Pharmaceutical compounds

Abstract

The present invention relates to compounds of formula (I) useful as inhibitors of ubiquitin-specific protease USP19 activity. The invention also relates to pharmaceutical compositions comprising these compounds, and methods of using these compounds in therapy. (I)

Description

Technical Field

[0001] This invention relates to an inhibitor of ubiquitin-specific protease 19 (USP19) and its method of use. Background Technology

[0002] Over the past decade, protein ubiquitination has emerged as an important post-translational modification, playing a role in a variety of cellular processes, including proteolysis, gene expression, DNA repair, immune responses, metabolism, and cell cycle regulation. Dysregulation of the ubiquitin-proteasome system (UPS) is also associated with the pathogenesis of a number of human diseases, including but not limited to cancer (Hoeller D. et al.). Nat.Rev.Cancer (2006), 6, 776-788), viral infection (Gao et al., Can.J.Physiol., Pharmacol (2006), 84, 5-14), metabolic or neurodegenerative diseases (van Loosdregt J. et al., Immunity (2013), 39, 259-271; Rubinsztein D. et al., Nature (2006), 443, 780-786) and immune and inflammation-related medical conditions (Wang J. et al., Cell Mol.Immunol (2006), 3, 255-261; Corn J. et al., Nat.Struct.Mol.Biol (2014), 21, 297-300; Nicholson B. et al., Cell Biochem.Biophys (2011), 60, 61-68).

[0003] The approval and clinical success of the proteasome inhibitors Velcade® (bortezomib) or Kyprolis® (carfilzomib) for the treatment of mantle cell lymphoma (MCL) and multiple myeloma (MM) have confirmed UPS as a suitable cancer target for pharmacological intervention. Despite their efficacy, their clinical application is severely limited due to their poor selectivity and acute toxicity issues. By inhibiting the 26S proteasome, current proteasome inhibitors indiscriminately impair proteolysis in both cancer and normal cells, and their therapeutic index is low. To avoid this problem, a promising alternative may be to target UPS upstream of the proteasome. Interfering with ubiquitin (Ub) conjugation / unconjugation mechanisms, for example at the level of ubiquitin-specific proteases (USPs), would allow for the development of improved therapeutics with enhanced specificity and reduced toxicity.

[0004] USP is the largest subfamily of deubiquitinases (DUB) reported to date, with over 60 family members (Komander D. et al.). Nat.Rev.Mol.Cell Biol.(2009), 10, 550-563; Clague M. et al., Physiol.Rev (2013), 93, 1289-1315). USPs are typically cysteine ​​proteases that catalyze the removal of Ub from specific target substrates, thereby preventing their proteasome-induced degradation, or regulating their activation and / or subcellular localization (Daviet L. et al., Biochimie (2008), 90, 270-283; Nicholson B. et al., Cell Biochem.Biophys (2011), 60, 61-68). It is now well understood that USPs regulate the stability and activation of various proteins (including oncogenes and tumor suppressors) involved in the pathogenesis of human diseases. Therefore, USPs represent an emerging and attractive class of targets for pharmacological intervention.

[0005] Among all USPs, USP19 is an important member because it is associated with many important pathways involved in pathological conditions, including but not limited to cancer, neurodegenerative and degenerative diseases, and antiviral immune responses. USP19 is expressed in multiple isoforms ranging in length from 71.09 kDa (isoform 2) to 156.03 kDa (isoform 5), with the standard sequence (isoform 1) measuring 145.65 kDa (uniprot.org). The cellular localization of USP19 can be cytoplasmic or bound to the endoplasmic reticulum (Lee J. et al., J.Biol.Chem. (2014), 289, 3510-3517; Lee J. et al., Nat.Cell Biol. (2016), 18, 765-776). USP19, located in the endoplasmic reticulum, is a key component of the endoplasmic reticulum-associated degradation (ERAD) pathway (Hassink B. et al., EMBO Rep. (2009), 10, 755-761; Lee J. et al., J.Biol.Chem. (2014), 289, 3510-3517; Lee J. et al., Nat.Cell Biol. (2016), 18, 765-776). Specifically, USP19 participates in the final step of the protein quality control mechanism, rescuing ERAD substrates that have been retrogradely transported into the cytoplasm. USP19 has also been shown to regulate the stability of the E3 ligases MARCH6 and HRD1 (Nakamura N. et al., Exp.Cell Res. (2014), 328, 207-216; Harada K. et al., Int.J.Mol.Sci.(2016), 17, 1829). Furthermore, USP19 has recently been found to be associated with the stability of several potentially important protein substrates. For example, USP19 interacts with SIAH proteins to rescue HIF1α from degradation under hypoxic conditions (Altun M. et al., J.Biol.Chem .(2012), 287, 1962-1969; Velasco K. et al., Biochem.Biophys.Res.Commun (2013), 433, 390-395). USP19 also stabilizes the KPC1 ubiquitin ligase, which is involved in p27. Kip1 Regulation by cyclin-dependent kinase inhibitors (Lu Y. et al., Mol.Cell Biol (2009), 29, 547-558). Knockout of USP19 via RNAi resulted in p27... Kip1 Accumulation and inhibition of cell proliferation (Lu Y). And others, PLoS ONE (2011), 6, e15936). It was also found that USP19 interacts with apoptosis inhibitors (IAPs), including c-IAP1 and c-IAP2 (Mei Y. et al., J.Biol.Chem (2011), 286, 35380-35387). Knockdown of USP19 reduced the total levels of these c-IAPs, while overexpression increased the levels of BIRC2 / cIAP1 and BIRC3 / cIAP2. Knockdown of USP19 also enhanced TNFα-induced caspase activation and apoptosis in a BIRC2 / c-IAP1 and BIRC3 / c-IAP2-dependent manner. In addition to its direct involvement in regulating hypoxia response and ER stress, USP19 has recently been considered a positive regulator of autophagy and a negative regulator of type I interferon signaling (IFN, antiviral immune response) by deubiquitinizing Beclin-1. It was found that USP19 stabilizes Beclin-1 at post-translational levels by removing the K11-linked ubiquitin chain at lysine 437 (Jin S. et al., 2011). EMBO J (Jin S. et al., 2016), 35, 866-880). USP19 negatively regulates type I IFN signaling pathways by blocking RIG-I-MAVS interactions in a Beclin-1-dependent manner. Depletion of USP19 or Beclin-1 inhibits autophagic flux and promotes type I IFN signaling and cellular antiviral immunity (Jin S. et al., 2016). EMBO J (2016), 35, 866-880; Cui J. et al., Autophagy(2016), 12, 1210-1211). Recent studies have also shown that USP19 can negatively affect cellular antiviral type I IFN signaling by modulating TRAF3 substrates (Gu Z. et al., Future Microbiol. (2017), 12, 767-779). USP19 has also recently been shown to participate in the Wnt signaling pathway through the stable co-receptor LRP6 (Perrody E. et al., eLife (2016), 5, e19083), and by regulating HDAC1 and HDAC2 proteins in DNA repair processes, most notably chromosome stability and integrity (Wu M. et al., Oncotarget (2017), 8, 2197-2208).

[0006] Besides cancer and related conditions, USP19 has been linked to wasting syndrome and other skeletal muscle atrophy diseases in gene knockout studies (Wing S., Int.J.Biochem.Cell Biol .(2013), 45, 2130-2135; Wing S., Int.J.Biochem.Cell Biol (2016), 79, 426-468; Wiles B. et al., Mol.Biol.Cell (2015), 26, 913-923; Combaret L. et al., Am.J.Physiol.Endocrinol.Metab. (2005), 288, E693-700, each incorporated herein by reference). Muscle loss is known to impair quality of life and response to treatment in conditions such as cachexia, which increases morbidity and mortality in cancer patients. Muscle loss is also associated with other serious diseases such as HIV / AIDS, heart failure, rheumatoid arthritis, and chronic obstructive pulmonary disease (Wiles B. et al., Mol.Biol.Cell (2015), 26, 913-923). Muscle loss is also a prominent feature of aging.

[0007] In addition to the aforementioned pathological symptoms, USP19 can also participate in the pathogenesis of degenerative diseases (including but not limited to Parkinson's disease and other prion-like infectious diseases) by regulating important substrates (e.g., proteins containing α-synuclein or polyglutamine, ataxin3, and huntingtin) (He W. et al.). PLoS ONE (2016), 11, e0147515; Bieri G. et al., Neurobiol Dis.(2018), 109B, 219-225). It has been demonstrated that regulation of coronin 2A (CORO2A) through USP19 activity affects the transcriptional repressive activity of the retinoic acid receptor (RAR), suggesting that USP19 may also be involved in the regulation of RAR-mediated adipogenesis (Lim K. et al., 2018). Oncotarget (2016), 7, 34759-34772).

[0008] WO2022 / 200523 A1 discloses compounds that can be used as inhibitors of the activity of ubiquitin-specific protease USP19, and also relates to pharmaceutical compositions comprising these compounds and methods of using these compounds in treatment.

[0009] The established links between USP19 and multiple proteins involved in human pathology suggest that small-molecule inhibitors of USP19 could have broad therapeutic applications beneficial to human health. Identifying such inhibitors with drug-like potential is crucial and of high priority. Summary of the Invention

[0010] In the first aspect, compounds of formula (I) are provided: (I) in R 1 It is an optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted 3- to 11-membered heterocyclic alkyl, optionally substituted aryl, or optionally substituted 5- to 8-membered heteroaryl; R 2 and R 3 Each is independently selected from H and C1-C6 alkyl groups, or R. 2 and R 3 Together with the carbons they are attached to, they form C3-C8 cycloalkyl, C3-C8 cycloalkenyl, or 3- to 8-membered heterocyclic alkyl groups; M is N or CR a , where R a It is H, halogen, optionally substituted C3-C8 cycloalkyl or optionally substituted C1-C6 alkyl; A, D, E, and G do not exist, and X is NR 15 Or CH; Y is CR 4 Either N or it does not exist; Z is CR 5 NR 6 Or O; R 4It is a halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, 4- to 10-membered fused-ring heterocyclic, optionally substituted C1-C6 alkylthioalkyl, sulfoxide, sulfone, sulfoxide imine, optionally substituted amino, optionally substituted 3- to 8-membered heterocyclic alkyl, or OR 20 ; Where R 20 It is an optional substituted C1-C6 alkyl group; R 5 H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, optionally substituted 3- to 8-membered heterocyclic alkyl, amide, sulfoxide imine, CN, halogen, C(O)OR 21 OR 22 or NR 23 R 24 ; Where R 21 Selected from H and C1-C6 alkyl groups; R 22 Selected from H and C1-C6 alkyl groups; R 23 and R 24 Independently selected from H and optionally substituted C1-C6 alkyl groups; R 15 It is an H or C1-C6 alkyl group; Or R 4 and R 5 Together with the Y and Z groups to which they are attached, they form 3 to 8-membered heterocyclic alkyl or aryl groups; Or R 4 and R 15 Together with the X and Y they are attached to, they form 5-membered cycloalkyl, heterocycloalkyl, or heteroaryl groups; R 6 It is H, C1-C6 alkyl, optionally substituted aryl or C3-C8 cycloalkyl; Or A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N, and G is CR 14 Or N, and X is N or C; Y is C; Z is CR 20 , N, NR 11 Or O, Where R 11 It is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl or optionally substituted 5 to 8-membered heteroaryl; Where R 20H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, optionally substituted 3- to 8-membered heterocyclic alkyl, amide, sulfoxide imine, CN, halogen, C(O)OR 25 OR 26 or NR 27 R 28 ; Where R 25 Selected from H and C1-C6 alkyl groups; R 26 Selected from H and C1-C6 alkyl groups; R 27 and R 28 Independently selected from H and C1-C6 alkyl groups; R 7 It is H, halogen, C1-C6 alkyl or OR 19 ; Where R 19 It is an optional substituted C1-C6 alkyl group; R 12 It is H, halogen, or C1-C6 alkyl; R 13 It is H, halogen, C1-C6 alkyl, OR 16 or NR 17 R 18 ; Where R 16 It is an optional substituted C1-C6 alkyl group. R 17 and R 18 Independently selected from H and C1-C6 alkyl groups, or wherein R 17 and R 18 Together with the nitrogen atoms to which they are attached, they form 5- to 6-membered heterocyclic alkyl groups; and R 14 It is H, halogen, or C1-C6 alkyl; Or its stereoisomers, tautomers, hydrates, N -Oxide derivatives or pharmaceutically acceptable salts.

[0011] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound according to the first aspect, a stereoisomer, a tautomer, a hydrate, N -Oxide derivatives or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers or diluents.

[0012] In another aspect, the present invention provides compounds, stereoisomers, tautomers, hydrates, and other treatments according to the first aspect. N -Oxide derivatives or pharmaceutically acceptable salts or pharmaceutical compositions according to the second aspect.

[0013] In another aspect, the present invention provides compounds, stereoisomers, tautomers, hydrates, etc., according to the first aspect for use as pharmaceuticals. N -Oxide derivatives or pharmaceutically acceptable salts or pharmaceutical compositions according to the second aspect.

[0014] In another aspect, the present invention provides compounds, stereoisomers, tautomers, hydrates, and other similar products according to the first aspect for the treatment of muscle atrophy, obesity, insulin resistance, or type II diabetes. N -Oxide derivatives or pharmaceutically acceptable salts or pharmaceutical compositions according to the second aspect.

[0015] In another aspect, the present invention provides compounds, stereoisomers, tautomers, hydrates, and other similar products according to the first aspect for treating muscle atrophy, cachexia, or sarcopenia. N -Oxide derivatives or pharmaceutically acceptable salts or pharmaceutical compositions according to the second aspect, wherein the muscle atrophy, cachexia, and sarcopenia are associated with or induced by cancer.

[0016] In another aspect, the present invention provides a method for treating obesity, insulin resistance, type II diabetes, or muscle atrophy, comprising administering to a subject in need an effective amount of the compound, stereoisomer, tautomer, hydrate, or other product according to the first aspect. N -Oxide derivatives or pharmaceutically acceptable salts or pharmaceutical compositions according to the second aspect.

[0017] On the other hand, the present invention provides a method for reducing muscle mass loss in a subject, comprising administering to the subject in need an effective amount of the compound, stereoisomer, tautomer, hydrate, according to the first aspect. N -Oxide derivatives or pharmaceutically acceptable salts or pharmaceutical compositions according to the second aspect.

[0018] USP19 is associated with a variety of diseases and conditions, including (but not limited to) cancer and neoplastic conditions. Knocking out USP19 via RNAi results in p27. Kip1 Accumulation and inhibition of cell proliferation (Lu Y). And others, PLoS ONE (2011), 6, e15936). It was also found that USP19 interacts with apoptosis inhibitors (IAPs), including c-IAP1 and c-IAP2 (Mei Y. et al., J.Biol.Chem(2011), 286, 35380-35387). Knockdown of USP19 reduced the total levels of these c-IAPs, while overexpression increased the levels of BIRC2 / cIAP1 and BIRC3 / cIAP2. Knockdown of USP19 also enhanced TNFα-induced caspase activation and apoptosis in a BIRC2 / c-IAP1 and BIRC3 / c-IAP2-dependent manner. USP19 has also recently been shown to participate in the Wnt signaling pathway through its stable co-receptor LRP6 (Perrody E. et al., 2011), 286, 35380-35387. eLife (2016), 5, e19083), and by regulating HDAC1 and HDAC2 proteins in DNA repair processes, most notably chromosome stability and integrity (Wu M. et al., Oncotarget (2017), 8, 2197-2208).

[0019] This paper also demonstrates that the USP19 inhibitor compounds described in the first aspect exhibit cell permeability and effective target binding in cancer cell lines. The cell permeability and target binding in cancer cells are comparable to those observed in muscle cells. As demonstrated in this paper, USP19 inhibitors show effective in vivo therapeutic effects on muscle loss. Therefore, it is inferred that, given the similar target binding observed in cancer cells, pharmacologically proven USP19 inhibitors are also expected to exert effective therapeutic effects in cancer due to the association between USP19 and the aforementioned oncogenic processes.

[0020] In vivo studies have also demonstrated that mice lacking the USP19 gene (USP19 KO mice) exhibited reduced fat quality when fed a high-fat diet (Coyne E. et al., Diabetologia (2019), 62, 136-146, which is incorporated herein by reference). USP19 KO mice also exhibited greater glucose tolerance and greater insulin sensitivity when fed a high-fat diet.

[0021] These gene knockout studies describe the relationship between USP19 and obesity, as well as between USP19 and insulin sensitivity. WO2020 / 115500 and WO2020 / 115501 describe in vivo studies demonstrating that pharmacological inhibitors of USP19 are an effective approach for treating obesity and insulin resistance.

[0022] USP19 is also associated with muscle atrophy, wasting syndrome, and other skeletal muscle atrophy (Wing S., Int.J.Biochem.Cell Biol .(2013), 45, 2130-2135; Wing S., Int.J.Biochem.Cell Biol(2016), 79, 462-468; Wiles B. et al., Mol.Biol.Cell (2015), 26, 913-923; Combaret L. et al., Am.J.Physiol.Endocrinol.Metab. (2005), 288, E693-700). For example, studies have shown that USP19 silencing induces myofibrillar protein expression and promotes myogenesis, which supports the above view (Sundaram P. et al., Am.J.Physiol.Endocrinol.Metab (2009), 297, E1283-E1290; Ogawa M. et al., J.Biol.Chem (2011), 286, 41455-41465; Ogawa M. et al., J.Endocrinol (2015), 225, 135-145).

[0023] Knockout studies have demonstrated that mice lacking the USP19 gene are resistant to muscle wasting induced by glucocorticoids (a common systemic cause of muscle atrophy) and denervation (a model of disuse atrophy) (Bédard N. et al.). FASEB J. (2015), 29, 3889-3898, which is incorporated herein by reference).

[0024] As described in the accompanying examples, this paper demonstrates that pharmacological treatment with a USP19 inhibitor can induce therapeutic effects in wild-type in vivo models.

[0025] In particular, it was demonstrated that USP19 inhibitors reduce fat deposition in in vivo models, suggesting that USP19 inhibitors may be an effective treatment for obesity.

[0026] Similarly, this paper demonstrates that USP19 inhibitors can reduce muscle mass loss in an in vivo model of muscle atrophy.

[0027] Similarly, this article demonstrates that USP19 inhibitors can treat symptoms of insulin resistance, manifested as improved glucose response.

[0028] The compounds according to the invention are capable of selectively inhibiting USP19 activity. Examples also demonstrate that compounds that effectively inhibit USP19 activity can be effective therapeutic compounds. Therefore, the compounds of the invention are suitable for therapeutic treatments. Indications suitable for treatment with the compounds of the invention include: treatment and prevention of cancer and neoplastic conditions; immune and inflammatory conditions, such as by promoting antiviral immune responses; treatment and prevention of muscle atrophy, such as cachexia and sarcopenia; treatment and prevention of obesity; treatment and prevention of insulin resistance, such as diabetes; treatment and prevention of neurodegenerative diseases, including Parkinson's disease and other prion-based diseases.

[0029] Therefore, on the other hand, a compound according to the first aspect or its stereoisomers, tautomers, hydrates, etc., are provided for treatment. N -Oxide derivatives or pharmaceutically acceptable salts, or pharmaceutical compositions according to the second aspect.

[0030] On the other hand, a compound or its stereoisomers, tautomers, hydrates, or other similar substances according to the first aspect provide a method for treating or preventing cancer. N - An oxide derivative or a pharmaceutically acceptable salt, or a pharmaceutical composition according to the second aspect. In some preferred embodiments, the cancer to be treated is breast cancer or neuroblastoma.

[0031] On the other hand, a compound or its stereoisomers, tautomers, hydrates, or other similar compounds according to the first aspect are provided for methods of treating or preventing muscle atrophy, optionally cachexia or sarcopenia. N -Oxide derivatives or pharmaceutically acceptable salts, or pharmaceutical compositions according to the second aspect.

[0032] On the other hand, a compound or its stereoisomers, tautomers, hydrates, or other similar substances according to the first aspect provide a method for treating or preventing obesity. N -Oxide derivatives or pharmaceutically acceptable salts, or pharmaceutical compositions according to the second aspect.

[0033] On the other hand, the compound or its stereoisomers, tautomers, hydrates, etc., according to the first aspect provide a method for treating or preventing insulin resistance. N -Oxide derivatives or pharmaceutically acceptable salts, or pharmaceutical compositions according to the second aspect.

[0034] On the other hand, a compound or its stereoisomers, tautomers, hydrates, or other similar substances according to the first aspect provide a method for treating or preventing type 2 diabetes. N -Oxide derivatives or pharmaceutically acceptable salts, or pharmaceutical compositions according to the second aspect.

[0035] On the other hand, a compound or its stereoisomers, tautomers, hydrates, or other similar substances according to the first aspect provide a method for treating or preventing Parkinson's disease. N -Oxide derivatives or pharmaceutically acceptable salts, or pharmaceutical compositions according to the second aspect.

[0036] On the other hand, methods for treating cancer are provided, which include administering to a subject an effective amount of the compound according to the first aspect or its stereoisomers, tautomers, hydrates, N-Oxide derivatives or pharmaceutically acceptable salts, or pharmaceutical compositions according to the second aspect.

[0037] On the other hand, a method for treating muscle atrophy is provided, comprising administering to a subject an effective amount of the compound according to the first aspect or its stereoisomers, tautomers, hydrates, N -Oxide derivatives or pharmaceutically acceptable salts, or pharmaceutical compositions according to the second aspect.

[0038] On the other hand, a method for treating Parkinson's disease is provided, which includes administering to a subject an effective amount of the compound according to the first aspect or its stereoisomers, tautomers, hydrates, N -Oxide derivatives or pharmaceutically acceptable salts, or pharmaceutical compositions according to the second aspect.

[0039] Compounds or their stereoisomers, tautomers, hydrates, N -Oxide derivatives or pharmaceutically acceptable salts may be used as monotherapy or as a combination therapy with radiation and / or other therapeutic agents.

[0040] Without being bound by theory, it is believed that the compounds of the present invention tend to exhibit the beneficial effects discussed above, at least in part due to the presence of a carbon atom between position 'M' and the carbonyl group in formula (I).

[0041] As shown in Table 1, compared with analogues in which a nitrogen atom exists between the 'M' position and the carbonyl group, the compounds of the present invention exhibit improved in vitro physicochemical properties, such as higher kinetic solubility (KSol), and improved in vitro ADME properties, such as higher metabolic stability (using human liver microsomal data, lower estimated intrinsic clearance, CL) int (to prove) and lower CYP3A4 inhibition. As shown in Table 2, compared with analogs in which a nitrogen atom exists between the 'M' position and the carbonyl group, the compounds of the present invention exhibit improved in vitro physicochemical properties, such as higher kinetic solubility (KSol), and improved in vitro ADME properties, such as lower hERG inhibition and lower CYP3A4 inhibition. As shown in Table 3, compared with analogues in which a nitrogen atom exists between position 'M' and the carbonyl group, the compounds of the present invention exhibit improved in vitro ADME properties, such as higher metabolic stability (using mouse or rat liver microsomal data, lower estimated intrinsic clearance, CL) int (to prove) and lower CYP3A4 inhibition. Other preferred embodiments of the compounds provided herein appear throughout the specification, particularly in the examples. Those named compounds that have been tested to have higher activity are particularly preferred. Compounds with higher activity are preferred over compounds with lower activity.

[0042] Each aspect or embodiment as defined herein may be combined with any other aspect or embodiment unless expressly stated otherwise. Specifically, any feature designated as preferred or advantageous may be combined with any one or more other features designated as preferred or advantageous. Attached Figure Description

[0043] Figure 1 Effects of USP19 pharmacological inhibition on tibialis anterior muscle mass. (A) Tibialis anterior muscle mass (mg) from mice treated with the solvent or the USP19 inhibitor compound ADC-141. Masses given are from muscles of limbs undergoing sciatic denervation (DEN) and muscles of limbs undergoing nerve innervation (INN). (B) Percentage of tibialis anterior muscle mass loss due to denervation in mice treated with the solvent and the USP19 inhibitor (ADC-141). Percentages are calculated as the proportion of muscle mass from limbs undergoing nerve innervation from the same mouse. (C) Tibialis anterior muscle mass loss (mg) due to denervation in mice treated with the solvent and the USP19 inhibitor (ADC-141). P < 0.025.

[0044] Figure 2 Effects of USP19 pharmacological inhibition on gastrocnemius muscle mass. (A) Gastrocnemius muscle mass (mg) from mice treated with either the solvent or the USP19 inhibitor compound ADC-141. Masses given are from muscles of limbs undergoing sciatic denervation (DEN) and those from nerve-innervated limbs (INN). (B) Percentage of gastrocnemius muscle mass loss due to denervation in mice treated with the solvent and the USP19 inhibitor (ADC-141). Percentages are calculated as the proportion of muscle mass from nerve-innervated limbs of the same mouse. (C) Gastrocnemius muscle mass loss (mg) due to denervation in mice treated with the solvent and the USP19 inhibitor (ADC-141).

[0045] Figure 3(A) Effect of USP19 pharmacological inhibition on fat mass. Epididymal fat pads were collected from mice treated with the solvent and the USP19 inhibitor (ADC-141), with the USP19 inhibitor-treated mice showing a significant reduction in fat mass. (B) Effect of USP19 pharmacological inhibition on liver mass. Liver samples were collected from mice treated with the solvent and the USP19 inhibitor (ADC-141). An increase in liver mass was observed, likely due to the accumulation of the drug compound in the liver. (C) Percentage change in total weight in solvent-treated control DIO mice. Bars from left to right: USP19 inhibitor 5 mg / kg ipBID, USP19 inhibitor 25 mg / kg ipBID, or positive control liraglutide 0.1 mg / kg scBID; (D) percentage change in total lean body mass and (E) percentage change in total fat mass in mice treated with the solvent, USP19 inhibitor 5 mg / kg, USP19 inhibitor 25 mg / kg, and liraglutide (from left to right). ***p<0.001 relative to the solvent.

[0046] Figure 4 USP19 inhibitor compounds bind to their cellular targets in breast cancer, neuroblastoma, and skeletal muscle cell lines. EC was measured using optical density assay. 50 .

[0047] Figure 5 Responses in the oral glucose tolerance test (OGTT) in obese mice. (A) Timelines of plasma glucose responses in solvent-treated control mice (circles), USP19 inhibitor 5 mg / kg ipBID (triangles), USP19 inhibitor 25 mg / kg ipBID (solid circles), or positive control liraglutide 0.1 mg / kg scBID (diamonds); (B) glucose AUC (mM.h) and (C) insulin AUC (ng.h / mL) for solvent, USP19 inhibitor 5 mg / kg, USP19 inhibitor 25 mg / kg, and liraglutide (from left to right). ** p < 0.01 relative to solvent; *** p < 0.001 relative to solvent. Detailed Implementation

[0048] Unless otherwise defined herein, scientific and technical terms used in connection with this invention shall have the meanings commonly understood by one of ordinary skill in the art. The meanings and scopes of terms shall be clear; however, in the event of any potential ambiguity, the definitions provided herein shall prevail over any dictionary or external definition.

[0049] As used in the specification and appended claims, unless otherwise specified, the following terms shall have the meanings indicated herein: The term "alkyl" (alone or in combination with other terms) refers to a straight-chain or branched saturated hydrocarbon substituent that typically contains 1 to 15 carbon atoms, such as 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. "C n An "alkyl" group refers to an aliphatic group containing n carbon atoms. For example, C1-C 10 Alkyl groups contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The connection to the alkyl group occurs through the carbon atom. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (branched or unbranched), hexyl (branched or unbranched), heptyl (branched or unbranched), octyl (branched or unbranched), nonyl (branched or unbranched), and decyl (branched or unbranched).

[0050] The term "alkenyl" (alone or in combination with other terms) refers to a straight-chain or branched hydrocarbon substituent containing one or more double bonds, and typically contains 2 to 15 carbon atoms, such as 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. Examples of such substituents include vinyl, 1-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl, and hexenyl.

[0051] The term "alkynyl" (alone or in combination with other terms) refers to a straight-chain or branched hydrocarbon substituent containing one or more triple bonds, and typically contains 2 to 15 carbon atoms, such as 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. Examples of such substituents include ethynyl, 1-propynyl, 3-propynyl, 1-butynyl, 3-butynyl, and 4-butynyl.

[0052] The term "heteroalkyl" (alone or in combination with other terms) refers to a straight-chain or branched saturated hydrocarbon substituent that typically contains 1 to 15 atoms, such as 1 to 10, 1 to 8, 1 to 6, or 1 to 4 atoms, wherein at least one atom is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining atoms are carbon atoms. "C" n A "heteroalkyl" group refers to an aliphatic group containing n carbon atoms and one or more heteroatoms (e.g., one heteroatom). For example, C1-C 10 Heteroalkyl groups contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms and one or more heteroatoms, such as a single heteroatom. The connection to a heteroalkyl group occurs either through a carbon atom or through a heteroatom.

[0053] The term "heterenyl" (alone or in combination with other terms) refers to a straight-chain or branched saturated hydrocarbon substituent containing one or more carbon-carbon double bonds, typically containing 2 to 15 atoms, such as 2 to 10, 2 to 8, 2 to 6, or 2 to 4 atoms, wherein at least one atom is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining atoms are carbon atoms. "C" n A "heterene" group refers to an aliphatic group containing n carbon atoms and one or more heteroatoms (e.g., one heteroatom). For example, C2-C 10 Heterene groups contain 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms and one or more heteroatoms, such as a single heteroatom. The connection to the heterene group occurs either through a carbon atom or through a heteroatom.

[0054] The term "heterynyl" (alone or in combination with other terms) refers to a straight-chain or branched saturated hydrocarbon substituent containing one or more carbon-carbon triple bonds, typically containing 2 to 15 carbon atoms, such as 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms, wherein at least one atom is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining atoms are carbon atoms. "C" n A "heterynyl" group refers to an aliphatic group containing n carbon atoms and one or more heteroatoms (e.g., one heteroatom). For example, C2-C 10 The pyrynyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms and one or more heteroatoms, such as a single heteroatom. The connection to the pyrynyl group occurs either through a carbon atom or through a heteroatom.

[0055] The term "carbocyclic" (alone or in combination with other terms) refers to a saturated cyclic (i.e., "cycloalkyl"), partially saturated cyclic (i.e., "cycloalkenyl"), or fully unsaturated (i.e., "aryl") hydrocarbon substituent containing 3 to 14 carbocyclic atoms ("cyclic atom" is an atom of one or more rings bonded together to form a cyclic substituent). Carbocyclic groups can be monocyclic (single-ringed) or polycyclic cyclic structures.

[0056] Carbocyclic groups can be monocyclic structures, typically containing 3 to 8 ring atoms, more typically 3 to 7 ring atoms, and even more typically 5 to 6 ring atoms. Examples of such monocyclic carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. Alternatively, carbocyclic groups can be polycyclic (i.e., may contain more than one ring). Examples of polycyclic carbocyclic groups include bridged, fused, and spirocyclic carbocyclic groups. In spirocyclic carbocyclic groups, one atom is shared by two different rings. An example of a spirocyclic carbocyclic group is spiropentyl. In bridged carbocyclic groups, the rings share at least two common non-adjacent atoms. Examples of bridged carbocyclic groups include bicyclic [2.2.1]heptyl, bicyclic [2.2.1]hept-2-enyl, and adamantyl. For example, the bridged aziridine heptane can be 8-oxa-3-azabicyclo[3.2.1]octane-3-yl. In fused-ring carbocyclic systems, two or more rings can be fused together such that the two rings share a common bond. Examples of difused or trifused carbocyclic groups include naphthyl, tetrahydronaphthyl, indenyl, indenyl (dihydroindenyl), anthracel, phenanthryl, and decahydronaphthyl.

[0057] The term "cycloalkyl" (alone or in combination with other terms) refers to a saturated cyclic hydrocarbon substituent containing 3 to 14 carbon ring atoms. A cycloalkyl group can be a single carbon ring, typically containing 3 to 8 carbon ring atoms, more typically 3 to 6 ring atoms. It should be understood that the connection to a cycloalkyl group occurs through the ring atoms of the cycloalkyl group. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Alternatively, a cycloalkyl group can be polycyclic or contain more than one ring. Polycyclic cycloalkyl groups include bridged, fused, and spirocyclic cycloalkyl groups.

[0058] The term "alkylcycloalkyl" refers to a cycloalkyl substituent linked by an alkyl chain. Examples of alkylcycloalkyl substituents include cyclohexylethane, where the cyclohexane is linked by an ethane linker. Other examples include cyclopropylethane, cyclobutylethane, cyclopentylethane, cycloheptylethane, and cyclohexylmethane. In "C n "In alkyl cycloalkyl groups, C n This includes carbon atoms in alkyl chains and cycloalkyl rings. For example, cyclohexylethane is a C8 alkylcycloalkyl group.

[0059] The term "aryl" (alone or in combination with other terms) refers to an aromatic carbocyclic group containing 5 to 14 carbon ring atoms, optionally 5 to 8, 5 to 7, or optionally 5 to 6 carbon ring atoms. "C n An aryl group is an aromatic group containing n carbon atoms. For example, C6-C 10The aryl group contains 6, 7, 8, 9, or 10 carbon atoms. The linkage with the aryl group occurs through the carbon atoms. The aryl group can be monocyclic or polycyclic (i.e., it can contain more than one ring). In the case of polycyclic aromatic rings, only one ring in the polycyclic system is required to be unsaturated, while the remaining rings can be saturated, partially saturated, or unsaturated. The linkage with the aryl group occurs through the carbon atoms contained in the ring. Examples of aryl groups include phenyl, naphthyl, acridine, indenyl, indenyl, and tetrahydronaphthyl.

[0060] The term "arylalkyl" refers to an aryl substituent linked by an alkyl chain. Examples of arylalkyl substituents include benzyl and phenylethane / ethylbenzene, where the ethane chain connects the phenyl group to the linking point. In "C n "In arylalkyl groups, C n This includes carbon atoms in alkyl chains and aryl groups. For example, ethylbenzene is a C8 arylalkyl group.

[0061] The term "heterocyclic group" (alone or in combination with other terms) refers to a saturated (i.e., "heterocyclic alkyl"), partially saturated (i.e., "heterocyclic alkenyl"), or fully unsaturated (i.e., "heteroaryl") ring structure containing a total of 3 to 14 ring atoms, of which at least one ring atom is a heteroatom (e.g., oxygen, nitrogen, or sulfur), and the remaining ring atoms are carbon atoms. A heterocyclic group may, for example, contain one, two, three, four, or five heteroatoms. Connection to a heterocyclic group can occur through the carbon atoms and / or one or more heteroatoms contained in the ring. A heterocyclic group can be a monocyclic (monocyclic) or polycyclic ring structure.

[0062] Heterocyclic groups can be monocyclic, typically containing 3 to 7 ring atoms, more typically 3 to 6 ring atoms, or even more typically 5 to 6 ring atoms. Examples of monocyclic heterocyclic groups include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophene (thiafuranyl), dihydrothiophene, tetrahydrothiophene, pyrrolyl, pyrrololinyl, pyrrolylalkyl, imidazolyl, imidazolinyl, imidazolinyl, pyrazole, pyrazole, pyrazolelinyl, pyrazolealkyl, triazolyl, tetraazolyl, oxazolyl, oxazolyl, isoxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolinyl, isothiazolyl, thiazolidinyl, thiazolidinyl, thiadiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (furazanyl) or 1,3,4-oxadiazolyl), oxtriazolyl, dioxazolyl, oxothiazolidinyl, pyranyl, and dihydropyranyl. Tetrahydropyranyl, thiaranyl, tetrahydrothiaranyl, pyridyl (azaphenyl), piperidinyl, diazinyl (including pyridazinyl (1,2-diazinyl), pyrimidinyl (1,3-diazinyl) or pyrazinyl (1,4-diazinyl)), piperazinyl, triazinyl (including 1,3,5-triazinyl, 1,2,4-triazinyl and 1,2,3-triazinyl), oxazinyl (including 1,2-oxazinyl, 1,3-oxazinyl or 1,4-oxazinyl), oxadiazinyl (including 1,2,3-oxadiazinyl, 1,2,4-oxadiazinyl, 1,4,2-oxadiazinyl or 1,3,5-oxadiazinyl)), morpholinyl, azacycloheptanetrienyl, oxazacycloheptanetrienyl, thiocycloheptanetrienyl and diazacycloheptanetrienyl.

[0063] Alternatively, the heterocyclic group can be polycyclic (i.e., it can contain more than one ring). Examples of polycyclic heterocyclic groups include bridging, fused, and spirocyclic heterocyclic groups. In a spirocyclic heterocyclic group, one atom is common to two different rings. In a bridging heterocyclic group, the rings share at least two common non-adjacent atoms. In a fused heterocyclic group, two or more rings can be fused together such that the two rings share a common bond. Examples of fused heterocyclic groups containing two or three rings include indazinyl, pyranopyrroleyl, 4H-quinazinyl, purinyl, naphthidyl, pyridopyridyl (including pyrido[3,4- b ]-pyridyl, pyrido[3,2- b ]-pyridyl or pyrido[4,3- b[-pyridyl] and pteridinyl. Other examples of fused-ring heterocyclic groups include benzofused heterocyclic groups, such as indolyl, isoindolyl (isobenzozalyl, pseudoisoindolyl), indololinyl (pseudoindolyl), isoinzozalyl (benzopyrazolyl), benzozazinyl (including quinolinyl (1-benzozazinyl) or isoquinolinyl (2-benzozazinyl)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cenolinyl (1,2-benzodiazinyl) or quinazolinyl (1,3-benzodiazinyl)), benzopyranyl (including chromanyl or isochoryl) and benzoisooxazinyl (including 1,2-benzoisooxazinyl or 1,4-benzoisooxazinyl).

