, further such as 2 to 6, carbon atoms. Examples of alkenyl groups (e.g., C2-6 alkenyl) include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.

[0069] The term "alkynyl," as used herein, refers to a hydrocarbon group selected from straight-chain and branched-chain hydrocarbon groups containing at least one C≡C triple bond and 2 to 18, such as 2 to 8, further such as 2 to 6, carbon atoms. Examples of alkynyl groups (e.g., C2-6 alkynyl) include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0070] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyls.

[0071] 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. Further, for example, the cycloalkyl group can be selected from monocyclic groups containing 3 to 12, such as 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, saturated monocyclic cycloalkyl (e.g., C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, cycloalkyl is a monocyclic ring containing 3 to 6 carbon atoms (C), including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3-6(Abbreviated as cycloalkyl). Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.

[0072] The term "deuterated" is used herein to modify a chemical structure or organic group or radical in which one or more carbon-bonded hydrogen(s) are replaced with one or more deuterium(s), e.g., "deuterated alkyl," "deuterated cycloalkyl," "deuterated heterocycloalkyl," "deuterated aryl," "deuterated morpholinyl," etc. For example, the term "deuterated alkyl," as defined above, refers to an alkyl group, as defined herein, in which at least one carbon-bonded hydrogen atom has been replaced with deuterium. A deuterated alkyl group has at least one carbon atom bonded to deuterium, and a carbon atom can be bonded to two or more deuterium atoms, and it is also possible for two or more carbon atoms in an alkyl group to be bonded to deuterium.

[0073] The term "aryl" used alone or in combination with other terms,

[0074] 5- and 6-membered carbocyclic aromatic rings, for example, phenyl;

[0075] Bicyclic ring systems, for example, 7-12 membered bicyclic ring systems in which at least one ring is carbocyclic and aromatic, such as naphthyl and indanyl, and

[0076] It refers to a group selected from tricyclic ring systems, such as 10-15 membered tricyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example, fluorenyl.

[0077] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0078] As used herein, the term "heteroaryl" refers to

[0079] a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom, e.g., 1 to 4, or in some embodiments 1 to 3, and in some embodiments 1 to 2 heteroatoms, selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring atoms being carbon;

[0080] a 7-12 membered bicyclic ring containing as ring member(s) at least one heteroatom, e.g., 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, selected from nitrogen, oxygen, or optionally oxidized sulfur, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being in the aromatic ring; and

[0081] It refers to a group selected from 11-14 membered tricyclic rings containing as ring member(s) at least one heteroatom, e.g., 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, selected from nitrogen, oxygen, or optionally oxidized sulfur, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being in the aromatic ring.

[0082] When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is 1 or less. When a heteroaryl group contains two or more heteroatom ring members, the heteroatoms can be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group can be oxidized to form an N-oxide.

[0083] As used herein, the term "optionally oxidized sulfur" refers to -S-, SO, or SO2.

[0084] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 ring members, including 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring members being carbon. In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring containing 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a monocyclic, 5-6 membered heteroaryl ring having 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a bicyclic 8-10 membered heteroaryl ring having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0085] Examples of heteroaryl groups or monocyclic or bicyclic aromatic heterocycles include, but are not limited to, (numbering from the attachment position assigned priority 1) 1H-pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, or 1H-pyrazol-5-yl), pyridyl or pyridinyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, or 2,4-pyridyl), cinnolinyl, pyrazinyl, pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, or 2,4-pyridyl), 1H-pyrazolyl (e.g., 1H-pyrazolyl, 1H-pyrazolyl, or 1H-pyrazolyl ... imidazolyl (e.g., 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, or 2,4-imidazolyl), imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), tetrazolyl, thienyl (e.g., thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl, or furyl. Indolyl, benzofuryl, benzimidazolyl, indolyl (e.g., 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, or 1H-indol-7-yl), isoindolyl, indolinyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl (e.g., pyrazin-2-yl), pyridazinyl, pyrrolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl), quinolinyl (e.g., quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, or quinolin-7-yl), isoquinolinyl (e.g., isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, or isoquinolin-8-yl), pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl (e.g., furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophenyl, benzothiazolyl aryl, 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, quinoxalinyl (e.g., quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, or quinoxalin-8-yl), naphthyridinyl (e.g., 1,8-naphthyridin-2-yl, 1,8-naphthyridin-3-yl, or 1,8-naphthyridin-4-yl), 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl (e.g., 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl), furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-8-yl, azol-5-yl, benzo[d]thiazol-6-yl, or benzo[d]thiazol-7-yl), benzo[d]imidazolyl (e.g., 1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-4-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, or 1H-benzo[d]imidazol-7-yl), [1,2,4]triazolo[1,5-a]pyridinyl (e.g., [1,2,4]triazolo[1,5-a]pyridin-2-yl, [1,2,4]triazolo[1,[1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-7-yl, or [1,2,4]triazolo[1,5-a]pyridin-8-yl), 3H-imidazo[4,5-b]pyridinyl (e.g., 3H-imidazo[4,5-b]pyridin-2-yl, 3H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl, or 3H-imidazo[4,5-b]pyridin-7-yl), 1H-imidazo[4,5-b]pyridinyl (e.g., 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-b] pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-7-yl), [1,2,4]triazolo[1,5-a]pyridinyl (e.g., [1,2,4]triazolo[1,5-a]pyridin-2-yl, 1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-7-yl, or [1,2,4]triazolo[1,5-a]pyridin-8-yl), indazolyl (e.g., 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0086] Additionally, a "heteroaryl" fused with a "heterocyclyl" is defined as a "heteroaryl."

[0087] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to non-aromatic heterocyclyl groups containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spirocyclic groups, i.e., monocyclic, heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclic groups.

[0088] The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle may be saturated or partially saturated.

[0089] Exemplary monocyclic 4- to 9-membered heterocyclyl groups include, but are not limited to, (numbered from the bond position assigned priority 1) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, and morpholinyl. , morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridin-1-yl, aziridin-2-yl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxyl Thiazepanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1,4-oxathienyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl, and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathienyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothiepan ... nyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, or 1,1-dioxo-thiomorpholinyl.

[0090] The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl having rings connected through a common carbon atom (called a spiro atom), containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings in a spiroheterocyclyl group may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably, the spiroheterocyclyl has 6 to 14 members, more preferably 7 to 12 members. Depending on the number of common spiro atoms, spiroheterocyclyl is divided into monospiroheterocyclyl, dispiroheterocyclyl, or polyspiroheterocyclyl, preferably monospiroheterocyclyl or dispiroheterocyclyl, more preferably 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl.

[0091] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclyl group, in which each ring in the system shares an adjacent atom pair (carbon atom and carbon atom, or carbon atom and nitrogen atom) with another ring and contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings in the fused heterocyclic group may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably, the fused heterocyclyl has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of membered rings, the fused heterocyclyl is divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, and preferably refers to a bicyclic or tricyclic fused heterocyclyl, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl. Representative examples of fused heterocycles include, but are not limited to, octahydrocyclopenta[c]pyrrole (e.g., octahydrocyclopenta[c]pyrrol-2-yl), octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindolinyl (e.g., isoindolin-2-yl), and octahydro-benzo[b][1,4]dioxine groups.

[0092] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic alkyl group, which shares two disconnected atoms between each of the two rings in the system and contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings in the bridged heterocyclyl group may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably, the bridged heterocyclyl has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of ring members, the bridged heterocyclyl is divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, and preferably refers to a bicyclic, tricyclic, or tetracyclic bridged heterocyclyl, more preferably a bicyclic or tricyclic bridged heterocyclyl. Representative examples of bridged heterocyclyls include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl groups.

[0093] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. When the compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All possible stereoisomers are intended to be included, including substantially purely resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts are intended to be included. Unless otherwise specified, a reference to one isomer applies to any possible isomer. Whenever the isomeric composition is not specified, all possible isomers are included.

[0094] As used herein, the phrase "substantially pure" means that the title stereoisomer contains 35% by weight or less, such as 30% by weight or less, further such as 25% by weight or less, further such as 20% by weight or less of any other stereoisomer(s). In some embodiments, the phrase "substantially pure" means that the title stereoisomer contains 10% by weight or less, such as 5% by weight or less, such as 1% by weight or less of any other stereoisomer(s).

[0095] When compounds disclosed herein contain olefinic double bonds, unless otherwise specified, it is intended that such double bond include both E and Z geometric isomers.

[0096] When the compounds disclosed herein contain a disubstituted cyclohexyl or disubstituted cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring may adopt cis and trans configurations, where cis configuration means that both substituents are found on the upper side of the arrangement of the two substituents on the carbon, while trans means that they are on opposite sides.

[0097] It may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps may be separated and / or purified to the desired degree of homogeneity (hereinafter, "separated") by techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or flash column chromatography. Flash column chromatography may involve any number of methods, including, for example, reverse-phase and normal-phase, size-exclusion, ion-exchange, high-, medium-, and low-pressure liquid flash column chromatography methods and apparatus, small-scale analytical, simulated moving bed ("SMB"), and preparative thin- or thick-layer flash column chromatography, and small-scale thin-layer and flash column techniques. Those skilled in the art will utilize the technique most likely to achieve the desired separation.

[0098] "Diastereomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as flash column chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereoisomers to the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by use of a chiral HPLC column.

[0099] Single stereoisomers, e.g., substantially pure enantiomers, can be obtained by resolution of racemic mixtures using methods such as the formation of diastereomers using optically active resolving agents [Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H., et al. "Flash column chromatographic resolution of enantiomers: Selective review," J. Chromatogr., 113(3)(1975): pp. 283-302]. Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of diastereomers, and conversion to pure stereoisomers, and (3) direct separation of substantially pure or enriched stereoisomers under chiral conditions. See Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993. The absolute configuration of a chiral center in a compound can be determined using methods known to those skilled in the art, such as single crystal X-ray crystallography or co-crystal formation of the compound of interest with a target protein, optionally in combination with spectroscopic techniques, such as NMR spectroscopy. In some embodiments, the absolute configuration of a chiral center in a compound can be elucidated from the X-ray single crystal structure of the compound. In some embodiments, the absolute configuration of a chiral center elucidated by the X-ray crystal structure of a compound can be used to infer the absolute configuration of a corresponding chiral center in another compound or intermediate obtained from the same or similar synthetic method.

[0100] "Pharmaceutically acceptable salt" refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that correspond to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base function with a suitable organic acid, or an acidic group with a suitable base.

[0101] "Selective inhibitory activity" or "selectivity" refers to the difference in the degree of inhibition against DGKα and DGKζ; the greater the degree of inhibition affected for a particular isoform compared to another isoform, the more selective the inhibitor is for that particular isoform. In some embodiments, a "compound that exhibits selective inhibitory activity of DGKα relative to DGKζ" refers to a compound having an IC50 for DGKα of about 2000 nM or less and a ratio of the IC50 for DGKζ to the IC50 for DGKα of about 20 or more; a "compound that exhibits selective inhibitory activity of DGKζ relative to DGKα" refers to a compound having an IC50 for DGKζ of about 2000 nM or less and a ratio of the IC50 for DGKα to the IC50 for DGKζ of about 20 or more; and a "compound that exhibits dual inhibitory activity" refers to a compound that exhibits inhibitory activity against both DGKα and DGKζ of about 500 nM or less and a ratio of the two IC50 values ​​of 20 or less.

[0102] In addition, when a compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0103] As defined herein, "pharmaceutically acceptable salts thereof" includes salts of at least one compound of formula (I), and salts of stereoisomers of compounds of formula (I), e.g., salts of enantiomers and / or diastereomers.

[0104] As used herein, the terms "administration," "administering," "treating," and "treatment," when used with respect to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to the contact of an exogenous pharmaceutical, therapeutic, diagnostic, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contacting a reagent with the cell as well as contacting a reagent with a fluid that contacts the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment, e.g., of a cell with a reagent, diagnostic, binding compound, or with another cell. As used herein, the term "subject" includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit), and most preferably a human.

[0105] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient, such as a compound, that, when administered to a subject to treat a disease or at least one clinical symptom of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or condition. A "therapeutically effective amount" can vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. The appropriate amount in any given case will be apparent to one of ordinary skill in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, that is effective in "treating" a disease or disorder in a subject, as defined above. In the case of a combination therapy, a "therapeutically effective amount" refers to the total amount of the combined components for effective treatment of a disease, disorder, or condition.

[0106] Pharmaceutical compositions comprising the compounds disclosed herein can be administered to subjects in need thereof via oral, inhalation, rectal, parenteral, or topical administration.For oral administration, pharmaceutical compositions can be conventional solid formulations such as tablets, powders, granules, capsules, etc., liquid formulations such as water or oil suspensions, or other liquid formulations such as syrups, solutions, suspensions, etc.For parenteral administration, pharmaceutical compositions can be solutions, aqueous solutions, oil suspension concentrates, freeze-dried powders, etc.Preferably, the formulation of pharmaceutical compositions is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably tablets or capsules.Pharmaceutical compositions can be administered in a single dose at a precise dosage.In addition, pharmaceutical compositions can further comprise additional active ingredients.

[0107] All formulations of the pharmaceutical compositions disclosed herein can be prepared by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients to prepare the desired formulation. "Pharmaceutically acceptable excipients" refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as diluents, vehicles such as water, various organic solvents, excipients such as starch, sucrose, binders such as cellulose derivatives, alginates, gelatin, polyvinylpyrrolidone (PVP), wetting agents such as glycerol, disintegrants such as agar, calcium carbonate, sodium bicarbonate, absorption enhancers such as quaternary ammonium compounds, surfactants such as hexadecanol, absorption carriers such as kaolin and soap clay, lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition may further comprise other pharmaceutically acceptable excipients, such as dispersing agents, stabilizers, thickening agents, complexing agents, buffers, penetration enhancers, polymers, flavoring agents, sweetening agents, and dyes.

[0108] The term "disease" refers to any disease, ailment, illness, symptom or indication, and may be used interchangeably with the terms "disorder" or "condition."

[0109] Throughout this specification and the claims that follow, unless the context otherwise requires, the word "comprise," as well as variations such as "comprises" and "comprising," are intended to specify the presence of the subsequent feature but do not exclude the presence or addition of one or more other features. As used herein, the word "comprising" can be replaced with the words "containing," "including," or, in some cases, "having."

[0110] Throughout this specification and the claims that follow, the term "Cn-m" denotes a range inclusive of the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 , C 1-6 Examples include:

[0111] Unless otherwise defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0112] [Table 2-1] [Table 2-2] [Table 2-3]

[0113] General synthetic scheme The compounds disclosed herein (including salts thereof) can be prepared using known organic synthesis techniques, or can be synthesized according to any of a number of possible synthetic routes.

[0114] The reaction for preparing the compounds disclosed herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.Suitable solvents can be substantially non-reactive with starting materials, intermediates, or products at the temperature at which the reaction is carried out, for example, at temperatures that can vary from room temperature to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of solvents.

[0115] The selection of an appropriate protecting group can be readily determined by one of ordinary skill in the art.

[0116] Reactions can be monitored according to any suitable method known in the art, such as NMR, UV, HPLC, LC-MS, and TLC. Compounds can be purified by a variety of methods, including HPLC and normal phase silica flash column chromatography.

[0117] Chiral analytical HPLC was used for retention time analysis of various chiral examples, and the conditions were divided into the following methods according to the column, mobile phase, and solvent ratio used. Preparation of homochiral examples can be carried out by techniques known to those skilled in the art. Absolute stereochemistry was not assigned at the newly formed carbon-nitrogen bond.

[0118] The compounds disclosed herein can be prepared by following Schemes I-III.

[0119] [ka]

[0120] where R 1 From R 9 and R 8L Substitution to (L 1 -Cy 1 (corresponding to) is as defined above in formula (I).

[0121] In Scheme I, commercially available compound 1 is protected with THP or SEM to give compound 2. Compound 2 is reduced under reducing conditions (e.g., Pd—C / H or Fe powder / NH Cl) to form compound 3 as an amine. Compound 3 is acetylated with acetyl chloride or acetic anhydride to give compound 4, which is then converted to the appropriate R-substitution group under basic conditions (e.g., CsCO, NaH, or t-BuOK). 1 -X / R 1 -OTf 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 trifluoromethosulfonate reagent (e.g., TfO or PhNTf) or phosphoryl chloride to give compound 7. Compound 7 is reacted with an appropriate chiral secondary amine via a nucleophilic aromatic substitution reaction to give compound 8. The protecting group on the amine of compound 8 is removed under acid conditions (e.g., a 4 M solution of TFA or HCl in 1,4-dioxane) to give compound 9. The most frequently used procedure is via phosphonium salt-mediated alkylation of the amine with the corresponding alcohol, followed by N-alkylation of the secondary amine compound 9 by treatment with an alkylating agent (e.g., alkyl halide or alkyl sulfonate) or reductive alkylation with an aldehyde or ketone to prepare the tertiary amine compound 10 (Florencio Zaragoza and Henrik Stephensen, J. Org. Chem. 2001, 66, 2518-2521). Compound 10 is deprotected using acid conditions (e.g., a 4 M solution of TFA or HCl in 1,4-dioxane) to give compound 11. Compound 11 can be alkylated, alkenylated, acylated, or sulfonylated by conventional methods, such as with the corresponding alkenyl borate using a copper-catalyzed Chan-Lam reaction, or the corresponding alkyl halide under basic conditions (e.g., CsCO, NaH, or t-BuOK), or the corresponding alkylsulfonyl chloride / aliphatic acyl chloride using condensation conditions (e.g., EtN / HATU) to give compound 12 (R 2 is H), and Equation 12 (R2 is H) with an electrophilic halogenating reagent (e.g., NBS, NCS, or selectfluor) to give a compound of formula 12 (R 2 is F, Cl, or Br), and then compound of formula I (R 2 is Br) with Zn(CN) and 2,4,6-trimethylboroxine to give compounds of formula 12 (where R 2 is CN or Me).

[0122] Compound 10d disclosed herein can also be prepared according to Scheme II below.

[0123] [ka]

[0124] In Scheme II, PG 2 The introduction of compound 4 into the appropriate R 1 The alkylation reaction proceeds with X (e.g., PMB-Cl or DMB-Cl) under basic conditions (e.g., CsCO or NaH) to give compound 5d, which is cyclized under basic conditions (e.g., lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide) to give compound 6d, which is subsequently reacted with a trifluoromethosulfonate reagent (e.g., trifluoromethanesulfonic anhydride, N-phenylbis(trifluoromethanesulfonimide) or phosphoryl chloride to give compound 7d, which is reacted with the corresponding secondary amine 3b via a nucleophilic aromatic substitution reaction to give compound 8d. The protecting group of compound 8d is removed under strong acid conditions (e.g., TfOH or TFA) to give compound 9d, which undergoes selective N-alkylation on the pyrazole of compound 9d by treatment with the corresponding alkyl halide to give compound 10d.

[0125] Compounds of formula 10A disclosed herein can also be prepared by following Scheme III.

[0126] [ka]

[0127] In Scheme III, commercially available compound 1A is obtained via aminolysis to give compound 2A, which is then reduced under suitable reducing conditions (e.g., Pd—C / H or Fe powder / NH4Cl) to give compound 3A. Compound 3A is then reacted with the corresponding sulfonyl chloride under basic conditions (e.g., Et3N or pyridine) to give compound 4A, which can be converted to the appropriate R 1 X / R 1 Reaction with OTf affords compound 5A. The protecting group on the amine of compound 5A is removed with 2-mercaptoacetic acid to afford compound 6A. Treatment of compound 6A with 1,1'-carbonyldiimidazole under basic conditions (e.g., NaH) affords cyclized compound 7A. Introduction of the amine moiety 3b proceeds via chlorination with phosphoryl chloride to afford a chlorinated intermediate, which reacts with 3b to prevent hydrolysis and afford compound 8A. Deprotection of this intermediate using acidic conditions (e.g., TFA or HCl in 1,4-dioxane, 4 M solution) affords compound 9A. Alkylation of compound 9A with the corresponding alkyl halide under basic conditions (e.g., CsCO or NaH) affords compound 10A. [Example]

[0128] The following examples are intended to be merely illustrative and should not be construed as limiting in any way. Unless otherwise specified, the experimental methods in the examples described below are conventional. Unless otherwise specified, all reagents and materials are commercially available. All solvents and chemicals used are of analytical grade or chemical purity. All solvents are redistilled before use. All anhydrous solvents are prepared according to standard or reference methods. Silica gel (100-200 mesh) for flash column chromatography and silica gel (GF254) for thin-layer flash column chromatography (TLC) are commercially available from Tsingdao Haiyang Chemical Co., Ltd. or Yantai Chemical Co., Ltd., China. Unless otherwise specified, all are eluted with petroleum ether (60-90°C) / ethyl acetate (v / v) and visualized with an ethanolic solution of iodo- or molybdophosphoric acid. Unless otherwise specified, all extraction solvents are dried over anhydrous Na2SO4.

[0129] 1 H NMR spectra were recorded on a Bruck-400 nuclear magnetic resonance spectrometer using TMS (tetramethylsilane) as an internal standard. LC / MS data were recorded using an Agilent 1100 high-performance liquid flash column chromatography-ion trap mass spectrometer (LC-MSD trap) equipped with a diode array detector (DAD) and an ion trap (ESI source) detecting at 214 nm and 254 nm. All compound names, except for reagent names, were generated using ChemDraw®.

[0130] synthesis

[0131] [Table 3]

[0132] [Table 4]

[0133] Intermediate 1: 4-methyl-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate [ka]

[0134] Step A: Methyl 4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate [ka]

[0135] To a solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (85.5 g, 0.5 mol) and TsOH.HO (9.5 g, 0.05 mol) in THF (0.6 L) was added DHP (84 g, 1 mol) in several portions. 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 flash column chromatography to give the title compound (121 g, 94%). 1 H NMR (400 MHz, CDCl3): δ 8.38 (s, 1H), 5.43 (dd, J = 2.4, 8.8 Hz, 1H), 4.15 - 4.05 (m, 1H), 3.99 (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) + .

[0136] Step B: Methyl 4-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate [ka]

[0137] 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) was added (6 g). The mixture was stirred under an H atmosphere at room temperature, filtered, and washed with MeOH. The combined filtrate was concentrated to give the title compound (96 g, 90%). 1 H NMR (400 MHz, CDCl3): δ 7.21 (s, 1H), 5.33 (dd, J = 2.4, 9.6 Hz, 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) + .

[0138] Step C: Methyl 4-acetamido-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate [ka] 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) was added AcO (60 mL) dropwise to maintain the temperature below 20 °C. The resulting mixture was stirred at room temperature for 3 hours and concentrated to dryness. The resulting residue was recrystallized from PE / EA to give the title compound (84 g, 74%). 1 H NMR (400 MHz, CDCl3): δ 8.99 (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) + .

[0139] Step D: Methyl 4-(N-methylacetamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate [ka]

[0140] 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) was added CsCO (306 g, 943 mmol), followed by CHI (134 g, 943 mmol). The reaction was stirred at room temperature (RT) for 16 h. The reaction mixture was filtered through Celite and washed with DCM. The filtrate was concentrated, and the resulting residue was then diluted with water, extracted with DCM (400 mL x 2), washed with brine, dried over NaSO, filtered, and concentrated to give the title compound (92 g, crude). 1 H NMR (400 MHz, CDCl3): δ 7.67 (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) + .

[0141] Step E: 7-Hydroxy-4-methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one [ka]

[0142] 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) was added a solution of LiHMDS (approximately 500 mL, 1 mol / L, approximately 1.6 equiv.) dropwise at -70°C (a suspension formed). The reaction was stirred for 0.5 h, quenched with water, and allowed to warm slowly to room temperature. The resulting mixture was extracted with EA. The aqueous phase was collected, treated with citric acid to pH 3-4, and stirred at room temperature for 0.5 h to give a suspension. The suspension was filtered and dried to give the title compound (45.5 g). 1 H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.07 (s, 1H), 5.65 (s, 1H), 5.51 (dd, J = 2.4 Hz, 10.0 Hz, 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) + .

[0143] Step F: 4-methyl-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate (Intermediate 1) [ka]

[0144] To 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 added K2CO3 (55 g, 400 mmol), followed by 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (100 g, 943 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was filtered through Celite 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 flash column chromatography and further slurried with EA / PE to give the title compound (70 g, 90%). 1 H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 6.58 (s, 1H), 5.58 (dd, J = 2.8 Hz, 8.0 Hz, 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) + .

[0145] Intermediate 2: 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 [ka]

[0146] Step A: Methyl (R)-2-(benzylamino)butanoate [ka]

[0147] To a solution of methyl (R)-2-aminobutanoate (100.0 g, 0.85 mol) in CHCN (1000 mL) was added benzyl bromide (146.1 g, 0.85 mol) at 0° C. under a N atmosphere. The reaction was stirred at room temperature overnight and concentrated under reduced pressure. The resulting residue was dissolved in EA (1000 mL) and washed with water (1000 mL×3). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (PE:EA=10:1) to give the title compound (106 g, 60%). MS: M / e 208 (M+1) + .

[0148] Step B: Methyl (R)-2-((S)-N-benzyl-2-((tert-butoxycarbonyl)amino)butanamido)butanoate [ka]

[0149] To a solution of methyl (R)-2-(benzylamino)butanoate (117.0 g, 0.56 mol), (S)-2-((tert-butoxycarbonyl)amino)butanoic acid (170.5 g, 0.84 mmol), and 4-methylmorpholine (113.1 g, 1.12 mmol) in DCM (2000 mL) was added HATU (319.0 g, 0.84 mmol) at 0° C. The reaction was stirred overnight at room temperature, quenched with water, and washed with water (1500 mL × 2). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (PE:EA=10:1) to give the title compound product (178 g, 80%). MS: M / e 393 (M+1) + .

[0150] Step C: Methyl (R)-2-((S)-2-amino-N-benzylbutanamido)butanoate [ka]

[0151] To a solution of methyl (R)-2-((S)-N-benzyl-2-((tert-butoxycarbonyl)amino)butanamido)butanoate (178 g, 0.45 mol) in 1,4-dioxane (100 mL) was added HCl (400 mL, 4 M in 1,4-dioxane) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours and concentrated in vacuo to give the crude product (200 g, crude). MS: M / e 293 (M+1). + .

[0152] Step D: (3S,6R)-1-benzyl-3,6-diethylpiperazine-2,5-dione [ka]

[0153] To a solution of methyl (R)-2-((S)-2-amino-N-benzylbutanamido)butanoate (200 g, crude) in EA (1000 mL) was added aqueous NaHCO3 (300 mL) at room temperature. The reaction mixture was stirred at room temperature for an additional 2 h. The organic layer was concentrated under reduced pressure. The resulting residue was triturated with MTBE to give the title compound (61 g, 52% (2 steps), ee: 97%). MS: M / e 261 (M+1) +

[0154] Step E: (2R,5S)-1-benzyl-2,5-diethylpiperazine [ka]

[0155] To a solution of LiAlH4 (26.5 g, 0.69 mol) in THF (1000 mL) was slowly added (3S,6R)-1-benzyl-3,6-diethylpiperazine-2,5-dione (61.0 g, 0.23 mol) in THF (500 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours and then at 80°C overnight. The reaction was slowly quenched with water (27 mL) at 0°C. 1N aqueous NaOH solution (54 mL) and water (81 mL) were then added sequentially. The resulting mixture was stirred for 2 hours. The formed white precipitate 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 under vacuum and dried to give the title compound (51 g, 95%). MS: M / e 233 (M+1) + .

[0156] 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 [ka]

[0157] A mixture of 4-methyl-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate (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 CHCN (50 mL) was heated to 105 °C overnight under a N atmosphere. The solvent was removed under vacuum. The crude product was purified by flash column chromatography (DCM:MeOH = 15:1) to give the title compound (4.2 g, 90%). MS: M / e 464 (M+1). + .

