Pharmaceutical compounds

Abstract

JPEG2026525352000192.jpg3981 The present invention relates to compounds of formula (I) that are useful as inhibitors of ubiquitin-specific protease USP19 activity. The present invention also relates to pharmaceutical compositions comprising these compounds and methods of using these compounds in therapeutics.

Description

[Technical Field]

[0001] Field of Invention The present invention relates to a ubiquitin-specific protease 19 (USP19) inhibitor and a method for using the same. [Background technology]

[0002] background Over the past decade, protein ubiquitination has emerged as a crucial post-translational modification, playing a significant role in a wide range of cellular processes, including, among others, proteolysis, gene expression, DNA repair, immune responses, and metabolic or cell cycle regulation. Dysregulation of the ubiquitin-proteasome system (UPS) is also associated with cancer (Hoeller D. et al., Nat. Rev. Cancer (2006), 6, 776-788), viral infections (Gao et al., Can. J. Physiol., Pharmacol. (2006), 84, 5-14), metabolic or neurodegenerative disorders (van Loosdregt J. et al., Immunity (2013), 39, 259-271; Rubinsztein D., et al., Nature (2006), 443, 780-786), and medical conditions related to immunity and inflammation (Wang J. et al., Cell Mol. Immunol. (2006), 3, 255-261; Corn J. et al., Nat. Struct. Mol. Biol. (2014), 21, It has been associated with the pathogenesis of several human diseases, including, but not limited to, those mentioned above (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) has led to the recognition of UPS as a pharmacologically intervenable cancer target. While effective, its clinical utility is severely limited, on the one hand, due to poor selectivity and acute toxicity issues. By inhibiting the 26S proteasome, current proteasome inhibitors indiscriminately impair proteolysis in both cancer and normal cells and are characterized by a low therapeutic index. To circumvent this problem, a promising alternative approach may be to target UPS upstream of the proteasome. Interference with ubiquitin (Ub) coupling / uncoupling mechanisms, for example at the ubiquitin-specific protease (USP) level, would enable the development of improved therapies with increased specificity and reduced toxicity profiles.

[0004] USP is the largest subfamily of the deubiquitinating enzyme (DUB) family, with over 60 family members reported to date (Komander D. et al., Nat. Rev. Mol. Cell Biol. (2009), 10, 550-563; Clague M. et al., Physiol. Rev. (2013), 93, 1289-1315). USP is a cysteine ​​protease that typically catalyzes the removal of Ub from specific target substrates, and therefore inhibits proteasome-mediated degradation or regulates its activation and / or intracellular 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 established that USPs control the stability and activation of numerous proteins involved in the pathogenesis of human diseases, including both oncogenes and tumor suppressors. In other words, USPs represent an emerging and attractive class of targets for pharmacological intervention.

[0005] Of all USPs, USP19 is an important member because it is associated with several key pathways linked to pathological conditions including, but not limited to, cancer, neurodegenerative and degenerative diseases, and antiviral immune responses. USP19 varies in length from 71.09 kDa (isoform 2) to 156.03 kDa (isoform 5) and is expressed as multiple isoforms with a 145.65 kDa canonical sequence (isoform 1) (uniprot.org). The cellular localization of USP19 is cytoplasmic or endoplasmic reticulum-bound (Lee J. et al., J. Biol. Chem. (2014), 289, 3510-3517; Lee J. et al., Nat. Cell Biol. (2016), 18, 765-776). Due to its localization to the endoplasmic reticulum, USP19 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). In particular, USP19 is involved in subsequent steps of protein quality control mechanisms that rescue ERAD substrates being transported retrogradely into the cytoplasm. USP19 has also been shown to regulate the stability of 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 associated with the stabilization of several important and potentially significant protein substrates. For example, under hypoxic conditions, USP19 interacts with the SIAH protein to rescue HIF1α from degradation (Altun M. et al., J. Biol. Chem. (2012), 287, 1962-1969; Velasco K. et al., Biochem. Biophys. Res. Commun. (2013), 433, 390-395).The USP19 is also on page 27. Kip1 The KPC1 ubiquitin ligase, which is involved in the regulation of cyclin-dependent kinase inhibitors, is also stabilized (Lu Y. et al., Mol. Cell Biol. (2009), 29, 547-558). RNAi-mediated USP19 knockout is p27 Kip1This leads to accumulation and inhibition of cell proliferation (Lu Y. et al., PLoS ONE (2011), 6, e15936). USP19 was also found to interact with apoptosis inhibitory molecules (IAPs), including c-IAP1 and c-IAP2 (Mei Y. et al., J. Biol. Chem. (2011), 286, 35380-35387). Knockdown of USP19 reduces the total level of these c-IAPs, while overexpression increases the levels of both BIRC2 / cIAP1 and BIRC3 / cIAP2. Knockdown of USP19 also enhances TNFα-induced caspase activation and apoptosis in a BIRC2 / c-IAP1 and BIRC3 / c-IAP2-dependent manner. In addition to several direct involvements in hypoxic response and ER stress control, USP19 has also recently been associated with being a positive regulator of autophagy and a negative regulator of type I interferon signaling (IFN, antiviral immune response) by deubiquitinating beclin-1. USP19 has been found to stabilize beclin-1 at the posttranslational level by removing the K11-binding ubiquitin chain of beclin-1 at lysine 437 (Jin S. et al., EMBO J. (2016), 35, 866-880). USP19 negatively regulates the type I IFN signaling pathway by blocking the RIG-I-MAVS interaction in a beclin-1-dependent manner. USP19 or becrin-1 depletion inhibits the autophagy flux and promotes type I IFN signaling and cellular antiviral immunity (Jin S. et al., EMBO J. (2016), 35, 866-880; Cui J. et al., Autophagy (2016), 12, 1210-1211). Recent findings also suggest that USP19 may negatively affect cellular antiviral type I IFN signaling by regulating TRAF3 substrates (Gu Z. et al., Future Microbiol. (2017), 12, 767-779).USP19 has also recently been linked to the Wnt signaling pathway through the stabilization of the co-receptor LRP6 (Perrody E. et al., eLife (2016), 5, e19083) and to DNA repair processes regulated by HDAC1 and HDAC2 proteins, most specifically to chromosome stability and integrity (Wu M. et al., Oncotarget (2017), 8, 2197-2208).

[0006] In addition to cancer and related conditions, USP19 has also been associated with muscle wasting syndrome and other skeletal muscle atrophy disorders 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 of which is incorporated herein by reference). Muscle wasting associated with conditions such as cachexia is known to impair quality of life and response to treatment, and to increase morbidity and mortality in cancer patients. Muscle wasting is also associated with other serious illnesses 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 wasting is also a prominent characteristic of aging.

[0007] In addition to the above-mentioned pathological conditions, USP19 may also be associated with the pathogenesis of degenerative diseases, including but not limited to Parkinson's disease and other prion-like transmission disorders, by regulating important substrates such as α-synuclein or polyglutamine-containing proteins, ataxin 3, and Huntington (He W. et al., PLoS ONE (2016), 11, e0147515; Bieri G. et al., Neurobiol Dis. (2018), 109B, 219-225). Regulation of coronin 2A (CORO2A) via USP19 activity has been shown to affect the transcriptional repression activity of the retinoic acid receptor (RAR), suggesting that USP19 may also be associated with the regulation of RAR-mediated adipogenesis (Lim K. et al., Oncotarget (2016), 7, 34759 - 34772).

[0008] WO2022 / 200523A1 discloses compounds useful as inhibitors of the activity of the ubiquitin-specific protease USP19, and also relates to pharmaceutical compositions containing these compounds and methods for using these compounds in therapy. [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] The establishment of associations between USP19 and numerous proteins involved in human pathogenesis suggests that small molecule inhibitors of USP19 may have broad therapeutic applications beneficial to human health. Identifying such inhibitors with drug-like potential is of paramount importance and high priority. [Means for solving the problem]

[0010] Summary of the Invention In the first embodiment, equation (I) [ka] [During the ceremony, R 1is C1-C6 alkyl optionally substituted, amino optionally substituted, 3- to 11-member heterocycloalkyl optionally substituted, aryl optionally substituted, or 5- to 8-member heteroaryl optionally substituted; R 2 and R 3 are each independently selected from the group consisting of H and C1-C6 alkyl, or R 2 and R 3 together with the carbon to which they are attached form C3-C8 cycloalkyl, C3-C8 cycloalkenyl or 3- to 8-member heterocycloalkyl; M is N or CR a wherein, R a is H, halo, C3-C8 cycloalkyl optionally substituted, or C1-C6 alkyl optionally substituted; A, D, E and G are absent and X is NR 15 or CH; Y is CR 4 or N or is absent; Z is CR 5 , NR 6 or O; R 4 is halo, C1-C6 alkyl optionally substituted, C3-C8 cycloalkyl optionally substituted, aryl optionally substituted, 5- to 8-member heteroaryl optionally substituted, 4- to 10-member fused-ring heterocyclyl, C1-C6 alkylsulfanyl optionally substituted, sulfoxide, sulfone, sulfoximine, amino optionally substituted, 3- to 8-member heterocycloalkyl optionally substituted, or OR 20 ; wherein, R 20 is C1-C6 alkyl optionally substituted; R 5H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5-8 member heteroaryl, optionally substituted 3-8 member heterocycloalkyl, amide, sulfoxymine, CN, halo, C(O)OR 21 , OR 22 , or NR 23 R 24 and; Here, R 21 The elements are selected from H and C1-C6 alkyl groups; R 22 The elements are selected from H and C1-C6 alkyl groups; R 23 and R 24 These are independently selected from H and optionally substituted C1-C6 alkyl groups; R 15 is H or C1-C6 alkyl; or R 4 and R 5 They, together with the Y and Z to which they are bound, form 3- to 8-membered heterocycloalkyl or aryl groups; or R 4 and R 15 They, together with X and Y to which they are bound, form a five-membered cycloalkyl, heterocycloalkyl, or heteroaryl group; R 6 is H, C1-C6 alkyl, optionally substituted aryl, or C3-C8 cycloalkyl; Or A is CR 12 Or N, and D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 or N and X is either N or C; Y is C; Z is CR 20 , N, NR 11 , or O, Here, R 11is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted 5-8 membered heteroaryl; Here, R 20 H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5-8 member heteroaryl, optionally substituted 3-8 member heterocycloalkyl, amide, sulfoxymine, CN, halo, C(O)OR 25 , OR 26 , or NR 27 R 28 and; Here, R 25 The elements are selected from H and C1-C6 alkyl groups; R 26 The elements are selected from H and C1-C6 alkyl groups; R 27 and R 28 These are independently selected from H and C1-C6 alkyl groups; R 7 is H, halo, C1-C6 alkyl, or OR 19 and; Here, R 19 is a C1-C6 alkyl group which is optionally substituted; R 12 is H, halo, or C1-C6 alkyl; R 13 H, halo, C1-C6 alkyl, OR 16 ; or NR 17 R 18 and; Here, R 16 This is a C1-C6 alkyl group that is optionally substituted. R 17 and R 18 The elements are independently selected from H and C1-C6 alkyl groups or R 17 and R 18 They combine with the nitrogen atom to which they are bonded to form a 5-6 member heterocycloalkyl group; and R 14[This is H, halo, or C1-C6 alkyl.] The present invention provides compounds thereof, their stereoisomers, tautomers, hydrates, N-oxide derivatives, or pharmaceutically acceptable salts.

[0011] In a second embodiment, the present invention provides a pharmaceutical composition comprising a compound according to the first embodiment, a stereoisomer, a tautomer, a hydrate, an N-oxide derivative or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or diluent.

[0012] In a further embodiment, the present invention provides compounds, stereoisomers, tautomers, hydrates, N-oxide derivatives or pharmaceutically acceptable salts according to a first embodiment, or pharmaceutical compositions according to a second embodiment, for therapeutic use.

[0013] In a further embodiment, the present invention provides compounds, stereoisomers, tautomers, hydrates, N-oxide derivatives or pharmaceutically acceptable salts, or pharmaceutical compositions, in a first embodiment, for use as pharmaceuticals.

[0014] In a further embodiment, the present invention provides compounds, stereoisomers, tautomers, hydrates, N-oxide derivatives or pharmaceutically acceptable salts or pharmaceutical compositions in a second embodiment for use in the treatment of muscle atrophy, obesity, insulin resistance, or type II diabetes.

[0015] In a further embodiment, the present invention provides compounds, stereoisomers, tautomers, hydrates, N-oxide derivatives or pharmaceutically acceptable salts or pharmaceutical compositions in a second embodiment for use in the treatment of muscle atrophy, cachexia or sarcopenia, in which muscle atrophy, cachexia and sarcopenia are associated with or induced by cancer.

[0016] In a further embodiment, the present invention provides a method for treating obesity, insulin resistance, type II diabetes, or muscle atrophy, comprising administering an effective amount of a compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt or a pharmaceutical composition in a second embodiment to a subject in need thereof.

[0017] In a further embodiment, 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 a compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt or a pharmaceutical composition in a second embodiment.

[0018] USP19 is associated with several diseases and conditions, including (but not limited to) cancer and neoplasms. Knockout of USP19 by RNAi is p27 Kip1 This leads to accumulation and inhibition of cell proliferation (Lu Y. et al., PLoS ONE (2011), 6, e15936). USP19 was also found to interact with apoptosis inhibitory molecules (IAPs), including c-IAP1 and c-IAP2 (Mei Y. et al., J. Biol. Chem. (2011), 286, 35380-35387). Knockdown of USP19 reduces the total level of these c-IAPs, while overexpression increases the levels of both BIRC2 / cIAP1 and BIRC3 / cIAP2. Knockdown of USP19 also enhances TNFα-induced caspase activation and apoptosis in a BIRC2 / c-IAP1 and BIRC3 / c-IAP2-dependent manner. USP19 has also recently been linked to the Wnt signaling pathway through the stabilization of the co-receptor LRP6 (Perrody E. et al., eLife (2016), 5, e19083) and to DNA repair processes regulated by HDAC1 and HDAC2 proteins, most specifically to chromosome stability and integrity (Wu M. et al., Oncotarget (2017), 8, 2197-2208).

[0019] Furthermore, in relation to the first aspect, the USP19 inhibitor compounds described herein have been shown to exhibit cell permeability and potent target binding in cancer cell lines. The cell permeability and target binding in cancer cells are equivalent to those observed in muscle cells. As shown herein, USP19 inhibitors exhibit potent in vivo therapeutic effects on muscle wasting. Therefore, extending this line of reasoning, since similar target binding is observed in cancer cells, it is predicted that pharmacological USP19 inhibitors will be effective in exerting therapeutic effects in cancer due to the aforementioned relationship between USP19 and the carcinogenic process.

[0020] In vivo studies also showed that mice lacking the USP19 gene (USP19 KO mice) exhibited increased fat content 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 showed greater glucose tolerance and higher insulin sensitivity when fed a high-fat diet.

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

[0022] USP19 has also been associated with muscle atrophy, muscle wasting syndrome, and other skeletal muscle atrophy disorders (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). This is supported, for example, by studies showing that USP19 silencing induces myofibrillar protein expression and promotes myogenesis (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 shown that mice lacking the USP19 gene were resistant to both muscle wasting in response to glucocorticoids, a common systemic cause of muscle atrophy, and denervation, a model of disuse atrophy (Bedard N. et al., FASEB J. (2015), 29, 3889-3898, which is incorporated herein by reference).

[0024] As shown in the attached examples, it is demonstrated here that pharmacological treatment with a USP19 inhibitor can induce a therapeutic effect in a wild-type in vivo model.

[0025] In particular, this study demonstrates that USP19 inhibitors reduce fat deposition in an in vivo model, suggesting that USP19 inhibitors may be an effective treatment for obesity.

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

[0027] Similarly, it is shown here that USP19 inhibitors can treat symptoms of insulin resistance, as demonstrated by improved response to glucose.

[0028] The compounds of the present invention can selectively inhibit USP19 activity. The examples further demonstrate that compounds that can potently inhibit USP19 activity may be effective therapeutic compounds. The compounds of the present invention are therefore suitable for use in therapeutic methods. Suitable indications for treatment with the compounds of the present invention include: cancer and neoplasms; treatment and prevention of immunological and inflammatory conditions, e.g., by promoting antiviral immune responses; treatment and prevention of muscle atrophy, e.g., cachexia and sarcopenia; treatment and prevention of obesity; treatment and prevention of insulin resistance, e.g., diabetes mellitus; and treatment and prevention of neurodegenerative diseases, including Parkinson's disease and other prion-based disorders.

[0029] Accordingly, in a further embodiment, a compound according to the first embodiment, or its stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt, or a pharmaceutical composition according to the second embodiment, is provided for therapeutic use.

[0030] In a further embodiment, a compound according to the first embodiment, or a stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second embodiment, is provided for use in methods of treating or preventing the compound according to the first embodiment, or a stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second embodiment. In one preferred embodiment, the cancer to be treated is breast cancer or neuroblastoma.

[0031] In a further embodiment, a compound according to the first embodiment, or a stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second embodiment, is provided for use in methods of treating or preventing the compound according to the first embodiment, or a stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second embodiment.

[0032] In a further embodiment, a compound according to the first embodiment, or a stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second embodiment, is provided for use in methods of treating or preventing the compound according to the first embodiment, or a stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second embodiment.

[0033] In a further embodiment, a compound according to the first embodiment, or a stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second embodiment, is provided for use in methods of treating or preventing the compound according to the first embodiment, or a stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second embodiment.

[0034] In a further embodiment, a compound according to the first embodiment, or a stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second embodiment, is provided for use in methods of treating or preventing the compound according to the first embodiment, or a stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second embodiment.

[0035] In a further embodiment, a compound according to the first embodiment, or a stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second embodiment, is provided for use in methods of treating or preventing the compound according to the first embodiment, or a stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second embodiment.

[0036] In a further embodiment, a method for treating cancer is provided, comprising administering to a subject an effective amount of the compound according to the first embodiment, or its stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt, or a pharmaceutical composition according to the second embodiment.

[0037] In a further embodiment, a method for treating muscle atrophy is provided, comprising administering to a subject an effective amount of the compound according to the first embodiment, or its stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt, or a pharmaceutical composition according to the second embodiment.

[0038] In a further embodiment, a method for treating Parkinson's disease is provided, comprising administering to a subject an effective amount of the compound according to the first embodiment, or its stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt, or a pharmaceutical composition according to the second embodiment.

[0039] This compound, or its stereoisomers, tautomers, hydrates, N-oxide derivatives, or pharmaceutically acceptable salts, may be used as monotherapy or in combination with radiotherapy and / or further therapeutic agents.

[0040] While we do not wish to be bound by theory, the compounds of the present invention tend to exhibit the above-mentioned advantageous effects, at least in part, due to the presence of a carbon atom between the 'M' position and the carbonyl group in formula (I).

[0041] As shown in Table 1, the compounds of the present invention exhibit improved in vitro physicochemical properties such as high kinetic solubility (KSol) and high metabolic stability (low estimated endogenous clearance, CL, using human liver microsome data) compared to analogs in which a nitrogen atom exists between the 'M' position and the carbonyl group. int It shows improvements in in vitro ADME properties, such as (as indicated by) and low CYP3A4 inhibition.

[0042] [Table 1]

[0043] As shown in Table 2, the compounds of the present invention exhibit improved in vitro physicochemical properties such as high kinetic solubility (KSol) and high metabolic stability (low estimated endogenous clearance, CL, using human liver microsome data) compared to analogs in which a nitrogen atom exists between the 'M' position and the carbonyl group. int It shows improvements in in vitro ADME properties, such as (as indicated by) and low CYP3A4 inhibition.

[0044] [Table 2]

[0045] As shown in Table 3, the compounds of the present invention exhibit high metabolic stability (low estimated endogenous clearance, CL) compared to analogs in which a nitrogen atom exists between the 'M' position and the carbonyl group (using mouse or rat liver microsome data). int It shows improvements in in vitro ADME properties, such as (as shown by) and low CYP3A4 inhibition.

[0046] [Table 3]

[0047] Other preferred embodiments of the compounds provided herein will become apparent through the specification and, in particular, the examples. Of particular preference are the compounds listed as having high activity in testing. Compounds with high activity are preferred over those with low activity.

[0048] Each aspect or embodiment defined herein may be combined with any other aspect or embodiment unless it is clearly shown to be contrary to that aspect. Any characteristic shown as particularly preferred or advantageous may be combined with any one or more other characteristics shown as preferred or advantageous. [Brief explanation of the drawing]

[0049] [Figure 1] Effect of USP19 pharmacological inhibition on tibialis anterior muscle mass. (A) Tibialis anterior muscle mass (mg) from mice treated with the medium or the USP19 inhibitor compound ADC-141. Mass is shown for muscle from limbs that underwent sciatic denervation (DEN) and limbs that were also innervated (INN). (B) Percentage of tibialis anterior muscle mass loss as a result of denervation in mice treated with the medium and the USP19 inhibitor (ADC-141). The percentage was calculated as the ratio of muscle mass from the innervated limb of the same mouse. (C) Loss of tibialis anterior muscle mass (mg) as a result of denervation in mice treated with the medium and the USP19 inhibitor (ADC-141). P<0.025.