[0064] The term "heterocyclic alkyl" (alone or in combination with other terms) refers to a saturated heterocyclic group. An "x- to y-membered heterocyclic alkyl" group is a cyclic aliphatic group containing x to y ring atoms (including at least one heteroatom (e.g., nitrogen), with the remainder being carbon atoms). For example, 3- to 8-membered heterocyclic alkyl groups contain a total of 3 to 8 ring atoms, where at least one ring atom is a heteroatom (e.g., nitrogen, oxygen, sulfur), and the remainder are carbon atoms. Connection to a heterocyclic alkyl group occurs through a carbon atom or at least one heteroatom.

[0065] The term "heteroaryl" (alone or in combination with other terms) refers to an aromatic heterocyclic group containing 5 to 14 ring atoms. An "x- to y-membered heteroaryl" group refers to an aromatic group containing x to y ring atoms (including at least one heteroatom (e.g., nitrogen), with the remainder being carbon atoms). For example, a 5- to 8-membered heteroaryl group contains a total of 5 to 8 ring atoms, where at least one ring atom is a heteroatom (e.g., nitrogen, oxygen, sulfur), and the remainder are carbon atoms. The connection to the heteroaryl group occurs through a carbon atom or through a heteroatom. Heteroaryl groups can be monocyclic or polycyclic. A heteroaryl group can be monocyclic or composed of 2 or 3 fused rings. Examples of monocyclic heteroaryl groups include 6-membered rings, such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and 1,3,5-triazinyl, 1,2,4-triazinyl, or 1,2,3-triazinyl; and 5-membered rings, such as imidazolyl, furanyl, thiopheneyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, or 1,3,4-oxadiazolyl and isothiazolyl. Polycyclic heteroaryl groups can have 2 or 3 fused rings. Examples of polycyclic heteroaryl groups include 6 / 5-membered fused ring groups, such as benzothiofuranyl, benzoisoxazolyl, benzoxazolyl, and purine; and 6 / 6-membered fused ring groups, such as benzopyranyl, quinolinyl, isoquinolinyl, borolinyl, quinazolinyl, and benzoxazinyl. In the case of polycyclic heteroaryl groups, only one ring in the polycyclic system is required to be unsaturated, while the remaining rings can be saturated, partially saturated, or unsaturated.

[0066] The term "amino" refers to the -NR'R'' group. Amino groups can optionally be substituted. In unsubstituted amino groups, R' and R'' are hydrogen. In substituted amino groups, R' and R'' can each independently be, but are not limited to, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheteroalkyl, alkoxy, sulfonyl, alkenyl, alkanoyl, aryl, arylalkyl, or heteroaryl, provided that R' and R'' are not both hydrogen. In substituted amino groups, R' and R'' can be cyclized to form cyclic amino groups, such as pyrrolidinyl or piperidine groups. Such cyclic amino groups can introduce other heteroatoms, such as piperazine or morpholine groups. Such cyclic amino groups can optionally be substituted, for example, by amino, hydroxyl, or oxo groups.

[0067] The term "alkylamino" refers to -R a NR'R'' group, where R a It is an alkyl chain as defined above, and NR'R'' is an optionally substituted amino group as defined above. "C n An "alkylamino" group refers to a group containing n carbon atoms. For example, C1-C 10 Alkylamino groups contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. When the amino group of an alkylamino group is a substituted amino group, the number of carbon atoms includes any carbon atoms in the substituents. The connection to an alkylamino group is via R... a The carbon atom of the alkyl group undergoes substituent formation. Examples of alkylamino substituents include methylamine, ethylamine, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, methylpyrrolidine, and ethylpyrrolidine.

[0068] The term "amide group" refers to a –C(=O)-NR- group. The linkage can be via a carbon or nitrogen atom. For example, an amide group can be linked solely by a carbon atom as a substituent, in which case the nitrogen atom has two linked R groups (-C(=O)-NR2). An amide group can also be linked solely by a nitrogen atom, in which case the carbon atom has a linked R group (-NR-C(=O)R).

[0069] The term "alkylthioalkyl" refers to -SR a Group, wherein R a It is an alkyl chain as defined above. "C n The "alkylthioalkyl" group refers to a group containing n carbon atoms. For example, C1-C 10 Alkyl thioalkyl groups contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The connection to an alkyl thioalkyl group is via SR. a The sulfur atom of the group undergoes a reaction. Alkylthioalkyl groups may optionally be substituted. Examples of alkylthioalkyl substituents include SMe (methylthioalkyl), ethylthioalkyl, propylthioalkyl, and benzylthioalkyl.

[0070] The term "sulfonyl imine" refers to an S-linked or N-linked sulfonyl imine substituent, meaning the link can be via a sulfur or nitrogen atom. For example, a sulfonyl imine group can be linked via a sulfur atom as a substituent, in which case the sulfur atom has a single R group in addition to the oxo group, and the sulfur-bonded nitrogen atom has a linked R group, i.e., the group is –S(O)(R)NR'. As another example, a sulfonyl imine group can be linked via a nitrogen atom as a substituent, in which case the sulfur atom has two linked R groups in addition to the oxo group, i.e., the group is –NS(O)RR'. In an unsubstituted sulfonyl imine group, R and R' are each H. Alternatively, the sulfonyl imine group can be substituted at one or both of R and R', for example, forming a dimethyl sulfonyl imine, where both R and R' are methyl groups.

[0071] The term "ether" refers to -O-alkyl or -alkyl-O-alkyl, such as methoxy, methoxymethyl, or ethoxyethyl. The alkyl chain of an ether can be straight, branched, or cyclic. The ether group may optionally be substituted with one or more substituents ("substituted ethers"). n An ether is an ether group that has n carbons in all alkyl chains of the ether group. For example, CH(CH3)-O-C6H 11 The ether is a C8 ether group.

[0072] The term "alkoxy" refers to an -O-alkyl group. Alkoxy groups can be straight-chain, branched, or cyclic, saturated or unsaturated oxy-hydrocarbon chains, including, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, and pentoxy. Alkoxy groups may optionally be substituted with one or more alkoxy substituents ("substituted alkoxy groups").

[0073] The term "aryloxy group" refers to an -O-aryl group, such as a phenoxy group. The aryloxy substituent itself can be optionally substituted, for example, by a halogen.

[0074] The term "alkyl ester" refers to a -C(O)OR group, where R is an alkyl group as defined herein. An example of an alkyl ester is ethyl formate—that is, R is ethyl.

[0075] The term "hydroxyl group" refers to the -OH group.

[0076] The term "oxo group" refers to an (=O) group, which is a substituent oxygen atom attached to another atom via a double bond. For example, a carbonyl group (-C(=O)-) is an oxo group where a carbon atom is attached to an oxygen atom via a double bond. Examples of carbonyl substituents include aldehydes (-C(=O)H), acetyl groups (-C(=O)CH3), and carboxyl / carboxylic acid groups (-C(=O)OH).

[0077] The term "halogen" refers to a substituent selected from chlorine, fluorine, bromine, and iodine. Preferably, the halogen substituent is selected from chlorine, fluorine, and bromine. More preferably, the halogen substituent is selected from chlorine and fluorine.

[0078] Alkyl, alkenyl, alkynyl, carbocyclic (including cycloalkyl, cycloalkenyl, and aryl), heterocyclic (including heterocyclic alkyl, heterocyclic alkenyl, heteroaryl, and nitrogen-containing heterocyclic), amino, amide, ester, ether, alkoxy, or sulfonamide groups may optionally be substituted by one or more substituents, which may be the same or different. Substituents may be linked to carbon atoms and / or heteroatoms in alkyl, alkenyl, alkynyl, carbocyclic (including cycloalkyl, cycloalkenyl, and aryl), heterocyclic (including heterocyclic alkyl, heterocyclic alkenyl, heteroaryl, nitrogen-containing heterocyclic, and nitrogen-containing heteroaryl), amino, amide, ester, ether, alkoxy, or sulfonamide groups. The term "substituent" (or "free radical") includes, but is not limited to, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aralkyl, substituted aralkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, hydroxyl, cyano, amino, acylamino, alkylamino, arylamino, carbocyclic, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, nitro, thio, alkanoyl, hydroxyl, aryloxy, alkoxy, alkylthio, arylthio, arylalkoxy, arylalkylthio, carboxyl, alkoxycarbonyl, oxo, alkylsulfonyl, arylsulfonyl, and sulfoxide imine.

[0079] In some respects, the substituents are alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, hydroxyl, cyano, amino, amide, alkylamino, arylamino, carbocyclic, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, nitro, thio, alkanoyl, hydroxyl, aryloxy, alkoxy, alkylthio, arylthio, arylalkoxy, arylalkylthio, carboxyl, alkoxycarbonyl, oxo, alkylsulfonyl and arylsulfonyl.

[0080] If a group, such as an alkyl group, is "optionally substituted", it should be understood that the group has one or more connected substituents (substituted) or no connected substituents (unsubstituted).

[0081] If a group is replaced by another optionally substituted group, it should be understood that the first substituted group itself can be unsubstituted or substituted.

[0082] For completeness, it should also be noted that some chemical formulas used herein define delocalized systems. This definition is known in the art as the definition of aromaticity and can, for example, indicate the presence of (4... nThe existence of planar monocyclic, bicyclic, or tricyclic systems with +2 electrons (where n is an integer). In other words, these systems can exhibit Hückel aromaticity.

[0083] In any respect, the compounds of the present invention may have some aspects of stereochemistry. For example, the compounds may have a chiral center and / or a planar and / or symmetry axis. Therefore, unless otherwise stated, the compounds may be provided as a single stereoisomer, a single diastereomer, a mixture of stereoisomers, or as a racemic mixture. Stereoisomers are known in the art to be molecules having the same molecular formula and bonded atomic sequence but with different spatial orientations of their atoms and / or groups.

[0084] Furthermore, the compounds of the present invention can exhibit tautomerism. Each tautomer is intended to fall within the scope of the present invention.

[0085] Furthermore, the compounds of the present invention can be provided as prodrugs. Prodrugs are typically converted from one form to the active form of the drug described herein in vivo.

[0086] Furthermore, it should be understood that the elements described herein may be common isotopes or isotopes different from common isotopes. For example, a hydrogen atom may be... 1 H, 2 H (deuterium) or 3 H (tritium).

[0087] Furthermore, the compounds of the present invention may be provided in the form of their pharmaceutically acceptable salts or as cocrystals.

[0088] The term "pharmaceutically acceptable salt" refers to an ionic compound formed by adding an acid to a base. This term refers to salts that are considered suitable in the art for contact with patients, such as in the body, and pharmaceutically acceptable salts are generally chosen because of their non-toxic and non-irritating properties.

[0089] The term "eutectic" refers to a multicomponent molecular crystal that can contain nonionic interactions.

[0090] Pharmaceutically acceptable salts and cocrystals can be prepared by ion-exchange chromatography, or by reacting a compound in its free base or acidic form with a stoichiometric or excess amount of the desired salt-forming inorganic or organic acid or base in one or more suitable solvents, or by mixing the compound with another pharmaceutically acceptable compound capable of forming a cocrystal.

[0091] Salts known in the art to be generally suitable for patient contact include those derived from inorganic and / or organic acids, including hydrobromides, hydrochlorides, sulfates, hydrogen sulfates, nitrates, acetates, oxalates, oleates, palmitates, stearates, laurates, benzoates, lactates, phosphates, toluenesulfonates, citrates, maleates, fumarates, succinates, and tartrates. These salts may contain alkali metal and alkaline earth metal-based cations, such as sodium, potassium, calcium, and magnesium, as well as ammonium, tetramethylammonium, and tetraethylammonium. Further references can be made to numerous literatures that review suitable pharmaceutically acceptable salts, such as the IUPAC Handbook of Pharmaceutical Salts.

[0092] Furthermore, the compounds of the present invention can sometimes exist as zwitterions, which are also considered part of the present invention.

[0093] As used herein, a USP19 inhibitor refers to a compound that acts on USP19 to reduce the activity of the enzyme. Examples of USP19 inhibitors are the exemplary compounds described herein. Preferably, the USP19 inhibitor exhibits an IC50 value of [missing information - likely an IC50 value]. 50 Less than 5 μM, preferably less than 0.5 μM.

[0094] As used herein, “obesity” refers to a medical condition characterized by excessive body fat. Characteristics of obesity may include, for example, a body mass index (BMI) greater than 30. Treatment of obesity can be demonstrated, for example, by a reduction in body fat (in percentage and / or absolute mass). Treatment of obesity can also be illustrated by a decrease in the rate of body fat accumulation in the subject compared to before treatment.

[0095] As used in this article, “insulin resistance” refers to a medical condition characterized by an abnormally impaired response to insulin. Because insulin resistance is usually not treated with exogenous insulin, this resistance is typically against insulin produced by the body, although resistance to exogenous insulin is also possible. “Insulin resistance” encompasses both prediabetes and type 2 diabetes. Insulin resistance can be diagnosed, for example, by a glucose tolerance test (GTT) showing a blood glucose level of 7.8 mmol / L or higher. Type 2 diabetes is typically diagnosed after a GTT showing a blood glucose level of 11.1 mmol / L or higher.

[0096] Treatment for insulin resistance can be demonstrated by an improvement (i.e., a decrease) in the subject's GTT (Gross Spectrum Trip) compared to pre-treatment levels. Treatment can also be demonstrated by a decrease in the subject's blood glucose concentration under normal conditions compared to pre-treatment levels.

[0097] As used herein, “muscle atrophy” and “muscle loss” are used interchangeably to refer to a decrease in muscle mass in a subject, including, for example, in cases of cachexia or sarcopenia. Muscle atrophy can be due to temporary or permanent disability, temporary or permanent immobilization of a limb, prolonged bed rest, cachexia (e.g., due to cancer, heart failure, or COPD), or sarcopenia.

[0098] Treatment for muscle atrophy can manifest as a slowing of the atrophy rate—that is, treatment results in a reduction in muscle mass loss over a given period of time. Preferably, successful treatment results in no muscle mass loss.

[0099] Therefore, in the first aspect, compounds of formula (I) are provided: (I) in R 1 It is an optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted 3- to 11-membered heterocyclic alkyl, optionally substituted aryl, or optionally substituted 5- to 8-membered heteroaryl; R 2 and R 3 Each is independently selected from H and C1-C6 alkyl groups, or R. 2 and R 3 Together with the carbons they are attached to, they form C3-C8 cycloalkyl, C3-C8 cycloalkenyl, or 3- to 8-membered heterocyclic alkyl groups; M is N or CR a , where R a It is H, halogen, optionally substituted C3-C8 cycloalkyl or optionally substituted C1-C6 alkyl; A, D, E, and G do not exist, and X is NR 15 Or CH; Y is CR 4 Either N or it does not exist; Z is CR 5 NR 6 Or O; R 4 It is a halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, 4- to 10-membered fused-ring heterocyclic, optionally substituted C1-C6 alkylthioalkyl (optionally SMe), sulfoxide, sulfone, sulfoxide imine, optionally substituted amino, optionally substituted 3- to 8-membered heterocyclic alkyl or OR 20 ; Where R 20 It is an optional substituted C1-C6 alkyl group; R 5H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, optionally substituted 3- to 8-membered heterocyclic alkyl, amide, sulfoxide imine, CN, halogen, C(O)OR 21 OR 22 or NR 23 R 24 ; Where R 21 Selected from H and C1-C6 alkyl groups; R 22 Selected from H and C1-C6 alkyl groups; R 23 and R 24 Independently selected from H and optionally substituted C1-C6 alkyl groups; R 15 It is an H or C1-C6 alkyl group; Or R 4 and R 5 Together with the Y and Z groups to which they are attached, they form 3 to 8-membered heterocyclic alkyl or aryl groups; Or R 4 and R 15 Together with the X and Y they are attached to, they form 5-membered cycloalkyl, heterocycloalkyl, or heteroaryl groups; R 6 It is H, C1-C6 alkyl, optionally substituted aryl or C3-C8 cycloalkyl; Or A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N and G is CR 14 Or N, and X is N or C; Y is C; Z is CR 20 , N, NR 11 Or O, Where R 11 It is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl or optionally substituted 5 to 8-membered heteroaryl; Where R 20 H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, optionally substituted 3- to 8-membered heterocyclic alkyl, amide, sulfoxide imine, CN, halogen, C(O)OR 25 OR 26 or NR 27 R 28 ; Where R 25 Selected from H and C1-C6 alkyl groups; R26 Selected from H and C1-C6 alkyl groups; R 27 and R 28 Independently selected from H and C1-C6 alkyl groups; R 7 It is H, halogen, C1-C6 alkyl or OR 19 ; Where R 19 It is an optional substituted C1-C6 alkyl group; R 12 It is H, halogen, or C1-C6 alkyl; R 13 It is H, halogen, C1-C6 alkyl, OR 16 or NR 17 R 18 ; Where R 16 It is an optional substituted C1-C6 alkyl group. R 17 and R 18 Independently selected from H and C1-C6 alkyl groups, or wherein R 17 and R 18 Together with the nitrogen atoms to which they are attached, they form 5- to 6-membered heterocyclic alkyl groups; and R 14 It is H, halogen, or C1-C6 alkyl; Or its stereoisomers, tautomers, hydrates, N -Oxide derivatives or pharmaceutically acceptable salts.

[0100] In Equation (I), the dashed lines represent optional bonds. That is, the dashed lines indicate that the rings including positions X, Y, Z, and M can be aliphatic (e.g., saturated or partially unsaturated) or aromatic. Similarly, in Equation (I), the dashed lines indicate that, when present, the rings including positions A, D, E, and G can be aliphatic (e.g., saturated or partially unsaturated) or aromatic.

[0101] To avoid ambiguity, when A, D, E, and G are absent and Y is absent, X is directly bonded to Z. In other words, when A, D, E, and G are absent and Y is absent, the ring containing X, Z, and M is pentadic.

[0102] For compounds of formula (I), for each optionally substituted group, there are one or more independently selected optional substituents. In some embodiments, each of the one or more optional substituents is independently selected from alkyl, alkoxy, oxo, halogen, cycloalkyl, heterocycloalkyl, aryl, aryl substituted with one or more halogens, aryl substituted with both halogen and alkyl, aryl substituted with both halogen and alkoxy, heteroaryl, hydroxyl, CR 8 R9 R 10 NR 8 NR 8 R 9 ,NHC(O)R 8 NHCR 8 R 9 R 10 NHCH2CR 8 R 9 R 10 and NHCH2C(O)R 8 , where R 8 R 9 and R 10 Each is independently selected from H, halogen, hydroxyl, alkyl, cycloalkyl, cycloalkyl substituted with one or more halogens or alkyl groups, heterocycloalkyl substituted with one or more alkyl groups or oxo groups, heteroaryl, alkoxy, CH2OH and CH2CH2OH.

[0103] In some implementations, R 1 It is an optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted 3- to 8-membered heterocyclic alkyl, optionally substituted aryl, or optionally substituted 5- to 8-membered heteroaryl.

[0104] In some preferred embodiments, R 1 It is an optionally substituted 3- to 11-membered heterocyclic alkyl group. More preferably, R 1 It is an optionally substituted 3- to 8-membered heterocyclic alkyl group. More preferably, R 1 It is an optionally substituted 5- to 8-membered heterocyclic alkyl group. Even more preferably, R 1 It is an optional substituted 5- to 6-membered heterocyclic alkyl group.

[0105] In some preferred embodiments, R 1 It is optionally substituted morpholine, bridged aziridine, diaziridine, thiomorpholine, pyrrolidine, piperazine, or piperidine. In a preferred embodiment of this type, R 1 It is optionally substituted with morpholine, thiomorpholine, pyrrolidine, piperazine, or piperidine. Preferably, R 1 It is a piperidine with optional substitution.

[0106] In some preferred embodiments, R 1 Aryl, oxo, cycloalkyl, heterocycloalkyl, aryl, aryl substituted with one or more halogens, heteroaryl, NR 8 NR 8 R 9 ,NHC(O)R 8 NHCR 8 R 9 R 10 NHCH2CR8 R 9 R 10 and NHCH2C(O)R 8 Replace, where R 8 R 9 and R 10 Each is independently selected from H, halogen, hydroxyl, alkyl, cycloalkyl, cycloalkyl substituted with one or more halogens or alkyl groups, heterocycloalkyl substituted with one or more alkyl groups or oxo groups, heteroaryl and alkoxy groups.

[0107] In some preferred embodiments, R1 is NR 8 R 9 ,NHC(O)R 8 or NHCH2CR 8 R 9 R 10 Replace, where R 8 R 9 and R 10 Each is independently selected from H, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, CH2OH, CH2CH2OH and optionally substituted C3-C6 cycloalkyl.

[0108] In some preferred embodiments, R1 is NR 8 R 9 ,NHC(O)R 8 or NHCH2CR 8 R 9 R 10 Replace, where R 8 R 9 and R 10 Each is independently selected from H, C1-C6 alkyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, CH2OH, CH2CH2OH, fluorinated C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted with C1-C6 alkyl and pyridine substituted C1-C6 alkyl.

[0109] In some preferred embodiments, R 1 A phenyl group substituted with a phenyl group or a phenyl group substituted with one or more halogens, wherein R 1 It may be optionally substituted by one or more other substituents.

[0110] In some preferred embodiments, R 1 A phenyl group substituted with a phenyl group or a phenyl group substituted with one or more fluorine molecules, wherein R 1 Optionally substituted with one or more other substituents. In some preferred embodiments, R 1 It is replaced by difluorophenyl.

[0111] In some preferred embodiments, R1 The phenyl group is substituted with halogens and C1-C6 alkyl groups, wherein R 1 Optionally substituted with one or more other substituents. In some preferred embodiments, R 1 The phenyl group is substituted with halogen and C1-C6 alkoxy groups, wherein R 1 Optionally substituted with one or more other substituents. In some preferred embodiments, R 1 The phenyl group is replaced by fluorine and methyl, wherein R 1 Optionally substituted with one or more other substituents. In some preferred embodiments, R 1 Phenyl groups substituted with fluorine and methoxy groups, wherein R 1 It may be optionally substituted by one or more other substituents.

[0112] In some preferred embodiments, R 1 NR 8 R 9 ,NHC(O)R 8 or NHCH2CR 8 R 9 R 10 Replace, and where R 1 Optionally substituted with one or more other substituents. In some preferred embodiments, R 1 Further substituted with a phenyl group or a phenyl group substituted with one or more halogens. In some preferred embodiments, R 1 Further substituted with a phenyl group or a phenyl group substituted with one or more fluorine molecules. In some preferred embodiments, R 1 It is further replaced by difluorophenyl.

[0113] In some preferred embodiments, R 1 It is an optionally substituted C1-C6 alkyl group. Preferably, each optional substituent is selected from halogens, alkoxy groups, cycloalkyl groups, and hydroxyl groups.

[0114] In some preferred embodiments, R 1 It is an optionally substituted 6-membered heteroaryl group, preferably a pyridyl group substituted with a phenyl group.

[0115] In some preferred embodiments, R 1 It is an optionally substituted amino group. More preferably, R 1 It is a phenyl group substituted with one or more halogens or an amino group substituted with one or more halogens by a benzyl group.

[0116] In certain preferred embodiments of the compound of formula (I), R 1 It is NR b R c or NR b CH2Rc , where R b and R c The group is independently selected from H, methyl, ethyl, propyl, CF3, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted pyridyl, pyrazole, imidazole, furan, benzo[a]dioxane, optionally substituted oxadiazole, thiazole, and thiophene, wherein one or more optional substituents are each independently selected from halogen, methyl, cyclopropyl, and CN. Optionally, R 1 It is NR a CH2R b Furthermore, the methylene group is replaced by CF3.

[0117] In some implementations, R 1 It is NR b R c And R b and R c Together with the N atoms to which they are attached, they form optional substituted C3-C9 heterocycles.

[0118] In some implementations, R 1 It is NR b R c And R b and R c Together with the N atoms to which they are attached, they form optionally substituted C3-C9 heterocycles, wherein one or more optional substituents are each selected from OH, oxo, C1-C3 alkyl optionally substituted with OH and / or halogen, optionally substituted phenyl, optionally substituted benzyl, C1-C3 alkoxy, NR m R n ,NHC(O)R m and NHCH2R n , Where R m and R n Independently selected from H; C1-C3 alkyl groups optionally substituted with OH, methoxy, or halogen; C3-C4 cycloalkyl groups optionally substituted with methyl and / or halogen; C3-C4 heterocycloalkyl groups optionally substituted with oxo, methyl, or fluoro-methyl; C3-C5 heteroaryl groups optionally substituted with methyl; and Boc; and / or wherein R n Further selections are made from CH2OCH3, COOH, and COOCH3. Or R m and R n Together with the N to which they are attached, they form C3-C5 heterocyclic groups, optionally wherein R m and R n Together with the N atoms they are attached to, they form morpholino groups.

[0119] In some implementations, R 1 It is NR b R c And R b and R c Together with the N atoms to which they are attached, they form optionally substituted C3-C9 heterocycles, wherein one or more optional substituents are each selected from optionally halogenated phenyl, NR... m R n ,NHC(O)R m and NHCH2R n , Where R m and R n Independently selected from H; C1-C3 alkyl groups optionally substituted with OH, methoxy, or halogen; C3-C4 cycloalkyl groups optionally substituted with methyl and / or halogen; C3-C4 heterocycloalkyl groups optionally substituted with oxo, methyl, or fluoro-methyl; C3-C5 heteroaryl groups optionally substituted with methyl; and Boc; and / or wherein R n Further selections are made from CH2OCH3, COOH, and COOCH3. Or R m and R n Together with the N to which they are attached, they form C3-C5 heterocyclic groups, optionally wherein R m and R n Together with the N atoms they are attached to, they form morpholino groups.

[0120] In some implementations, R 1 It is NR b R c And R b and R c Together with the N atoms to which they are attached, they form substituted C3-C9 heterocycles, wherein one or more substituents are each selected from OH, CH2OH, CH2OCH3, oxo, NH2, C1-C3 aminoalkyl, amino-thioheterocyclic butane dioxide, methyl, ethyl, propyl, CF3, phenyl, substituted phenyl and benzyl.

[0121] In some implementations, R 1 It is NR b R c And R b and R cTogether with the N atoms to which they are attached, they form optionally substituted heterocycles, wherein the heterocycles are selected from pyrrolidinyl, pyrimidinyl, piperidinyl, morpholinyl, piperazineyl, and thiomorpholinyl. In some such embodiments, the heterocycles are optionally substituted by one or more substituents independently selected from methyl, spirocyclopropyl, C1-C3 aminoalkyl, NH2, CH2OH, CH2CF3, oxo, thiophene, phenyl groups optionally substituted with F or CF3, and OH, provided that the same ring carbons are not simultaneously substituted with methyl groups.

[0122] In some implementations, R 1 It is NR b R c And R b and R c Together with the N atoms they are attached to, they form heterocycles, wherein the heterocycles are selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazineyl, and thiomorpholinyl. The heterocycle is optionally substituted by one or more substituents independently selected from methyl, NH2, C1 or C2 aminoalkyl, CH2CF3, oxo, thiophene, phenyl optionally substituted with F or CF3, and OH, provided that the same ring carbon is not simultaneously substituted by methyl.

[0123] In some implementations, R 1 It is NR b R c And R b and R c Together with the N atoms to which they are attached, they form heterocycles, wherein the heterocycles are selected from piperidinyl and piperazineyl groups. The heterocycle is optionally substituted by one or more substituents independently selected from methyl, NH2, C1 or C2 aminoalkyl, CH2CF3, oxo, thiophene, phenyl optionally substituted with F or CF3, and OH, provided that the same ring carbon is not simultaneously substituted by methyl.

[0124] In some implementations, R 1 It is NR b R c And R b and R c Together with the N atoms to which they are attached, they form optionally substituted heterocycles, wherein the heterocycles are selected from piperidinyl and piperazineyl.

[0125] Preferably, R 1 It forms a piperazine group that is substituted with fluoro-phenyl or difluorophenyl.

[0126] In some embodiments, the piperazine group is optionally further substituted with a methyl group.

[0127] In some embodiments, the piperazine group may optionally be further substituted with CH2OH or spiro-cyclopropyl.

[0128] In some implementations, R 1 It is NR b R c And R b and R c The alternatively substituted heterocycle is formed, wherein the heterocycle is a piperidinyl group substituted with a phenyl group, wherein the phenyl group is optionally substituted with one or more halogen (e.g., fluorine) substituents. In some preferred embodiments of this kind, the piperidinyl group is optionally further substituted with NH2 or NHCH3.

[0129] In some implementations, R 1 It is NR b R c And R b and R c Together with the N atoms to which they are attached, they form piperidinyl groups optionally substituted with phenyl, fluoro-phenyl, or difluoro-phenyl groups, wherein the piperidinyl groups are optionally further substituted with NR. m R n ,NHC(O)R m or NHCH2R n replace, Where R m and R n Independently selected from H; C1-C3 alkyl groups optionally substituted with OH, methoxy, or halogen; C3-C4 cycloalkyl groups optionally substituted with methyl and / or halogen; C3-C4 heterocycloalkyl groups optionally substituted with oxo, methyl, or fluoro-methyl; C3-C5 heteroaryl groups optionally substituted with methyl; and Boc; and / or wherein R n Further selections are made from CH2OCH3, COOH, and COOCH3. Or R m and R n Together with the N to which they are attached, they form C3-C5 heterocyclic groups, optionally wherein R m and R n Together with the N atoms they are attached to, they form morpholino groups.

[0130] In some implementations, R 1 It is NR b R c And R b and R c Together with the N atoms to which they are attached, they form piperidinyl groups optionally substituted with phenyl, fluoro-phenyl, or difluoro-phenyl groups, wherein the piperidinyl groups are optionally further substituted with NR. m R n ,NHC(O)R m or NHCH2R n replace, Where R mSelected from H; C1-C3 alkyl groups optionally substituted with OH or halogen; C3-C4 cycloalkyl groups optionally substituted with methyl and / or halogen; C3-C4 heterocycloalkyl groups optionally substituted with oxo, methyl, or fluoro-methyl; C3-C5 heteroaryl groups optionally substituted with methyl; and Boc; and Where R n Selected from H; C1-C3 alkyl groups optionally substituted with OH or halogen; C3-C4 cycloalkyl groups optionally substituted with methyl and / or halogen; C3-C4 heterocycloalkyl groups optionally substituted with oxo, methyl or fluoro-methyl; C3-C5 heteroaryl groups optionally substituted with methyl; Boc; COOH and COOCH3.

[0131] In some preferred embodiments, by R 1 The formed piperidinyl ring is NR m R n Replace, where R m and R n Independently selected from H; C1-C3 alkyl groups optionally substituted with OH or halogen (preferably F); C3-C4 cycloalkyl groups optionally substituted with methyl and / or halogen (preferably F); C3-C4 heterocycloalkyl groups optionally substituted with oxo, methyl or fluoro-methyl; C3-C5 heteroaryl groups optionally substituted with methyl; and Boc.

[0132] In some preferred embodiments, wherein R 1 NR m R n Replace, R m It is H.

[0133] In some preferred embodiments, R m It is H and R n Selected from: H; methyl; ethyl optionally substituted with fluorine or OH; propyl (including isopropyl); cyclopropyl optionally substituted with methyl; cyclobutyl optionally substituted with fluorine; and oxacyclobutane optionally substituted with methyl or fluoro-methyl.

[0134] In some preferred embodiments, by R 1 The formed piperidinyl ring is formed by NHC(O)R m Replace, where R m Selected from H; C1-C3 alkyl groups optionally substituted with OH or halogen (preferably F); C3-C4 cycloalkyl groups optionally substituted with methyl and / or halogen (preferably F); C3-C4 heterocycloalkyl groups optionally substituted with oxo, methyl or fluoro-methyl; C3-C5 heteroaryl groups optionally substituted with methyl; and Boc.

[0135] In some preferred embodiments, wherein R 1 by NHC(O)R mReplace, R m It is selected from C1-C3 alkyl, C3-C4 cycloalkyl and C4-C5 heteroaryl, such as pyridine.

[0136] In some implementations, R 1 It is NR b R c And R b and R c Together with the N atoms to which they are attached, they form piperidinyl groups optionally substituted with phenyl, fluoro-phenyl, or difluoro-phenyl groups, wherein the piperidinyl groups are optionally further substituted with NR. m R n replace, Where R m and R n Together with the N atoms to which they are attached, they form C3-C5 heterocyclic groups. In some such embodiments, R m and R n Together with the N atoms they are attached to, they form morpholino groups.

[0137] In some implementations, R 1 It is NR b R c And R b and R c Together with the N atoms to which they are attached, they form piperidinyl groups optionally substituted with phenyl, fluoro-phenyl, or difluoro-phenyl groups, wherein the piperidinyl groups are optionally further substituted with NH2, NHCH3, or NHCH2CH3.

[0138] In which R 1 In some embodiments where the formed heterocyclic ring is replaced, it is replaced at the para position (4-position).

[0139] In which R 1 In some embodiments where the formed heterocycle is replaced, it is replaced at the adjacent (2-position).

[0140] In some such implementations, by R 1 The resulting heterocycle is substituted at the adjacent and para positions (positions 2 and 4).

[0141] In some implementations, by R 1 The resulting heterocyclic ring is substituted at the meta position (position 3). In some such embodiments, R... 1 The resulting heterocycle is substituted at the adjacent and metapositions (positions 2 and 3).

[0142] In some implementations, by R 1 The resulting heterocycle is substituted at positions 3 and 5.

[0143] In some preferred embodiments, R 1 It is NRb R c And R b and R c Together with the N atoms to which they are attached, they form a piperidinyl group, wherein the piperidinyl group is NR-dependent at the 4-position. m R n ,NHC(O)R m and NHCH2R n The substituted compound is further substituted at the 2-position with a phenyl, fluoro-phenyl, or difluoro-phenyl group. In such embodiments, R... m and R n As defined above and elsewhere in this article.

[0144] In which R 1 In preferred embodiments of this type, the compound is a heterocycle that is substituted at the ortho or 2 position (e.g., substituted with a phenyl group) and is chiral, in which position the compound is ( R )- configuration. In which R 1 In a preferred embodiment where the compound is substituted at the ortho or 2 position (e.g., substituted with a phenyl group) and is chiral, the compound is ( S )-configuration.

[0145] In which R 1 In certain preferred embodiments, the compound is a heterocycle substituted at the ortho or 2-position and at the meta or 3-position, and is chiral. S )- configuration and in the meta position is ( S )- configuration. In which R 1 In certain preferred embodiments where the compound is substituted at the ortho or 2-position and meta or 3-position and is chiral, the compound is ( R )- configuration and in the meta position is ( R )-configuration.

[0146] In some preferred embodiments, R 1 It is the heterocyclic ring that is substituted at positions 3 and 4. In a preferred embodiment of this type, and in R 1 In the case of chirality, the compound is ( ) at position 3. R )- configuration and is in position 4 ( R )-configuration.

[0147] In certain preferred implementations, R 1 The heterocyclic rings are substituted at positions 3 and 5. In a preferred embodiment of this type, and in R... 1 In the case of chirality, the compound is ( ) at position 3. R )- configuration and is in position 5 ( S )-configuration.

[0148] In some preferred embodiments, R 1These are heterocyclic rings that are substituted at positions 1, 2, and 5. In a preferred embodiment of this type, and in R... 1 In the case of chirality, the compound is ( ) at position 1. S )- configuration, in position 2 is ( R )- configuration and is in position 5 ( R )-configuration.

[0149] In which R 1 In preferred embodiments of this type, the compound is a heterocyclic compound that is substituted at the ortho or 2 position and at the para or 4 position (e.g., substituted with NH2 or C1-C2 alkylamino groups) and is chiral, wherein the compound is ( R )- configuration and in the adjacent position is ( S )- configuration. In which R 1 In preferred embodiments where the compound is substituted at the ortho or 2-position and the para or 4-position (e.g., substituted with NH2 or C1-C2 alkylamino groups) and is chiral, the compound is ( S )- configuration and in the adjacent position is ( R )-configuration.

[0150] In some preferred embodiments, R 1 A piperazine group is formed, substituted with a phenyl, fluorophenyl, difluorophenyl, or thiophene group. In some preferred embodiments, R 1 Forming a 4-aminopiperidinyl group substituted with a phenyl, fluoro-phenyl, difluoro-phenyl, or thiophene group. Preferably, R 1 Forming a piperazine group or a 4-aminopiperidinyl group substituted with a phenyl group. Preferably, R 1 Forming a piperazinyl or 4-aminopiperidinyl group substituted with a fluoro-phenyl group. Preferably, R 1 It forms a piperazine group or a 4-aminopiperidin group that is substituted with difluoro-phenyl.

[0151] In which R 1 In a preferred embodiment where the substituent is difluoro-phenyl, the substituent is 2,5-difluoro-phenyl or 3,5-difluoro-phenyl.

[0152] In some embodiments, the piperazinyl or 4-aminopiperidinyl group may optionally be further surrounded by one or both (preferably one). N -Alkyl (e.g., methyl or ethyl) substitution.

[0153] In some preferred embodiments, R 1 yes: , or .

[0154] In some preferred embodiments, R 1 yes: , or .

[0155] In some preferred embodiments, R 1 yes: .

[0156] In some preferred embodiments, R 1 yes: .

[0157] In some preferred embodiments of this type, the phenyl ring is mono- or di-substituted with fluorine.