[0158] 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 2) [ka]

[0159] 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% in water) in MeOH (50 mL) was shaken overnight at room temperature under N2 atmosphere (50 psi). The reaction mixture was filtered through Celite. 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) + .

[0160] Intermediate 3: 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 [ka]

[0161] Step A: tert-Butyl (2R,5S)-2,5-diethyl-4-(4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylate [ka]

[0162] To a stirred solution of 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 (3 g, 8.04 mmol) in MeOH (20 mL) was added HCl (5 mL, 4.0 M in 1,4-dioxane). The reaction mixture was stirred over the weekend and concentrated to give a residue, which was treated with THF / HO (50 mL / 20 mL, v / v), and KCO (3.3 g, 24.1 mmol) was added, followed by BocO (1.75 g, 8.04 mmol). The mixture was then stirred for 1 h, acidified with citric acid to pH = 4-5, and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (1.4 g, 45%). MS: M / e 390 (M+1). + .

[0163] Step B: tert-Butyl (2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazine-1-carboxylate [ka]

[0164] To a stirred solution of tert-butyl (2R,5S)-2,5-diethyl-4-(4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylate (1.4 g, 3.6 mmol) in DMF / HO (10 mL / 2 mL) was added KCO (1.49 g, 10.8 mmol), followed by 2-iodoacetonitrile (482.4 mg, 7.2 mmol). The reaction mixture was stirred overnight, poured into HO (30 mL), and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (1 g, 65%). MS: M / e 429 (M+1). + .

[0165] Step C: 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 (Intermediate 3) [ka]

[0166] To a stirred solution of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazine-1-carboxylate (1 g, 2.34 mmol) in CHCl (15 mL) was added TFA (3 mL). The reaction mixture was then stirred for 5 h and concentrated to give a residue, which was basified with saturated aqueous NaHCO to pH = 10-11 and extracted with CHCl / IPA (3 / 1, 30 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound (752 mg, 98%). 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 5.59 (s, 2H), 5.35 (s, 1H), 4.31 (s, 1H), 4.08 (d, J = 13.2 Hz, 1H), 3.23 (s, 3H), 3.04 (dd, J = MS: M / e 329 (M+1) + .

[0167] Intermediate 4: 4-Methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-d]pyrimidine-5,7(6H)-dione [ka]

[0168] Step A: 4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide [ka]

[0169] Ethyl 4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (8 g, 29.7 mmol) was added to a solution of NH3 (7 M) in MeOH (80 mL). The reaction mixture was stirred at 80 °C for 16 hours, cooled to room temperature, and concentrated to dryness. The resulting residue was slurried with PE / EA to give the title compound (6.8 g, 95%). MS: M / e 241 (M+1) + .

[0170] Step B: 4-Amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide [ka]

[0171] 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) was added Pd / C (0.6 g, 10% in water). The resulting mixture was stirred at room temperature under an H atmosphere. The reaction mixture was filtered and washed with MeOH. The combined filtrate was concentrated to give the title compound (5.1 g, 94%). MS: M / e 211 (M+1) + .

[0172] Step C: 4-((2,4-dinitrophenyl)sulfonamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide [ka]

[0173] 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) was added 2,4-dinitrobenzenesulfonyl chloride (6.11 g, 23 mmol) dropwise. 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 flash column chromatography to give the title compound (5.3 g, 55%). MS: M / e 441 (M+1) + .

[0174] Step D: 4-((N-methyl-2,4-dinitrophenyl)sulfonamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide [ka]

[0175] 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) was added KCO (3.3 g, 24 mmol), followed by CHI (3.4 g, 24 mmol). The reaction mixture was stirred at room temperature 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 NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (4.8 g, 88%). MS: M / e 455 (M+1) + .

[0176] Step E: 4-(methylamino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide [ka]

[0177] 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) was added 2-mercaptoacetic acid (1.36 g, 14.8 mmol). 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 resulting residue was purified by flash column chromatography (DCM:MeOH = 10:1) to give the title compound (1.8 g, 75%). MS: M / e 225 (M+1) + .

[0178] Step F: 4-Methyl-2-(tetrahydro-2H-pyran-2-yl)-2,4-dihydro-5H-pyrazolo[4,3-d]pyrimidine-5,7(6H)-dione (Intermediate 4) [ka]

[0179] To a solution of 4-(methylamino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide (680 mg, 3 mmol) in DMF (15 mL) was added NaH (240 mg, 6 mmol) at 0 °C. After 1 h, CDI (972 mg, 6 mmol) was added to the reaction, and the resulting mixture was heated to 80 °C overnight. The reaction mixture was cooled to room temperature, quenched with HO, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH = 10:1) to give the title compound (0.6 g, 80%). 1 H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.15 (s, 1H), 5.55 (dd, J = 2.4, 9.2 Hz, 1H), 3.98 - 3.89 (m, 1H), 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 / e 251 (M+1) + .

[0180] Intermediate 5: 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 [ka]

[0181] Step A: tert-Butyl (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-carboxylate (Intermediate 5A) [ka]

[0182] To a solution of tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (2.56 g, 12 mmol) and Intermediate 2 (3.81 mg, 10 mmol) in CHCN (15 mL) was added DIPEA (3.87 g, 30 mmol). The mixture was then heated at 90 °C under N for 16 h. The mixture was cooled to room temperature, diluted with water (150 mL), and extracted with EA (80 mL × 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH = 15:1) to give the title compound (4.9 g, crude). MS: M / e 446 (M+1) + .

[0183] 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 5B) [ka]

[0184] To a solution of Intermediate 5A (4.9 g, crude) in DCM (20 mL) was added TFA (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with water, basified with saturated NaHCO solution, extracted with DCM:IPA (3:1, 80 mL × 3), dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH = 5:1, 1 mol / L NH / MeOH) to give the title compound (2.9 g, 84% (2 steps)). 1H NMR (400 MHz, CD3OD) δ 8.03 (d, J = 2.8 Hz, 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) + .

[0185] Step C: tert-Butyl (2R,5S)-2,5-dimethyl-4-(4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylate [ka]

[0186] To a stirred solution of Intermediate 5B (3 g, 8.70 mmol) in MeOH (20 mL) was added dioxane / HCl(g) (4.0 M, 5 mL). After the addition, the reaction was stirred over the weekend. The reaction mixture was concentrated to a residue, which was treated with THF / H2O (50 mL / 20 mL), and K2CO3 (3.60 g, 26.08 mmol) was added, followed by Boc2O (1.90 g, 8.70 mmol). The mixture was then stirred for 1 h. The mixture was acidified with citric acid to pH = 4-5 and extracted with EtOAc (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 flash column chromatography to give the title compound (1.7 g, 54%). MS: M / e 362 (M+1) + .

[0187] Step D: tert-Butyl (2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0188] To a stirred solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylate (1.7 g, 4.71 mmol) in DMF / HO (10 mL / 2 mL) was added KCO (1.95 g, 14.1 mmol), followed by 2-iodoacetonitrile (1.18 g, 7.06 mmol). After the addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into HO (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (1.3 g, 69%). MS: M / e 401 (M+1) + .

[0189] Step E: 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 [ka]

[0190] To a stirred solution of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (1.3 g, 3.25 mmol) in CHCl (15 mL) was added TFA (3 mL). The mixture was then stirred for 5 h. The reaction mixture was concentrated to give a residue, which was basified with aqueous NaHCO to pH 10-11 and extracted with CHCl / IPA (3 / 1, 30 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound (870 mg, 89%). MS: M / e 301 (M+1). + .

[0191] Intermediate 6: 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 [ka]

[0192] Step A: tert-Butyl (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-carboxylate [ka]

[0193] A mixture of 4-methyl-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate (19 g, 50 mmol), tert-butyl (2R,5S)-2-ethyl-5-methylpiperazine-1-carboxylate (12.54 g, 55 mmol), and DIPEA (12.9 g, 0.1 mol) in CHCN (200 mL) was stirred at 100 °C overnight in a sealed tube. The reaction mixture was concentrated to dryness. The resulting residue was dissolved in CHCl (200 mL), washed with H0, brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (20 g, 83.5%). MS: M / e 480 (M+1). + .

[0194] Step B: 7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one [ka]

[0195] To a stirred solution of tert-butyl (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-carboxylate (6 g, 12.5 mmol) in MeOH (50 mL) was added dioxane / HCl (g) (4.0 M, 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 in the next step. MS: M / e 276 (M+1) + .

[0196] Step C: tert-Butyl (2R,5S)-2-ethyl-5-methyl-4-(4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylate [ka]

[0197] 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 / HO (80 mL / 80 mL) and then basified with NaHCO to pH=7-8. To the reaction mixture was added NaHCO (2.1 g, 25 mmol), followed by BocO (3.28 g, 15 mmol). After the 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 NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (3.8 g, 81%). MS: M / e 376 (M+1) + .

[0198] Step D: tert-Butyl (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-carboxylate [ka]

[0199] To a stirred solution of tert-butyl (2R,5S)-2-ethyl-5-methyl-4-(4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylate (3.8 g, 10.1 mmol) in DMF / HO (30 mL / 10 mL) was added KCO (2.78 g, 20.2 mmol), followed by 1-bromobut-2-yne (2.02 g, 15.2 mmol). After the addition, the reaction was stirred at room temperature overnight. The reaction mixture was poured into HO (50 mL) and then extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (2.2 g, 51%). MS: M / e 428 (M+1) + .

[0200] 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 [ka]

[0201] To a stirred solution of tert-butyl (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-carboxylate (2.2 g, 5.15 mmol) in CHCl (50 mL) was added TMSOTf (2.3 g, 10.3 mmol). The mixture was then stirred for 2 h. The mixture was quenched with aqueous NaCO and extracted with CHCl / IPA (3 / 1, 50 mL×4). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound (1.8 g, 99%). MS: M / e 328 (M+1) + .

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

[0203] Step A: tert-Butyl (2R,5S)-2,5-diethyl-4-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylate [ka]

[0204] A mixture of 4-methyl-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate (5 g, 13.1 mmol), tert-butyl (2R,5S)-2,5-diethylpiperazine-1-carboxylate (3.8 g, 15.7 mmol), and DIPEA (4.2 g, 32.8 mmol) in DMAc (50 mL) was stirred at 100 °C overnight. The reaction mixture was diluted with CHCl (300 mL) and extracted with H0 (500 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (7.5 g). MS: M / e 474 (M+1) + .

[0205] Step B: 7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one [ka]

[0206] To a stirred solution of tert-butyl (2R,5S)-2,5-diethyl-4-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylate (7.5 g, 15.8 mmol) in MeOH (50 mL) was added 1,4-dioxane / HCl(g) (4 M, 20 mL). After the addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to give the title compound (crude), which was used directly in the next step. MS: M / e 290 (M+1) + .

[0207] Step C: tert-Butyl (2R,5S)-2,5-diethyl-4-(4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylate [ka]

[0208] To a stirred solution of 7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (crude, 15.8 mmol) in THF (50 mL) / HO (20 mL) was added NaHCO (4 g, 47.4 mmol), followed by (Boc)O (6.8 g, 31.6 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with CHCl (200 mL × 2), dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (4.4 g, 3 steps, 86%). MS: M / e 390 (M+1). + .

[0209] Step D: tert-Butyl (2R,5S)-4-(2-(but-2-yn-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazine-1-carboxylate [ka]

[0210] To a stirred solution of tert-butyl (2R,5S)-2,5-diethyl-4-(4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylate (4.4 g, 11.3 mmol) in DMF (50 mL) / HO (10 mL) was added KCO (4.7 g, 33.9 mmol), followed by 1-bromobut-2-yne (3 g, 22.6 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with CHCl (200 mL × 2), washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (2.5 g, 50%). MS: M / e 442 (M+1). + .

[0211] Step E: 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one [ka]

[0212] To a stirred solution of tert-butyl (2R,5S)-4-(2-(but-2-yn-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazine-1-carboxylate (2.5 g, 5.7 mmol) in CHCl (30 mL) was added trimethylsilyl trifluoromethanesulfonate (1.9 g, 8.5 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was quenched with aqueous NaCO and extracted with CHCl / IPA (3 / 1, 100 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (2 g, 100%). MS: M / e 342 (M+1)+ .

[0213] Intermediate 8: 2-(7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0214] Step A: tert-Butyl (2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate [ka]

[0215] To a stirred solution of tert-butyl (2R,5S)-2-ethyl-5-methyl-4-(4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)piperazine-1-carboxylate (14 g, 37.3 mmol) in DMF (100 mL) was added KCO (10.3 g, 74.7 mmol), followed by 2-chloroacetonitrile (4.2 g, 56 mmol). After the addition, the reaction was stirred overnight. The reaction mixture was poured into HO (300 mL) and then extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine, dried over NaSO, concentrated, and purified by flash column chromatography to give the title compound (14 g, 90.7%). MS: M / e 415 (M+1) + .

[0216] Step B: 2-(7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0217] To a stirred solution of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate (14 g, 33.8 mmol) in CHCl (200 mL) was added TMSOTf (15 g, 67.6 mmol). The mixture was then stirred for 2 h. The mixture was quenched with aqueous NaCO and extracted with CHCl / IPA (3 / 1, 50 mL × 4). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the desired compound (10 g, 94.2%). MS: M / e 315 (M+1) + .

[0218] Compound A1: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(3-methoxyazetidine-1-carbonyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0219] Step A: 1-(4-(3-methoxyazetidine-1-carbonyl)phenyl)ethan-1-one [ka]

[0220] To a solution of 4-acetylbenzoic acid (164 mg, 1 mmol), 3-methoxyazetidine hydrochloride (150 mg, 1.2 mmol), and HATU (456 mg, 1.2 mmol) in DCM (10 mL) was added DIPEA (258 mg, 2 mmol). The reaction mixture was stirred at 25 °C overnight. The mixture was diluted with water, extracted with DCM (80 mL), washed with brine, dried over Na SO , filtered, and concentrated to dryness (300 mg, crude). MS: M / e 234 (M+1) + .

[0221] Step B: (4-(1-hydroxyethyl)phenyl)(3-methoxyazetidin-1-yl)methanone [ka]

[0222] To a solution of 1-(4-(3-methoxyazetidine-1-carbonyl)phenyl)ethan-1-one (300 mg, crude) in MeOH (5 mL) was added NaBH (76 mg, 2 mmol) slowly at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with HO (0.5 mL) and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the desired product (160 mg, 68% (2 steps)). 1 H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 5.26 (d, J = 4.4 Hz, 1H), 4.80 - 4.69 (m, 1H), 4.47 - 4.36 (m, 1H), 4.28 - 4.06 (m, 3H), 3.89 - 3.75 (m, 1H), 3.21 (s, 3H), 1.32 (d, J = 6.4 Hz, 3H) ppm.

[0223] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(3-methoxyazetidine-1-carbonyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0224] To a solution of (4-(1-hydroxyethyl)phenyl)(3-methoxyazetidin-1-yl)methanone (46 mg, 0.2 mmol), 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 (33 mg, 0.1 mmol), and (cyanomethyl)trimethylphosphonium iodide (73 mg, 0.3 mmol) in CHCN (1 mL) was added DIPEA (65 mg, 0.5 mmol). The mixture was sealed in a bottle and heated at 100° C. for 16 h. The mixture was cooled to room temperature, diluted with water, extracted with EA (60 mL), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) and preparative HPLC (Method B) to give the title Compound A1a (6 mg) and Compound A1b (10 mg).

[0225] Compound A1a (early peak): 11H NMR (500 MHz, CD3OD) δ 7.91 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 5.55 (s, 1H), 5.46 (s, 2H), 4.60 - 4.48 (m, 1H), 4.40 - 4.19 (m, 3H), 4.02 - 3.96 (m, 1H), 3.85 - 3.76 (m, 1H), 3.43 (s, 3H), 3.32 (s, 3H), 3.35 - 3.31 (m, 2H), 3.30 - 3.24 (m, 1H), 3.05 - 2.98 (m, 1H), 2.91 - 2.84 (m, 1H), 2.44 - 2.34 (m, 1H), 2.18 - 2.05 (m, 1H), 1.89 - 1.77 (m, 1H), 1.60 - 1.49 (m, 2H), 1.35 (d, J = 7.5 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H), 0.69 (t, J = 7.5 Hz, 3H) ppm. MS: M / e 546 (M+1) + .

[0226] Compound A1b (later peak): 1H NMR (500 MHz, CD3OD) δ 7.92 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 5.55 (s, 1H), 5.46 (s, 2H), 4.57 - 4.44 (m, 1H), 4.40 - 4.14 (m, 3H), 4.02 - 3.94 (m, 1H), 3.72 - 3.63 (m, 1H), 3.53 - 3.47 (m, 1H), 3.43 (s, 3H), 3.37 - 3.31 (m, 5H), 3.19 - 3.12 (m, 1H), 2.71 - 2.61 (m, 1H), 2.36 - 2.28 (m, 1H), 2.02 - 1.89 (m, 1H), 1.73 - 1.50 (m, 3H), 1.32 (d, J = 6.5 Hz, 3H), 1.02 (t, J = 7.5 Hz, 3H), 0.62 (t, J = 7.5 Hz, 3H) ppm. MS: M / e 546 (M+1) + .

[0227] Compound A2: 4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-N,N-dimethylbenzamide [ka]

[0228] Step A: 4-Acetyl-N,N-dimethylbenzamide [ka]

[0229] To a solution of 4-acetylbenzoic acid (164 mg, 1 mmol), dimethylamine hydrochloride (97 mg, 1.2 mmol), and HATU (456 mg, 1.2 mmol) in DCM (10 mL) was added DIPEA (258 mg, 2 mmol). The reaction mixture was stirred at 25 °C overnight. The mixture was diluted with water, extracted with DCM (80 mL), washed with brine, dried over Na SO , filtered, and concentrated to dryness (290 mg, crude). MS: M / e 192 (M+1) + .

[0230] Step B: 4-(1-hydroxyethyl)-N,N-dimethylbenzamide [ka]

[0231] To a solution of 4-acetyl-N,N-dimethylbenzamide (290 mg, crude) in MeOH (5 mL) was added NaBH (76 mg, 2 mmol) slowly at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with HO (0.5 mL) and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the desired product (140 mg, 72% (2 steps)). 1 H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 5.22 (d, J = 3.6 Hz, 1H), 4.80 - 4.68 (m, 1H), 2.97 (s, 3H), 2.91 (s, 3H), 1.32 (d, J = 6.4 Hz, 3H) ppm.

[0232] Step C: 4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-N,N-dimethylbenzamide [ka]

[0233] To a solution of 4-(1-hydroxyethyl)-N,N-dimethylbenzamide (39 mg, 0.2 mmol), 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 (33 mg, 0.1 mmol), and (cyanomethyl)trimethylphosphonium iodide (73 mg, 0.3 mmol) in CHCN (1 mL) was added DIPEA (65 mg, 0.5 mmol). The mixture was sealed in a bottle and heated at 100 °C for 16 h. The mixture was cooled to room temperature, diluted with water, extracted with EA (60 mL), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) and preparative HPLC (Method B) to give the title Compound A2a (6 mg) and Compound A2b (9 mg).

[0234] Compound A2a (early peak): 1 H NMR (500 MHz, CD3OD) δ 7.91 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 5.55 (s, 1H), 5.46 (s, 2H), 3.83 - 3.76 (m, 1H), 3.43 (s, 3H), 3.35 -3.31 (m, 2H), 3.28 - 3.24 (m, 1H), 3.11 (s, 3H), 3.02 (s, 3H), 3.02 - 2.98 (m, 1H), 2.91 - 2.84 (m, 1H), 2.46 - 2.35 (m, 1H), 2.16 - 2.05 (m, 1H), 1.87 - 1.76 (m, 1H), 1.59 - 1.48 (m, 2H), 1.36 (d, J = 6.5 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H), 0.69 (t, J = 7.5 Hz, 3H) ppm. MS: M / e 504 (M+1) + .

[0235] Compound A2b (later peak): 1 H NMR (500 MHz, CD3OD) δ 7.92 (s, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 5.55 (s, 1H), 5.46 (s, 2H), 3.69 - 3.61 (m, 1H), 3.54 - 3.46 (m, 1H), 3.43 (s, 3H), 3.35 -3.31 (m, 2H), 3.19 - 3.12 (m, 1H), 3.10 (s, 3H), 3.00 (s, 3H), 2.69 - 2.63 (m, 1H), 2.39 - 2.32 (m, 1H), 2.02 - 1.89 (m, 1H), 1.71 - 1.50 (m, 3H), 1.33 (d, J = 7.0 Hz, 3H), 1.03 (t, J = 7.5 Hz, 3H), 0.62 (t, J = 7.5 Hz, 3H) ppm. MS: M / e 504 (M+1) + .

[0236] Compound A3: 4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-2,6-difluoro-N,N-dimethylbenzamide [ka]

[0237] Step A: 4-Bromo-2,6-difluoro-N,N-dimethylbenzamide [ka]

[0238] A solution of 4-bromo-2,6-difluorobenzoic acid (1 g, 4.22 mmol), dimethylamine hydrochloride (0.42 g, 5.12 mmol), HATU (2.41 g, 6.34 mmol), and DIPEA (1.63 g, 12.64 mmol) in DMF (10 mL) was stirred overnight at room temperature. The solution was poured into water (20 mL) and extracted with EA (15 mL × 2). The organic layer was dried over Na2SO4 and concentrated to dryness. The resulting residue was purified by flash column chromatography (0-30% EtOAc / PE) to give the title compound (1.1 g, 98%). MS: M / e 264 (M+1). + .

[0239] Step B: 4-Acetyl-2,6-difluoro-N,N-dimethylbenzamide [ka]

[0240] A solution of 4-bromo-2,6-difluoro-N,N-dimethylbenzamide (500 mg, 1.89 mmol), ethyl tributylstannanecarboxylate (850 mg, 2.35 mmol), and Pd(PPh3)2Cl2 (66 mg, 0.094 mmol) in toluene (10 mL) was stirred at 100 °C overnight. The solution was cooled to room temperature. HCl / 1,4-dioxane (4 M, 2 mL) was added and stirred at room temperature for 10 minutes. The solution was diluted with EtOAc (20 mL), washed with aqueous Na2CO3 (10 mL × 2), dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography (20-50% EA / PE) to give the title compound (430 mg, 100%). MS: M / e 228 (M+1). + .

[0241] Step C: 2,6-Difluoro-4-(1-hydroxyethyl)-N,N-dimethylbenzamide [ka]

[0242] A solution of 4-acetyl-2,6-difluoro-N,N-dimethylbenzamide (430 mg, 1.89 mmol) and NaBH (72 mg, 1.89 mmol) in MeOH (6 mL) was stirred at room temperature for 15 minutes. The solution was diluted with EtOAc (15 mL), washed with brine (10 mL x 2), dried over NaSO, and concentrated to dryness to give the title compound (430 mg, 99%), which was used directly in the next step without further purification. MS: M / e 230 (M+1). + .

[0243] Step D: 4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-2,6-difluoro-N,N-dimethylbenzamide [ka]

[0244] A solution of 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 (50 mg, 0.15 mmol), 2,6-difluoro-4-(1-hydroxyethyl)-N,N-dimethylbenzamide (52.4 mg, 0.23 mmol), (cyanomethyl)trimethylphosphonium iodide (111 mg, 0.46 mmol), and DIPEA (197 mg, 1.53 mmol) in CHCN (2 mL) was stirred at 100° C. overnight. The reaction was diluted with EtOAc (15 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound A3, which was further separated by preparative HPLC (Method A) into compound A3a (4 mg) and compound A3b (5 mg).

[0245] Compound A3a (early peak): 11H NMR (500 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.22 (d, J = 9.2 Hz, 2H), 5.61 (s, 2H), 5.39 (s, 1H), 3.83 (q, J = 6.5 Hz, 1H), 3.32 - 3.29 (m, 2H), 3.27 (s, 3H), 3.19 (d, J = 11.2 Hz, 1H), 3.02 (s, 3H), 2.88 (s, 3H), 2.87-2.83 (m, 1H), 2.78 (dd, J = 11.8, 3.5 Hz, 1H), 2.36 (s, 1H), 2.05 - 1.95 (m, 1H), 1.69 - 1.58 (m, 1H), 1.52-1.42 (m, 2H), 1.28 (d, J = 6.5 Hz, 3H), 0.85 (t, J = 7.3 Hz, 3H), 0.69 (t, J = 7.3 Hz, 3H) ppm. MS: M / e 540 (M+1) + .

[0246] Compound A3b (later peak): 1 1H NMR (500 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.23 (t, J = 10.1 Hz, 2H), 5.61 (s, 2H), 5.40 (s, 1H), 3.66 (q, J = 6.2 Hz, 1H), 3.35 (d, J = 22.3 Hz, 2H), 3.31 - 3.29 (m, 1H), 3.27 (s, 3H), 3.02 (s, 1H), 3.02 (s, 3H), 2.85 (s, 3H), 2.59 (d, J = 9.9 Hz, 1H), 2.22 (d, J = 11.8 Hz, 1H), 1.95-1.85 (m, 1H), 1.64-1.35 (m, 3H), 1.25 (d, J = 6.5 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H), 0.58 (t, J = 7.3 Hz, 3H) ppm. MS: M / e 540 (M+1) + .

[0247] Compound A4: 4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-2-fluoro-N,N-dimethylbenzamide [ka]

[0248] Step A: 4-Acetyl-2-fluoro-N,N-dimethylbenzamide [ka]

[0249] A mixture of 4-bromo-2-fluoro-N,N-dimethylbenzamide (500 mg, 2.04 mmol), tributyl(1-ethoxyvinyl)stannane (737 mg, 2.04 mmol), and Pd(PPh3)2Cl2 (143 mg, 0.20 mmol) in toluene (10 mL) was stirred overnight at 100 °C under N2. To this solution was added HCl (0.3 mL, 4 M in 1,4-dioxane), and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was diluted with EA and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (300 mg, 70%). MS: M / e 210 (M+1) + .

[0250] Step B: 2-Fluoro-4-(1-hydroxyethyl)-N,N-dimethylbenzamide [ka]

[0251] To a solution of 4-acetyl-2-fluoro-N,N-dimethylbenzamide (300 mg, 1.43 mmol) in MeOH (15 mL) was added NaBH (109 mg, 2.87 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over NaSO, and concentrated to give the title compound (220 mg, 73%). MS: M / e 212 (M+1) + .

[0252] Step C: 4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-2-fluoro-N,N-dimethylbenzamide [ka]

[0253] To a solution of 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 (50 mg, 0.15 mmol) in CHCN (3 mL) was added 2-fluoro-4-(1-hydroxyethyl)-N,N-dimethylbenzamide (32 mg, 0.15 mmol), (cyanomethyl)trimethylphosphonium iodide (112 mg, 0.46 mmol), and DIPEA (98 mg, 0.76 mmol). The resulting mixture was stirred at 105 °C overnight. The reaction solvent was removed under reduced pressure to give the crude product. The resulting residue was purified by preparative HPLC (Method A) to give the title compound A4a (10 mg) and compound A4b (12 mg, 28%).

[0254] Compound A4a (early peak): 11H NMR (400 MHz, CD3OD) δ 7.90 (s, 1H), 7.34 (t, J = 7.2 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 10.4 Hz, 1H), 5.55 (s, 1H), 5.44 (s, 2H), 4.81 - 4.11 (m, 2H), 3.81 (d, J = 6.5 Hz, 1H), 3.46 (s, 1H), 3.41 (s, 3H), 3.10 (s, 3H), 2.99 (d, J = 11.7 Hz, 1H), 2.95 (s, 3H), 2.86 (d, J = 10.8 Hz, 1H), 2.42 (s, 1H), 2.16 - 2.05 (m, 1H), 1.87 - 1.77 (m, 1H), 1.58 - 1.48 (m, 2H), 1.33 (d, J = 6.4 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H), 0.71 (t, J = 7.1 Hz, 3H). MS: M / e 522(M+1) + .