[0050] [Figure 2]Effect of USP19 pharmacological inhibition on gastrocnemius muscle mass. (A) Gastrocnemius muscle mass (mg) from mice treated with the medium or the USP19 inhibitor compound ADC-141. Mass is shown for muscle from limbs that underwent sciatic denervation (DEN) and limbs that were also innervated (INN). (B) Percentage of gastrocnemius muscle mass loss as a result of denervation in mice treated with the medium and the USP19 inhibitor (ADC-141). The percentage was calculated as the ratio of muscle mass from the innervated limb of the same mouse. (C) Loss of gastrocnemius muscle mass (mg) as a result of denervation in mice treated with the medium and the USP19 inhibitor (ADC-141).

[0051] [Figure 3] (A) Effect of USP19 pharmacological inhibition on fat mass. Epididymal fat pads were collected from mice treated with the vehicle and those treated with the USP19 inhibitor (ADC-141). The USP19 inhibitor-treated mice showed a significant reduction in fat mass. (B) Effect of USP19 pharmacological inhibition on liver mass. Livers were collected from mice treated with the vehicle and those treated with the USP19 inhibitor (ADC-141). An increase in liver mass was observed, likely due to drug compound accumulation in the liver. (C) Percentage change in total body weight in vehicle-treated control DIO mice. (D) Percentage change in total lean body mass and (E) Percentage change in total fat mass in mice treated with USP19 inhibitor 5 mg / kg ip BID, USP19 inhibitor 25 mg / kg ip BID, or positive control liraglutide 0.1 mg / kg sc BID (bars from left to right, respectively); medium, USP19 inhibitor 5 mg / kg, USP19 inhibitor 25 mg / kg, and liraglutide (bars from left to right, respectively). ***p<0.001 vs. medium

[0052] [Figure 4] Cellular target binding of USP19 inhibitor compounds to breast cancer, neuroblastoma, and skeletal muscle cell lines. EC50 was determined by densitometry.

[0053] [Figure 5]Response to oral glucose tolerance test (OGTT) in obese mice. (A) Timelines of plasma glucose response in media-treated control mice (circles), USP19 inhibitor 5 mg / kg ip BID (triangles), USP19 inhibitor 25 mg / kg ip BID (black circles), or positive control liraglutide 0.1 mg / kg sc BID (diamonds); (B) Glucose AUC (mM. time) and (C) Insulin AUC (ng. time / mL) for media, USP19 inhibitor 5 mg / kg, USP19 inhibitor 25 mg / kg, and liraglutide (from left to right, respectively). **p<0.01 vs. media; ***p<0.001 vs. media. [Modes for carrying out the invention]

[0054] Detailed description of the invention Unless otherwise defined herein, scientific and technical terms used in connection with this invention have the meanings generally understood by those skilled in the art. The meaning and scope of terms should be clear, but where there is any ambiguity, the definitions provided herein shall take precedence over any dictionary or external definitions.

[0055] To the extent that they are used herein and in the appended claims, unless otherwise specified, the following terms have the meanings shown: The term “alkyl group” (alone or in combination with other terms) typically refers to a linear or branched saturated hydrocarbon substituent containing 1 to 15 carbon atoms, e.g., 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. n An alkyl group is an aliphatic group containing n carbon atoms. For example, C1-C 10Alkyl alkyl groups contain one, two, three, four, five, six, seven, eight, nine, or ten carbon atoms. Bonding to alkyl groups occurs via carbon atoms. 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).

[0056] The term “alkenyl group” (alone or in combination with other terms) refers to a linear or branched hydrocarbon substituent containing one or more double bonds and typically 2 to 15 carbon atoms; for example, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. Examples of such substituents include ethenyl (vinyl), 1-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl, and hexenyl.

[0057] The term “alkynyl group” (alone or in combination with other terms) refers to a linear or branched hydrocarbon substituent containing one or more triple bonds and typically 2 to 15 carbon atoms; for example, 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.

[0058] The term "heteroalkyl group" (on its own or in combination with other terms) typically refers to a linear or branched saturated hydrocarbyl substituent containing 1 to 15 atoms, e.g., 1 to 10, 1 to 8, 1 to 6, or 1 to 4 atoms, where at least one of the atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur) and the remaining atoms are carbon atoms. n A "heteroalkyl" group refers to an aliphatic group containing n carbon atoms and one or more heteroatoms, for example, one heteroatom. 10A heteroalkyl group contains one or more heteroatoms, for example, one heteroatom plus one, two, three, four, five, six, seven, eight, nine, or ten carbon atoms. Bonding to the heteroalkyl group occurs via carbon atoms or via heteroatoms.

[0059] The term “heteroalkenyl group” (alone or in combination with other terms) means a linear or branched hydrocarbon substituent containing one or more carbon-carbon double bonds and typically 2 to 15 atoms; for example, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 atoms, where at least one of the atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur) and the remaining atoms are carbon atoms. n A heteroalkenyl group is an aliphatic group containing n carbon atoms and one or more heteroatoms, for example, one heteroatom. 10 A heteroalkenyl group contains one or more heteroatoms, for example, one heteroatom plus two, three, four, five, six, seven, eight, nine, or ten carbon atoms. Bonding to the heteroalkenyl group occurs via carbon atoms or via heteroatoms.

[0060] The term “heteroalkynyl group” (alone or in combination with other terms) means a linear or branched hydrocarbon substituent containing one or more carbon-carbon triple bonds and typically 2 to 15 carbon atoms; for example, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms, where at least one of the atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur) and the remaining atoms are carbon atoms. n A heteroalkynyl group refers to an aliphatic group containing n carbon atoms and one or more heteroatoms, for example, one heteroatom. 10 A heteroalkynyl group contains one or more heteroatoms, for example, one heteroatom plus one, two, three, four, five, six, seven, eight, nine, or ten carbon atoms. Bonding to the heteroalkynyl group occurs via carbon atoms or via heteroatoms.

[0061] The term "carbocyclyl group" (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 carbon ring atoms ("ring atoms" being atoms that bond together to form one or more rings of a cyclic substituent). Carbocyclyls can be monocyclic (monocyclic formula) or polycyclic ring structures.

[0062] Carbocyclyls can be monocyclic structures, typically containing 3–8 ring atoms, more typically 3–7 ring atoms, and more typically 5–6 ring atoms. Examples of such monocyclic carbocyclyls include cyclopropyl (cyclopropanyl), cyclobutyl (cyclobutanyl), cyclopentyl (cyclopentanyl), cyclopentenyl, cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl, cyclohexadienyl, and phenyl. Carbocyclyls can also be polycyclic (i.e., containing more than one ring). Examples of polycyclic carbocyclyls include bridging, condensed, and spirocyclic carbocyclyls. In spirocyclic carbocyclyls, one atom is common to two different rings. An example of a spirocyclic carbocyclyl is spiropentanyl. In bridging carbocyclyls, the rings share at least two common non-adjacent atoms. Examples of crosslinked carbocyclyls include bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl. For example, crosslinked azepane may be 8-oxa-3-azabicyclo[3.2.1]octan-3-yl. In fused-ring carbocyclyl systems, two or more rings may be fused such that two rings share one common bond. Examples of 2 or 3-fused-ring carbocyclyls include naphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl, phenantrenyl, and dekalinyl.

[0063] The term "cycloalkyl group" (alone or in combination with other terms) refers to a saturated cyclic hydrocarbon substituent containing 3 to 14 carbocyclic atoms. Cycloalkyl groups can be monocyclic, typically containing 3 to 8 carbocyclic atoms and more typically 3 to 6 ring atoms. Bonding to a cycloalkyl group is understood to be via the ring atoms of the cycloalkyl group. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups may be polycyclic or contain more than one ring. Polycyclic cycloalkyl groups include crosslinked, condensed, and spirocyclic cycloalkyl groups.

[0064] The term "alkylcycloalkyl" refers to a cycloalkyl substituent linked via an alkyl chain. An example of alkylcycloalkyl substituents is cyclohexylethane, where cyclohexane is linked via an ethane linker. Other examples include cyclopropylethane, cyclobutylethane, cyclopentylethane, cycloheptylethane, and cyclohexylmethane. n In alkylcycloalkyl groups, C n It contains a carbon atom in an alkyl chain and a cycloalkyl ring. For example, cyclohexylethane is a C8 alkylcycloalkyl.

[0065] The term "aryl group" (alone or in combination with other terms) refers to an aromatic carbocyclyl containing 5 to 14 carbocyclic atoms, preferably 5 to 8, 5 to 7, or preferably 5 to 6 carbocyclic atoms. n An "aryl" group is an aromatic group containing n carbon atoms. For example, C6-C 10An aryl group contains 6, 7, 8, 9, or 10 carbon atoms. Bonding to an aryl group occurs via carbon atoms. An aryl group can be monocyclic or polycyclic (i.e., it can contain more than one ring). In the case of a polycyclic aromatic ring, only one ring in the polycyclic system needs to be unsaturated, while the remaining rings may be saturated, partially saturated, or unsaturated. Bonding to an aryl group occurs via carbon atoms in the ring. Examples of aryl groups include phenyl, naphthyl, acridinyl, indenyl, indanyl, and tetrahydronaptyl.

[0066] The term "arylalkyl" refers to an aryl substituent that is bonded via an alkyl chain. Examples of arylalkyl substituents include benzyl and phenylethane / ethylbenzene, where the ethane chain is bonded to the phenyl group. n In arylalkyl groups, C n It contains the carbon atoms of the alkyl chain and the aryl group. For example, ethylbenzene is a C8 arylalkyl.

[0067] The term “heterocyclyl group” (alone or in combination with other terms) refers to a saturated (i.e., “heterocycloalkyl”), partially saturated (i.e., “heterocycloalkenyl”), or completely unsaturated (i.e., “heteroaryl”) ring structure containing a total of 3 to 14 ring atoms, where at least one of the ring atoms is a heteroatom (e.g., oxygen, nitrogen, or sulfur) and the remaining ring atoms are carbon atoms. A heterocyclyl group may contain, for example, one, two, three, four, or five heteroatoms. Bonding to a heterocyclyl group may occur via carbon atoms and / or one or more heteroatoms contained in the ring. Heterocyclyls can be monocyclic (monocyclic) or polycyclic ring structures.

[0068] Heterocyclyl groups can be monocyclic, typically containing 3 to 7 ring atoms, more typically 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples of monocyclic heterocyclines include furanil, dihydrofuranil, tetrahydrofuranil, thiophenyl (thiofuranil), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinil, pyrrolidinil, imidazolyl, imidazolinil, imidazolidinil, pyrazolyl, pyrazolinil, pyrazolidinil, triazolyl, tetrazolyl, oxazolyl, oxazolidinil, isoxazolidinil, isoxazolyl, thiazolyl, isothiazolyl, thiazolinil, isothiazolinil, thiazolidinil, isothiazolidinil, thiodiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (flazanil) or 1,3,4-oxadiazolyl), oxatriazolyl, and dioxazolyloxathiolyl , including pyranil, dihydropyranil, tetrahydropyranil, thiopyranil, tetrahydrothiopyranil, pyridinyl (α-diazinyl), 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)), oxadiadinyl (including 1,2,3-oxadiadinyl, 1,2,4-oxadiadinyl, 1,4,2-oxadiadinyl, or 1,3,5-oxadiadinyl)), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.

[0069] Heterocyclyl groups may be polycyclic (i.e., may contain more than one ring). Examples of polycyclic heterocyclyl groups include bridged, condensed, and spirocyclic heterocyclyl groups. In spirocyclic heterocyclyl groups, one atom is common to two distinct rings. In bridged heterocyclyl groups, the rings share at least two common non-adjacent atoms. In condensed heterocyclyl groups, two or more rings may be condensed such that two rings share one common bond. Examples of condensed heterocyclyl groups containing two or three rings include indolidinyl, pyranopyrrolyl, 4H-quinolidinyl, prinyl, naphthilidinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl. Other examples of fused ring heterocyclyl groups include benzo-fused heterocyclyl groups, such as indolyl, isoindolyl (isobenzazolyl, pseudoisoindolyl), indolinyl (pseudoindolyl), isoindazolyl (benzpyrazolyl), benzazinyl (including quinolinyl (1-benzazinyl) or isoquinolinyl (2-benzazinyl)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiadinyl (including sinnolinyl (1,2-benzodiadinyl) or quinazolinyl (1,3-benzodiadinyl)), benzopyranil (including chromanil or isochromanil), and benzisoxazinyl (including 1,2-benzisoxazinyl or 1,4-benzisoxazinyl).

[0070] The term "heterocycloalkyl group" (alone or in combination with other terms) refers to a saturated heterocycline. An "x-y membered heterocycloalkyl group" is a cyclic aliphatic group containing x-y ring atoms, with at least one heteroatom (e.g., nitrogen) and the rest being carbon atoms. For example, a 3-8 membered heterocycloalkyl group contains a total of 3-8 ring atoms, where at least one of the ring atoms is a heteroatom (e.g., nitrogen, oxygen, sulfur) and the remaining atoms are carbon atoms. Bonding to a heterocycloalkyl group occurs via a carbon atom or one of the at least one heteroatom.

[0071] The term "heteroaryl group" (alone or in combination with other terms) refers to an aromatic heterocycline containing 5 to 14 ring atoms. An "x-y membered heteroaryl" group refers to an aromatic group containing x to y ring atoms, with at least one heteroatom (e.g., nitrogen) and the rest being carbon atoms. For example, a 5-8 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 remaining atoms are carbon atoms. Bonding to a heteroaryl group occurs via carbon atoms or via heteroatoms. Heteroaryl groups can be monocyclic or polycyclic. Heteroaryls can be monocyclic or fused with two or three rings. Examples of monocyclic heteroaryl groups include six-membered rings such as pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, and 1,3,5-, 1,2,4- or 1,2,3-triazinyl; and five-membered rings such as imidazolyl, furanil, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-oxadiazolyl and isothiazolyl. Polycyclic heteroaryl groups can be two or three fused rings. Examples of polycyclic heteroaryl groups include six- and five-membered fused rings such as benzothiofuranil, benzoisoxazolyl, benzoxazolyl, and prinyl; and six- and six-membered fused rings such as benzopyranil, quinolinyl, isoquinolinyl, sinnolinyl, quinazolinyl, and benzoxazinyl. In the case of polycyclic heteroaryl groups, only one ring in the polycyclic system needs to be unsaturated, while the remaining rings may be saturated, partially saturated, or unsaturated.

[0072] The term "amino group" refers to the -NR'R'' group. The amino group may be substituted as desired. In an unsubstituted amino group, R' and R'' are hydrogen. In a substituted amino group, R' and R'' may independently be hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, sulfonyl, alkenyl, alkanoyl, aryl, arylalkyl, or heteroaryl group, provided that neither R' nor R'' is hydrogen. In a substituted amino group, R' and R'' may cyclize to form a cyclic amino group, such as a pyrrolidine or piperidine group. Such a cyclic amino group may incorporate other heteroatoms to form, for example, a piperazine or morpholine group. Such a cyclic amino group may be substituted as desired with, for example, an amino group, a hydroxyl group, or an oxo group.

[0073] The term "alkylamino" group is -R a This refers to the NR'R'' group, where R a is the alkyl chain defined above, and NR'R'' is the optionally substituted amino group defined above. n An alkylamino group is a group containing n carbon atoms. For example, C1-C 10 An alkylamino group contains 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 in the substituent is R. a It is produced via the carbon atom of the alkyl group. Examples of alkylamino substituents include methylamine, ethylamine, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, methylpyrrolidine, and ethylpyrrolidine.

[0074] The term "amide group" refers to the -C(=O)-NR- group. Bonding can be via a carbon or nitrogen atom. For example, an amide group may be bonded as a substituent via a carbon atom, in which case the nitrogen atom has two R groups to which it is bonded (-C(=O)-NR2). An amide group may be bonded by a nitrogen atom alone, in which case the carbon atom has one R group to which it is bonded (-NR-C(=O)R).

[0075] The term "alkylsulfanyl" is -SR a It refers to the base, and here, R a This is the alkyl chain defined above. n An alkylsulfanyl group is a group containing n carbon atoms. For example, C1-C 10 The alkylsulfanyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Bonding to the alkylsulfanyl group is SR a It is generated via the sulfur atom of the group. The alkylsulfanyl group may be substituted as desired. Examples of alkylsulfanyl substituents include SMe (methylsulfanyl group), ethylsulfanyl group, propylsulfanyl group, and benzylsulfanyl group.

[0076] The term "sulfoximine" refers to a sulfoximine substituent, where the bond is via an S bond or an N bond—that is, the bond can be via a sulfur or nitrogen atom. For example, a sulfoximine group may be bonded as a substituent via a sulfur atom, in which case the sulfur has one R group in addition to the oxo group, and the sulfur-bonded nitrogen atom has one R group to which it bonds—that is, the group is -S(O)(R)NR'. As a further example, a sulfoximine group may be bonded as a substituent via a nitrogen atom, in which case the sulfur atom has two R groups to which it bonds in addition to the oxo group—that is, the group is -NS(O)RR'. In an unsubstituted sulfoximine group, each of R and R' is H. Alternatively, a sulfoximine group may be substituted with one or both of R and R', for example, forming dimethylsulfoximine where both R and R' are methyl.

[0077] The term "ether" refers to an -O-alkyl group or an -alkyl-O-alkyl group, such as a methoxy group, a methoxymethyl group or an ethoxyethyl group. The alkyl chain of the ether can be linear, branched or cyclic. The ether group may optionally be substituted with one or more substituents ("substituted ether"). C n Ether refers to an ether group having n carbons in all alkyl chains of the ether group. For example, CH(CH3)-O-C6H 11 Ether is a C8 ether group.

[0078] The term "alkoxy group" refers to an -O-alkyl group. The alkoxy group can refer to a linear, branched, or cyclic, saturated or unsaturated oxy-hydrocarbon chain, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, t-butoxyl and pentoxyl. The alkoxy group may optionally be substituted with one or more alkoxy group substituents ("substituted alkoxy").

[0079] The term "aryloxy group" refers to an -O-aryl group, such as a phenoxy group. The aryloxy substituent itself may optionally be substituted, for example, with a halogen.

[0080] 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 methanoate - that is, R is an ethyl group.

[0081] <00者1533>The term "hydroxyl" refers to an -OH group.

[0082] The term "oxo group" refers to a (=O) group, that is, a substituted oxygen atom bonded to another atom by a double bond. For example, a carbonyl group (-C(=O)-) is a carbon atom bonded to an oxygen atom by a double bond, that is, an oxo group bonded to a carbon atom. Examples of carbonyl substituents include aldehyde (-C(=O)H), acetyl (-C(=O)CH3) and carboxyl / carboxylic acid group (-C(=O)OH).

[0083] ]> The term "halo" refers to a substituent selected from chlorine, fluorine, bromine, and iodine. Preferably, the halo substituent is selected from chlorine, fluorine, and bromine. More preferably, the halo substituent is selected from chlorine and fluorine.

[0084] Alkyl, alkenyl, alkynyl, carbocyryl (including cycloalkyl, cycloalkenyl, and aryl), heterocyclyl (including heterocycloalkyl, heterocycloalkenyl, heteroaryl, and nitrogen-containing heterocyclyl), amino, amide, ester, ether, alkoxy, or sulfonamide groups may optionally be substituted with one or more substituents, which may be the same or different. The substituents may be bonded via carbon atoms and / or heteroatoms of the alkyl, alkenyl, alkynyl, carbocyryl (including cycloalkyl, cycloalkenyl, and aryl), heterocyclyl (including heterocycloalkyl, heterocycloalkenyl, heteroaryl, nitrogen-containing heterocyclyl, and nitrogen-containing heteroaryl), amino, amide, ester, ether, alkoxy, or sulfonamide groups. The term “substituent” (or “radical”) includes, but is not limited to, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aralkyl, substituted aralkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halo, hydroxyl, cyano, amino, amide, alkylamino, arylamino, carbocykyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, nitro, thio, alkanoyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, alkylsulfonyl, arylsulfonyl, and sulfoxyiminyl.

[0085] In one embodiment, the substituents are alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halo, hydroxyl, cyano, amino, amide, alkylamino, arylamino, carbocykyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, nitro, thio, alkanoyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, alkylsulfonyl, and arylsulfonyl.

[0086] If a group, for example an alkyl group, is "optionally substituted," then that group is understood to have one or more substituents attached (substituted) or to have no substituents attached (unsubstituted).

[0087] If a group is further substituted with a group which is optionally substituted, then the first substituent is understood to be either unsubstituted or substituted in itself.

[0088] For completeness, a certain chemical formula used here defines a delocalized system. This definition is known in this field as the definition of aromaticity and can, for example, represent a planar mono, dicyclic, or tricyclic system containing (4n+2) electrons (where n is an integer). In other words, these systems can exhibit Hückel aromaticity.