[0158] In some preferred embodiments, R 1 Selected from: In certain preferred embodiments of the compound of formula (I), R 1 It is NR b R c or NR b CH2R c , where R b and R c Independently selected from H, methyl, ethyl, propyl, CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, pyridyl, pyrazole, imidazole, or R. b and R c Together with the N atoms to which they are attached, they form C3-C5 heterocycles, which may optionally be substituted with OH, CH2OH, CH2OCH3, methyl, ethyl, propyl, CF3, phenyl, or benzyl.

[0159] In some preferred embodiments, R 1 It is NR b CH2R c , where R b It is H or methyl, and R c Selected from cyclobutyl, cyclohexyl, phenyl, furan and thiophene optionally substituted with F, wherein the methylene group is optionally substituted with CF3.

[0160] In some preferred embodiments of this kind, R c It is a phenyl or a fluorine-substituted phenyl.

[0161] In some preferred embodiments, R 2 and R 3 Each is independently H or methyl, or R 2 and R 3Together with the carbons they are attached to, they form C3-C6 cycloalkyl, cyclopentenyl, or 4- to 6-membered heterocyclic alkyl groups. In some such embodiments, R 2 and R 3 Together with the carbon atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, oxecyclobutyl, or oxecyclohexyl groups. More preferably, R 2 and R 3 Each is independently H or methyl, or R 2 and R 3 Together they form a cyclopentyl group. More preferably, R 2 and R 3 Together with the carbon atoms they are attached to, they form cyclopentyl groups.

[0162] In some preferred embodiments, M is N or CR a , where R a It is an H, halogen, cyclopropyl, or optionally substituted C1-C6 alkyl group.

[0163] In some preferred embodiments, M is N or CR a , where R a It is a C1-C6 alkyl group that is H, fluorine, chlorine, cyclopropyl, or optionally substituted with one or more halogen groups.

[0164] In some preferred embodiments, M is N or CR a , where R a It is H, fluorine, chlorine, cyclopropyl, CF3, or C1-C6 alkyl.

[0165] In some preferred embodiments, M is N or CR a , where R a It is H or an optionally substituted C1-C6 alkyl group. More preferably, M is N or C1-C6. a , where R a It is H or C1-C6 alkyl.

[0166] In some preferred embodiments, M is CR a In some such implementations, R a It is H, cyclopropyl, CF3, or methyl.

[0167] In some preferred embodiments, R a It is H or methyl. More preferably, R a It is H.

[0168] In some preferred embodiments, M is N.

[0169] In some preferred embodiments, R 15 It is H or methyl.

[0170] In some preferred embodiments: A, D, E, and G do not exist, and X is NR 15 Or CH; Y is CR 4 N or does not exist; Z is CR 5 NR 6 Or O; R 4 It is a halogen, an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted aryl, an optionally substituted 5- to 8-membered heteroaryl, a 4- to 10-membered fused-ring heterocyclic or C1-C6 alkylthioalkyl. R 5 It is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, optionally substituted 3- to 8-membered heterocyclic alkyl, amide, sulfoxide imine, CN or halogen; or R 4 and R 5 Together with the Y and Z groups to which they are attached, they form 3 to 8-membered heterocyclic alkyl or aryl groups; R 6 It is H, C1-C6 alkyl, aryl, or C3-C8 cycloalkyl; R 15 It is an H or C1-C6 alkyl group; Or R 4 and R 15 Together with the X and Y to which they are attached, they form a 5-membered heterocyclic alkyl or heteroaryl group, optionally wherein R 4 and R 15 Together with the X and Y they are connected to, they form dihydrothiazolium; Or A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N, and G is CR 14 Or N, and X is N or C; Y is C; Z represents CH, N, NR 11 Or O, Where R 11 It is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl or optionally substituted 5 to 8-membered heteroaryl; R 7 It is H, halogen, C1-C6 alkyl; R 12 It is H, halogen, or C1-C6 alkyl; R 13It is H, halogen, C1-C6 alkoxy or C1-C6 alkyl; and R 14 It is H, halogen, or C1-C6 alkyl; Or its stereoisomers, tautomers, hydrates, N -Oxide derivatives or pharmaceutically acceptable salts.

[0171] In some preferred embodiments: A, D, E, and G do not exist, and X is NH or CH; Y is CR 4 Or N.

[0172] In some preferred embodiments: A, D, E, and G do not exist, and X is NH or CH; Y is CR 4 Or N; Z is CR 5 NR 6 Or O; R 4 It is a halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, 4- to 10-membered fused-ring heterocyclic group, C1-C6 alkylthioalkyl (optionally SMe), sulfoxide, sulfone, sulfoxide imine, optionally substituted amino or optionally substituted 3- to 8-membered heterocyclic alkyl. R 5 It is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, optionally substituted 3- to 8-membered heterocyclic alkyl, amide, sulfoxide imine, CN or halogen; Or R 4 and R 5 Together with the Y and Z groups to which they are attached, they form 3 to 8-membered heterocyclic alkyl or aryl groups; and R 6 It is H, C1-C6 alkyl or C3-C8 cycloalkyl.

[0173] In some preferred embodiments, Z is CR when A, D, E, and G are absent. 5 or NR 6 .

[0174] In some preferred embodiments, when A, D, E, and G are absent, R 6 It is H or C1-C6 alkyl.

[0175] In some preferred embodiments, when A, D, E, and G are absent, R 4It is a halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, 4- to 10-membered fused-ring heterocyclic group, SMe, sulfoxide, sulfone, sulfoxide imine, optionally substituted amino, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted morpholine, or optionally substituted piperazine. More preferably, when A, D, E, and G are absent, R 4 It is a halogen, an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted aryl, an optionally substituted 5- to 8-membered heteroaryl or a 4- to 10-membered fused-ring heterocyclic group.

[0176] In some preferred embodiments, when A, D, E, and G are absent, R 5 It is H.

[0177] In some preferred embodiments, when A, D, E, and G are absent, Y is CR. 4 .

[0178] In some preferred embodiments, Y is N when A, D, E, and G are absent.

[0179] In some preferred embodiments, X is NH when A, D, E, and G are absent.

[0180] In some preferred embodiments, X is CH when A, D, E, and G are absent.

[0181] In some preferred embodiments, when A, D, E, and G are absent, R 4 It is a C1-C6 alkyl group, a C1-C6 alkyl group substituted with one or more halogen groups, a halogen, a cycloalkyl group, a cycloalkyl group substituted with one or more C1-C6 alkyl groups, a heteroaryl group, a heteroaryl group substituted with a C1-C6 alkyl group, a dihydrobenzofuran, a phenyl group, or a phenyl group substituted with one or more C1-C6 alkyl groups, an alkoxy group (optionally C1-C6 alkoxy groups), or a halogen group. More preferably, when A, D, E, and G are absent, R... 4 It is methyl, CF3, CHF2, chlorine, cyclopropyl, methyl-substituted cyclopropyl, thiophene, methyl-substituted pyrazole, 2,3-dihydrobenzofuran, phenyl or phenyl substituted with methyl, methoxy or fluorine.

[0182] In some preferred embodiments, when A, D, E, and G are absent, R 4 It is a phenyl or a phenyl substituted with methyl, methoxy or fluorine.

[0183] In some preferred embodiments, when A, D, E, and G are absent, R 4 and R 5 Together with the Y and Z atoms to which they are attached, they form a 6-membered heterocyclic alkyl or aryl group.

[0184] In some preferred embodiments, Z is CH when A, D, E, and G are absent.

[0185] In some preferred embodiments, Z is NR when A, D, E, and G are absent. 6 .

[0186] In some preferred embodiments, when A, D, E, and G are absent, R 6 It is H, methyl, or cyclopropyl. More preferably, when A, D, E, and G are absent, R 6 It is H or methyl.

[0187] In some preferred embodiments, Y is CR 4 , where R 4 It is a C1-C6 alkylthioalkyl group, preferably SMe, and Z is CR. 5 , where R 5 It's CN.

[0188] In some preferred embodiments, M is N, X is CH, and Y is CR. 4 And Z is NH. In a preferred embodiment of this type, R 4 It is phenyl.

[0189] In some preferred embodiments: A, D, E, and G do not exist; X is CH; Y is CR 4 ; Z is NR 6 ;and M is CR a Or N, Where R a R 4 and R 6 As defined above in this article.

[0190] In some preferred embodiments: A, D, E, and G do not exist; X is NH; Y is CR 4 ; Z is CR 5 ;and M is CR a , Where R a R 4 and R 5 As defined above in this article.

[0191] In some preferred embodiments: A, D, E, and G do not exist; X is NH; Y is CR 4 ; M is CR a ;and Z is N, Where R a and R 4 As defined above in this article.

[0192] In some preferred embodiments: A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N and G is CR 14 Or N, and X is N or C; Y is C; Z represents CH, N, NR 11 Or O, where R 11 It is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl or optionally substituted 5 to 8-membered heteroaryl; R 7 It is H, halogen, or C1-C6 alkyl; R 12 It is H, halogen, or C1-C6 alkyl; R 13 It is H, halogen, C1-C6 alkoxy or C1-C6 alkyl; and R 14 It is H, halogen, or C1-C6 alkyl.

[0193] In some preferred embodiments, when A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N and G is CR 14 When Z is CH, N, or NR, or N is N. 11 .

[0194] In some preferred embodiments, when A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N and G is CR 14 When Z is CH, N, or O, or N is N.

[0195] In some preferred embodiments, when A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N and G is CR 14 When Z is CH or N, Z is CH or N.

[0196] In some preferred embodiments, when A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N and G is CR 14 When R is N or N, 7 It is H, methyl, or halogen.

[0197] In some preferred embodiments, when A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N and G is CR 14 When R is N or N, 12 It is H.

[0198] In some preferred embodiments, A is CR 12 Or N, D is CR 7 E is CR 13 Or N and G is CR 14 Or N.

[0199] In some preferred embodiments, when A is CR 12 When N or D is CR 7 Or N, E is CR 13 And G is CR 14 Or N.

[0200] In some preferred embodiments, when A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N and G is CR 14 When R is N or N, 13 It is H.

[0201] In some preferred embodiments, when A is CR 12 When N or D is CR 7 Or N, E is CR 13 Or N and G is CR 14 .

[0202] In some preferred embodiments, when A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N and G is CR 14 When R is N or N, 14 It is H.

[0203] In some preferred embodiments, when A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N and G is CR14 When X is N or N, X is N.

[0204] In some preferred embodiments, A is CH and D is CR. 7 Or N, E is CR 13 Or N and G is CR 14 Or N.

[0205] In some preferred embodiments, A is N and D is CR. 7 Or N, E is CR 13 Or N and G is CR 14 Or N.

[0206] In some preferred embodiments, when A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N and G is CR 14 When R is N or N, 7 It is H or halogen, optionally fluorine.

[0207] In some preferred embodiments, when A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N and G is CR 14 When Z is N, Z is CH.

[0208] In some preferred embodiments, when A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N and G is CR 14 When Z is N, Z is N.

[0209] In some preferred embodiments, when A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N and G is CR 14 When Z is N, Z is O.

[0210] In some preferred embodiments, when A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N and G is CR 14 When Z is N or N, Z is NR. 11 .

[0211] In some preferred embodiments, when A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N, G is CR 14 Or N and Z is NR11 At that time, R 11 It is H, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl. More preferably, when A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N, G is CR 14 Or N and Z is NR 11 At that time, R 11 It is a methyl group. More preferably, when A is a CR group. 12 Or N, D is CR 7 Or N, E is CR 13 Or N, G is CR 14 Or N and Z is NR 11 At that time, R 11 It is H.

[0212] In some preferred embodiments, X is N; Y is C; Z is N; M is CR a A and G are each CH; D is CR. 7 And E is CR 13 , where R a R 7 and R 11 As defined above in this article.

[0213] In some preferred embodiments, X and Y are each C; Z is O; A, E, G, and M are each CH; and D is CR7, where R 7 As defined above in this article.

[0214] In some preferred embodiments, X and Y are each C; Z is NR. 11 A, E, G, and M are each CH; and D is N, where R 11 As defined above in this article.

[0215] In some preferred embodiments, X and Y are each C; Z is NH; E is N; and A, D, G and M are each CH.

[0216] In some preferred embodiments, A, D, E, and G are absent; X is NR. 15 Y is CR 4 Z is N; M is CH; and R 4 and R 15 Together with the X and Y they are connected to, they form a 5-membered heterocyclic alkyl group. In some preferred embodiments, R 4 and R 15 Together with the X and Y they are connected to, they form dihydrothiazole.

[0217] In some preferred embodiments: A, D, E, and G do not exist. X is NH or CH; Y is CR 4 ; Z is CR 5 or NR 6 ; R 1 It is either a piperidine or a piperazine that has been optionally substituted. R 2 and R 3 Together with the carbon atoms they are attached to, they form a cyclopentyl group. R 4 It is phenyl. R 5 It is H, and R 6 It is H or methyl. Each of the optional substituents is selected from phenyl, difluorophenyl, NHCH3, NHCH2CH3, NHCH(CH3)2, NHC(O)CH3, N(CH3)2, NHCH2CHF2, NHCH2CH2F, NHCH2CH2OH and NHCH2CH2OCH3.

[0218] In some preferred embodiments: A, D, E, and G do not exist; X is NH or CH; Y is CR 4 ; Z is CR 5 or NR 6 ; R 1 It is piperidine or piperazine, each of which is substituted with difluoro-phenyl and further substituted with an amino group, which is optionally substituted with one or more C1-C3 alkyl groups, oxo-substituted C1-C3 alkyl groups, fluorine-substituted C1-C3 alkyl groups, CH2CH2OH, C1-C3 alkoxy groups, fluorine-substituted C3-C6 cycloalkyl groups, C3-C6 cycloalkyl groups substituted with C1-C3 alkyl groups, or pyridine-substituted C1-C3 alkyl groups. R 2 and R 3 Each is a methyl group, or R 2 and R 3 Together with the carbon atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, oxecyclobutyl, or oxecyclohexyl groups; R 4 It is methyl, dihydrobenzofuran, phenyl, methyl-substituted phenyl, F-substituted phenyl, OMe-substituted phenyl, SMe-substituted phenyl, OH-substituted phenyl or thiophene; R 5It is H, methyl, or CN; and R 6 It is H or methyl.

[0219] In some preferred embodiments: X is N or C; Y is C; Z is N, NR 11 Or O, where R 11 It is H or methyl; M is CR a , where R a It is H, methyl, or cyclopropyl; A is C; D is CR 7 , where R 7 It is H, methyl, F, Cl, Br; E is N or CR 13 , where R 13 It is H, Cl, or OMe; G is C; R 1 It is piperidine or piperazine, each substituted with a difluorophenyl and further substituted with an amino group, which is optionally substituted with one or more C1-C3 alkyl groups, fluorinated C1-C3 alkyl groups, CH2CH2OH, or C1-C3 alkoxy groups; and R 2 and R 3 Each is a methyl group, or R 2 and R 3 Together with the carbon atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, oxetyl, or oxetyl.

[0220] In some preferred embodiments, compounds selected from the following are provided: ( R )-6-phenyl-3-((4-(3-phenylmorpholine-4-carbonyl)piperazin-1-yl)methyl)pyridine-2(1 H )-ketone; ( R )-3-((2,2-dimethyl-4-(3-phenylmorpholine-4-carbonyl)piperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)quinoline-2(1 H )-ketone; N -((2 S 4 R )-2-(2,5-difluorophenyl)-1-(6-((2-oxo-6-phenyl-1,2-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidin-4-yl)acetamide; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1,5,7,8-tetrahydro-2 H -pyrano[4,3- b ]Pyridin-2-one; N -(2,4-difluorobenzyl)-6-((2-oxo-6-phenyl-1,2-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxamide; ( R )-6-phenyl-3-((9-(4,4,4-trifluoro-2-methylbutyryl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H )-ketone; 3-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; ( R )-3-((9-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 6-Phenylacetyl-3-((9-((3) R 4 R)-3-phenylpiperidine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-4-((3,3-difluorocyclobutyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; ( S )-6-phenyl-3-((9-(4,4,4-trifluoro-2-(methoxymethyl)butyryl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1 H )-ketone; ( R )-3-((9-(3-cyclohexyl-2-methylpropionyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 6-Phenylacetyl-3-((9-(3-phenylisonicotinyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-4-((2-hydroxyethyl)amino)-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2,2-dimethylpiperazin-1-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((7-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-4,7-diazaspiro[2,5]octane-4-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 6-Phenylacetyl-3-((9-((2) S 4 R)-2-phenyl-4-((pyridin-2-ylmethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridin-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(3,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( R )-3-((9-(2-methyl-2-phenylpiperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( R )-5-((9-(3-(2,5-difluorophenyl)morpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( S )-5-((9-(3-(2,5-difluorophenyl)morpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R)-2-(2,3-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-4-(methylamino)-2-phenylpiperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-4-(cyclopropylamino)-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( R )-5-((9-(2-(2,5-difluorophenyl)-1,4-diazacycloheptane-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( S )-5-((9-(2-(2,5-difluorophenyl)-1,4-diazacycloheptane-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( R )-5-((9-(3-(2,5-difluorophenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( S )-5-((9-(3-(2,5-difluorophenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4R )-2-(2,6-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 3-((9-((3 R 5 S )-3-(2,5-difluorophenyl)-5-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((8-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-5,8-diazaspiro[3.5]nonane-5-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((8-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2-oxa-5,8-diazaspiro[3.5]nonane-5-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 3-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2,2-dimethylpiperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((7-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-4,7-diazaspiro[2,5]octane-4-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-4-amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((8-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-5,8-diazaspiro[3.5]nonane-5-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((8-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2-oxa-5,8-diazaspiro[3.5]nonane-5-yl)methyl)-6-phenylpyridine-2(1H )-ketone; 3-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(pyrrolidine-1-yl)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-3-yl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(1-methyl-1 H -pyrazole-5-yl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-methyl-5-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-2-yl)pyridine-4(1 H )-ketone; ( R )-3-((9-(3-cyclohexyl-2-methylpropionyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 5-((9-((2 S 4 R )-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-4-morpholinyl-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-fluorophenyl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(o-tolyl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-methoxyphenyl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-4 H -chromone-4-one; 3-((9-((2 S 4 R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-4 H -chromone-4-one; ( R )-3-((9-(3-cyclohexyl-2-methylpropionyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H -chromone-4-one; ( R )-3-((9-(3-cyclohexyl-2-methylpropionyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-4 H -chromone-4-one; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2,3-dihydrobenzofuran-7-yl)pyridine-4(1 H )-ketone; ( R )-3-((9-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-4 H -chromone-4-one; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(1-methyl-1 H -pyrazole-3-yl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2,2-dimethylpiperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 1-Cyclopropyl-5-((9-((2)S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-methylpyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-5,6-dimethylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-4 H -pyrimidin[1,2- b ]pyridazin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoroquinoline-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(2-hydroxyphenyl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-methyl-2-propylpyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-5-(trifluoromethyl)pyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(o-tolyl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2,3-dihydrobenzofuran-7-yl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-methoxyphenyl)pyridine-4(1 H )-ketone; ( R )-5-((9-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( R )-3-((9-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H -pyrido[1,2-a]pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 5-((9-((2 S 4 R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(4-fluorophenyl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(3-fluorophenyl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(m-tolyl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(2-methoxyphenyl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2,3-dihydrobenzofuran-7-yl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(o-tolyl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(m-tolyl)pyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(3-fluorophenyl)pyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(4-fluorophenyl)pyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(3-fluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(methylthio)-6-oxo-1,6-dihydropyridine-3-carboxynitrile; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyrimidine-4(3 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1,7-naphthidine-4(1 H )-ketone; 5-((9-((2 S 4 R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyrimidine-4(3 H )-ketone; 5-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-2-yl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-2-yl)pyridine-4(1 H )-ketone; 5-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2,6-dimethylpyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R)-2-(2,5-difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((4-((2 S 5 R )-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; ( R )-6-phenyl-3-((4-(3-phenylmorpholine-4-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)pyridine-2(1 H )-ketone; ( R )-3-((4-(3-(4-fluorophenyl)morpholine-4-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((4-((2 R 5 R )-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2-fluoro-5-methylphenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2-fluoro-5-methoxyphenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 5 R )-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4R )-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-phenylpyrimidine-4(3 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; N -((2 S 4 R )-2-(2,5-difluorophenyl)-1-(6-((7-fluoro-4-oxo-4) H -pyrido[1,2- a [Pyrimidin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidin-4-yl)acetamide; N -((2 S 4 R )-2-(2,5-difluorophenyl)-1-(6-((7-fluoro-4-oxo-4) H -pyrido[1,2- a [Pyrimidin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidin-4-yl)cyclopropaneformamide; 3-((9-((2 S 4 R )-4-((1,1-dioxothioheterobutane-3-yl)amino)-2-phenylpiperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-4-((2,2-difluoroethyl)amino)-2-(3,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(thiophene-3-yl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; ( S )-6-(2-methoxyphenyl)-3-((9-(2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1 H )-ketone; ( S )-6-phenyl-3-((7-(2-phenylpyrrolidine-1-carbonyl)-4,7-diazaspiro[2.5]octane-4-yl)methyl)pyridine-2(1 H )-ketone; ( S )-6-phenyl-3-((4-(2-phenylpyrrolidine-1-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)pyridine-2(1 H )-ketone; 5-((9-((2 R 5 R )-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( S )-3-((4-(2-(2,5-difluorophenyl)pyrrolidine-1-carbonyl)-2,2-dimethylpiperazin-1-yl)methyl)-6-(1-methyl-1 H -pyrazole-5-yl)pyridine-2(1 H )-ketone; ( S )-3-((2,2-dimethyl-4-(2-phenylpyrrolidine-1-carbonyl)piperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; (S )-6-phenyl-3-((8-(2-phenylpyrrolidine-1-carbonyl)-2-oxa-5,8-diazaspiro[3.5]nonane-5-yl)methyl)pyridine-2(1 H )-ketone; 3-((4-((1 S ,2 R 5 R )-2-(2,5-difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)piperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((1 S ,2 R 5 R )-2-(2,5-difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((1 S ,2 R 5 R )-2-(2,5-difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(2-fluorophenyl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-1-methylquinoline-4(1 H )-ketone; 3-((9-((2 R ,3 R )-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S ,3S )-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(1-methyl-1 H -pyrazole-5-yl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(trifluoromethyl)pyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(trifluoromethyl)pyridine-4(1 H )-ketone; 3-((4-((2 R ,3 R )-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((4-((2 S ,3 S )-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 R ,3 R )-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S ,3 S )-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H )-ketone; 3-((9-((2 R 4 R )-4-amino-2-ethylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 R 4 R )-2-ethyl-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)(methyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(1-methyl-1 H -pyrazole-3-yl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-3-yl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-hydroxypiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2-a ]Pyrimidin-4-one; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(1-methyl-1 H -pyrazole-3-yl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropyl(methyl)amino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-methoxyethyl)(methyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-hydroxypiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(thiophene-3-yl)pyridine-4(1 H )-ketone; 3-((( S )-4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-2-methylpiperazin-1-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 7-Chloro-3-((9-((2) S 4 R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidin-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-2,2-dimethylpiperazin-1-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((( R )-4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-2-methylpiperazin-1-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(thiophen-3-yl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)(methyl)amino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(ethyl(methyl)amino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-methyl-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-8-methoxy-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 5-((9-((2 S 4 S )-4-amino-2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 S )-4-(isopropylamino)-2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7,8-dihydropyrrolo[1,2- a ]Pyrimidine-4(6 H )-ketone; 3-((9-((2 S 4 R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7,8-dihydropyrrolo[1,2- a ]Pyrimidine-4(6 H )-ketone; 3-((9-(5-amino-2',5'-difluoro-[1,1'-biphenyl]-2-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-2-methyl-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-fluoroethyl)amino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-fluoroethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 7-Fluoro-3-((9-((2) S 4 S )-4-(isopropylamino)-2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-methyl-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-2-methyl-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 4-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-1-phenyl-1,2-dihydro-3 H -Pyrazol-3-one; 4-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-methyl-1-phenyl-1,2-dihydro-3 H -Pyrazol-3-one; 7-Chloro-3-((9-((2) S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(ethylamino)piperidin-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 7-Chloro-3-((9-((2) S 4 R )-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-4H -pyrido[1,2- a ]Pyrimidin-4-one; 6-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-5 H -Thiazo[3,2- a ]Pyrimidin-5-one; 6-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-5 H -Thiazo[3,2- a ]Pyrimidin-5-one; 7-Fluoro-3-((9-((2) S 4 R )-4-((3-methyloxacyclobutane-3-yl)amino)-2-phenylpiperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-methyl-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-2-methyl-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 2-Cyclopropyl-3-((9-((2) S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 2-Cyclopropyl-3-((9-((2) S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridazine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridazine-4(1 H )-ketone; 3-((9-((2 S 4 R )-4-amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4,5]dec-2-en-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 7-Bromo-3-((9-((2) S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 8-Chloro-3-((9-((2) S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-4 H-pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-2-(trifluoromethyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-2-(trifluoromethyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-1,6-naphthidine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((1-methylcyclopropyl)amino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; and 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(1-methylcyclopropyl)pyridine-4(1 H )-ketone; Or its stereoisomers, tautomers, hydrates, N -Oxide derivatives or pharmaceutically acceptable salts.

[0221] In some embodiments, compounds, stereoisomers, tautomers, hydrates, as described above are provided. N -Oxide derivatives or pharmaceutically acceptable salts that are inhibitors of USP19, preferably human USP19 inhibitors.

[0222] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound according to the first aspect, a stereoisomer, a tautomer, a hydrate, N -Oxide derivatives or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers or diluents.

[0223] Pharmaceutical compositions can be formulated by mixing, for example, excipients, binders, lubricants, disintegrants, coating materials, emulsifiers, suspending agents, solvents, stabilizers, absorption enhancers, and / or ointment bases, depending on their specific use and purpose. The composition may be suitable for oral, injectable, rectal, or topical application.

[0224] Suitable pharmaceutically acceptable excipients will be those known to those skilled in the art, such as: fats, water, physiological saline, alcohols (e.g., ethanol), glycerol, polyols, aqueous glucose solutions, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavoring agents or aroma agents, concentrates, diluents, buffers, solvents or solubilizers, chemicals for achieving storage effects, salts for adjusting osmotic pressure, coating agents or antioxidants, sugars such as lactose or glucose; starch from corn, wheat or rice; fatty acids, such as stearic acid; inorganic salts, such as magnesium aluminum metasilicate or anhydrous calcium phosphate; synthetic polymers, such as polyvinylpyrrolidone or polyalkylene glycols; alcohols, such as stearyl alcohol or benzyl alcohol; synthetic cellulose derivatives, such as methylcellulose, carboxymethylcellulose, ethylcellulose or hydroxypropyl methylcellulose; and other conventionally used additives, such as gelatin, talc, vegetable oils and gum arabic.

[0225] For example, the pharmaceutical composition can be administered orally, such as in the form of tablets, coated tablets, hard or soft gelatin capsules, solutions, emulsions, or suspensions. It can also be administered rectally, such as with suppositories, topically or transdermally, such as with ointments, creams, gels, or solutions, or parenterally, such as with injectable solutions.

[0226] For the preparation of tablets, coated tablets, or hard gelatin capsules, the compounds of the present invention can be blended with pharmaceutically inert inorganic or organic excipients. Examples of suitable excipients include lactose, corn starch or derivatives thereof, talc or stearic acid or salts thereof. Excipients suitable for use with soft gelatin capsules include, for example, vegetable oils, waxes, fats, and semi-solid or liquid polyols.

[0227] For the preparation of solutions and syrups, excipients include, for example, water, polyols, sucrose, invert sugar, and glucose.

[0228] For injectable solutions, excipients include, for example, water, alcohols, polyols, glycerols, and vegetable oils.

[0229] For suppositories and for both topical and transdermal applications, excipients include, for example, natural or hardened oils, waxes, fats, and semi-solid or liquid polyols.

[0230] The pharmaceutical composition may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, buffers, coating agents, and / or antioxidants.

[0231] For combination therapies, the second drug may be provided in the pharmaceutical composition together with the present invention, or it may be provided alone.

[0232] Therefore, pharmaceutical preparations for oral administration can be, for example, granules, tablets, sugar-coated tablets, capsules, pills, suspensions, or emulsions. For parenteral injections intended for intravenous, intramuscular, or subcutaneous use, sterile aqueous solutions may be provided, which may contain other substances, including, for example, saline and / or glucose, to make the solution isotonic. Anticancer agents can also be administered in the form of suppositories or vaginal suppositories, or applied topically as lotions, solutions, creams, ointments, or powders.

[0233] In another aspect, the present invention provides compounds according to the first aspect for therapeutic purposes, including stereoisomers, tautomers, hydrates, etc. N -Oxide derivatives or pharmaceutically acceptable salts.

[0234] In another aspect, the present invention provides a pharmaceutical composition according to the second aspect for treatment.

[0235] In another aspect, the present invention provides compounds, or stereoisomers, tautomers, hydrates, or other embodiments thereof, according to any embodiment of the first aspect for the treatment and / or prevention of cancer. N -Oxide derivatives or pharmaceutically acceptable salts.

[0236] In another aspect, the present invention provides a pharmaceutical composition according to the second aspect for treating and / or preventing cancer.

[0237] In another aspect, the present invention provides a method for treating or preventing cancer, comprising administering to a subject a compound according to any embodiment of the first aspect of the invention, including its stereoisomers, tautomers, hydrates, etc. N - An oxide derivative or a pharmaceutically acceptable salt, or a pharmaceutical composition according to any embodiment of the second aspect of the invention.

[0238] In another aspect, the present invention provides compounds according to any embodiment of the first aspect, including their stereoisomers, tautomers, hydrates, N - The use of oxide derivatives or pharmaceutically acceptable salts in the preparation of medicaments for the treatment or prevention of cancer.

[0239] Cancers or tumors suitable for treatment with the compounds or compositions according to the present invention include, for example, prostate cancer, colon cancer, breast cancer, lung cancer, kidney cancer, CNS cancers (e.g., neuroblastoma, glioblastoma), osteosarcoma, and hematologic malignancies (e.g., leukemia, multiple myeloma, and mantle cell lymphoma). In some preferred embodiments, the cancer is associated with p53 dysregulation. In some preferred embodiments, the cancer is selected from hematologic malignancies (e.g., mantle cell lymphoma, multiple myeloma), prostate cancer, neuroblastoma, or glioblastoma. In some preferred embodiments, the cancer is neuroblastoma or breast cancer.

[0240] This article demonstrates that effective USP19 inhibitory compounds effectively reduce body fat accumulation. Gene knockout studies have described a possible link between USP19 and fat accumulation (Coyne et al., Diabetologia (2019, 62, 136-146, incorporated herein by reference). However, the effects observed in these studies need to be considered in conjunction with potential confounding factors inherent in knockout studies, such as altered developmental or underlying physiological processes. For these reasons, acute or chronic pharmacological inhibition of enzymes does not always produce physiological outcomes similar to gene knockout.

[0241] The data presented in this article indicate that pharmacological inhibition of USP19 can reduce fat accumulation in the wild-type background. In conclusion, in vitro and in vivo data suggest that compounds that effectively inhibit USP19 activity may be effective in treating obesity.

[0242] On the other hand, a compound according to the first aspect, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or other compound thereof, is provided for a method of treating obesity. N -Oxide derivatives.

[0243] On the other hand, a pharmaceutical composition according to the second aspect is provided for a method of treating obesity.

[0244] According to the present invention, a method for treating obesity is also provided, the method comprising administering to a subject in need an effective amount of the compound according to the first aspect, a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or... N -Oxide derivatives, or an effective amount of the pharmaceutical composition according to the second aspect.

[0245] This article also demonstrates that the effective USP19 inhibitory compounds presented herein can effectively treat insulin resistance. Gene knockout studies have described the association between USP19 and insulin sensitivity (Coyne et al., ibid.). Coyne et al. described improved insulin sensitivity in USP19 knockout mice, but as stated above, this effect cannot be assumed to translate into pharmacological inhibition of USP19 in wild-type subjects.

[0246] The data presented in this article indicate that pharmacological inhibition of USP19 can be effective in treating insulin resistance (e.g., type 2 diabetes).

[0247] On the other hand, a method for treating insulin resistance is provided using a compound defined in the first aspect of the invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or other similar compound thereof. N -Oxide derivatives.

[0248] In another aspect of the invention, a method for treating type II diabetes is provided using a compound defined in the first aspect of the invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or thereof. N -Oxide derivatives.

[0249] In another aspect of the invention, a pharmaceutical composition according to the second aspect is provided for a method of treating insulin resistance.

[0250] In another aspect of the invention, a pharmaceutical composition according to the second aspect is provided for a method of treating type II diabetes.

[0251] According to the present invention, a method for treating insulin resistance is also provided, the method comprising administering to a subject in need an effective amount of the compound defined in relation to the first aspect of the invention, a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or... N -Oxide derivatives, or an effective amount of a pharmaceutical composition comprising the compound defined with respect to the first aspect of the invention, a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or N -Oxide derivatives.

[0252] According to the present invention, a method for treating type II diabetes is also provided, the method comprising administering to a subject in need an effective amount of the compound defined in relation to the first aspect of the invention, a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or... N -Oxide derivatives, or an effective amount of a pharmaceutical composition comprising the compound defined with respect to the first aspect of the invention, a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or N -Oxide derivatives.

[0253] The accompanying examples demonstrate that the compounds provided herein are potent USP19 inhibitors, and further demonstrate that potent USP19 inhibitory compounds effectively treat muscle loss in in vivo disease models. In summary, in vitro and in vivo data suggest that compounds that effectively inhibit USP19 activity can effectively treat muscle atrophy.

[0254] On the other hand, a method for treating muscular atrophy is provided using a compound defined in the first aspect of the invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or other similar compound thereof. N -Oxide derivatives.

[0255] In another aspect of the invention, a method for treating cachexia or sarcopenia is provided using a compound defined in the first aspect, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or thereof. N -Oxide derivatives.

[0256] In another aspect of the invention, a pharmaceutical composition according to the second aspect is provided for a method of treating muscle atrophy.

[0257] In another aspect of the invention, a pharmaceutical composition according to the second aspect is provided for a method of treating cachexia or sarcopenia.

[0258] According to the present invention, a method for treating muscle atrophy is also provided, the method comprising administering to a subject in need an effective amount of the compound defined in relation to the first aspect of the invention, a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or... N -Oxide derivatives, or an effective amount of a pharmaceutical composition comprising the compound defined with respect to the first aspect of the invention, a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or N -Oxide derivatives.

[0259] According to the present invention, a method for treating cachexia or sarcopenia is also provided, the method comprising administering to a subject in need an effective amount of the compound, pharmaceutically acceptable salt, tautomer, stereoisomer, or [other compound defined in relation to the first aspect of the invention] N -Oxide derivatives, or an effective amount of a pharmaceutical composition comprising the compound defined with respect to the first aspect of the invention, a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or N -Oxide derivatives.

[0260] Muscle atrophy, cachexia, or sarcopenia may be associated with or caused by the following conditions: HIV infection / AIDS, heart failure, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, multiple sclerosis, motor neuron disease (MND), Parkinson's disease, dementia, or cancer.

[0261] In another aspect, the present invention provides compounds or compositions according to any embodiment of the first or second aspect for the treatment and / or prevention of Parkinson's disease. In another aspect, the present invention provides a method of treating or preventing Parkinson's disease, comprising administering to a subject an effective amount of a compound according to the present invention, a pharmaceutically acceptable salt, tautomer, stereoisomer, or... N -Oxide derivatives, or pharmaceutical compositions. In another aspect, the present invention provides compounds according to the invention or pharmaceutically acceptable salts, tautomers, stereoisomers, or... N - Use of oxide derivatives in the preparation of drugs for the treatment of Parkinson's disease.

[0262] The compounds or compositions of the present invention can be used in monotherapy and / or combination therapy. Suitable agents for use in such combination with the compounds or compositions according to the present invention include one or more anticancer agents, anti-inflammatory agents, immunomodulators (e.g., immunosuppressants), neuropharmaceuticals, antidiabetic agents, antiviral agents, antibacterial agents, and / or radiotherapy.

[0263] Agents used in combination with the compounds of the present invention may target the same or similar biological pathways as those targeted by the compounds of the present invention, or may act on different or unrelated pathways.

[0264] Depending on the disease to be treated, multiple combination therapies may be administered in conjunction with the compounds of this invention. The second active ingredient may include, but is not limited to: alkylating agents, including cyclophosphamide, ifosfamide, thiotepa, melphalan, chloroethylnitrosourea, and bendamustine; platinum derivatives, including cisplatin, oxaliplatin, carboplatin, and saplatin; antimitotic agents, including vinblastine alkaloids (vincristine, vinorelbine, and vincristine), taxanes (paclitaxel, docetaxel), epopycin, and inhibitors of mitotic kinases, including aurora kinase and polo kinase; topoisomerase inhibitors, including anthracyclines, epipodophyllotoxin, camptothecin, and camptothecin analogues; antimetabolites, including 5-fluorouracil, capecitabine, cytarabine, gemcitabine, 6-mercaptopurine, 6-thioguanine, fludarabine, methotrexate, and... Pemetrexed; protein kinase inhibitors, including imatinib, gefitinib, sorafenib, sunitinib, erlotinib, dasatinib, and lapatinib; proteasome inhibitors, including bortezomib; histone deacetylase inhibitors, including valproate and SAHA; anti-angiogenic drugs, including bevacizumab; monoclonal antibodies, including trastuzumab, rituximab, alemtuzumab, tosimomumab, cetuximab, and panitumumab; monoclonal antibody conjugates, including gemtuzumab, oxorubicin, and teimomab; hormone therapy, including anti-estrogens (tamoxifen, raloxifene, anastrozole, letrozole, exemestane), anti-androgens (flutamide, bicalutamide), and luteinizing hormone analogs or antagonists.