[0255] Compound A-4b (later peak): 1 1H NMR (400 MHz, CD3OD) δ 7.90 (s, 1H), 7.33 - 7.26 (m, 3H), 5.54 (s, 1H), 5.45 (s, 2H), 4.78 - 4.00 (m, 2H), 3.66 (d, J = 6.4 Hz, 1H), 3.49 (d, J = 13.2 Hz, 1H), 3.41 (s, 3H), 3.14 (s, 1H), 3.10 (s, 3H), 2.93 (s, 3H), 2.67 (d, J = 10.3 Hz, 1H), 2.33 (d, J = 12.3 Hz, 1H), 2.01 - 1.92 (m, 1H), 1.71 - 1.61 (m, 2H), 1.56 - 1.49 (m, 1H), 1.31 (d, J = 6.4 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H), 0.64 (t, J = 7.0 Hz, 3H). MS: M / e 522(M+1) + .

[0256] Compound A5: 2-(7-((2S,5R)-4-(1-(4-((1,1-dioxidothiomorpholino)methyl)-3,5-difluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0257] Step A: 5-Bromo-2-(bromomethyl)-1,3-difluorobenzene [ka]

[0258] To a solution of 5-bromo-1,3-difluoro-2-methylbenzene (2.07 g, 10 mmol) and NBS (1.96 g, 11 mmol) in CHCN (20 mL) was added AIBN (50 mg). The reaction mixture was stirred overnight at 95 °C under N. The mixture was cooled to room temperature, diluted with MTBE (40 mL), filtered, and the filtrate was concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (2.63 g, 92%). 1 H NMR (500 MHz, CDCl3) δ 7.15 - 7.10 (m, 2H), 4.64 (s, 2H) ppm.

[0259] Step B: 4-(4-bromo-2,6-difluorobenzyl)thiomorpholine 1,1-dioxide [ka]

[0260] To a solution of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (855 mg, 3 mmol) and thiomorpholine 1,1-dioxide (405 mg, 3 mmol) in CHCN (6 mL) was added KCO (822 mg, 6 mmol). The reaction was stirred at 25 °C overnight. The mixture was diluted with HO, extracted with EA (80 mL), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (685 mg, 67%). MS: M / e 340 (M+1) + .

[0261] Step C: 1-(4-((1,1-dioxidothiomorpholino)methyl)-3,5-difluorophenyl)ethan-1-one [ka]

[0262] To a solution of 4-(4-bromo-2,6-difluorobenzyl)thiomorpholine 1,1-dioxide (680 mg, 2 mmol) in toluene (8 mL) were added tributyl(1-ethoxyvinyl)stannane (948 mg, 3 mmol) and Pd(PPh2)2Cl2 (70 mg, 0.1 mmol). The reaction mixture was protected with a N2 atmosphere and stirred at 100 °C overnight. The mixture was cooled to room temperature, and a 4 M solution of HCl in dioxane (2 mL) was added. The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with H2O and saturated NaHCO3 solution, extracted with EA (60 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (230 mg, 38%). MS: M / e 340 (M+1) + .

[0263] Step D: 4-(2,6-difluoro-4-(1-hydroxyethyl)benzyl)thiomorpholine 1,1-dioxide [ka]

[0264] To a solution of 1-(4-((1,1-dioxidothiomorpholino)methyl)-3,5-difluorophenyl)ethan-1-one (230 mg, 0.76 mmol) in MeOH / DCM (8 mL / 4 mL) was added NaBH (32 mg, 0.85 mmol) slowly at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with HO (10 mL), extracted with DCM (60 mL), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the desired product (160 mg, 69%). 1 H NMR (500 MHz, DMSO-d6) δ 7.11 - 7.04 (m, 2H), 5.39 (d, J = 4.5 Hz, 1H), 4.76 - 4.69 (m, 1H), 3.74 (s, 2H), 3.12 - 3.06 (m, 4H), 2.90 - 2.83 (m, 4H), 1.31 (d, J = 6.5 Hz, 3H) ppm.

[0265] Step E: 2-(7-((2S,5R)-4-(1-(4-((1,1-dioxidothiomorpholino)methyl)-3,5-difluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0266] To a solution of 4-(2,6-difluoro-4-(1-hydroxyethyl)benzyl)thiomorpholine 1,1-dioxide (60 mg, 0.2 mmol), 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 (33 mg, 0.1 mmol), and (cyanomethyl)trimethylphosphonium iodide (73 mg, 0.6 mmol) in CHCN (1 mL) was added DIPEA (65 mg, 0.5 mmol). The mixture was sealed in a bottle and heated at 100° C. for 16 h. The mixture was cooled to room temperature, diluted with water, extracted with EA (60 mL), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give the title compound (20 mg, 32%). 1 H NMR (500 MHz, CD3OD) δ 7.94 - 7.91 (m, 1H), 7.12 - 7.02 (m, 2H), 5.58 - 5.54 (m, 1H), 5.49 - 5.44 (m, 2H), 3.83 (s, 2H), 3.81 - 3.77 (m, 1H), 3.68 - 3.58 (m, 0.5H), 3.54 - 3.45 (m, 0.5H), 3.43 (s, 3H), 3.35 -3.31 (m, 2H), 3.21 - 2.80 (m, 9.5H), 2.74 - 2.62 (m, 0.5H), 2.47 - 2.25 (m, 1H), 2.17 - 1.45 (m, 4H), 1.36 - 1.26 (m, 3H), 1.06 - 0.90 (m, 3H), 0.81 - 0.60 (m, 3H) ppm. MS: M / e 616 (M+1) + .

[0267] Compound A6: 2-(7-((2S,5R)-4-(1-(2,4-dimethylphenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0268] Step A: 1-(2,4-dimethylphenyl)ethan-1-ol [ka]

[0269] A solution of 1-(2,4-dimethylphenyl)ethan-1-one (200 mg, 1.35 mmol) and NaBH (51 mg, 1.34 mmol) in MeOH (2 mL) was stirred at room temperature for 20 min. The reaction was quenched with brine (10 mL) and then extracted with EA (10 mL × 2). The organic layer was dried over NaSO and concentrated to dryness to give the title compound (200 mg, 99%), which was used directly in the next step without further purification. 1 H NMR (400 MHz,CDCl3) δ 7.40 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.96 (s, 1H), 5.11 (q, J = 6.4 Hz, 1H), 2.32 (s, 3H), 2.30 (s, 3H), 1.46 (d, J = 6.4 Hz, 3H) ppm.

[0270] Step B: 2-(7-((2S,5R)-4-(1-(2,4-dimethylphenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0271] A solution of 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 (60 mg, 0.18 mmol), 1-(2,4-dimethylphenyl)ethan-1-ol (41.2 mg, 0.27 mmol), (cyanomethyl)trimethylphosphonium iodide (133 mg, 0.55 mmol), and DIPEA (236 mg, 1.83 mmol) in CHCN (2 mL) was stirred at 100° C. overnight. The reaction was diluted with EtOAc (15 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (0-5% MeOH / DCM) and then further purified by preparative HPLC (Method A) to give the title compound (23 mg). 1 H NMR (500 MHz, DMSO-d6) δ 8.32 (s, 0.18H), 7.97 (s, 1H), 7.38 (d, J = 7.8 Hz, 0.5H), 7.28 (d, J = 7.8 Hz, 0.5H), 6.96 (dd, J = 17.5, 9.0 Hz, 2H), 5.61 (s, 2H), 5.40 (s, 1H), 3.86 (q, J = 6.4 Hz, 0.5H), 3.78 (q, J = 6.4 Hz, 0.5H), 3.34 (s, 3.5H), 3.27 (s, 3H), 3.12 (s, 0.5H), 3.03 (d, J = 10.0 Hz, 0.5H), 2.92 (d, J = 11.9 Hz, 0.5H), 2.72 (d, J = 11.0 Hz, 0.5H), 2.32 (s, 1.5H), 2.28 (s, 1.5H), 2.24 (d, J = 3.6 Hz, 3H), 2.21 (s, 0.5H), 2.06-1.82 (m, 1H), 1.67-1.32 (m, 3H), 1.20 (dd, J = 26.6, 6.4 Hz, 3H), 0.92 (dt, J = 55, 5 Hz, 3H), 0.58 (dt, J = 17.3, 5 Hz, 3H) ppm. MS: M / e 461 (M+1) + .

[0272] Compound A7: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-ethylphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0273] Step A: 1-(4-ethylphenyl)ethan-1-ol [ka]

[0274] A solution of 1-(4-ethylphenyl)ethan-1-one (200 mg, 1.35 mmol) and NaBH (51 mg, 1.34 mmol) in MeOH (2 mL) was stirred at room temperature for 60 min. The reaction was quenched with brine (10 mL) and then extracted with EA (10 mL × 2). The organic layer was dried over NaSO and concentrated to dryness to give the title compound (200 mg, 99%), which was used directly in the next step without further purification. 1 H NMR (500 MHz, CDCl3) δ 7.30 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 4.93 - 4.82 (m, 1H), 2.65 (q, J = 7.6 Hz, 2H), 1.50 (d, J = 6.5 Hz, 3H), 1.24 (t, J = 7.6 Hz, 3H) ppm.

[0275] Step B: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-ethylphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0276] A solution of 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 (60 mg, 0.18 mmol), 1-(2,4-dimethylphenyl)ethan-1-ol (41.2 mg, 0.27 mmol), (cyanomethyl)trimethylphosphonium iodide (133 mg, 0.55 mmol), and DIPEA (236 mg, 1.83 mmol) in CHCN (2 mL) was stirred at 100 °C overnight. The reaction was diluted with EtOAc (15 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (0–5% MeOH / DCM) followed by preparative HPLC (Method A) to give the title compound (31 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 0.13H), 7.97 (d, J = 1.9 Hz, 1H), 7.26 (dd, J = 10.2, 8.1 Hz, 2H), 7.16 (dd, J = 11.8, 8.0 Hz, 2H), 5.61 (s, 2H), 5.38 (s, 1H), 3.65 (q, J = 6.5 Hz, 0.5H), 3.52 (q, J = 6.4 Hz, 0.5H), 3.37 (s, 2H), 3.27 (s, 3H), 3.03 (dd, J = 30, 9.6 Hz, 1H), 2.89 (d, J = 9.6 Hz,, 0.5H), 2.75 (dd, J = 30, 9.6 Hz, 0.5H), 2.62-2.54 (m, 2H), 2.47 (s, 1H), 2.31 (s, 0.5H), 2.25 (d, J = 12.1 Hz, 0.5H), 2.07-1.96 (m, 0.5H), 1.90-1.79 (m, 0.5H), 1.68-1.36 (m, 3H), 1.21 (ddd, J = 31.9, 17.1, 7.0 Hz, 6H), 0.90 (dt, J = 39.3, 7.3 Hz, 3H), 0.58 (dt, J = 22.5, 15.1 Hz, 3H) ppm. MS: M / e 461 (M+1) + .

[0277] Compound A8: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methyl-4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0278] To a solution of 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 (33 mg, 0.1 mmol), 1-(3-methyl-4-(trifluoromethyl)phenyl)ethan-1-ol (41 mg, 0.2 mmol), and (cyanomethyl)trimethylphosphonium iodide (85 mg, 0.35 mmol) in CHCN (1 mL) was added DIPEA (85 mg, 0.66 mmol). The mixture was stirred at 100 °C for 16 h in a sealed tube. The mixture was cooled, diluted with EtOAc (10 mL), washed with brine (5 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC to give the title compound (25 mg, 49%). 1 H NMR (500 MHz, CD3OD) δ 7.97 - 7.86 (m, 1H), 7.63 - 7.52 (m, 1H), 7.46 - 7.32 (m, 2H), 5.60 - 5.51 (m, 1H), 5.50 - 5.41 (m, 2H), 4.83 - 3.92 (m, 1H), 3.86 - 3.61 (m, 1H), 3.56 - 3.32 (m, 4H), 3.30 - 3.25 (m, 1H), 3.21 - 2.61 (m, 2H), 2.54 - 2.27 (m, 4H), 2.20 - 1.92 (m, 1H), 1.87 - 1.47 (m, 3H), 1.38 - 1.29 (m, 3H), 1.10 - 0.88 (m, 3H), 0.77 - 0.55 (m, 3H). MS: M / e 515 (M+1) + .

[0279] Compound A9: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-methoxy-3-methylphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0280] Step A: 1-(4-methoxy-3-methylphenyl)ethan-1-ol [ka]

[0281] A solution of 1-(4-methoxy-3-methylphenyl)ethan-1-one (200 mg, 1.22 mmol) and NaBH (46 mg, 1.21 mmol) in MeOH (2 mL) was stirred at room temperature for 60 min. The reaction was quenched with brine (10 mL) and then extracted with EA (10 mL × 2). The organic layer was dried over NaSO and concentrated to dryness to give the title compound (200 mg, 99%), which was used directly in the next step without further purification. 1 H NMR (500 MHz, CDCl3) δ 7.19-7.14 (m, 2H), 6.80 (d, J = 9.0 Hz, 1H), 4.83 (q, J = 6.4 Hz, 1H), 3.83 (s, 3H), 2.23 (s, 3H), 1.48 (d, J = 6.4 Hz, 3H) ppm.

[0282] Step B: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-methoxy-3-methylphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0283] A solution of 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 (60 mg, 0.18 mmol), 1-(4-methoxy-3-methylphenyl)ethan-1-ol (45.6 mg, 0.27 mmol), (cyanomethyl)trimethylphosphonium iodide (133 mg, 0.55 mmol), and DIPEA (236 mg, 1.83 mmol) in CHCN (2 mL) was stirred at 100° C. overnight. The reaction was diluted with EtOAc (15 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (0-5% MeOH / DCM) followed by preparative HPLC (Method A) to give the title compound (16 mg). 1 H NMR (500 MHz, DMSO-d6) δ 8.23 ​​(s, 0.2H), 7.97 (d, J = 2.8 Hz, 1H), 7.17 - 7.08 (m, 2H), 6.87 (dd, J = 13.1, 8.2 Hz, 1H), 5.61 (s, 2H), 5.38 (d, J = 5.7 Hz, 1H), 3.76 (d, J = 6.3 Hz, 3H), 3.58 (q, J = 6.5 Hz, 0.5H), 3.47 (q, J = 6.4 Hz, 0.5H), 3.34 (s, 2H), 3.27 (s, 3H), 3.05 (dd, J = 30.3, 10.5 Hz, 1H), 2.89 (d, J = 11.4 Hz, 0.5H), 2.76 - 2.69 (m, 0.5H), 2.45 (d, J = 10.6 Hz, 1H), 2.35-2.26 (m, 1H), 2.14 (d, J = 8.9 Hz, 3H), 2.06 - 1.86 (m, 1H), 1.67-1.36 (m, 3H), 1.22 (dd, J = 20.2, 6.4 Hz, 3H), 0.90 (dt, J = 40.5, 7.2 Hz, 3H), 0.59 (dt, J = 20.5, 13.1 Hz, 3H) ppm. MS: M / e 477 (M+1) + .

[0284] Compound A10: 2-(7-((2S,5R)-4-(1-(4-(1,1-difluoroethyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0285] Step A: 1-(4-(1,1-difluoroethyl)phenyl)ethan-1-one [ka]

[0286] A mixture of 1-bromo-4-(1,1-difluoroethyl)benzene (442 mg, 2 mmol), tributyl(1-ethoxyvinyl)stannane (1.08 g, 3 mmol), and Pd(PPh3)2Cl2 (140 mg, 0.2 mmol) in toluene (5 mL) was stirred overnight at 100 °C under N2. HCl (0.5 mL, concentrated) was added dropwise to the resulting solution, and the mixture was stirred at room temperature for 30 min. The mixture was treated with saturated aqueous NaHCO3 solution until the pH reached approximately 8, extracted with EtOAc (10 mL x 3), washed with brine (20 mL x 3), dried, and concentrated to dryness. The resulting residue was purified by flash column chromatography (EtOAc:PE = 0-50%, 25 min) to give the title compound (300 mg, 82%). 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 2.63 (s, 3H), 1.93 (t, J = 18.2 Hz, 3H) ppm. MS: M / e 185 (M+1) + .

[0287] Step B: 1-(4-(1,1-difluoroethyl)phenyl)ethan-1-ol [ka]

[0288] To a solution of 1-(4-(1,1-difluoroethyl)phenyl)ethan-1-one (300 mg, 1.63 mmol) in MeOH (5 mL) was added NaBH (49 mg, 1.3 mmol) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The resulting mixture was treated with water and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (20 mL × 1), dried over NaSO, and concentrated to dryness. The resulting residue (250 mg, crude) was used in the next step. MS: M / e 187 (M+1) + .

[0289] Step C: 2-(7-((2S,5R)-4-(1-(4-(1,1-difluoroethyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0290] A mixture of 1-(4-(1,1-difluoroethyl)phenyl)ethan-1-ol (28 mg, 0.15 mmol), 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 (33 mg, 0.1 mmol), (cyanomethyl)trimethylphosphonium iodide (48 mg, 0.2 mmol), and DIPEA (51 mg, 0.4 mmol) in MeCN (2 mL) was stirred at 100° C. overnight. The reaction mixture was diluted with EtOAc (10 mL), washed with brine (10 mL × 2), dried over NaSO, and concentrated to dryness. The resulting residue was purified by column chromatography (MeOH:DCM=0-10%, 20 min) to give the title compound (18 mg, 36%). 1H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 1.4 Hz, 1H), 7.50 (dt, J = 24.9, 8.1 Hz, 4H), 5.61 (d, J = 2.8 Hz, 2H), 5.39 (s, 1H), 3.81-3.61 (m, 1H), 3.41 - 3.32 (m, 1H), 3.28 (d, J = 13.2 Hz, 4H), 3.15-3.02 (m, 1H), 2.95-2.74(m, 1H), 2.54 (s, 1H), 2.32 - 2.17 (m, 1H), 2.08 - 1.79 (m, 4H), 1.69 - 1.41 (m, 3H), 1.26 (dd, J = 15.7, 6.5 Hz, 3H), 0.98-0.82 (m, 3H), 0.65-0.49 (m, 3H) ppm. MS: M / e 497 (M+1) + .

[0291] Compound A11: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(2-methoxyethoxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0292] Step A: 1-(4-(2-methoxyethoxy)phenyl)ethan-1-one [ka]

[0293] To a solution of 1-(4-hydroxyphenyl)ethan-1-one (270 mg, 2 mmol) in CHCN (10 mL) was added 1-bromo-2-methoxyethane (417 mg, 3 mmol) and KCO (552 mg, 4 mmol). The reaction mixture was stirred at 70 °C overnight in a sealed bottle. An additional portion of 1-bromo-2-methoxyethane (417 mg, 3 mmol) was added, and the resulting mixture was heated at 70 °C for 5 h. The mixture was cooled to room temperature, diluted with HO, extracted with EA (80 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (330 mg, 85%). MS: M / e 195 (M+1) + .

[0294] Step B: 1-(4-(2-methoxyethoxy)phenyl)ethan-1-ol [ka]

[0295] To a solution of 1-(4-(2-methoxyethoxy)phenyl)ethan-1-one (330 mg, 1.7 mmol) in MeOH (5 mL) was added NaBH (65 mg, 1.7 mmol) slowly at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with HO (10 mL), extracted with EA (80 mL), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the desired product (160 mg, 48%). 1 H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 5.01 (d, J = 4.0 Hz, 1H), 4.70 - 4.58 (m, 1H), 4.05 (t, J = 4.8 Hz, 2H), 3.64 (t, J = 4.8 Hz, 2H), 3.32 (s, 3H), 1.28 (d, J = 6.4 Hz, 3H) ppm.

[0296] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(2-methoxyethoxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0297] To a solution of 1-(4-(2-methoxyethoxy)phenyl)ethan-1-ol (39 mg, 0.2 mmol), 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 (33 mg, 0.1 mmol), and (cyanomethyl)trimethylphosphonium iodide (73 mg, 0.3 mmol) in CHCN (1 mL) was added DIPEA (65 mg, 0.5 mmol). The mixture was sealed in a bottle and heated at 100 °C for 16 h. The mixture was cooled to room temperature, diluted with water, extracted with EA (60 mL), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM / MeOH=25 / 1) and then by preparative HPLC (Method A) to give the title compound (5 mg, 10%). 1H NMR (400 MHz, CD3OD) δ 7.93 - 7.90 (m, 1H), 7.33 - 7.24 (m, 2H), 6.94 - 6.86 (m, 2H), 5.54 (s, 1H), 5.48 - 5.44 (m, 2H), 4.14 - 4.06 (m, 2H), 3.78 - 3.72 (m, 2H), 3.71 - 3.65 (m, 0.5H), 3.60 - 3.40 (m, 7.5H), 3.35 -3.31 (m, 2H), 3.18 - 3.07 (m, 0.5H), 3.02 - 2.95 (m, 0.5H), 2.89 -2.80 (m, 0.5H), 2.64 - 2.56 (m, 0.5H), 2.50 - 2.38 (m, 1H), 2.15 - 1.45 (m, 4H), 1.36 - 1.26 (m, 3H), 1.05 - 0.91 (m, 3H), 0.75 - 0.55 (m, 3H) ppm. MS: M / e 507 (M+1) + .

[0298] Compound A12: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-methoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0299] Step A: 1-(2-fluoro-4-methoxyphenyl)ethan-1-ol [ka]

[0300] To a solution of 1-(2-fluoro-4-methoxyphenyl)ethan-1-one (336 mg, 2 mmol) in MeOH (10 mL) was added NaBH (76 mg, 2 mmol) slowly at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with HO (20 mL), extracted with EA (80 mL), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the desired product (300 mg, 87%). 1 H NMR (500 MHz, DMSO-d6) δ 7.39 (t, J = 8.5 Hz, 1H), 6.79 - 6.70 (m, 2H), 5.15 (d, J = 4.5 Hz, 1H), 4.95 - 4.86 (m, 1H), 3.74 (s, 3H), 1.30 (d, J = 6.5 Hz, 3H) ppm.

[0301] Step B: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-methoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0302] To a solution of 1-(2-fluoro-4-methoxyphenyl)ethan-1-ol (33 mg, 0.2 mmol), 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 (33 mg, 0.1 mmol), and (cyanomethyl)trimethylphosphonium iodide (75 mg, 0.3 mmol) in CHCN (1 mL) was added DIPEA (65 mg, 0.5 mmol). The mixture was sealed in a bottle and heated at 100 °C for 16 h. The mixture was cooled to room temperature, diluted with water, extracted with EA (60 mL), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM / MeOH=20 / 1) and then by preparative HPLC (Method A) to give the title compound (2 mg, 4%). 1 H NMR (500 MHz, CD3OD) δ 7.91 - 7.89 (m, 1H), 7.51 - 7.37 (m, 1H), 6.82 - 6.60 (m, 2H), 5.54 (s, 1H), 5.49 - 5.44 (m, 2H), 4.12 - 4.04 (m, 0.5H), 3.98 - 3.90 (m, 0.5H), 3.80 (s, 1.5H), 3.78 (s, 1.5H), 3.51 - 3.40 (m, 4H), 3.35 -3.31 (m, 2H), 3.18 - 3.08 (m, 0.5H), 2.97 - 2.84 (m, 1H), 2.70 - 2.60 (m, 0.5H), 2.49 - 2.36 (m, 1H), 2.21 - 1.40 (m, 4H), 1.38 - 1.26 (m, 3H), 1.05 - 0.91 (m, 3H), 0.78 - 0.61 (m, 3H) ppm. MS: M / e 481 (M+1) + .

[0303] Compound A13: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0304] Step A: 1-(2-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)ethan-1-one [ka]

[0305] To a solution of 1-(2-fluoro-4-hydroxyphenyl)ethan-1-one (462 mg, 3 mmol) in CHCN (10 mL) was added tetrahydrofuran-3-yl 4-methylbenzenesulfonate (363 mg, 1.5 mmol) and KCO (820 mg, 6 mmol). The reaction mixture was stirred at 90 °C overnight in a sealed bottle. The mixture was cooled to room temperature, diluted with HO, extracted with EA (60 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (130 mg). MS: M / e 225 (M+1) + .

[0306] Step B: 1-(2-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)ethan-1-ol [ka]

[0307] To a solution of 1-(2-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)ethan-1-one (130 mg, 0.58 mmol) in MeOH (5 mL) was added NaBH (44 mg, 1.16 mmol) slowly at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with HO (10 mL), extracted with EA (80 mL), washed with brine, dried over NaSO, filtered, and concentrated to give the desired product (110 mg, 84%). 1 H NMR (400 MHz, DMSO-d6) δ 7.39 (t, J = 8.5 Hz, 1H), 6.78 - 6.69 (m, 2H), 5.15 (d, J = 4.5 Hz, 1H), 5.04 - 4.98 (m, 1H), 4.94 - 4.85 (m, 1H), 3.90 - 3.70 (m, 4H), 2.26 - 2.17 (m, 1H), 1.98 - 1.89 (m, 1H), 1.30 (d, J = 6.5 Hz, 3H) ppm.

[0308] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0309] To a solution of 1-(2-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)ethan-1-ol (45 mg, 0.2 mmol), 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 (33 mg, 0.1 mmol), and (cyanomethyl)trimethylphosphonium iodide (73 mg, 0.3 mmol) in CHCN (1 mL) was added DIPEA (65 mg, 0.5 mmol). The mixture was sealed in a bottle and heated at 100° C. for 16 h. The mixture was cooled to room temperature, diluted with water, extracted with EA (60 mL), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (8 mg, 14%). 1 H NMR (500 MHz, CD3OD) δ 7.93 - 7.91 (m, 1H), 7.52 - 7.37 (m, 1H), 6.80 - 6.60 (m, 2H), 5.54 (s, 1H), 5.48 - 5.44 (m, 2H), 5.05 - 4.95 (m, 1H), 4.12 - 4.04 (m, 0.5H), 4.00 - 3.83 (m, 4.5H), 3.51 - 3.44 (m, 0.5H), 3.43 (s, 3H), 3.35 -3.31 (m, 2H), 3.29 -3.24 (m, 0.5H), 3.15 - 3.06 (m, 0.5H), 2.96 - 2.84 (m, 1H), 2.69 -2.61 (m, 0.5H), 2.48 - 2.36 (m, 1H), 2.31 - 2.20 (m, 1H), 2.15 - 1.90 (m, 2H), 1.85 - 1.45 (m, 3H), 1.35 (d, J = 6.5 Hz, 1.5H), 1.30 (d, J = 6.5 Hz, 1.5H), 1.02 (t, J = 7.5 Hz, 1.5H), 0.95 (t, J = 7.5 Hz, 1.5H), 0.74 (t, J = 7.5 Hz, 1.5H), 0.65(t, J = 7.5Hz, 1.5H) ppm. MS: M / e 537 (M+1)+ .

[0310] Compound A14: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-methoxy-2-methylphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0311] Step A: 1-(4-Methoxy-2-methylphenyl)ethan-1-one [ka]

[0312] To a solution of 1-(4-hydroxy-2-methylphenyl)ethan-1-one (450 mg, 3 mmol) and CHCl (511 mg, 3.6 mmol) in acetone (5 mL) was added KCO (828 mg, 6 mmol). The reaction mixture was stirred overnight at 90° C. under N. The mixture was cooled to room temperature, diluted with water, extracted with EA (80 mL), washed with brine, dried over NaSO, filtered, and concentrated to give the title compound (420 mg, 84%). MS: M / e 165 (M+1) + .

[0313] Step B: 1-(4-Methoxy-2-methylphenyl)ethan-1-ol [ka]

[0314] To a solution of 1-(4-methoxy-2-methylphenyl)ethan-1-one (420 mg, 2.56 mmol) in MeOH (10 mL) was added NaBH (200 mg, 5.26 mmol) slowly at 0 °C. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with HO (10 mL), extracted with EA (80 mL), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the desired product (360 mg, 84%).