[0089] In any embodiment, the compounds of the present invention may have certain stereochemical characteristics. For example, the compounds may have chiral centers and / or planes and / or axes of symmetry. That is, unless otherwise specified, the compounds may be provided as single stereoisomers, single diastereomers, mixtures of stereoisomers, or racemic mixtures. It is known in the art that stereoisomers are molecules that have the same molecular formula and arrangement of bonding atoms but differ in the spatial orientation of atoms and / or groups.

[0090] Furthermore, the compounds of the present invention may exhibit tautomerism. Each tautomeral form is intended to fall within the scope of the present invention.

[0091] Furthermore, the compounds of the present invention may be provided as prodrugs. Prodrugs are generally converted in vivo from one form of the drug described herein to the active form.

[0092] Furthermore, it should be understood that the elements listed here may be common isotopes or non-common isotopes. For example, the hydrogen atom 1 H, 2 H (deuterium) or 3 It could be H (tritium).

[0093] Furthermore, the compounds of the present invention may be provided in the form of their pharmaceutically acceptable salts or as cocrystals.

[0094] The term "pharmaceutically acceptable salt" refers to an ionic compound formed by the addition of an acid to a base. This term refers to a salt considered suitable in the field for use in contact with patients, for example, in vivo. Pharmaceutically acceptable salts are generally selected based on their non-toxic and non-irritating characteristics.

[0095] The term "cocrystal" refers to a multi-component molecular crystal that may contain nonionic interactions.

[0096] Pharmaceutically acceptable salts and cocrystals can be prepared by ion-exchange chromatography, or by reacting a free base or an acidic form of the compound with a stoichiometric amount or excess of the desired salt-forming inorganic or organic acid or base in one or more suitable solvents, or by mixing it with other pharmaceutically acceptable compounds that can form cocrystals with the compound.

[0097] Salts known in this field to be generally suitable for contact with patients include salts derived from inorganic and / or organic acids, including hydrobromide, hydrochloride, sulfate, bicarbonate, nitrate, acetate, oxalate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, and tartrate. These may contain cations based on alkali and alkaline earth metals such as sodium, potassium, calcium, and magnesium, as well as ammonium, tetramethylammonium, and tetraethylammonium. For further research on suitable pharmaceutically acceptable salts, please refer to several publications, e.g., the Handbook of Medicinal Salts published by IUPAC.

[0098] Furthermore, the compounds of the present invention may exist as zwitterions, which can be considered part of the present invention.

[0099] The USP19 inhibitor used herein refers to a compound that acts on USP19 and reduces the activity of the enzyme. Examples of USP19 inhibitors are the compounds exemplified herein. Preferably, the USP19 inhibitor has an IC5 concentration of less than 5 μM, preferably less than 0.5 μM. 50 This indicates.

[0100] As used herein, "obesity" refers to a medical condition characterized by excessive body fat. Obesity can be characterized, for example, by a Body Mass Index (BMI) greater than 30. Treatment of obesity can be demonstrated, for example, by a reduction in body fat in terms of percentage and / or absolute weight. Treatment of obesity can also be exemplified by a reduction in the subject's body fat accumulation rate compared to before treatment.

[0101] The term "insulin resistance" used here refers to a medical condition characterized by an abnormally weak response to insulin. Since insulin resistance is typically not treated by exogenous insulin therapy, the resistance is usually to insulin produced in the subject's own body, although the subject may also be resistant to exogenous insulin. "Insulin resistance" includes the conditions of "prediabetes" and type II diabetes. Insulin resistance can be demonstrated, for example, by glucose tolerance test (GTT) glucose levels of 7.8 mmol / L or higher. Type II diabetes is typically diagnosed after a glucose tolerance test (GTT) glucose level of 11.1 mmol / L or higher.

[0102] Treatment of insulin resistance may be indicated by an improvement (i.e., reduction) in the subject's GTT glycosaturation compared to before treatment. Treatment may also be indicated by a decrease in the subject's blood glucose level to below normal compared to before treatment.

[0103] The terms “muscle atrophy” and “muscle wasting” used herein are interchangeable and refer to a decrease in muscle mass in an object, including, for example, in the context of cachexia or sarcopenia. Muscle atrophy may result from temporary or permanent disability, temporary or permanent immobilization of a limb, prolonged rest, cachexia (e.g., as a result of cancer, heart failure, or COPD), or sarcopenia.

[0104] Treatment of muscle atrophy can be characterized as a delay in the rate of atrophy—that is, the treatment results in a reduction in muscle mass loss over a certain period. Preferably, the success of the treatment does not result in a reduction in muscle mass.

[0105] Therefore, in the first embodiment, equation (I) [ka] [During the ceremony, R 1is C1-C6 alkyl optionally substituted, amino optionally substituted, 3-11 member heterocycloalkyl optionally substituted, aryl optionally substituted, or 5-8 member heteroaryl optionally substituted; R 2 and R 3 are each independently selected from the group consisting of H and C1-C6 alkyl, or R 2 and R 3 together with the carbon to which they are attached form C3-C8 cycloalkyl, C3-C8 cycloalkenyl or 3-8 member heterocycloalkyl; M is N or CR a wherein, R a is H, halo, C3-C8 cycloalkyl optionally substituted, or C1-C6 alkyl optionally substituted; A, D, E and G are absent and X is NR 15 or CH; Y is CR 4 or N or is absent; Z is CR 5 , NR 6 or O; R 4 is halo, C1-C6 alkyl optionally substituted, C3-C8 cycloalkyl optionally substituted, aryl optionally substituted, 5-8 member heteroaryl optionally substituted, 4-10 member fused ring heterocyclyl, C1-C6 alkylsulfanyl optionally substituted (optionally SMe), sulfoxide, sulfone, sulfoximine, amino optionally substituted, 3-8 member heterocycloalkyl optionally substituted, or OR 20 ; wherein, R 20 is C1-C6 alkyl optionally substituted; R 5H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5-8 member heteroaryl, optionally substituted 3-8 member heterocycloalkyl, amide, sulfoxymine, CN, halo, C(O)OR 21 , OR 22 , or NR 23 R 24 and; Here, R 21 The elements are selected from H and C1-C6 alkyl groups; R 22 The elements are selected from H and C1-C6 alkyl groups; R 23 and R 24 These are independently selected from H and optionally substituted C1-C6 alkyl groups; R 15 is H or C1-C6 alkyl; or R 4 and R 5 They, together with the Y and Z to which they are bound, form 3- to 8-membered heterocycloalkyl or aryl groups; or R 4 and R 15 They, together with X and Y to which they are bound, form a five-membered cycloalkyl, heterocycloalkyl, or heteroaryl group; R 6 is H, C1-C6 alkyl, optionally substituted aryl, or C3-C8 cycloalkyl; Or A is CR 12 Or N, and D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 or N and X is either N or C; Y is C; Z is CR 20 , N, NR 11 , or O, Here, R 11is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted 5-8 membered heteroaryl; Here, R 20 H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5-8 member heteroaryl, optionally substituted 3-8 member heterocycloalkyl, amide, sulfoxymine, CN, halo, C(O)OR 25 , OR 26 , or NR 27 R 28 and; Here, R 25 The elements are selected from H and C1-C6 alkyl groups; R 26 The elements are selected from H and C1-C6 alkyl groups; R 27 and R 28 These are independently selected from H and C1-C6 alkyl groups; R 7 is H, halo, C1-C6 alkyl, or OR 19 and; Here, R 19 is a C1-C6 alkyl group which is optionally substituted; R 12 is H, halo, or C1-C6 alkyl; R 13 H, halo, C1-C6 alkyl, OR 16 ; or NR 17 R 18 and; Here, R 16 This is a C1-C6 alkyl group that is optionally substituted. R 17 and R 18 The elements are independently selected from H and C1-C6 alkyl groups or R 17 and R 18 They combine with the nitrogen atom to which they are bonded to form a 5-6 member heterocycloalkyl group; and R 14[This is H, halo, or C1-C6 alkyl.] Compounds thereof or their stereoisomers, tautomers, hydrates, N-oxide derivatives, or pharmaceutically acceptable salts are provided.

[0106] In equation (I), the dotted line represents an arbitrary bond. That is, the dotted line indicates that the ring containing positions X, Y, Z, and M can be aliphatic (e.g., saturated or partially unsaturated) or aromatic. Similarly, in equation (I), the dotted line, when present, indicates that the ring containing positions A, D, E, and G can be aliphatic (e.g., saturated or partially unsaturated) or aromatic.

[0107] To avoid any doubt, 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 5-membered.

[0108] For the compound of formula (I), each optionally substituted group has one or more independently selected optional substituents. In one embodiment, each of the one or more optional substituents is alkyl, alkoxy, oxo, halo, cycloalkyl, heterocycloalkyl, aryl, aryl substituted with one or more halos, aryl substituted with halo and alkyl, aryl substituted with halo 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 Selected independently from, where R 8 , R 9 and R 10Each of these is independently selected from H, halo, hydroxyl, alkyl, cycloalkyl, cycloalkyl substituted with one or more halo or alkyl groups, heterocycloalkyl substituted with one or more alkyl or oxo groups, heteroaryl, alkoxy, CH2OH, and CH2CH2OH.

[0109] One reason, R 1 is optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted 3-8 member heterocycloalkyl, optionally substituted aryl, or optionally substituted 5-8 member heteroaryl.

[0110] One preferred reason is, R 1 R is a 3- to 11-membered heterocycloalkyl that is optionally substituted. More preferably, 1 R is a 3- to 8-membered heterocycloalkyl that is optionally substituted. More preferably, 1 is a 5-8 member heterocycloalkyl which is optionally substituted. More preferably still R 1 This is a 5-6 member heterocycloalkyl that is optionally substituted.

[0111] One preferred reason is, R 1 R is optionally substituted with morpholine, cross-linked azepane, diazepane, thiomorpholine, pyrrolidine, piperazine, or piperidine. In a preferred embodiment, R 1 is optionally substituted with morpholine, thiomorpholine, pyrrolidine, piperazine, or piperidine. Preferably R 1 This is a piperidine that is substituted as desired.

[0112] One preferred reason is, R 1 NR is an aryl, heteroaryl, or aryl substituted with one or more alkyl, oxo, cycloalkyl, heterocycloalkyl, or aryl molecules, or one or more halo molecules. 8 , NR 8 R9 NHC(O)R 8 NHCR 8 R 9 R 10 NHCH2CR 8 R 9 R 10 and NHCH2C(O)R 8 It is replaced with, here, R 8 , R 9 and R 10 Each of these is independently selected from H, halo, hydroxyl, alkyl, cycloalkyl, cycloalkyl substituted with one or more halo or alkyl groups, heterocycloalkyl, heteroaryl, and alkoxy groups substituted with one or more alkyl or oxo groups.

[0113] One preferred reason is, R 1 is NR 8 R 9 NHC(O)R 8 , or NHCH2CR 8 R 9 R 10 It is replaced with, here, R 8 , R 9 and R 10 Each of these is independently selected from H, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, CH2OH, CH2CH2OH, and optionally substituted C3-C6 cycloalkyl.

[0114] One preferred reason is, R 1 is NR 8 R 9 NHC(O)R 8 , or NHCH2CR 8 R 9 R 10 It is replaced with, here, R 8 , R 9 and R 10Each of these is independently selected from H, C1-C6 alkyl, fluorosubstituted C1-C6 alkyl, C1-C6 alkoxy, CH2OH, CH2CH2OH, fluorosubstituted C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted with C1-C6 alkyl, and pyridine substituted C1-C6 alkyl.

[0115] One preferred reason is, R 1 R is substituted with phenyl or phenyl substituted with one or more halos, where R 1 It is optionally substituted with one or more additional substituents.

[0116] One preferred reason is, R 1 R is substituted with phenyl or phenyl substituted with one or more fluorocarbons, where R 1 R is optionally substituted with one or more further substituents. In one preferred embodiment, R 1 It is substituted with difluorophenyl.

[0117] One preferred reason is, R 1 R is substituted with a halo and a phenyl that is substituted with a C1-C6 alkyl, where R 1 R is optionally substituted with one or more further substituents. In one preferred embodiment, R 1 R is substituted with a halo and a phenyl that is substituted with a C1-C6 alkoxy, where R 1 R is optionally substituted with one or more further substituents. In one preferred embodiment, R 1 R is substituted with phenyl which is substituted with fluoro and methyl, where R 1 R is optionally substituted with one or more further substituents. In one preferred embodiment, R 1 R is substituted with phenyl which is substituted with fluoro and methoxy, where R 1 It is optionally substituted with one or more additional substituents.

[0118] One preferred reason is, R 1 is NR 8 R 9 NHC(O)R 8 , or NHCH2CR 8 R 9 R 10 It is replaced with, here, R 1 R is optionally substituted with one or more further substituents. In one preferred embodiment, R 1 R is further substituted with phenyl or phenyl substituted with one or more halos. In one preferred embodiment, R 1 R is further substituted with phenyl or phenyl substituted with one or more fluorocarbons. In one preferred embodiment, R 1 It is further substituted with difluorophenyl.

[0119] One preferred reason is, R 1 is a C1-C6 alkyl group which is optionally substituted. Preferably, each optional substituent is selected from halo, alkoxy, cycloalkyl, and hydroxyl groups.

[0120] One preferred reason is, R 1 This is a 6-membered heteroaryl compound that is optionally substituted, preferably a pyridinyl compound substituted with phenyl.

[0121] One preferred reason is, R 1 R is an amino acid which is optionally substituted. More preferably, 1 is an amino acid substituted with one or more halos, which is either a phenyl molecule substituted with one or more halos, or a benzyl molecule substituted with one or more halos.

[0122] In one preferred embodiment of the compound of formula (I), R 1 is NR b R c or NR b CH2R c And here, R b and R cis 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 pyridinyl, pyrazole, imidazole, furan, benzodioxo, optionally substituted oxadiazole, thiazole, and thiophene, where each of one or more optional substituents is independently selected from halo, methyl, cyclopropyl, and CN, optionally R 1 is NR a CH2R b The methylene group is substituted with CF3.

[0123] One reason, R 1 is NR b R c And R b and R c These atoms, together with the N atoms to which they are bound, form a C3-C9 heteroring that is optionally substituted.

[0124] One reason, R 1 is NR b R c And R b and R c These atoms, together with the N to which they are bonded, form a optionally substituted C3-C9 heteroring, where each of one or more optional substituents is substituted with OH, oxo, optionally OH and / or halo, C1-C3 alkyl, optionally substituted phenyl, optionally substituted benzyl, C1-C3 alkoxy, or NR. m R n NHC(O)R m , and NHCH2R n Selected from, Here, R m and R nR is independently selected from H; optionally substituted with OH, methoxy or halo; optionally substituted with methyl and / or halo; optionally substituted with oxo, methyl or fluoromethyl; optionally substituted with C3-C4 heterocycloalkyl; optionally substituted with methyl; and Boc; and / or R n Furthermore, the following are selected from CH2OCH3, COOH, and COOCH3: Or, here, R m and R n These combine with the N to which they bind to form a C3-C5 heterocyclyl group, and optionally, R m and R n These groups, together with the nitrogen atom to which they bond, form a morpholinyl group.

[0125] One reason, R 1 is NR b R c And R b and R c These atoms, together with the N to which they are bonded, form a optionally substituted C3-C9 heteroring, where each of one or more optional substituents may be a halosubstituted phenyl or NR. m R n NHC(O)R m , and NHCH2R n Selected from, Here, R m and R n R is independently selected from H; optionally substituted with OH, methoxy or halo; optionally substituted with methyl and / or halo; optionally substituted with oxo, methyl or fluoromethyl; optionally substituted with C3-C4 heterocycloalkyl; optionally substituted with methyl; and Boc; and / or R n Furthermore, the following are selected from CH2OCH3, COOH, and COOCH3: Or, here, R m and R nThese combine with the N to which they bind to form a C3-C5 heterocyclyl group, and optionally, R m and R n These groups, together with the nitrogen atom to which they bond, form a morpholinyl group.

[0126] One reason, R 1 is NR b R c And R b and R c These atoms, together with the N to which they are bonded, form a substituted C3-C9 heterocycle, where each of the one or more substituents is selected from OH, CH2OH, CH2OCH3, oxo, NH2, C1-C3 aminoalkyl, amino-thietanedioxide, methyl, ethyl, propyl, CF3, phenyl, substituted phenyl, and benzyl.

[0127] One reason, R 1 is NR b R c And R b and R c These atoms, together with the N to which they are bonded, form a heterocycle which is optionally substituted, where the heterocycle is selected from pyrrolidinyl, pyrimidinyl, piperidinyl, morpholino, piperazinyl, and thiomorpholino. In one such embodiment, the heterocycle is optionally independently substituted with one or more substituents selected from methyl, spirocyclopropyl, C1-C3 aminoalkyl, NH2, CH2OH, CH2CF3, oxo, thiophene, phenyl optionally substituted with F or CF3, and OH, provided that the same ring carbon is not also substituted with methyl.

[0128] One reason, R 1 is NR b R c And R b and R c These molecules, together with the N to which they bind, form a heterocycle, where the heterocycle is selected from pyrrolidinyl, piperidinyl, morpholino, piperazinyl, and thiomorpholino. Here, the heterocycle is optionally independently substituted with one or more substituents 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 again substituted with methyl.

[0129] One reason, R 1 is NR b R c And R b and R c These combine with the N to which they bind to form a heterocycle, where the heterocycle is selected from piperidinyl and piperazinyl. Here, the heterocycle is optionally independently substituted with one or more substituents 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 again substituted with methyl.

[0130] One reason, R 1 is NR b R c And R b and R c These molecules, together with the N to which they bind, form a heterocycle which is optionally substituted, and the heterocycle is selected from piperidinyl and piperazinyl.

[0131] Preferably R 1 This forms a piperazinyl group substituted with fluorophenyl or difluorophenyl.

[0132] In one embodiment, the piperazinyl group is optionally further substituted with methyl.

[0133] In one embodiment, the piperazinyl group may be further substituted with CH2OH or spirocyclopropyl as desired.

[0134] One reason, R 1 is NRb R c And R b and R c The heterocycle optionally forms a heterocycle, where the heterocycle is a piperidinyl group substituted with phenyl, where phenyl is optionally substituted with one or more halo (e.g., fluoro) substituents. In one preferred such embodiment, the piperidinyl group is optionally further substituted with NH2 or NHCH3.

[0135] One reason, R 1 is NR b R c And R b and R c These groups, together with the N to which they are bonded, form a piperidinyl group which is optionally substituted with phenyl, fluorophenyl, or difluorophenyl, where the piperidinyl group is optionally NR m R n NHC(O)R m , or NHCH2R n It is further replaced by, Here, R m and R n R is independently selected from H; optionally substituted with OH, methoxy or halo; optionally substituted with methyl and / or halo; optionally substituted with oxo, methyl or fluoromethyl; optionally substituted with C3-C4 heterocycloalkyl; optionally substituted with methyl; and Boc; and / or R n Furthermore, the following are selected from CH2OCH3, COOH, and COOCH3: Or, here, R m and R n These combine with the N to which they bind to form a C3-C5 heterocyclyl group, and optionally, R m and R n These groups, together with the nitrogen atom to which they bond, form a morpholinyl group.

[0136] One reason, R1 is NR b R c And R b and R c These groups, together with the N to which they are bonded, form a piperidinyl group which is optionally substituted with phenyl, fluorophenyl, or difluorophenyl, where the piperidinyl group is optionally NR m R n NHC(O)R m , or NHCH2R n It is further replaced by, Here, R m C1-C3 alkyls substituted with H, optionally OH or halo; C3-C4 cycloalkyls substituted with methyl and / or halo, optionally substituted with oxo, methyl or fluoromethyl; C3-C5 heteroaryls substituted with methyl, optionally substituted with Boc; and Here, R n The group is selected from H; optionally substituted with OH or halo; optionally substituted with methyl and / or halo; optionally substituted with oxo, methyl or fluoromethyl; optionally substituted with methyl; optionally substituted with C3-C5 heteroaryl; Boc; COOH and COOCH3.

[0137] One preferred reason is, R 1 The piperidinyl ring formed by this is NR m R n It is replaced with, here, R m and R n C1-C3 alkyl groups independently selected from H; optionally substituted with OH or halo (preferably F); optionally substituted with methyl and / or halo (preferably F); optionally substituted with oxo, methyl or fluoromethyl; optionally substituted with C3-C4 heterocycloalkyl groups; optionally substituted with methyl; and Boc.

[0138] One preferred reason is, R 1 NR m R n When it is replaced by R m H is H.

[0139] One preferred reason is, R m H is R n The compounds are selected from: H; methyl; ethyl (including isopropyl) optionally substituted with fluoro or OH; propyl (including isopropyl); cyclopropyl optionally substituted with methyl; cyclobutyl optionally substituted with fluoro; and oxetanyl optionally substituted with methyl or fluoromethyl.

[0140] One preferred reason is, R 1 The piperidinyl ring formed by this process is NHC(O)R m It is replaced with, here, R m The group is selected from H; optionally substituted with OH or halo (preferably F); optionally substituted with methyl and / or halo (preferably F); optionally substituted with oxo, methyl or fluoromethyl; optionally substituted with C3-C4 heterocycloalkyl; optionally substituted with methyl; and Boc.