[0265] Regarding aspects of the invention relating to the therapeutic use of compounds according to the invention, the compounds may be administered to a subject in need of treatment in an "effective amount." The term "effective amount" refers to the amount or dose of a compound that provides therapeutic efficacy for the treatment of a disease after administration of a single dose or multiple doses to a subject. Therapeutic effective amounts of compounds according to the invention may include amounts from about 0.1 mg / kg to about 20 mg / kg per single dose. Therapeutic effective amounts for any individual patient can be determined by a medical professional using methods known to a technician. The amount of compound administered at any given point in time may be varied such that the optimal amount of compound is administered during the course of treatment, whether used alone or in combination with any other therapeutic agent. Administration of compounds according to the invention or pharmaceutical compositions comprising such compounds in combination with any other cancer treatments as a combination therapy is also contemplated.

[0266] For combination therapies, the second drug may be provided in the pharmaceutical composition together with the present invention, or it may be provided alone.

[0267] Application route In some preferred embodiments, the treatment according to the invention comprises parenteral administration of a therapeutic agent (i.e., a compound, pharmaceutically acceptable salt, tautomer, stereoisomer, or... according to the invention). N -Oxide derivatives or pharmaceutical compositions).

[0268] In some preferred embodiments, the therapeutic agent is administered orally.

[0269] In some preferred embodiments, the therapeutic agent is administered intravenously. In some preferred embodiments, the therapeutic agent is administered intraperitoneally. In some preferred embodiments, the therapeutic agent is administered subcutaneously.

[0270] Dosage regimen In some preferred embodiments of the invention, treatment comprises administering a therapeutic agent (i.e., a compound, pharmaceutically acceptable salt, tautomer, stereoisomer, or compound used according to the invention) at a dose of 10 to 150 mg / kg. N -Oxide derivatives or pharmaceutical compositions). In such embodiments, dosage refers to the amount of active ingredient administered to the subject per single application.

[0271] In some preferred embodiments, treatment comprises administering a therapeutic agent at a dose of 25 to 125 mg / kg. In some preferred embodiments, treatment comprises administering a therapeutic agent at a dose of 50 to 100 mg / kg.

[0272] In some preferred embodiments, the method includes administering the therapeutic agent at a dose of 75 mg / kg.

[0273] In some preferred embodiments, treatment comprises administering the therapeutic agent (i.e., the compound, pharmaceutically acceptable salt, tautomer, stereoisomer, or compound used according to the invention) once, twice, three times, or four times daily. N -Oxide derivatives or pharmaceutical compositions). In some preferred embodiments, the therapeutic agent is administered once or twice daily, more preferably twice daily.

[0274] In some preferred embodiments, the therapeutic agent is administered at a daily dose of 10 to 300 mg / kg. In other words, the total amount of active agent administered to the subject in a day is 10-300 mg / kg. In such embodiments, the therapeutic agent may be administered once or more daily as described herein, provided that the total daily dose is within the specified range.

[0275] In some preferred embodiments, the therapeutic agent is administered at a daily dose of 50 to 250 mg / kg. In some preferred embodiments, the therapeutic agent is administered at a daily dose of 75 to 250 mg / kg. In some preferred embodiments, the therapeutic agent is administered at a daily dose of 100 to 200 mg / kg. In some preferred embodiments, the therapeutic agent is administered at a daily dose of 150 mg / kg.

[0276] In some preferred embodiments, the therapeutic agent (e.g., a compound as provided herein) is administered twice daily at a dose of 75 mg / kg.

[0277] Regarding aspects of the invention relating to the therapeutic use of compounds according to the invention, in a preferred embodiment, the subject to be treated is a human being.

[0278] In another aspect, the present invention provides compounds, stereoisomers, tautomers, hydrates, etc., according to the first aspect for use as pharmaceuticals. N -Oxide derivatives or pharmaceutically acceptable salts or pharmaceutical compositions according to the second aspect.

[0279] In another aspect, the present invention provides compounds, stereoisomers, tautomers, hydrates, and other similar products according to the first aspect for the treatment of muscle atrophy, obesity, insulin resistance, or type II diabetes. N -Oxide derivatives or pharmaceutically acceptable salts or pharmaceutical compositions according to the second aspect.

[0280] In another aspect, the present invention provides a method for treating obesity, insulin resistance, type II diabetes, or muscle atrophy, comprising administering to a subject in need an effective amount of the compound, stereoisomer, tautomer, hydrate, or other product according to the first aspect. N -Oxide derivatives or pharmaceutically acceptable salts or pharmaceutical compositions according to the second aspect.

[0281] On the other hand, the present invention provides a method for reducing muscle mass loss in a subject, comprising administering to the subject in need an effective amount of the compound, stereoisomer, tautomer, hydrate, according to the first aspect. N -Oxide derivatives or pharmaceutically acceptable salts or pharmaceutical compositions according to the second aspect.

[0282] When describing elements of this disclosure or preferred embodiments thereof, the articles “a,” “an,” “the,” and “the” are intended to indicate the presence of one or more elements. The terms “comprising,” “including,” and “having” are intended to be inclusive and mean that other elements besides those listed may be present.

[0283] The foregoing detailed description is provided by way of explanation and illustration, but is not intended to limit the scope of the appended claims. Many variations of the preferred embodiments of the invention shown herein will be apparent to those skilled in the art and fall within the scope of the appended claims and their equivalents.

[0284] Example The invention will now be described in conjunction with several embodiments.

[0285] The examples shown below are synthesized according to the methods described below. The determination of IC is as follows. 50 The values ​​are listed in the table below: Table 4. Inhibition of USP19 by exemplary compounds. USP19 inhibitory activities are categorized as follows: USP19 activity was determined in a homogeneous fluorescence polarization (FP) assay using isopyubiquitin-Lys-TAMRA substrates (AUB-101, Almac Sciences Scotland Limited or U-558, Boston Biochem, both yielding the same results). Full-length USP19 was purchased from Boston Biochem (E-576). All other reagents were purchased from Sigma unless otherwise specified. Enzymatic reactions were performed in black flat-bottomed polystyrene 384-well plates (Nunc) in a total volume of 30 μL. USP19 (2.5 nM, 10 μL) was incubated in assay buffer (50 mM HEPES (pH 7.4), 150 mM NaCl, 5 mM DTT, 0.05% BSA (w / v), 0.05% CHAPS) with or without inhibitor (10 µL). StoragePods were used. ®The system (Roylan Developments) stored the inhibitor in 10 mM DMSO stock solution under inert conditions (low humidity, darkness, low oxygen, room temperature) and prepared serial dilutions in buffer (from 200 μM to 2 pM, 8–18 data point curves) prior to assay. After incubation at room temperature for 30 min, the enzymatic reaction was initiated by dispensing 10 μL of Ub substrate (500 nM). Using a Synergy 4 microplate reader (BioTek), the amount of parallel and perpendicular light at 575 nm was measured at 530 nm excitation, with FP measured every 15 minutes over a 90-minute period (within the linear range of the assay). The FP signal was then normalized to a compound-free control. The data were plotted and fitted, and the concentration (IC50) resulting in 50% inhibition was calculated using a nonlinear regression curve fitting model using Prism (GraphPad). 50 The IC50 of the inhibitor of this invention. 50 The values ​​are summarized in Table 4 and represent the average of at least two repeated experiments.

[0286] Cellular target binding using protein blotting Cells from breast cancer cell lines, neuroblastoma cell lines, and mouse skeletal muscle cell lines were treated with a USP19 inhibitor compound (ADC-141) for 2 h and lysed (lysis buffer: 50 mM Tris pH 7.4; 150 mM NaCl; 5 mM MgCl2; 0.5 mM EDTA; 0.5% NP-40; 10% glycerol; 2 mM DTT). Ubiquitin-propargylamine (Ub-PA; UbiQ) or ubiquitin-vinyl methyl ester (Ub-VME; Almac Sciences Scotland Limited) were then added. Samples were analyzed by Western blot detection of USP19 (EC50 was determined by densitometry). 50 In each cell line, the USP19 inhibitor compounds exhibited good cell penetration and low nanomolar EC50. 50 Results for each cell line were shown in Figure 4 middle.

[0287] Kinetic solubility (KSol) determination The test compound (5 μL of 10 mM DMSO stock solution) was added to the MultiScreen... ®Solubility filters (Millipore) were prepared by mixing 245 μL of phosphate-buffered saline (PBS) buffer (Dulbecco A) at pH 7.4 at 300 rpm for 90 minutes on a plate shaker at room temperature. Simultaneously, a 5-point calibration curve was established for each compound in a mixture of acetonitrile / PBS buffer (maximum concentration 200 μM). After filtration and matrix matching, both calibration and assay plates were analyzed on a BioTek Synergy 4 microplate reader (240–400 nm). The final concentration of the test compound in the filtrate was calculated using the slope of the calibration curve.

[0288] Determination of the intrinsic clearance rate of liver microsomes (HLM / MLM / RLM) in humans, mice, and rats The test compound (final concentration = 1 μM; final DMSO concentration = 0.1% v / v) was incubated with human, mouse, or rat liver microsomes (0.5 mg protein / mL) (as needed) in 0.1 M PBS buffer (Dulbecco A) at pH 7.4 at 37°C. The reaction was initiated by adding NADPH (final concentration = 1 mM) to 0.1 M PBS buffer (Dulbecco A) at pH 7.4. 40 μL aliquots were collected at time points of 2, 5, 10, 15, 20, 30, 40, and 50 minutes. The reaction was quenched with 80 μL of ice-cold methanol. The samples were then frozen overnight and centrifuged at 3500 rpm for 20 minutes at 4°C. The supernatant was collected and transferred to an analytical plate for analysis by LC / MS / MS.

[0289] LC / MS / MS method: All samples were analyzed on a Waters ACQUITY I-Class UPLC connected to a Waters Xevo TQD mass spectrometer. A Waters BEH C18 column (2.1 × 50 mm, 1.7 μm) was used, with a mobile phase of water and methanol containing 0.1% v / v formic acid as a modifier. Analyses were performed using multiple reaction monitoring, and conditions were optimized for each test compound.

[0290] Data Analysis: Based on the peak area versus time curve, determine the slope of the line. Then, calculate the half-life and inherent clearance rate using the following equation: Sweep rate constant (k) = (-slope) Half-life (t) 1 / 2 (minutes) = Inherent clearance rate (CL) int (µL / min / million cells) = Where V = incubation volume (µL) / number of cells Cytochrome P450 (CYP) inhibition assay CYP inhibition of five major isotypes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) was simultaneously evaluated using a commercially available mixture of isotypes heterologously expressed in *E. coli* (Cypex). This method is applicable to Weaver R. et al. Drug Metab Disposal (2003), 31, 955-966. By using selectivity for each subtype and FDA-approved substrates in their publicly disclosed... K m The activity of each isoform was evaluated by assessing the appearance of isoform-specific metabolites at nearby concentration measurements. Test compounds were analyzed at eight concentrations (half-log dilutions), typically from 50 μM to 0.023 μM final concentration. A mixture of 4x the desired final concentration of the test compound in 0.1 M PBS buffer (Dulbecco A) at pH 7.4 and 2x the mixture of the CYP isoform and substrate was incubated at 37°C for 3 min. Then, 4 mM NADPH solution in 0.1 M PBS buffer (Dulbecco A) at pH 7.4 was added to initiate the reaction. After 10 min of incubation, the reaction was terminated by adding methanol containing an internal standard and 0.1% v / v formic acid. Metabolites of each CYP substrate were quantified by LC / MS / MS using a Waters ACQUITY I-Class mass spectrometer connected to a Waters Xevo TQD instrument. A Waters BEH C18 column (2.1 × 50 mm, 1.7 μm) was used, with a mobile phase of water and methanol containing 0.1% v / v formic acid as a modifier. Analysis was performed using multiple reaction monitoring, and conditions were optimized for each metabolite.

[0291] Data Analysis: The CYP activity of the test compound at each concentration was converted to a percentage of the control activity (CA), and log(concentration) was plotted against activity to generate a pseudo-Hill plot. The IC50 of the test compound for each CYP isotype was calculated using the slope and y-intercept according to the following equation. 50 value: hERG ion channel inhibition assay The inhibition of the human Ether-α-go-go-related gene (hERG) by the test compound was determined at an external supplier using a QPatch II (Sophion Bioscience) automated patch clamp. Six-point concentration-response curves were generated using serial dilutions of the test compound at a maximum concentration of 100 μM to determine the IC50 after curve fitting. 50 Values. Plot each data point, with a minimum of n=3 cells.

[0292] in vivo activity The following data from in vivo models demonstrate that USP19 inhibitors can be used to treat muscle loss, reduce fat deposition, and improve insulin sensitivity. These data indicate that compounds that effectively inhibit USP19 activity can effectively treat muscle atrophy, obesity, and / or insulin resistance.

[0293] method: To induce muscle loss, a 1 cm segment of the sciatic nerve in the thigh was removed from mice (8-10 week old male C57bl / 6 mice; n=10 per group) under isoflurane anesthesia and carbofen analgesia. A sham operation was performed in the opposite leg as a control.

[0294] Mice were randomly assigned to either the solvent group or the test group, and all animals were weighed to ensure that the average weight of each group was similar. Starting from the evening after surgery, 75 mg / kg of the USP19 inhibitor ADC-141 or the solvent was administered intraperitoneally twice daily.

[0295] Mice were sacrificed 14 days later. Fat pads, liver, gastrocnemius muscle, and tibialis anterior muscle were collected. Tissue mass was measured in both groups.

[0296] To assess obesity and insulin resistance, a diet-induced obesity mouse model was used. Diet-induced obesity (DIO) mice are a well-defined model of obesity that exhibits increased obesity, insulin resistance, and impaired glucose tolerance.

[0297] Throughout the study, male C57BL6 / J mice were provided with a high-fat diet (D12451, 45% kcal, as fat; Research Diets, New Jersey, USA) and filtered tap water, with free access to food. Starting from day 0, mice were administered a solvent (intraperitoneally, twice daily), a USP19 inhibitor (ADC-141) (intraperitoneally, at 5 mg / kg or 25 mg / kg twice daily), or a positive control liraglutide (0.1 mg / kg, subcutaneously, twice daily).

[0298] Measuring body weight daily. On day 13, body composition was assessed using DEXA. On day 15, fasting glucose and insulin levels were measured before and during the oral glucose tolerance test (OGTT) to assess improvement in glucose control. The OGTT was performed after an overnight fast. Therefore, on day 14, food (but not water) was withdrawn immediately after administration at approximately 16:45 PM. The OGTT was performed the following morning (approximately 16 hours after fasting). The solvent or test compound was administered to mice 30 minutes before the glucose loading (2.0 g / kg, orally) according to the predetermined schedule (starting at 08:45). Blood samples were collected immediately before administration (B1), immediately before glucose administration (B2), and at 15, 30, 60, and 120 minutes after glucose administration.

[0299] ADC-141 is 1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropionyl)-10-hydroxy-7-azaspiro[4.5]decane-10-yl)methyl)-4-phenyl-5-(piperazin-1-carbonyl)pyridine-2(1 H )-ketone, corresponding to example compound 212 provided in WO2018 / 020242. Using the above-described fluorescence polarization assay, both ADC-141 and the compound provided herein showed USP19 inhibitory activity. Therefore, it is expected that the USP19 inhibitor compound provided herein will exhibit similar efficacy levels to ADC-141 described below.

[0300] result: Muscle atrophy like Figure 1 As shown, compared with mice that received only the solvent, mice that received the USP19 inhibitor had significantly reduced muscle mass loss in the tibialis anterior muscle. (From percentage mass (...)) Figure 1 B) and absolute muscle mass ( Figure 1 C) From both perspectives, the reduction in muscle atrophy is significant.

[0301] In the gastrocnemius muscle, muscle loss is also reduced. Figure 2 Although this trend did not reach significance. Similarly, from the percentage quality ( Figure 2 B) and absolute muscle mass ( Figure 2 C) From both perspectives, mice receiving USP19 inhibitors showed less muscle loss.

[0302] These data demonstrate that pharmacological inhibition of USP19 in vivo can reduce muscle atrophy. The data suggest that pharmacological inhibition of USP19 will be particularly effective in reducing muscle loss due to inactivity, immobilization, or other disuse. Based on the results presented in this paper, pharmacological inhibition of USP19 is also expected to be effective in treating muscle atrophy due to cachexia or sarcopenia.

[0303] obesity Figure 3 A shows the quality of the epididymal fat pad in mice after 2 weeks of treatment with either a USP19 inhibitor or solvent only. Figure 3 As shown, mice receiving the USP19 inhibitor had significantly smaller fat pads compared to mice treated with solvent.

[0304] Figure 3 B shows an increase in liver mass in mice treated with the USP19 inhibitor. This is believed to be a result of drug accumulation in the liver.

[0305] Figure 3 C shows that mice receiving a USP19 inhibitor exhibited a reduced increase in overall body weight when fed a high-fat diet. Figure 3 D and 3E indicate this is due to a reduction in fat mass, but lean body mass is maintained. DIO mice treated with the USP19 inhibitor also showed a reduction in cumulative food intake compared to solvent control mice.

[0306] Figure 3 The data shown indicate that pharmacological inhibition of USP19 can reduce fat accumulation in a wild-type background. Gene knockout studies have described a possible association between USP19 and fat accumulation (Coyne E. et al., Diabetologia (2019), 62, 136-146, incorporated herein by reference). However, acute or chronic pharmacological inhibition of enzymes does not always produce physiological outcomes similar to gene knockout.

[0307] The in vivo pharmacological inhibition data provided in this article indicate that compounds that effectively inhibit USP19 activity can effectively treat obesity.

[0308] Insulin resistance Figure 5 Results of an oral glucose tolerance test (OGTT) were shown in mice with diet-induced obesity. Untreated mice exhibited signs of insulin resistance, characterized by elevated plasma glucose and plasma insulin levels. Mice treated with a USP19 inhibitor showed a dose-dependent improvement in the OGTT response, characterized by decreased plasma glucose and decreased plasma insulin levels.

[0309] Figure 5 The data shown indicate that pharmacological inhibition of USP19 can reduce insulin resistance in a wild-type background. Gene knockout studies have also described the association between USP19 and insulin sensitivity (Coyne E et al., ibid.). Coyne et al. described improved insulin sensitivity in USP19 knockout mice, but as stated above, this effect cannot be assumed to translate into pharmacological inhibition of USP19 in wild-type subjects.

[0310] The data presented in this article demonstrate that the pharmacological inhibition of USP19 is effective in treating insulin resistance.

[0311] The data presented in this article demonstrate the therapeutic efficacy of pharmacological inhibition of USP19. Therefore, the USP19 inhibitor compounds presented in this article may be effective in treating muscle atrophy, obesity, and / or insulin resistance.

[0312] Experimental Section Abbreviations and acronyms AcOH: Acetic acid; aq: Aqueous solution; atm: Atmospheric pressure; Boc: Tert-butoxycarbonyl; br: Broad band; Cbz: Benzyloxycarbonyl; d: Double peak (spectrum); DCM: Dichloromethane; Desmond-Martin periodoylene: 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzoiodazaoxacyclopentane-3-(1 H )-ketone; DIPEA: diisopropylethylamine; DMF: N,N -Dimethylformamide; DMS: Dimethyl sulfide; DMSO: Dimethyl sulfoxide; dpm: Dipentanoylmethane; dppf: 1,1'-Bis(diphenylphosphino)ferrocene; EDA: Ethyl-1,2-diamine; equiv.: Equivalent; EtOAc: Ethyl acetate; EtOH: Ethanol; ESI: Electrospray ionization; h: Hour; HATU: N -[(dimethylamino)-1 H -1,2,3-triazolo[4,5- b ]pyridin-1-ylmethylene]- N methylmethylammonium hexafluorophosphate N -Oxides; hept: septet (spectrum); HPLC: High-performance liquid chromatography; IPA: 2-propanol; LC: Liquid chromatography; LCMS: Liquid chromatography-mass spectrometry; M: mole; m / z: mass-to-charge ratio; MeCN: acetonitrile; MeOH: methanol; min: minutes; mmol: millimoles; MS: Mass spectrometry; MTBE: methyl tert-butyl ether; m: multiplet (spectrum); NBS: N - Bromosuccinimide; NMR: Nuclear Magnetic Resonance; pent: Quintet (spectrum); ppm: Parts per million; q: Quartet (spectrum); R TRetention time; rt: room temperature; s: singlet; SCX: strong cation exchange; sept: septet (spectrum); SFC: supercritical fluid chromatography; TBAF: tetra-n-butylammonium fluoride; TBDMS: tert-butyldimethylsilyl; Teoc: 2-(trimethylsilyl)ethoxycarbonyl; TFA: trifluoroacetic acid; THF: tetrahydrofuran; t: triplet; UV: ultraviolet; v / v: volume per unit volume; wt%: weight percentage; w / v: weight per unit volume; w / w: weight per unit weight; XPhos-Pd-G2: chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0313] General experimental conditions Solvents and reagents Commonly used organic solvents (e.g., THF, DMF, DCM, and MeOH) were purchased from Sigma-Aldrich®'s Sure / Seal. TM Bottled anhydrous reagents were properly treated under nitrogen protection. Water was deionized using Elga PURELAB Option-Q. All other solvents used (i.e., those used in post-processing and purification) were generally HPLC grade and were purchased from various commercial sources and used directly. Unless otherwise specified, all starting materials used were purchased from commercial suppliers and used directly.

[0314] Automated Synthesis Automated experiments were performed using the Synple 2 instrument. This system, using kits, can automate various synthetic reaction procedures with appropriate reactants (including...). N The system encompasses heterocycle formation, reductive amination, Mitsunobu reaction, amide formation, deoxyfluorination, Suzuki coupling, etc., including reaction, post-treatment, and purification steps to obtain the desired reaction product. The system exhibits good reproducibility and allows modification of certain reaction parameters (e.g., time and temperature).

[0315] Microwave Synthesis Microwave experiments were conducted using the Biotage Initiator™ Eight instrument. This system exhibits good reproducibility and control over a temperature range of 60–250°C and a maximum pressure of 20 bar.

[0316] Rapid chromatography Rapid chromatographic purification of compounds was performed using the Biotage Isolera Four system. Unless otherwise specified, Biotage Sfär Silica D columns (10-340 g) or Grace GraceResolv columns (4-330 g) were used, along with the aforementioned solvent system and a suitable solvent gradient determined according to the polarity of the compound. For some highly polar and basic compounds, Biotage Sfär KP-Amino D columns (11-28 g) were used.

[0317] NMR spectrum 1 1H NMR spectra were recorded at ambient temperature using a Bruker Avance III (400 MHz) or Bruker Ascend (500 MHz) spectrometer. All chemical shifts (δ) are expressed in ppm. The residual solvent signal was used as an internal standard and based on... J.Org.Chem. The reference data outlined in 1997, 62, pp. 7512-7515 corrected for characteristic solvent peaks; in other cases, the NMR solvent contained tetramethylsilane, which was used as an internal standard.

[0318] Liquid chromatography-mass spectrometry (LCMS) Used to determine retention time (R) T The liquid chromatography-mass spectrometry experiments of ions and related mass spectrometric ions were performed using the following methods: Method A The system consisted of an Agilent Technologies 6140 single quadrupole mass spectrometer connected to an Agilent Technologies 1290 Infinity LC system (equipped with a UV diode array detector and autosampler). The mass spectrometer was equipped with a multi-mode ionization source (electrospray and atmospheric pressure chemical ionization) capable of operating in both positive and negative ion modes. LCMS experiments were performed on each submitted sample under the following conditions: LC column: Zorbax Eclipse Plus C18 RRHD, 1.8 µm, 50 x 2.1 mm, maintained at 40°C. Mobile phase: A) 0.1% (v / v) formic acid in water; B) 0.1% (v / v) formic acid in MeCN. Method BThe system consisted of an Agilent Technologies 6130 quadrupole mass spectrometer connected to an Agilent Technologies 1290 Infinity LC system (equipped with a UV diode array detector and autosampler). The mass spectrometer was equipped with an electrospray ionization source, capable of operating in both positive and negative ion modes. LCMS experiments were performed on each submitted sample under the following conditions: LC column: Agilent Eclipse Plus C18 RRHD, 1.8 µm, 50 x 2.1 mm, maintained at 40°C. Mobile phase: A) 0.1% (v / v) formic acid in water; B) 0.1% (v / v) formic acid in MeCN. Method C The system consisted of a Waters ACQUITY QDa mass spectrometer connected to a Waters ACQUITY I-Class UPLC system (equipped with a TUV detector). The mass spectrometer was equipped with an electrospray ionization source and could operate in both positive and negative ion modes. LCMS experiments were performed on each submitted sample under the following conditions: LC column: Zorbax Eclipse Plus C18RRHD, 1.8 µm, 50 x 2.1 mm, maintained at 40°C. Mobile phase: A) 0.1% (v / v) formic acid in water; B) 0.1% (v / v) formic acid in MeCN. Method D The system consists of any of the following instruments: an Agilent Technologies 1100 series LC / MSD system equipped with a UV diode array detector and an evaporative light scattering detector (DAD / ELSD) and an Agilent LC / MSDVL (G1956A) or SL (G1956B) mass spectrometer; or an Agilent 1200 series LC / MSD system equipped with a DAD / ELSD and an Agilent LC / MSD SL (G6130A) or SL (G6140A) mass spectrometer. All LCMS data were acquired in atmospheric pressure chemical ionization mode with switching between positive and negative ion modes, and the scan range was [missing information]. m / z 80-1000. LCMS experiments were performed on each submitted sample under the following conditions: LC column: Zorbax SB-C18 RRHD, 1.8 µm, 4.6 x 15 mm. Mobile phase: A) 0.1% (v / v) formic acid in water; B) 0.1% (v / v) formic acid in MeCN. Method E The system consisted of a Shimadzu Prominence HPLC / Applied Biosystem LCMS / MS API2000 instrument. Mass spectrometry ionization technology: ESI using an API source operating in positive ion mode. LCMS experiments were performed on each submitted sample under the following conditions: LC column: XBridge C18, 5 µm, 4.6 x 50 mm, maintained at 25°C. Mobile phase: A) 10 mM ammonium acetate (aq); B) MeCN. Method F The system consisted of a Waters ACQUITY SQD 2 mass spectrometer connected to a Waters ACQUITY H-Class UPLC system (equipped with a TUV detector). The mass spectrometer was equipped with an electrospray ionization source and could operate in both positive and negative ion modes. LCMS experiments were performed on each submitted sample under the following conditions: LC column: XBridge C18, 3.5 µm, 3.0 x 50 mm, maintained at 50°C. Mobile phase: A) 5 mM ammonium acetate (aq); B) 5 mM ammonium acetate in a 9:1 MeCN / water ratio. Preparative high-performance liquid chromatography The system consisted of an Agilent Technologies 6120 single quadrupole mass spectrometer connected to an Agilent Technologies 1200 preparative LC system (equipped with a multi-wavelength detector and autosampler). The mass spectrometer employed a multi-mode ionization source (electrospray and atmospheric pressure chemical ionization) and could operate in both positive and negative ion modes. Fraction collection was mass-triggered (multi-mode positive and negative ion). Purification experiments, unless otherwise specified, were performed under alkaline conditions with a suitable solvent gradient, typically determined based on retention times measured using appropriate LCMS methods. Acidic conditions were used when alkaline conditions were unsuccessful.

[0319] alkaline conditions: LC column: Waters XBridge™ Prep C18 5 μm OBD TM 30 x 100 mm column, room temperature. Mobile phase: A) 0.1% (v / v) ammonium hydroxide in water; B) 0.1% (v / v) ammonium hydroxide in 95:5 MeCN / water. Total experimental time was approximately 10 minutes, and the general method is as follows: Chiral separation of stereoisomers by supercritical fluid chromatography (SFC) The stereoisomer mixture was separated using the following general procedure. The stereoisomer mixture was dissolved in MeOH at 50 mg / mL and purified by SFC under the stated conditions. The combined fractions of each stereoisomer were evaporated to near dryness using a rotary evaporator, transferred to a final container with DCM, the DCM was removed under a compressed air stream at 40°C, and then stored in a vacuum oven at 40°C and 5 mbar for 16 hours.

[0320] Chiral separation of stereoisomers by HPLC The stereoisomer mixture was separated using the following general procedure. The stereoisomer mixture was dissolved in MeOH at 66 mg / mL and purified by HPLC under the stated conditions. The combined fractions of each stereoisomer were evaporated to near dryness using a rotary evaporator, transferred to a final container with MeOH, and DCM was removed under a compressed air stream at 35°C. The mixture was then stored in a vacuum oven at 35°C and 5 mbar for 16 hours.

[0321] Chiral purity analysis After chiral separation of the stereoisomer mixture, each stereoisomer is analyzed under the stated conditions using a suitable analytical SFC or HPLC method to determine its chiral purity.

[0322] Nomenclature Unless otherwise stated, the naming of structures was determined using the "Structure-to-Name" function of ChemDraw Professional 21.0 (CambridgeSoft / PerkinElmer). The stereochemical configurations of the examples were determined by inference from the intermediate precursors used to prepare them, whose absolute stereochemistry is known (i.e., commercial reagents) or inferred from previous studies (e.g., intermediates WO2022 / 200523). In the case of using novel intermediates, the configuration was assigned using the relative activity of enantiomer pairs by comparison with similar products from previous studies. However, it should be noted that for some or all of the examples herein, there may be instances where incorrect configurations are assigned due to errors in the process, and therefore these compounds may have configurations opposite to those described. In any case, the most active stereoisomer is preferred and is explicitly included herein.

[0323] General Program General Procedure 1: Deprotection of Boc to Free Base The Boc-protected amine (1 equivalent) is dissolved in DCM. 1,4-dioxane with TFA or 4 M HCl (as described) is added. The reaction is stirred at room temperature for 1–24 hours. The mixture is loaded onto a pre-equilibrated SCX-2 column. The column is washed with a 4:1 DCM / MeOH mixture, and basic compounds are eluted with a 4:1 DCM / 7 M NH3 / MeOH mixture. The ammoniacal fraction is concentrated under vacuum to give the desired product, which can be used directly in the next step or further purified under the conditions described if necessary.

[0324] General Procedure 2: Automated Synthesis of N-Heterocycles Using Synple 2 This program utilizes the Synple 2 integrated console for "capsule-based automated organic synthesis" Chem.Sci. (2021, 12, 6977-6982), the aim is to use the tinamine scheme (SnAP) to chemically form N-heterocyclic rings ( Org.Lett. (2014, 16, 1236-1239). Place the appropriate aldehyde and stir bar in the reaction flask and connect the tubing cap. Scan the appropriate kit to load the reaction program and conditions, place it in the rack, and lock it in place. Connect the solvents used in the program to the corresponding solvent lines: DCM (S1), hexafluoroisopropanol (S2), MeOH (S3), 35:65 diisopropylamine / THF (S4). Introduce a nitrogen flow. Start the reaction program using standard conditions (unless otherwise specified) by pressing "Start". After the reaction is complete, analyze the resulting product solution by LCMS to determine if further purification (i.e., rapid chromatography or preparative HPLC) is required. Remove the solvent under vacuum to obtain the desired product, which can be used directly in the next step or further purified under the conditions described as needed.

[0325] General Procedure 3: Formation of urea via carbamoyl chloride intermediate Add pyridine or DIPEA (2-5 equivalents) to a MeCN solution of triphosgene (0.3-0.6 equivalents) at 0°C and stir the solution for 10 minutes. Add a MeCN solution of the first suitable amine (1 equivalent), stir the reaction and heat to room temperature for 1-24 hours. Add the mixture to a second suitable amine (1 equivalent), followed by DIPEA (2-5 equivalents), and stir again for 1-24 hours. Add a saturated aqueous solution of sodium bicarbonate. Extract the resulting mixture with DCM (x 3) using a phase separator. Concentrate the combined organic phases under reduced pressure and purify the residue by rapid chromatography to obtain the desired product.

[0326] General Procedure 4: Deprotection of trifluoroacetamide to free base Dissolve a suitable amount of trifluoroacetamide (1 unit) in a 10:1 MeOH / water mixture and add potassium carbonate (5-10 equivalents). Stir the resulting mixture at room temperature or, if necessary, up to 50°C for 1-18 hours. Remove the solvent under vacuum and partition the remaining residue between DCM and water or DCM and a saturated aqueous solution of sodium bicarbonate, separating the resulting two-phase mixture. Extract the aqueous phase with additional DCM (x 2) and concentrate the combined organic phases under vacuum. [Alternatively, dilute the reaction mixture with DCM and load it onto a pre-equilibrated SCX-2 column. Wash the column with a 4:1 DCM / MeOH mixture and elute basic compounds with a 4:1 DCM / 7M NH3 / MeOH mixture. Concentrate the ammoniacal fraction under vacuum.] Purify the residue by rapid chromatography to obtain the desired product.

[0327] General Procedure 5: HATU Coupling A suitable amine (1 equivalent), carboxylic acid (1.0–1.5 equivalents), and HATU (1–1.5 equivalents) were dissolved in DCM, and DIPEA (1–4 equivalents) was added. The reaction was stirred for 1–24 hours as needed, and then quenched by adding a saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with DCM (x 3) using a phase separator. The combined organic extracts were concentrated under reduced pressure, and the remaining residue was purified by rapid chromatography to obtain the desired product.

[0328] General Procedure 6: Formation of Carbamoyl Chloride At 0°C, pyridine (10 monotonies) is added dropwise to a stirred solution of triphosgene (1 equivalent) in DCM. After 30 minutes, at 0°C, a suitable amine (1 monotony) in DCM, or an amine salt (1 equivalent) and DIPEA (1.5 equivalents) in DCM, is added dropwise. The temperature is allowed to rise to room temperature, and stirring is performed for 1–18 hours as needed. The reaction mixture is quenched by adding 1 M hydrochloric acid aqueous solution, and the resulting mixture is extracted with DCM (x 3) using a phase separator. The combined organic phases are concentrated under vacuum to obtain the desired product, which is typically used directly for the next step without further purification.

[0329] General Procedure 7: Formation of Urea using Carbamoyl Chloride Intermediate A suitable amount of carbamoyl chloride (1-2 equivalents), amine or amine hydrochloride (1-3 equivalents), and DIPEA (2-6 equivalents) are stirred in the solvent at room temperature for 1-18 hours (as needed), then quenched with 0.5 M hydrochloric acid aqueous solution and extracted with DCM (x 3) using a phase separator. The combined organic phases are concentrated under vacuum, and the residues are purified by rapid chromatography to obtain the desired product.

[0330] General Procedure 8: Reductive Alkylation of Amines A solution of an amine (1 equivalent) and a suitable aldehyde or ketone (5 equivalents) in MeOH was stirred at room temperature. After 2 hours, sodium triacetoxyborohydride (10 monotonies) was added. After another 1 hour, the reaction progress was monitored by LCMS. Depending on the reaction progress, additional portions of the aldehyde / ketone and sodium triacetoxyborohydride could be added until the reaction was complete. The reaction mixture was diluted with MeOH and loaded onto a pre-equilibrated SCX-2 column. The column was washed with a 4:1 DCM / MeOH mixture, and basic compounds were eluted with a 4:1 DCM / 7 M NH3 / MeOH mixture. The ammoniacal fraction was concentrated under vacuum and further purified by rapid chromatography (typically 0-20% MeOH / DCM or 0-20% MeOH / EtOAc) to obtain the desired product.

[0331] General Procedure 9: Deprotection of Cbz to free base using H-Cube® Pro A Cbz-protected amine (e.g., 1.0 mmol) was dissolved in EtOAc (20 mL) / EtOH (20 mL), and the solution was passed through an H-Cube® Pro hydrogenation flow cytometer containing a 10% w / w Pd / C column at 60°C using the "Control Mode" setting with a hydrogen pressure of 1 bar. The degree of reaction completion was determined by LCMS, and if necessary, the material could be passed through the system again until complete reaction. The solvent was removed under vacuum, and any remaining residues were purified by rapid chromatography to obtain the desired product.

[0332] Intermediate 1: 6-Phenylacetyl-3-(piperazin-1-ylmethyl)pyridine-2(1 H )-Ketodihydrochloride Step 1: 3-(hydroxymethyl)-6-phenylpyridine-2(1H)-one: A THF solution (1200 mL) of a 1 M borane DMS complex of 2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxylic acid (53.3 g, 248 mmol) [commercially available] was added to a THF solution (991 mL, 991 mmol) of the borane DMS complex, and the suspension was stirred at room temperature. After 18 hours, MeOH was slowly added until gas expulsion ceased. The reaction mixture was partitioned between EtOAc and brine, separated, and the organic phase was dried (Na2SO4), filtered, evaporated to dryness, and purified by rapid chromatography (0–5% MeOH / DCM) to give the title compound (33.1 g, 66%). LCMS (Method D): R T = 0.69 min, m / z = 202 [M+H] + .

[0333] Step 2: 2-Oxo-6-phenyl-1,2-dihydropyridine-3-carboxaldehyde: At 0°C, 3-(hydroxymethyl)-6-phenylpyridine-2(1H DCM (250 mL) of ketone (8.0 g, 40 mmol) was stirred and then 22.0 g, 52 mmol of Des Martin periodane was added. After 10 hours, 2 M sodium carbonate aqueous solution (300 mL) was added. After 2 hours, the resulting precipitate was filtered and dried under vacuum to give the title compound (7.2 g, 90%). 1 H NMR (400 MHz, DMSO- d 6): δ 12.61 (s,1H), 10.14 (s, 1H), 8.05-7.96 (m, 4H), 7.70 (m, 1H), 7.55 (m, 1H), 6.80 (m,1H).