[0315] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-methoxy-2-methylphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0316] To a solution of 1-(4-methoxy-2-methylphenyl)ethan-1-ol (34 mg, 0.2 mmol), 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 (33 mg, 0.1 mmol), and (cyanomethyl)trimethylphosphonium iodide (75 mg, 0.3 mmol) in CHCN (1 mL) was added DIPEA (65 mg, 0.5 mmol). The mixture was sealed in a bottle and heated at 100 °C for 16 h. The mixture was cooled to room temperature, diluted with water, extracted with EA (60 mL), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (14 mg, 29%). 1H NMR (500 MHz, CD3OD) δ 7.91 - 7.89 (m, 1H), 7.48 - 7.32 (m, 1H), 6.77 - 6.66 (m, 2H), 5.57 - 5.52 (m, 1H), 5.49 - 5.44 (m, 2H), 3.95 - 3.80 (m, 1H), 3.76 (s, 3H), 3.52 - 3.44 (m, 0.5H), 3.43 (s, 3H), 3.35 -3.31 (m, 2H), 3.18 - 3.10 (m, 1H), 3.05 - 3.00 (m, 0.5H), 2.88 - 2.78 (m, 0.5H), 2.66 - 2.56 (m, 0.5H), 2.52 - 2.44 (m, 0.5H), 2.42 - 2.31 (m, 3.5H), 2.21 - 1.40 (m, 4H), 1.32 - 1.21 (m, 3H), 1.05 - 0.87 (m, 3H), 0.72 - 0.58 (m, 3H) ppm. MS: M / e 477 (M+1) + .

[0317] Compound A15: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0318] Step A: 1-(4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl)ethan-1-one [ka]

[0319] To a solution of 1-(4-(bromomethyl)phenyl)ethan-1-one (300 mg, 1.42 mmol) in DMF (3 mL) was added tetrahydro-2H-pyran-4-ol (173 mg, 1.70 mmol), TBAB (46 mg, 0.14 mmol), and CsCO (923 mg, 2.83 mmol). The resulting mixture was stirred at 80 °C overnight. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over NaSO, and concentrated to give the title compound (290 mg, 88%). MS: M / e 235 (M+1) + .

[0320] Step B: 1-(4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl)ethan-1-ol [ka]

[0321] To a solution of 1-(4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl)ethan-1-one (290 mg, 1.24 mmol) in MeOH (15 mL) was added NaBH4 (94 mg, 2.48 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over Na2SO4, and concentrated to give the title compound (270 mg, 92%). MS: M / e 237 (M+1) + .

[0322] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0323] To a solution of 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 (50 mg, 0.15 mmol) in CHCN (3 mL) was added 1-(4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl)ethan-1-ol (36 mg, 0.15 mmol), (cyanomethyl)trimethylphosphonium iodide (112 mg, 0.46 mmol), and DIPEA (98 mg, 0.76 mmol). The resulting mixture was stirred at 105° C. overnight. The reaction solvent was removed under reduced pressure to give the crude product. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (19 mg, 23%). 1 H NMR (400 MHz, CD3OD) δ 7.91 (d, J = 3.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.36 - 7.29 (m, 3H), 5.55 (s, 1H), 5.46 (d, J = 5.0 Hz, 2H), 4.57 (d, J = 4.3 Hz, 2H), 3.95 - 3.89 (m, 2H), 3.77 - 3.44 (m, 5H), 3.43 (s, 3H), 3.30 - 3.09 (m, 3H), 3.02 - 2.37 (m, 2H), 2.11 - 1.83 (m, 3H), 1.58 (ddd, J = MS: M / e 547 (M+1) + .

[0324] Compound A16: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-((oxetan-3-yloxy)methyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0325] Step A: 1-(4-((oxetan-3-yloxy)methyl)phenyl)ethan-1-one [ka]

[0326] To a solution of 1-(4-(bromomethyl)phenyl)ethan-1-one (300 mg, 1.42 mmol) in DMF (3 mL) was added oxetan-3-ol (173 mg, 1.70 mmol), TBAB (46 mg, 0.14 mmol), and CsCO (923 mg, 2.83 mmol). The resulting mixture was stirred at 80 °C overnight. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over NaSO, and concentrated to give the title compound (230 mg, 79%). MS: M / e 207 (M+1) + .

[0327] Step B: 1-(4-((oxetan-3-yloxy)methyl)phenyl)ethan-1-ol [ka]

[0328] To a solution of 1-(4-((oxetan-3-yloxy)methyl)phenyl)ethan-1-one (230 mg, 1.12 mmol) in MeOH (15 mL) was added NaBH4 (85 mg, 2.23 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over Na2SO4, and concentrated to give the title compound (200 mg, 86%). MS: M / e 209 (M+1) + .

[0329] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-((oxetan-3-yloxy)methyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0330] To a solution of 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 (50 mg, 0.15 mmol) in CHCN (3 mL) was added 1-(4-((oxetan-3-yloxy)methyl)phenyl)ethan-1-ol (32 mg, 0.15 mmol), (cyanomethyl)trimethylphosphonium iodide (112 mg, 0.46 mmol), and DIPEA (98 mg, 0.76 mmol). The resulting mixture was stirred at 105° C. overnight. The reaction solvent was removed under reduced pressure to give the crude product. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (20 mg, 25%). 1H NMR (400 MHz, CD3OD) δ 7.91 (d, J = 3.4 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.38 - 7.30 (m, 3H), 5.55 (s, 1H), 5.46 (d, J = 4.9 Hz, 2H), 4.83 - 4.65 (m, 4H), 4.55 - 4.51 (m, 2H), 4.47 (d, J = 4.5 Hz, 2H), 3.76 - 3.58 (m, 1H), 3.54 - 3.44 (m, 1H), 3.43 (s, 3H), 3.27 - 2.96 (m, 2H), 2.90 - 2.57 (m, 1H), 2.48 - 2.32 (m, 1H), 2.17 - 1.41 (m, 4H), 1.32 (dd, J = 17.1, 6.5 Hz, 3H), 0.99 (dt, J = 29.4, 7.4 Hz, 3H), 0.65 (dt, J = 25.5, 7.2 Hz, 3H) ppm. MS: M / e 519 (M+1) + .

[0331] Compound A17: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0332] Step A: 1-(4-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl)ethan-1-one [ka]

[0333] To a solution of 1-(4-(bromomethyl)phenyl)ethan-1-one (300 mg, 1.42 mmol) in DMF (3 mL) was added tetrahydrofuran-3-ol (149 mg, 1.70 mmol), TBAB (46 mg, 0.14 mmol), and CsCO (923 mg, 2.83 mmol). The resulting mixture was stirred at 80 °C overnight. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over NaSO, and concentrated to give the title compound (270 mg, 87%). MS: M / e 221 (M+1) + .

[0334] Step B: 1-(4-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl)ethan-1-ol [ka]

[0335] To a solution of 1-(4-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl)ethan-1-one (270 mg, 1.23 mmol) in MeOH (15 mL) was added NaBH4 (94 mg, 2.45 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over Na2SO4, and concentrated to give the title compound (250 mg, 92%). MS: M / e 223 (M+1) + .

[0336] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0337] To a solution of 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 (50 mg, 0.15 mmol) in CHCN (3 mL) was added 1-(4-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl)ethan-1-ol (34 mg, 0.15 mmol), (cyanomethyl)trimethylphosphonium iodide (112 mg, 0.46 mmol), and DIPEA (98 mg, 0.76 mmol). The resulting mixture was stirred at 105° C. overnight. The reaction solvent was removed under reduced pressure to give the crude product. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (28 mg, 34%). 1 H NMR (400 MHz, CD3OD) δ 7.91 (d, J = 3.5 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.36 - 7.28 (m, 3H), 5.55 (s, 1H), 5.46 (d, J = 4.8 Hz, 2H), 4.54 - 4.46 (m, 2H), 4.29 - 4.24 (m, 1H), 3.90 - 3.74 (m, 4H), 3.62 - 3.50 (m, 1H), 3.49 - 3.43 (m, 1H), 3.43 (d, J = 1.2 Hz, 3H), 3.29 - 3.24 (m, 2H), 3.19 - 2.59 (m, 2H), 2.48 - 2.34 (m, 1H), 2.17 - 1.92 (m, 3H), 1.85 - 1.46 (m, 3H), 1.32 (dd, J = 16.2, 6.5 Hz, 3H), 0.99 (dt, J = 29.5, 7.2 Hz, 3H), 0.65 (dt, J = 29.2, 7.3 Hz, 3H) ppm. MS: M / e 533 (M+1) + .

[0338] Compound A18: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-((2-methoxyethoxy)methyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0339] Step A: Methyl 4-(1-((tert-butyldimethylsilyl)oxy)ethyl)benzoate [ka]

[0340] To a stirred solution of methyl 4-(1-hydroxyethyl)benzoate (5 g, 27.78 mmol) and imidazole (2.27 g, 33.33 mmol) in DCM (200 mL) was added TBDMSCl (4.17 g, 27.78 mmol). The mixture was then stirred for 3 h. The mixture was diluted with CHCl (20 mL) and then washed with H0, brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (8 g, 98%). MS: M / e 295 (M+1) + .

[0341] Step B: (4-(1-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)methanol [ka]

[0342] To a stirred solution of methyl 4-(1-((tert-butyldimethylsilyl)oxy)ethyl)benzoate (8 g, 27.21 mmol) in THF (200 mL) was added lithium aluminum(III) hydride (1.0 M, 32.65 mmol, 32.65 mL) at 0 °C. The mixture was then stirred at room temperature for 5 h. The mixture was quenched with aqueous NaOH, filtered, and extracted with CHCl. ​​The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound (6.7 g, 92%). MS: M / e 267 (M+1) + .

[0343] Step C: tert-butyl(1-(4-((2-methoxyethoxy)methyl)phenyl)ethoxy)dimethylsilane [ka]

[0344] To a mixture of (4-(1-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)methanol (200 mg, 0.75 mmol) in THF (20 mL) was added NaH (36 mg, 0.90 mmol) at 0° C. and stirred for 1 h. Then 1-bromo-2-methoxyethane (156 mg, 1.13 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was extracted with EA, washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (170 mg, 70%). MS: M / e 325 (M+1) + .

[0345] Step D: 1-(4-((2-methoxyethoxy)methyl)phenyl)ethan-1-ol [ka]

[0346] To a solution of tert-butyl(1-(4-(methoxymethyl)phenyl)ethoxy)dimethylsilane (170 mg, 0.52 mmol) in THF (5 mL) was added TBAF (1 mL, 1 mmol). The reaction mixture was stirred at room temperature for 3 hours. 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 flash column chromatography to give the title compound (80 mg, 72%). MS: M / e 211 (M+1) + .

[0347] Step E: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-((2-methoxyethoxy)methyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0348] To a solution of 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 (50 mg, 0.15 mmol) in CHCN (3 mL) was added 1-(4-((2-methoxyethoxy)methyl)phenyl)ethan-1-ol (32 mg, 0.18 mmol), (cyanomethyl)trimethylphosphonium iodide (112 mg, 0.46 mmol), and DIPEA (98 mg, 0.76 mmol). The resulting mixture was stirred at 105° C. overnight. The reaction solvent was removed under reduced pressure to give the crude product. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (32 mg, 40%). 1H NMR (400 MHz, CD3OD) δ 7.92 (d, J = 2.3 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.37 - 7.30 (m, 3H), 5.55 (s, 1H), 5.46 (d, J = 4.3 Hz, 2H), 4.54 (d, J = 6.1 Hz, 2H), 3.88 - 3.64 (m, 1H), 3.64 - 3.59 (m, 2H), 3.59 - 3.56 (m, 2H), 3.54 - 3.44 (m, 1H), 3.43 (s, 3H), 3.36 (d, J = 2.8 Hz, 3H), 3.28 - 3.01 (m, 3H), 2.93 - 2.39 (m, 2H), 2.18 - 1.87 (m, 1H), 1.84 - 1.49 (m, 3H), 1.35 (dd, J = 22.7, 6.4 Hz, 3H), 0.99 (dt, J = 28.1, 7.4 Hz, 3H), 0.65 (dt, J = 32.0, 7.4 Hz, 3H) ppm. MS: M / e 521 (M+1) + .

[0349] Compound A19: 2-(7-((2S,5R)-4-(1-(4-(difluoromethoxy)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0350] Step A: 1-(4-(difluoromethoxy)phenyl)ethan-1-ol [ka]

[0351] To a solution of 1-(4-(difluoromethoxy)phenyl)ethan-1-one (558 mg, 3 mmol) in MeOH (10 mL) was added NaBH (114 mg, 3 mmol) slowly at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with HO (20 mL), extracted with EA (80 mL), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was used directly in the next step (500 mg, 88%). 1 H NMR (500 MHz, DMSO-d6) δ 7.41 - 7.35 (m, 2H), 7.11 (d, J = 8.5 Hz, 2H), 7.34 - 7.02 (m, 1H), 5.18 (d, J = 4.5 Hz, 1H), 4.76 - 4.68 (m, 1H), 1.30 (d, J = 6.5 Hz, 3H) ppm.

[0352] Step B: 2-(7-((2S,5R)-4-(1-(4-(difluoromethoxy)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0353] To a solution of 1-(4-(difluoromethoxy)phenyl)ethan-1-ol (39 mg, 0.2 mmol), 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 (33 mg, 0.1 mmol), and cyanomethyl)trimethylphosphonium iodide (73 mg, 0.3 mmol) in CHCN (1 mL) was added DIPEA (65 mg, 0.5 mmol). The mixture was sealed in a bottle and heated at 100° C. for 16 h. The mixture was cooled to room temperature, diluted with water, extracted with EA (60 mL), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM / MeOH=20 / 1) and preparative HPLC (Method A) to give the title compound A19a (7 mg) and compound A19b (6 mg).

[0354] Compound A19a (early peak): 1 H NMR (500 MHz, CD3OD) δ 7.91 (s, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 6.96 - 6.64 (m, 1H), 5.55 (s, 1H), 5.46 (s, 2H), 3.79 - 3.73 (m, 1H), 3.46 - 3.43 (m, 1H), 3.43 (s, 3H), 3.35 -3.31 (m, 1H), 3.28 - 3.24 (m, 1H), 3.03 - 2.97 (m, 1H), 2.91 - 2.82 (m, 1H), 2.46 - 2.35 (m, 1H), 2.16 - 2.05 (m, 1H), 1.87 - 1.76 (m, 1H), 1.59 - 1.46 (m, 2H), 1.33 (d, J = 6.5 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H), 0.69 (t, J = 7.5 Hz, 3H) ppm. MS: M / e 499 (M+1) + .

[0355] Compound A19b (later peak): 1H NMR (500 MHz, CD3OD) δ 7.92 (s, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 6.96 - 6.64 (m, 1H), 5.55 (s, 1H), 5.46 (s, 2H), 3.65 - 3.57 (m, 1H), 3.54 - 3.45 (m, 1H), 3.43 (s, 3H), 3.35 -3.31 (m, 2H), 3.20 - 3.10 (m, 1H), 2.66 - 2.60 (m, 1H), 2.39 - 2.32 (m, 1H), 2.02 - 1.89 (m, MS: M / e 499 (M+1) + .

[0356] Compound A20: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro-4-methoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0357] Step A: 1-(3-fluoro-4-methoxyphenyl)ethan-1-one [ka]

[0358] To a solution of 1-(3-fluoro-4-hydroxyphenyl)ethan-1-one (616 mg, 4 mmol) and CHI (705 mg, 5 mmol) in CHCN (15 mL) was added KCO (1.1 g, 8 mmol). The reaction mixture was stirred at 90 °C overnight. The mixture was cooled to room temperature, diluted with water, extracted with EA (80 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by Combiflash to give the title compound (560 mg, 82%). MS: M / e 169 (M+1) + .

[0359] Step B: 1-(3-fluoro-4-methoxyphenyl)ethan-1-ol [ka]

[0360] To a solution of 1-(3-fluoro-4-methoxyphenyl)ethan-1-one (560 mg, 3.33 mmol) in MeOH (10 mL) was added NaBH (127 mg, 3.33 mmol) slowly at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with HO (10 mL), extracted with EA (80 mL), washed with brine, dried over NaSO, filtered, and concentrated to dryness to give the desired product (500 mg, 89%). MS: M / e 153 (M-HO+1). + .

[0361] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro-4-methoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0362] To a solution of 1-(3-fluoro-4-methoxyphenyl)ethan-1-ol (34 mg, 0.2 mmol), 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 (33 mg, 0.1 mmol), and (cyanomethyl)trimethylphosphonium iodide (75 mg, 0.3 mmol) in CHCN (1 mL) was added DIPEA (65 mg, 0.5 mmol). The mixture was sealed in a bottle and heated at 100° C. for 16 h. The mixture was cooled to room temperature, diluted with water, extracted with EA (60 mL), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give the title compound (8 mg, 16%). 1 H NMR (500 MHz, CD3OD) δ 7.93 - 7.91 (m, 1H), 7.21 - 6.95 (m, 3H), 5.55 (s, 1H), 5.49 - 5.44 (m, 2H), 3.94 - 3.77 (m, 3.5H), 3.75 - 3.66 (m, 0.5H),3.59 - 3.41 (m, 1.5H), 3.43 (s, 3H), 3.35 -3.31 (m, 1H), 3.28 - 3.25 (m, 0.5H), 3.18 - 3.08 (m, 0.5H), 3.02 - 2.96 (m, 0.5H), 2.89 - 2.81 (m, 0.5H), 2.66 - 2.58 (m, 0.5H), 2.49 - 2.35 (m, 1H), 2.16 - 1.46 (m, 4H), 1.36 - 1.24 (m, 3H), 1.05 - 0.91 (m, 3H), 0.76 - 0.59 (m, 3H) ppm. MS: M / e 481 (M+1) + .

[0363] Compound A21: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methyl-4-(oxetan-3-yloxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0364] Step A: 1-(3-methyl-4-(oxetan-3-yloxy)phenyl)ethan-1-one [ka]

[0365] To a solution of 1-(4-hydroxy-3-methylphenyl)ethan-1-one (500 mg, 3.33 mmol) in DMF (3 mL) was added oxetan-3-yl 4-methylbenzenesulfonate (760 mg, 3.33 mmol), TBAB (107 mg, 0.33 mmol), and CsCO (2.17 g, 6.67 mmol). The resulting mixture was stirred at 80 °C overnight. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over NaSO, and concentrated to give the title compound (470 mg, 68%). MS: M / e 207 (M+1) + .

[0366] Step B: 1-(3-methyl-4-(oxetan-3-yloxy)phenyl)ethan-1-ol [ka]

[0367] To a solution of 1-(3-methyl-4-(oxetan-3-yloxy)phenyl)ethan-1-one (470 mg, 2.28 mmol) in MeOH (15 mL) was added NaBH (173 mg, 4.56 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over NaSO, and concentrated to give the title compound (400 mg, 84%). MS: M / e 209 (M+1) + .

[0368] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methyl-4-(oxetan-3-yloxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0369] To a solution of 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 (50 mg, 0.15 mmol) in CHCN (3 mL) was added 1-(3-methyl-4-(oxetan-3-yloxy)phenyl)ethan-1-ol (32 mg, 0.15 mmol), (cyanomethyl)trimethylphosphonium iodide (112 mg, 0.46 mmol), and DIPEA (98 mg, 0.76 mmol). The resulting mixture was stirred at 105 °C overnight. The reaction solvent was removed under reduced pressure to give the crude product. The resulting residue was purified by preparative HPLC (Method A) to give the title compound A21a (20 mg) and compound A21b (15 mg).

[0370] Compound A21a (early peak): 11H NMR (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.22 (d, J = 11.5 Hz, 1H), 7.16 - 7.07 (m, 1H), 6.46 (dd, J = 18.8, 8.3 Hz, 1H), 5.55 (d, J = 3.1 Hz, 1H), 5.47 (d, J = 1.6 Hz, 2H), 5.31 - 5.24 (m, 1H), 5.03 (dd, J = 12.6, 6.3 Hz, 2H), 4.72 - 4.67 (m, 2H), 3.91 - 3.60 (m, J = 113.1 Hz, 1H), 3.59 - 3.43 (m, 1H), 3.43 (s, 3H), 3.33 - 3.31 (m, J = 1.6 Hz, 1H), 3.05 (d, J = 3.3 Hz, 2H), 2.65 (s, 1H), 2.65 - 2.42 (m, 1H), 2.26 (d, J = 11.0 Hz, 3H), 2.06 - 1.49 (m, 4H), 1.37 (dd, J = 39.9, 6.5 Hz, 3H), 0.99 (dt, J = 25.0, 7.4 Hz, 3H), 0.68 (dt, J = 36.6, 7.3 Hz, 3H) ppm. MS: M / e 519 (M+1) + .

[0371] Compound A21b (later peak): 1H NMR (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.14 - 6.99 (m, 2H), 6.35 (dd, J = 8.4, 4.2 Hz, 1H), 5.48 - 5.43 (m, 1H), 5.24 - 5.17 (m, 1H), 5.10 - 4.96 (m, 3H), 4.71 - 4.61 (m, 2H), 4.22 - 3.91 (m, 1H), 3.48 (s, 3H), 3.44 - 3.30 (m, 3H), 3.29 - 3.13 (m, 1H), 3.06 - 2.63 (m, 3H), 2.19 (s, 3H), 1.67 (dd, J = 16.8, 7.3 Hz, 3H), 1.62 - 1.07 (m, 4H), 0.90 - 0.76 (m, 6H) ppm. MS: M / e 519 (M+1) + .

[0372] Compound A22: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-(oxetan-3-yloxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0373] Step A: 1-(2-fluoro-4-(oxetan-3-yloxy)phenyl)ethan-1-one [ka]

[0374] To a solution of 1-(2-fluoro-4-hydroxyphenyl)ethan-1-one (500 mg, 3.25 mmol) in DMF (3 mL) was added oxetan-3-yl 4-methylbenzenesulfonate (740 mg, 3.24 mmol), TBAB (107 mg, 0.32 mmol), and CsCO (2.12 g, 6.49 mmol). The resulting mixture was stirred at 80 °C overnight. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over NaSO, and concentrated to give the title compound (500 mg, 73%). MS: M / e 211 (M+1). + .

[0375] Step B: 1-(2-fluoro-4-(oxetan-3-yloxy)phenyl)ethan-1-ol [ka]

[0376] To a solution of 1-(2-fluoro-4-(oxetan-3-yloxy)phenyl)ethan-1-one (500 mg, 2.38 mmol) in MeOH (15 mL) was added NaBH (181 mg, 4.76 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over NaSO, and concentrated to give the title compound (460 mg, 91%). MS: M / e 213 (M+1) + .

[0377] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-(oxetan-3-yloxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0378] To a solution of 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 (50 mg, 0.15 mmol) in CHCN (3 mL) was added 1-(2-fluoro-4-(oxetan-3-yloxy)phenyl)ethan-1-ol (32 mg, 0.15 mmol), (cyanomethyl)trimethylphosphonium iodide (112 mg, 0.46 mmol), and DIPEA (98 mg, 0.76 mmol). The resulting mixture was stirred at 105° C. overnight. The reaction solvent was removed under reduced pressure to give the crude product. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (30 mg, 38%). 1 H NMR (400 MHz, CD3OD) δ 7.92 (d, J = 2.9 Hz, 1H), 7.46 (dt, J = 37.5, 8.5 Hz, 1H), 6.66 - 6.58 (m, 1H), 6.52 (ddd, J = 14.5, 11.9, 2.5 Hz, 1H), 5.54 (s, 1H), 5.46 (d, J = 3.9 Hz, 2H), 5.27 (dt, J = 10.9, 5.4 Hz, 1H), 5.01 (dd, J = 11.5, 6.4 Hz, 2H), 4.69 - 4.64 (m, 2H), 4.11 - 3.93 (m, 1H), 3.58 - 3.44 (m, 1H), 3.43 (s, 3H), 3.30 - 3.21 (m, 2H), 3.18 - 2.63 (m, 2H), 2.49 - 2.30 (m, 1H), 2.10 - 1.88 (m, 1H), 1.86 - 1.65 (m, 1H), 1.65 - 1.52 (m, 1H), 1.52 - 1.41 (m, 1H), 1.32 (dd, J = 21.8, 6.6 Hz, 3H), 0.98 (dt, J = 35.0, 7.4 Hz, 3H), 0.69 (dt, J = 46.0, 7.4 Hz, 3H). MS: M / e 523 (M+1) + .

[0379] Compound A23: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro-4-(oxetan-3-yloxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0380] Step A: 1-(3-fluoro-4-(oxetan-3-yloxy)phenyl)ethan-1-one [ka]

[0381] To a solution of 1-(3-fluoro-4-hydroxyphenyl)ethan-1-one (500 mg, 3.25 mmol) in DMF (3 mL) was added oxetan-3-yl 4-methylbenzenesulfonate (740 mg, 3.24 mmol), TBAB (107 mg, 0.32 mmol), and CsCO (2.12 g, 6.49 mmol). The resulting mixture was stirred at 80 °C overnight. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over NaSO, and concentrated to give the title compound (500 mg, 73%). MS: M / e 211 (M+1). + .

[0382] Step B: 1-(3-fluoro-4-(oxetan-3-yloxy)phenyl)ethan-1-ol [ka]

[0383] To a solution of 1-(3-fluoro-4-(oxetan-3-yloxy)phenyl)ethan-1-one (500 mg, 2.38 mmol) in MeOH (15 mL) was added NaBH (181 mg, 4.76 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over NaSO, and concentrated to give the title compound (460 mg, 91%). MS: M / e 213 (M+1) + .

[0384] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro-4-(oxetan-3-yloxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0385] To a solution of 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 (50 mg, 0.15 mmol) in CHCN (3 mL) was added 1-(3-fluoro-4-(oxetan-3-yloxy)phenyl)ethan-1-ol (32 mg, 0.15 mmol), (cyanomethyl)trimethylphosphonium iodide (112 mg, 0.46 mmol), and DIPEA (98 mg, 0.76 mmol). The resulting mixture was stirred at 105 °C overnight. The reaction solvent was removed under reduced pressure to give the crude product. The resulting residue was purified by preparative HPLC (Method A) to give the title compound A23a (17 mg) and compound A23b (15 mg).

[0386] Compound A23a (early peak): 11H NMR (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.21 (dd, J = 12.5, 1.9 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.71 (t, J = 8.4 Hz, 1H), 5.55 (s, 1H), 5.47 (s, 2H), 5.31 - 5.25 (m, 1H), 4.99 (t, J = 6.7 Hz, 2H), 4.84 - 4.78 (m, 2H), 4.74 - 4.70 (m, 2H), 3.55 (q, J = 6.6 Hz, 1H), 3.48 (d, J = 11.8 Hz, 1H), 3.43 (s, 3H), 3.11 (d, J = 10.0 Hz, 1H), 2.62 (dd, J = 12.4, 3.7 Hz, 1H), 2.36 (d, J = 12.4 Hz, 1H), 2.03 - 1.86 (m, 1H), 1.69 - 1.59 (m, 2H), 1.56 - 1.48 (m, 1H), 1.27 (d, J = 6.5 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H), 0.65 (t, J = 7.4 Hz, 3H) ppm. MS: M / e 523 (M+1) + .

[0387] Compound A23b (later peak): 1H NMR (400 MHz, CD3OD) δ 7.91 (s, 1H), 7.17 (dd, J = 12.4, 1.9 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.73 (t, J = 8.5 Hz, 1H), 5.55 (s, 1H), 5.46 (s, 2H), 5.32 - 5.27 (m, 1H), 5.00 (t, J = 6.8 Hz, 2H), 4.74 (t, J = 5.6 Hz, 2H), 3.70 (q, J = 6.3 Hz, 1H), 3.43 (s, 3H), 3.30 - 3.25 (m, 3H), 2.97 (d, J = 10.2 Hz, 1H), 2.85 (dd, J = 12.0, 3.9 Hz, 1H), 2.42 (s, 1H), 2.15 - 2.03 (m, 1H), 1.86 - 1.76 (m, 1H), 1.55 - 1.46 (m, 2H), 1.30 (d, J = 6.5 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H), 0.71 (t, J = 7.4 Hz, 3H) ppm. MS: M / e 523 (M+1) + .