[0141] One preferred reason is, R 1 NHC(O)R m When it is replaced by R m The C1-C3 alkyl, C3-C4 cycloalkyl, and C4-C5 heteroaryl compounds are selected from, for example, pyridine.

[0142] One reason, R 1 is NR b R c And R b and R cThese groups, together with the N to which they are bonded, form a piperidinyl group which is optionally substituted with phenyl, fluorophenyl, or difluorophenyl, where the piperidinyl group is optionally NR m R n It is further replaced by, Here, R m and R n These, together with the N to which they bind, form a C3-C5 heterocyclyl group. In one such embodiment, R m and R n These groups, together with the nitrogen atom to which they bond, form a morpholinyl group.

[0143] One reason, R 1 is NR b R c And R b and R c These groups, together with the N to which they are bonded, form a piperidinyl group which is optionally substituted with phenyl, fluorophenyl, or difluorophenyl, where the piperidinyl group is optionally further substituted with NH2, NHCH3, or NHCH2CH3.

[0144] One reason, R 1 When the heterocycle formed by this process is substituted, the substitution occurs at the para position (position 4).

[0145] One reason, R 1 When the heterocycle formed by this process is substituted, the substitution occurs at the ortho position (position 2).

[0146] In one such configuration, R 1 The heterocycle formed by this process is substituted at the ortho and para (2,4) positions.

[0147] One reason, R 1 The heterocycle formed by is substituted at the meta position (position 3). In one such embodiment, R 1The heterocycle formed by this process is substituted at the ortho and meta (2,3) positions.

[0148] One reason, R 1 The heterocycle formed by this process is substituted at positions 3 and 5.

[0149] One preferred reason is, R 1 is NR b R c And R b and R c These combine with the N to which they bond to form a piperidinyl group, where the piperidinyl group is NR m R n NHC(O)R m , and NHCH2R n The 4th position is substituted, and the 2nd position is further substituted with phenyl, fluorophenyl, or difluorophenyl. In such embodiments, R m and R n This is defined above and elsewhere in this specification.

[0150] R 1 In this preferred embodiment, where is a heterocyclic ring substituted at the ortho or 2 position (e.g., with phenyl) and is chiral, the compound is in the (R) configuration at that position. 1 In a preferred embodiment where the compound is substituted at the ortho or 2-position (e.g., with phenyl) and is chiral, the compound is in the (S) configuration at that position.

[0151] R 1 However, in one preferred embodiment, where the heterocycle is substituted at the ortho or 2nd position and the meta or 3rd position and is chiral, the compound is in the (S) configuration at the ortho position and the (S) configuration at the meta position. 1 However, in one preferred embodiment, the compound is substituted at the ortho or 2nd position and the meta or 3rd position and is chiral, and the compound is in the (R) configuration at the ortho position and the (R) configuration at the meta position.

[0152] One preferred reason is, R1 is a heterocycle substituted at the 3,4 positions. In this preferred embodiment, and R 1 When a compound is chiral, it has a (R) configuration at position 3 and a (R) configuration at position 4.

[0153] One preferred reason is, R 1 is a heterocycle substituted at the 3,5 positions. In this preferred embodiment, and R 1 When a compound is chiral, it has a (R) configuration at position 3 and a (S) configuration at position 5.

[0154] One preferred reason is, R 1 is a heterocycle substituted at positions 1, 2, and 5. In this preferred embodiment, and R 1 When a compound is chiral, it has an (S) configuration at position 1, an (R) configuration at position 2, and an (R) configuration at position 5.

[0155] R 1 In a preferred embodiment where is a heterocycle substituted at the ortho or 2-position and the para or 4-position (e.g., with NH2 or C1-C2 alkylamino) and is chiral, the compound is in the (R) configuration at the para position and the (S) configuration at the ortho position. 1 In a preferred embodiment in which the ortho or 2-position and para or 4-position are substituted (e.g., with NH2 or C1-C2 alkylamino) and the compound is chiral, the compound is in the (S) configuration at the para position and the (R) configuration at the ortho position.

[0156] One preferred reason is, R 1 This forms a piperazinyl group substituted with phenyl, fluorophenyl, difluorophenyl, or thiophenyl. In one preferred embodiment, R 1 This forms a 4-aminopiperidinyl group substituted with phenyl, fluorophenyl, difluorophenyl, or thiophenyl. Preferably R 1This forms a piperazinyl or 4-aminopiperidinyl group substituted with phenyl. Preferably R 1 This forms a piperazinyl or 4-aminopiperidinyl group substituted with fluorophenyl. Preferably R 1 This forms a piperazinyl or 4-aminopiperidinyl group substituted with difluorophenyl.

[0157] R 1 In a preferred embodiment in which is substituted with difluorophenyl, the substituent is 2,5-difluorophenyl or 3,5-difluorophenyl.

[0158] In one embodiment, the piperazinyl or 4-aminopiperidinyl group may be further substituted with one or two, preferably one, N-alkyl group, such as methyl or ethyl.

[0159] One preferred reason is, R 1 teeth: [ka] That is the case.

[0160] One preferred reason is, R 1 teeth: [ka] That is the case.

[0161] One preferred reason is, R 1 teeth: [ka] That is the case.

[0162] One preferred reason is, R 1 teeth: [ka] That is the case.

[0163] In one preferred embodiment, the phenyl ring is fluorosubstituted with one or two fluoropolymers.

[0164] One preferred reason is, R 1 teeth: [ka] Selected from.

[0165] In one preferred embodiment of the compound of formula (I), R 1 is NR b R c or NR b CH2R c And here, R b and R c is independently selected from H, methyl, ethyl, propyl, CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, pyridinyl, pyrazole, imidazole, or R b and R c These atoms, together with the N to which they are bonded, form a C3-C5 heterocycle which may be optionally substituted with OH, CH2OH, CH2OCH3, methyl, ethyl, propyl, CF3, phenyl, or benzyl.

[0166] One preferred reason is, R 1 is NR b CH2R c And here, R b is H or methyl, R c The compound is optionally selected from cyclobutyl, cyclohexyl, phenyl, furan, and thiophene substituted with F, and optionally the methylene group is substituted with CF3.

[0167] In one preferred such embodiment, R c It is phenyl or fluorosubstituted phenyl.

[0168] One preferred reason is, R 2 and R 3 Each is independently either H or methyl, or R 2 and R 3 They combine with the carbon to which they are bonded to form a C3-C6 cycloalkyl, cyclopentenyl, or 4-6 membered heterocycloalkyl. In one such embodiment, R 2 and R 3 These combine with the carbon atoms to which they are bonded to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, oxetanyl, or oxanyl. More preferably, R 2 and R 3 Each is independently either H or methyl, or R 2 and R 3 These combine to form cyclopentyl. More preferably, R 2 and R 3 These combine with the carbon atoms they bond to to form cyclopentyl.

[0169] In one preferred embodiment, M is N or CR a And here, R a is H, halo, cyclopropyl, or a C1-C6 alkyl group which is optionally substituted.

[0170] In one preferred embodiment, M is N or CR a And here, R a The C1-C6 alkyl group is substituted with H, fluoro, chloro, cyclopropyl, or optionally one or more halo groups.

[0171] In one preferred embodiment, M is N or CR a And here, R a These are H, fluoro, chloro, cyclopropyl, CF3, or C1-C6 alkyl groups.

[0172] In one preferred embodiment, M is N or CR a And here, R ais H, or optionally substituted C1-C6 alkyl. More preferably, M is N or CR a And here, R a is H, or a C1-C6 alkyl group.

[0173] In one preferred embodiment, M is CR a In one such example, R a The ions are H, cyclopropyl, CF3, or methyl.

[0174] One preferred reason is, R a is H or methyl. More preferably R a H is H.

[0175] In one preferred embodiment, M is N.

[0176] One preferred reason is, R 15 It is either H or methyl.

[0177] One preferred embodiment: A, D, E, and G do not exist and X is NR 15 or CH; Y is CR 4 , N or not present; Z is CR 5 , NR 6 or O; R 4 The compounds are halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5-8 membered heteroaryl, 4-10 membered condensed ring heterocyclyl, or C1-C6 alkylsulfanyl; R 5 is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5-8 member heteroaryl, optionally substituted 3-8 member heterocycloalkyl, amide, sulfoxymine, CN, or halo; or R 4 and R 5 They, together with the Y and Z to which they are bound, form 3- to 8-membered heterocycloalkyl or aryl groups; R 6 These are H, C1-C6 alkyl, aryl, or C3-C8 cycloalkyl; R 15 is H or C1-C6 alkyl; or R 4 and R 15 They combine with X and Y to form a 5-membered heterocycloalkyl or heteroaryl group, and optionally here R 4 and R 15 They combine with X and Y, to which they are bound, to form dihydrothiazole; Or A is CR 12 Or N, and D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 or N and X is either N or C; Y is C; Z stands for CH, N, NR 11 , or O, Here, R 11 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted 5-8 membered heteroaryl; R 7 H, halo, and C1-C6 alkyl are; R 12 is H, halo, or C1-C6 alkyl; R 13 is H, halo, C1-C6 alkoxy, or C1-C6 alkyl; and R 14 is H, halo, or C1-C6 alkyl; or its stereoisomers, tautomers, hydrates, N-oxide derivatives, or pharmaceutically acceptable salts.

[0178] One preferred embodiment: A, D, E, and G do not exist and X is either NH or CH; Y is CR 4 Or it is N.

[0179] One preferred embodiment: A, D, E, and G do not exist and X is either NH or CH; Y is CR 4 or N; Z is CR 5 , NR 6 or O; R 4 The compounds are halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5-8 member heteroaryl, 4-10 member condensed ring heterocyclyl, C1-C6 alkylsulfanyl (optionally SMe), sulfoxide, sulfone, sulfoximine, optionally substituted amino, or optionally substituted 3-8 member heterocycloalkyl; R 5 is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5-8 member heteroaryl, optionally substituted 3-8 member heterocycloalkyl, amide, sulfoxymine, CN, or halo; or R 4 and R 5 They combine with Y and Z, to which they are bound, to form 3- to 8-membered heterocycloalkyl or aryl groups; and R 6 is H, C1-C6 alkyl, or C3-C8 cycloalkyl.

[0180] In one preferred embodiment, when A, D, E, and G are absent, Z is CR 5 or NR 6 That is the case.

[0181] In one preferred embodiment, when A, D, E, and G are absent, R 6 It is H or C1-C6 alkyl.

[0182] In one preferred embodiment, when A, D, E, and G are absent, R 4 is a halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5-8 member heteroaryl, 4-10 member condensed ring heterocyclyl, SMe, sulfoxide, sulfone, sulfoximine, 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 The compound is a halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5-8 membered heteroaryl, or 4-10 membered condensed ring heterocyclyl.

[0183] In one preferred embodiment, when A, D, E, and G are absent, R 5 H is H.

[0184] In one preferred embodiment, when A, D, E, and G are absent, Y is CR 4 That is the case.

[0185] In one preferred embodiment, when A, D, E, and G are absent, Y is N.

[0186] In one preferred embodiment, when A, D, E, and G are absent, X is NH.

[0187] In one preferred embodiment, when A, D, E, and G are absent, X is CH.

[0188] In one preferred embodiment, when A, D, E, and G are absent, R 4 is a C1-C6 alkyl group, a C1-C6 alkyl group substituted with one or more halo groups, a halo, 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 (preferably a C1-C6 alkoxy group), or a halo group. More preferably, when A, D, E, and G are absent, R 4 These are methyl, CF3, CHF2, chloro, cyclopropyl, methyl-substituted cyclopropyl, thiophene, methyl-substituted pyrazole, 2,3-dihydrobenzofuran, phenyl, or phenyl substituted with methyl, methoxy, or fluoro.

[0189] In one preferred embodiment, when A, D, E, and G are absent, R 4 It is phenyl or phenyl substituted with methyl, methoxy, or fluoro.

[0190] In one preferred embodiment, when A, D, E, and G are absent, R 4 and R 5 These, together with the Y and Z to which they are bound, form a 6-membered heterocycloalkyl or aryl group.

[0191] In one preferred embodiment, when A, D, E, and G are absent, Z is CH.

[0192] In one preferred embodiment, when A, D, E, and G are absent, Z is NR 6 That is the case.

[0193] In one preferred embodiment, when A, D, E, and G are absent, R 6 is H, methyl, or cyclopropyl. More preferably, when A, D, E, and G are absent, R6 It is either H or methyl.

[0194] In one preferred embodiment, Y is CR 4 And here, R 4 Z is a C1-C6 alkylsulfanyl, preferably SMe, and Z is CR 5 And here, R 5 is CN.

[0195] In one preferred embodiment, M is N, X is CH, and Y is CR 4 And Z is NH. In this preferred embodiment, R 4 It is phenyl.

[0196] One preferred embodiment: A, D, E, and G do not exist; X is CH; Y is CR 4 and; Z is NR 6 and M is CR a or N, Here, R a , R 4 and R 6 It is defined as above.

[0197] One preferred embodiment: A, D, E, and G do not exist; X is NH; Y is CR 4 and; Z is CR 5 and M is CR a And, Here, R a , R 4 and R 5 It is defined as above.

[0198] One preferred embodiment: A, D, E, and G do not exist; X is NH; Y is CR 4 and; M is CR a and Z is N, Here, R a and R 4 It is defined as above.

[0199] One preferred embodiment: A is CR 12 Or N, and D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 or N and X is either N or C; Y is C; Z stands for CH, N, NR 11 , or O, where R 11 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted 5-8 membered heteroaryl; R 7 is H, halo, or C1-C6 alkyl; R 12 is H, halo, or C1-C6 alkyl; R 13 is H, halo, C1-C6 alkoxy, or C1-C6 alkyl; and R 14 is H, halo, or C1-C6 alkyl.

[0200] In one preferred embodiment, A is CR 12 Or, when it is N, D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 Or N, and Z is CH, N, or NR 11 That is the case.

[0201] In one preferred embodiment, A is CR 12Or, when it is N, D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 Or it is N, and Z is CH, N, or O.

[0202] In one preferred embodiment, A is CR 12 Or, when it is N, D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 Or it is N, and Z is CH or N.

[0203] In one preferred embodiment, A is CR 12 Or, when it is N, D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 or N, R 7 is H, methyl, or halo.

[0204] In one preferred embodiment, A is CR 12 Or, when it is N, D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 or N, R 12 H is H.

[0205] In one preferred embodiment, A is CR 12 Or N, and D is CR 7 And E is CR 13 Or N, and G is CR 14 Or it is N.

[0206] In one preferred embodiment, A is CR 12 Or, when it is N, D is CR 7 Or it is N, and E is CR 13 And G is CR 14 Or it is N.

[0207] In one preferred embodiment, A is CR 12Or, when it is N, D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 or N, R 13 H is H.

[0208] In one preferred embodiment, A is CR 12 Or, when it is N, D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 That is the case.

[0209] In one preferred embodiment, A is CR 12 Or, when it is N, D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 or N, R 14 H is H.

[0210] In one preferred embodiment, A is CR 12 Or, when it is N, D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 Or N, and X is N.

[0211] In one preferred embodiment, A is CH and D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 Or it is N.

[0212] In one preferred embodiment, A is N and D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 Or it is N.

[0213] In one preferred embodiment, A is CR 12 Or, when it is N, D is CR 7 Or it is N, and E is CR 13Or N, and G is CR 14 or N, R 7 It is H or halo, and fluoro if desired.

[0214] In one preferred embodiment, A is CR 12 Or, when it is N, D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 Or N, and Z is CH.

[0215] In one preferred embodiment, A is CR 12 Or, when it is N, D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 Or it is N, and Z is N.

[0216] In one preferred embodiment, A is CR 12 Or, when it is N, D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 Or N, and Z is O.

[0217] In one preferred embodiment, A is CR 12 Or, when it is N, D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 Or N, and Z is NR 11 That is the case.

[0218] In one preferred embodiment, A is CR 12 Or, when it is N, D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 Or N, and Z is NR 11 And R 11 A is H, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, or 5-7 member heteroaryl. More preferably, A is CR 12Or, when it is N, D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 Or N, and Z is NR 11 And R 11 is methyl. More preferably, A is CR 12 Or, when it is N, D is CR 7 Or it is N, and E is CR 13 Or N, and G is CR 14 Or N, and Z is NR 11 And R 11 H is H.

[0219] In one preferred embodiment, X is N; Y is C; Z is N; M is CR a A and G are CH respectively; D is CR 7 And E is CR 13 And here, R a , R 7 and R 11 It is defined as above.

[0220] In one preferred embodiment, X and Y are C, respectively; Z is O; A, E, G, and M are CH, respectively; and D is CR. 7 And here, R 7 It is defined as above.

[0221] In one preferred embodiment, X and Y are C, respectively; Z is NR 11 And A, E, G and M are CH respectively; and D is N, where R 11 It is defined as above.

[0222] In one preferred embodiment, X and Y are C, respectively; Z is NH; E is N; and A, D, G, and M are CH, respectively.

[0223] In a more preferable case, A, D, E, and G do not exist; X is NR 15 Therefore; Y is CR4 And; Z is N; M is CH; and R 4 and R 15 They combine with X and Y to form a 5-membered heterocycloalkyl group. In one preferred embodiment, R 4 and R 15 These, together with X and Y to which they are bound, form a dihydrothiazole.

[0224] One preferred embodiment: A, D, E, and G do not exist. X is either NH or CH; Y is CR 4 and; Z is CR 5 or NR 6 and; R 1 This is a piperidine or piperazine which is optionally substituted, R 2 and R 3 These combine with the carbon atoms to form cyclopentyl, R 4 It is phenyl, R 5 is H, and R 6 is H or methyl, Here, each arbitrary substituent is selected from phenyl, difluorophenyl, NHCH3, NHCH2CH3, NHCH(CH3)2, NHC(O)CH3, N(CH3)2, NHCH2CHF2, NHCH2CH2F, NHCH2CH2OH, and NHCH2CH2OCH3.

[0225] One preferred embodiment: A, D, E, and G do not exist; X is either NH or CH; Y is CR 4 and; Z is CR 5 or NR 6 and; R 1is piperidine or piperazine, each substituted with difluorophenyl and optionally with one or more C1-C3 alkyl groups: amino, oxo-substituted C1-C3 alkyl, fluoro-substituted C1-C3 alkyl, CH2CH2OH, C1-C3 alkoxy, fluoro-substituted C3-C6 cycloalkyl, C1-C3 alkyl-substituted C3-C6 cycloalkyl, or pyridine-substituted C1-C3 alkyl; R 2 and R 3 Each of these is either methyl or, together with the carbon to which they are bonded, forms cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, oxetanyl, or oxanyl; R 4 is methyl, dihydrobenzofuran, phenyl, methyl-substituted phenyl, F-substituted phenyl, OMe-substituted phenyl, SMe-substituted phenyl, OH-substituted phenyl, or thiophene; R 5 is H, methyl or CN; and R 6 It is either H or methyl.

[0226] One preferred embodiment: X is either N or C; Y is C; Z is N, NR 11 Or O, where R 11 is H or methyl; M is CR a And here, R a is H, methyl, or cyclopropyl; A is C; D is CR 7 And here, R 7 These are H, methyl, F, Cl, and Br; E is N or CR 13 And here, R 13 is H, Cl, or OMe; G is C; R1 is a piperidine or piperazine, each substituted with a difluorophenyl molecule and optionally with one or more C1-C3 alkyl groups, and is substituted with amino, fluorosubstituted C1-C3 alkyl, CH2CH2OH, or C1-C3 alkoxy molecules; and R 2 and R 3 Each of these atoms is either methyl or, together with the carbon atom to which they are bonded, forms cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, oxetanyl, or oxanyl.