[0334] Step 3: 4-((2-oxo-6-phenyl-1,2-dihydropyridin-3-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester: To a stirred solution of 2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxaldehyde (1.5 g, 7.5 mmol) in DCM (50 mL), tert-butyl piperazine-1-carboxylate (2.1 g, 11.2 mmol) was added, followed by sodium triacetoxyborohydride (4.8 g, 22.5 mmol). After 3 hours, the reaction mixture was heated to 55°C. After another 10 hours, a saturated aqueous solution of sodium bicarbonate (150 mL) was carefully added, and the mixture was stirred for another 30 minutes. The resulting two-phase mixture was separated, and the organic phase was dried (Na₂SO₄), filtered, evaporated to dryness, and purified by rapid chromatography (0–5% MeOH / DCM) to give the title compound (1.6 g, 58%). LCMS (Method D): R T = 0.85 min, m / z = 370 [M+H] + .

[0335] Step 4: 6-Phenyl-3-(piperazin-1-ylmethyl)pyridine-2(1H)-one dihydrochloride: The title compound (46.3 mg, quantified) [presumably dihydrochloride] was prepared according to General Procedure 1 using tert-butyl 4-((2-oxo-6-phenyl-1,2-dihydropyridin-3-yl)methyl)piperazine-1-carboxylate (50.0 mg, 0.14 mmol), 1,4-dioxane (3 mL) in 4 M HCl, and DCM (4 mL), but without SCX-2 purification, to give the title compound (46.3 mg, quantified). LCMS (Method A): R T = 0.41 min, m / z = 270[M+H] + .

[0336] Intermediate 2: 3-((2,2-dimethylpiperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone The title compound is similar to 6-phenyl-3-(piperazin-1-ylmethyl)pyridine-2(1 H The compound was prepared via a ketone (intermediate 1), but using tert-butyl 3,3-dimethylpiperazine-1-carboxylate [commercially available] instead of tert-butyl piperazine-1-carboxylate (step 3), and using TFA instead of 1,4-dioxane in 4 M HCl, and included SCX-2 purification (step 4) to give the title compound as a free base. LCMS (Method A): R T = 0.44 min, m / z = 298 [M+H] + .

[0337] Intermediate 3: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone Step 1: 3-(chloromethyl)-6-phenylpyridine-2(1H)-one: To 3-(hydroxymethyl)-6-phenylpyridine-2(1 H A solution of 33.0 g (165 mmol) of thionyl chloride (200 mL, 2.78 mol) in DCM (1200 mL) was added with stirring. The reaction mixture was heated to 40°C. After 24 hours, the volatiles were removed under vacuum, and co-evaporation with MeCN was performed to give the title compound (36.2 g, quantified), which was used directly in the next step without purification.

[0338] Step 2: 6-((2-oxo-6-phenyl-1,2-dihydropyridin-3-yl)-methyl)-6,9-diazaspiro[4.5]decane tert-butyl alkyl-9-carboxylate: To 3-(chloromethyl)-6-phenylpyridine-2(1 H DIPEA (15 g, 116 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (9.3 g, 39 mmol) [commercially available] were added to a MeCN (300 mL) solution of 4,9-diazaspiro[4.5]decane-9-carboxylate, and the suspension was stirred at 80°C for 18 hours. The reaction mixture was concentrated and partitioned between DCM and brine, separated, and the organic phase was dried (Na2SO4), filtered, evaporated to dryness, and purified by rapid chromatography (0-5% MeOH / DCM) to give the title compound (10.1 g, 61%). LCMS (Method D): R T = 0.64 min, m / z = 424 [M+H] + .

[0339] Step 3: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridin-2(1H)-one:The title compound (75.5 mg, 99%) was prepared according to general procedure 1 using 6-((2-oxo-6-phenyl-1,2-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester (100.0 mg, 0.24 mmol), TFA (1.1 mL), and anhydrous DCM (1 mL). LCMS (Method A): R T = 0.50 min, m / z = 324 [M+H] + .

[0340] Intermediate 4: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)quinoline-2(1 H )-ketone Step 1: 6-((2-oxo-1,2-dihydroquinolin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester: To a solution of 2-oxo-1,2-dihydroquinoline-3-carboxaldehyde [commercially available] (1.50 g, 8.7 mmol) in 1,2-dichloroethane (50 mL), tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (3.10 g, 13.5 mmol) was added, followed by fractional addition of sodium triacetoxyborohydride (5.50 g, 26.1 mmol), and the suspension was stirred at 60°C. After 18 hours, the solvent was removed under vacuum, and the remaining residue was partitioned and separated between EtOAc and brine. The organic phase was washed with saturated aqueous sodium bicarbonate solution, dried (Na2SO4), filtered, evaporated to dryness, and purified by rapid chromatography (0–5% MeOH / DCM) to give the title compound (0.50 g, 14%). LCMS (Method D): R T = 0.75 min, m / z = 398 [M+H] + .

[0341] Step 2: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)quinoline-2(1H)-one: The title compound (75.1 mg, quantified) was prepared according to general procedure 1 using tert-butyl 6-((2-oxo-1,2-dihydroquinolin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (100.0 mg, 0.25 mmol), TFA (0.5 mL), and anhydrous DCM (1 mL). LCMS (Method A): R T = 0.47 min, m / z = 298 [M+H] + .

[0342] Intermediate 5: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1,5,7,8-tetrahydro-2 H -pyran [4,3- b ]Pyridin-2-one Step 1: 6-((2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-3-yl)methyl)-6,9-di tert-butyl zeolite of zeolite[4.5]decane-9-carboxylate: To 2-oxo-2,5,7,8-tetrahydro-1 H -pyrano[4,3- b 6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester (1.00 g, 4.2 mmol) was added to a solution of pyridine-3-carboxaldehyde (0.50 g, 2.8 mmol) in 1,2-dichloroethane (30 mL), followed by fractional addition of sodium triacetoxyborohydride (1.80 g, 8.4 mmol), and the suspension was stirred at 60°C. After 18 hours, the solvent was removed under vacuum, and the remaining residue was partitioned and separated between EtOAc and brine. The organic phase was washed with saturated aqueous sodium bicarbonate solution, dried (Na2SO4), filtered, evaporated to dryness, and purified by rapid chromatography (0-10% MeOH / DCM) to give the title compound (0.10 g, 9%). LCMS (Method D): R T = 1.01 min, m / z = 404 [M+H] + .

[0343] Step 2: 3-((6,9-diazaspiro[4,5]decane-6-yl)methyl)-1,5,7,8-tetrahydro-2H-pyrano[4, 3-b]Pyridin-2-one: According to general procedure 1, 6-((2-oxo-1,5,7,8-tetrahydro-2-) H -pyrano[4,3- b The title compound (30 mg, 40%) was prepared by reacting 100 mg (100 mg, 0.25 mmol), TFA (0.5 mL), and DCM (1 mL) with pyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester (100 mg, 0.25 mmol), TFA (0.5 mL), and DCM (1 mL). LCMS (Method B): R T = 0.27 min (solvent front), m / z = 304 [M+H] + .

[0344] Intermediate 6: ((2) S 4 R 2-(2,5-difluorophenyl)piperidin-4-yl)(methyl)carbamate tert-butyl Step 1: 2-(2,5-Difluorophenyl)isonicotinic acid:To a solution of methyl 2-bromoisocyanate (250 g, 1.16 mol) and (2,5-difluorophenyl)boronic acid (200 g, 1.27 mol) in 1,4-dioxane (8.0 L) and water (2.6 L), Pd(dppf)Cl2 (47.5 g, 5 mol%) and tripotassium phosphate (735 g, 3.46 mol) were added. The reaction mixture was refluxed for 16 hours and evaporated to dryness. The residue was dissolved in hot water (4 L) and filtered. The pH of the filtrate was adjusted to pH 3 using an aqueous hydrochloric acid solution, the precipitate was filtered, washed with water (2 L), and dried in a vacuum oven to give the title compound (260 g, 95%). LCMS (Method D): R T = 1.15 min, m / z = 236 [M+H] + .

[0345] Step 2: rac-(2S,4R)-2-(2,5-difluorophenyl)piperidine-4-carboxylic acid: 10% w / w Pd / C (6.0 g, 10% w / w) was added to a well-stirred suspension of 2-(2,5-difluorophenyl)isonicotinic acid (60.0 g, 0.255 mol) in MeOH (2.4 L), and the resulting mixture was reacted with hydrogen (50 atm) in an autoclave at 50°C. The reaction was carried out by... 1 After sampling the reaction mixture by HNMR (to determine the starting material consumption), the solvent was evaporated to dryness to give the crude title compound (65.3 g, assumed to be 0.255 mol, contaminated with residual Pd / C catalyst), which was used for the next step without further purification.

[0346] Step 3: rac-(2S,4R)-1-((benzyloxy)carbonyl)-2-(2,5-difluorophenyl)piperidine-4-carboxylic acid: Towards rac -(2 S 4 R NaOH (221 g, 5.54 mol) was added to a suspension of 1,4-dioxane (5.0 L) and water (2.5 L) containing 2-(2,5-difluorophenyl)piperidin-4-carboxylic acid (284 g, assumed 1.11 mol, contaminated with Pd / C). The reaction mixture was cooled to 0°C, and then benzyl chloroformate (282 g, 1.66 mol) was added dropwise. After 16 hours, the resulting mixture was evaporated to dryness, and the residue was dissolved in water (5 L) and extracted with MTBE (2 L). The aqueous phase was acidified with aqueous hydrochloric acid (pH = 3) and extracted with ethyl acetate (3 L). The organic phase was dried (Na2SO4), filtered, and evaporated to dryness to give the title compound (313 g, 75.3%) as a white solid. LCMS (Method D): R T = 1.27 min,m / z = 374 [MH] - .

[0347] Step 4: rac-(2S,4R)-2-(2,5-difluorophenyl)-4-(((2-(trimethylsilyl)ethoxy)carbonyl) Benzyl 1-aminopiperidine-1-carboxylate: Towards rac -(2 S 4 R Triethylamine (253 g, 2.50 mol) was added to a suspension of 1-((benzyloxy)carbonyl)-2-(2,5-difluorophenyl)piperidin-4-carboxylic acid (313 g, 0.834 mol) in toluene (4.0 L), followed by DPPA (298 g, 1.08 mol). The reaction mixture was heated at 75°C for 4 hours until gas release ceased, followed by the addition of 2-(trimethylsilyl)ethanol (296 g, 2.50 mol). The reaction mixture was heated at 110°C for 24 hours. The reaction mixture was extracted with a 15% w / v aqueous solution of NaOH (2 × 2 L), the organic phase was dried (Na₂SO₄), filtered, and evaporated to dryness to give the title compound (375 g, 92%). 1 H NMR (400 MHz, CDCl3): δ 7.31-7.16 (m, 5H), 6.99-6.84 (m, 3H), 5.28 (m, 1H), 5.08 (m, 2H), 4.46 (m, 1H), 4.16-4.07 (m,3H), 3.90 (m, 1H), 3.50 (m, 1H), 2.29-2.09 (m, 3H), 1.64 (m, 1H), 0.90 (m,1H), 0.04 (s, 9H).

[0348] Step 5: rac-(2S,4R)-4-((tert-butoxycarbonyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylic acid benzyl ester :Towards rac -(2 S 4 R Benzyl piperidine-1-carboxylate (375 g, 0.764 mol) in THF (3.0 L) was added to a THF solution of 1 M TBAF (2292 mL, 2.29 mol), and the resulting mixture was heated at 55°C for 48 hours. The reaction mixture was concentrated under vacuum, and the remaining residue was partitioned and separated between EtOAc (3 L) and a 15% w / v NH4Cl aqueous solution (2 L). The organic phase was washed with water (1 L), followed by brine (1 L), dried (Na2SO4), filtered, and the solvent was concentrated to dryness. The resulting crude product was... rac-(2 S 4 R The 4-amino-2-(2,5-difluorophenyl)piperidine-1-carboxylic acid benzyl ester was dissolved in MeOH (2.5 L), cooled to 0°C, and Boc₂O (200 g, 0.917 mol) was added dropwise at room temperature. After 24 hours, the solvent was evaporated, and the remaining residue was purified by rapid chromatography (0-20% EtOAc / hexane) to give the title compound (250 g, 74%). LCMS (Method D): R T = 1.32 min, m / z = 347 [M-Boc+H] + .

[0349] Step 6: rac-(2S,4R)-4-((tert-butoxycarbonyl)(methyl)amino)-2-(2,5-difluorophenyl)piperidine- 1-Benzyl formate: At 0°C, towards rac -(2 S 4 R NaH (55% in mineral oil, 2.7 g, 61.7 mmol) was added to a stirred solution of 200 mL DMF containing benzyl 4-((tert-butoxycarbonyl)amino)-2-(2,5-difluorophenyl)piperidin-1-carboxylate (25 g, 56 mmol). After 3 hours, methyl iodoform (9.6 g, 67.3 mmol) was added, and the temperature was raised to room temperature. After another 24 hours, the reaction mixture was partitioned between EtOAc (400 mL) and 15% w / v NH4Cl aqueous solution (500 mL), separated, and the organic phase was washed with water (500 mL) and brine (500 mL), dried (Na2SO4), and the solvent was removed under vacuum. The remaining residue was purified by rapid chromatography (0–20% EtOAc / hexane) to give the title compound (22.1 g, 86%). LCMS (Method D): R T = 1.61 min, m / z = 361 [M-Boc+H] + .

[0350] Step 7: (2S,4R)-4-((tert-butoxycarbonyl)(methyl)amino)-2-(2,5-difluorophenyl)piperidine-1-methyl benzyl ester: Using CHIRALCEL ® An OJ-H (20 mm x 250 mm, 5 µm) column was used for chiral HPLC to transport rac-(2... S 4 R18.0 g of benzyl 4-((tert-butoxycarbonyl)(methyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate was resolved into a single stereoisomer using isocratic solvent conditions: 90:5:5 hexane / IPA / MeOH. The first eluent (R...) T =16.12 min), yielding the title compound (6.95 g). LCMS (Method D): R T = 1.61 min, m / z = 361 [M-Boc+H] + ; and the second eluting substance (R) T = 24.90 min), resulting in (2 R 4 S 4-((tert-butoxycarbonyl)(methyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylic acid benzyl ester (7.74 g). LCMS (Method D): R T = 1.61 min, m / z = 361 [M-Boc+H] + .

[0351] Step 8: ((2S,4R)-2-(2,5-difluorophenyl)piperidin-4-yl)(methyl)carbamate tert-butyl ester: (2) S 4 R Benzyl 4-((tert-butoxycarbonyl)(methyl)amino)-2-(2,5-difluorophenyl)piperidin-1-carboxylate (6.95 g, 15.1 mmol) was dissolved in MeOH (150 mL), 10% w / w Pd / C (0.7 g) was added to the solution, and the reaction mixture was hydrogenated at room temperature (~1 atm, balloon). After 24 hours, the reaction mixture was filtered through a silica gel pad and evaporated to dryness to give the title compound (4.59 g, 93%). Chiral HPLC (CHIRALCEL) ® The OJ-H (4.6 mm x 250 mm, 5 µm) column was used under isocratic solvent conditions: 95:2.5:2.5 hexane / IPA / MeOH:R T = 9.05 min. LCMS (Method D): R T =1.04 min, m / z = 327 [M+H] + [α] D 21 = +34.6 (c 0.25 in CHCl3).

[0352] Intermediate 7: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-phenylpyridine-4(1 H )- ketone Step 1: 5-(hydroxymethyl)-2-phenylpyridine-4(1H)-one: Ethyl 4-oxo-6-phenyl-1,4-dihydropyridine-3-carboxylate (30.4 g, 125 mmol) [according to] Chem.Pharm.Bull [Preparation of the title compound] 1.0 M borane-DMS complex in THF (1100 mL) solution was added to a THF solution (485 mL, 485 mmol) and the suspension was stirred at room temperature. After 18 hours, MeOH was slowly added until gas expulsion ceased. The resulting mixture was partitioned between EtOAc and brine, and the organic layer was dried (Na2SO4). The solvent was removed under vacuum, and the residue was purified by rapid chromatography (0-10% EtOAc / hexane) to give the title compound (16.5 g, 66%). LCMS (Method D): R T = 0.59 min, m / z =202 [M+H] + .

[0353] Step 2: 5-(chloromethyl)-2-phenylpyridine-4(1H)-one: To 5-(hydroxymethyl)-2-phenylpyridine-4(1 H A solution of 16.3 g (82 mmol) of ketone in DCM (600 mL) was mixed with thionyl chloride (100 mL, 1.39 mol) and the suspension was stirred at 40°C. After 24 hours, the volatiles were removed under vacuum, and co-evaporation with MeCN-assisted extraction was performed to give the title compound (18.0 g, quantified), which was used directly in the next step without purification.

[0354] Step 3: 6-((4-oxo-6-phenyl-1,4-dihydropyridin-3-yl)-methyl)-6,9-diazaspiro[4.5]decane tert-butyl alkyl-9-carboxylate: To 5-(chloromethyl)-2-phenylpyridine-4(1 H DIPEA (15 g, 116 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (9.3 g, 39 mmol) were added to a MeCN (300 mL) solution of ketone (8.5 g, 39 mmol), and the resulting suspension was stirred at 80°C. After 24 hours, the solvent was removed under vacuum, and the remaining residue was partitioned between DCM and brine, separated, and the organic phase was dried (Na2SO4). The solvent was removed under vacuum, and the residue was purified by rapid chromatography (0-5% MeOH / DCM) to give the title compound (11.4 g, 69%). LCMS (Method D): R T = 0.93 min, m / z= 424 [M+H] + .

[0355] Step 4: 6-((1-methyl-4-oxo-6-phenyl-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro [4.5] tert-butyl decane-9-carboxylate: Under argon atmosphere, sodium hydride (55% in mineral oil, 28 mg, 0.65 mmol) was added to a DMF (2 mL) solution of 6-((4-oxo-6-phenyl-1,4-dihydropyridin-3-yl)-methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester (0.212 mg, 0.5 mmol) (2.5 mL). After 1 hour, iodomethane (92 mg, 0.65 mmol) was added. After 4 hours, the solvent was removed under vacuum, the residue was partitioned between DCM and brine, separated, and the organic phase was dried (Na2SO4). The solvent was removed under vacuum, and the remaining residue was purified by reversed-phase preparative HPLC (C18 column) to give the title compound (11.4 g, 69%). LCMS (Method D): R T = 1.09 min, m / z = 438 [M+H] + .

[0356] Step 5: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-phenylpyridine-4(1H)- ketone: The title compound (49.5 mg, quantified) was prepared according to General Procedure 1 using 6-((1-methyl-4-oxo-6-phenyl-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester (60.2 mg, 0.14 mmol), TFA (0.5 mL), and anhydrous DCM (1 mL). LCMS (Method A): R T = 0.44 min, m / z = 338 [M+H] + .

[0357] Intermediate 8: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone The title compound (20 mg, 87%) was prepared according to general procedure 1 using tert-butyl 6-((4-oxo-6-phenyl-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (30 mg, 70.8 µmol), TFA (0.5 mL), and DCM (1 mL). LCMS (Method C): R T = 0.43 min, m / z = 324 [M+H]+ .

[0358] Intermediate 9: ((2) S 4 R 2-(2,5-difluorophenyl)piperidin-4-yl)(2-methoxyethyl)carbamate tert-butyl ester Step 1: rac-(2S,4R)-4-((tert-butoxycarbonyl)(2-methoxyethyl)amino)-2-(2,5-difluorobenzene) Benzyl piperidine-1-carboxylate: At 0°C, towards rac -(2 S 4 R Sodium hydride (55% in mineral oil, 0.78 g, 13.3 mmol) was added to a DMF (120 mL) solution of 4-((tert-butoxycarbonyl)amino)-2-(2,5-difluorophenyl)piperidin-1-carboxylic acid benzyl ester (4.50 g, 10.2 mmol). After 3 hours, 1-iodo-2-methoxyethane (4.20 g, 22.4 mmol) was added. After another 24 hours, the reaction mixture was partitioned and separated between EtOAc (200 mL) and 15% NH4Cl aqueous solution (300 mL). The organic phase was washed with water (300 mL), followed by brine (300 mL) and dried (Na2SO4). The solvent was removed under vacuum, and the residue was purified by rapid chromatography (0-40% CHCl3 / hexane) to give the title compound (3.01 g, 59%). LCMS (Method D): R T = 1.58 min, m / z = 405 [M-Boc+H] + .

[0359] Step 2: (2S,4R)-4-((tert-butoxycarbonyl)(2-methoxyethyl)amino)-2-(2,5-difluorophenyl)piperazine Benzyl 1-pyridinecarboxylate: Using CHIRALPAK ® An AD-H (4.6 mm x 250 mm, 5 µm) column was used for chiral HPLC to transport rac-(2... S 4 R 2.98 g of benzyl 4-((tert-butoxycarbonyl)(2-methoxyethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate was resolved into a single stereoisomer using isocratic solvent conditions: 95:2.5:2.5 hexane / IPA / MeOH. The first eluent (R...) T = 19.25 min), yielding the title compound (1.21 g). LCMS (Method D): R T = 1.58min, m / z = 405 [M-Boc+H] + ; and the second eluting substance (R) T= 25.65 min), resulting in (2 R 4 S )-4-((tert-butoxycarbonyl)(2-methoxyethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylic acid benzyl ester (1.16 g). LCMS (Method D): R T = 1.58 min, m / z = 405 [M-Boc+H] + .

[0360] Step 3: ((2S,4R)-2-(2,5-difluorophenyl)piperidin-4-yl)(2-methoxyethyl)carbamate tert-butyl ester: (2) S 4 R Benzyl 4-((tert-butoxycarbonyl)(2-methoxyethyl)amino)-2-(2,5-difluorophenyl)piperidin-1-carboxylate (1.21 g, 2.4 mmol) was dissolved in MeOH (50 mL) and 10% w / w Pd / C (0.12 g), and the reaction mixture was hydrogenated at room temperature (~1 atm, balloon). After 24 hours, the reaction mixture was filtered through a silica gel pad and evaporated to dryness to give the title compound (0.88 g, 99%). Chiral HPLC (CHIRALPAK) ® IC (4.6 mm x 250 mm, 5 µm) column with isocratic solvent conditions: 98:1:1 hexane (0.1% EDA) / IPA / MeOH): R T = 7.12 min. LCMS (Method D): R T = 1.12 min, m / z = 371 [M+H] + .

[0361] Intermediate 10: 5-((2,2-dimethylpiperazin-1-yl)methyl)-2-phenylpyridine-4(1 H )-ketone Step 1: 3,3-Dimethyl-4-((4-oxo-6-phenyl-1,4-dihydropyridin-3-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester: The title compound was prepared in a manner similar to that of 6-((4-oxo-6-phenyl-1,4-dihydropyridin-3-yl)-methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate tert-butyl ester (intermediate 7, steps 1 to 3), but using 3,3-dimethylpiperazine-1-carboxylate tert-butyl ester instead of 6,9-diazaspiro[4.5]decane-9-carboxylate tert-butyl ester. LCMS (Method D): R T = 1.01min, m / z = 398 [M+H] + .

[0362] Step 2: 5-((2,2-dimethylpiperazin-1-yl)methyl)-2-phenylpyridin-4(1H)-one: The title compound (44.0 mg, 98%) was prepared according to general procedure 1 using tert-butyl 3,3-dimethyl-4-((4-oxo-6-phenyl-1,4-dihydropyridin-3-yl)methyl)piperazine-1-carboxylate (60.0 mg, 151 µmol), TFA (0.13 mL), and DCM (2 mL). LCMS (Method A): R T = 0.38 min, m / z = 298 [M+H] + .

[0363] Intermediate 11: 5-((4,7-diazaspiro[2.5]octane-4-yl)methyl)-2-phenylpyridine-4(1 H )-ketone The title compound is similar to 5-((2,2-dimethylpiperazin-1-yl)methyl)-2-phenylpyridine-4(1 H The title compound was prepared via a ketone (intermediate 10), but using tert-butyl 4,7-diazaspiro[2,5]octane-7-carboxylate [commercially available] instead of tert-butyl 3,3-dimethylpiperazine-1-carboxylate. LCMS (Method A): R T = 0.44 min, m / z = 296[M+H] + .

[0364] Intermediate 12: ((2) S 4 R 2-(3,4-difluorophenyl)piperidin-4-yl)(methyl)carbamate tert-butyl The title compound is similar to ((2) S 4 R It was prepared by means of 2-(2,5-difluorophenyl)piperidin-4-yl)(methyl)carbamate tert-butyl ester (intermediate 6), but using (3,4-difluorophenyl)boronic acid instead of (2,5-difluorophenyl)boronic acid (step 1), and using CHIRALPAK. ® AD-H (4.6 mm x 250 mm, 5 µm) column, isocratic solvent conditions: 70:15:15 hexane / IPA / MeOH for chiral HPLC separation of enantiomers (step 7) to obtain the title compound. Chiral HPLC (CHIRALPAK) ® AD-H (4.6 mm x 250 mm, 5 µm) columns were prepared under isocratic solvent conditions: 5:5:90 hexane / IPA / MeOH containing 0.1% v / v EDA: R T = 6.19 min. LCMS (Method D): R T = 0.80 min,m / z = 327 [M+H] + [α] D 21 = +25.3 (c 0.50 in CHCl3).

[0365] Intermediate 13: 3-(2,5-difluorophenyl)morpholine Using SnAP chemistry, according to general procedure 2, using N - The heterocyclic "morpholine" kit (H101) reacts 2,5-difluorobenzaldehyde (0.05 mL, 0.50 mmol) under full-sequence conditions (11 hours) to give the substance requiring further purification by rapid chromatography to obtain the title compound (35 mg, 35%) [assumed to be a racemic mixture of 1:1 enantiomers]. LCMS (Method A): R T = 0.42 min, m / z = 200 [M+H] + .

[0366] Intermediate 14: tert-butyl 3-(2,5-difluorophenyl)-1,4-diazacycloheptane-1-carboxylate Using SnAP chemistry, according to general procedure 2, using N - Heterocyclic formation "Diazaheptanane" kit (H106) reacts 2,5-difluorobenzaldehyde (0.05 mL, 0.50 mmol) under full-sequence conditions (11 hours) to give the substance requiring further purification by rapid chromatography to obtain the title compound (18 mg, 12%) [assumed to be racemic, a 1:1 mixture of enantiomers]. LCMS (Method A): R T = 0.77 min, m / z = 257 [M-Butene + H] + .

[0367] Intermediate 15: 3-(2,5-difluorophenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylic acid benzyl ester Using SnAP chemistry, according to general procedure 2, using N- Heterocyclic formation using the "morpholine-2-spiro-(4-piperidine)" kit (H111) involves reacting 2,5-difluorobenzaldehyde (0.05 mL, 0.50 mmol) under full-sequence conditions (11 hours) to yield the substance requiring further purification by rapid chromatography to obtain the title compound (66 mg, 33%) [assumed to be a racemic mixture of 1:1 enantiomers]. LCMS (Method A): R T = 0.91 min, m / z = 403 [M+H] + .

[0368] Intermediate 16: ((2 S 4 R 2-(2,6-difluorophenyl)piperidin-4-yl)(methyl)carbamate tert-butyl The title compound is similar to ((2) S 4 R It was prepared by means of 2-(2,5-difluorophenyl)piperidin-4-yl)(methyl)carbamate tert-butyl ester (intermediate 6), but using (2,6-difluorophenyl)boronic acid instead of (2,5-difluorophenyl)boronic acid (step 1), and using CHIRALCEL. ® AD-H (4.6 mm x 250 mm, 5 µm) column, isocratic solvent conditions: 70:15:15 hexane / IPA / MeOH for chiral HPLC separation of enantiomers (step 7) to obtain the title compound. Chiral HPLC (CHIRALCEL) ® The OJ-H (4.6 mm x 250 mm, 5 µm) column was subjected to isocratic solvent conditions: 90:5:5 hexane / IPA / MeOH:R T = 7.80 min. LCMS (Method D): R T = 0.76 min, m / z = 327 [M+H] + [α] D 21 = +42.9 (c 0.20 in CHCl3).

[0369] Intermediate 17: ((2 S 4 R 2-(2,4-difluorophenyl)piperidin-4-yl)(methyl)carbamate tert-butyl The title compound is similar to ((2) S 4 R It was prepared by means of 2-(2,5-difluorophenyl)piperidin-4-yl)(methyl)carbamate tert-butyl ester (intermediate 6), but using (2,4-difluorophenyl)boronic acid instead of (2,5-difluorophenyl)boronic acid (step 1), and using CHIRALPAK.® IJ (4.6 mm x 250 mm, 5 µm) column, isocratic solvent conditions: 80:10:10 hexane / IPA / MeOH for chiral HPLC separation of enantiomers (step 7) to obtain the title compound. Chiral HPLC (CHIRALCEL) ® The OD-H (4.6 mm x 250 mm, 5 µm) column was subjected to isocratic solvent conditions: 98:1:1 hexane / IPA / MeOH:R T = 6.39 min. LCMS (Method D): R T = 1.07 min, m / z = 327 [M+H] + [α] D 21 = +24.9 (c 0.25 in CHCl3).

[0370] Intermediate 18: rac -(3 R 5 S )-3-(2,5-difluorophenyl)-5-methylmorpholine and Using SnAP chemistry, according to general procedure 2, using N - Heterocyclic formation using the "3-methylmorpholine" kit (H107) involved reacting 2,5-difluorobenzaldehyde (0.05 mL, 0.50 mmol) under full-sequence conditions (11 h) to give the title compound (35 mg, 33%), which was used in the next step without further purification. LCMS (Method A): R T = 0.379 min, m / z = 214 [M+H] + . 1 ¹H NMR (500 MHz, CDCl₃): δ 7.31 (ddd, 1H), 6.97 (td, 1H), 6.93–6.87 (m, 1H), 4.37–4.30 (m, 1H), 3.89 (dd, 1H), 3.83–3.74 (m, 1H), 3.20 (t, 1H), 3.16–3.10 (m, 2H), 1.06–1.01 (m, 3H). [Note: NMR data indicate the presence of only the cis stereoisomer; the trans stereoisomer was not observed.]

[0371] Intermediate 19: 5-((5,8-diazaspiro[3.5]nonane-5-yl)methyl)-2-phenylpyridine-4(1 H )-ketone The title compound is similar to 5-((2,2-dimethylpiperazin-1-yl)methyl)-2-phenylpyridine-4(1 H The title compound was prepared via a ketone (intermediate 10), but using tert-butyl 5,8-diazaspiro[3,5]nonane-8-carboxylate [commercially available] instead of tert-butyl 3,3-dimethylpiperazine-1-carboxylate. LCMS (Method C): R T = 0.41 min, m / z = 310[M+H] + .

[0372] Intermediate 20: 5-((2-oxa-5,8-diazaspiro[3.5]nonane-5-yl)methyl)-2-phenylpyridine-4 (1 H )-ketone The title compound is similar to 5-((2,2-dimethylpiperazin-1-yl)methyl)-2-phenylpyridine-4(1 H The title compound was prepared via a ketone (intermediate 10), but using tert-butyl 2-oxa-5,8-diazaspiro[3,5]nonane-8-carboxylate [commercially available] instead of tert-butyl 3,3-dimethylpiperazine-1-carboxylate. LCMS (Method C): R T = 0.42 min, m / z = 312 [M+H] + .

[0373] Intermediate 21: 5-((1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1 H )-ketone The title compound is similar to 5-((2,2-dimethylpiperazin-1-yl)methyl)-2-phenylpyridine-4(1 H The title compound was prepared by means of 1,4-diazaspiro[5.5]undecane-4-carboxylate tert-butyl ester [commercially available] instead of 3,3-dimethylpiperazine-1-carboxylate. LCMS (Method C): R T = 0.47 min, m / z =338 [M+H] + .

[0374] Intermediate 22: 5-((9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4 (1 H )-ketone The title compound is similar to 5-((2,2-dimethylpiperazin-1-yl)methyl)-2-phenylpyridine-4(1 HThe title compound was prepared via a ketone (intermediate 10), but using 9-oxa-1,4-diazaspiro[5.5]undecane-4-carboxylate tert-butyl ester [commercially available] instead of 3,3-dimethylpiperazine-1-carboxylate. LCMS (Method C): R T = 0.42min, m / z = 340 [M+H] + .

[0375] Intermediate 23: 3-((4,7-diazaspiro[2.5]octane-4-yl)methyl)-6-phenylpyridine-2(1 H )-ketone The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H The title compound was prepared via a ketone (intermediate 3), but using 4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester [commercially available] instead of 6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester. LCMS (Method C): R T = 0.58min, m / z = 296 [M+H] + .

[0376] Intermediate 24: 3-((5,8-diazaspiro[3.5]nonane-5-yl)methyl)-6-phenylpyridine-2(1 H )-ketone The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H The title compound was prepared via a ketone (intermediate 3), but using 5,8-diazaspiro[3.5]nonane-8-carboxylic acid tert-butyl ester [commercially available] instead of 6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester. LCMS (Method C): R T = 0.50min, m / z = 310 [M+H] + .

[0377] Intermediate 25: 3-((2-oxa-5,8-diazaspiro[3.5]nonane-5-yl)methyl)-6-phenylpyridine-2 (1 H )-ketone The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 HThe title compound was prepared via a ketone (intermediate 3), but using 2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylic acid tert-butyl ester [commercially available] instead of 6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester to obtain the title compound. LCMS (Method C): R T = 0.55 min, m / z = 312 [M+H] + .

[0378] Intermediate 26: 3-((1,4-diazaspiro[5.5]undecane-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H The title compound was prepared via a ketone (intermediate 3), but using 1,4-diazaspiro[5.5]undecane-4-carboxylate tert-butyl ester [commercially available] instead of 6,9-diazaspiro[4.5]decane-9-carboxylate. LCMS (Method C): R T =0.55 min, m / z = 338 [M+H] + .

[0379] Intermediate 27: 3-((9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-6-phenylpyridine-2 (1 H )-ketone The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H The title compound was prepared via a ketone (intermediate 3), but using 9-oxa-1,4-diazaspiro[5.5]undecane-4-carboxylic acid tert-butyl ester [commercially available] instead of 6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester. LCMS (Method C): R T = 0.55 min, m / z = 340 [M+H] + .

[0380] Intermediate 28: (2 S 4 R 2-(2,5-difluorophenyl)-4-(pyrrolidone-1-yl)piperidine hydrochloride Step 1: (2S)-2-(2,5-difluorophenyl)-4-(pyrrolidone-1-yl)piperidine-1-carboxylic acid tert-butyl ester: At room temperature, to ( S1.5 g (4.82 mmol) of tert-butyl 2-(2,5-difluorophenyl)-4-oxopiperidin-1-carboxylate (1.5 g, 4.82 mmol) [prepared according to WO2022200523 Intermediate 19, step 5] in MeOH (10 mL) was mixed with acetic acid (3 drops) and pyrrolidine (0.6 mL, 7.23 mmol). After 2 hours, NaBH3CN (0.9 g, 14.5 mmol) was added. After another 16 hours, the reaction mixture was concentrated under reduced pressure and the residue was purified by rapid chromatography to give the title compound (1.6 g, 91%). LCMS (Method E): R T = 3.15 min, m / z = 367 [M+H] + .

[0381] Step 2: (2S,4R)-2-(2,5-difluorophenyl)-4-(pyrrolidone-1-yl)piperidine-1-carboxylic acid tert-butyl ester: The (2) were obtained by reversed-phase preparative HPLC (C18 column). S 1.6 g of tert-butyl 2-(2,5-difluorophenyl)-4-(pyrrolidone-1-yl)piperidine-1-carboxylate was isolated into a single stereoisomer to give (2 S 4 S 2-(2,5-difluorophenyl)-4-(pyrrolidone-1-yl)piperidin-1-carboxylic acid tert-butyl ester (first eluting isomer: 200 mg). LCMS (Method E): R T = 3.15 min, m / z = 367[M+H] + ; and the title compound (second eluting isomer: 750 mg). LCMS (Method E): R T = 3.15 min, m / z =367 [M+H] + .

[0382] Step 3: (2S,4R)-2-(2,5-difluorophenyl)-4-(pyrrolidone-1-yl)piperidine hydrochloride: At room temperature, to (2 S 4 R 1,4-Dioxane (6 mL) of 4 M HCl was added to a stirred solution of tert-butyl piperidine-1-carboxylate (890 mg 2.43 mmol) in DCM (10 mL). After 3 hours, the solvent was evaporated under reduced pressure, and the residue was ground with DCM and pentane, followed by lyophilization to give the title compound (770 mg, quantified). LCMS (Method E): R T = 1.26 min, m / z = 267 [M+H] + .

[0383] Intermediate 29: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4 (1 H )-ketone Step 1: Methyl 4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridine-3-c carboxylate: Sodium hydride (55% in mineral oil, 10.0 g, 226 mmol) was added to a THF (400 mL) solution of ethyl (Z)-2-(aminomethylene)-3-oxobutyrate (13.6 g, 87 mmol) in mineral oil. After 1 hour, methyl thiophene-3-carboxylate (25.0 g, 174 mmol) was slowly added, and the resulting mixture was stirred at 60°C. After 4 hours, the solvent was removed under vacuum, and the residue was dissolved in anhydrous MeOH (300 mL), followed by dropwise addition of thionyl chloride (31 g, 261 mmol). The reaction mixture was refluxed for 10 hours. The solvent was removed under vacuum, and the residue was partitioned between DCM and a saturated aqueous sodium bicarbonate solution. The resulting two-phase mixture was separated, the organic layer was dried (Na₂SO₄), the solvent was removed under vacuum, and the residue was purified by rapid chromatography (0-10% EtOAc / hexane) to give the title compound (7.1 g, 34%). LCMS (Method D): R T = 0.70 min, m / z =236 [M+H] + .