[0388] Compound A24: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-((3-methyloxetan-3-yl)oxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0389] Step A: 4-((3-methyloxetan-3-yl)oxy)benzonitrile [ka]

[0390] To a solution of 4-fluorobenzonitrile (200 mg, 1.65 mmol) in DMF (3 mL) was added 3-methyloxetan-3-ol (291 mg, 3.31 mmol), TBAB (53 mg, 0.16 mmol), and potassium t-butoxide (370 g, 3.31 mmol). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over NaSO, and concentrated to give the title compound (275 mg, 88%). MS: M / e 190 (M+1) + .

[0391] Step B: 1-(4-((3-methyloxetan-3-yl)oxy)phenyl)ethan-1-one [ka]

[0392] To a solution of 4-((3-methyloxetan-3-yl)oxy)benzonitrile (275 mg, 1.45 mmol) in THF (15 mL) was added methylmagnesium bromide (2.2 mL, 2.18 mmol) at −78° C., and the resulting mixture was stirred at room temperature for 2 minutes. Concentrated HCl (1 mL) was added to the mixture, and the mixture was stirred for 1 hour. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over NaSO, and concentrated to give the title compound (200 mg, 67%). MS: M / e 207 (M+1) + .

[0393] Step C: 1-(4-((3-methyloxetan-3-yl)oxy)phenyl)ethan-1-ol [ka]

[0394] To a solution of 1-(4-((3-methyloxetan-3-yl)oxy)phenyl)ethan-1-one (200 mg, 0.97 mmol) in MeOH (15 mL) was added NaBH (55 mg, 1.45 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over NaSO, and concentrated to give the title compound (180 mg, 89%). MS: M / e 209 (M+1) + .

[0395] Step D: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-((3-methyloxetan-3-yl)oxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0396] To a solution of 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 (50 mg, 0.15 mmol) in CHCN (3 mL) was added 1-(4-((3-methyloxetan-3-yl)oxy)phenyl)ethan-1-ol (32 mg, 0.15 mmol), (cyanomethyl)trimethylphosphonium iodide (112 mg, 0.46 mmol), and DIPEA (98 mg, 0.76 mmol). The resulting mixture was stirred at 105° C. overnight. The reaction solvent was removed under reduced pressure to give the crude product. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (30 mg, 38%). 1H NMR (400 MHz, CD3OD) δ 7.91 (d, J = 2.6 Hz, 1H), 7.28 (dd, J = 14.5, 8.6 Hz, 2H), 6.65 (dd, J = 10.2, 8.7 Hz, 2H), 5.54 (d, J = 3.3 Hz, 1H), 5.46 (d, J = 3.7 Hz, 2H), 4.89 (d, J = 7.0 Hz, 2H), 4.87 (s, 1H), 4.60 (dd, J = 8.7, 4.8 Hz, 2H), 3.73 - 3.50 (m, 1H), 3.48 (s, 1H), 3.43 (d, J = 0.7 Hz, 3H), 3.17 (dd, J = 42.3, 27.6 Hz, 1H), 3.03 - 2.80 (m, 1H), 2.62 - 2.42 (m, 1H), 2.39 - 2.03 (m, 1H), 2.00 - 1.76 (m, 1H), 1.70 (d, J = 8.9 Hz, 3H), 1.68 - 1.41 (m, 3H), 1.30 (dd, J = 14.8, 6.5 Hz, 3H), 0.98 (dt, J = 31.5, 7.4 Hz, 3H), 0.65 (dt, J = 35.5, 7.3 Hz, 3H) ppm. MS: M / e 519 (M+1) + .

[0397] Compound A25: 2-(7-((2S,5R)-4-(1-(4-((dimethylamino)methyl)-3,5-difluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0398] Step A: 1-(4-bromo-2,6-difluorophenyl)-N,N-dimethylmethanamine [ka]

[0399] A solution of 4-bromo-2,6-difluorobenzaldehyde (500 mg, 2.26 mmol), dimethylamine hydrochloride (223 mg, 2.72 mmol), and STAB (719 mg, 3.39 mmol) in DCM (10 mL) was stirred at room temperature overnight. The solution was diluted with DCM (10 mL), washed with brine (10 mL), dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography (0-20% EtOAc / PE) to give the title compound (510 mg, 90%). MS: M / e 250 (M+1). + .

[0400] Step B: 1-(4-((dimethylamino)methyl)-3,5-difluorophenyl)ethan-1-one [ka]

[0401] A solution of 1-(4-bromo-2,6-difluorophenyl)-N,N-dimethylmethanamine (510 mg, 2.04 mmol), ethyl tributylstannanecarboxylate (921 mg, 2.55 mmol), and Pd(PPh3)2Cl2 (71.6 mg, 0.10 mmol) in toluene (10 mL) was stirred at 100 °C overnight. The solution was cooled to room temperature. HCl / 1,4-dioxane (4 M, 2 mL) was added and stirred at room temperature for 10 minutes. The solution was diluted with EtOAc (20 mL), washed with aqueous Na2CO3 (10 mL × 2), dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography (15-40% EA / PE) to give the title compound (283 mg, 65%). MS: M / e 214 (M+1). + .

[0402] Step C: 1-(4-((dimethylamino)methyl)-3,5-difluorophenyl)ethan-1-ol [ka]

[0403] A solution of 1-(4-((dimethylamino)methyl)-3,5-difluorophenyl)ethan-1-one (283 mg, 1.33 mmol) and NaBH4 (50.5 mg, 1.33 mmol) in MeOH (4 mL) was stirred at room temperature for 15 min. The solution was diluted with EtOAc (15 mL), washed with brine (10 mL x 2), dried over Na2SO4, and concentrated to dryness to give the title compound (268 mg, 93%), which was used directly in the next step without further purification. MS: M / e 216 (M+1) + .

[0404] Step D: 2-(7-((2S,5R)-4-(1-(4-((dimethylamino)methyl)-3,5-difluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0405] A solution of 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 (50 mg, 0.15 mmol), 1-(4-((dimethylamino)methyl)-3,5-difluorophenyl)ethan-1-ol (49.2 mg, 0.23 mmol), (cyanomethyl)trimethylphosphonium iodide (111 mg, 0.46 mmol), and DIPEA (197 mg, 1.53 mmol) in CHCN (2 mL) was stirred at 100° C. overnight. The reaction was diluted with EtOAc (15 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound A25, which was further separated by preparative HPLC (Method A) into compound A25a (8.5 mg) and compound A25b (9.3 mg).

[0406] Compound A25a (previous peak): 1 H NMR (500 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.98 (s, 1H), 7.09 (d, J = 8.3 Hz, 2H), 5.61 (s, 2H), 5.40 (s, 1H), 3.77 (q, J = 6.5 Hz, 1H), 3.46 (s, 2H), 3.35 (s, 2H), 3.27 (s, 3H), 3.18 (d, J = 6.5 Hz, 1H), 2.85 (d, J = 6.5 Hz, 1H), 2.76 (d, J = 6.5 Hz, 1H), 2.33 (s, 1H), 2.14 (s, 6H), 2.05 - 1.94 (m, 1H), 1.68 - 1.57 (m, 1H), 1.50 - 1.41 (m, 2H), 1.27 (d, J = 6.4 Hz, 3H), 0.85 (t, J = 7.1 Hz, 3H), 0.66 (t, J = 7.3 Hz, 3H) ppm. MS: M / e 526 (M+1) + .

[0407] Compound A25b (subsequent peak): 1H NMR (500 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.98 (s, 1H), 7.10 (d, J = 8.4 Hz, 2H), 5.61 (s, 2H), 5.39 (s, 1H), 3.61 (q, J = 6.2 Hz, 1H), 3.47 (q, J = 8.9 Hz, 2H), 3.35 (d, J = 11.0 Hz, 2H), 3.27 (s, 3H), 3.02 (d, J = 9.9 Hz, 1H), 2.54 (d, J = 9.9 Hz, 2H), 2.21 (d, J = 12.4 Hz, 1H), 2.11 (s, 6H), 1.96-1.84 (m, 1H), 1.64-1.53 ​​(m, 1H), 1.50-1.35 (m, 2H), 1.24 (d, J = 6.4 Hz, 3H), 0.94 (t, J = 7.1 Hz, 3H), 0.56 (t, J = 7.0 Hz, 3H) ppm. MS: M / e 526 (M+1) + .

[0408] Compound A26: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(pyrrolidin-1-ylmethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0409] Step A: 1-(4-Bromobenzyl)pyrrolidine [ka]

[0410] A solution of 4-bromobenzaldehyde (500 mg, 2.70 mmol), pyrrolidine (230 mg, 3.24 mmol), and STAB (859 mg, 4.05 mmol) in DCM (10 mL) was stirred at room temperature for 5 hours. The solution was diluted with DCM (10 mL), washed with brine (10 mL), dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography (0-10% MeOH / DCM) to give the title compound (630 mg, 97%). MS: M / e 240,242 (M+1). + .

[0411] Step B: 1-(4-(pyrrolidin-1-ylmethyl)phenyl)ethan-1-one [ka]

[0412] A solution of 1-(4-bromobenzyl)pyrrolidine (630 mg, 2.63 mmol), ethyl tributylstannanecarboxylate (1.42 g, 3.93 mmol), and Pd(PPh3)2Cl2 (92 mg, 0.13 mmol) in toluene (10 mL) was stirred at 100 °C overnight. The solution was cooled to room temperature. HCl / 1,4-dioxane (4 M, 2 mL) was added and stirred at room temperature for 10 minutes. The solution was diluted with EtOAc (20 mL), washed with aqueous Na2CO3 (10 mL x 2), dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography (0-10% MeOH / DCM) to give the title compound (316 mg, 59%). MS: M / e 204 (M+1). + .

[0413] Step C: 1-(4-(pyrrolidin-1-ylmethyl)phenyl)ethan-1-ol [ka]

[0414] A solution of 1-(4-(pyrrolidin-1-ylmethyl)phenyl)ethan-1-one (316 mg, 1.56 mmol) and NaBH (59.2 mg, 1.56 mmol) in MeOH (5 mL) was stirred at room temperature for 15 min. The solution was diluted with EtOAc (15 mL), washed with brine (10 mL x 2), dried over NaSO, and concentrated to dryness to give the title compound (300 mg, 94%), which was used directly in the next step without further purification. MS: M / e 206 (M+1) + .

[0415] Step D: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(pyrrolidin-1-ylmethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0416] A solution of 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 (50 mg, 0.15 mmol), 1-(4-(pyrrolidin-1-ylmethyl)phenyl)ethan-1-ol (62.5 mg, 0.30 mmol), (cyanomethyl)trimethylphosphonium iodide (111 mg, 0.46 mmol), and DIPEA (197 mg, 1.53 mmol) in CHCN (2 mL) was stirred at 100° C. overnight. The reaction was diluted with EtOAc (15 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound A26, which was further separated by preparative HPLC (Method A) into compound A26a (11 mg) and compound A26b (1 mg).

[0417] Compound A26a (early peak): 11H NMR (500 MHz, DMSO-d6) δ 8.22 (s, 1.4H), 7.97 (s, 1H), 7.27 (d, J = 1.5 Hz, 4H), 5.60 (s, 2H), 5.38 (s, 1H), 3.67 (q, J = 6.5 Hz, 1H), 3.57 (s, 2H), 3.33 (s, 1H), 3.27 (s, 4H), 3.10 (d, J = 12.0 Hz, 1H), 2.90 (d, J = 11.5 Hz, 1H), 2.74 (d, J = 8.4 Hz, 1H), 2.43 (s, 4H), 2.31 (s, 1H), 2.07-1.96 (m, 1H), 1.73-1.67 (m, 4H), 1.65-1.57 (m, 1H), 1.48-1.38 (m, 2H), 1.27 (d, J = 6.4 Hz, 3H), 0.86 (t, J = 7.1 Hz, 3H), 0.58 (t, J = 7.3 Hz, 3H) ppm. MS: M / e 516 (M+1) + .

[0418] Compound A26b (later peak): 1 1H NMR (500 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.97 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 5.61 (s, 2H), 5.38 (s, 1H), 3.54 (s, 3H), 3.27 (s, 7H), 3.04 (d, J = 10.4 Hz, 1H), 2.40 (s, 4H), 2.24 (d, J = 12.1 Hz, 1H),​​​​​Compound A27: 2-(7-((2S,5R)-4-(1-(4-((3,3-difluoroazetidin-1-yl)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0420] Step A: 1-(4-((3,3-difluoroazetidin-1-yl)methyl)phenyl)ethan-1-one [ka]

[0421] A solution of 1-(4-(bromomethyl)phenyl)ethan-1-one (500 mg, 2.36 mmol), 3,3-difluoroazetidine hydrochloride (307 mg, 2.36 mmol), and DIPEA (913 mg, 7.08 mmol) in THF (6 mL) was stirred at room temperature for 6 hours. The solution was diluted with EA (10 mL), washed with brine (10 mL), dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography (0-20% EA / PE) to give the title compound (380 mg, 72%). MS: M / e 226 (M+1). + .

[0422] Step B: 1-(4-((3,3-difluoroazetidin-1-yl)methyl)phenyl)ethan-1-ol [ka]

[0423] A solution of 1-(4-((3,3-difluoroazetidin-1-yl)methyl)phenyl)ethan-1-one (380 mg, 1.69 mmol) and NaBH4 (64 mg, 1.68 mmol) in MeOH (5 mL) was stirred at room temperature for 15 min. The solution was diluted with EtOAc (15 mL), washed with brine (10 mL x 2), dried over Na2SO4, and concentrated to dryness to give the title compound (380 mg, 99%), which was used directly in the next step without further purification. MS: M / e 228 (M+1) + .

[0424] Step C: 2-(7-((2S,5R)-4-(1-(4-((3,3-difluoroazetidin-1-yl)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0425] A solution of 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 (50 mg, 0.15 mmol), 1-(4-((3,3-difluoroazetidin-1-yl)methyl)phenyl)ethan-1-ol (104 mg, 0.46 mmol), (cyanomethyl)trimethylphosphonium iodide (111 mg, 0.46 mmol), and DIPEA (197 mg, 1.53 mmol) in CHCN (2 mL) was stirred at 100° C. overnight. The reaction was diluted with EtOAc (15 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography followed by preparative HPLC (Method A) to give the title compound (19 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.36 (s, 0.15H), 7.97 (d, J = 2.1 Hz, 1H), 7.34-7.22 (m, 4H), 5.61 (s, 2H), 5.38 (s, 1H), 3.72-3.66 (m, 2.5H), 3.57 (q, J = 12.6 Hz, 4.5H), 3.34 (s, 3H), 3.27 (s, 3H), 3.07 (dd, J = 30.2, 10.0 Hz, 1H), 2.90 (d, J = 11.4 Hz, 0.5H), 2.74 (d, J = 8.4 Hz, 0.5H), 2.30 (s, 0.5H), 2.22 (d, J = 11.7 Hz, 0.5H), 2.06-1.81 (m, 1H), 1.66-1.51 (m, 1H), 1.50- 1.39 (m, 2H), 1.25 (dd, J = 16.7, 6.4 Hz, 3H), 0.90 (dt, J = 41.8, 7.3 Hz, 3H), 0.57 (dt, J = 41.8, 7.5 Hz, 3H) ppm. MS: M / e 538 (M+1) + .

[0426] Compound A28: 2-(7-((2S,5R)-4-(1-(4-((dimethylamino)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0427] Step A: 1-(4-((dimethylamino)methyl)phenyl)ethan-1-one [ka]

[0428] To a stirred solution of 1-(4-(bromomethyl)phenyl)ethan-1-one (213 mg, 1 mmol), dimethylamine hydrochloride (81.5 mg, 1 mmol) in EtOH / CHCl (5 mL / 3 mL) was added DIPEA (258 mg, 2 mmol). After the addition, the reaction was stirred for 3 h. The reaction was poured into H0 (10 mL) and extracted with CHCl (10 mL x 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (80 mg, 45%). MS: M / e 178 (M+1) + .

[0429] Step B: 1-(4-((dimethylamino)methyl)phenyl)ethan-1-ol [ka]

[0430] To a stirred solution of 1-(4-((dimethylamino)methyl)phenyl)ethan-1-one (80 mg, 0.45 mmol) in MeOH (5 mL) was added NaBH (17 mg, 0.45 mmol). The mixture was then stirred for 20 min. The reaction was quenched with HO and concentrated to give the aqueous layer, which was extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound (80 mg, 100%). MS: M / e 180 (M+1) + .

[0431] Step C: 2-(7-((2S,5R)-4-(1-(4-((dimethylamino)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0432] A mixture of 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 (32.8 mg, 0.1 mmol), 1-(4-((dimethylamino)methyl)phenyl)ethan-1-ol (28 mg, 0.15 mmol), (cyanomethyl)trimethylphosphonium iodide (72.9 mg, 0.3 mmol), and DIPEA (129 mg, 1 mmol) in CHCN (4 mL) was stirred at 100 °C overnight in a sealed tube. The reaction mixture was diluted with EtOAc (15 mL), washed with HO, brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (2 mg).

[0433] 1 H NMR (500 MHz, CD3OD) δ 7.94 - 7.90 (m, 1H), 7.53 - 7.37 (m, 4H), 5.57 - 5.52 (m, 1H), 5.49 - 5.43 (m, 2H), 3.99 (s, 2H), 3.83 - 3.61 (m, 1H), 3.53 - 3.45 (m, 1H), 3.43 (s, 3H), 3.18 - 2.99 (m, 1H), 2.90 - 2.73 (m, 1H), 2.69 - 2.56 (m, 7H), 2.44 - 2.32 (m, 1H), 2.16 - 1.77 (m, 2H), 1.73 - 1.48 (m, 3H), 1.42 - 1.29 (m, 3H), 1.07 - 0.93 (m, 3H), 0.70 - 0.57 (m, 3H) ppm. MS: M / e 490 (M+1) + .

[0434] Compound A29: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-((methylamino)methyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0435] Step A: tert-Butyl (4-cyanobenzyl)(methyl)carbamate [ka]

[0436] To a stirred solution of 4-formylbenzonitrile (1.31 g, 10 mmol) in CHCl (20 mL) was added NHMe (2.0 M, 10 mL, 20 mmol), followed by AcOH (0.5 mL). After stirring for 1 h, NaBH(OAc) (3.18 g, 15 mmol) was added, and the mixture was stirred overnight. HO (20 mL) was added, and the mixture was extracted with CHCl (20 mL × 2). The combined organic layers were combined with HO (10 mL), and KCO (2.76 g, 20 mmol) was added, followed by BocO (3.27 g, 1.5 mmol). The mixture was then stirred for 2 h. The organic layer was separated, washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (1.5 g, 61%). MS: M / e 247 (M+1). + .

[0437] Step B: tert-Butyl (4-acetylbenzyl) (methyl)carbamate [ka]

[0438] To a stirred solution of tert-butyl (4-cyanobenzyl)(methyl)carbamate (492 mg, 2 mmol) in THF (10 mL) was added MeMgBr (3.0 M, 0.8 mL, 2.4 mmol) dropwise at 0 °C. The mixture was then stirred overnight. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (213 mg, 40%). MS: M / e 264 (M+1) + .

[0439] Step C: tert-Butyl (4-(1-hydroxyethyl)benzyl)(methyl)carbamate [ka]

[0440] To a stirred solution of tert-butyl (4-acetylbenzyl)(methyl)carbamate (213 mg, 0.81 mmol) in MeOH (5 mL) was added NaBH (30.8 mg, 0.81 mmol). The reaction mixture was then stirred for 10 minutes. The reaction mixture was quenched with HO, and most of the MeOH was then removed to obtain the aqueous layer, which was then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound (200 mg, 93.1%). MS: M / e 266 (M+1) + .

[0441] Step D: tert-Butyl (4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)benzyl)(methyl)carbamate [ka]

[0442] A solution of 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 (32.8 mg, 0.1 mmol), tert-butyl(4-(1-hydroxyethyl)benzyl)(methyl)carbamate (53.4 mg, 0.2 mmol), (cyanomethyl)trimethylphosphonium iodide (72.9 mg, 0.3 mmol), and DIPEA (64.5 mg, 0.5 mmol) in CHCN (4 mL) was stirred at 100° C. overnight in a sealed tube. The reaction mixture was diluted with EtOAc (10 mL), then washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by preparative TLC (CH2Cl2 / MeOH=10:1) to give the title compound (15 mg). MS: M / e 576 (M+1) + .

[0443] Step E: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-((methylamino)methyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0444] To a stirred solution of tert-butyl (4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)benzyl)(methyl)carbamate (15 mg, 0.026 mmol) in CHCl (5 mL) was added TFA (2 mL). The mixture was then stirred for 2 h. The reaction mixture was concentrated to give a residue which was purified by preparative HPLC (Method A) to give the title compound (3 mg). 1H NMR (400 MHz, CD3OD) δ 8.42 (s, 1H), 7.96 - 7.90 (m, 1H), 7.57 - 7.40 (m, 4H), 5.55 (s, 1H), 5.50 - 5.42 (m, 2H), 4.20 - 4.14 (m, 2H), 3.85 - 3.62 (m, 1H), 3.54 - 3.46 (m, 0.5H), 3.43 (s, 3H), 3.32 - 3.22 (m, 2.5H), 3.19 - 3.11 (m, 1H), 3.06 - 2.84 (m, 1H), 2.75 - 2.69 (m, 3H), 2.68 - 2.61 (m, 0.5H), 2.45 - 2.32 (m, 1H), 2.17 - 1.48 (m, 4H), 1.40 - 1.27 (m, 3H), 1.07 - 0.92 (m, 3H), 0.72 - 0.58 (m, 3H) ppm. MS: M / e 476 (M+1) + .

[0445] Compound A30: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0446] Step A: 1-(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)ethan-1-one [ka]

[0447] A mixture of (4-acetylphenyl)boronic acid (200 mg, 1.22 mmol), 4-bromo-1-methyl-1H-1,2,3-triazole (196 mg, 1.22 mmol), potassium carbonate (337 mg, 2.44 mmol), and Pd(dppf)Cl (89 mg, 0.12 mmol) in dioxane (3 mL) and water (0.5 mL) was stirred overnight at 100 °C under N. The reaction mixture was diluted with EA and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (180 mg, 73%). MS: M / e 202 (M+1) + .

[0448] Step B: 1-(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)ethan-1-ol [ka]

[0449] To a solution of 1-(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)ethan-1-one (180 mg, 0.89 mmol) in MeOH (15 mL) was added NaBH (68 mg, 1.79 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water, dried over NaSO, and concentrated to give the title compound (180 mg, 99%). MS: M / e 204 (M+1) + .

[0450] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0451] To a solution of 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 (50 mg, 0.15 mmol) in CHCN (3 mL) was added 1-(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)ethan-1-ol (31 mg, 0.15 mmol), (cyanomethyl)trimethylphosphonium iodide (112 mg, 0.46 mmol), and DIPEA (98 mg, 0.76 mmol). The resulting mixture was stirred at 105° C. overnight. The reaction solvent was removed under reduced pressure to give the crude product. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (21 mg, 26%). 1 H NMR (400 MHz, CD3OD) δ 8.25 (d, J = 4.5 Hz, 1H), 7.92 (d, J = 3.4 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.49 - 7.44 (m, 2H), 5.55 (s, 1H), 5.46 (d, J = 5.2 Hz, 2H), 4.15 (d, J = 3.0 Hz, 3H), 3.81 - 3.62 (m, 1H), 3.51 (d, J = 12.2 Hz, 1H), 3.43 (d, J = 1.1 Hz, 3H), 3.29 - 3.17 (m, 2H), 3.16 - 3.00 (m, J = 11.7 Hz, 1H), 2.92 - 2.63 (m, 1H), 2.52 - 2.39 (m, 1H), 2.19 - 1.91 (m, 1H), 1.86 - 1.52 (m, 3H), 1.36 (dd, J = 16.7, 6.5 Hz, 3H), 1.00 (dt, J = 30.0, 7.4 Hz, 3H), 0.67 (dt, J = 32.4, 7.3 Hz, 3H) ppm. MS: M / e 514(M+1) + .

[0452] Compound A31: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-isopropylphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0453] Step A: 1-(4-isopropylphenyl)ethan-1-ol [ka]

[0454] To a solution of 1-(4-isopropylphenyl)ethan-1-one (320 mg, 2 mol) in MeOH was added NaBH (76 mg, 2 mmol). The reaction mixture was stirred at room temperature for 15 minutes. HO (20 mL) was added to the mixture, and the mixture was extracted with DCM (20 mL x 3). The organic phase was dried over NaSO and concentrated using a rotary evaporator to obtain a residue. The resulting residue was purified by flash column chromatography to obtain the title compound (300 mg, 91%). MS: M / e 165 (M+1) + .

[0455] Step B: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-isopropylphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0456] To a solution of 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 (30 mg, 0.1 mmol), 1-(4-isopropylphenyl)ethan-1-ol (50 mg, 0.3 mmol), and (cyanomethyl)trimethylphosphonium iodide (120 mg, 0.5 mmol) in CHCN (10 mL) was added DIPEA (258 mg, 2 mmol). The reaction mixture was sealed in a bottle and heated at 105 °C for 16 h, then cooled to room temperature, diluted with water, and extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method B) to give the title compound (8 mg, 17%). 1 H NMR (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.28 (m, 2H), 7.19 (m, 2H), 5.54 (s, 1H), 5.46 (d, J = 3.1 Hz, 2H), 3.69 (s, 0.5H), 3.55 (s, 0.5H), 3.48 (d, J = 12.2 Hz, 1H), 3.43 (s, 3H), 3.35 (s,1H), 3.25 (s, 1H), 3.13 (s, 0.5H), 2.99 (d, J = 11.3 Hz, 0.5H), 2.89 (d, J = 6.4 Hz, 1.5H), 2.58 (s, 0.5H), 2.41 (m, 1H), 1.88 (m, 1H), 1.57 (m, 3H), 1.33 (m,3H), 1.24 (t, J = 6.6 Hz, 6H), 0.99 (dt, J = 24.3, 7.2 Hz, 3H), 0.68 (t, J = 7.3 Hz, 1.5H), 0.61 (t, J = 7.3 Hz, 1.5H) ppm. MS: M / e 475 (M+1) + .

[0457] Compound A32: 2-(7-((2S,5R)-4-(1-(4-cyclopropoxyphenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0458] Step A: 1-(4-cyclopropoxyphenyl)ethan-1-one [ka]

[0459] To a solution of 1-(4-hydroxyphenyl)ethan-1-one (1.36 g, 10 mol) in DMF, bromocyclopropane (1.8 g, 15 mmol) and CsCO (6.5 g, 20 mmol) were added. The reaction mixture was stirred at 100 °C overnight. H0 (20 ml) was added to the mixture, and the mixture was extracted with EA (20 mL x 3). The organic phase was dried over NaSO and concentrated using a rotary evaporator to obtain a residue. The resulting residue was purified by flash column chromatography to obtain the title compound (30 mg, 1.7%). MS: M / e 177 (M+1) + .

[0460] Step B: 1-(4-cyclopropoxyphenyl)ethan-1-ol [ka]

[0461] To a solution of 1-(4-cyclopropoxyphenyl)ethan-1-one (30 mg, 0.17 mol) in MeOH was added NaBH (19 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 15 minutes. HO (20 mL) was added to the mixture, and the mixture was extracted with DCM (20 mL x 3). The organic phase was dried over NaSO and concentrated using a rotary evaporator to obtain a residue. The resulting residue was purified by flash column chromatography to obtain the title compound (25 mg, 83%). MS: M / e 179 (M+1) + .