[0227] One preferred embodiment: (R)-6-phenyl-3-((4-(3-phenylmorpholin-4-carbonyl)piperazine-1-yl)methyl)pyridine-2(1H)-one; (R)-3-((2,2-dimethyl-4-(3-phenylmorpholine-4-carbonyl)piperazine-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)quinoline-2(1H)-one; N-((2S,4R)-2-(2,5-difluorophenyl)-1-(6-((2-oxo-6-phenyl-1,2-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidine-4-yl)acetamide; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridine-2-one; N-(2,4-difluorobenzyl)-6-((2-oxo-6-phenyl-1,2-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxamide; (R)-6-phenyl-3-((9-(4,4,4-trifluoro-2-methylbutanoyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 3-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; (R)-3-((9-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 6-phenyl-3-((9-((3R,4R)-3-phenylpiperidine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1H)-one; 3-((9-((2S,4R)-4-((3,3-difluorocyclobutyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; (S)-6-phenyl-3-((9-(4,4,4-trifluoro-2-(methoxymethyl)butanoyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1H)-one; (R)-3-((9-(3-cyclohexyl-2-methylpropanoyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 6-Phenyl-3-((9-(3-phenylisonicotinoyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1H)-one; 3-((9-((2S,4R)-4-((2-hydroxyethyl)amino)-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2,2-dimethylpiperazine-1-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-4,7-diazaspiro[2.5]octan-4-yl)methyl)-2-phenylpyridine-4(1H)-one; 6-phenyl-3-((9-((2S,4R)-2-phenyl-4-((pyridine-2-ylmethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1H)-one; 5-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(3,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; (R)-3-((9-(2-methyl-2-phenylpiperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; (R)-5-((9-(3-(2,5-difluorophenyl)morpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; (S)-5-((9-(3-(2,5-difluorophenyl)morpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,3-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-4-(cyclopropylamino)-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; (R)-5-((9-(2-(2,5-difluorophenyl)-1,4-diazepan-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; (S)-5-((9-(2-(2,5-difluorophenyl)-1,4-diazepan-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; (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(1H)-one; (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(1H)-one; 5-((9-((2S,4R)-2-(2,6-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 3-((9-((3R,5S)-3-(2,5-difluorophenyl)-5-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((8-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-5,8-diazaspiro[3.5]nonanane-5-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((8-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2-oxa-5,8-diazaspiro[3.5]nonanane-5-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1H)-one; 3-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2,2-dimethylpiperazine-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-4,7-diazaspiro[2.5]octan-4-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-4-amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((8-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-5,8-diazaspiro[3.5]nonanane-5-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((8-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2-oxa-5,8-diazaspiro[3.5]nonanane-5-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(pyrrolidine-1-yl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(1-methyl-1H-pyrazole-5-yl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-methyl-5-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-2-yl)pyridine-4(1H)-one; (R)-3-((9-(3-cyclohexyl-2-methylpropanoyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 5-((9-((2S,4R)-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-4-morpholino-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-fluorophenyl)pyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(o-tolyl)pyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-methoxyphenyl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-chromen-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-4H-chromen-4-one; (R)-3-((9-(3-cyclohexyl-2-methylpropanoyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-chromen-4-one; (R)-3-((9-(3-cyclohexyl-2-methylpropanoyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-4H-chromen-4-one; 5-((9-((2S,4R)-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(1H)-one; (R)-3-((9-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-4H-chromen-4-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(1-methyl-1H-pyrazole-3-yl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2,2-dimethylpiperazine-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 1-Cyclopropyl-5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-methylpyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-5,6-dimethylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoroquinoline-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-hydroxyphenyl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-methyl-2-propylpyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-5-(trifluoromethyl)pyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(o-tolyl)pyridine-4(1H)-one; 5-((9-((2S,4R)-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(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-methoxyphenyl)pyridine-4(1H)-one; (R)-5-((9-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; (R)-3-((9-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(4-fluorophenyl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(3-fluorophenyl)pyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(m-tolyl)pyridine-4(1H)-one; 5-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-methoxyphenyl)pyridine-4(1H)-one; 5-((9-((2S,4R)-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(1H)-one; 5-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(o-tolyl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(m-tolyl)pyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(3-fluorophenyl)pyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(4-fluorophenyl)pyridine-2(1H)-one; 5-((9-((2S,4R)-2-(3-fluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-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-carbonitrile; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyrimidine-4(3H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1,7-naphthyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyrimidine-4(3H)-one; 5-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-2-yl)pyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-2-yl)pyridine-4(1H)-one; 5-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2,6-dimethylpyridine-4(1H)-one; 3-((9-((2S,4R)-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((4-((2S,5R)-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazine-1-yl)methyl)-6-phenylpyridine-2(1H)-one; (R)-6-phenyl-3-((4-(3-phenylmorpholine-4-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)pyridine-2(1H)-one; (R)-3-((4-(3-(4-fluorophenyl)morpholine-4-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((4-((2R,5R)-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazine-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2-fluoro-5-methylphenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2-fluoro-5-methoxyphenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,5R)-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyrimidine-4(3H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; N-((2S,4R)-2-(2,5-difluorophenyl)-1-(6-((7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidine-4-yl)acetamide; N-((2S,4R)-2-(2,5-difluorophenyl)-1-(6-((7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidine-4-yl)cyclopropanecarboxamide; 3-((9-((2S,4R)-4-((1,1-dioxidethietan-3-yl)amino)-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-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)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(thiophen-3-yl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; (S)-6-(2-methoxyphenyl)-3-((9-(2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1H)-one; (S)-6-phenyl-3-((7-(2-phenylpyrrolidine-1-carbonyl)-4,7-diazaspiro[2.5]octan-4-yl)methyl)pyridine-2(1H)-one; (S)-6-phenyl-3-((4-(2-phenylpyrrolidine-1-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)pyridine-2(1H)-one; 5-((9-((2R,5R)-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; (S)-3-((4-(2-(2,5-difluorophenyl)pyrrolidin-1-carbonyl)-2,2-dimethylpiperazine-1-yl)methyl)-6-(1-methyl-1H-pyrazole-5-yl)pyridine-2(1H)-one; (S)-3-((2,2-dimethyl-4-(2-phenylpyrrolidine-1-carbonyl)piperazine-1-yl)methyl)-6-phenylpyridine-2(1H)-one; (S)-6-phenyl-3-((8-(2-phenylpyrrolidine-1-carbonyl)-2-oxa-5,8-diazaspiro[3.5]nonanane-5-yl)methyl)pyridine-2(1H)-one; 3-((4-((1S,2R,5R)-2-(2,5-difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octan-3-carbonyl)piperazin-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((1S,2R,5R)-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(1H)-one; 5-((9-((1S,2R,5R)-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(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-fluorophenyl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-1-methylquinoline-4(1H)-one; 3-((9-((2R,3R)-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,3S)-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(1-methyl-1H-pyrazole-5-yl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(trifluoromethyl)pyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(trifluoromethyl)pyridine-4(1H)-one; 3-((4-((2R,3R)-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazine-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((4-((2S,3S)-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazine-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2R,3R)-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,3S)-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 3-((9-((2R,4R)-4-amino-2-ethylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2R,4R)-2-ethyl-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)(methyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(1-methyl-1H-pyrazole-3-yl)pyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-hydroxypiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(1-methyl-1H-pyrazole-3-yl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropyl(methyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-methoxyethyl)(methyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-hydroxypiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1H)-one; 3-(((S)-4-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-2-methylpiperazine-1-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 7-Chloro-3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-2,2-dimethylpiperazine-1-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-(((R)-4-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-2-methylpiperazine-1-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 5-((9-((2S,4R)-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(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)(methyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethyl(methyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-methyl-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidine-4-one; 5-((9-((2S,4S)-4-amino-2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4S)-4-(isopropylamino)-2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 3-((9-((2S,4R)-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(6H)-one; 3-((9-((2S,4R)-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(6H)-one; 3-((9-(5-amino-2',5'-difluoro-[1,1'-biphenyl]-2-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-fluoroethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-fluoroethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 7-Fluoro-3-((9-((2S,4S)-4-(isopropylamino)-2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-methyl-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one; 4-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-phenyl-1,2-dihydro-3H-pyrazole-3-one; 4-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-methyl-1-phenyl-1,2-dihydro-3H-pyrazole-3-one; 7-Chloro-3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 7-Chloro-3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 6-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-5H-thiazolo[3,2-a]pyrimidine-5-one; 6-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-5H-thiazolo[3,2-a]pyrimidine-5-one; 7-Fluoro-3-((9-((2S,4R)-4-((3-methyloxetan-3-yl)amino)-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-methyl-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one; 2-Cyclopropyl-3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 2-Cyclopropyl-3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridazine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridazine-4(1H)-one; 3-((9-((2S,4R)-4-amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]dec-2-en-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 7-Bromo-3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 8-Chloro-3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-1,6-naphthyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((1-methylcyclopropyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; and 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(1-methylcyclopropyl)pyridine-4(1H)-one; A compound selected from, or its stereoisomers, tautomers, hydrates, N-oxide derivatives, or pharmaceutically acceptable salts, is provided.

[0228] In one embodiment, the above-mentioned compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt is provided, which is an inhibitor of USP19, preferably human USP19.

[0229] In a second embodiment, the present invention provides a pharmaceutical composition comprising a compound according to the first embodiment, a stereoisomer, a tautomer, a hydrate, an N-oxide derivative or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or diluent.

[0230] Pharmaceutical compositions can be formulated for specific uses and purposes by, for example, mixing additives, binders, lubricants, disintegrants, coatings, emulsifiers, suspending agents, solvents, stabilizers, absorption enhancers, and / or ointment bases. Compositions may be suitable for oral, injectable, rectal, or topical administration.

[0231] Suitable pharmaceutically acceptable additives are known to those skilled in the art and include, for example: fats, water, physiological saline, alcohols (e.g., ethanol), glycerol, polyols, aqueous glucose solutions, bulking agents, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavoring agents or fragrances, concentrators, diluents, buffers, solvents or solubilizers, chemicals for achieving preservative effects, salts for modifying 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 aluminometasilicate or anhydrous calcium phosphate; synthetic polymers such as polyvinylpyrrolidone or polyalkylene glycol; alcohols such as stearyl alcohol or benzyl alcohol; synthetic cellulose derivatives such as methylcellulose, carboxymethylcellulose, ethylcellulose or hydroxypropylmethylcellulose; and other conventionally used additives such as gelatin, talc, vegetable oils and gum arabic.

[0232] For example, pharmaceutical compositions may be administered orally in the form of tablets, coated tablets, hard or soft gelatin capsules, solutions, emulsions, or suspensions. Administration may also be carried out rectally, for example using suppositories; topically or transdermally using, for example, ointments, creams, gels, or solutions; or non-enterally using, for example, injectable solutions.

[0233] For the preparation of tablets, coated tablets, or hard gelatin capsules, the compounds of the present invention may be mixed with pharmaceutically inert inorganic or organic additives. Examples of suitable additives include lactose, maize starch or its derivatives, talc, or stearic acid or its salts. Suitable additives for use in soft gelatin capsules include, for example, vegetable oils, waxes, fats, and semi-solid or liquid polyols.

[0234] For the preparation of solutions and syrups, additives include, for example, water, polyols, sucrose, invert sugar, and glucose.

[0235] Additives for injectable solutions include, for example, water, alcohol, polyol, glycerin, and vegetable oil.

[0236] For suppositories and topical and transdermal applications, additives may include, for example, natural or hydrogenated oils, waxes, fats, and semi-solid or liquid polyols.

[0237] The pharmaceutical composition also contains preservatives, solubilizers, stabilizers, humectants, emulsifiers, sweeteners, colorants, odorants, buffers, coating agents, and / or antioxidants.

[0238] For combination therapy, the second drug may be provided together with the present invention in a pharmaceutical composition or separately.

[0239] Therefore, oral pharmaceutical formulations may be, for example, granules, tablets, sugar-coated tablets, capsules, pills, suspensions, or emulsions. For example, for non-enteral injection for intravenous, intramuscular, or subcutaneous use, sterile aqueous solutions may be provided that may contain other substances, such as salts and / or glucose to make the solution isotonic. Anticancer agents may also be administered in the form of suppositories or pessaries, or applied topically in the form of lotions, solutions, creams, ointments, or powders.

[0240] In a further embodiment, the present invention provides compounds of the first embodiment, comprising stereoisomers, tautomers, hydrates, N-oxide derivatives, or pharmaceutically acceptable salts thereof, for therapeutic use.

[0241] In a further embodiment, the present invention provides a second-acting pharmaceutical composition for therapeutic use.

[0242] In a further embodiment, the present invention provides compounds of any embodiment of the first aspect, or stereoisomers, tautomers, hydrates, N-oxide derivatives, or pharmaceutically acceptable salts thereof, for use in the treatment and / or prevention of cancer.

[0243] In a further embodiment, the present invention provides a second-aspect pharmaceutical composition for use in the treatment and / or prevention of cancer.

[0244] In a further embodiment, the present invention provides a method for treating or preventing cancer, comprising administering to a subject a compound comprising a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof according to any embodiment of the first aspect of the present invention, or a pharmaceutical composition according to any embodiment of the second aspect of the present invention.

[0245] In a further embodiment, the present invention provides the use of compounds comprising stereoisomers, tautomers, hydrates, N-oxide derivatives, or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for the treatment or prevention of cancer, according to any embodiment of the first aspect.

[0246] Cancers or neoplasms suitable for treatment with the compounds or compositions of the present invention include, for example: prostate cancer, colon cancer, breast cancer, lung cancer, kidney cancer, CNS cancers (e.g., neuroblastoma, glioblastoma), osteosarcoma, and hematological malignancies (e.g., leukemia, multiple myeloma, and mantle cell lymphoma). In one preferred embodiment, the cancer is associated with p53 dysregulation. In one preferred embodiment, the cancer is selected from hematological malignancies (e.g., mantle cell lymphoma, multiple myeloma), prostate cancer, neuroblastoma, or glioblastoma. In one preferred embodiment, the cancer is neuroblastoma or breast cancer.

[0247] Potent USP19 inhibitory compounds have been shown to effectively reduce fat accumulation in vivo. Gene knockout studies explain the possible relationship between USP19 and fat accumulation (Coyne et al., Diabetologia, 2019, 62, 136-146, incorporated herein by reference). However, the effects observed in these studies must be considered along with the potential confounding factors inherent to knockout studies, such as alterations of developmental or underlying physiological processes. For these reasons, acute or chronic pharmacological inhibition of the enzyme does not necessarily produce physiological outcomes similar to genetic removal.

[0248] The data presented here demonstrate that pharmacological inhibition of USP19 can reduce fat accumulation in a wild-type background. In summary, in vitro and in vivo data indicate that compounds that potently inhibit USP19 activity can effectively treat obesity.

[0249] In a further embodiment, compounds of the first embodiment, or pharmaceutically acceptable salts, tautomers, stereoisomers, or N-oxide derivatives thereof, are provided for use in methods of treating obesity.

[0250] In a further embodiment, a second-aspect pharmaceutical composition is provided for use in a method for treating obesity.

[0251] The present invention also provides a method for treating obesity, comprising administering to a subject in need an effective amount of a compound according to the first embodiment, a pharmaceutically acceptable salt, a tautomer, a stereoisomer or N-oxide derivative, or an effective amount of a pharmaceutical composition according to the second embodiment.

[0252] The potent USP19 inhibitory compounds provided herein are also shown to be able to effectively treat insulin resistance. Gene knockout studies have described the relationship between USP19 and insulin sensitivity (Coyne et al., supra). Coyne et al. describe improved insulin sensitivity in USP19 knockout mice, but as mentioned above, it cannot be inferred that this effect would translate to pharmacological inhibition of USP19 in wild-type subjects.

[0253] The data presented here demonstrate that pharmacological inhibition of USP19 can effectively treat insulin resistance (e.g., type 2 diabetes).

[0254] In a further embodiment, compounds defined in relation to the first aspect of the present invention, or pharmaceutically acceptable salts, tautomers, stereoisomers, or N-oxide derivatives thereof, are provided for use in methods for treating insulin resistance.

[0255] In a further embodiment of the present invention, compounds defined in relation to the first aspect of the present invention, or pharmaceutically acceptable salts, tautomers, stereoisomers, or N-oxide derivatives thereof, are provided for use in methods for treating type II diabetes.

[0256] In a further embodiment of the present invention, a second-acting pharmaceutical composition is provided for use in a method for treating insulin resistance.

[0257] In a further embodiment of the present invention, a second embodiment of a pharmaceutical composition is provided for use in a method for treating type II diabetes.

[0258] The present invention also provides a method for treating insulin resistance, comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative as defined in relation to a first aspect of the present invention, or an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative as defined in relation to a first aspect of the present invention.

[0259] The present invention also provides a method for treating type II diabetes mellitus, comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative as defined in relation to a first aspect of the present invention, or an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative as defined in relation to a first aspect of the present invention.

[0260] The compounds provided herein are potent USP19 inhibitors, and the attached examples demonstrate that even more potent USP19 inhibitory compounds effectively treat muscle loss in in vivo disease models. In summary, the in vitro and in vivo data show that compounds that potently inhibit USP19 activity can effectively treat muscle atrophy.

[0261] In a further embodiment, compounds defined in relation to the first aspect of the present invention, or pharmaceutically acceptable salts, tautomers, stereoisomers, or N-oxide derivatives thereof, are provided for use in methods for treating muscle atrophy.

[0262] In a further embodiment, the present invention provides compounds as defined in relation to the first embodiment, or pharmaceutically acceptable salts, tautomers, stereoisomers, or N-oxide derivatives thereof, for use in methods of treating cachexy or sarcopenia.

[0263] In a further embodiment of the present invention, a second embodiment of a pharmaceutical composition is provided for use in a method for treating muscle atrophy.

[0264] In a further embodiment of the present invention, a second embodiment of a pharmaceutical composition is provided for use in a method for treating cachexy or sarcopenia.

[0265] The present invention also provides a method for treating muscle atrophy, comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative as defined in relation to a first aspect of the present invention, or an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative as defined in relation to a first aspect of the present invention.

[0266] The present invention also provides a method for treating cachexia or sarcopenia, comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative as defined in relation to a first aspect of the present invention, or an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative as defined in relation to a first aspect of the present invention.

[0267] Muscle atrophy, cachexia, or sarcopenia may be associated with or induced by HIV infection / AIDS, heart failure, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, multiple sclerosis, motor neuron disorders (MND), Parkinson's disease, dementia, or cancer.

[0268] In a further embodiment, the present invention provides compounds or compositions in any embodiment of the first or second embodiment for use in the treatment and / or prevention of Parkinson's disease. In a further embodiment, the present invention provides a method for treating or preventing Parkinson's disease, comprising administering to a subject an effective amount of the compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof, or pharmaceutical composition according to the present invention. In a further embodiment, the present invention provides the use of the compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof, in the manufacture of a pharmaceutical for the treatment of Parkinson's disease.

[0269] The compounds or compositions of the present invention may be used in monotherapy and / or combination modalities. Suitable agents to be used with the compounds or compositions of the present invention in such combination modalities include one or more anticancer agents, anti-inflammatory agents, immunomodulators, such as immunosuppressants, neurological agents, antidiabetic agents, antiviral agents, antibacterial agents, and / or radiotherapy agents.

[0270] A drug used in combination with the compound of the present invention may target the same or similar biological pathways targeted by the compound of the present invention, or it may act on different or unrelated pathways.

[0271] Depending on the disease being treated, a variety of combination partners may be administered together with the compounds of the present invention. The second active ingredients include: alkylating agents including cyclophosphamide, ifosfamide, thiotepa, melphalan, chloroethylnitrosourea, and bendamustine; platinum derivatives including cisplatin, oxaliplatin, carboplatin, and satraplatin; mitotic inhibitors including vinca alkaloids (vincristine, vinorelbine, and vinblastine), taxanes (paclitaxel, docetaxel), epothilon, aurora, and polokinase; topoisomerase inhibitors including anthracyclines, epipodophyllotoxin, camptothecin, and camptothecin analogs; and 5-fluoroura. Antimetabolites including sil, capecitabine, cytarabine, gemcitabine, 6-mercaptopurine, 6-thioguanine, fludarabine, methotrexate and pemetrexed; protein kinase inhibitors including, but not limited to, imatinib, gefitinib, sorafenib, sunitinib, erlotinib, dasatinib and lapatinib; proteosome inhibitors including bortezomib; histone deacetylase inhibitors including valoproate and SAHA; anti-angiogenic drugs including bevacizumab; monoclonal antibodies including trastuzumab, rituximab, alemtuzumab, tocitumomab, cetuximab and panitumumab; gemtuzumab Myoclonal antibody conjugates including ozogamicin, ibritumomab, and tiuxetan; hormone therapies including anti-estrogens (tamoxifen, raloxifene, anastrozole, letrozole, exemestane), anti-androgens (flutamide, bicalutamide), and luteinizing hormone analogs or antagonists; but not limited to these.

[0272] With regard to embodiments of the present invention relating to the therapeutic use of the compounds according to the present invention, the compounds may be administered in an “effective dose” to a subject requiring treatment. The term “effective dose” refers to the amount or dosage of the compound that provides therapeutic efficacy in the treatment of a disease through a single or multiple administration to the subject. The therapeutic effective dose of the compounds according to the present invention may include an amount of about 0.1 mg / kg to about 20 mg / kg per single administration. The therapeutic effective dose for any individual patient may be determined by a healthcare professional in a manner understood by those skilled in the art. The amount of the compound administered at any given time, whether alone or in combination with some other therapeutic agent, may vary so that the optimal amount of the compound is administered during the course of the treatment. It is also intended that the compounds according to the present invention, or pharmaceutical compositions containing such compounds, be administered as combination therapy in combination with any other cancer treatment.

[0273] Regarding combination therapy, the second drug may be provided together with the present invention in a pharmaceutical composition, or separately.

[0274] Route of administration In one preferred embodiment, the treatment according to the present invention involves administering a therapeutic agent (i.e., a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative, or pharmaceutical composition for use according to the present invention) non-enterally.

[0275] In one preferred embodiment, the therapeutic agent is administered orally.