[0384] Step 2: 5-(hydroxymethyl)-2-(thiophen-3-yl)pyridin-4(1H)-one: At room temperature, a borane DMS complex (6.4 g, 84 mmol) was added to a stirred solution of methyl 4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridine-3-carboxylate (6.6 g, 28 mmol) in THF (250 mL). After 30 hours, MeOH was slowly added until gas expulsion ceased. The solvent was removed under vacuum, and co-evaporation was assisted with additional MeOH to give the title compound (5.8 g, quantified). LCMS (Method D): R T =0.51 min, m / z = 208 [M+H] + .

[0385] Step 3: 5-(chloromethyl)-2-(thien-3-yl)pyridin-4(1H)-one: At 40°C, 5-(hydroxymethyl)-2-(thiophen-3-yl)pyridine-4(1 HThe 29 mmol DCM solution of 6.0 g-ketone in 200 mL was mixed with 40 mL of thionyl chloride (0.55 mol). After 24 hours, the solvent was removed under vacuum and co-evaporated with MeCN to give the title compound (6.5 g, quantified), which was used directly in the next step without further purification.

[0386] Step 4: 6-((4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro [4.5] tert-butyl decane-9-carboxylate: To 5-(chloromethyl)-2-(thiophen-3-yl)pyridine-4(1 H DIPEA (3.6 g, 28 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (2.7 g, 11 mmol) were added to a MeCN (90 mL) solution of ketone (2.1 g, 9.3 mmol), and the suspension was stirred at 80°C. After 24 hours, the solvent was removed under vacuum, and the residue was partitioned and separated between DCM and brine. The organic phase was dried (Na2SO4), the solvent was removed under vacuum, and the residue was purified by rapid chromatography (0-5% MeOH / DCM) to give the title compound (1.9 g, 47%). LCMS (Method D): R T = 0.85min, m / z = 430 [M+H] + .

[0387] Step 5: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1H)- ketone: The title compound (46.0 mg, quantified) was prepared according to general procedure 1 using 6-((4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester (60 mg, 140 µmol), TFA (0.3 mL), and DCM (1.5 mL). LCMS (Method A): R T = 0.42 min, m / z = 330 [M+H] + .

[0388] Intermediate 30: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(1-methyl-1 H -pyrazole-5-yl) Pyridine-4(1) H )-ketone The title compound is similar to 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1 H It was prepared by the method of )-ketone (intermediate 29), but using 1-methyl-1 Hmethyl pyrazole-5-carboxylate was substituted for methyl thiophene-3-carboxylate to obtain the title compound (via 6-((6-(1-methyl-1-carboxylate)). H -pyrazol-5-yl)-4-oxo-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester). LCMS (Method A): R T = 0.34 min, m / z = 328 [M+H] + .

[0389] Intermediate 31: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-methyl-5-phenylpyridine-2 (1 H )-ketone The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H It was prepared by the method of )-ketone (intermediate 3), but using 3-(hydroxymethyl)-6-methyl-5-phenylpyridine-2(1 H )-ketones (prepared similarly to 3-(hydroxymethyl)-6-phenylpyridine-2(1 H )-ketone, but using 6-methyl-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxylic acid [commercially available] instead of 2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxylic acid) instead of 3-(hydroxymethyl)-6-phenylpyridine-2(1 H )-ketone, to obtain the title compound. LCMS (Method A): R T = 0.57 min, m / z = 338 [M+H] + .

[0390] Intermediate 32: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-2-yl)pyridine-4 (1 H )-ketone The title compound is similar to 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1 H The title compound was prepared via a methyl thiophene-2-carboxylate (intermediate 29), but using methyl thiophene-3-carboxylate instead of methyl thiophene-2-carboxylate. LCMS (Method A): R T = 0.43 min, m / z = 330 [M+H] + .

[0391] Intermediate 33: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H -pyrido[1,2- a Pyrimidine-4- ketone Step 1: 3-Bromo-4H-pyrido[1,2-a]pyrimidin-4-one: At room temperature, to 4 H -pyrido[1,2- a NBS (8.05 g, 45 mmol, 1.1 equivalents) was added in portions to a stirred solution of DCM (200 mL) containing pyrimidin-4-one (6.00 g, 41 mmol) [commercially available]. After 10 hours, 1 M sodium carbonate aqueous solution (150 mL) was added. After another 2 hours, the two-phase mixture was separated, the organic phase was dried (Na2SO4), and the solvent was removed under vacuum to give the title compound (6.2 g, 69%). 1 H NMR (400 MHz, CDCl3): δ 9.07 (d, 1H), 8.55 (s, 1H), 7.78 (t, 1H), 7.67 (d, 1H), 7.22 (t, 1H).

[0392] Step 2: 3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one: To 3-bromo-4 H -pyrido[1,2- a Tributyltin alkyl methanol (9.25 g, 29 mmol) and XPhos-Pd-G2 (1.62 g, 2.0 mmol) were added to a stirred solution of pyrimidin-4-one (4.40 g, 19 mmol) in 1,4-dioxane (250 mL). The reaction mixture was degassed and backfilled with argon, then heated to 100°C. After 48 hours, the solvent was removed under vacuum, and the residue was ground with diethyl ether (150 mL), filtered, and given the crude title compound (3.2 g, 68%). [Contamination present] 4 H-pyrido[1,2-] a [Pyrimidin-4-one]. LCMS (Method D): R T = 0.43 min, m / z = 177 [M+H] + .

[0393] Step 3: 3-(chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one: At 40°C, towards 3-(hydroxymethyl)-4 H -pyrido[1,2- a A solution of pyrimidin-4-one (3.0 g, 17 mmol) in DCM (200 mL) was mixed with thionyl chloride (40 mL, 0.55 mol). After 24 hours, the solvent was removed under vacuum, and co-evaporation with MeCN was performed to give the title compound (3.2 g, quantified), which was used directly in the next step without further purification.

[0394] Step 4: 6-((4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)methyl)-6,9-diazaspiro[4.5]decane tert-butyl alkyl-9-carboxylate: At 80°C, towards 3-(chloromethyl)-4 H -pyrido[1,2- a DIPEA (6.2 g, 48 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (3.4 g, 16 mmol) were added to a stirred solution of pyrimidin-4-one (3.0 g, 16 mmol) in MeCN (150 mL). After 18 hours, the solvent was removed under vacuum, and the residue was partitioned and separated between DCM and brine. The organic phase was dried (Na2SO4), the solvent was removed under vacuum, and the residue was purified by rapid chromatography (0–5% MeOH / DCM) to give the title compound (1.1 g, 27%). LCMS (Method D): R T = 0.81 min, m / z = 399 [M+H] + .

[0395] Step 5: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-one: According to general procedure 1, using 6-((4-oxo-4) H -pyrido[1,2- a The title compound (85.0 mg, 95%) was prepared by reacting tert-butyl pyrimidin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (120 mg, 300 µmol), TFA (0.7 mL), and DCM (1.5 mL). LCMS (Method A): R T = 0.41 min, m / z = 299 [M+H] + .

[0396] Intermediate 34: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-fluorophenyl)pyridine-4(1 H )- Ketone hydrochloride The title compound is similar to 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1 H The compound was prepared via a method involving 2-fluorobenzoate (intermediate 29), but with methyl 2-fluorobenzoate used instead of methyl thiophene-3-carboxylate in step 1, and with 1,4-dioxane / 1,4-dioxane in 4M HCl used instead of TFA / DCM in step 5, omitting SCX-2 purification, to obtain the title compound. LCMS (Method A): R T = 0.43 min,m / z = 342 [M+H] + .

[0397] Intermediate 35: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(o-tolyl)pyridine-4(1 H )- ketone The title compound is similar to 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1 H The compound was prepared by means of 2-methylbenzoate (intermediate 29), but methyl 2-methylbenzoate was used instead of methyl thiophene-3-carboxylate to obtain the title compound.

[0398] LCMS (Method A): R T = 0.45 min, m / z = 338 [M+H] + .

[0399] Intermediate 36: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-methoxyphenyl)pyridine-4 (1 H )-Keto hydrochloride The title compound is similar to 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1 H The compound was prepared by means of 2-methyl 2-methoxybenzoate instead of methyl thiophene-3-carboxylate in step 1, and in step 5, 1,4-dioxane / 1,4-dioxane in 4M HCl was used instead of TFA / DCM and SCX-2 purification was omitted to obtain the title compound.

[0400] LCMS (Method A): R T = 0.55 min, m / z = 354 [M+H] + [Note: In step 4, a 2:1 mixture of 6-((6-(2-methoxyphenyl)-4-oxo-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester / 6-((6-(2-hydroxyphenyl)-4-oxo-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester was obtained, which required RP preparative HPLC purification.]

[0401] Intermediate 37: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H 4-chromene hydrochloride Step 1: 3-(hydroxymethyl)-4H-chromen-4-one: At 0°C, towards 4-oxo-4 H NaBH(OAc)3 (1.80 g, 8.61 mmol) was added to a stirred solution of 12 mL of DCM containing chromene-3-carboxaldehyde (500 mg, 2.87 mmol) [commercially available], and the resulting mixture was warmed to room temperature. After 16 hours, the reaction mixture was diluted with water and extracted with DCM (2 x 100 mL). The combined organic phases were washed with brine (100 mL), dried (Na2SO4), the solvent was removed under vacuum, and the remaining residue was purified by rapid chromatography (0-50% EtOAc / hexane) to give the title compound (300 mg, 59%). LCMS (Method E): R T = 2.07 min, m / z = 177 [M+H] + .

[0402] Step 2: 3-(chloromethyl)-4H-chromene-4-one: At 0°C, towards 3-(hydroxymethyl)-4 H SOCl2 (1.2 mL, 17.0 mmol) was added dropwise to a stirred solution of 1.00 g (5.67 mmol) of 4-chromone-4-one in 20 mL of DCM, and the resulting mixture was warmed to room temperature. After 3 hours, the reaction mixture was diluted with water and extracted with DCM (2 x 200 mL). The combined organic phases were washed with brine (200 mL), dried (Na2SO4), and the solvent was removed under vacuum to give the title compound (640 mg, 58%), which was used in the next step without further purification. LCMS (Method E): R T = 2.93 min, m / z = 195[M+H] + .

[0403] Step 3: 6-((4-oxo-4H-chromene-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester: At room temperature, towards 3-(chloromethyl)-4 H To a stirred solution of 20 mL of MeCN containing chromone-4-one (640 mg, 3.28 mmol), tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (869 mg, 3.61 mmol) was added, followed by Cs₂CO₃ (2.10 g, 6.57 mmol). The reaction mixture was heated to 90°C. After 3 hours, the reaction mixture was passed through a Celite tube. ®The filtrate was filtered, evaporated under reduced pressure, and the remaining residue was purified by rapid chromatography (0-30% EtOAc / hexane) to give the title compound (900 mg, 69%). LCMS (Method E): R T = 10.22 min, m / z = 399 [M+H] + .

[0404] Step 4: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-chromene-4-one hydrochloride: According to general procedure 1, using 6-((4-oxo-4) H The title compound (50 mg, 99%) was prepared by tert-butyl decane-9-carboxylate (60.0 mg, 151 µmol), 1,4-dioxane (0.38 mL) in 4 M HCl, and 1,4-dioxane (1 mL), omitting SCX-2 purification. LCMS (Method A): R T = 0.56 min, m / z = 299 [M+H] + .

[0405] Intermediate 38: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-4 H 4-chromene hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H It was prepared via the method of chromene-4-one hydrochloride (intermediate 37), but using 6-fluoro-4-oxo-4-one hydrochloride. H -chrome-3-formaldehyde replaced by 4-oxo-4 H -chromene-3-carboxaldehyde, to obtain the title compound. LCMS (Method A): R T = 0.62 min, m / z = 317 [M+H] + .

[0406] Intermediate 39: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2,3-dihydrobenzofuran-7- pyridine-4(1) H )-Keto hydrochloride The title compound is similar to 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1 HThe title compound was prepared via a method involving methyl 2,3-dihydrobenzofuran-7-carboxylate (intermediate 29), but in step 1, methyl 2,3-dihydrobenzofuran-7-carboxylate was used instead of methyl thiophene-3-carboxylate, and in step 5, 1,4-dioxane / 1,4-dioxane in 4M HCl was used instead of TFA / DCM, and SCX-2 purification was omitted. LCMS (Method A): R T = 0.59 min, m / z = 366 [M+H] + .

[0407] Intermediate 40: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(1-methyl-1 H -pyrazole-3-yl) Pyridine-4(1) H )-ketone The title compound is similar to 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1 H It was prepared by the method of )-ketone (intermediate 29), but using 1-methyl-1 H Methyl pyrazole-3-carboxylate was substituted for methyl thiophene-3-carboxylate to obtain the title compound. LCMS (Method A): R T = 0.38 min, m / z = 328 [M+H] + .

[0408] Intermediate 41: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-cyclopropyl-2-methylpyridine-4 (1 H )-Keto hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H It was prepared by the method of )-ketone (intermediate 3), but using 1-cyclopropyl-5-(hydroxymethyl)-2-methylpyridine-4 (1 H )-ketones (prepared similarly to 3-(hydroxymethyl)-6-phenylpyridine-2(1 H )-ketone, but using 1-cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid [commercially available] instead of 2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxylic acid) instead of 3-(hydroxymethyl)-6-phenylpyridine-2(1 H The title compound was obtained by using 1,4-dioxane / 1,4-dioxane in 4M HCl instead of TFA / DCM and omitting SCX-2 purification in the final step. LCMS (Method A): R T = 0.34 min, m / z = 302 [M+H] + .

[0409] Intermediate 42: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-5,6-dimethylpyridine-2(1 H )-ketone hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H It was prepared by the method of )-ketone (intermediate 3), but using 3-(hydroxymethyl)-5,6-dimethylpyridine-2(1 H )-ketones (prepared similarly to 3-(hydroxymethyl)-6-phenylpyridine-2(1 H )-ketone, but using 5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid [commercially available] instead of 2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxylic acid) instead of 3-(hydroxymethyl)-6-phenylpyridine-2(1 H The title compound was obtained by using 1,4-dioxane / 1,4-dioxane in 4M HCl instead of TFA / DCM and omitting SCX-2 purification in the final step. LCMS (Method A): R T = 0.36 min, m / z = 276[M+H] + .

[0410] Intermediate 43: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H -pyrimidin[1,2- b ]Dyridazine-4- Ketone hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H Prepared via 3-(hydroxymethyl)-4-one (intermediate 3), but using 3-(hydroxymethyl)-4-one. H -pyrimidin[1,2- b ] Pyridazin-4-one (preparation similar to 3-(hydroxymethyl)-6-phenylpyridine-2(1 H )-ketone, but using 4-oxo-4 H -pyrimidin[1,2- b [Pyridazine-3-carboxylic acid [commercially available] replacing 2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxylic acid] replacing 3-(hydroxymethyl)-6-phenylpyridine-2(1 H The title compound was obtained by using 1,4-dioxane / DCM in 4M HCl instead of TFA / DCM and omitting SCX-2 purification in the final step. LCMS (Method A): RT = 0.35 min, m / z = 300 [M+H] + .

[0411] Intermediate 44: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoroquinoline-4(1 H )-Keto hydrochloride Step 1: 6-Fluoro-3-(hydroxymethyl)quinoline-4(1H)-one: At room temperature, a 2M solution of LiAlH4 in THF (3.2 mL, 6.4 mmol) was added to a stirred solution of ethyl 6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.5 g, 6.38 mmol) [commercially available] in dimethoxyethane (45 mL). The reaction mixture was heated to 75°C. After 2 hours, the reaction mixture was cooled and rinsed with saturated Na2SO4. 4(aq) Quench the solution (50 mL) and use Celite ® Filtration. Extract the filtrate with 3:2 EtOAc / THF (2 x 50 mL). Dry the combined organic phases (Na2SO4) and remove the solvent under vacuum to give the title compound (640 mg, 52%). LCMS (Method E): R T = 1.52 min, m / z = 194 [M+H] + .

[0412] Step 2: 3-(chloromethyl)-6-fluoroquinoline-4(1H)-one: At 0°C, 6-fluoro-3-(hydroxymethyl)quinoline-4(1 H SOCl2 (0.11 mL, 1.55 mmol) was added to a stirred solution of 100 mg (0.52 mmol) of ketone in DCM (6 mL). The reaction mixture was heated to 50°C. After 16 hours, the solvent was removed under vacuum to give the title compound (101 mg, 92%). 1 H NMR (400 MHz, DMSO- d 6): δ 12.21 (s, 1H), 8.29-8.27 (m, 1H), 7.79-7.76 (m, 1H), 7.64-7.59 (m, 2H), 4.66 (s, 2H).

[0413] Step 3: 6-((6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl)methyl)-6,9-diazaspiro[4.5]decane- 9-Tert-butyl formate: At room temperature, 3-(chloromethyl)-6-fluoroquinoline-4(1 H6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester (647 mg, 2.96 mmol) and Cs₂CO₃ (1.17 g, 3.59 mmol) were added to a stirred solution of 6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester (647 mg, 2.96 mmol) and 1.17 g, 3.59 mmol. After 2 hours, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine (50 mL), dried (Na₂SO₄), the solvent was removed under vacuum, and the remaining residue was purified by rapid chromatography (0-30% EtOAc / hexane) followed by preparative HPLC by RP to give the title compound (80 mg, 11%). LCMS (Method E): R T = 2.50 min, m / z = 416 [M+H]+.

[0414] Step 4: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoroquinoline-4(1H)-one hydrochloride: The title compound (49 mg, quantified) was prepared according to General Procedure 1 using tert-butyl 6-((6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (58 mg, 140 µmol), 1,4-dioxane in 4M HCl (0.42 mL), and DCM (1.0 mL), but without the need for SCX-2 purification. LCMS (Method A): R T = 0.41min, m / z = 316 [M+H] + .

[0415] Intermediate 45: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-hydroxyphenyl)pyridine-4 (1 H )-Keto hydrochloride 6-((6-(2-hydroxyphenyl)-4-oxo-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester (50 mg, 114 µmol) [obtained as a byproduct in the preparation of 6-((6-(2-methoxyphenyl)-4-oxo-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-methoxyphenyl)pyridin-4(1 H Step 4 in the synthesis procedure of )-keto hydrochloride (intermediate 36) is performed according to general procedure 1. N-Boc deprotection was performed using 1,4-dioxane (0.43 mL) and 1,4-dioxane (1 mL) in 4 M HCl, but without SCX-2, to give the title compound (42 mg, 98%). LCMS (Method A): R T = 0.45 min, m / z = 340 [M+H] + .

[0416] Intermediate 46: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-methyl-2-propylpyridine-4 (1 H )-ketone The title compound is similar to 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1 H The compound was prepared via a method involving ketone (intermediate 29), but step 1 was omitted, and in step 2, methyl 6-methyl-4-oxo-2-propyl-1,4-dihydropyridine-3-carboxylate [commercially available] was used instead of methyl 4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridine-3-carboxylate to obtain the title compound. LCMS (Method A): R T = 0.40 min, m / z = 304 [M+H] + .

[0417] Intermediate 47: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]pyrethrum 4-Pyridine-keto hydrochloride Step 1: 3-Bromo-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one: At room temperature, to 7-fluoro-4 H -pyrido[1,2- a NBS (5.37 g, 30 mmol) was added in portions to a stirred solution of DCM (120 mL) containing pyrimidin-4-one (4.50 g, 27 mmol) [commercially available]. After 10 hours, 1 M sodium carbonate aqueous solution (150 mL) was added. After another 2 hours, the two-phase mixture was separated, the organic phase was dried (Na2SO4), and the solvent was removed under vacuum to give the title compound (4.9 g, 75%). 1 HNMR (400 MHz, CDCl3): δ 8.98 (m, 1H), 8.67 (s, 1H), 8.15 (m, 1H), 7.86 (m,1H).

[0418] Step 2: 3-Hydroxymethyl-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one: To 3-bromo-7-fluoro-4 H -pyrido[1,2-a In a stirred solution of pyrimidin-4-one (4.40 g, 18 mmol) in 1,4-dioxane (250 mL), (tributyltin-alkyl)methanol (9.25 g, 29 mmol) and XPhos-Pd-G2 (1.62 g, 2.0 mmol) were added. The reaction mixture was degassed and backfilled with argon, then heated to 100°C. After 48 hours, the solvent was removed under vacuum, and the residue was ground with diethyl ether (150 mL), filtered, to give the crude title compound (3.2 g crude, obtained by...). 1 ¹H NMR analysis confirmed it to be a 1:2 mixture containing 7-fluoro-4 H -pyrido[1,2- a [Pyrimidin-4-one], which is used in the next step and requires no further purification. LCMS (Method D): R T = 0.51 min, m / z = 195 [M+H] + .

[0419] Step 3: 3-Chloromethyl-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one: At 40°C, 3-hydroxymethyl-7-fluoro-4 H -pyrido[1,2- a Pyrimidine-4-one [Contamination with 7-fluoro-4] H -pyrido[1,2- a [Pyrimidin-4-one] (3.2 g crude, assumed 6 mmol) was added to a stirred solution of DCM (200 mL) with thionyl chloride (40 mL, 0.55 mol). After 24 hours, the solvent was removed under vacuum, and co-evaporation with MeCN was performed to give the crude title compound (3.2 g crude), which was used directly in the next step without further purification.

[0420] Step 4: 6-((7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)methyl)-6,9-diazaspiro [4.5] tert-butyl decane-9-carboxylate: At 80°C, 3-chloromethyl-7-fluoro-4 H -pyrido[1,2- a DIPEA (2.3 g, 18 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (1.28 g, 6 mmol) were added to a stirred solution of pyrimidin-4-one (3.0 g, assumed 6 mmol) in MeCN (150 mL). After 18 hours, the solvent was removed under vacuum, the residue was partitioned between DCM and brine, and the resulting two-phase mixture was separated. The organic phase was dried (Na2SO4), the solvent was removed under vacuum, and the remaining residue was purified by preparative HPLC (RP) to give the title compound (0.5 g, 7% in 3 steps). LCMS (Method D): R T=0.81 min, m / z = 417 [M+H] + .

[0421] Step 5: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine- 4-Keto hydrochloride: According to general procedure 1, using 6-((7-fluoro-4-oxo-4) H -pyrido[1,2- a The title compound (51 mg, 97%) was prepared by reacting tert-butyl pyrimidin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (60 mg, 144 µmol), 1,4-dioxane (0.36 mL) and 1,4-dioxane (2 mL) in 4 M HCl, without the need for SCX-2 purification. LCMS (Method A): R T = 0.45 min, m / z = 317 [M+H] + .

[0422] Intermediate 48: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-5-(trifluoromethyl)pyridine-2(1 H )- Ketone hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H Prepared via 3-(hydroxymethyl)-5-(trifluoromethyl)pyridine-2(1)-ketone (intermediate 3), but using 3-(hydroxymethyl)-5-(trifluoromethyl)pyridine-2(1) H )-ketones (prepared similarly to 3-(hydroxymethyl)-6-phenylpyridine-2(1 H )-ketone, but using 2-oxo-5-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid [commercially available] instead of 2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxylic acid) instead of 3-(hydroxymethyl)-6-phenylpyridine-2(1 H The title compound was obtained by using 1,4-dioxane / 1,4-dioxane in 4M HCl instead of TFA / DCM and omitting SCX-2 purification in the final step. LCMS (Method A): R T = 0.50 min, m / z =316 [M+H] + .

[0423] Intermediate 49: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(4-fluorophenyl)pyridine-4(1 H )- Ketone hydrochloride The title compound is similar to 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1 H The compound was prepared via a method involving methyl 4-fluorobenzoate (intermediate 29), but in step 1, methyl 4-fluorobenzoate was used instead of methyl thiophene-3-carboxylate, and in step 5, 1,4-dioxane / 1,4-dioxane in 4M HCl was used instead of TFA / DCM, and SCX-2 purification was omitted to obtain the title compound. LCMS (Method A): R T = 0.45 min, m / z = 342 [M+H] + .

[0424] Intermediate 50: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(3-fluorophenyl)pyridine-4(1 H )- Ketone hydrochloride The title compound is similar to 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1 H The title compound was prepared via a method involving methyl 3-fluorobenzoate (intermediate 29), but with methyl 3-fluorobenzoate used instead of methyl thiophene-3-carboxylate in step 1, and with 1,4-dioxane / 1,4-dioxane in 4M HCl used instead of TFA / DCM in step 5, omitting SCX-2 purification. LCMS (Method A): R T = 0.45 min, m / z = 342 [M+H] + .

[0425] Intermediate 51: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-( m-Tolyl )Pyridine-4(1 H )- Ketone hydrochloride The title compound is similar to 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1 H The compound was prepared via a method involving methyl 3-methylbenzoate (intermediate 29), but in step 1, methyl 3-methylbenzoate was used instead of methyl thiophene-3-carboxylate, and in step 5, 1,4-dioxane / 1,4-dioxane in 4M HCl was used instead of TFA / DCM, and SCX-2 purification was omitted to obtain the title compound. LCMS (Method A): R T = 0.49 min, m / z = 338 [M+H] + .

[0426] Intermediate 52: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-( m-Tolyl )Pyridine-2(1 H )- Ketone hydrochloride Step 1: 2-O-6-(m-Tolyl)-1,2-Dihydropyridine-3-carboxylic acid: To a solution of 6-bromo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (3.3 g, 15 mmol) in 1,4-dioxane (150 mL) and water (50 mL), m-tolylboronic acid (2.3 g, 16.5 mmol), Pd(dppf)Cl₂ (0.62 g, 0.8 mmol), and sodium carbonate (4.8 g, 45.6 mmol) were added. The reaction mixture was degassed and backfilled with argon, then heated to reflux. After 24 hours, the solvent was evaporated. The remaining residue was dissolved in hot water (200 mL), filtered, and acidified to ~pH 3 with aqueous hydrochloric acid. The resulting precipitate was filtered, washed with water, and dried under vacuum to give the title compound (3.0 g, 86%) as a gray solid. LCMS (Method D): R T =0.87 min, m / z = 230 [M+H] + .

[0427] Step 2: 3-(hydroxymethyl)-6-(m-tolyl)pyridine-2(1H)-one: At room temperature, to 2-oxo-6-( between Tolyl A 1 M borane DMS complex solution of 1 M 1,2-dihydropyridine-3-carboxylic acid (2.9 g, 12.6 mmol) in THF (120 mL) was added to a stirred solution of 1,2-dihydropyridine-3-carboxylic acid (2.9 g, 12.6 mmol) in THF (120 mL). After 18 hours, MeOH was slowly added until gas expulsion ceased. The resulting solution was partitioned between EtOAc and brine, separated, and the organic phase was dried (Na₂SO₄) and the solvent was removed under vacuum. The remaining residue was purified by rapid chromatography (0–5% MeOH / DCM) to give the title compound (2.6 g, 96%) as a pale yellow solid, which was used directly in the next step. LCMS (Method D): R T = 1.03 min, m / z = 216 [M+H] + .

[0428] Step 3: 3-(chloromethyl)-6-(m-tolyl)pyridine-2(1H)-one: To 3-(hydroxymethyl)-6-( m-Toluene base )Pyridine-2(1 HA solution of 2.5 g (11.6 mmol) of thionyl chloride (20 mL, 0.278 mol) in DCM (100 mL) was added, and the suspension was stirred at 40°C. After 24 hours, the solvent was removed under vacuum, the residue was dissolved in MeCN and re-evaporated to give the title compound (2.5 g, 92%) as a brown solid, which was used directly in the next step without further purification.

[0429] Step 4: 6-((2-oxo-6-(m-tolyl)-1,2-dihydropyridin-3-yl)methyl)-6,9-diazaspiro [4.5] tert-butyl decane-9-carboxylate: To 3-(chloromethyl)-6-( m-Tolyl )Pyridine-2(1 H DIPEA (3.9 g, 30 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (2.4 g, 10 mmol) were added to a MeCN (100 mL) solution of ketone (2.4 g, 10 mmol). The resulting suspension was stirred at 80°C. After 18 hours, the reaction mixture was evaporated, partitioned between DCM and brine, separated, the organic phase was dried (Na2SO4), and the solvent was removed under vacuum. The remaining residue was purified by rapid chromatography (0–5% MeOH / DCM) to give the title compound (1.2 g, 27%) as a pale yellow solid. LCMS (Method D): R T = 1.00 min, m / z = 438 [M+H] + .

[0430] Step 5: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(m-tolyl)pyridin-2(1H)-one Hydrochloride: According to general procedure 1, using 6-((2-oxo-6-( m-Tolyl The title compound (51 mg, 99%) was prepared by reacting tert-butyl 1,2-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (60 mg, 137 µmol), 1,4-dioxane (0.411 mL) in 4 M HCl, and DCM (1.0 mL) without SCX-2 purification. LCMS (Method A): R T = 0.59 min, m / z = 338 [M+H] + .

[0431] Intermediate 53: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(3-fluorophenyl)pyridine-2(1 H )- Ketone hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(m-tolyl)pyridine-2(1 H The title compound was prepared via )-ketohydrochloride (intermediate 52), but in step 1, 3-fluorophenylboronic acid was used instead of m-tolylboronic acid to obtain the title compound. LCMS (Method A): R T = 0.54 min, m / z = 342 [M+H] + .

[0432] Intermediate 54: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(4-fluorophenyl)pyridine-2(1 H )- Ketone hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(m-tolyl)pyridine-2(1 H The title compound was prepared via )-ketohydrochloride (intermediate 52), but in step 1, 4-fluorophenylboronic acid was used instead of m-tolylboronic acid to obtain the title compound. LCMS (Method A): R T = 0.53 min, m / z = 342 [M+H] + .

[0433] Intermediate 55: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(methylthio)-6-oxo-1,6- Dihydropyridine-3-carboxynitrile hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H It is prepared by the method of 5-(hydroxymethyl)-2-(methylthio)-6-oxo-1,6-dihydropyridine-3-carboxynitrile (prepared similarly to 3-(hydroxymethyl)-6-phenylpyridine-2(1-ethylhexyl)-ketone (intermediate 3), but using 5-(hydroxymethyl)-2-(methylthio)-6-oxo-1,6-dihydropyridine-3-carboxynitrile (prepared similarly to 3-(hydroxymethyl)-6-phenylpyridine-2- ... H )-ketone, but using 5-cyano-6-(methylthio)-2-oxo-1,2-dihydropyridine-3-carboxylic acid [commercially available] instead of 2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxylic acid) instead of 3-(hydroxymethyl)-6-phenylpyridine-2(1 H The title compound was obtained by using 1,4-dioxane / 1,4-dioxane in 4M HCl instead of TFA / DCM and omitting SCX-2 purification in the final step. LCMS (Method A): R T =0.54 min, m / z = 319 [M+H]+ .

[0434] Intermediate 56: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyrimidine-4(3) H )-Ketohydrochloric acid Salt The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H It was prepared by the method of 5-(hydroxymethyl)-2-phenylpyrimidine-4(3-)-one (intermediate 3), but using 5-(hydroxymethyl)-2-phenylpyrimidine-4(3-)-one (intermediate 3). H )-ketones (prepared similarly to 3-(hydroxymethyl)-6-phenylpyridine-2(1 H )-ketone, but using 6-oxo-2-phenyl-1,6-dihydropyrimidin-5-carboxylic acid [commercially available] instead of 2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxylic acid) instead of 3-(hydroxymethyl)-6-phenylpyridine-2(1 H The title compound was obtained by using 1,4-dioxane / DCM in 4M HCl instead of TFA / DCM and omitting SCX-2 purification in the final step. LCMS (Method A): R T = 0.49 min, m / z = 325 [M+H] + .

[0435] Intermediate 57: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1,7-naphthidium-4(1H)-one hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H -pyrido[1,2- a It is prepared by means of pyrimidin-4-one (intermediate 33), but 1,7-naphthidine-4 (1 H )-Ketone [commercially available] as a substitute for 4 H -pyrido[1,2- a The title compound was obtained by using 1,4-dioxane / 1,4-dioxane in 4M HCl instead of TFA / DCM and omitting SCX-2 purification in the final step. LCMS (Method C): R T = 0.32min, m / z = 299 [M+H] + .

[0436] Intermediate 58: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2,6-dimethylpyridine-4(1 H )-ketone hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H -pyrido[1,2- a It is prepared by means of pyrimidin-4-one (intermediate 33), but 2,6-dimethylpyridine-4 (1) is used in step 1. H )-Ketone [commercially available] as a substitute for 4 H -pyrido[1,2- a The title compound was obtained by using 1,4-dioxane / DCM in 4M HCl instead of TFA / DCM and omitting SCX-2 purification in the final step. LCMS (Method A): R T = 0.24 min, m / z = 276 [M+H] + .

[0437] Intermediate 59: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(thiophen-3-yl)pyridine Pyridine-4(1) H )-Keto hydrochloride Step 1: 6-((1-methyl-4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridin-3-yl)methyl)-6,9-di tert-butyl zeolite of zeolite[4.5]decane-9-carboxylate: Under argon atmosphere, mineral oil (56 mg, 1.3 mmol) of 55% sodium hydride was added to a DMF (2 mL) solution of 6-((4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester (429 mg, 1 mmol) and the solution was stirred at room temperature. After 1 hour, iodomethane (184 mg, 1.3 mmol) was added and the solution was stirred at room temperature. After 14 hours, the solvent was removed under vacuum, the remaining residue was partitioned between DCM and brine, separated, and the organic phase was dried (Na2SO4). The solvent was removed under vacuum, and the remaining residue was purified by preparative HPLC to give the title compound (0.2 g, 48%) as a white solid. LCMS (Method D): R T = 1.05 min, m / z =444 [M+H] + .

[0438] Step 2: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(thiophen-3-yl)pyridine-4 (1H)-Keto hydrochloride:According to General Procedure 1, the title compound (42 mg, 98%) was prepared using tert-butyl 6-((1-methyl-4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (50 mg, 113 µmol), 1,4-dioxane in 4 M HCl (0.338 mL), and DCM (1.0 mL), without the need for SCX-2 purification. LCMS (Method A): R T = 0.42 min, m / z = 344 [M+H] + .

[0439] Intermediate 60: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(2-methoxyphenyl)pyridine-2 (1 H )-Keto hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(m-tolyl)pyridine-2(1 H The title compound was prepared by means of )-ketohydrochloride (intermediate 52), but in step 1, 2-methoxyphenylboronic acid [commercially available] was used instead of m-tolylboronic acid, and in step 5, 1,4-dioxane / 1,4-dioxane in 4M HCl was used instead of TFA / DCM, and SCX-2 purification was omitted to obtain the title compound. LCMS (Method A): R T = 0.55 min, m / z =354 [M+H] + .

[0440] Intermediate 61: 3-((2,2-dimethylpiperazin-1-yl)methyl)-6-(1-methyl-1 H -pyrazole-5-yl)pyridine-2 (1 H )-Keto hydrochloride Step 1: 4-((6-chloro-2-(2-(trimethylsilyl)ethoxy)pyridin-3-yl)methyl)-3,3-dimethyl Piperazine-1-carboxylic acid tert-butyl ester:At 0°C under a nitrogen atmosphere, triethylamine (167 µL, 1.20 mmol) and methanesulfonyl chloride (85.7 µL, 1.10 mmol) were added sequentially to a stirred solution of (6-chloro-2-(2-(trimethylsilyl)ethoxy)pyridin-3-yl)methanol (260 mg, 1.00 mmol) [prepared according to WO2018195321] in DCM (10 mL). After stirring at 0°C for 30 min, the ice bath was removed, and the reaction mixture was stirred at room temperature for 3 h. The reaction was cooled to 0°C, and then another 167 μL, 1.20 mmol, and methanesulfonyl chloride (85.7 μL, 1.10 mmol) were added sequentially. After stirring at 0°C for 30 min, the ice bath was removed, and the reaction mixture was stirred at room temperature for 19 h. The reaction mixture was cooled to 0°C, and then triethylamine (167 μL, 1.20 mmol) and methanesulfonyl chloride (85.7 μL, 1.10 mmol) were added sequentially. After stirring at 0°C for 30 minutes, the ice bath was removed, and the reaction mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was separated sequentially using water (10 mL) and 1M NaOH using a phase separator. (aq) Wash with solution (10 mL) and brine (10 mL). The organic layer was concentrated under reduced pressure, and then MeCN (1 mL), tert-butyl 3,3-dimethylpiperazine-1-carboxylate (236 mg, 1.10 mmol), and DIPEA (227 μL, 1.30 mmol) were added. After stirring the resulting suspension at room temperature for 4 days, the temperature was raised to 40°C to obtain a solution, which was stirred at 40°C for another 2 days. After cooling to room temperature, water (15 mL) was added, and the resulting mixture was extracted with DCM (3 × 10 mL) using a phase separator. The combined organic phases were concentrated under reduced pressure, and the residue was purified by rapid chromatography to give the title compound (322 mg, 70%) as a colorless oil. LCMS (Method A): R T = 1.26 min, m / z = 456, 457 [M+H] + .