[0462] Step C: 2-(7-((2S,5R)-4-(1-(4-cyclopropoxyphenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0463] To a solution of 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 (30 mg, 0.1 mmol), 1-(4-cyclopropoxyphenyl)ethan-1-ol (25 mg, 0.14 mmol), and (cyanomethyl)trimethylphosphonium iodide (120 mg, 0.5 mmol) in CHCN (10 mL) was added DIPEA (129 mg, 1 mmol). The reaction mixture was sealed in a bottle and heated at 105 °C for 16 h, then cooled to room temperature, diluted with water, and extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method B) to give the title compound (2 mg, 5%). 1H NMR (400 MHz, CD3OD) δ 7.90 (s, 1H), 7.25 (m, 2H), 6.98 (m, 2H), 5.52 (s, 1H), 5.45 (d, J = 3.0 Hz, 2H), 3.74 (d, J = 3.1 Hz, 1H), 3.65 (d, J = 6.5 Hz, 0.5H), 3.52 (d, J = 6.4 Hz, 0.5H), 3.45 (d, J = 14.5 Hz, 1H), 3.41 (s, 3H), 3.23 (s, 1H), 3.11 (s, 0.6H), 2.96 (d, J = 11.8 Hz, 0.4H), 2.84 (d, J = 3.6 Hz, 0.4H), 2.57 (d, J = 9.1 Hz, 0.6H), 2.39 (d, J = 12.5 Hz, 1H), 2.06 (s, 1H), 1.88 (m, 1H), 1.54 (m, 3H), 1.29 (dd, J = 13.9, MS: M / e 489 (M+1) + .

[0464] Compound A33: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-isopropoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0465] Step A: 1-(4-isopropoxyphenyl)ethan-1-one [ka]

[0466] A mixture of 1-(4-hydroxyphenyl)ethan-1-one (680 mg, 5 mmol), 2-iodopropane (1.3 g, 7.5 mmol), and potassium carbonate (1.4 g, 10 mmol) in DMF (10 mL) was stirred at 70 °C overnight. The mixture was treated with water (50 mL), extracted with EtOAc (20 mL x 3), washed with brine (50 mL), dried, and concentrated to dryness. The resulting residue was purified by flash column chromatography (EtOAc:PE = 0-80%, 25 min) to give the title compound (800 mg, 90%). MS: M / e 179 (M+1). + .

[0467] Step B: 1-(4-isopropoxyphenyl)ethan-1-ol [ka]

[0468] To a solution of 1-(4-isopropoxyphenyl)ethan-1-one (470 mg, 2.6 mmol) in MeOH (5 mL) was added NaBH (79 mg, 2.1 mmol) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The resulting mixture was treated with water (50 mL) and extracted with DCM (20 mL x 2). The combined organic layers were dried over NaSO and concentrated to dryness. The resulting residue (450 mg, crude) was used directly in the next step. MS: M / e 181 (M+1) + .

[0469] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-isopropoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0470] A mixture of 1-(4-isopropoxyphenyl)ethan-1-ol (270 mg, 1.5 mmol), 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 (164 mg, 0.5 mmol), (cyanomethyl)trimethylphosphonium iodide (363 mg, 1.5 mmol), and DIPEA (322 mg, 2.5 mmol) in MeCN (4 mL) was stirred at 100° C. overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with water (10 mL × 2), dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography (MeOH:DCM = 0 to 10%, 30 min) to obtain the compound (approximately 200 mg, crude), which was separated into compound A33a (49 mg) and compound A33b (59 mg) by preparative chiral HPLC. The chiral separation conditions are shown below. [Table 5]

[0471] Compound A33a (early peak): 11H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.19 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 5.57 (s, 2H), 5.35 (s, 1H), 4.54 (dt, J = 12.1, 6.0 Hz, 1H), 3.65 - 3.52 (m, 1H), 3.27 (s, 2H), 3.23 (s, 3H), 3.05 (d, J = 10.3 Hz, 1H), 2.85 (d, J = 11.2 Hz, 1H), 2.69 (d, J = 8.3 Hz, 1H), 2.28 (s, 1H), 2.04 - 1.88 (m, 1H), 1.58 (d, J = 6.8 Hz, 1H), 1.39 (d, J = 7.3 Hz, 2H), 1.29 - 1.14 (m, 9H), 0.82 (t, J = 7.3 Hz, 3H), 0.57 (t, J = 7.2 Hz, 3H) ppm. MS: M / e 491 (M+1) + .

[0472] Compound A33b (later peak): 1 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.21 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 5.58 (s, 2H), 5.34 (s, 1H), 4.53 (dt, J = 12.0, 5.9 Hz, 1H), 3.45 (d, J = 6.3 Hz, 1H), 3.27 (s, 2H), 3.23 (s, 3H), 2.98 (d, J = 9.5 Hz, 1H), 2.42 (s, 2H), 2.23 (d, J = 12.2 Hz, 1H), 1.89 - 1.74 (m, 1H), 1.48 (dd, J = 24.2, 16.3 Hz, 3H), 1.26 - 1.12 (m, 9H), 0.90 (t, J = 7.2 Hz, 3H), 0.51 (dd, J = 21.3, 14.5 Hz, 3H) ppm.MS: M / e 491 (M+1) + .

[0473] Compound A34: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-methoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0474] To a solution of 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 (300 mg, 0.91 mmol) in CHCN (3 mL) was added 1-(4-methoxyphenyl)ethan-1-ol (139 mg, 0.91 mmol), (cyanomethyl)trimethylphosphonium iodide (670 mg, 2.74 mmol), and DIPEA (590 mg, 4.57 mmol). The resulting mixture was stirred at 105 °C overnight. The reaction solvent was removed under reduced pressure to give the crude product. The resulting residue was purified by preparative HPLC (Method A) to give the title compound A34a (60 mg) and compound A34b (80 mg).

[0475] Compound A34a (early peak): 11H NMR (400 MHz, CD3OD) δ 7.91 (s, 1H), 7.26 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 8.3 Hz, 2H), 5.54 (s, 1H), 5.46 (s, 2H), 3.79 (s, 3H), 3.66 (d, J = 6.5 Hz, 1H), 3.43 (s, 3H), 3.26 (d, J = 13.7 Hz, 2H), 2.98 (d, J = 11.2 Hz, 1H), 2.84 (d, J = 8.2 Hz, 1H), 2.47 - 2.40 (m, 1H), 2.13 - 2.04 (m, 1H), 1.84 - 1.75 (m, 1H), 1.54 - 1.45 (m, 2H), 1.34 - 1.27 (m, 4H), 0.95 (t, J = 7.4 Hz, 3H), 0.68 (t, J = 7.3 Hz, 3H). MS: M / e 463(M+1) + .

[0476] Compound A34b (later peak): 1 1H NMR (400 MHz, CD3OD) δ δ 7.92 (s, 1H), 7.29 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 5.53 (s, 1H), 5.46 (s, 2H), 3.78 (s, 3H), 3.53 (d, J = 6.5 Hz, 1H), 3.47 (d, J = 12.7 Hz, 1H), 3.43 (s, 3H), 3.29 - 3.24 (m, 2H), 3.13 (s, 1H), 2.58 (d, J = 8.6 Hz, 1H), 2.41 (d, J = 12.5 Hz, 1H), 1.94 (d, J = 5.9 Hz, 1H), 1.68 - 1.54 (m, 3H), 1.28 (d, J = 6.5 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H), 0.62 (t, J = 7.4 Hz, 3H). MS: M / e 463(M+1) + .

[0477] Compound A35: 2-(7-((2S,5R)-4-(1-(4,5-dimethylthiazol-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0478] Step A: 1-(4,5-dimethylthiazol-2-yl)ethan-1-ol [ka]

[0479] To a solution of 2-bromo-4,5-dimethylthiazole (500 mg, 2.6 mmol) in THF (5 mL) at −70° C., n-BuLi (1.6 M, 2.0 mL, 3.2 mmol) was added dropwise under N2. After stirring at −70° C. for 10 min, a solution of acetaldehyde (350 mg, 8.0 mmol) in THF (1 mL) was added. The mixture was then warmed to room temperature and stirred for 1 h. An aqueous solution of NH4Cl (20 mL) was added, and the mixture was extracted with EtOAc (10 mL × 3). The organics were combined, washed with brine (10 mL × 2), dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title compound (340 mg, 83%). 1 H NMR (500 MHz, DMSO-d6) δ 5.88 (d, J = 5.5 Hz, 1H), 4.85 - 4.73 (m, 1H), 2.28 (s, 3H), 2.19 (s, 3H), 1.38 (d, J = 6.5 Hz, 3H). MS: M / e 158 (M+1) + .

[0480] Step B: 2-(7-((2S,5R)-4-(1-(4,5-dimethylthiazol-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0481] To a solution of 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 (33 mg, 0.1 mmol), 1-(4,5-dimethylthiazol-2-yl)ethan-1-ol (32 mg, 0.2 mmol), and (cyanomethyl)trimethylphosphonium iodide (85 mg, 0.35 mmol) in CHCN (1 mL) was added DIPEA (85 mg, 0.66 mmol). The mixture was stirred at 100 °C for 20 h in a sealed tube. The mixture was cooled, diluted with EtOAc (10 mL), washed with brine (5 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography and preparative HPLC (Method A) to give the title compound A35a (5 mg) and compound A35b (5 mg).

[0482] Compound A35a (early peak): 11H NMR (500 MHz, CD3OD) δ 7.93 (s, 1H), 5.58 (s, 1H), 5.47 (s, 2H), 4.58 (s, 2H), 4.12 (q, J = 6.5 Hz, 1H), 3.49 - 3.35 (m, 4H), 3.00 (dd, J = 12.0, 4.0 Hz, 1H), 2.89 (dd, J = 12.0, 2.0 Hz, 1H), 2.63 (s, 1H), 2.35 (s, 3H), 2.28 (s, 3H), 2.15 - 2.03 (m, 1H), 1.90 - 1.77 (m, 1H), 1.74 - 1.49 (m, 2H), 1.43 (d, J = 7.0 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H), 0.87 (t, J = 7.5 Hz, 3H) ppm. MS: M / e 468 (M+1) + .

[0483] Compound A35b (later peak): 1 1H NMR (500 MHz, CD3OD) δ 7.93 (s, 1H), 5.56 (s, 1H), 5.48 (s, 2H), 4.58 (s, 2H), 3.92 (q, J = 6.5 Hz, 1H), 3.50 (d, J = 13.5 Hz, 1H), 3.​​​​​Compound A36: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0485] Step A: 2-Bromo-4,5,6,7-tetrahydrobenzo[d]thiazole [ka]

[0486] To a solution of 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (465 mg, 3.0 mmol) in MeCN (6 mL) at 0° C., tert-butyl nitrite (620 mg, 6.0 mmol) was added, followed by the portionwise addition of CuBr (1.34 g, 6.0 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (30 mL), and the suspension was filtered through a Celite pad. The filtrate was washed with brine (10 mL × 2), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound (300 mg, yield: 46%). 1 H NMR (500 MHz, DMSO-d6) δ 2.73 - 2.61 (m, 4H), 1.86 - 1.69 (m, 4H). MS: M / e 218 (M+1) + .

[0487] Step B: 1-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)ethan-1-ol [ka]

[0488] To a solution of 2-bromo-4,5,6,7-tetrahydrobenzo[d]thiazole (300 mg, 1.37 mmol) in THF (5 mL) at −70° C., n-BuLi (1.6 M, 1.0 mL, 1.6 mmol) was added dropwise under N2. After stirring at −70° C. for 10 min, a solution of acetaldehyde (1800 mg, 4.1 mmol) in THF (1 mL) was added. The mixture was then warmed to room temperature and stirred for 1 h. An aqueous solution of NH4Cl (20 mL) was added, and the mixture was extracted with EtOAc (10 mL × 3). The organics were combined, washed with brine (10 mL × 2), dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title compound (210 mg, yield: 83%). 1 H NMR (500 MHz, DMSO-d6) δ 5.91 (d, J = 5.0 Hz, 1H), 4.89 - 4.75 (m, 1H), 2.76 - 2.66 (m, 2H), 2.65 - 2.57 (m, 2H), 1.82 - 1.71 (m, 4H), 1.40 (d, J = 6.5 Hz, 3H). MS: M / e 184 (M+1) + .

[0489] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0490] To a solution of 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 (33 mg, 0.1 mmol), 1-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)ethan-1-ol (37 mg, 0.2 mmol), and (cyanomethyl)trimethylphosphonium iodide (85 mg, 0.35 mmol) in CHCN (1 mL) was added DIPEA (85 mg, 0.66 mmol). The mixture was stirred at 100 °C for 20 h in a sealed tube. The mixture was cooled, diluted with EtOAc (10 mL), washed with brine (5 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography and preparative HPLC (Method A) to give the title compound A36a (5 mg) and compound A36b (5 mg).

[0491] Compound A36a (early peak): 1 H NMR (400 MHz, CD3OD) δ 7.93 (s, 1H), 5.58 (s, 1H), 5.48 (s, 2H), 4.59 (s, 2H), 4.14 (q, J = 6.8 Hz, 1H), 3.49 - 3.36 (m, 4H), 3.08 - 2.97 (m, 1H), 2.95 - 2.84 (m, 1H), 2.83 - 2.68 (m, 4H), 2.67 - 2.62 (m, 1H), 2.14 - 1.96 (m, 1H), 1.94 - 1.78 (m, 5H), 1.75 - 1.48 (m, 2H), 1.44 (d, J = 6.8 Hz, 3H), 0.94 (t, J = 7.6 Hz, 3H), 0.87 (t, J = 7.6 Hz, 3H). MS: M / e 494 (M+1) + .

[0492] Compound A36a (later peak): 1H NMR (400 MHz, CD3OD) δ 7.93 (s, 1H), 5.57 (s, 1H), 5.48 (s, 2H), 4.58 (s, 2H), 4.04 - 3.88 (m, 1H), 3.58 - 3.40 (m, 4H), 3.12 - 3.00 (m, 1H), 2.89 - 2.64 (m, 5H), 2.62 - 2.52 (m, 1H), 2.00 - 1.81 (m, 5H), 1.80 - 1.54 (m, 2H), 1.51 - 1.37 (m, 4H), 0.99 (t, J = 7.6 Hz, 3H), 0.79 (t, J = 7.6 Hz, 3H). MS: M / e 494 (M+1) + .

[0493] Compound A37: 2-(7-((2S,5R)-4-(1-(6-cyclopropoxypyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0494] Step A: 5-Bromo-2-cyclopropoxypyridine [ka]

[0495] To a suspension of CsCO (1.3 g, 4 mmol) in DMF (10 mL), 5-bromo-2-fluoropyridine (352 mg, 2 mmol) and cyclopropanol (174 mg, 3 mmol) were added, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (50 mL) and then extracted with EA (20 mL × 3). The combined organic portions were concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (EtOAc:PE = 0-50%, 30 min) to give the title compound (350 mg, 82%). MS: M / e 214 (M+1). +.

[0496] Step B: 1-(6-cyclopropoxypyridin-3-yl)ethan-1-one [ka]

[0497] A mixture of 5-bromo-2-cyclopropoxypyridine (350 mg, 1.6 mmol), tributyl(1-ethoxyvinyl)stannane (711 mg, 2 mmol), and Pd(PPh3)2Cl2 (112 mg, 0.16 mmol) in toluene (5 mL) was stirred at 100 °C for 16 h under N2. HCl (0.5 mL, concentrated) was added dropwise to the resulting solution, and the mixture was stirred at room temperature for 30 min. The mixture was treated with saturated aqueous NaHCO3 (20 mL), extracted with EtOAc (10 mL × 2), washed with brine (20 mL), dried, and concentrated to dryness. The resulting residue was purified by flash column chromatography (EtOAc:PE = 0-50%, 20 min) to give the title compound (90 mg, 32%). MS: M / e 178 (M+1). + .

[0498] Step C: 1-(6-cyclopropoxypyridin-3-yl)ethan-1-ol [ka]

[0499] To a solution of 1-(6-cyclopropoxypyridin-3-yl)ethan-1-one (90 mg, 0.51 mmol) in MeOH (3 mL) was added NaBH (15 mg, 0.41 mmol) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The resulting mixture was treated with water and extracted with DCM (10 mL x 2). The combined organic layers were dried over NaSO and concentrated to dryness. The resulting residue (80 mg, crude) was used in the next step. MS: M / e 180 (M+1) + .

[0500] Step D: 2-(7-((2S,5R)-4-(1-(6-cyclopropoxypyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0501] A mixture of 1-(6-cyclopropoxypyridin-3-yl)ethan-1-ol (27 mg, 0.15 mmol), 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 (33 mg, 0.1 mmol), (cyanomethyl)trimethylphosphonium iodide (48 mg, 0.2 mmol), and DIPEA (51 mg, 0.4 mmol) in MeCN (2 mL) was stirred at 100° C. overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with water (10 mL × 2), dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography (MeOH:DCM=0-10%, 20 min) to give the title compound (10 mg, 20%). 1H NMR (500 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.98 (d, J = 1.7 Hz, 1H), 7.71 (dt, J = 8.5, 2.4 Hz, 1H), 6.84 (dd, J = 13.5, 8.5 Hz, 1H), 5.62 (d, J = 8.4 Hz, 2H), 5.40 (d, J = 9.8 Hz, 1H), 4.18 (ddd, J = 9.1, 6.0, 3.0 Hz, 1H), 3.75-3.55 (m, 1H), 3.34 (s, 1H), 3.27 (s, 3H), 3.16-3.00 (m, 1H), 2.90-2.74 (m, 1H), 2.33 - 2.20 (m, 1H), 2.03 - 1.73 (m, 1H), 1.66 - 1.20 (m, 7H), 0.97 - 0.79 (m, 4H), 0.76 - 0.50 (m, 7H) ppm. MS: M / e 490 (M+1) + .

[0502] Compound A38: 2-(7-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0503] Step A: 1-(6-cyclopropylpyridin-3-yl)ethan-1-one [ka]

[0504] A mixture of 1-(6-bromopyridin-3-yl)ethan-1-one (1 g, 5 mmol), cyclopropylboronic acid (473 mg, 5.5 mmol), tricyclohexylphosphane (140 mg, 0.5 mmol), potassium phosphate (1.6 g, 7.5 mmol), and Pd(OAc) (112 mg, 0.5 mmol) in toluene (15 mL) and water (1.5 mL) was stirred overnight at 100 °C under N. The mixture was treated with water (50 mL), extracted with EtOAc (20 mL × 3), washed with brine (50 mL), dried, and concentrated to dryness. The resulting residue was purified by flash column chromatography (EtOAc:PE = 0 to 50%, 25 min) to give the title compound (620 mg, 77%). MS: M / e 162 (M+1). + .

[0505] Step B: 1-(6-cyclopropylpyridin-3-yl)ethan-1-ol [ka]

[0506] To a solution of 1-(6-cyclopropylpyridin-3-yl)ethan-1-one (620 mg, 3.8 mmol) in MeOH (10 mL) was added NaBH (117 mg, 3.1 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 min. The resulting mixture was treated with water (100 mL) and extracted with DCM (20 mL × 2). The combined organic layers were dried over NaSO and concentrated to dryness. The resulting residue was purified by flash column chromatography (EtOAc: PE = 0-100%, 25 min) to give the title compound (420 mg, 68%). MS: M / e 164 (M+1) + .

[0507] Step C: 2-(7-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0508] A mixture of 1-(6-cyclopropylpyridin-3-yl)ethan-1-ol (149 mg, 0.91 mmol), 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 (200 mg, 0.6 mmol), (cyanomethyl)trimethylphosphonium iodide (290 mg, 1.2 mmol), and DIPEA (310 mg, 2.4 mmol) in MeCN (5 mL) was stirred at 100° C. overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with water (10 mL × 2), dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography (MeOH:DCM = 0 to 10%, 20 min) to obtain the compound (approximately 130 mg, crude), which was separated into compound A38a (30 mg) and compound A38b (38 mg) by preparative chiral HPLC. The chiral separation conditions are shown below. [Table 6]

[0509] Compound A38a (early peak): 11H NMR (500 MHz, DMSO-d6) δ 8.34 (d, J = 1.9 Hz, 1H), 7.97 (s, 1H), 7.60 (dd, J = 8.0, 2.2 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 5.61 (s, 2H), 5.38 (s, 1H), 3.71 (q, J = 6.5 Hz, 1H), 3.32 (s, 1H), 3.28 (d, J = 13.6 Hz, 4H), 3.11 (d, J = 11.9 Hz, 1H), 2.87 (d, J = 11.0 Hz, 1H), 2.76 (dd, J = 11.9, 3.8 Hz, 1H), 2.27 (s, 1H), 2.07 (s, 1H), 2.02 - 1.91 (m, 1H), 1.69 - 1.56 (m, 1H), 1.51 - 1.39 (m, 2H), 1.28 (d, J = 6.5 Hz, 3H), 0.96 - 0.80 (m, 7H), 0.62 (t, J = 7.3 Hz, 3H) ppm. MS: M / e 474 (M+1) + .

[0510] Compound A38b (later peak): 1H NMR (500 MHz, DMSO-d6) δ 8.34 (d, J = 1.9 Hz, 1H), 7.98 (s, 1H), 7.61 (dd, J = 8.0, 2.1 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 5.61 (s, 2H), 5.38 (s, 1H), 3.58 (q, J = 6.4 Hz, 1H), 3.35 (s, 2H), 3.28 (d, J = 13.1 Hz, 4H), 3.03 (d, J = 9.9 Hz, 1H), 2.53-2.50 (m, 1H), 2.19 (d, J = 12.0 Hz, 1H), 2.11 - 2.02 (m, 1H), 1.80 (dt, J = 16.0, 7.9 Hz, 1H), 1.60 - 1.39 (m, 3H), 1.24 (d, J= 6.5 Hz, 3H), 0.98 - 0.82 (m, 7H), 0.53 (t, J = 7.0 Hz, 3H) ppm.MS: M / e 474 (M+1) + .

[0511] Compound A39: 2-(but-2-yn-1-yl)-7-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one [ka]

[0512] A mixture of 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (102 mg, 0.3 mmol), 1-(6-cyclopropylpyridin-3-yl)ethan-1-ol (99 mg, 0.6 mmol), (cyanomethyl)trimethylphosphonium iodide (219 mg, 0.9 mmol), and DIPEA (192 mg, 1.5 mmol) in CHCN (8 mL) was stirred in a sealed tube at 100° C. overnight. The reaction mixture was diluted with EtOAc (15 mL), washed with HO, brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound, which was further separated by preparative HPLC (Method B) into Compound A39a (24 mg) and Compound A39b (30 mg).

[0513] Compound A39a (early peak): 1 H NMR (500 MHz, CD3OD) δ 8.30 (d, J = 2.0 Hz, 1H), 7.88 (s, 1H), 7.70 (dd, J = 8.0, 2.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 5.52 (s, 1H), 5.04-5.01 (m, 2H), 3.77 (q, J = 6.4 Hz, 1H), 3.43 (s, 3H), 3.33-3.31 (m, 2H), 3.28-3.23 (m, 1H), 2.99 - 2.83 (m, 2H), 2.38-2.32 (m, 1H), 2.12 - 2.03 (m, 2H), 1.84 (t, J = 2.4 Hz, 3H), 1.83 - 1.75 (m, 1H), 1.58 - 1.46 (m, 2H), 1.35 (d, J = 6.4 Hz, 3H), 1.06 - 1.01 (m, 2H), 0.98 - 0.91 (m, 5H), 0.71 (t, J = 7.2 Hz, 3H) ppm. MS: M / e 487(M+1) + .

[0514] Compound A39b (later peak): 1 H NMR (500 MHz, CD3OD) δ 8.33 (d, J = 2.0 Hz, 1H), 7.89 (s, 1H), 7.72 (dd, J = 8.0, 2.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 5.51 (s, 1H), 5.04 (dd, J = 4.8, 2.4 Hz, 2H), 3.62 (q, J = 6.4 Hz, 1H), 3.49-3.44 (m, 1H), 3.43 (s, 3H), 3.31 - 3.29 (m, 2H), 3.15-3.09 (m, 1H), 2.67-2.61 (m, 1H), 2.33-2.28 (m, 1H), 2.11 - 2.05 (m, 1H), 1.95 - 1.87 (m, 1H), 1.85 (t, J = 2.4 Hz, 3H), 1.70 - 1.48 (m, 3H), 1.31 (d, J = 6.4 Hz, 3H), 1.05 - 0.99 (m, 5H), 0.98 - 0.89 (m, 2H), 0.62 (t, J = 7.2 Hz, 3H) ppm. MS: M / e 487(M+1) + .

[0515] Compound A40: 2-(7-((2S,5R)-4-(1-(6-cyclopropyl-5-fluoropyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0516] Step A: Methyl 6-cyclopropyl-5-fluoronicotinate [ka]

[0517] To a mixture of methyl 6-bromo-5-fluoronicotinate (1 g, 4.27 mmol), cyclopropylboronic acid (0.55 g, 6.41 mmol) in dioxane (20 mL) was added Pd(dppf)Cl (314 mg, 0.43 mmol), followed by KCO (1.18 g, 8.54 mmol). After the addition, the mixture was stirred overnight at 100 °C under N. The reaction mixture was treated with H O and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine, dried over Na SO and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (280 mg, 34%). MS: M / e 196 (M+1) + .

[0518] Step B: 6-Cyclopropyl-5-fluoro-N-methoxy-N-methylnicotinamide [ka]

[0519] To a stirred solution of methyl 6-cyclopropyl-5-fluoronicotinate (300 mg, 1.54 mmol) in MeOH (8 mL) was added HO (2 mL), followed by NaOH (123 mg, 3.07 mmol). The mixture was then stirred overnight. The reaction mixture was concentrated to give an aqueous layer, which was acidified with aqueous HCl to pH 5-6 and then extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the intermediate (245 mg, 87.8%). To a stirred solution of the intermediate in CHCl (10 mL), N,O-dimethylhydroxylamine hydrochloride (158 mg, 1.62 mmol), HATU (619 mg, 1.62 mmol), and DIPEA (348.3 mg, 2.7 mmol) were added and then stirred overnight. The reaction mixture was washed with HO and extracted with CHCl (15 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (290 mg, 96%). MS: M / e 225 (M+1). + .

[0520] Step C: 1-(6-cyclopropyl-5-fluoropyridin-3-yl)ethan-1-one [ka]

[0521] To a stirred solution of 6-cyclopropyl-5-fluoro-N-methoxy-N-methylnicotinamide (290 mg, 1.29 mmol) in THF (10 mL) was added MeMgBr (3.0 M, 0.56 mL, 1.68 mmol) dropwise at 0 °C. The mixture was then stirred for 30 min. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (162 mg, 70%). MS: M / e 180 (M+1) + .

[0522] Step D: 1-(6-cyclopropyl-5-fluoropyridin-3-yl)ethan-1-ol [ka]

[0523] To a stirred solution of 1-(6-cyclopropyl-5-fluoropyridin-3-yl)ethan-1-one (162 mg, 0.9 mmol) in MeOH (5 mL) was added NaBH (34.4 mg, 0.9 mmol). The reaction mixture was then stirred for 10 minutes. The reaction mixture was quenched with HO, and most of the MeOH was then removed to obtain the aqueous layer, which was then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound (150 mg, 92%). MS: M / e 182 (M+1) + .

[0524] Step E: 2-(7-((2S,5R)-4-(1-(6-cyclopropyl-5-fluoropyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0525] A solution of 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 (32.8 mg, 0.1 mmol), 1-(6-cyclopropyl-5-fluoropyridin-3-yl)ethan-1-ol (36.2 mg, 0.2 mmol), (cyanomethyl)trimethylphosphonium iodide (72.9 mg, 0.3 mmol), and DIPEA (64.5 mg, 0.5 mmol) in CHCN (4 mL) was stirred in a sealed tube at 100° C. overnight. The reaction mixture was diluted with EtOAc (10 mL), then washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by preparative TLC (CH2Cl2 / MeOH=10:1) to give the title compound (22 mg). 1H NMR (400 MHz, CD3OD) δ 8.23 ​​- 8.15 (m, 1H), 7.93 (s, 1H), 7.58 - 7.47 (m, 1H), 5.56 (s, 1H), 5.47 (s, 2H), 3.89 - 3.64 (m, 1H), 3.53 - 3.46 (m, 0.5H), 3.43 (s, 3H), 3.30 - 3.26 (m, 2H), 3.18 - 3.10 (m, 0.5H), 3.00 - 2.85 (m, 1H), 2.73 - 2.64 (m, 0.5H), 2.43-2.25 (m, 2H), 2.12 - 1.76 (m, MS: M / e 492 (M+1) + .