[0276] In one preferred embodiment, the therapeutic agent is administered intravenously. In one preferred embodiment, the therapeutic agent is administered intraperitoneally. In one preferred embodiment, the therapeutic agent is administered subcutaneously.

[0277] Administration regimen In one preferred embodiment of the present invention, the treatment involves administering a therapeutic agent (i.e., a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative, or pharmaceutical composition for use in the present invention) in a dose ranging from 10 to 150 mg / kg. In such embodiments, the dose refers to the amount of the active ingredient administered to the subject per single dose.

[0278] In one preferred embodiment, the treatment includes administering the therapeutic agent in a dose ranging from 25 to 125 mg / kg. In another preferred embodiment, the treatment includes administering the therapeutic agent in a dose ranging from 50 to 100 mg / kg.

[0279] In one preferred embodiment, the method includes administering the therapeutic agent at a dose of 75 mg / kg.

[0280] In one preferred embodiment, the treatment involves administering a therapeutic agent (i.e., a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative, or pharmaceutical composition for use in the present invention) once, twice, three or four times daily. In one preferred embodiment, the therapeutic agent is administered once or twice daily, most preferably twice daily.

[0281] In one preferred embodiment, the therapeutic agent is administered in a daily dose in the range of 10 to 300 mg / kg. That is, the total amount of the active agent administered to the subject per day is in the range of 10 to 300 mg / kg. In such embodiments, the therapeutic agent may be administered once or multiple times per day as described herein, provided that the total daily dose is within the indicated range.

[0282] In one preferred embodiment, the therapeutic agent is administered in a daily dose ranging from 50 to 250 mg / kg. In another preferred embodiment, the therapeutic agent is administered in a daily dose ranging from 75 to 250 mg / kg. In yet another preferred embodiment, the therapeutic agent is administered in a daily dose ranging from 100 to 200 mg / kg. In yet another preferred embodiment, the therapeutic agent is administered in a daily dose of 150 mg / kg.

[0283] In one preferred embodiment, the therapeutic agent (e.g., the compound provided herein) is administered at a dose of 75 mg / kg twice daily.

[0284] With regard to aspects of the present invention relating to therapeutic uses of compounds according to the present invention, in a preferred embodiment, the subject to treatment is a human being.

[0285] In a further embodiment, the present invention provides compounds, stereoisomers, tautomers, hydrates, N-oxide derivatives or pharmaceutically acceptable salts according to a first embodiment, or pharmaceutical compositions according to a second embodiment, for use as pharmaceuticals.

[0286] In a further embodiment, the present invention provides compounds, stereoisomers, tautomers, hydrates, N-oxide derivatives or pharmaceutically acceptable salts according to a first embodiment, or pharmaceutical compositions according to a second embodiment, for use in the treatment of muscle atrophy, obesity, insulin resistance, or type II diabetes.

[0287] In a further embodiment, the present invention provides a method for treating obesity, insulin resistance, type II diabetes, or muscle atrophy, comprising administering an effective amount of a compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt or a pharmaceutical composition in a second embodiment to a subject in need thereof.

[0288] In a further embodiment, 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 a compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt or a pharmaceutical composition in a second embodiment.

[0289] When introducing elements of the present invention or its preferred embodiments, singular expressions are intended to mean that there are one or more elements. The terms “include,” “contain,” and “have” are intended to be comprehensive and mean that there may be further elements other than those listed.

[0290] The details described herein are provided for illustrative and illustrative purposes only and are not intended to limit the scope of the attached claims. Many variations of the currently preferred embodiments described herein will be apparent to those skilled in the art and remain within the scope of the attached claims and their equivalents. [Examples]

[0291] The present invention will now be described in relation to several embodiments.

[0292] The following examples were synthesized by the method described below. IC 50 The values ​​were determined as follows and are shown in the following table: [Table 4] [Table 5] [Table 6]

[0293] USP19 activity was determined by a fluorescence polarization (FP) homogeneous assay using the isopeptide ubiquitin-Lys-TAMRA substrate (AUB-101, Almac Sciences Scotland Limited, or U-558, Boston Biochem; both yielded identical results). Full-length USP19 was purchased from Boston Biochem (E-576). Unless otherwise noted, all other reagents were purchased from Sigma. Enzymatic reactions were performed in 384-well black flat-bottom polystyrene plates (Nunc) with 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) in or without the inhibitor (10 μL). The inhibitor was stored in StoragePod. (登録商標) Using a system (Roylan Developments), the compound was stored as a 10 mM DMSO stock in an inert environment (low humidity, dark, low oxygen, rt), and serial dilutions were prepared in buffer immediately before assay (200 μM to 2 pM, 8 to 18 data point curves). After incubation at rt for 30 minutes, the enzymatic reaction was initiated by dispensing Ub substrate (500 nM, 10 μL). FP was measured every 15 minutes over a 90-minute period (within the linear range of the assay) using a Synergy 4 plate reader (BioTek) excited at 530 nm, with the amount of horizontal and vertical polarization measured at 575 nm. The FP signal was then normalized to no compound control. The data were plotted and fitted to determine the concentration (IC) that yielded 50% inhibition. 50 The IC of the inhibitor of the present invention was calculated using a nonlinear regression curve fitting model with Prism (GraphPad). 50 The values ​​are compiled in Table 4 and represent the average of at least two duplicate experiments.

[0294] Cellular target binding using Western 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 hours and lysed (lysation 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), and then ubiquitin-propargylamine (Ub-PA; UbiQ) or ubiquitin-vinyl methyl ester (Ub-VME; Almac Sciences Scotland Limited) was added. Samples were analyzed by Western blotting with USP19 probing (EC by densitometry). 50 (Decision). In each cell line, the USP19 inhibitor compound showed good cell permeability, and EC 50 The concentration was low nanomolar. The results for each cell line are shown in Figure 4.

[0295] Dynamic solubility (KSol) assay The test compound (5 μL of 10 mM DMSO stock) was placed in a MultiScreen (登録商標) The compounds were added to 245 μL of phosphate-buffered saline (PBS) buffer (Dulbecco A) at pH 7.4 in a Solubility filter plate (Millipore), and mixed on a plate shaker at 300 rpm for 90 minutes. During this time, a 5-point calibration curve for each compound was established using an acetonitrile / PBS buffer (maximum concentration 200 μM) mixture. After filtration and matrix matching, the calibrated and assay plates were analyzed using a BioTek Synergy 4 plate reader (240–400 nm). The final concentration of the test compound in the filtrate was calculated using the slope of the calibration curve.

[0296] Determination of endogenous clearance in human / mouse / rat liver microsomes (HLM / MLM / RLM) 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) in 0.1 M PBS buffer (Dulbecc's A) at pH 7.4, at 37°C, if necessary. The reaction was initiated by adding NADPH (final concentration = 1 mM) in 0.1 M PBS buffer (Dulbecc's A) at pH 7.4. 40 μL aliquots were taken at 2, 5, 10, 15, 20, 30, 40, and 50 minutes. The reaction was quenched with 80 μL of ice-cold methanol. Subsequently, the samples were frozen overnight and then centrifuged at 3500 rpm for 20 minutes at 4°C. The supernatant was removed and transferred to an analytical plate for analysis by LC / MS / MS.

[0297] LC / MS / MS method: All samples were analyzed using a Waters ACQUITY I-Class UPLC coupled with a Waters Xevo TQD mass spectrometer. A Waters BEH C18 column (2.1 × 50 mm, 1.7 μm) was used, and the mobile phase consisted of water and methanol with 0.1% v / v formic acid as a modifier. The analysis conditions were optimized for each test compound through multiple reaction monitoring.

[0298] Data analysis: The linear gradient was determined from the plot of ln peak area against time. Then, the half-life and intrinsic clearance were calculated using the following formula:

number

[0299] Cytochrome P450 (CYP) Inhibition Assay CYP inhibition was evaluated for five major isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) using a commercially available heterologously expressed isoform mixture (Cypex) in E. coli. The method followed that described in Weaver R. et al., Drug Metab. Dispos. (2003), 31, 955-966. The activity of each isoform was measured using the published K values ​​for each isoform. m The appearance of isoform-specific metabolites was evaluated by measuring the presence of selective and FDA-receptor substrates at nearby concentrations. Test compounds were assayed over eight concentrations (semi-logarithmic dilutions) typically ranging from 50 μM to 0.023 μM final concentration. 4× of the desired final concentration of the test compound in 0.1 M PBS buffer (Dulbecc's A) at pH 7.4 was incubated with a 2× mixture of CYP isoforms and substrate mixes at 37°C for 3 minutes. The reaction was then initiated by adding a 4 mM NADPH solution in 0.1 M PBS buffer (Dulbecc's A) at pH 7.4. After 10 minutes of incubation, the reaction was stopped by adding an internal standard and methanol containing 0.1% v / v formic acid. Metabolites for each CYP substrate were quantified by LC / MS / MS using a Waters ACQUITY I-Class connected to a Waters Xevo TQD mass spectrometer. A Waters BEH C18 column (2.1 × 50 mm, 1.7 μm) was used, and the mobile phase consisted of water and methanol containing 0.1% v / v formic acid as modifiers. The analysis was optimized for each metabolite through multiple reaction monitoring.

[0300] Data analysis: The CYP activity of the test compound at each concentration was converted to a percentage of the control activity (CA), and a pseudo-Hill plot was created by plotting log (concentration) versus activity. Using slope and y-axis intercept, the IC of the test compound for each CYP isoform was calculated according to the following formula. 50 The value was calculated:

number

[0301] hERG ion channel inhibition assay The test compounds were assayed for inhibition of human delayed-rectifying potassium ion channel genes (hERGs) using QPatch II (Sophion Bioscience) automated patch-clamp assays provided by external providers. Six concentration-response curves were prepared from the 100 μM maximum concentration of the test compound through serial dilutions, and ICs were obtained after curve fitting. 50 Value determination was made possible. Each data point is plotted starting from a minimum of n=3 cells.

[0302] 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 show that compounds that potently inhibit USP19 activity can effectively treat muscle atrophy, obesity, and / or insulin resistance.

[0303] method: To induce muscle wasting, a 1 cm segment of the sciatic nerve in the femur was excised from mice (8-10 week old male C57bl / 6 mice; n=10 / group) under isoflurane anesthesia and carprofen analgesia. A simulated surgery was performed on the opposite leg as a control.

[0304] Mice were randomized into either a vehicle or a test group, and all animals were weighed to ensure that the mean body weight of each group was similar. ADC-141, a USP19 inhibitor, or the vehicle was administered intravenously twice daily, starting on the evening after surgery.

[0305] Mice were sacrificed after 14 days. Fat pads, liver, and calf and tibialis anterior muscles were collected. Tissue mass was measured in both groups.

[0306] A diet-induced obesity mouse model was used to evaluate obesity and insulin resistance. Diet-induced obesity (DIO) mice are a well-characterized model of obesity, exhibiting increased steatosis, insulin resistance, and glucose intolerance.

[0307] Male C57BL6 / J mice were given free access to a high-fat diet (D12451, 45% fat; Research Diets, New Jersey, USA) and filtered tap water throughout the study period. From day 0, mice were administered either a medium ip BID, a USP19 inhibitor (ADC-141) ip BID at 5 mg / kg or 25 mg / kg, or a positive control liraglutide 0.1 mg / kg sc BID.

[0308] Weight was measured daily. On day 13, body composition was measured by DEXA. On day 15, fasting glucose and insulin levels were measured before and during the oral glucose tolerance test (OGTT) to evaluate improvement in glucose control. The OGTT was performed after an overnight fast. Therefore, on day 14, food (but not water) was eliminated starting at approximately 16:45 immediately after PM administration. The OGTT was performed the following morning (16 hours after fasting). Mice were administered the medium or test compound (starting at 08:45) up to a time-specified schedule 30 minutes before glucose loading (2.0 g / kg po) administration. Blood samples were taken immediately before administration (B1), immediately before glucose administration (B2), and 15, 30, 60, and 120 minutes after glucose administration.

[0309] ADC-141 is 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decane-10-yl)methyl)-4-phenyl-5-(piperazine-1-carbonyl)pyridine-2(1H)-one, corresponding to Exemplary Compound 212 provided in WO2018 / 020242. Both ADC-141 and the compounds provided herein have been shown to possess USP19 inhibitory activity using the fluorescence polarization assay described above. Therefore, it is predicted that the USP19 inhibitor compounds provided herein will exhibit efficacy levels similar to those of ADC-141 as described below.

[0310] result: Muscle atrophy As shown in Figure 1, muscle mass loss in the tibialis anterior muscle of mice treated with the USP19 inhibitor was significantly lower compared to mice treated with the medium alone. Preservation of muscle atrophy was evident in both percentage mass (Figure 1B) and absolute muscle mass (Figure 1C).

[0311] Muscle wasting also decreased in the gastrocnemius muscle (Figure 2), but this trend was not statistically significant. Similarly, mice treated with the USP19 inhibitor showed less muscle wasting in terms of both percentage mass (Figure 2B) and absolute muscle mass (Figure 2C).

[0312] These data demonstrate that pharmacological inhibition of USP19 can reduce muscle atrophy in vivo. The data show that pharmacological inhibition of USP19 is particularly effective in reducing muscle wasting resulting from inactivity, immobilization, or other disuse. Based on the results presented here, pharmacological inhibition of USP19 is also expected to be effective in treating muscle atrophy resulting from cachexia or sarcopenia.

[0313] obesity Figure 3A shows the mass of the epididymal fat pad in mice after receiving either a USP19 inhibitor or the media alone for two weeks. As shown in Figure 3, mice treated with the USP19 inhibitor had a significantly smaller fat pad compared to mice treated with the media.

[0314] Figure 3B shows an increase in liver mass in mice treated with a USP19 inhibitor. This is thought to be a result of drug accumulation in the liver.

[0315] Figure 3C shows that mice treated with the USP19 inhibitor showed reduced overall body weight gain when fed a high-fat diet. Figures 3D and 3E show that this is due to a reduction in fat mass, while lean body mass is maintained. DIO mice treated with the USP19 inhibitor also showed reduced cumulative food intake compared to medium control mice.

[0316] The data shown in Figure 3 demonstrate that pharmacological inhibition of USP19 can reduce fat accumulation in a wild-type background. Gene knockout studies explain the possible relationship 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 the enzyme does not necessarily produce physiological outcomes similar to genetic removal.

[0317] The in vivo pharmacological inhibition data presented here demonstrate that compounds that potently inhibit USP19 activity can effectively treat obesity.

[0318] Insulin resistance Figure 5 shows the results of an oral glucose tolerance test (OGTT) in diet-induced obese mice. Untreated mice exhibit symptoms of insulin resistance characterized by elevated plasma glucose and plasma insulin levels. Mice treated with a USP19 inhibitor show a dose-dependent improvement in the OGTT response, characterized by decreased plasma glucose and plasma insulin levels.

[0319] The data shown in Figure 5 demonstrate that pharmacological inhibition of USP19 can reduce insulin resistance in a wild-type background. Gene knockout studies also explain the relationship between USP19 and insulin sensitivity (Coyne E. et al., supra). Coyne et al. describe improved insulin sensitivity in USP19 knockout mice, but as mentioned above, it cannot be inferred that this effect would translate to pharmacological inhibition of USP19 in wild-type subjects.

[0320] The data presented here demonstrate that pharmacological inhibition of USP19 can effectively treat insulin resistance.

[0321] The data presented here demonstrate the therapeutic effects of pharmacological inhibition of USP19. Therefore, the USP19 inhibitor compounds presented here can effectively treat muscle atrophy, obesity, and / or insulin resistance.

[0322] Experiment Section Abbreviations and acronyms AcOH: Acetic acid; aq: Aqueous solution; atm: Atmosphere (s); Boc: Tert-butyloxycarbonyl; br: Broad; Cbz: Carboxybenzyl; d: Doublet (spectrum); DCM: Dichloromethane; Des Martin Periodinane: 1,1,1-Tris(acetyloxy)-1,1-Dihydro-1,2-Benziodoxol-3-(1H)-one; DIPEA: Diisopropylethylamine; DMF: N,N-Dimethylformamide; DMS: Dimethyl sulfide; DMSO: Dimethyl sulfoxide; dpm: Dipivaloylmethanate; dppf: 1,1'-Bis(diphenylphosphino)ferrocene; EDA: Ethane-1,2-diamine; equiv.: Equivalent; Â: Ethyl acetate; EtOH: Ethanol; ESI: Electrospray ionization; h: Time; HATU :N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridine-1-ylmethylene]-N-methylmethaneaminium hexafluorophosphate N-oxide; hept: heptate (spectrum); HPLC: high-performance liquid chromatography; IPA: 2-propanol; LC: liquid chromatography; LCMS: liquid chromatography mass spectrometry; M: molar concentration; m / z: mass-to-charge ratio; MeCN: acetonitrile; MeOH: methanol; min: minutes (s); mmol: millimolar concentration; MS: mass spectrometry; MTBE: methyl tert-butyl ether; m: multiple t (spectrum); NBS: N-bromosuccinimide; NMR: nuclear magnetic resonance; pent: quintate (spectrum); ppm: parts per million; q: quadrant (spectrum); R T: Retention time; rt: Room temperature; s: Singlet; SCX: Strong cation exchange; sept: Heptat (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 / unit volume; wt%: Weight percent; w / v: Weight / unit volume; w / w: Weight / unit weight; XPhos-Pd-G2: Chloro(2-dicyclohexylphosphin-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] Palladium(II).

[0323] General experimental conditions Solvents and reagents The common organic solvents used in the reaction (e.g., THF, DMF, DCM, and MeOH) are Sure / Seal TM Sigma-Aldrich in a bottle (登録商標) The water was purchased anhydrous and handled properly under nitrogen. The water was deionized using Elga PURELAB Option-Q. All other solvents used (i.e., post-treatment procedures and purification) were generally HPLC grade and used as supplied from various commercial sources. Unless otherwise noted, all starting materials used were purchased from commercial sources and used as supplied.

[0324] Automated synthesis Automated experiments were conducted using the Simple 2 instrument. This system includes a reagent cartridge that enables the application of appropriate reactants to various synthetic reaction procedures (particularly N-heterocycle formation, reductive amination, Mitsunobu, amide formation, deoxygenation fluorination, and Suzuki) in an automated manner, and includes reaction, workup, and purification steps to obtain the desired reaction product. This system exhibits good reproducibility, and some reaction parameters (e.g., time and temperature) can be modified.

[0325] Microwave synthesis Microwave experiments, Biotage Initiator TM The test was performed using an Eight instrument. This system exhibits good reproducibility and can be controlled within a temperature range of 60 to 250°C and a maximum pressure of 20 bar.

[0326] Flash chromatography The compounds were purified by flash chromatography using the Biotage Isolera Four system. Unless otherwise specified, Biotage Sfaer Silica D cartridge columns (10–340 g) or Grace GraceResolv cartridge columns (4–330 g) were used with appropriate solvent gradients according to the solvent system and compound polarity. For some more polar and basic compounds, Biotage Sfaer KP-Amino D cartridge columns (11–28 g) were used.

[0327] NMR spectroscopy 1 ¹H NMR spectra were recorded at ambient temperature using a Bruker Avance III (400 MHz) or Bruker Ascend (500 MHz) spectrometer. Total chemical shift (δ) is expressed in ppm. The residual solvent signal was used as an internal standard, and characteristic solvent peaks were corrected against the reference data outlined in J. Org. Chem., 1997, 62, pp. 7512-7515; otherwise, the NMR solvent included tetramethylsilane, which was used as an internal standard.