[0441] Step 2: 3,3-Dimethyl-4-((6-(1-methyl-1H-pyrazole-5-yl)-2-(2-(trimethylsilyl)ethyl) tert-butyl pyridin-3-yl)methyl)piperazine-1-carboxylate: The container, containing 96.6 mg (0.212 mmol) of 4-((6-chloro-2-(2-(trimethylsilyl)ethoxy)pyridin-3-yl)methyl)-3,3-dimethylpiperazine-1-carboxylic acid tert-butyl ester and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-methylpiperazine-1-carboxylic acid tert-butyl ester, was sealed three times by vacuuming and refilling with nitrogen. H-Pyrazole (88.1 mg, 0.424 mmol), potassium phosphate (135 mg, 0.635 mmol), Pd(dppf)Cl2.DCM (9 mg, 0.0106 mmol), 1,4-dioxane (1.5 mL) and water (0.5 mL) were degassed in sealed 2-5 mL microwave tubes. The reaction mixture was heated at 120°C for 30 min under microwave irradiation. After cooling to room temperature, the reaction mixture was poured into a mixture of brine (20 mL) and water (40 mL), and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried (phase separator) and concentrated under reduced pressure. The residues were purified by rapid chromatography to give the title compound (91.3 mg, 85%). LCMS (Method A): R T = 1.15 min, m / z = 502 [M+H] + .

[0442] Step 3: 3-((2,2-dimethylpiperazin-1-yl)methyl)-6-(1-methyl-1H-pyrazole-5-yl)pyridine-2 (1H)-Keto hydrochloride : 3,3-Dimethyl-4-((6-(1-methyl-1) H A mixture of tert-butyl pyrazol-5-yl)-2-(2-(trimethylsilyl)ethoxy)pyridin-3-yl)methyl)piperazine-1-carboxylate (91.3 mg, 0.182 mmol), 1,4-dioxane in 4 M HCl (908 µL, 3.63 mmol), and DCM (1.8 mL) was stirred at room temperature for 16 hours. The resulting suspension was filtered, and the solid was washed with DCM (3 x 2 mL) and dried in a vacuum oven at 50°C to give the title compound (56 mg, 82%) as a yellow solid. LCMS (Method A): R T = 0.33 min, m / z = 302 [M+H] + .

[0443] Intermediate 62: (1 S ,2 R 5 R )-2-(2,5-difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane Step 1: (R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)dihydrofuran-2(3H)-one: At 0°C, towards ( R )-5-(hydroxymethyl)dihydrofuran-2(3 Htert-butylchlorodiphenylsilane (2.91 mL, 11.2 mmol) was added to a stirred solution of 10 mL of DMF containing 1.00 g (8.61 mmol) of ketone (1.17 g, 17.2 mmol) and imidazole (1.17 g, 17.2 mmol). The reaction mixture was warmed to room temperature. After 16 hours, EtOAc (50 mL) was added, and the resulting mixture was washed with 1:1 brine / water (3 × 50 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure. The remaining residue was purified by rapid chromatography to give the title compound (2.74 g, 89%). LCMS (Method A): R T = 1.70 min, m / z = 277 [M-Ph] + . 1 H NMR (500 MHz, CDCl3): δ 7.70-7.61 (m, 4H), 7.48-7.34 (m, 6H), 4.66-4.56 (m, 1H), 3.88 (dd, 1H), 3.69 (dd, 1H), 2.67 (ddd, 1H), 2.51 (ddd, 1H), 2.37-2.15 (m,2H), 1.06 (s, 9H).

[0444] Step 2: (5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-ol: At -78°C under nitrogen atmosphere, towards ( R )-5-(((tert-butyldiphenylsilyl)oxy)methyl)dihydrofuran-2(3 H A solution of 1 M diisobutylaluminum hydride in DCM (11.6 mL, 11.6 mmol) was added to a stirred solution of 2.74 g (7.72 mmol) of ketone in 40 mL of diethyl ether. After incubation at -78°C for 5 hours, the reaction mixture was quenched by adding 5 mL of MeOH. After another 15 minutes at -78°C, the reaction mixture was warmed to room temperature, diluted with 150 mL of diethyl ether, and quenched with 0.2 M sodium tartrate. (aq) Wash with solution (3 × 100 mL) and brine. Dry the organic phase (MgSO4), filter, and concentrate under reduced pressure to give the title compound (2.75 g, quantitative). LCMS (Method A): R T = 1.69 min, m / z = 339 [M-OH] + .

[0445] Step 3: (R)-tert-butyl((2,3-dihydrofuran-2-yl)methoxy)diphenylsilane: At -50°C under nitrogen atmosphere, towards (5 RMethanesulfonyl chloride (748 µL, 9.64 mmol) was added to a stirred solution of 50 mL of DCM containing 2.75 g (7.71 mmol) of tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-ol (4.09 mL, 29.3 mmol) and triethylamine (50 mL). After incubation at -50°C for 3 hours, the reaction mixture was warmed to room temperature and then stirred under reflux for another 18 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the remaining residue was purified by rapid chromatography to give the title compound (1.37 g, 52%). 1 H NMR (500 MHz, CDCl3): δ 7.74-7.65 (m, 4H), 7.45-7.34 (m,6H), 6.27 (q, 1H), 4.85 (q, 1H), 4.71-4.58 (m, 1H), 3.75 (dd, 1H), 3.68 (dd,1H), 2.64 (ddt, 1H), 2.47 (ddt, 1H), 1.06 (s, 9H).

[0446] Step 4: (R)-(2,3-dihydrofuran-2-yl)methyl 4-methylbenzenesulfonate: Towards( R )- tert-butyl ((2,3-dihydrofuran-2-yl)methoxy)diphenylsilane (1.37 g, 4.05 mmol) was added to a 1 M TBAF solution in THF (4.05 mL, 4.05 mmol), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (25 mL) and cooled to 0°C, and then triethylamine (5.64 mL, 40.5 mmol) and 4-methylbenzenesulfonyl chloride (3.86 g, 20.3 mmol) were added. The reaction mixture was stirred for 19 hours and warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in EtOAc (50 mL) and washed with 1:1 brine / water (2 × 50 mL). The organic layer was dried (MgSO4), filtered, concentrated under reduced pressure, and the remaining residue was purified by rapid chromatography to give the title compound (858 mg, 83%). LCMS (Method B): R T = 1.40 min, m / z = 255 [M+H] + .

[0447] Step 5: (R)-2-((2,3-dihydrofuran-2-yl)methyl)isoindoline-1,3-dione At 75°C, under nitrogen atmosphere, ( RA mixture of (2,3-dihydrofuran-2-yl)methyl4-methylbenzenesulfonate (858 mg, 3.74 mmol) and 1,3-dioxoisoindoline-2-potassium (937 mg, 5.06 mmol) in DMF (13 mL) was stirred for 19 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (50 mL) and washed with 1:1 brine / water (3 × 50 mL). The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The remaining residue was purified by rapid chromatography to give the title compound (623 mg, 80%). LCMS (Method A): R T = 1.10 min, m / z = 230 [M+H] + .

[0448] Step 6: (R)-(2,3-dihydrofuran-2-yl)methylamine: Towards( R Hydrazine monohydrate (250 μL, 8.1 mmol) was added to MeOH (5.5 mL) containing 310 mg (1.35 mmol) of 2-((2,3-dihydrofuran-2-yl)methyl)isoindoline-1,3-dione, and the resulting mixture was heated at 60°C for 2 hours. After cooling to room temperature, 2M sodium hydroxide was added. (aq) The solution (10 mL) was extracted with DCM (3 × 20 mL). The combined phases were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure (41°C, 220 mbar) to give the title compound (140 mg, crude), which was used in the next step without purification.

[0449] Step 7: (1S,2R,5R)-2-(2,5-difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane: At room temperature, to the crude product ( R3 Å molecular sieves (300 mg) were added to DCM (1.4 mL) containing 2,5-difluorobenzaldehyde (192 mg, 1.35 mmol) and (134 mg, 1.35 mmol). After 16 hours, the reaction mixture was filtered (using a syringe filter), and the volatiles were evaporated under reduced pressure (40°C, 210 mbar). The resulting crude imine was transferred to a 20 mL microwave-safe bottle and dissolved in 2-propanol (13 mL). Mn(dpm)3 (40.9 mg, 0.068 mmol) was added and the bottle was sealed. PhSiH3 (0.33 mL, 2.71 mmol) was added, and the reaction was heated at 85°C for 5 hours. Due to incomplete reaction, additional PhSiH3 (0.33 mL, 2.71 mmol) was added, and the reaction was continued at 85°C for 16 hours. Since the reaction was incomplete, additional PhSiH3 (0.33 mL, 2.71 mmol) was added, and the reaction was continued at 85°C for 4 hours. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The remaining residue was purified by rapid chromatography (20–100% EtOAc / cyclohexane) to give the title compound (57 mg, 19%). LCMS (Method C): R T = 0.50 min, m / z = 226 [M+H] + .

[0450] Intermediate 63: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-1-methylquinoline-4(1 H )- ketone Step 1: 6-Fluoro-3-(hydroxymethyl)-1-methylquinoline-4(1H)-one: At room temperature, 6-fluoro-3-(hydroxymethyl)quinoline-4(1 H NaOH (260 mg, 6.49 mmol) was added to a stirred solution of ketone (965 mg, 5.00 mmol) in water (40 mL), followed by dimethyl sulfate (1.40 mL, 19.0 mmol). After 3 hours, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (0.79 g, 76%) as a grayish-white solid. LCMS (Method E): R T =1.80 min, m / z = 208 [M+H] + .

[0451] Step 2: 3-(chloromethyl)-6-fluoro-1-methylquinoline-4(1H)-one: At 50°C, 6-fluoro-3-(hydroxymethyl)-1-methylquinoline-4(1 HSOCl2 (0.31 mL, 4.34 mmol) was added to a stirred solution of 10 mL of DCM containing the ketone (300 mg, 1.45 mmol). After 16 hours, the solvent was evaporated under reduced pressure to give the title compound (0.32 g, 98%), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO- d 6): δ 8.38 (s, 1H), 7.97-7.85 (m,1H), 7.82-7.79 (m, 1H), 7.72-7.68 (m, 1H), 4.64 (s, 2H), 3.87 (s, 3H).

[0452] Step 3: 6-((6-fluoro-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)methyl)-6,9-diazaspiro [4.5] tert-butyl decane-9-carboxylate: At room temperature, 3-(chloromethyl)-6-fluoro-1-methylquinoline-4(1 H 6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester (0.511 g, 2.13 mmol) and DIPEA (0.74 mL, 4.25 mmol) were added to a stirred solution of 6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester (0.511 g, 2.13 mmol) and DIPEA (0.74 mL, 4.25 mmol). After 2 hours, the reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC to give the title compound (0.1 g, 16%) as a grayish-white solid. LCMS (Method F): R T = 2.68 min, m / z = 430 [M+H] + .

[0453] Step 4: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-1-methylquinoline-4(1H)-one: The title compound (35.7 mg, 93%) was prepared according to general procedure 1 using 6-((6-fluoro-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester (50 mg, 116 µmol), TFA (0.5 mL), and DCM (1.0 mL). LCMS (Method C): R T = 0.46 min, m / z = 330 [M+H] + .

[0454] Intermediate 64: rac -(2 R ,3 R )-3-(2,5-difluorophenyl)-2-methylmorpholine and (1:1) At room temperature, 3 Å molecular sieve (300 mg) was added to a DCM mixture of 2-ethoxyethylamine (100 mg, 1.15 mmol) and 2,5-difluorobenzaldehyde (163 mg, 1.15 mmol) (1.4 mL). After 16 hours, the reaction mixture was filtered (using a syringe filter) and evaporated under reduced pressure (40°C, 210 mbar). The resulting crude imine was transferred to a 20 mL microwave-safe bottle and dissolved in 2-propanol (12 mL). Mn(dpm)3 (34.8 mg, 0.0575 mmol) was added and the bottle was sealed. PhSiH3 (0.28 mL, 2.30 mmol) was added, and the reaction was heated at 85°C for 5 hours. Due to incomplete reaction, additional PhSiH3 (0.28 mL, 2.30 mmol) was added, and the reaction was continued at 85°C for 16 hours. Since the reaction was incomplete, additional PhSiH3 (0.28 mL, 2.30 mmol) was added, and the reaction was continued at 85°C for 4 hours. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The remaining residue was purified by rapid chromatography (20–100% EtOAc / cyclohexane) to give the title compound (22 mg, 9%). LCMS (Method C): R T = 0.52 min, m / z = 214 [M+H] + .

[0455] Intermediate 65: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(1-methyl-1 H -pyr (Azol-5-yl)pyridine-4(1) H )-ketone The title compound is similar to 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(thiophen-3-yl)pyridine-4(1 H It was prepared by the method of )-keto hydrochloride (intermediate 59), but in step 1, 6-((6-(1-methyl-1-keto hydrochloride) was used. H 6-((1-methyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester was used instead of 6-((1-methyl-4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester, and in the final step, 1,4-dioxane / DCM with TFA / DCM was used instead of 4M HCl and included SCX-2 purification to obtain the title compound. LCMS (Method C): R T = 0.38 min, m / z = 342[M+H]+ .

[0456] Intermediate 66: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(trifluoromethyl)pyridine-2(1 H )- Ketone hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H -pyrido[1,2- a The preparation method is as follows: pyrimidin-4-one (intermediate 33), but step 1 is omitted, and 3-bromo-6-(trifluoromethyl)pyridine-2 (1) is used in step 2. H )-Ketone [commercially available] as a substitute for 3-bromo-4 H -pyrido[1,2- a The title compound was obtained by using 1,4-dioxane / 1,4-dioxane in 4M HCl instead of TFA / DCM and omitting SCX-2 purification in the final step. LCMS (Method A): R T = 0.51 min, m / z = 316 [M+H] + .

[0457] Intermediate 67: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(trifluoromethyl)pyridine-4(1 H )- Ketone hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H -pyrido[1,2- a The preparation method is as follows: pyrimidin-4-one (intermediate 33), but step 1 is omitted, and 5-bromo-2-(trifluoromethyl)pyridine-4 (1) is used in step 2. H )-Ketone [commercially available] as a substitute for 3-bromo-4 H -pyrido[1,2- a The title compound was obtained by using 1,4-dioxane / 1,4-dioxane in 4M HCl instead of TFA / DCM and omitting SCX-2 purification in the final step. LCMS (Method A): R T = 0.55 min, m / z = 316 [M+H] + .

[0458] Intermediate 68: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(1-methyl-1 H -pyr (Azol-3-yl)pyridine-4(1) H )-Keto hydrochloride The title compound is similar to 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(thiophen-3-yl)pyridine-4(1 H It was prepared by the method of )-keto hydrochloride (intermediate 59), but in step 1, 6-((6-(1-methyl-1-keto hydrochloride) was used. H 6-((1-methyl-4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester was substituted for 6-((1-methyl-4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester to obtain the title compound. LCMS (Method A): R T = 0.37 min, m / z = 342[M+H] + .

[0459] Intermediate 69: ( S )-7-fluoro-3-((2-methylpiperazin-1-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a It is prepared by means of pyrimidine-4-one hydrochloride (intermediate 47), but in step 4, ( S 3-Methylpiperazine-1-carboxylic acid tert-butyl ester [commercially available] was substituted for 6,9-diazaspiro[4,5]decane-9-carboxylic acid tert-butyl ester to give the title compound. LCMS (Method A): R T = 0.31 min, m / z = 277 [M+H] + .

[0460] Intermediate 70: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-chloro-4 H -pyrido[1,2- a ]pyrethrum 4-Pyridine-keto hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a It is prepared by means of pyrimidine-4-one hydrochloride (intermediate 47), but 7-chloro-4-one hydrochloride is used in step 1. H -pyrido[1,2- a Pyrimidin-4-one [commercially available] as a substitute for 7-fluoro-4 H -pyrido[1,2- a[Pyrimidin-4-one, to obtain the title compound. LCMS (Method A): R] T = 0.53 min, m / z = 333 [M+H] + .

[0461] Intermediate 71: 3-((1,4-diazaspiro[5.5]undecane-1-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ] Pyrimidine-4-one hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a The title compound was prepared via pyrimidine-4-one hydrochloride (intermediate 47), but in step 4, tert-butyl 1,4-diazaspiro[5.5]undecane-4-carboxylate [commercially available] was used instead of tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate to obtain it. LCMS (Method A): R T = 0.48 min, m / z = 331 [M+H] + .

[0462] Intermediate 72: 3-((2,2-dimethylpiperazin-1-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a The title compound was prepared via pyrimidine-4-one hydrochloride (intermediate 47), but in step 4, tert-butyl 3,3-dimethylpiperazine-1-carboxylate [commercially available] was used instead of tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate to obtain it. LCMS (Method A): R T = 0.36 min, m / z = 291 [M+H] + .

[0463] Intermediate 73: ( R )-7-fluoro-3-((2-methylpiperazin-1-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- aIt is prepared by means of pyrimidine-4-one hydrochloride (intermediate 47), but in step 4, ( R 3-Methylpiperazine-1-carboxylic acid tert-butyl ester [commercially available] was substituted for 6,9-diazaspiro[4,5]decane-9-carboxylic acid tert-butyl ester to give the title compound. LCMS (Method A): R T = 0.26 min, m / z = 277 [M+H] + .

[0464] Intermediate 74: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-methyl-4 H -pyrido[1,2- a ] Pyrimidine-4-one hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a It is prepared by means of pyrimidine-4-one hydrochloride (intermediate 47), but 7-methyl-4-one hydrochloride is used in step 1. H -pyrido[1,2- a Pyrimidin-4-one [commercially available] as a substitute for 7-fluoro-4 H -pyrido[1,2- a [Pyrimidin-4-one, to obtain the title compound. LCMS (Method A): R] T = 0.46 min, m / z = 313 [M+H] + .

[0465] Intermediate 75: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-8-methoxy-4 H -pyrido[1,2- a Pyrimidine-4-one hydrochloride At room temperature, 2,2-dimethyl-1,3-dioxane-4,6-dione (20.1 g, 140 mmol) and triethyl orthoformate (20.7 g, 140 mmol) were added to a stirred solution of 4-methoxy-2-aminopyridine (15.8 g, 127 mmol) in EtOH (300 mL). The reaction mixture was stirred under reflux for 24 hours, evaporated to dryness, and the residue was dissolved in diphenyl ether (100 mL) and heated to 240°C for 3 hours. After cooling to room temperature, the reaction mixture was poured into hexane (1.5 L), and the resulting precipitate was filtered and washed with hexane to give 8-methoxy-4 H -pyrido[1,2- a Pyrimidin-4-one (11.1 g, 50%). LCMS (Method D): R T= 0.72 min, m / z = 177 [M+H] + .

[0466] Subsequently, the title compound was described as similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a It is prepared by means of pyrimidine-4-one hydrochloride (intermediate 47), but 8-methoxy-4-one hydrochloride is used in step 1. H -pyrido[1,2- a [Pyrimidin-4-one instead of 7-fluoro-4] H -pyrido[1,2- a [Pyrimidin-4-one, to obtain the title compound. LCMS (Method A): R] T = 0.44 min, m / z = 329 [M+H] + .

[0467] Intermediate 76: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7,8-dihydropyrrolo[1,2- a ]pyrethrum Pyridine-4(6) H )-ketone The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a It was prepared by means of pyrimidine-4-one hydrochloride (intermediate 47), but in step 1, 7,8-dihydropyrrolo[1,2- a ]Pyrimidine-4(6 H )-Ketone [commercially available] as a substitute for 7-fluoro-4 H -pyrido[1,2- a The title compound was obtained by purifying 1,4-dioxane / 1,4-dioxane with TFA / DCM instead of 4M HCl in a final step, including SCX-2 purification. LCMS (Method C): R T = 0.42 min, m / z = 289 [M+H] + .

[0468] Intermediate 77: 5-((tert-butoxycarbonyl)amino)-2 ' ,5 ' -difluoro-[1,1] ' [-biphenyl]-2-carboxylic acid Step 1: 5-Amino-2 ',5 ' -difluoro-[1,1] ' [-biphenyl]-2-carboxylic acid: 2',5'-Difluoro-5-nitro-[1,1'-biphenyl]-2-carboxylic acid (0.1 g, 0.35 mmol) [commercially available] was dissolved in MeOH (3 mL), and the solution was passed through an H-Cube containing a 10% w / w Pd / C kit at 30°C. ® Pro hydrogenation flow cytometer, flow rate 1 mL / min. After one cycle, the solvent was removed under vacuum to obtain the title compound (0.09 g, 98%). LCMS (Method A): R T = 0.90 min, m / z = 250 [M+H] + .

[0469] Step 2: 5-((tert-butoxycarbonyl)amino)-2 ' ,5 ' -difluoro-[1,1] ' [-biphenyl]-2-carboxylic acid: Boc₂O (0.16 mL, 0.71 mmol) was added to a stirred solution of 5-amino-2',5'-difluoro-[1,1'-biphenyl]-2-carboxylic acid (0.09 g, 0.35 mmol) and triethylamine (0.15 mL, 1.06 mmol) in 1,4-dioxane (4 mL) / water (2 mL). The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under vacuum, and 3M HCl was added dropwise to the remaining residue. (aq) Solution (10 mL). The resulting precipitate was filtered, washed with water, and dried under vacuum to give the title compound (0.076 g, 61%). LCMS (Method A): R T = 1.31 min, m / z = 348 [MH] - .

[0470] Intermediate 78: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-2-methyl-4 H -pyridyl [1,2- a Pyrimidine-4-one hydrochloride At room temperature, 2,2-dimethyl-1,3-dioxane-4,6-dione (14.1 g, 98 mmol) and triethyl orthoacetate (15.9 g, 98 mmol) were added to a stirred solution of 5-fluoro-2-aminopyridine (10.0 g, 89 mmol) in EtOH (200 mL). The reaction mixture was stirred under reflux for 24 hours, evaporated to dryness, and the residue was dissolved in diphenyl ether (90 mL) and heated to 240°C for 3 hours. After cooling to room temperature, the reaction mixture was poured into hexane (1.0 L), and the resulting precipitate was filtered and washed with hexane to give 7-fluoro-2-methyl-4-dione. H -pyrido[1,2- a [Pyrimidin-4-one (6.2 g, 39%). Subsequently, the title compound was described as similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4- H -pyrido[1,2- a It is prepared by means of pyrimidine-4-one hydrochloride (intermediate 47), but 7-fluoro-2-methyl-4-one is used in step 1. H -pyrido[1,2- a [Pyrimidin-4-one instead of 7-fluoro-4] H -pyrido[1,2- a [Pyrimidin-4-one, to obtain the title compound. LCMS (Method A): R] T = 0.47 min, m / z = 331 [M+H] + .

[0471] Intermediate 79: ((2) S 4 R 2-(2,5-difluorophenyl)piperidin-4-yl)(2-fluoroethyl)carbamate tert-butyl Step 1: (2S,4R)-4-((tert-butoxycarbonyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylic acid benzyl ester: Towards N -[(2 S 4 R[2,5-Difluorophenyl]-4-piperidinyl] tert-butyl carbamate (0.3 g, 0.96 mmol) was mixed with 2 mL of THF and (2,5-dioxopyrrolidone-1-yl)benzyl carbonate (0.28 g, 1.15 mmol), followed by 2 mL of an aqueous solution of sodium bicarbonate (0.16 g, 192 mmol). After 24 hours, the reaction mixture was partitioned and separated between EtOAc (10 mL) and brine (10 mL). The organic phase was washed with water (10 mL), followed by brine (10 mL). The solvent was removed under vacuum, and the remaining residue was purified by rapid chromatography (0-60% EtOAc / cyclohexane) to give the title compound (0.31 g, 59%). LCMS (Method A): R T = 1.56 min, m / z = 347 [M-Boc+H] + .

[0472] Step 2: (2S,4R)-4-((tert-butoxycarbonyl)(2-fluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine- 1-Benzyl formate: At 0°C, towards (2 S 4 R A mineral oil dispersion of 55% sodium hydride (0.035 g, 0.87 mmol) was added to a stirred solution of 4-((tert-butoxycarbonyl)amino)-2-(2,5-difluorophenyl)piperidin-1-carboxylic acid benzyl ester (0.3 g, 0.67 mmol) in DMF (3 mL). After 30 minutes, 1-fluoro-2-iodoethane (0.07 mL, 0.80 mmol) was added. After 24 hours, additional 1-fluoro-2-iodoethane (0.07 mL, 0.80 mmol) and sodium hydride (55%, in mineral oil, 0.035 g, 0.87 mmol) were added. After another 24 hours, the reaction mixture was dissolved in EtOAc (30 mL) and 15% NH4Cl. (aq) The solutions (10 mL) were partitioned and separated. The organic phase was washed with water (10 mL), followed by washing with brine (10 mL) and dried (Mg2SO4). The solvent was removed under vacuum, and the remaining residue was purified by rapid chromatography (0-40% EtOAc / cyclohexane) to give the title compound (0.1 g, 30%). LCMS (Method A): R T = 1.68 min, m / z = 393 [M-Boc+H] + .

[0473] Step 3: ((2S,4R)-2-(2,5-difluorophenyl)piperidin-4-yl)(2-fluoroethyl)carbamate tert-butyl ester: (2) S4 R Benzyl 4-((tert-butoxycarbonyl)(2-fluoroethyl)amino)-2-(2,5-difluorophenyl)piperidin-1-carboxylate (0.08 g, 0.16 mmol) was dissolved in MeOH (3 mL) and the solution was passed through an H-Cube® Pro hydrogenation flow cytometer containing a 10% w / w Pd / C kit at 50°C at a flow rate of 1 mL / min. After one cycle, the solvent was removed under vacuum to give the title compound (0.05 g, 85%). LCMS (Method A): R T = 0.778 min, m / z = 359 [M+H] + .

[0474] Intermediate 80: 4-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-phenyl-1,2-dihydro-3 H -pyr 3-oxazolone Step 1: Ethyl 3-oxo-1-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate: At room temperature, to N Diethyl 2-(ethoxymethylene)malonate (14.8 g, 73.2 mmol) was added to a solution of '-phenylacetylhydrazine (10.0 g, 66.6 mmol) in POCl3 (37.4 mL, 400 mmol), and the resulting reaction mixture was heated at 70°C. After 3 hours, the reaction mixture was cooled and quenched with ice-cold water. The resulting precipitate was filtered and washed with water. The residual solid was dissolved in EtOAc (200 mL), washed with brine (100 mL), dried (Na2SO4), and the solvent was removed under vacuum to give the title compound (15.4 g, 16%). LCMS (Method E): R T = 3.02 min, m / z = 233 [M+H] + .

[0475] Step 2: Ethyl 3-methoxy-1-phenyl-1H-pyrazole-4-carboxylate: At room temperature, to 3-oxo-1-phenyl-2,3-dihydro-1 HIodimethane (96.5 µL, 1.55 mmol) was added to a stirred solution of ethyl pyrazole-4-carboxylate (300 mg, 1.29 mmol) and K₂CO₃ (250 mg, 1.80 mmol) in DMF (5 mL). After 4 hours, the reaction mixture was diluted with ice-cold water and extracted with EtOAc (50 mL). The organic phase was washed with brine (20 mL), dried (Na₂SO₄), the solvent was removed under vacuum, and the remaining residue was purified by rapid chromatography (0–20% EtOAc / hexane) to give the title compound (220 mg, 69.1%). LCMS (Method E): R T = 3.48 min, m / z = 247 [M+H] + .

[0476] Step 3: (3-Methoxy-1-phenyl-1H-pyrazole-4-yl)methanol: At -78°C, to 3-methoxy-1-phenyl-1 H To a stirred solution of ethyl pyrazole-4-carboxylate (100 mg, 0.41 mmol) in diethyl ether (2 mL), 1 M DIBAL-H toluene (0.046 mL, 1.22 mmol) was added. The temperature of the reaction mixture was raised to -10°C and maintained at that temperature. After 4 hours, the reaction mixture was saturated with NH4Cl. (aq) The solution was quenched and extracted with EtOAc (20 mL). The organic phase was washed with brine (20 mL), dried (Na2SO4), the solvent was removed under vacuum, and the remaining residue was purified by rapid chromatography (0-50% EtOAc / hexane) to give the title compound (60 mg, 72%). LCMS (Method E): R T = 2.78 min, m / z = 205 [M+H] + .

[0477] Step 4: 4-(bromomethyl)-3-methoxy-1-phenyl-1H-pyrazole: At room temperature, to (3-methoxy-1-phenyl-1 H Triphenylphosphine (806 mg, 3.07 mmol) and CBr4 (1.0 g, 3.07 mmol) were added to a stirred solution of pyrazol-4-yl)methanol (570 mg, 2.79 mmol) in DCM (85 mL). After 16 hours, the reaction mixture was concentrated under vacuum to give the title compound (crude, 570 mg), which was used in the next step without further purification.

[0478] Step 5: 6-((3-methoxy-1-phenyl-1H-pyrazol-4-yl)methyl)-6,9-diazaspiro[4.5]decane-9- tert-butyl formate:At room temperature, 4-(bromomethyl)-3-methoxy-1-phenyl-1 H Cs₂CO₃ (1.39 g, 4.26 mmol) was added to a stirred solution of pyrazole (570 mg, 2.13 mmol) in MeCN (45 mL). After 30 minutes, tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (1.02 g, 4.26 mmol) was added. After 16 hours, the reaction mixture was concentrated under vacuum, diluted with EtOAc (100 mL), washed with brine (50 mL), and dried over Na₂SO₄. The solvent was removed under vacuum, and the remaining residue was purified by rapid chromatography (0–5% MeOH / DCM) to give the title compound (700 mg, 2 steps, 59%). LCMS (Method E): R T = 4.18 min, m / z = 427 [M+H] + .

[0479] Step 6: 4-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-phenyl-1,2-dihydro-3H-pyrazole-3- ketone: 6-((3-methoxy-1-phenyl-1) H 670 mg (1.57 mmol) of tert-butyl pyrazol-4-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate slurry in 33% HBr and AcOH (4 mL) was heated at 100°C. After 2 hours, the reaction mixture was concentrated under reduced pressure, and the remaining residue was ground with diethyl ether (3 × 20 mL) to give crude product (800 mg). 150 mg of this crude product was purified by preparative HPLC to give the title compound (52 mg, 35% recovery), and the remaining product (650 mg) was retained for subsequent reactions without further purification. LCMS (Method E): R T = 1.97 min, m / z = 313 [M+H] + .

[0480] Intermediate 81: 4-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-methyl-1-phenyl-1,2-dihydro- 3 H pyrazole-3-one hydrochloride Step 1: 6-((3-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-4-yl)methyl)-6,9-diazaspiro[4.5] tert-butyl decane-9-carboxylate: At room temperature, 4-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-phenyl-1,2-dihydro-3 HTriethylamine (0.4 mL, 2.29 mmol) was added to a stirred solution of pyrazol-3-one (180 mg, 0.46 mmol) in DCM (4 mL), followed by Boc₂O (0.09 mL, 0.41 mmol). After 2 hours, the reaction mixture was diluted with water and extracted with 9:1 DCM / MeOH (3 x 20 mL). The combined organic phases were washed with water (10 mL), followed by washing with brine (10 mL) and dried (Na₂SO₄). The solvent was removed under vacuum, and the remaining residue was purified by rapid chromatography (0–5% MeOH / DCM) to give the title compound (90 mg, 47%). LCMS (Method E): R T = 1.90 min, m / z = 413 [M+H] + .

[0481] Step 2: 6-((2-methyl-3-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-4-yl)methyl)-6,9-diaza Spiro[4.5]decane-9-carboxylic acid tert-butyl ester: At room temperature, 6-((3-oxo-1-phenyl-2,3-dihydro-1) H 1,9-Diazolazo[4,5]decane-9-carboxylic acid tert-butyl ester (150 mg, 0.36 mmol) was added to a stirred solution of 1:1 DCM / MeOH (5 mL) in pyrazol-4-yl)methyl)-6,9-diazaspiro[4,5]decane-9-carboxylic acid tert-butyl ester (150 mg, 0.36 mmol) in 5 mL DCM / MeOH. After 5 hours, the reaction mixture was diluted with water (20 mL) and extracted with 9:1 DCM / MeOH (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SO4), and the solvent was removed under vacuum. The remaining residue was purified by rapid chromatography (0-15% EtOAc / hexane, then 10% MeOH / DCM) to give 6-((3-methoxy-1-phenyl-1-) H -pyrazol-4-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester (25 mg, 16.8%, first elution): LCMS (Method E): R T = 3.56min, m / z = 427 [M+H] + ; and the title compound (35 mg, 21%, second elution): LCMS (Method E): R T = 2.60min, m / z = 427 [M+H] + .

[0482] Step 3: 4-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-methyl-1-phenyl-1,2-dihydro-3H- Pyrazole-3-one hydrochloride: According to General Procedure 1, 6-((2-methyl-3-oxo-1-phenyl-2,3-dihydro-1-yl) H The title compound (28.0 mg, quantified) was prepared by reacting 1,4-dioxane (0.375 mL) and 1,4-dioxane (3.0 mL) in 4 M HCl with pyrazol-4-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester (32 mg, 75.0 µmol), 1,4-dioxane (3.0 mL) in 4 M HCl. LCMS (Method A): R T = 0.42 min, m / z = 327 [M+H] + .

[0483] Intermediate 82: 6-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-5 H -Thiazo[3,2- a Pyrimidine-5- Ketone hydrochloride The title compound is similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a It is prepared by means of pyrimidine-4-one hydrochloride (intermediate 47), but 5% is used in step 1. H -Thiazo[3,2- a Pyrimidine-5-one [commercially available] as a substitute for 7-fluoro-4-one H -pyrido[1,2- a [Pyrimidin-4-one, to obtain the title compound. LCMS (Method A): R] T = 0.39 min, m / z = 305 [M+H] + .

[0484] Intermediate 83: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-cyclopropyl-7-fluoro-4 H -pyridyl [1,2- a ]Pyrimidin-4-one 5-Fluoro-2-aminopyridine (5.0 g, 45 mmol), ethyl 3-cyclopropyl-3-oxopropionate (16.4 g, 90 mmol), and bismuth(III) chloride (0.7 g, 2.2 mmol) were stirred under reflux for 24 hours. The reaction mixture was evaporated to dryness, dissolved in diphenyl ether (100 mL), and heated to 100°C for 24 hours. After cooling to room temperature, the reaction mixture was purified by rapid chromatography to give 2-cyclopropyl-7-fluoro-4-oxopropionate. H -Pyrido[1,2-a]pyrimidin-4-one (4.1 g, 43%). LCMS (Method D): R T= 0.87 min, m / z = 205 [M+H] + Subsequently, the title compound is described in a manner similar to 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4- H -pyrido[1,2- a It is prepared by means of pyrimidine-4-one hydrochloride (intermediate 47), but 2-cyclopropyl-7-fluoro-4-one hydrochloride is used in step 1. H -pyrido[1,2- a [Pyrimidin-4-one instead of 7-fluoro-4] H -pyrido[1,2- a [Pyrimidin-4-one, and in the final step, the HCl salt is dissolved and washed with a saturated aqueous sodium bicarbonate solution to give the title compound as a free base. LCMS (Method A): R] T = 0.59 min, m / z = 357 [M+H] + .

[0485] Intermediate 84: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridazine-4(1 H )-Ketohydrochloric acid Salt Step 1: 4-Methoxy-6-phenylpyridazine-3(2H)-one: To 4-methoxy-6-chloropyridazine-3(2 H Phenylated boric acid (5.0 g, 41 mmol), Pd(dppf)Cl2 (1.5 g, 5 mol%), and tripotassium phosphate (24.0 g, 112 mmol) were added to a stirred solution of 1,4-dioxane (130 mL) / water (45 mL) containing 6.0 g (37.5 mmol) of ketone [commercially available]. The reaction mixture was degassed and backfilled with argon, and heated to reflux. After 24 hours, the solvent was removed under vacuum, and the remaining residue was dissolved in hot water (200 mL), filtered, and acidified to ~pH 3 with aqueous hydrochloric acid. The resulting precipitate was filtered, washed with water, and dried under vacuum to give the title compound (7.1 g, 94%). LCMS (Method D): R T = 0.98 min, m / z = 203[M+H] + .

[0486] Step 2: 3-Chloro-4-methoxy-6-phenylpyridazine: 4-methoxy-6-phenylpyridazine-3(2) HThe ketone (6.5 g, 62 mmol) was suspended in POCl3 (80 mL) and stirred under reflux for 4 hours. After evaporating excess POCl3, ice water was added to the remaining residue. After 1 hour, the aqueous mixture was extracted with DCM. The combined organic phases were concentrated under reduced pressure, and the resulting residue was dissolved in MeCN and redistilled to give the title compound (4.4 g, 98%). LCMS (Method D): R T = 1.16 min, m / z = 221 [M+H] + .

[0487] Step 3: (4-Methoxy-6-phenylpyridazine-3-yl)methanol: Tributyltin alkyl methanol (6.94 g, 24 mmol) and XPhos Pd G4 (0.9 g, 10 mol%) were added to a stirred solution of 3-chloro-4-methoxy-6-phenylpyridazine (3.6 g, 16 mmol) in 1,4-dioxane (90 mL). The reaction mixture was degassed and purged with argon, and heated to 60°C. After 48 hours, the solvent was removed under vacuum, and the remaining residue was ground in diethyl ether (70 mL), filtered, and purified by rapid chromatography to give the title compound (0.4 g, 43%). LCMS (Method D): R T = 0.60 min, m / z = 251 [M+Cl] - .

[0488] Step 4: 6-((4-oxo-6-phenyl-1,4-dihydropyridazin-3-yl)methyl)-6,9-diazaspiro[4.5]decane tert-butyl alkyl-9-carboxylate:At room temperature, thionyl chloride (3.0 mL) was added to a stirred solution of (4-methoxy-6-phenylpyridazine-3-yl)methanol (0.38 g, 1.8 mmol) in DCM (20 mL). After 4 hours, the solvent was removed under vacuum, and the remaining residue was dissolved in MeCN (100 mL), followed by the addition of DIPEA (0.7 g, 5.4 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (0.45 g, 1.9 mmol). The resulting suspension was stirred at 80°C for 24 hours. The reaction mixture was concentrated under reduced pressure, and the remaining residue was partitioned between DCM and brine, separated, and the organic phase was dried (Na2SO4). The solvent was removed under vacuum, and the remaining residue was dissolved in 40% HBr aqueous solution (15 mL) and heated at 80°C. After 48 hours, the reaction mixture was concentrated under reduced pressure, and the remaining residue was suspended in MeCN (25 mL) and triethylamine (1.5 mL). After cooling to 0°C, Boc₂O (0.42 g, 1.9 mmol) was added dropwise. The solvent was removed under vacuum, and the remaining residue was washed with water and purified by preparative HPLC to give the title compound (0.10 g, 22%). LCMS (Method D): R T = 0.86min, m / z = 425 [M+H] + .