[0526] Compound A41: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-methoxypyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0527] Step A: 1-(6-methoxypyridin-3-yl)ethan-1-ol [ka]

[0528] To a solution of 1-(6-methoxypyridin-3-yl)ethan-1-one (302 mg, 2 mmol) in MeOH (5 mL) was added NaBH (61 mg, 1.6 mmol) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The resulting mixture was treated with water (50 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over NaSO and concentrated to dryness. The resulting residue (250 mg, crude) was used in the next step. MS: M / e 154 (M+1) + .

[0529] Step B: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-methoxypyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0530] A mixture of 1-(6-methoxypyridin-3-yl)ethan-1-ol (23 mg, 0.15 mmol), 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 (33 mg, 0.1 mmol), (cyanomethyl)trimethylphosphonium iodide (48 mg, 0.2 mmol), and DIPEA (52 mg, 0.4 mmol) in MeCN (2 mL) was stirred at 100° C. overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with water (10 mL × 2), dried over NaSO, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (3.5 mg, 8%). 1H NMR (500 MHz, CD3OD) δ 8.05 (dd, J = 13.9, 2.2 Hz, 1H), 7.92 (d, J = 2.7 Hz, 1H), 7.80 - 7.70 (m, 1H), 6.81 (dd, J = 15.6, 8.6 Hz, 1H), 5.55 (s, 1H), 5.46 (d, J = 4.0 Hz, 2H), 3.90 (d, J = 5.0 Hz, 3H), 3.80-3.58 (m, 1H), 3.53-3.35 (m, 4H), 3.28 - 3.09 (m, 2H), 3.01 - 2.84 (m, 1H), 2.65 (dd, J = 8.2, 4.1 Hz, 1H), 2.37 (d, J = 12.5 Hz, 1H), 2.12-0.85 (m, 1H), 1.84 - 1.48 (m, 3H), 1.34 (dd, J = 16.4, 6.5 Hz, 3H), 1.05-0.92 (m, 3H), 0.77-0.60 (m, 3H) ppm. MS: M / e 464 (M+1) + .

[0531] Compound A42: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-(methoxymethyl)pyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [ka]

[0532] Step A: 5-Bromo-2-(methoxymethyl)pyridine [ka]

[0533] A solution of (5-bromopyridin-2-yl)methanol (1 g, 5.32 mmol) and NaH (60%, 266 mg, 6.65 mmol) in THF (10 ml) was stirred at 0 °C for 10 min. MeI (0.94 g, 6.62 mmol) was added to the above solution at 0 °C, followed by stirring at room temperature for 1 h. The solution was quenched with water (10 ml) and extracted with EA (10 ml × 2). The organic layer was dried over Na2SO4 and concentrated to dryness. The resulting residue was purified by flash column chromatography (0-10% EA / PE) to give the title compound (1 g, 93%). MS: M / e 202 (M+1) + .

[0534] Step B: 1-(6-(methoxymethyl)pyridin-3-yl)ethan-1-one [ka]

[0535] A solution of 5-bromo-2-(methoxymethyl)pyridine (500 mg, 2.49 mmol), ethyl tributylstannanecarboxylate (1.35 g, 3.74 mmol), and Pd(PPh3)2Cl2 (87 mg, 0.12 mmol) in toluene (10 mL) was stirred at 100 °C overnight. The solution was cooled to room temperature. HCl / 1,4-dioxane (4 M, 2 mL) was added and stirred at room temperature for 10 minutes. The solution was diluted with EtOAc (20 mL), washed with a...

Claims

1. A compound of formula (I), 【Chemical 865】 or a stereoisomer or a pharmaceutically acceptable salt thereof, During the ceremony, X １ is C or N, R １ is hydrogen or alkyl optionally substituted with deuterium, halogen, hydroxy, alkoxy, or cycloalkyl; R ２ is hydrogen, halogen, alkyl, or cyano, with the proviso that X １ If is N, then R ２ Provided that there is no R ４ is hydrogen, halogen, or alkyl, said alkyl being optionally substituted with deuterium or halogen; R ５ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cyano, or heterocyclyl, wherein said alkyl or said alkenyl is unsubstituted or substituted with halogen, cyano, heterocyclyl, alkoxy, hydroxy, cycloalkyl; R ７ , R ９ , R ８ , and R １０ are each independently hydrogen, alkyl, or alkoxy, wherein said alkyl is unsubstituted or substituted with halogen, with the proviso that R ７ and R ９ is not hydrogen; L １ is a direct bond or -C(R Ｌ１ ) (R Ｌ２ ) and the R Ｌ１ , the R Ｌ２ each independently is hydrogen or C optionally substituted with deuterium, halogen, alkyl, alkylene, alkynyl, cyano １－４ is alkyl, Cy １ is aryl, heterocyclyl, heteroaryl, or cycloalkyl, each of which is unsubstituted or contains one, two, or three substituents R ３ａ and each R ３ａ are independently hydroxy, alkoxy, alkyl, halogen, aminoalkyl, 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 -O-C(O)-, cycloalkyl, heterocyclyl, or heterocyclyloxy, each alkyl portion of which is unsubstituted or substituted with deuterium, halogen, alkoxy, hydroxy, cyano, or heterocyclyl, and said cycloalkyl or said heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy; R ３ｂ and R ３ｃ are each independently hydrogen or alkyl, or R ３ｂ and R ３ｃ together form at least one -CH ２ - forming a bridge containing a moiety, However, the compound may be 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2,4-Dimethyl-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(2,2,2-trifluoroethyl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-(2-methoxyethyl)-4-methyl-2 , 4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetamide, methyl 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetate nitrate, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)propanenitrile, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-(2-hydroxyethyl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(cyclopropylmethyl)-7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-(2-(dimethylamino)ethyl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin- 1-yl)-4-methyl-2-(oxiran-2-ylmethyl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(methylsulfonyl)-2H-pyrazolo[4,3-b]pyridin-5(4H)-one, 2-cyclobutyl-7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro 2-(cyclopropanecarbonyl)-7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 1-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)cyclopropane isopropylpropane-1-carbonitrile, 2-cyclopropyl-7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-2-isopropyl-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(3-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile, 3-cyclopentyl-3-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)propanenitrile, 7-((2S,5R)- 2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(prop-2-yn-1-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethyl-4-( 1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-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, 7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2-(prop-1-en-2-yl)- 5-((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, 7-((2S,5R)-2,5-diethyl-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, 7-((2S,5R)-2,5-diethyl-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, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 2-(7- ((2S,5R)-4-(1-(4-fluoro-3-(methoxymethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-(methoxymethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-( 2-(7-((2S,5R)-4-(1-(5-fluoropyridin-2-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-([1,2,4]triazolo[1,5- a]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,5-difluoro-4-methoxyphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-cyclopropylphenyl)propyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-phenylethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-methoxyphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-((2S,5R)-4-(1-(quinolin-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinolin-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, tolyl, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(2-methylbenzo[d]oxazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(2-methylbenzo[d]oxazol-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, (7-((2S,5R)-4-(1-(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, 2-(7-((2S,5R)-2,5-dimethyl-4-(quinoxalin-6-ylmethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile,5-dimethyl-4-(1-(2-methylbenzo[d]oxazol-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5, a mixture of 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 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; 2-(7-((2S,5R)-2,5-diethyl-4-(1-(isoquinolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-([1,2,4]triazolo[1,5-a]pyridin-7-yl)ethyl)-2,5-diene 2-(7-((2S,5R)-2,5-diethyl-4-(1-(naphthalen-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-(methyl-d3)-5- oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(benzo[d]thiazol-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-((4-fluoro-2-methoxyphenyl)(4-fluorophenyl)methyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(quinoxalin-6-ylmethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinolin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinolin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinolin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, (1-(isoquinolin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinolin-6-yl)ethyl)piperazin-1-yl) )ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinolin-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(isoquinolin-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(1,8-naphthyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-methyl-1H-benzo[d]imidazol-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H- pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methylquinoxalin-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-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl) ) mixture with acetonitrile, 2-(7-((2S,5R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonite 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 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,5-diethyl-4-(4-fluorobenzyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 2-(7-((2S,5R)-4-(1-(4-cyclopropyl-2-fluorophenyl)ethyl)- 2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-fluoropyridin-2-yl)ethyl)piperazin-1-yl) 2-(7-((2S,5R)-4-(2,4-difluorobenzyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-cyclopropyl-2-fluorophenyl)propyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, -dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methoxy-4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-(trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-isopropoxypyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-3-methoxyphenyl ... (2S,5R)-4-(1-(2,6-difluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 2-(7-((2S,5R)-2,5-diethyl-4-(1- (4-fluoro-2-(2-methoxyethoxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3,5-difluoropyridin-4-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyrazin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyra, 2-(7-((2S,5R)-2,5-diethyl-4-(1-phenylethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, -(7-((2S,5R)-2,5-diethyl-4-(1-(3-methoxypyridin-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methoxypyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 5R)-2,5-diethyl-4-(1-(3-(methoxymethyl)pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2,6-dimethoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S ,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-(2-hydroxyethyl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2-ethyl-5-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5S)-5-(hydroxymethyl)-2-methyl- 4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5S)-5-(methoxymethyl)-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2R,5R)-2-(hydroxymethyl)-5-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl) 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methoxypyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-(methoxymethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile lysin-2-yl)acetonitrile, 3-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)benzamide, N-(3-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)phenyl)acetamide, 2-(7-((2S,5R )-2,5-diethyl-4-(1-(3-methyl-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 2-(7-((2S,5R)-2,5-diethyl-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, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-fluoro-4-(trifluoromethyl)pyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-fluoro-4-(trifluoromethyl)pyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile,5-diethyl-4-(1-(5-methyl-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 2-(7-((2S, 5R)-4-(1-(2-chloro-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methyl-6-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5 R)-2,5-diethyl-4-(1-(3-(trifluoromethyl)pyridin-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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 tolyl, 4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)benzamide, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-(hydroxymethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(4-methyl-5-oxo-7-(5-( 1-(quinoxalin-6-yl)ethyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 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, 2-(7-((2S,5R)-4-(1-(4-(difluoromethyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazine-1- 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyrimidin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyrimidin-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyrimidin-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,2-(7-((2S,5R)-4-(1-(2,4-difluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(6-chloro-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, , 2-(cyanomethyl)-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridine-6-carbonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 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, 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, 2-(7-(( 2S,5R)-4-(1-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-(2,2-difluoroethyl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, -(7-((2S,5R)-2,5-diethyl-4-(1-(5-isopropoxypyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-ethoxy-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-isopropoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2R,5R)-2-(methoxymethyl)-5-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-((2S,5R)-2-(2-hydroxyethyl)-5-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2-(2-hydroxyethyl)-5-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 5R)-2,5-diethyl-4-(1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3,5-difluoropyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(2, 3-dihydro-1H-inden-1-yl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(chroman-4-yl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-((dimethylamino)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(hydroxymethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)piperazin-1-yl) 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo- so-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(cyanomethyl)-7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridine-6-carbonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methoxy-4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-di hydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-((2S,5R)-1-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-5-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-isopropoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((3R)-3-ethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile acetonitrile, 2-(6-chloro-7-((3R)-3-ethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(methylamino)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, )-2-(2-methoxyethyl)-5-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, N-(2-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)phenyl)acetamide, 2-(7-((2S,5R)-2,5-diethyl-4-(1- (1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(4-(cyclopropylmethyl)-7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-6-fluoro-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(cyanomethyl)-7-((2S,5R)-3-ethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridine-6-carbonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2 2-(7-((2S,5R)-4-(1-(2-(difluoromethoxy)-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, ...methyl)-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, methyl 4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-1-(1-(quinoxalin-6-yl)ethyl)piperazine-2-carboxylate, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-1H-imidazol-2-yl)ethyl)piperazin-1-yl)- 4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-cyclopropyl-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-1H-indol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(4-methyl-7-((3S)-3-methyl-4-(, 1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(6-bromo-7-((2S,5R)-3-ethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6-(difluoromethoxy)pyridin-3-yl)ethyl)-2, 5-Diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-5-methyl-1H-imidazol-2-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-(1-ethyl-4-methyl-1H-imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-4-(1-(1-ethyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-(3-(hydroxymethyl)-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-(3-(hydroxymethyl)-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-ethyl-3H-imidazo[4,2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-4-(1-(5-chloro-1-ethyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(1-hydroxyethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(1-hydroxyethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2,2'-(6-cyano-7-((2S, 5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-2H-pyrazolo[4,3-b]pyridin-2,4(5H)-diyl)diacetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-isopropyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-chloro-1-ethyl)piperazin-1-yl)- 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-propyl-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-propyl-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile,5-diethyl-4-(1-(1-isopropyl-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-6-fluoro-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-fluoro 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 1-(2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-1-(1-(quinoxalin-6-yl)ethyl)piperazine-2-carboxamide, 2-(7-((2S,5R)-4-(1-(4-cyclopropyl-2-methoxyphenyl)ethyl)-2,5-diethylpiperazine-1 -yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(cyanomethyl)-7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridine-6-carbonitrile, 2-(7-((2S,5R)-4-(1-(2,4-difluoro-6-methoxyphenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-4-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl) 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-ethyl-4-fluorophenyl)ethyl)piperazin-1-yl) 2-(7-((2S,5R)-2,5-diethyl-4-(3-(trifluoromethyl)benzoyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-6-oxo-1,6-dihydropyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-2-methyl-1H-imidazol-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-2-methyl-1H-imidazol-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)ethyl)piperazin-1-yl) piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-chloro-1-ethyl-1H-pyrazol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-ethyl-1-methyl-1H-pyrazole 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-(2-hydroxyethyl)-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-(2-hydroxyethyl)-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-( 1-ethyl-1H-imidazo[4,5-b]pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-4-methyl-1H-pyrazol-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-(trifluoromethyl)pyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1, -(1-ethyl-2-methyl-1H-imidazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, or 2-(7-((2S,5R)-2,5-dimethyl-4-((R)- 1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-ethyl-7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(2,2-difluoroethyl)-7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl) 2-(7-((2S,5R)-4-(1-cyclohexylethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazine-1 -yl)ethyl)-5-fluorobenzonitrile, 2-(7-((2R,5R)-5-ethyl-2-(methoxymethyl)-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6-chloro-4-(trifluoromethyl)pyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-4-methyl-1H-pyrazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 7-((2S,5R)-4-(1-(1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile Lysin-5-one, 2-(7-((2R,5R)-5-ethyl-2-(hydroxymethyl)-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile ]pyridin-2-yl)acetonitrile, 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, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-methyl-3-(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, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-methyl-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, 2-(7-((2S,5R)-4-(1-(5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-methyl-4-(trifluoromethyl)pyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[ 4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(1-(2,2-difluoroethyl)-1H-imidazol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-2,4- Dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-ethyl-2-(trifluoromethyl)-1H-imidazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 3-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin 2-(7-((2S,5R)-2,5-diethyl-4-(4-fluoro-2-(trifluoromethyl)benzyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(tetrahydro-2H-pyran-4-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile,2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile or 2-(7-((2S,5R)-2,5-dimethyl-4-((R)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile -pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-b]pyridin-1-yl)acetonitrile or 2-(7-((2S,5R)-2,5-dimethyl-4-((R)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-3-(trifluoromethyl)-4,5 -dihydro-1H-pyrazolo[4,3-b]pyridin-1-yl)acetonitrile, 2-(3-chloro-7-((2S,5R)-2,5-dimethyl-4-((R)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, or 2-(3-chloro-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro- 2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(4-fluoro-2-(trifluoromethyl)benzyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-(difluoromethoxy)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,2-(7-((2S,5R)-4-(1-(2-omethoxy-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethoxy)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, -pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-chloro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo -4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-(difluoromethyl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-(1,1-difluoroethyl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)propyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)propyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-fluoro, -2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-(methyl-d3)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((R)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-3-fluoro-4-methyl-5-oxo-4,5-dihydro-1H-pyrazolo[4,3-b]pyridin-1-yl)acetonitrile or 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-3-fluoro-4-methyl-5-oxo-4,5-dihydro-1H-pyrazolo[4,3-b]pyridin-1-yl)acetonitrile, 2-(7-((2R,5R)-5-ethyl-2-((R)-1-hydroxyethyl)-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)acetonitrile 2-(7-((2S,5R)-2,5-dimethyl-4-((R)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((R)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, or 2-(7 -((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2R,5R)-2-(difluoromethyl)-5-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo- 4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(2,2-difluoro-1-(quinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(3-chloro-7-((2S,5R)-2,5-dimethyl-4-((R)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, or 2-(3-chloro-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5- Ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-3-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-3,4-dimethyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl-2,3-d2)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-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-dimethyl-4-(1-(2-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(2-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, -((R)-1-(2-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-((2S,5R)-4-(1-(3-methoxyquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(3-hydroxyoxetan-3-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,6-dichloro-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3,4-difluoro-2-methoxyphenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-6-methoxy-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl) piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-(methyl-d3)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-chloro-2-(trifluoromethyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl) -4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-ethylquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-hydroxyquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4, 5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-chloroquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methoxyquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-hydroxyquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-methoxyquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-methoxyquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl) Acetonitrile, 2-(7-((2S,5R)-4-(1-(2-hydroxyquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-(dimethylphosphoryl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile , 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(1-methoxyethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-(cyanomethyl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 7-((2S,5R)-4-(1-(3,4-difluoro-2-(trifluoromethyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-5-fluorobenzamide, methyl 2-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-5-fluorobenzoate, 2-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-5-fluoro-N-methylbenzamide, 2-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-5-fluoro-N,N-dimethylbenzamide, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,3-dimethylquinoxaline 6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((3R,4R)-3-ethoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4, 3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)-N-(2-methoxyethyl)-2-(4-(trifluoromethyl)phenyl)acetamide, 2-(7-((2S,5R)-4-(2-(4-fluorophenyl)propan-2-yl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-(2,5-dimethyl-4-(methyl(3-methylquinoxalin-6-yl)amino)piperidin-1-yl)- 4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-allyl-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, or 2-allyl-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, 2-(but-3-en-1-yl)-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, or 2-(but-3-en-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, 2- allyl-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-en-1-yl)-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(3,3-difluoroallyl)-7-((2 S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-methylisoquinolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(isoquinolin-3-yl)ethyl )-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(2-methylquinolin-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 7-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-(hydroxymethyl)quinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, Hydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-cyclopropylquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-(difluoromethyl)quinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-((2S,5R)-4-(1-(3-(1,1-difluoroethyl)quinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-(methyl-d3)quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-(methyl-d3)quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo [4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-(trifluoromethyl)quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(2-(trifluoromethyl)quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,2-(7-((2S,5R)-4-(1-(2-hydroxy-3-methylquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-6-fluoro-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile [4,3-b]pyridin-2-yl)acetonitrile, 2-(cyanomethyl)-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridine-6-carbonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4, 3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(2-methylbenzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile -pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(benzo[d]thiazol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3H-spiro[benzo[b][1,4]dioxin-2,1′-cyclopropan]-7-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile,5-Dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl) 2-(7-((2S,5R)-4-(1-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(1- 2-(7-((2S,5R)-4-(1-(2-(1-(difluoromethoxy)ethyl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-(1-(difluoromethoxy)ethyl)-4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-fluoro-2-(1-methoxycyclohexyl) 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4,4-difluorochroman-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-4-((4-fluorophenyl)(5-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpiperazin-1-yl)-4-methyl-5-oxo, -4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(di-p-tolylmethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-dimethyl-4-((S)-1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, Lysin-5-one, 2-(7-((2S,5R)-4-(1-(2,3-dihydrofuro[2,3-b]pyridin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)phenyl)-2-methylpropanediol tolyl, 2-(4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)propyl)phenyl)-2-methylpropanenitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-methylphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-((2,2-dimethylmorpholino)methyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-((2,2-dimethylmorpholino)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S, 5R)-4-(1-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-((4,4-difluoropiperidin-1-yl)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile tolyl, 2-(4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-3-fluorophenyl)-2-methylpropanenitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-methylpyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-( (2S,5R)-4-(1-(5-(difluoromethyl)pyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-methylpyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6-(difluoromethyl)pyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrofuro[3,2-b]pyridin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrofuro[3,2-b]pyridin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, Ethyl-4-(1-(6-fluoropyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-( 5,6-dimethylpyrazin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-methylpyrazin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5,6,7,8-tetrahydroquinoxalin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-6-isopropoxypyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-6-isopropoxypyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile -(1-(3-fluoro-5-methylpyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(5-chloropyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1- (5-(trifluoromethoxy)pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro-5-(trifluoromethoxy)pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)- 4-(1-(5,6-dimethylpyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-methoxy-6-methylpyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-methylpyridazin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methylisoquinolin-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-methylisoquinolin-7-yl)ethyl)piperazin-1-yl) 2-(7-((2S,5R)-4-(1-(2,6-naphthyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,6-naphthyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(4-cyclopropylbenzoyl)-2,5-diethylpiperazin-1-yl )-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(5-methylpicolinoyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(2,6-naphthyridine-3-carbonyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3 -b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(isoquinoline-3-carbonyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(quinoline-7-carbonyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(quinoline-7-carbonyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile,5-diethyl-4-(quinoxaline-2-carbonyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-((tetrahydrofuran-3-yl)oxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, Nitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-((tetrahydrofuran-3-yl)methoxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-methoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, -(7-((2S,5R)-2,5-diethyl-4-(1-(4-(oxetan-3-yloxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(oxetan-3-ylmethoxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 7-((2S,5R)-2,5-diethyl-4-(1-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6-((4,4-difluoropiperidin-1-yl)methyl)pyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3 -b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-(4,4-difluoropiperidine-1-carbonyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(morpholinomethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,2-(7-((2S,5R)-4-(1-(3,4-dimethylphenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4,5-dimethylpyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile tolyl, 2-(6-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)pyridin-3-yl)-2-methylpropanenitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro-5-isopropoxypyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl) Acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(imidazo[1,2-a]pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyrazolo[1,5-a]pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile , 2-(but-2-yn-1-yl)-7-((2S,5R)-4-(1-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-5-ethyl-4-(1-(isoquinolin-3-yl)ethyl)-2-methylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, provided that the compound is not 2-(but-2-yn-1-yl)-7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-2-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, or 2-(but-2-yn-1-yl)-7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinolin-7-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one.

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

3. R １ is hydrogen, methyl, ethyl, isopropyl, n-propyl, methyl-d3, preferably R １ is hydrogen, methyl, ethyl, methyl-d3, more preferably R １ The compound according to any one of claims 1 to 2, wherein is methyl.

4. R ２ But hydrogen, halogen, C １－４ alkyl, or cyano, provided that X １ is C, preferably R ２ is hydrogen, F, Br, Cl, methyl, ethyl, or —CN, more preferably R ２ The compound of any one of claims 1 to 3, wherein is F, Br, methyl, or -CN.

5. R ４ is hydrogen, halogen, or alkyl, preferably R ４ The compound according to any one of claims 1 to 4, wherein is hydrogen.

6. R ５ is hydrogen, alkyl, alkenyl, or alkynyl, wherein said alkyl is unsubstituted or substituted with cyano, cycloalkyl, or cycloalkoxy, preferably R ５ But C １－６ Alkyl, C ２－６ alkenyl, or C ２－６ alkynyl, wherein the alkyl is cyano, C ３－６ cycloalkyl, or C ２－６ The compound of any one of claims 1 to 5, which is substituted with cycloalkoxy.

7. R ５ is hydrogen, -CH ２ -CN, -CH(CH ３ )CN, -CH ２ -CH ２ -CN, -CH ２ -CH ２ -CH ２ -CN, -CH(CH ３ )-CH ２ -CN, -CH ２ -CH(CH ３ )-CN,-CH(CH ２ CH ３ )-CN, oxiran-2-ylmethyl, oxiran-2-yl, oxetan-3-ylmethyl, oxetan-2-methyl, oxetan-3-yl, oxetan-2-yl, prop-2-yn-1-yl, but-2-yn-1-yl, but-3-yn-1-yl, pent-2-yn-1-yl, pent-3-yn-1-yl, pent-4-yn-1-yl, prop-2-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, pent-2-en-1-yl, pent-3 -en-1-yl, pent-4-en-1-yl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, azetidin-2-yl, azetidin-3-yl, azetidin-3-ylmethyl, azetidin-1-yl, azetidin-1-ylmethyl, aziridin-1-yl, aziridin-1-ylmethyl, aziridin-2-yl, aziridin-2-ylmethyl, 1-cyanocyclopropyl, 2-cyanocyclopropyl, or 2-cyanocyclobutyl, preferably R ５ is hydrogen, -CH ２ -CN, -CH(CH ３ )CN, -CH ２ -CH ２ -CN, CH ２ -CH ２ -CH ２ -CN, -CH(CH ３ )-CH ２ -CN, -CH ２ -CH(CH ３ )-CN,-CH(CH ２ CH ３ )-CN, oxetan-3-ylmethyl, oxetan-2-methyl, oxetan-3-yl, oxetan-2-yl, prop-2-yn-1-yl, but-2-yn-1-yl, but-3-yn-1-yl, or pent-3-yn-1-yl, more preferably R ５ But CN-CH ２ -, -CH ２ -CH ２ The compound according to any one of claims 1 to 6, which is -CN, but-2-yn-1-yl, but-2-yn-1-yl, or oxetan-3-ylmethyl, oxetan-3-yl.

8. R ７ and R ９ are each independently hydrogen, alkyl, said alkyl being unsubstituted or substituted with halogen, preferably R ７ and R ９ Each of the above independently represents C １－４ alkyl, and more preferably, R ７ and R ９ Each of the above independently represents C １－２ The compound according to any one of claims 1 to 7, which is alkyl.

9. R ７ and R ９ are each independently hydrogen, methyl, ethyl, isopropyl, or n-propyl, with the proviso that R ７ and R ９ The compound of any one of claims 1 to 8, provided that at least one of: is not hydrogen.

10. R ７ is methyl, and R ９ is methyl, or R ７ is ethyl, and R ９ is ethyl, or R ７ is methyl, and R ９ is ethyl. The compound according to any one of claims 1 to 9.

11. R ８ and R １０ The compound of any one of claims 1 to 10, wherein each is hydrogen.

12. The compound according to any one of claims 8 to 11, wherein the carbon at position 2 on the piperazine ring is in the S configuration and the carbon at position 5 on the piperazine ring is in the R configuration.