[0328] Liquid chromatography mass spectrometry (LCMS) Retention time (R T Liquid chromatography-mass spectrometry (LCMS) experiments were performed to determine the mass ions and related mass ions using the following method: Method AThis system consisted of an Agilent Technologies 1290 Infinity LC system, an Agilent Technologies 6140 single quadrupole mass spectrometer connected to a UV diode array detector and autosampler. The spectrometer consisted of a multimode ion source (electrospray and atmospheric pressure chemical ionization) scanning in positive and negative ion modes. LC-MS experiments were performed on each sample provided under the following conditions: LC column: Zorbax Eclipse Plus C18 RRHD, 1.8 μm, 50 × 2.1 mm, maintained at 40°C. Mobile phase: A) 0.1% (v / v) formic acid aqueous solution; B) 0.1% (v / v) in MeCN. [Table 7]

[0329] Method B This system consisted of an Agilent Technologies 1290 Infinity LC system and an Agilent Technologies 6130 quadrupole mass spectrometer connected to a UV diode array detector and autosampler. The spectrometer consisted of an electrospray ionization source scanning in positive and negative ion modes. LC-MS experiments were performed on each sample provided under the following conditions: LC column: Agilent Eclipse Plus C18 RRHD, 1.8 μm, 50 × 2.1 mm, maintained at 40°C. Mobile phase: A) 0.1% (v / v) formic acid aqueous solution; B) 0.1% (v / v) in MeCN. [Table 8]

[0330] Method CThis system consisted of a Waters ACQUITY I-Class UPLC system and a Waters ACQUITY QDa mass spectrometer connected to a TUV detector. The spectrometer consisted of an electrospray ionization source scanning in positive and negative ion modes. LC-MS experiments were performed on each sample provided under the following conditions: LC column: Zorbax Eclipse Plus C18 RRHD, 1.8 μm, 50 × 2.1 mm, maintained at 40°C. Mobile phase: A) 0.1% (v / v) formic acid aqueous solution; B) 0.1% (v / v) in MeCN. [Table 9]

[0331] Method D This system consisted of an Agilent Technologies 1100 Series LC / MSD system with a UV diode array detector and an evaporative light scattering detector (DAD / ELSD) and either an Agilent (LC / MSD(VL((G1956A), SL((G1956B)) mass spectrometer or an Agilent (1200(Series(LC / MSD system with DAD / ELSD) and an Agilent (LC / MSD(SL((G6130A), SL((G6140A)) mass spectrometer. All LC / MS data were obtained using atmospheric pressure chemical ionization mode with positive and negative ion mode switching in the scanning range of m / z 80-1000. LC / MS experiments were performed on each sample provided under the following conditions: LC column: Zorbax SB - C18 RRHD, 1.8 μm, 4.6 × 15 mm. Mobile phase: A) 0.1% (v / v) formic acid aqueous solution; B) 0.1% (v / v) in MeCN. [Table 10]

[0332] Method EThis system consisted of a Shimadzu Prominence HPLC / Applied Biosystem LCMS / MS API 2000 instrument. Spectrometer ionization technique: ESI using an API source operating in cation mode. LCMS experiments were performed on each sample provided under the following conditions: LC column: XBridge C18, 5 μm, 4.6 × 50 mm, maintained at 25°C. Mobile phase: A) 10 mM ammonium acetate (aqueous); B) MeCN. [Table 11]

[0333] Method F This system consisted of a Waters ACQUITY H-Class UPLC system and a Waters ACQUITY SQD 2 mass spectrometer connected to a TUV detector. The spectrometer consisted of an electrospray ionization source scanning in positive and negative ion modes. LC-MS experiments were performed on each sample provided under the following conditions: LC column: XBridge C18, 3.5 μm, 3.0 × 50 mm, maintained at 50°C. Mobile phase: A) 5 mM ammonium acetate (aqueous); B) 9:1 MeCN / 5 mM ammonium acetate in water. [Table 12]

[0334] Preparative High-Performance Liquid Chromatography This system consisted of an Agilent Technologies 1200 preparative LC system and an Agilent Technologies 6120 single quadrupole mass spectrometer connected to a multi-wavelength detector and autosampler. The mass spectrometer used a multimode ion source (electrospray and atmospheric pressure chemical ionization) operating in positive and negative ion modes. Fraction sampling was mass-induced (multimode positive and negative ions). Purification experiments were performed under basic conditions with a suitable solvent gradient, determined by retention time, using typically appropriate LC-MS methods, unless otherwise specified. If basic conditions were unsuccessful, acidic conditions were used.

[0335] Basic conditions: LC column: Waters XBridge TM Prep C18 5μm OBD TM A 30 × 100 mm column was used. Mobile phase: A) 0.1% (v / v) ammonium hydroxide aqueous solution; B) 95:5, MeCN / 0.1% (v / v) ammonium hydroxide in water. The total experimental time was approximately 10 minutes, and the comprehensive method is shown below. [Table 13]

[0336] Chiral resolution 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 conditions described. The combined fractions of each stereoisomer were evaporated to near dryness using a rotary evaporator, transferred to a final container using DCM, removed under compressed air flow at 40°C, and then stored in a vacuum oven at 40°C and 5 mbar for 16 hours.

[0337] Chiral resolution 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 conditions described. The combined fractions of each stereoisomer were evaporated to near dryness using a rotary evaporator, transferred to a final container using MeOH, removed under compressed air at 35°C, and then stored in a vacuum oven at 35°C and 5 mbar for 16 hours.

[0338] Chiral purity analysis After chiral resolution of the stereoisomer mixture, each stereoisomer was analyzed, and its chiral purity was determined using an appropriate analytical SFC or HPLC method under the conditions described.

[0339] nomenclature Unless otherwise specified, structural nomenclature was determined using the 'Convert Structure to Name' function in ChemDraw Professional 21.0 (CambridgeSoft / PerkinElmer). The stereochemical configurations of the example compounds were determined by inference from intermediate precursors used in their preparation, either by already known absolute stereochemistry (i.e., commercially available reagents) or by inference from previous studies (e.g., WO2022 / 200523 intermediate). When novel intermediates were used, the relative potency of the enantiomer pair allowed for assignment by comparison with similar analogs from previous studies. However, it should be noted that for some or all of the example compounds presented here, errors in this process may have resulted in incorrect configuration assignments, and therefore, these compounds may have configurations opposite to those described. In any case, the most potent stereoisomers are preferred and are explicitly included herein.

[0340] General procedure General procedure 1: Boc deprotection to free base One equivalent of Boc-protected amine was dissolved in DCM. A solution of 1,4-dioxane in TFA or 4M HCl was added (as described). The reaction mixture was stirred at rt for 1 to 24 hours. The mixture was placed on a pre-equilibrated SCX-2 cartridge. The column was washed with a 4:1 mixture of DCM / MeOH, and the basic compound was eluted using a 4:1 mixture of DCM / 7M NH3 in MeOH. The ammonia-containing fraction was concentrated under reduced pressure to obtain the desired product, which was then used directly in the next step or re-purified under the conditions described as necessary.

[0341] General procedure 2: Automated synthesis using Synple 2 for N-heterocycle formation This procedure utilized the Simple 2 centralized console for "Capsule-Based Automated Organic Synthesis" (Chem. Sci., 2021, 12, 6977 - 6982) for the purpose of N-heterocycle formation using the Sn-amine protocol (SnAP) chemistry (Org. Lett., 2014, 16, 1236 - 1239). The appropriate aldehyde and stirring bar were placed in the reaction vial, and the line cap was connected. The appropriate reagent cartridge was manipulated to load the reaction procedure and conditions, placed in the cartridge holder, and secured in place. The solvents used in this procedure were connected to the appropriate solvent lines: DCM (S1), hexafluoroisopropanol (S2), MeOH (S3), 35:65 diisopropylamine / THF (S4). A nitrogen stream was applied. The reaction procedure was started by pressing "Start" under standard conditions (unless otherwise specified). At the end of this sequence, the resulting product solution was analyzed by LC-MS to determine whether further purification (i.e., flash chromatography or preparative HPLC) was required. The solvent was removed under reduced pressure to obtain the desired product, which was then either used directly in the next step or re-purified under the conditions described as necessary.

[0342] General procedure 3: Urea formation via carbamoyl chloride intermediate To a MeCN solution of triphosgene (0.3-0.6 equivalents), pyridine or DIPEA (2-5 equivalents) was added at 0°C, and the solution was stirred for 10 minutes. A MeCN solution of a suitable primary amine (1 equivalent) was added, and the reaction mixture was stirred for 1-24 hours while warming to rt. The mixture was added to a suitable secondary amine (1 equivalent), followed by the addition of DIPEA (2-5 equivalents), and stirred for a further 1-24 hours. Saturated NaHCO3 3(水性) The following was added. The resulting mixture was extracted using a phase separator with DCM (×3), the combined organic phase was concentrated under reduced pressure, and the residue was purified by flash chromatography to obtain the desired product.

[0343] General procedure 4: Trifluoroacetamide deprotection to free base A suitable trifluoroacetamide (1 equivalent) was dissolved in a 10:1 mixture of MeOH / water, and potassium carbonate (5-10 equivalents) was added. The resulting mixture was stirred as needed at rt or up to 50°C for 1-18 hours. The solvent was removed under reduced pressure, and the remaining residue was dissolved in DCM and water or DCM and saturated NaHCO3. 3(水性) The mixture was partitioned into solution, the resulting two-phase mixture was separated, the aqueous phase was further extracted using DCM (×2), and the combined organic phase was concentrated under reduced pressure. [Alternatively, the reaction mixture was diluted with DCM and placed on a pre-equilibrated SCX-2 cartridge. The column was washed with a 4:1 mixture of DCM / MeOH, and the basic compounds were eluted using a 4:1 mixture of DCM / 7M NH3 in MeOH. The ammonia-containing fraction was concentrated under reduced pressure.] The residue was purified by flash chromatography to obtain the desired product.

[0344] 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 mixture was stirred for 1-24 hours as needed, and then saturated NaHCO₃⁻ was added. 3(水性)Quenched by adding [substance name]. The resulting mixture was extracted by DCM (×3) using a phase separator. The combined organic extract was concentrated under reduced pressure, and the remaining residue was purified by flash chromatography to obtain the desired product.

[0345] General procedure 6: Carbamoyl chloride formation Pyridine (10 equivalents) was added dropwise to a DCM solution of triphosgene (1 equivalent) while stirring at 0°C. After 30 minutes, a DCM solution of a suitable amine (1 equivalent), or a DCM solution of an amine salt (1 equivalent) and DIPEA (1.5 equivalents) was added dropwise at 0°C. The temperature was increased to rt and stirred for 1 to 18 hours as needed. Reaction mixture: 1M HCl (水性) Quenched by adding [component name], the resulting mixture was extracted using a phase separator with DCM (×3). The combined organic phase was concentrated under reduced pressure to obtain the desired product, which was typically used in the next step without further purification.

[0346] General procedure 7: Urea formation using carbamoyl chloride intermediates Mix the appropriate carbamoyl chloride (1-2 equivalents), amine or amine HCl salt (1-3 equivalents), and DIPEA (2-6 equivalents) in the solvent as described, stirring at rt for 1-18 hours, and then add 0.5 M HCl. (水性) The mixture was quenched and extracted using DCM (×3) with a phase separator. The combined organic phase was concentrated under reduced pressure, and the residue was purified by flash chromatography to obtain the desired product.

[0347] General Procedure 8: Reductive Alkylation of Amines A solution of amine (1 equivalent) and a suitable aldehyde or ketone (5 equivalents) in MeOH was stirred under rt. After 2 hours, sodium triacetoxyborohydride (10 equivalents) was added. After another 1 hour, the reaction was confirmed by LC-MS. Depending on the reaction progress, further aldehyde / ketone and sodium triacetoxyborohydride may be added until the reaction is complete. The reaction mixture was diluted with MeOH and placed on a pre-equilibrated SCX-2 cartridge. The column was washed with a 4:1 mixture of DCM / MeOH, and the basic compound was eluted using a 4:1 mixture of DCM / 7M NH3 in MeOH. The ammonia-containing fraction was concentrated under reduced pressure and further purified by flash chromatography (typically in a 0-20% MeOH solution of DCM or a 0-20% MeOH solution of Â) to obtain the desired product.

[0348] General Procedure 9: H-Cube (登録商標) Cbz deprotection of free bases using Pro Dissolve a Cbz-protecting amine (e.g., 1.0 mmol) in ethyl(20 mL) / etho(20 mL) and prepare the solution in an H-Cube containing a 10% w / w Pd / C cartridge. (登録商標) The Pro hydrogenation flow reactor was used with a flow rate of 1 mL / min, 60°C, and a hydrogen pressure of 1 bar in "control mode". The completion of the reaction was determined by LC-MS, and the substance was passed through the system again until the reaction was complete, if necessary. The solvent was removed under reduced pressure, and the remaining residue was purified by flash chromatography to obtain the desired product.

[0349] Intermediate 1: 6-phenyl-3-(piperazine-1-ylmethyl)pyridine-2(1H)-one dihydrochloride [ka] Step 1: To a solution of 3-(hydroxymethyl)-6-phenylpyridine-2(1H)-one:2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxylic acid (53.3 g, 248 mmol) [commercially available] in THF (1200 mL), a solution of 1 M borane DMS complex in THF (991 mL, 991 mmol) was added, and the suspension was stirred at rt. After 18 hours, MeOH was slowly added until gas generation ceased. The reaction mixture was partitioned into RINKAN and brine, separated, the organic phase was dried (Na2SO4), filtered, evaporated to dryness, and purified by flash chromatography (DCM solution of 0-5% MeOH) to obtain the title compound (33.1 g, 66%). LCMS (Method D): R T = 0.69 min, m / z = 202 [M+H] + .

[0350] Step 2: 2-Oxo-6-phenyl-1,2-dihydropyridine-3-carboaldehyde: Dess Martin periodinane (22.0 g, 52 mmol) was added at 0°C to a solution of 3-(hydroxymethyl)-6-phenylpyridine-2(1H)-one (8.0 g, 40 mmol) in DCM (250 mL) while stirring. After 10 hours, 2M Na2CO₂ was added. 3(水性) (300 mL) was added. After 2 hours, the resulting precipitate was filtered and dried under vacuum to obtain the title compound (7.2 g, 90%). 1 H NMR (400 MHz, DMSO-d6): 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).

[0351] Step 3: tert-butyl 4-((2-oxo-6-phenyl-1,2-dihydropyridine-3-yl)methyl)piperazine-1-carboxylate: To a 50 mL solution of 2-oxo-6-phenyl-1,2-dihydropyridine-3-carboaldehyde (1.5 g, 7.5 mmol) in DCM, tert-butyl piperazine-1-carboxylate (2.1 g, 11.2 mmol), followed by sodium triacetoxyborohydride (4.8 g, 22.5 mmol), was added. After 3 hours, the reaction mixture was heated to 55°C. After a further 10 hours, saturated NaHCO3 was added. 3(水性) (150 mL) was carefully added and stirred for a further 30 minutes. The resulting two-phase mixture was separated, the organic phase was dried with (Na2SO4), filtered, evaporated to dryness, and purified by flash chromatography (0-5% MeOH in DCM solution) to obtain the title compound (1.6 g, 58%). LCMS (Method D): R T = 0.85 min, m / z = 370 [M+H] + .

[0352] Step 4: 6-phenyl-3-(piperazine-1-ylmethyl)pyridine-2(1H)-one dihydrochloride: Except for the absence of SCX-2 purification, the compound was prepared according to general procedure 1 using tert-butyl 4-((2-oxo-6-phenyl-1,2-dihydropyridine-3-yl)methyl)piperazine-1-carboxylate (50.0 mg, 0.14 mmol), 1,4-dioxane solution in 4M HCl (3 mL), and DCM (4 mL) to obtain the title compound (46.3 mg, quantitative) [presumed dihydrochloride]. LCMS (Method A): R T = 0.41 min, m / z = 270 [M+H] + .

[0353] Intermediate 2: 3-((2,2-dimethylpiperazine-1-yl)methyl)-6-phenylpyridine-2(1H)-one [ka] The title compound was prepared in the same manner as for 6-phenyl-3-(piperazine-1-ylmethyl)pyridine-2(1H)-one (intermediate 1), except that tert-butyl 3,3-dimethylpiperazine-1-carboxylate [commercially available] was used instead of tert-butyl piperazine-1-carboxylate (step 3), TFA was used instead of 1,4-dioxane solution in 4M HCl, and SCX-2 purification (step 4) was included, to obtain the title compound as a free base. LCMS (Method A): R T = 0.44 min, m / z = 298 [M+H] + .

[0354] Intermediate 3: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one [ka] Step 1: 3-(chloromethyl)-6-phenylpyridine-2(1H)-one: 33.0 g, 165 mmol of 3-(hydroxymethyl)-6-phenylpyridine-2(1H)-one (1200 mL) was mixed with thionyl chloride (200 mL, 2.78 mol) in a solution of DCM (1200 mL) while stirring. The reaction mixture was heated to 40°C. After 24 hours, volatiles were removed under reduced pressure using MeCN to aid co-evaporation to obtain the title compound (36.2 g, quantitative), which was used directly in the next step without purification.

[0355] Step 2: To a solution of tert-butyl 6-((2-oxo-6-phenyl-1,2-dihydropyridine-3-yl)-methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate:3-(chloromethyl)-6-phenylpyridine-2(1H)-one (8.5 g, 39 mmol) in MeCN (300 mL), 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, and the suspension was stirred at 80°C for 18 hours. The reaction mixture was concentrated, partitioned into DCM and brine, separated, the organic phase was dried (Na2SO4), filtered, evaporated to dryness, and purified by flash chromatography (DCM solution in 0-5% MeOH) to obtain the title compound (10.1 g, 61%). LCMS (Method D): R T = 0.64 min, m / z = 424 [M+H] + .

[0356] Step 3: Using 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one:tert-butyl 6-((2-oxo-6-phenyl-1,2-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (100.0 mg, 0.24 mmol), TFA (1.1 mL), and anhydrous DCM (1 mL), the title compound (75.5 mg, 99%) was prepared according to general procedure 1 to obtain the title compound (75.5 mg, 99%). LCMS (Method A): R T = 0.50 min, m / z = 324 [M+H] + .

[0357] Intermediate 4:3-((6,9-diazaspiro[4,5]decane-6-yl)methyl)quinoline-2(1H)-one [ka] Step 1: To a solution of tert-butyl 6-((2-oxo-1,2-dihydroquinoline-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate: 2-oxo-1,2-dihydroquinoline-3-carboaldehyde [commercial] (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 the gradual 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 reduced pressure, and the remaining residue was partitioned into siRNA and brine for separation. The organic phase was converted to saturated NaHCO3 3(水性) Washed with (Na2SO4), dried, filtered, evaporated to dryness, and purified by flash chromatography (DCM solution of 0-5% MeOH) to obtain the title compound (0.50 g, 14%). LCMS (Method D): R T = 0.75 min, m / z = 398 [M+H] + .

[0358] Step 2: Using 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)quinoline-2(1H)-one:tert-butyl 6-((2-oxo-1,2-dihydroquinoline-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), the title compound (75.1 mg, quantitative) was prepared according to general procedure 1 to obtain the title compound. LCMS (Method A): R T = 0.47 min, m / z = 298 [M+H] + .

[0359] Intermediate 5:3-((6,9-diazaspiro[4,5]decane-6-yl)methyl)-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridine-2-one [ka] Step 1: To a solution of tert-butyl 6-((2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate:2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carbaldehyde [commercial] (0.50 g, 2.8 mmol) in 1,2-dichloroethane (30 mL), tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (1.00 g, 4.2 mmol) was added, followed by the gradual 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 reduced pressure, and the remaining residue was separated by partitioning into phenylalanine and brine. The organic phase was then converted to saturated NaHCO3. 3(水性) Washed with (Na2SO4), dried, filtered, evaporated to dryness, and purified by flash chromatography (DCM solution of 0-10% MeOH) to obtain the title compound (0.10 g, 9%). LCMS (Method D): R T = 1.01 min, m / z = 404 [M+H] + .

[0360] Step 2: 3-((6,9-diazaspiro[4,5]decane-6-yl)methyl)-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridine-2-one:tert-butyl 6-((2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridine-3-yl)methyl)-6,9-diazaspiro[4,5]decane-9-carboxylate (100 mg, 0.25 mmol), TFA (0.5 mL), and DCM (1 mL) were prepared according to general procedure 1 to obtain the title compound (30 mg, 40%). LCMS (Method B): R T = 0.27 min (solvent tip), m / z = 304 [M+H] + .

[0361] Intermediate 6: tert-butyl ((2S,4R)-2-(2,5-difluorophenyl)piperidine-4-yl)(methyl)carbamate [ka] Step 1: To a solution of 2-(2,5-difluorophenyl)isonicotinate:methyl 2-bromoisonicotinate (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 HCl. (水性) The pH was adjusted to 3 using [method name], the precipitate was filtered, washed with water (2 L), and dried in a vacuum oven to obtain the title compound (260 g, 95%). LC-MS (Method D): R T = 1.15 min, m / z = 236 [M+H] + .

[0362] Step 2: rac-(2S,4R)-2-(2,5-difluorophenyl)piperidine-4-carboxylic acid: To a well-stirred suspension of 2-(2,5-difluorophenyl)isonicotinic acid (60.0 g, 0.255 mol) in MeOH (2.4 L), 10% w / w Pd / C (6.0 g, 10% w / w) was added, and the resulting mixture was reacted in an autoclave with hydrogen (50 atm) at 50°C. After the reaction was complete (to monitor the consumption of the starting materials, the reaction mixture was... 1 The solvent was evaporated to dryness (determined by 1H NMR sampling) to obtain the crude title compound (65.3 g, estimated 0.255 mol, contaminated with residual Pd / C catalyst), which was used in the next step without further purification.

[0363] Step 3: rac-(2S,4R)-1-((benzyloxy)carbonyl)-2-(2,5-difluorophenyl)piperidine-4-carboxylic acid: NaOH (221 g, 5.54 mol) was added to a suspension of rac-(2S,4R)-2-(2,5-difluorophenyl)piperidine-4-carboxylic acid (284 g, estimated 1.11 mol, contaminated with Pd / C) in 1,4-dioxane (5.0 L) and water (2.5 L). The reaction mixture was cooled to 0°C, and benzyl chloroformate (282 g, 1.66 mol) was subsequently added dropwise. After 16 hours, the resulting mixture was evaporated to dryness, the residue was dissolved in water (5 L), and extracted using MTBE (2 L). The aqueous phase was converted to HCl (水性) The solution was acidified (pH=3) and extracted with ethyl acetate (3L). The organic phase was dried with (Na2SO4), filtered, and evaporated to dryness to obtain the title compound (313g, 75.3%) as a white solid. LCMS (Method D): R T = 1.27 min, m / z = 374 [MHz] - .