[0489] Step 5: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridazine-4(1H)-one hydrochloride: According to General Procedure 1, the title compound (71 mg, 77%) was prepared using tert-butyl 6-((4-oxo-6-phenyl-1,4-dihydropyridazin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (109 mg, 257 µmol), 1,4-dioxane (1.28 mL) and 1,4-dioxane (4.0 mL) in 4 M HCl. LCMS (Method A): R T = 0.51min, m / z = 325 [M+H] + .

[0490] Intermediate 85: 3-((6,9-diazaspiro[4.5]dec-2-en-6-yl)methyl)-7-f...

Claims

1. Compounds of formula (I) or their stereoisomers, tautomers, hydrates, N -Oxide derivatives or pharmaceutically acceptable salts: (I) in R 1 It is an optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted 3- to 11-membered heterocyclic alkyl, optionally substituted aryl, or optionally substituted 5- to 8-membered heteroaryl; R 2 and R 3 Each is independently selected from H and C1-C6 alkyl groups, or R. 2 and R 3 Together with the carbons they are attached to, they form C3-C8 cycloalkyl, C3-C8 cycloalkenyl, or 3- to 8-membered heterocyclic alkyl groups; M is N or CR a , where R a It is H, halogen, optionally substituted C3-C8 cycloalkyl or optionally substituted C1-C6 alkyl; A, D, E, and G do not exist, and X is NR 15 Or CH; Y is CR 4 Either N or it does not exist; Z is CR 5 NR 6 Or O; R 4 It is a halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, 4- to 10-membered fused-ring heterocyclic, optionally substituted C1-C6 alkylthioalkyl, sulfoxide, sulfone, sulfoxide imine, optionally substituted amino, optionally substituted 3- to 8-membered heterocyclic alkyl, or OR 20 ; Where R 20 It is an optional substituted C1-C6 alkyl group; R 5 H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, optionally substituted 3- to 8-membered heterocyclic alkyl, amide, sulfoxide imine, CN, halogen, C(O)OR 21 OR 22 or NR 23 R 24 ; Where R 21 Selected from H and C1-C6 alkyl groups; R 22 Selected from H and C1-C6 alkyl groups; R 23 and R 24 Independently selected from H and optionally substituted C1-C6 alkyl groups; R 15 It is an H or C1-C6 alkyl group; or R 4 and R 5 Together with the Y and Z groups to which they are attached, they form 3 to 8-membered heterocyclic alkyl or aryl groups; or R 4 and R 15 Together with the X and Y they are attached to, they form 5-membered cycloalkyl, heterocycloalkyl, or heteroaryl groups; R 6 It is H, C1-C6 alkyl, optionally substituted aryl or C3-C8 cycloalkyl; Or A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N and G is CR 14 Or N, and X is N or C; Y is C; Z is CR 20 , N, NR 11 Or O, Where R 11 It is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl or optionally substituted 5 to 8-membered heteroaryl; Where R 20 H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, optionally substituted 3- to 8-membered heterocyclic alkyl, amide, sulfoxide imine, CN, halogen, C(O)OR 25 OR 26 or NR 27 R 28 ; Where R 25 Selected from H and C1-C6 alkyl groups; R 26 Selected from H and C1-C6 alkyl groups; R 27 and R 28 Independently selected from H and C1-C6 alkyl groups; R 7 It is H, halogen, C1-C6 alkyl or OR 19 ; Where R 19 It is an optional substituted C1-C6 alkyl group; R 12 It is H, halogen, or C1-C6 alkyl; R 13 It is H, halogen, C1-C6 alkyl, OR 16 or NR 17 R 18 ; Where R 16 It is an optional substituted C1-C6 alkyl group. R 17 and R 18 Independently selected from H and C1-C6 alkyl groups, or wherein R 17 and R 18 Together with the nitrogen atoms to which they are attached, they form 5- to 6-membered heterocyclic alkyl groups; and R 14 It is H, halogen, or C1-C6 alkyl.

2. The compound, stereoisomer, tautomer, hydrate, or other compound according to claim 1. N - An oxide derivative or a pharmaceutically acceptable salt, wherein for each optionally substituted group, one or more optional substituents are each independently selected from alkyl, alkoxy, oxo, halogen, cycloalkyl, heterocycloalkyl, aryl, aryl substituted with one or more halogens, aryl substituted with halogen and alkyl, aryl substituted with halogen and alkoxy, heteroaryl, hydroxyl, CR 8 R 9 R 10 NR 8 NR 8 R 9 ,NHC(O)R 8 NHCR 8 R 9 R 10 NHCH2CR 8 R 9 R 10 and NHCH2C(O)R 8 , Where R 8 R 9 and R 10 Each is independently selected from H, halogen, hydroxyl, alkyl, cycloalkyl, cycloalkyl substituted with one or more halogens or alkyl groups, heterocycloalkyl substituted with one or more alkyl groups or oxo groups, heteroaryl, alkoxy, CH2OH and CH2CH2OH.

3. The compound, stereoisomer, tautomer, hydrate, or other compound according to claim 1 or 2. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 1 It is an optional substituted 3- to 11-membered heterocyclic alkyl group.

4. The compound, stereoisomer, tautomer, hydrate, or other product according to any of the preceding claims. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 1 It is an optionally substituted 5- to 8-membered heterocyclic alkyl group, wherein R is optionally substituted. 1 It is an optional substituted 5- to 6-membered heterocyclic alkyl group.

5. The compound, stereoisomer, tautomer, hydrate, or other product according to any of the preceding claims. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 1 It is optionally substituted morpholine, bridged aziridine, diaziridine, thiomorpholine, pyrrolidine, piperazine, or piperidine.

6. The compound, stereoisomer, tautomer, hydrate, or other product according to any of the preceding claims. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 1 It is a piperidine with optional substitution.

7. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 3 to 6. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 1 Aryl, oxo, cycloalkyl, heterocycloalkyl, aryl, aryl substituted with one or more halogens, heteroaryl, NR 8 NR 8 R 9 ,NHC(O)R 8 NHCR 8 R 9 R 10 NHCH2CR 8 R 9 R 10 and NHCH2C(O)R 8 Replace, where R 8 R 9 and R 10 Each is independently selected from H, halogen, hydroxyl, alkyl, cycloalkyl, cycloalkyl substituted with one or more halogens or alkyl groups, heterocycloalkyl substituted with one or more alkyl groups or oxo groups, heteroaryl and alkoxy groups.

8. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 3 to 7. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 1 A phenyl substituted with a phenyl group or a phenyl group substituted with one or more halogens, wherein R 1 It may be optionally substituted by one or more other substituents.

9. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 3 to 8. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 1 A phenyl substituted with a phenyl group or a phenyl group substituted with one or more fluorine groups, wherein R 1 It may be optionally substituted by one or more other substituents.

10. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 3 to 9. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 1 It is replaced by difluoro-phenyl.

11. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 3 to 10. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 1 NR 8 R 9 ,NHC(O)R 8 or NHCH2CR 8 R 9 R 10 Replace, and where R 1 It may be optionally substituted by one or more other substituents.

12. The compound, stereoisomer, tautomer, hydrate, or any one of claims 2 to 11 N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 8 R 9 and R 10 Each is independently selected from H, C1-C6 alkyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, CH2OH, CH2CH2OH, fluorinated C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted with C1-C6 alkyl and pyridine substituted C1-C6 alkyl.

13. The compound, stereoisomer, tautomer, hydrate, or other compound according to claim 1 or 2. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 1 It is an optional substituted C1-C6 alkyl group.

14. The compound, stereoisomer, tautomer, hydrate, or other compound according to claim 13. N - An oxide derivative or a pharmaceutically acceptable salt, wherein each optional substituent is selected from halogens, C1-C6 alkoxy groups, cycloalkyl groups, and hydroxyl groups.

15. The compound, stereoisomer, tautomer, hydrate, or any one of claims 1 to 4 N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 1 It is an optional substituted amino group.

16. The compound, stereoisomer, tautomer, hydrate, or other compound according to claim 15. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 1 It is an amino group substituted with a phenyl group or substituted with a benzyl group or substituted with a halogen group.

17. The compound, stereoisomer, tautomer, hydrate, or other product according to any of the preceding claims. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 2 and R 3 Each is independently H or methyl, or R in which 2 and R 3 Together with the carbons they are attached to, they form C3-C6 cycloalkyl, cyclopentenyl, or 4- to 6-membered heterocyclic alkyl groups.

18. The compound, stereoisomer, tautomer, hydrate, or other product according to any of the preceding claims. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 2 and R 3 Each is independently H or methyl, or R in which 2 and R 3 Together they form a cyclopentyl group.

19. The compound, stereoisomer, tautomer, hydrate, or other product according to any of the preceding claims. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 2 and R 3 Together with the carbon atoms they are attached to, they form oxetane or oxetane-hexane.

20. The compound, stereoisomer, tautomer, hydrate, or other product according to any of the preceding claims. N -Oxide derivatives or pharmaceutically acceptable salts, where M is a CR a .

21. The compound, stereoisomer, tautomer, hydrate, or other product according to any of the preceding claims. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R a It is H, cyclopropyl, CF3, or methyl.

22. The compound, stereoisomer, tautomer, hydrate, or other product according to any of the preceding claims. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R a It is H.

23. The compound, stereoisomer, tautomer, hydrate, or other product according to any of the preceding claims. N -Oxide derivatives or pharmaceutically acceptable salts, wherein: A, D, E, and G do not exist, and X is NR 15 Or CH; Y is CR 4 N or does not exist; Z is CR 5 NR 6 Or O; R 4 It is a halogen, an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted aryl, an optionally substituted 5- to 8-membered heteroaryl, a 4- to 10-membered fused-ring heterocyclic or C1-C6 alkylthioalkyl. R 5 It is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, optionally substituted 3- to 8-membered heterocyclic alkyl, amide, sulfoxide imine, CN or halogen; or R 4 and R 5 Together with the Y and Z groups to which they are attached, they form 3 to 8-membered heterocyclic alkyl or aryl groups; R 6 It is H, C1-C6 alkyl, aryl, or C3-C8 cycloalkyl; R 15 It is an H or C1-C6 alkyl group; or R 4 and R 15 Together with the X and Y to which they are attached, they form a 5-membered heterocyclic alkyl or heteroaryl group, optionally wherein R 4 and R 15 Together with the X and Y they are connected to, they form dihydrothiazolium; Or A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N, G is CR 14 Or N, and X is N or C; Y is C; Z represents CH, N, NR 11 Or O, Where R 11 It is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl or optionally substituted 5 to 8-membered heteroaryl; R 7 It is H, halogen, C1-C6 alkyl; R 12 It is H, halogen, or C1-C6 alkyl; R 13 It is H, halogen, C1-C6 alkoxy or C1-C6 alkyl; and R 14 It is H, halogen, or C1-C6 alkyl.

24. The compound, stereoisomer, tautomer, hydrate, or other product according to any of the preceding claims. N -Oxide derivatives or pharmaceutically acceptable salts, wherein: A, D, E, and G do not exist, and X is NH or CH; Y is CR 4 Or N.

25. The compound, stereoisomer, tautomer, hydrate, or other product according to any of the preceding claims. N -Oxide derivatives or pharmaceutically acceptable salts, wherein: A, D, E, and G do not exist, and X is NH or CH; Y is CR 4 Or N; Z is CR 5 NR 6 Or O; R 4 It is a halogen, an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted aryl, an optionally substituted 5- to 8-membered heteroaryl, a 4- to 10-membered fused-ring heterocyclic group, a C1-C6 alkylthioalkyl, a sulfoxide, a sulfone, a sulfoxide imine, an optionally substituted amino, or an optionally substituted 3- to 8-membered heterocyclic alkyl. R 5 It is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, optionally substituted 3- to 8-membered heterocyclic alkyl, amide, sulfoxide imine, CN or halogen; or R 4 and R 5 Together with the Y and Z groups to which they are attached, they form 3 to 8-membered heterocyclic alkyl or aryl groups; and R 6 It is H, C1-C6 alkyl or C3-C8 cycloalkyl.

26. The compound, stereoisomer, tautomer, hydrate, or other compound according to claim 25. N -Oxide derivatives or pharmaceutically acceptable salts, where Z is CR 5 or NR 6 .

27. The compound, stereoisomer, tautomer, hydrate, or other compound according to claim 25 or 26 N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 6 It is H or C1-C6 alkyl.

28. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 25 to 27. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 4 It is a halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, 4- to 10-membered fused-ring heterocyclic group, SMe, sulfoxide, sulfone, sulfoxide imine, optionally substituted amino, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted morpholine or optionally substituted piperazine.

29. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 25 to 28. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 4 It is a halogen, an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted aryl, an optionally substituted 5- to 8-membered heteroaryl or a 4- to 10-membered fused-ring heterocyclic group.

30. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 25 to 29. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 5 It is H.

31. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 25 to 30. N -Oxide derivatives or pharmaceutically acceptable salts, where Y is a CR 4 .

32. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 25 to 31. N - An oxide derivative or a pharmaceutically acceptable salt, where Y is N.

33. The compound, stereoisomer, tautomer, hydrate, or any one of claims 25 to 32 N - An oxide derivative or a pharmaceutically acceptable salt, wherein X is NH.

34. The compound, stereoisomer, tautomer, hydrate, or any one of claims 25 to 32 N - An oxide derivative or a pharmaceutically acceptable salt, wherein X is CH.

35. The compound, stereoisomer, tautomer, hydrate, or any one of claims 25 to 34 N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 4 It is a C1-C6 alkyl group, a C1-C6 alkyl group substituted with one or more halogen groups, a halogen, a cycloalkyl group, a cycloalkyl group substituted with one or more C1-C6 alkyl groups, a heteroaryl group, a heteroaryl group substituted with a C1-C6 alkyl group, a dihydrobenzofuran, a phenyl group, or a phenyl group substituted with one or more C1-C6 alkyl groups, C1-C6 alkoxy groups, or halogen groups.

36. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 25 to 35. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 4 It is methyl, CF3, CHF2, chlorine, cyclopropyl, methyl-substituted cyclopropyl, thiophene, methyl-substituted pyrazole, 2,3-dihydrobenzofuran, phenyl or phenyl substituted with methyl, methoxy or fluorine.

37. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 25 to 36. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 4 It is a phenyl or a phenyl substituted with methyl, methoxy or fluorine.

38. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 25, 26, 31, 33, or 34. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 4 and R 5 Together with the Y and Z atoms to which they are attached, they form a 6-membered heterocyclic alkyl or aryl group.

39. The compound, stereoisomer, tautomer, hydrate, or any one of claims 25, 26, or 28 to 38 N -Oxide derivatives or pharmaceutically acceptable salts, where Z is CH.

40. The compound, stereoisomer, tautomer, hydrate, or any one of claims 25 to 38 N -Oxide derivatives or pharmaceutically acceptable salts, where Z is NR 6 .

41. The compound, stereoisomer, tautomer, hydrate, or any one of claims 25 to 37 or 40 N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 6 It is H or methyl.

42. The compound, stereoisomer, tautomer, hydrate, or any one of claims 25, 33, or 34 N -Oxide derivatives or pharmaceutically acceptable salts, where Y is a CR 4 , where R 4 It is a C1-C6 alkylthioalkyl group, optionally SMe, and wherein Z is a C1-C6 alkylthioalkyl group. 5 , where R 5 It's CN.

43. The compound, stereoisomer, tautomer, hydrate, or any one of claims 25, 28, 29, 35, 36, or 37 N -Oxide derivatives or pharmaceutically acceptable salts, where M is N, X is CH, and Y is CR. 4 And Z is NH, where R is chosen arbitrarily. 4 It is phenyl.

44. The compound, stereoisomer, tautomer, hydrate, or any one of claims 1 to 23 N -Oxide derivatives or pharmaceutically acceptable salts, wherein: A is CR 12 Or N, D is CR 7 Or N, E is CR 13 Or N, G is CR 14 Or N, and X is N or C; Y is C; Z represents CH, N, NR 11 Or O, where R 11 It is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl or optionally substituted 5 to 8-membered heteroaryl; R 7 It is H, halogen, or C1-C6 alkyl; R 12 It is H, halogen, or C1-C6 alkyl; R 13 It is H, halogen, C1-C6 alkoxy or C1-C6 alkyl; and R 14 It is H, halogen, or C1-C6 alkyl.

45. The compound, stereoisomer, tautomer, hydrate, or other compound according to claim 44. N - An oxide derivative or a pharmaceutically acceptable salt, wherein Z is CH, N, or NR. 11 .

46. ​​The compound, stereoisomer, tautomer, hydrate, or other compound according to claim 44. N - An oxide derivative or a pharmaceutically acceptable salt, wherein Z is CH, N, or O.

47. The compound, stereoisomer, tautomer, hydrate, or other compound according to claim 44. N - An oxide derivative or a pharmaceutically acceptable salt, wherein Z is CH or N.

48. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 44 to 47. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 7 It is H, methyl, or halogen.

49. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 44 to 48. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 12 It is H.

50. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 44 to 49. N -Oxide derivatives or pharmaceutically acceptable salts, where D is a CR 7 .

51. The compound, stereoisomer, tautomer, hydrate, or any one of claims 44 to 50 N -Oxide derivatives or pharmaceutically acceptable salts, where E is a CR 13 .

52. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 44 to 51 N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 13 It is H.

53. The compound, stereoisomer, tautomer, hydrate, or any one of claims 44 to 52 N -Oxide derivatives or pharmaceutically acceptable salts, where G is a CR 14 .

54. The compound, stereoisomer, tautomer, hydrate, or any one of claims 44 to 53 N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 14 It is H.

55. The compound, stereoisomer, tautomer, hydrate, or any one of claims 44 to 54 N - An oxide derivative or a pharmaceutically acceptable salt, where X is N.

56. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 44 to 55. N - An oxide derivative or a pharmaceutically acceptable salt, wherein A is CH.

57. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 44 to 55. N - An oxide derivative or a pharmaceutically acceptable salt, wherein A is N.

58. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 44 to 57. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 7 It is halogen.

59. The compound, stereoisomer, tautomer, hydrate, or any one of claims 44 to 58 N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 7 It's fluorine.

60. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 44 to 57. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 7 It is H.

61. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 44 to 60 N -Oxide derivatives or pharmaceutically acceptable salts, where Z is CH.

62. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 44 to 60. N - An oxide derivative or a pharmaceutically acceptable salt, where Z is N.

63. The compound, stereoisomer, tautomer, hydrate, or any of claims 44, 46, or 48 to 60 N - An oxide derivative or a pharmaceutically acceptable salt, wherein Z is O.

64. The compound, stereoisomer, tautomer, hydrate, or any one of claims 44, 45, or 48 to 60 N -Oxide derivatives or pharmaceutically acceptable salts, where Z is NR 11 .

65. The compound, stereoisomer, tautomer, hydrate, or compound according to any one of claims 44, 45, 48 to 60 or 64. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 11 It is H, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, or 5 to 7 heteroaryl.

66. The compound, stereoisomer, tautomer, hydrate, or compound according to any one of claims 44, 45, 48 to 60, 64, or 65. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 11 It is H.

67. The compound, stereoisomer, tautomer, hydrate, or compound according to any one of claims 44, 45, 48 to 60, 64, or 65. N -Oxide derivatives or pharmaceutically acceptable salts, wherein R 11 It is a methyl group.

68. The compound, stereoisomer, tautomer, hydrate, or any one of claims 1 to 25, 27 to 29, 35 to 37, or 41 N -Oxide derivatives or pharmaceutically acceptable salts, wherein: A, D, E, and G do not exist; M is CR a Or N; X is CH; Y is CR 4 ;and Z is NR 6 .

69. The compound, stereoisomer, tautomer, hydrate, or any one of claims 1 to 25, 28 to 30, 35 to 39, or 42 N -Oxide derivatives or pharmaceutically acceptable salts, wherein: A, D, E, and G do not exist; M is CR a ; X is NH; Y is CR 4 ;and Z is CR 5 .

70. The compound, stereoisomer, tautomer, hydrate, or any one of claims 1 to 25, 28, 29, 35, 36, or 37 N -Oxide derivatives or pharmaceutically acceptable salts, wherein: A, D, E, and G do not exist; M is CR a ; X is NH; Y is CR 4 ;and Z is N.

71. The compound, stereoisomer, tautomer, hydrate, or any one of claims 1 to 23, 44, 48, 52, 58, 59, or 60 N -Oxide derivatives or pharmaceutically acceptable salts, wherein: X is N; Y is C; Z is N; M is CR a ; A and G are each CH; D is CR 7 ;and E is CR 13 .

72. The compound, stereoisomer, tautomer, hydrate, or any one of claims 1 to 23, 44, 48, 58, 59, or 60 N -Oxide derivatives or pharmaceutically acceptable salts, wherein: X and Y are both C; Z is O; A, E, G, and M are each CH; and D is CR 7 .

73. The compound, stereoisomer, tautomer, hydrate, or any one of claims 1 to 23, 44, 65, 66, or 67 N -Oxide derivatives or pharmaceutically acceptable salts, wherein: X and Y are both C; Z is NR 11 ; A, E, G, and M are each CH; and D is N.

74. The compound, stereoisomer, tautomer, hydrate, or any one of claims 1 to 23 or 44 N -Oxide derivatives or pharmaceutically acceptable salts, wherein: X and Y are both C; Z is NH; E is N; and A, D, G, and M are each CH.

75. The compound, stereoisomer, tautomer, hydrate, or other product according to any of the preceding claims. N - An oxide derivative or a pharmaceutically acceptable salt, wherein the C1-C6 alkyl group is a C1-C3 alkyl group, optionally methyl.

76. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 12, 14, 23, 35, or 44. N - An oxide derivative or a pharmaceutically acceptable salt, wherein the C1-C6 alkoxy group is a methoxy or 2-methoxyethyl group.

77. The compound, stereoisomer, tautomer, hydrate, or other product according to any of the preceding claims. N -Oxide derivatives or pharmaceutically acceptable salts, wherein the C1-C6 alkylthioalkyl group is SMe.

78. The compound, stereoisomer, tautomer, hydrate, or other compound according to claim 1. N -Oxide derivatives or pharmaceutically acceptable salts, wherein: A, D, E, and G do not exist. X is NH or CH; Y is CR 4 ; Z is CR 5 or NR 6 ; R 1 It is either a piperidine or a piperazine that has been optionally substituted. R 2 and R 3 Together with the carbon atoms they are attached to, they form a cyclopentyl group. R 4 It is phenyl. R 5 It is H, and R 6 It is H or methyl. Each of the optional substituents is selected from phenyl, difluorophenyl, NHCH3, NHCH2CH3, NHCH(CH3)2, NHC(O)CH3, N(CH3)2, NHCH2CHF2, NHCH2CH2F, NHCH2CH2OH and NHCH2CH2OCH3.

79. The compound, stereoisomer, tautomer, hydrate, or other compound according to claim 1. N -Oxide derivatives or pharmaceutically acceptable salts, in which A, D, E, and G do not exist; X is NH or CH; Y is CR 4 ; Z is CR 5 or NR 6 ; R 1 It is piperidine or piperazine, each of which is substituted with difluorophenyl and further substituted with an amino group, which is optionally substituted with one or more of the following substituents: C1-C3 alkyl, oxo-substituted C1-C3 alkyl, fluorine-substituted C1-C3 alkyl, CH2CH2OH, C1-C3 alkoxy, fluorine-substituted C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted with C1-C3 alkyl or pyridine-substituted C1-C3 alkyl; R 2 and R 3 Each is a methyl group, or R 2 and R 3 Together with the carbon atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, oxecyclobutyl, or oxecyclohexyl groups; R 4 It is methyl, dihydrobenzofuran, phenyl, methyl-substituted phenyl, F-substituted phenyl, OMe-substituted phenyl, SMe-substituted phenyl, OH-substituted phenyl or thiophene; R 5 It is H, methyl, or CN; and R 6 It is H or methyl.

80. The compound, stereoisomer, tautomer, hydrate, or other compound according to claim 1. N -Oxide derivatives or pharmaceutically acceptable salts, in which X is N or C; Y is C; Z is N, NR 11 Or O, where R 11 It is H or methyl; M is CR a , where R a It is H, methyl, or cyclopropyl; A is C; D is CR 7 , where R 7 It is H, methyl, F, Cl, Br; E is N or CR 13 , where R 13 It is H, Cl, or OMe; G is C; R 1 It is piperidine or piperazine, each substituted with a difluorophenyl group and further substituted with an amino group, the amino group optionally being substituted with one or more of the following substituents: C1-C3 alkyl, fluorinated C1-C3 alkyl, CH2CH2OH, C1-C3 alkoxy; and R 2 and R 3 Each is a methyl group, or R 2 and R 3 Together with the carbon atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, oxetyl, or oxetyl.

81. A compound selected from: ( R )-6-phenyl-3-((4-(3-phenylmorpholine-4-carbonyl)piperazin-1-yl)methyl)pyridine-2(1 H )-ketone; ( R )-3-((2,2-dimethyl-4-(3-phenylmorpholine-4-carbonyl)piperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)quinoline-2(1 H )-ketone; N -((2 S 4 R )-2-(2,5-difluorophenyl)-1-(6-((2-oxo-6-phenyl-1,2-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidin-4-yl)acetamide; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1,5,7,8-tetrahydro-2 H -pyrano[4,3- b ]Pyridin-2-one; N -(2,4-difluorobenzyl)-6-((2-oxo-6-phenyl-1,2-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxamide; ( R )-6-phenyl-3-((9-(4,4,4-trifluoro-2-methylbutyryl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-4-(methylamino)-2-phenylpiperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; ( R )-3-((9-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 6-Phenylacetyl-3-((9-((3) R 4 R )-3-phenylpiperidine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-4-((3,3-difluorocyclobutyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; ( S )-6-phenyl-3-((9-(4,4,4-trifluoro-2-(methoxymethyl)butyryl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1 H )-ketone; ( R )-3-((9-(3-cyclohexyl-2-methylpropionyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 6-Phenylacetyl-3-((9-(3-phenylisonicotinyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-4-((2-hydroxyethyl)amino)-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2,2-dimethylpiperazin-1-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((7-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-4,7-diazaspiro[2,5]octane-4-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 6-Phenylacetyl-3-((9-((2) S 4 R )-2-phenyl-4-((pyridin-2-ylmethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridin-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(3,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( R )-3-((9-(2-methyl-2-phenylpiperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( R )-5-((9-(3-(2,5-difluorophenyl)morpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( S )-5-((9-(3-(2,5-difluorophenyl)morpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,3-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-4-(methylamino)-2-phenylpiperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-4-(cyclopropylamino)-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( R )-5-((9-(2-(2,5-difluorophenyl)-1,4-diazacycloheptane-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( S )-5-((9-(2-(2,5-difluorophenyl)-1,4-diazacycloheptane-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( R )-5-((9-(3-(2,5-difluorophenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( S )-5-((9-(3-(2,5-difluorophenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,6-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 3-((9-((3 R 5 S )-3-(2,5-difluorophenyl)-5-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((8-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-5,8-diazaspiro[3.5]nonane-5-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((8-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2-oxa-5,8-diazaspiro[3.5]nonane-5-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 3-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2,2-dimethylpiperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((7-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-4,7-diazaspiro[2,5]octane-4-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-4-amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((8-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-5,8-diazaspiro[3.5]nonane-5-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((8-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2-oxa-5,8-diazaspiro[3.5]nonane-5-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(pyrrolidine-1-yl)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-3-yl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(1-methyl-1 H -pyrazol-5-yl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-methyl-5-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-2-yl)pyridine-4(1 H )-ketone; ( R )-3-((9-(3-cyclohexyl-2-methylpropionyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 5-((9-((2 S 4 R )-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-4-morpholinyl-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-fluorophenyl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(o-tolyl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-methoxyphenyl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-4 H -chromone-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-4 H -chromone-4-one; ( R )-3-((9-(3-cyclohexyl-2-methylpropionyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H -chromone-4-one; ( R )-3-((9-(3-cyclohexyl-2-methylpropionyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-4 H -chromone-4-one; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2,3-dihydrobenzofuran-7-yl)pyridine-4(1 H )-ketone; ( R )-3-((9-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-4 H -chromone-4-one; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(1-methyl-1 H -pyrazole-3-yl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 1-Cyclopropyl-5-((9-((2) S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-methylpyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-5,6-dimethylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-4 H -pyrimidin[1,2- b ]pyridazin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoroquinoline-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(2-hydroxyphenyl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-methyl-2-propylpyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-5-(trifluoromethyl)pyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(o-tolyl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2,3-dihydrobenzofuran-7-yl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-methoxyphenyl)pyridine-4(1 H )-ketone; ( R )-5-((9-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( R )-3-((9-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H -pyrido[1,2-a]pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(4-fluorophenyl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(3-fluorophenyl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(m-tolyl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(2-methoxyphenyl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2,3-dihydrobenzofuran-7-yl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(o-tolyl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(m-tolyl)pyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(3-fluorophenyl)pyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(4-fluorophenyl)pyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(3-fluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(methylthio)-6-oxo-1,6-dihydropyridine-3-carboxynitrile; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyrimidine-4(3 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1,7-naphthidine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyrimidine-4(3 H )-ketone; 5-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-2-yl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-2-yl)pyridine-4(1 H )-ketone; 5-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2,6-dimethylpyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((4-((2 S 5 R )-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; ( R )-6-phenyl-3-((4-(3-phenylmorpholine-4-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)pyridine-2(1 H )-ketone; ( R )-3-((4-(3-(4-fluorophenyl)morpholine-4-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((4-((2 R 5 R )-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2-fluoro-5-methylphenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2-fluoro-5-methoxyphenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 5 R )-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-phenylpyrimidine-4(3 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; N -((2 S 4 R )-2-(2,5-difluorophenyl)-1-(6-((7-fluoro-4-oxo-4) H -pyrido[1,2- a [Pyrimidin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidin-4-yl)acetamide; N -((2 S 4 R )-2-(2,5-difluorophenyl)-1-(6-((7-fluoro-4-oxo-4) H -pyrido[1,2- a [Pyrimidin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidin-4-yl)cyclopropaneformamide; 3-((9-((2 S 4 R )-4-((1,1-dioxothioheterobutane-3-yl)amino)-2-phenylpiperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-4-((2,2-difluoroethyl)amino)-2-(3,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(thiophene-3-yl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; ( S )-6-(2-methoxyphenyl)-3-((9-(2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1 H )-ketone; ( S )-6-phenyl-3-((7-(2-phenylpyrrolidine-1-carbonyl)-4,7-diazaspiro[2.5]octane-4-yl)methyl)pyridine-2(1 H )-ketone; ( S )-6-phenyl-3-((4-(2-phenylpyrrolidine-1-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)pyridine-2(1 H )-ketone; 5-((9-((2 R 5 R )-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; ( S )-3-((4-(2-(2,5-difluorophenyl)pyrrolidine-1-carbonyl)-2,2-dimethylpiperazin-1-yl)methyl)-6-(1-methyl-1 H -pyrazole-5-yl)pyridine-2(1 H )-ketone; ( S )-3-((2,2-dimethyl-4-(2-phenylpyrrolidine-1-carbonyl)piperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; ( S )-6-phenyl-3-((8-(2-phenylpyrrolidine-1-carbonyl)-2-oxa-5,8-diazaspiro[3.5]nonane-5-yl)methyl)pyridine-2(1 H )-ketone; 3-((4-((1 S ,2 R 5 R )-2-(2,5-difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)piperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((1 S ,2 R 5 R )-2-(2,5-difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((1 S ,2 R 5 R )-2-(2,5-difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(2-fluorophenyl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-1-methylquinoline-4(1 H )-ketone; 3-((9-((2 R ,3 R )-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S ,3 S )-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(1-methyl-1 H -pyrazol-5-yl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(trifluoromethyl)pyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(trifluoromethyl)pyridine-4(1 H )-ketone; 3-((4-((2 R ,3 R )-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((4-((2 S ,3 S )-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazin-1-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 R ,3 R )-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S ,3 S )-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 3-((9-((2 R 4 R )-4-amino-2-ethylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 R 4 R )-2-ethyl-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)(methyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(1-methyl-1 H -pyrazole-3-yl)pyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-3-yl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-hydroxypiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(1-methyl-1 H -pyrazole-3-yl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropyl(methyl)amino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-methoxyethyl)(methyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-hydroxypiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(thiophene-3-yl)pyridine-4(1 H )-ketone; 3-((( S )-4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-2-methylpiperazin-1-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 7-Chloro-3-((9-((2) S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidin-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-2,2-dimethylpiperazin-1-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((( R )-4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-2-methylpiperazin-1-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(thiophen-3-yl)pyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)(methyl)amino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(ethyl(methyl)amino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-methyl-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-8-methoxy-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 5-((9-((2 S 4 S )-4-amino-2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 5-((9-((2 S 4 S )-4-(isopropylamino)-2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7,8-dihydropyrrolo[1,2- a ]Pyrimidine-4(6 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7,8-dihydropyrrolo[1,2- a ]Pyrimidine-4(6 H )-ketone; 3-((9-(5-amino-2',5'-difluoro-[1,1'-biphenyl]-2-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-6-phenylpyridine-2(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-2-methyl-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-fluoroethyl)amino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((2-fluoroethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1 H )-ketone; 7-Fluoro-3-((9-((2) S 4 S )-4-(isopropylamino)-2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-methyl-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-2-methyl-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 4-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-1-phenyl-1,2-dihydro-3 H -Pyrazol-3-one; 4-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-methyl-1-phenyl-1,2-dihydro-3 H -Pyrazol-3-one; 7-Chloro-3-((9-((2) S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((4-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(ethylamino)piperidin-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 7-Chloro-3-((9-((2) S 4 R )-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 6-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-5 H -Thiazo[3,2- a ]Pyrimidin-5-one; 6-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-5 H -Thiazo[3,2- a ]Pyrimidin-5-one; 7-Fluoro-3-((9-((2) S 4 R )-4-((3-methyloxetane-3-yl)amino)-2-phenylpiperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-methyl-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-2-methyl-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 2-Cyclopropyl-3-((9-((2) S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 2-Cyclopropyl-3-((9-((2) S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridazine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridazine-4(1 H )-ketone; 3-((9-((2 S 4 R )-4-amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidin-1-carbonyl)-6,9-diazaspiro[4,5]dec-2-en-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 7-Bromo-3-((9-((2) S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 8-Chloro-3-((9-((2) S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-2-(trifluoromethyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-2-(trifluoromethyl)-4 H -pyrido[1,2- a ]Pyrimidin-4-one; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-1,6-naphthidine-4(1 H )-ketone; 3-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-((1-methylcyclopropyl)amino)piperidin-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4 H -pyrido[1,2- a ]Pyrimidin-4-one; and 5-((9-((2 S 4 R )-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(1-methylcyclopropyl)pyridine-4(1 H )-ketone; Or its stereoisomers, tautomers, hydrates, N -Oxide derivatives or pharmaceutically acceptable salts.

82. The compound, stereoisomer, tautomer, hydrate, or other product according to any of the preceding claims. N - An oxide derivative or a pharmaceutically acceptable salt that is an inhibitor of USP19, preferably an inhibitor of human USP19.

83. A pharmaceutical composition comprising a compound, stereoisomer, tautomer, hydrate, or other compound according to any of the preceding claims. N -Oxide derivatives or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers or diluents.

84. The compound, stereoisomer, tautomer, hydrate, or any one of claims 1 to 82 N - An oxide derivative or a pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 83, for use in treatment.

85. The compound, stereoisomer, tautomer, hydrate, or any one of claims 1 to 82 N - An oxide derivative or a pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 83, which is used as a medicine.

86. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 1 to 82. N - An oxide derivative or a pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 83, for the treatment of muscle atrophy, obesity, insulin resistance, or type II diabetes.

87. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 1 to 82. N - An oxide derivative or a pharmaceutically acceptable salt or a pharmaceutical composition according to claim 83, for the treatment of muscle atrophy, cachexia, or sarcopenia, wherein the muscle atrophy, cachexia, or sarcopenia is associated with or induced by cancer.

88. The compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 1 to 82. N - An oxide derivative or a pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 83, for the treatment of cancer, preferably wherein the cancer is breast cancer or neuroblastoma.

89. The compound, stereoisomer, tautomer, hydrate, or any one of claims 1 to 82 N - An oxide derivative or a pharmaceutically acceptable salt or a pharmaceutical composition according to claim 83, used for the purposes according to claim 88, wherein said use includes the treatment of muscle atrophy, cachexia and / or sarcopenia.

90. A method for treating obesity, insulin resistance, type II diabetes, or muscle atrophy, comprising administering to a subject in need an effective amount of the compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 1 to 82. N - An oxide derivative or a pharmaceutically acceptable salt or a pharmaceutical composition according to claim 83.

91. A method for reducing muscle mass loss in a subject, comprising administering to the subject in need an effective amount of the compound, stereoisomer, tautomer, hydrate, or other compound according to any one of claims 1 to 82. N - An oxide derivative or a pharmaceutically acceptable salt or a pharmaceutical composition according to claim 83.

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