13. L １ is a direct bond, -C(R Ｌ１ ) (R Ｌ２ ) and the R Ｌ１ , the R Ｌ２ each independently being hydrogen or optionally substituted with deuterium, halogen, １－４ alkyl, preferably L １ is a direct bond, -CH ２ -, -CH(CH ３ ) -, -CH(CD ３ ) -, -CH(CH ２ CH ３ ) -, -CH(C ３ H ７ )-,-CH(CHF ２ ) - or -C(CH ３ ) ２ -, and more preferably, L １ But -CH(CH ２ CH ３ ) -, -CH(CH ３ ) -, or -CH(CD ３ 13. The compound according to any one of claims 1 to 12, wherein

14. Cy １ is aryl, heterocyclyl, heteroaryl, or cycloalkyl, each of which is unsubstituted or contains one, two, or three substituents R ３ａ and each R ３ａ are independently hydroxy, alkoxy, alkyl, halogen, aminoalkyl, cycloalkyl, R ３ｂ -C(O)-N(R ３ｃ ) -, N(R ３ｂ R ３ｃ )-C(O)-, cycloalkyl, heterocyclyl, or heterocyclyloxy, each alkyl portion of which is unsubstituted or substituted with halogen, alkoxy, hydroxy, or heterocyclyl, and said cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy; R ３ｂ and R ３ｃ are each independently hydrogen or alkyl, or R ３ｂ and R ３ｃ together form at least one -CH ２ - moiety, preferably R ３ａ Fluoro, bromo, chloro, methyl, ethyl, isopropyl, trifluoromethyl, hydroxyl, 1-methylpyrrolyl, 1-methylazetidinyl, 1-methylpiperidinyl, dimethylaminomethyl, 1,1-difluoroethyl, 3,3-difluoro-1-methylazetidinyl, dimethylaminyl, 1,1-dimethylmethyl, methoxy, cyclopropyl, cyclobutane, 2-fluoro-2-methylethyl, oxetan-3-ylmethyloxy, oxolan-3-ylmethyloxy, oxan-4-ylmethyloxy , oxetan-3-yloxy, oxolan-3-yloxy, oxan-3-yloxy, oxetan-3-methyl-3-yloxy, difluoromethoxy, 2-methoxyethoxy, (2-methoxyethoxy)methyl, 1,1-dioxidethiomorpholin-4-methyl, isopropoxy, dimethylcarbamoyl, (3-hydroxyazetidin-1-yl)methanone, formylamino, acetamido, propionamino, cyclopropoxy, or amino.

15. Cy １ The compound of any one of claims 1 to 14, wherein is phenyl.

16. Cy １ has one R at the 4-position as disclosed herein ３ａ 16. The compound of claim 15, wherein R is phenyl, optionally substituted at other positions with R3a.

17. Cy １ is unsubstituted or contains 1, 2, or 3 R ３ａ The compound of any one of claims 1 to 16, which is a monocyclic 5- to 9-membered heterocyclyl or a bicyclic 7- to 10-membered heterocyclyl substituted with:

18. The monocyclic 5- to 9-membered heterocyclyl is unsubstituted or contains 1, 2, or 3 R ３ａ is replaced by 【Chemical 866】 wherein X ４ , X ５ , X ６ , X ７ , and X ８ are each independently selected from N or C; ９ is C, N, S, or O, with the proviso that X ４ , X ５ , X ６ , X ７ , and X ８ If N, then X ４ , X ５ , X ６ , X ７ , and X ８ is each independently unsubstituted.

19. The monocyclic 5- to 9-membered heterocyclyl is thiazole, isothiazole, triazole, pyridine, pyrazine, pyrimidine, each of which is unsubstituted or contains one, two, or three R ３ａ 18. The compound of claim 17 substituted with:

20. The monocyclic 5- to 9-membered heteroaryl is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiazol-2-yl, thiazol-4-yl, isothiazol-3-yl, isothiazol-4-yl, pyrazin-1-yl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, each of which is unsubstituted or substituted with one, two, or three R ３ａ 18. The compound of claim 17 substituted with:

21. The monocyclic 5- to 9-membered heteroaryl ((4,4-difluoropiperidin-1-yl)methyl)pyridin-2-yl, 4-(oxetan-3-ylmethyl)phenyl, 6-aminopyridin-3-yl, 4-((4-methoxypiperidin-1-yl)methyl)phenyl, 4-(cyanomethyl)phenyl, 4-cyano-phenyl, 4-((1,1-dioxidethiomorpholino)methyl)phenyl, 4-(methylcarbamoyl)phenyl, (4-methoxypiperidine-1-carbonyl)phenyl, 4-((3-methoxypropyl)(methyl)carbamoyl)phenyl, 4-((methylsulfonyl)methyl)phenyl, 6-(1,1-difluoroethyl)pyridin-3-yl, 5-cyclopropoxypyridin-2-yl, 4-(3-methoxypyrrolidine-1-carbonyl)phenyl, 4-(methoxymethyl)phenyl; the bicyclic 7- to 10-membered heteroaryl is 6,7-dihydro-5H-cyclopenta[b]pyridine, 6,7-dihydro-5H-cyclopenta[c]pyridine, 2,3-dihydro-1H-indene, 2,3-dihydrobenzofuran, benzo[d][1,3]dioxole, 2-((methylsulfonyl)methyl)phenyl, 6-(1,1-difluoroethyl)pyridin-3-yl, 5-cyclopropoxypyridin-2-yl, 4-(3-methoxypyrrolidine-1-carbonyl)phenyl, 4-(methoxymethyl)phenyl; ,3-dihydrobenzo[b][1,4]dioxin, 4,5,6,7-tetrahydrobenzo[d]thiazole, 4,5,6,7-tetrahydrobenzo[d]isothiazole, quinoxaline, benzo[d]oxazole, benzo[d]thiazole, thiazolo[5,4-b]pyridine, thiazolo[4,5-b]pyridine, benzo[b]thiophene, benzofuran, benzo[c][1,2,5]thiadiazole, 1H-imidazo[4,5-b]pyridine, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine, imidazo[4,5-b]pyridine, benzo[c]isothiazole, thiazolo[4,5-c]pyridine, thiazolo[4,5-b]pyridine, thieno[2,3-b]pyridine, imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyrimidine, thieno[3,2-b]pyridine, pyrazolo[1,5-a]pyridine, [1,2,4]triazolo[4,3-a]pyridine, phthalazine, isoquinoline, 2,3-dihydrofuro[2,3-c]pyridine, 2,3-dihydrofuro[2,3-b]pyridine, each of which is unsubstituted or contains 1, 2, or 3 R, ３ 18. The compound of claim 17, substituted with a.

22. The bicyclic 7-10 membered heteroaryl may be 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, 6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl, 6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl, 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, benzo[d][1,3]dioxol-5-yl, 2,3-dihydrobenzo[b][ 1,4]dioxin-6-yl, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl, 4,5,6,7-tetrahydrobenzo[d]isothiazol-3-yl, quinolin-2-yl, quinolin-6-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, thiazolo[5,4-b]pyridin-5-yl, thiazolo[5,4-b]pyridin-6-yl, thiazolo[4,5-b]pyridin-5-yl, thiazolo[4,5-b] Pyridin-6-yl, benzo[b]thiophen-6-yl, benzofuran-6-yl, benzo[c][1,2,5]thiadiazol-5-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, pyrazolo[1,5-a]pyridin,5-yl, pyrazolo[1,5-a]pyridin-6-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1,2- a]pyridin-6-yl, pyrazolo[1,5-a]pyridin-6-yl, imidazo[1,5-a]pyridin-5-yl, imidazo[1,5-a]pyridin-6-yl, benzo[c]isothiazol-5-yl, benzo[c]isothiazol-6-yl, thiazolo[4,5-c]pyridin-5-yl, thiazolo[4,5-c]pyridin-6-yl, thiazolo[4,5-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-6-yl, thieno[2,3-b]pyridin-6-yl, thieno[2,3-b]pyridin-5-yl, thiazolo[5,4-b]phthalaz-2-yl, phthalaz-6-yl, phthalaz-5-yl, imidazo[1,2-b]pyridazin-6-yl, imidazo[1,2-b]pyridazin-5-yl, imidazo[1,2-b]pyridazin-2-yl pyrazolo[1,5-a]pyrimidin-5-yl, pyrazolo[1,5-a]pyrimidin-6-yl, thieno[3,2-b]pyridin-5-yl, thieno[3,2-b]pyridin-6-yl, pyrazolo[1,5-a]phthalaz-5-yl, pyrazolo[1,5-a]phthalaz-6-yl, [1,2,4]triazolo[4,3-a]phthalaz-7-yl, [1,2,4]triazolo[4,3-a]phthalaz-6-yl, phthalazolo and 2,3-dihydrofuro[2,3-c]pyridin-5-yl, 2,3-dihydrofuro[2,3-c]pyridin-6-yl, 2,3-dihydrofuro[2,3-b]pyridin-6-yl, or 2,3-dihydrofuro[2,3-b]pyridin-5-yl, each of which is unsubstituted or contains one, two, or three R, ３ａ 18. The compound of claim 17 substituted with:

23. Cy １ but 【Chemical 867】 and wherein each of ring A and ring B is independently a fused aryl, a fused 5- to 6-membered heteroaryl, or a fused 5- to 6-membered heterocyclyl; 15. The compound of any one of claims 1 to 14, wherein p and q are each independently 0, 1, 2, or 3, with the proviso that the sum of p and q is 3 or less.

24. 24. The compound of claim 23, wherein ring A is a fused 6-membered heterocyclyl, a fused 6-membered aryl, or a fused 6-membered cycloalkyl, preferably pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or phenyl, more preferably pyridinyl, pyrimidinyl, or pyridazinyl.

25. The compound according to claim 23, wherein Ring B is a fused 5-membered heterocyclyl or a fused 5-membered heteroaryl, preferably imidazole, thiazolyl, [1,2,4]triazolyl, tetrahydroimidazolyl, thiazolyl, pyrazolyl, thiazolyl, thienyl, oxazolyl, thiadiazolyl, thienyl, 1,2-dihydrothiazolyl, oxadiazolyl, [1,2,3]triazolyl, dioxolyl, or furanyl, more preferably thiazolyl, pyrazolyl, thiophenyl, or imidazole. 【Request Item 26】 【Chemistry 868】 but, 【Chemical 869】 The compound according to any one of claims 23 to 25, 【Request Item 27】 【Chemistry 870】 but, 【Chemistry 871】 The compound according to any one of claims 23 to 25,

28. Cy １ 4-(3-methoxyazetidine-1-carbonyl)phenyl, N,N-dimethylbenzamido-4-yl, 2,6-difluoro-N,N-dimethylbenzamido-4-yl, 2-fluoro-N,N-dimethylbenzamido-4-yl, 4-((1,1-dioxidothiomorpholino)methyl)-2,6-difluorophenyl, 2,4-dimethylphenyl, 4-ethylphenyl, 3-methyl-4-(trifluoromethyl)phenyl, 4-(1,1-difluorophenyl)phenyl, 4-(2-methoxyethoxy)phenyl, 2-fluoro-4-methoxyphenyl, 2-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl, 4-methoxy-2-methylphenyl, 4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl, 4-((oxetan-3-yloxy)methyl)phenyl, 4-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl, 4-((2-methyl (oxetan-3-yloxy)methyl)phenyl, 4-(difluoromethoxy)phenyl, 3-fluoro-4-methoxyphenyl, 3-methyl-4-(oxetan-3-yloxy)phenyl, 2-fluoro-4-(oxetan-3-yloxy)phenyl, 3-fluoro-4-(oxetan-3-yloxy)phenyl, 4-((3-methyloxetan-3-yl)oxy)phenyl, 4-((dimethylamino)methyl)-3,5-difluorophenyl, 4-(pyro 4-((3,3-difluoroazetidin-1-yl)methyl)phenyl, 4-((dimethylamino)methyl)phenyl, 4-((methylamino)methyl)phenyl, 4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl, 4-isopropylphenyl, 4-cyclopropoxyphenyl, 4-isopropoxyphenyl, 4-methoxyphenyl, 4,5-dimethylthiazol-2-yl, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl, 6-cyclopropoxypyridin-3-yl, 6-cyclopropylpyridin-3-yl, 6-cyclopropyl-5-fluoropyridin-3-yl, 6-methoxypyridin-3-yl, 6-(methoxymethyl)pyridin-3-yl, 6-isopropylpyridin-3-yl, 6-ethylpyridin-3-yl, 6-cyclopropyl-2-fluoropyridin-3-yl, 6-(2-fluoropropan-2-yl)pyridin-3-yl, 6-cyclopropyl-4-fluoropyridin-3-yl, 2-cyclopropyl propylpyrimidin-5-yl, 6-methyl-5-(trifluoromethyl)pyridin-2-yl, 5-isopropoxypyridin-2-yl, 5-cyclopropylpyridin-2-yl, 3,5-dimethylpyridin-2-yl, 5,6-dimethylpyridin-2-yl, 5-methoxy-6-methylpyridin-2-yl, 6-(methoxymethyl)-5-methylpyridin-2-yl, 5-cyclopropyl-3-methylpyridin-2-yl, 5-cyclopropyl-6-methylpyridin-2-yl, 5-methoxypyridin-2-yl, 5-methoxy-3-methylpyridin -2-yl, 1-(5-(methoxymethyl)pyridin-2-yl, 5-cyclopropyl-6-fluoropyridin-2-yl, 5-cyclopropyl-4-fluoropyridin-2-yl, 7-fluoro-2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3-dihydro-1H-inden-5-yl, 1,1-dimethyl-2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-5-yl, benzo[d][1,3]dioxol-5-yl, 4-fluoro-2,2-dimethylbenzo[d][1 ,3]dioxol-5-yl, 2,2-dimethylbenzo[d][1,3]dioxol-5-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, 2,3-dihydrofuro[3,2-b]pyridin-5-yl, 2,3-dihydrofuro[2,3-b]pyridin-5-yl, [1,3]dioxolo[4,5-b]pyridin-5-yl, 3-fluoropyrazolo[1,5-a]pyridin-6-yl, pyrazolo[1,5-a]pyridin-6-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 3-methylimidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-7-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,5-a]pyridin-6-yl, benzo[d]oxazol-6-yl, 7-fluoro-2-methylbenzo[d]oxazol-6-yl, 4-acetamido-2-fluoro-3-hydroxyphenyl, benzo[c]isothiazol-5-yl, benzo[b]thiophen-6-yl, benzo[d]thiazol-6-yl, 2-methylbenzo[d]thiazol-6-yl azol-6-yl, 2-ethylbenzo[d]thiazol-6-yl, thiazolo[5,4-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-6-yl, 4-fluorobenzo[d]thiazol-6-yl, 7-fluorobenzo[d]thiazol-6-yl, 5-fluorobenzo[d]thiazol-6-yl, 7-fluoro-2-methylbenzo[d]thiazol-6-yl, benzo[d]oxazol-5-yl, benzo[c][1,2,5]thiadiazol-5-yl, benzo[d]thiazol-5-yl, 2-methylbenzo[d]thiazo thieno[2,3-b]pyridin-6-yl, 2-methylthieno[2,3-b]pyridin-6-yl, 2-fluorothieno[2,3-b]pyridin-6-yl, 6-(1,1-difluoroethyl)pyridin-3-yl, 4-trifluoromethyl-phenyl, 4-fluoro-2-methyl-2-thiazolo[5,4-b]pyridin-5-yl, 2-ethylbenzo[d]thiazol-5-yl, 4-fluorobenzo[d]thiazol-5-yl, 3-methylquinoxalin-2-yl, 5-fluoro-2-methylbenzo[d]thiazol-6-yl, 2-methylthiazolo[5,4-b]pyridin-5-yl, thieno[2,3-b]pyridin-6-yl, 2-methylthieno[2,3-b]pyridin-6-yl, 2-fluorothieno[2,3-b]pyridin-6-yl, 6-(1,1-difluoroethyl)pyridin-3-yl, 4-trifluoromethyl-phenyl, 4-fluoro-2-methyl-2- ...4-fluoro-2-methyl-2-thiazolo[5,4-b]pyridin-6-yl, 4-fluoro-2-methyl-2-thiazolo[5,4-b]pyrid Thiazolo[5,4-b]pyridin-5-yl, 2-(difluoromethyl)thieno[2,3-b]pyridin-6-yl, 2-(methoxymethyl)benzo[d]thiazol-6-yl, 2-cyclopropoxythiazolo[5,4-b]pyridin-5-yl, 2-(2-fluoroethoxy)thiazolo[5,4-b]pyridin-5-yl, 2-(difluoromethyl)thieno[2,3-b]pyridin-6-yl, 2-methylimidazo[1,2-b]pyridazin-6-yl, 3-methylpyrazolo[1,5-a]pyrimidin-5-yl, 2-methylpyrazolo[1,5-a]pyrimidin-5-yl, 2-ethylimidazo[1,2-b]pyridazin-6-yl, pyrazolo[1,5-a]pyrimidin-5-yl, 2-methylthieno[3,2-b]pyridin-5-yl, 2,3-dimethylpyrazolo[1,5-a]pyrimidin-5-yl, 2-fluoropyrazolo[1,5-a]pyrimidin-5-yl, pyrazolo[1,5-a]pyridin-5-yl, 3-fluoro-2- Methylpyrazolo[1,5-a]pyrimidin-5-yl, 3-fluoropyrazolo[1,5-a]pyrimidin-5-yl, 2-methylpyrazolo[1,5-a]pyridin-5-yl, pyrazolo[1,5-a]pyrimidin-5-yl, 3-fluoropyrazolo[1,5-a]pyridin-5-yl, 3-chloroimidazo[1,2-b]pyridazin-6-yl, 3-fluoroimidazo[1,2-b]pyridazin-6-yl, 3-fluoro-2-methylpyrazolo[1,5- a]pyridin-5-yl, 2-chloropyrazolo[1,5-a]pyrimidin-5-yl, 2-chloro-3-fluoropyrazolo[1,5-a]pyrimidin-5-yl, 7-fluoro-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, imidazo[1,2-b]pyridazin-2-yl, thiazolo[5,4-b]pyridin-2-yl, [1,2,4]triazolo[4,3-a]pyridin-7-yl, phthalazin-6-yl, phthalazin-6-yl, The compound according to any one of claims 1 to 14, which is selected from the group consisting of quinoxalin-5-yl, quinoxalin-6 ...

29. 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(3-methoxyazetidine-1-carbonyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-N,N-dimethylbenzamide, 4-(1- ((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-2,6-difluoro-N,N-dimethylbenzamide, 4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-2-fluoro-N,N-dimethylbenzamide, 2-(7-( (2S,5R)-4-(1-(4-((1,1-dioxidothiomorpholino)methyl)-3,5-difluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,4-dimethylphenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, -(7-((2S,5R)-2,5-diethyl-4-(1-(4-ethylphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methyl-4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methyl-4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile,5-diethyl-4-(1-(4-methoxy-3-methylphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-(1,1-difluoroethyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4- (1-(4-(2-methoxyethoxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-methoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro- 4-((tetrahydrofuran-3-yl)oxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-methoxy-2-methylphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-( ((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-((oxetan-3-yloxy)methyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-((2-methoxyethoxy)methyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S ,5R)-4-(1-(4-(difluoromethoxy)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro-4-methoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4 -(1-(3-methyl-4-(oxetan-3-yloxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-(oxetan-3-yloxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5 -diethyl-4-(1-(3-fluoro-4-(oxetan-3-yl)oxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-((3-methyloxetan-3-yl)oxy)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-((dimethylamino)methyl)-3,5-difluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(pyrrolidin-1-ylmethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-( (2S,5R)-4-(1-(4-((3,3-difluoroazetidin-1-yl)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-((dimethylamino)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, -(7-((2S,5R)-2,5-diethyl-4-(1-(4-((methylamino)methyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile Nitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-isopropylphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-cyclopropoxyphenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile,5-diethyl-4-(1-(4-isopropoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-methoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4,5-dimethylthiazolinone) 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-( 6-cyclopropoxypyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6-cyclopropyl ...but-2-yn-1-yl)-7-(( 2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-4-(1-(6-cyclopropyl-5-fluoropyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-methoxypyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-(methoxymethyl)pyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-isopropylpyridine-, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-ethylpyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6-cyclopropyl-2-fluoropyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, )-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-(2-fluoropropan-2-yl)pyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6-cyclopropyl-4-fluoro 2-(7-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-6-fluoro-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-cyclopropylpyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-6-fluoro-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile,5-diethyl-4-(1-(5-isopropoxypyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(5-cyclopropylpyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3 ,5-dimethylpyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(5,6-dimethylpyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1- (5-methoxy-6-methylpyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-(methoxymethyl)-5-methylpyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(5- 2-(7-((2S,5R)-4-(1-(5-cyclopropyl-6-methylpyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-methoxypyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-methoxy-3-methylpyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-( 2-(7-((2S,5R)-4-(1-(5-cyclopropyl-6-fluoropyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(5-cyclopropyl-4 ... 2-(7-((2S,5R)-2,5-diethyl-4-(1-(7-fluoro-2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2 ,3-dihydro-1H-inden-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,3-dihydrobenzofuran-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(4-fluoro -2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, ((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-((2S,5R)-4-(1-(2,3-dihydrofuro[3,2-b]pyridin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,3-dihydrofuro[2,3 ...2-(7-((2S,5R)-4-(1-([1,3]dioxolo[4,5-b]pyridin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-fluoropyrazolo[1,5-a]pyridin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyrazolo[1,5-a]pyridin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methylimidazo[1,2-a]pyridin-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(imidazo[1,2-a]pyridin-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(imidazo[1,2-a]pyridin-7-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4 ,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-([1,2,4]triazolo[1,5-a]pyridin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(imidazo[1,2-a]pyridin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,2-(7-((2S,5R)-2,5-diethyl-4-(1-(imidazo[1,5-a]pyridin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(benzo[d]oxazol-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, , 2-(7-((2S,5R)-4-(1-(benzo[d]oxazol-6-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(7-fluoro-2-methylbenzo[d]oxazol-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile N-(4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-3-fluoro-2-hydroxyphenyl)acetamide, 2-(7-((2S,5R)-4-(1-(benzo[c]isothiazol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetamide acetonitrile, 2-(7-((2S,5R)-4-(1-(benzo[b]thiophen-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(benzo[d]thiazol-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, ((2S,5R)-2,5-diethyl-4-(1-(2-methylbenzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(benzo[d]thiazol-6-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(benzo[d]thiazol-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 7-((2S,5R)-4-(1-(benzo[d]thiazol-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridine-6-carbonitrile, 2-(7-((2S,5R)-4 -(1-(benzo[d]thiazol-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-6-bromo-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-ethylbenzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)- 2,5-diethyl-4-(1-(thiazolo[4,5-c]pyridin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(thiazolo[4,5-b]pyridin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2, 5-diethyl-4-(1-(thiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(thiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluorobenzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(7-fluorobenzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2, 5-diethyl-4-(1-(5-fluorobenzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-4-(1-(7-fluoro-2-methylbenzo[d]thiazol-6-yl)ethyl)-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-(( 2S,5R)-4-(1-(benzo[d]oxazol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(benzo[c][1,2,5]thiadiazol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S ,5R)-4-(1-(benzo[d]thiazol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylbenzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylbenzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile,5-diethyl-4-(1-(2-ethylbenzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro ...but-2-yn-1-yl)-7-((2S, 5R)-5-ethyl-2-methyl-4-(1-(3-methylquinoxalin-2-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-4-(1-(benzo[d]thiazol-6-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-2-(but-2-yn-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-4-(1-(benzo[d]thiazol-6-yl)ethyl) -2,5-diethylpiperazin-1-yl)-2-(but-2-yn-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethyl-4-(1-(2-methylbenzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-5-ethyl-2-methyl-4-(1-(2-methylbenzo[d]thiazol-6-yl)ethyl)piperazin-1-yl) 2-(but-2-yn-1-yl)-7-((2S,5R)-5-ethyl-4-(1-(7-fluoro-2-methylbenzo[d]thiazol-6-yl)ethyl)-2-methylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethyl-4-(1-(thiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-5-ethyl-2-methyl-4-(1-(thiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-4-(1-(benzo[d]thiazol-5-yl)ethyl)-5-ethyl-2-methylpiperazin-1- 1-(2-(2-yn-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-4-(1-(benzo[d]thiazol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-2-(but-2-yn-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-2-(oxetane -3-yl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 7-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-2-(oxetan-3-ylmethyl)-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-4-(1-(benzo[d]thiazol-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4 ,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylbenzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(7-fluoro-2-methylbenzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(thiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-di, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-fluoro-2-methylbenzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylthiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(thieno[2,3-b]pyridin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(2-methylthieno[2,3-b]pyridin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(2-methylthieno[2,3-b]pyridin-6-yl)ethyl)piperazine-1 -yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-4-(1-(2-fluorothieno[2,3-b]pyridin-6-yl)ethyl)-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylthiazolo[5,4-b]pyridin-5-yl) 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylthiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-4-(methyl-d3)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 7-((2S,5R)-2,5-diethyl-4-(1-(2-methylthiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-2-(oxetan-3-yl)-2,4-dihydro-5H- Pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethyl-4-(1-(2-methylthiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethyl-4-(1-(7-fluoro-2-methylbenzo[d]thiazolo 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethyl-4-(1-(4-fluorobenzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethyl-4-(1-(4-fluorobenzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, or 2-(cyanomethyl)-7-((2S,5R)- 2,5-diethyl-4-(1-(2-methylthiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridine-6-carbonitrile, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methylbenzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro -5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylthiazolo[5,4-b]pyridin-5-yl)ethyl-2,2,2-d3)piperazin-1-yl)-4-(methyl-d3)-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-(methoxymethyl)thiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-(difluoromethyl)thieno[2,3-b]pyridin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-(methoxy 2-(7-((2S,5R)-4-(1-(2-cyclopropoxythiazolo[5,4-b]pyridin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-cyclopropoxythiazolo[5,4-b]pyridin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2- (2-fluoroethoxy)thiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-(difluoromethyl)thieno[2,3-b]pyridin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, -diethyl-4-(1-(2-methylimidazo[1,2-b]pyridazin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylimidazo[1,2-b]pyridazin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2 ,5-diethyl-4-(1-(2-ethylimidazo[1,2-b]pyridazin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,3-dimethylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,3-dimethylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, Diethyl-4-(1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyrazolo[1,5-a]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R )-2,5-diethyl-4-(1-(3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylpyrazolo[1,5-a]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S, 5R)-2,5-diethyl-4-(1-(pyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S, 5R)-2,5-diethyl-4-(1-(3-fluoropyrazolo[1,5-a]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(pyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(3-chloroimidazo[1,2-b]pyridazin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-fluoroimidazo[1,2, -b]pyridazin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro-2-methylpyrazolo[1,5-a]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro- 2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)propyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)propyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-((2S,5R)-5-ethyl-4-(1-(3-fluoro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-5-ethyl-4-(1-(3-fluoro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, R)-4-(1-(3-chloroimidazo[1,2-b]pyridazin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-chloropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-chloro-3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2-chloropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]yridin-2-yl)acetonitrile tolyl, 2-(7-((2S,5R)-4-(1-(2-chloro-3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(7-fluoro-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, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(imidazo[1,2-b]pyridazin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(thiazolo[5,4-b]pyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H -pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(5-((4,4-difluoropiperidin-1-yl)methyl)pyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(oxetan-3-ylmethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-([1,2,4]triazolo[4,3-a]pyridin-7-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5 -dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(phthalazin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6-aminopyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile 2-(7-((2S,5R)-2,5-diethyl-4-(1-(1-methylisoquinolin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-((4-methoxypiperidin-1-yl)methyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile Nitrile, 2-(4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)phenyl)acetonitrile, 4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)benzonitrile, 2-(7-((2S,5R)-4-(1-(4-((1,1-dioxidethiomorpholino)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 4-(1-((2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2,5-diethylpiperazin-1-yl)ethyl)-N-methylbenzamide, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(4-methoxyphenyl)-2-methyl-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile N-(2 ... ]pyridin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]yridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4 -((methylsulfonyl)methyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-4-(1-(6-(1,1-difluoroethyl)pyridin-3-yl)ethyl)-2,5-diethyl ...but-2-yn-1-yl)-7-((2S,5R)-4-(1-(2,3-dihydrofuro[2,3-b]pyridin-6-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one, 2-(7-((2S,5R)-4-(1-(5-cyclopropoxypyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetate acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-(3-methoxypyrrolidine-1-carbonyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-((3-methoxypyrrolidin-1-yl)methyl)phenyl)ethyl)piperazin-1-yl )-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methylpyrazolo[1,5-a]pyridin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(7-((2S,5R)-2,5-diethyl-4-( 1-(4-(methoxymethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile, 2-(but-2-yn-1-yl)-7-((2S,5R)-2,5-diethyl-4-(1-(quinoxalin-2-yl)ethyl)piperazin-1-yl)-4-methyl-2,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one.

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

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

32. 31. A method of treating cancer, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of claims 1 to 30 or a pharmaceutical composition of claim 30.

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