[0364] Step 4: rac-benzyl (2S,4R)-2-(2,5-difluorophenyl)-4-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)piperidine-1-carboxylate: Triethylamine (253 g, 2.50 mol) and then DPPA (298 g, 1.08 mol) were added to a toluene (4.0 L) suspension of rac-(2S,4R)-1-((benzyloxy)carbonyl)-2-(2,5-difluorophenyl)piperidine-4-carboxylic acid. The reaction mixture was heated at 75°C for 4 hours until gas generation ceased, and then 2-(trimethylsilyl)ethanol (296 g, 2.50 mol) was added. The reaction mixture was heated at 110°C for 24 hours. Reaction mixture 15% w / v NaOH (水性) Extraction was performed using (2 × 2 L), the organic phase was dried (Na₂SO₄), filtered, and evaporated to dryness to obtain the title compound (375 g, 92%). 1H 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).

[0365] Step 5: rac-benzyl (2S,4R)-4-((tert-butoxycarbonyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate: To a solution of rac-benzyl (2S,4R)-2-(2,5-difluorophenyl)-4-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)piperidine-1-carboxylate (375 g, 0.764 mol) in THF (3.0 L), a solution of 1 M TBAF in THF (2292 mL, 2.29 mol) was added, and the resulting mixture was heated at 55 °C for 48 hours. The reaction mixture was concentrated under reduced pressure, and the remaining residue was dissolved in ELISA (3 L) and 15% w / v NH₄Cl (水性) The mixture was partitioned into (2 L) and separated. The organic phase was washed with water (1 L) followed by brine (1 L), dried, filtered, and the solvent was concentrated to dryness. The obtained crude rac-benzyl (2S,4R)-4-amino-2-(2,5-difluorophenyl)piperidine-1-carboxylate was dissolved in MeOH (2.5 L), cooled to 0°C, and Boc2O (200 g, 0.917 mol) was added dropwise at rt. After 24 hours, the solvent was evaporated, and the remaining residue was purified by flash chromatography (0-20% ethylphenyl hexane solution) to obtain the title compound (250 g, 74%). LCMS (Method D): R T = 1.32 min, m / z = 347 [M-Boc+H] + .

[0366] Step 6: rac-(2S,4R)-benzyl 4-((tert-butoxycarbonyl)(methyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate: To a solution of rac-benzyl (2S,4R)-4-((tert-butoxycarbonyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate (25 g, 56 mmol) in DMF (200 mL) while stirring, NaH (55% in mineral oil, 2.7 g, 61.7 mmol) was added at 0°C. After 3 hours, iodomethane (9.6 g, 67.3 mmol) was added and the temperature was raised to rt. After a further 24 hours, the reaction mixture was mixed with siRNA (400 mL) and 15% w / v NH4Cl (水性) The mixture was partitioned into (500 mL), separated, and the organic phase was washed with water (500 mL) and brine (500 mL). It was dried (Na2SO4) and the solvent was removed under reduced pressure. The remaining residue was purified by flash chromatography (0-20% HCl solution in hexane) to obtain the title compound (22.1 g, 86%). LC-MS (Method D): R T = 1.61 min, m / z = 361 [M-Boc+H] + .

[0367] Step 7: rac-(2S,4R)-benzyl 4-((tert-butoxycarbonyl)(methyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate (18.0g) into Chiralcel (登録商標) Chiral HPLC using an OJ-H (20mm x 250mm, 5μm) column was used to separate the product into single stereoisomers. The first substance to elute (R T = 16.12 min) is the title compound (6.95 g). LCMS (Method D): R T = 1.61 min, m / z = 361 [M-Boc+H] + This resulted in the second substance to leach out (R T= 24.90 min) is benzyl (2R,4S)-4-((tert-butoxycarbonyl)(methyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate (7.74 g). LCMS (Method D): R T = 1.61 min, m / z = 361 [M-Boc+H] + This brought about...

[0368] Step 8: tert-butyl ((2S,4R)-2-(2,5-difluorophenyl)piperidine-4-yl)(methyl)carbamate:benzyl (2S,4R)-4-((tert-butoxycarbonyl)(methyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate (6.95 g, 15.1 mmol) was dissolved in MeOH (150 mL), and 10% w / w Pd / C (0.7 g) was added to this solution. The reaction mixture was hydrogenated with rt (approximately 1 atm, balloon). After 24 hours, the reaction mixture was filtered through a silica pad and evaporated to dryness to obtain the title compound (4.59 g, 93%). Chiral HPLC (ChiralCell (登録商標) Standard solvent composition conditions: 95:2.5:2.5 hexane / IPA / MeOH) on an OJ-H (4.6mm x 250mm, 5μm) column: R T = 9.05 minutes. LCMS (Method D): R T = 1.04 min, m / z = 327 [M+H] + . [α] D 21 = +34.6 (c 0.25 in CHCl3).

[0369] Intermediate 7: 5-((6,9-diazaspiro[4,5]decane-6-yl)methyl)-1-methyl-2-phenylpyridine-4(1H)-one [ka] Step 1: To a solution of 5-(hydroxymethyl)-2-phenylpyridine-4(1H)-one:ethyl 4-oxo-6-phenyl-1,4-dihydropyridine-3-carboxylate (30.4 g, 125 mmol) [prepared according to Chem. Pharm. Bull., 1995, 43, pp. 450-460] in THF (1100 mL), a solution of 1.0 M borane DMS complex in THF (485 mL, 485 mmol) was added, and the suspension was stirred at rt. After 18 hours, MeOH was slowly added until gas generation ceased. The resulting mixture was partitioned into toluene and brine, and the organic layer was dried (Na2SO4). The solvent was removed under vacuum, and the residue was purified by flash chromatography (0-10% toluene in hexane solution) to obtain the title compound (16.5 g, 66%). LCMS (Method D): R T = 0.59 min, m / z = 202 [M+H] + .

[0370] Step 2: 5-(chloromethyl)-2-phenylpyridine-4(1H)-one: 16.3 g, 82 mmol of 5-(hydroxymethyl)-2-phenylpyridine-4(1H)-one (16.3 mL, 82 mmol) was dissolved in 600 mL of DCM, to which thionyl chloride (100 mL, 1.39 mol) was added, and the suspension was stirred at 40°C. After 24 hours, volatiles were removed under reduced pressure using MeCN to aid in co-evaporation to obtain the title compound (18.0 g, quantitative), which was used directly in the next step without purification.

[0371] Step 3: To a solution of tert-butyl 6-((4-oxo-6-phenyl-1,4-dihydropyridine-3-yl)-methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate:5-(chloromethyl)-2-phenylpyridine-4(1H)-one (8.5 g, 39 mmol) in MeCN (300 mL), DIPEA (15 g, 116 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (9.3 g, 39 mmol) were added, and the resulting suspension was stirred at 80°C. After 24 hours, the solvent was removed under reduced pressure, and the remaining residue was partitioned into DCM and brine, separated, and the organic phase was dried (Na2SO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (0-5% MeOH DCM solution) to obtain the title compound (11.4 g, 69%). LC-MS (Method D): R T = 0.93 min, m / z = 424 [M+H] + .

[0372] Step 4: tert-butyl 6-((1-methyl-4-oxo-6-phenyl-1,4-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate: Sodium hydride (55% in mineral oil, 28 mg, 0.65 mmol) was added to a solution of tert-butyl 6-((4-oxo-6-phenyl-1,4-dihydropyridine-3-yl)-methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (0.212 mg, 0.5 mmol) in DMF (2 mL) under argon. After 1 hour, iodomethane (92 mg, 0.65 mmol) was added. After 4 hours, the solvent was removed under reduced pressure, the residue was partitioned into DCM and brine, separated, and the organic phase was dried (Na2SO4). The solvent was removed under reduced pressure, and the remaining residue was purified by reverse-phase preparative HPLC (C18 column) to obtain the title compound (11.4 g, 69%). LC-MS (Method D): R T = 1.09 min, m / z = 438 [M+H] + .

[0373] Step 5: Using 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-phenylpyridine-4(1H)-one:tert-butyl 6-((1-methyl-4-oxo-6-phenyl-1,4-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (60.2 mg, 0.14 mmol), TFA (0.5 mL), and anhydrous DCM (1 mL), the title compound (49.5 mg, quantitative) was prepared according to general procedure 1 to obtain the title compound. LCMS (Method A): R T = 0.44 min, m / z = 338 [M+H] + .

[0374] Intermediate 8:5-((6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one [ka] The title compound (20 mg, 87%) was prepared using tert-butyl 6-((4-oxo-6-phenyl-1,4-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (30 mg, 70.8 μmol), TFA (0.5 mL), and DCM (1 mL) according to general procedure 1. LC-MS (Method C): R T = 0.43 min, m / z = 324 [M+H] + .

[0375] Intermediate 9: tert-butyl ((2S,4R)-2-(2,5-difluorophenyl)piperidine-4-yl)(2-methoxyethyl)carbamate [ka] Step 1: rac-benzyl (2S,4R)-4-((tert-butoxycarbonyl)(2-methoxyethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate: Sodium hydride (55% in mineral oil, 0.78 g, 13.3 mmol) was added to a solution of rac-benzyl (2S,4R)-4-((tert-butoxycarbonyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate (4.50 g, 10.2 mmol) in DMF (120 mL) at 0°C. After 3 hours, 1-iodo-2-methoxyethane (4.20 g, 22.4 mmol) was added. After a further 24 hours, the reaction mixture was mixed with ELISA (200 mL) and 15% NH4Cl. (水性) The mixture was partitioned into (300 mL) and separated. The organic phase was washed with water (300 mL), followed by brine (300 mL), and dried (Na2SO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (hexane solution of 0-40% CHCl3) to obtain the title compound (3.01 g, 59%). LC-MS (Method D): R T = 1.58 min, m / z = 405 [M-Boc+H] + .

[0376] Step 2: Benzyl (2S,4R)-4-((tert-butoxycarbonyl)(2-methoxyethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate:rac-benzyl (2S,4R)-4-((tert-butoxycarbonyl)(2-methoxyethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate (2.98g) (登録商標) The substance was separated into single stereoisomers by chiral HPLC using an AD-H (4.6 mm × 250 mm, 5 μm) column. The first substance to elute (R T = 19.25 min) is the title compound (1.21 g) (LCMS (Method D): R T = 1.58 min, m / z = 405 [M-Boc+H] + ) resulted in; the second substance to leach out (R T= 25.65 min) is benzyl (2R,4S)-4-((tert-butoxycarbonyl)(2-methoxyethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate (1.16 g) (LCMS (Method D): R T = 1.58 min, m / z = 405 [M-Boc+H] + ) brought about.

[0377] Step 3: tert-butyl ((2S,4R)-2-(2,5-difluorophenyl)piperidine-4-yl)(2-methoxyethyl)carbamate:benzyl (2S,4R)-4-((tert-butoxycarbonyl)(2-methoxyethyl)amino)-2-(2,5-difluorophenyl)piperidine-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 with rt (approximately 1 atm, balloon). After 24 hours, the reaction mixture was filtered through a silica pad and evaporated to dryness to obtain the title compound (0.88 g, 99%). Chiral HPLC (Chiralpak (登録商標) IC, 4.6 mm × 250 mm, 5 μm) column with constant composition solvent conditions: 98:1:1 hexane (0.1% EDA) / IPA / MeOH):R T = 7.12 minutes. LCMS (Method D): R T = 1.12 min, m / z = 371 [M+H] + .

[0378] Intermediate 10: 5-((2,2-dimethylpiperazine-1-yl)methyl)-2-phenylpyridine-4(1H)-one [ka] Step 1: tert-butyl 3,3-dimethyl-4-((4-oxo-6-phenyl-1,4-dihydropyridine-3-yl)methyl)piperazine-1-carboxylate: The title compound was prepared according to tert-butyl 6-((4-oxo-6-phenyl-1,4-dihydropyridine-3-yl)-methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (intermediate 7, steps 1-3), except that tert-butyl 3,3-dimethylpiperazine-1-carboxylate was used instead of tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate. LCMS (Method D): R T = 1.01 min, m / z = 398 [M+H] + .

[0379] Step 2: Using 5-((2,2-dimethylpiperazine-1-yl)methyl)-2-phenylpyridine-4(1H)-one:tert-butyl 3,3-dimethyl-4-((4-oxo-6-phenyl-1,4-dihydropyridine-3-yl)methyl)piperazine-1-carboxylate (60.0 mg, 151 μmol), TFA (0.13 mL), and DCM (2 mL), the title compound (44.0 mg, 98%) was prepared according to general procedure 1 to obtain the title compound. LCMS (Method A): R T = 0.38 min, m / z = 298 [M+H] + .

[0380] Intermediate 11: 5-((4,7-diazaspiro[2,5]octan-4-yl)methyl)-2-phenylpyridine-4(1H)-one [ka] The title compound was prepared according to the method for 5-((2,2-dimethylpiperazine-1-yl)methyl)-2-phenylpyridine-4(1H)-one (intermediate 10), except that tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate [commercially available] was used instead of tert-butyl 3,3-dimethylpiperazine-1-carboxylate. LCMS (Method A): R T = 0.44 min, m / z = 296 [M+H] + .

[0381] Intermediate 12: tert-butyl ((2S,4R)-2-(3,4-difluorophenyl)piperidine-4-yl)(methyl)carbamate [ka] The title compound was (3,4-difluorophenyl)boronic acid instead of (2,5-difluorophenyl)boronic acid (Step 1), and Chiralpak was used for the chiral HPLC separation of the enantiomer. (登録商標) The title compound was obtained by preparing tert-butyl ((2S,4R)-2-(2,5-difluorophenyl)piperidine-4-yl)(methyl)carbamate (intermediate 6) according to the procedure for tert-butyl ((2S,4R)-2-(2,5-difluorophenyl)piperidine-4-yl)(methyl)carbamate (intermediate 6), except for step 7, which used a fixed solvent composition of 70:15:15 hexane / IPA / MeOH on an AD-H (4.6 mm × 250 mm, 5 μm) column. Chiral HPLC (Chiral HPLC) was performed. (登録商標) AD-H (4.6 mm × 250 mm, 5 μm) column with constant solvent composition conditions: 5:5:90 hexane and 0.1% v / v EDA / IPA / MeOH):R T = 6.19 minutes. LCMS (Method D): R T = 0.80 min, m / z = 327 [M+H] + . [α] D 21 = +25.3 (c 0.50 in CHCl3).

[0382] Intermediate 13: 3-(2,5-difluorophenyl)morpholine [ka] 2,5-Difluorobenzaldehyde (0.05 mL, 0.50 mmol) was reacted using SnAP chemistry with an N-heterocyclic "morpholine" cartridge (H101) under complete sequencing conditions (11 hours) according to general procedure 2 to obtain the substance, which required further purification by flash chromatography to obtain the title compound (35 mg, 35%) [estimated racemic, 1:1 mixture of enantiomers]. LCMS (Method A): R T = 0.42 min, m / z = 200 [M+H] + .

[0383] Intermediate 14: tert-butyl 3-(2,5-difluorophenyl)-1,4-diazepane-1-carboxylate [ka] 2,5-Difluorobenzaldehyde (0.05 mL, 0.50 mmol) was reacted using SnAP chemistry with an N-heterocyclic "diazepane" cartridge (H106) under complete sequencing conditions (11 hours) according to general procedure 2 to obtain the substance, which required further purification by flash chromatography to obtain the title compound (18 mg, 12%) [estimated racemic, 1:1 mixture of enantiomers]. LCMS (Method A): R T = 0.77 min, m / z = 257 [M - butene + H] + .

[0384] Intermediate 15: Benzyl 3-(2,5-difluorophenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-9-carboxylate [ka] 2,5-Difluorobenzaldehyde (0.05 mL, 0.50 mmol) was reacted using SnAP chemistry with an N-heterocyclic "morpholine-2-spiro-(4-Pip)" cartridge (H111) under complete sequencing conditions (11 hours) according to general procedure 2 to obtain the substance, which required further purification by flash chromatography to obtain the title compound (66 mg, 33%) [estimated racemic, 1:1 mixture of enantiomers]. LCMS (Method A): R T = 0.91 min, m / z = 403 [M+H] + .

[0385] Intermediate 16: tert-butyl ((2S,4R)-2-(2,6-difluorophenyl)piperidine-4-yl)(methyl)carbamate [ka] Chiralcel for chiral HPLC separation of enantiomers, using (2,6-difluorophenyl)boronic acid instead of (2,5-difluorophenyl)boronic acid (Step 1) for the title compound. (登録商標)The title compound was obtained by preparing tert-butyl ((2S,4R)-2-(2,5-difluorophenyl)piperidine-4-yl)(methyl)carbamate (intermediate 6) according to the procedure for tert-butyl ((2S,4R)-2-(2,5-difluorophenyl)piperidine-4-yl)(methyl)carbamate (intermediate 6), except for step 7, which used a fixed solvent composition of 70:15:15 hexane / IPA / MeOH on an AD-H (4.6 mm × 250 mm, 5 μm) column. Chiral HPLC (ChiralCell (登録商標) Calculation performed on an OJ-H (4.6mm x 250mm, 5μm) column under constant solvent composition conditions: 90:5:5 hexane / IPA / MeOH):R T = 7.80 minutes. LCMS (Method D): R T = 0.76 min, m / z = 327 [M+H] + . [α] D 21 = +42.9 (c 0.20 in CHCl3).

[0386] Intermediate 17: tert-butyl ((2S,4R)-2-(2,4-difluorophenyl)piperidine-4-yl)(methyl)carbamate [ka] The title compound was (2,4-difluorophenyl)boronic acid instead of (2,5-difluorophenyl)boronic acid (step 1), and Chiralpak was used for the chiral HPLC separation of the enantiomer. (登録商標) The title compound was obtained by preparing tert-butyl ((2S,4R)-2-(2,5-difluorophenyl)piperidine-4-yl)(methyl)carbamate (intermediate 6) according to the procedure for tert-butyl ((2S,4R)-2-(2,5-difluorophenyl)piperidine-4-yl)(methyl)carbamate (intermediate 6), except for step 7, which used a fixed solvent composition of 80:10:10 hexane / IPA / MeOH on an IJ (4.6 mm × 250 mm, 5 μm) column. Chiral HPLC (ChiralCell (登録商標) OD-H (4.6 mm × 250 mm, 5 μm) column with fixed solvent composition conditions: 98:1:1 hexane / IPA / MeOH):R T = 6.39 minutes. LCMS (Method D): R T = 1.07 min, m / z = 327 [M+H] + . [α] D 21 = +24.9 (c 0.25 in CHCl3).

[0387] Intermediate 18: rac-(3R,5S)-3-(2,5-difluorophenyl)-5-methylmorpholine [ka] 2,5-Difluorobenzaldehyde (0.05 mL, 0.50 mmol) was reacted using SnAP chemistry with an N-heterocyclic "3-methylmorpholine" cartridge (H107) under complete sequencing conditions (11 hours) according to general procedure 2 to obtain 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: The NMR data suggests the existence of only cis stereoisomers; i.e., no trans stereoisomers were observed.]

[0388] Intermediate 19: 5-((5,8-diazaspiro[3,5]nonan-5-yl)methyl)-2-phenylpyridine-4(1H)-one [ka] The title compound was prepared according to the method for 5-((2,2-dimethylpiperazine-1-yl)methyl)-2-phenylpyridine-4(1H)-one (intermediate 10), except that tert-butyl 5,8-diazaspiro[3.5]nonane-8-carboxylate [commercially available] was used instead of tert-butyl 3,3-dimethylpiperazine-1-carboxylate. LCMS (Method C): R T = 0.41 min, m / z = 310 [M+H] + .

[0389] Intermediate 20: 5-((2-oxa-5,8-diazaspiro[3.5]nonan-5-yl)methyl)-2-phenylpyridine-4(1H)-one [ka] The title compound was prepared according to the method for 5-((2,2-dimethylpiperazine-1-yl)methyl)-2-phenylpyridine-4(1H)-one (intermediate 10), except that tert-butyl 2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate [commercially available] was used instead of tert-butyl 3,3-dimethylpiperazine-1-carboxylate. LCMS (Method C): R T = 0.42 min, m / z = 312 [M+H] + .

[0390] Intermediate 21: 5-((1,4-diazaspiro[5,5]undecane-1-yl)methyl)-2-phenylpyridine-4(1H)-one [ka] The title compound was prepared according to the method for 5-((2,2-dimethylpiperazine-1-yl)methyl)-2-phenylpyridine-4(1H)-one (intermediate 10), except that tert-butyl 1,4-diazaspiro[5.5]undecane-4-carboxylate [commercially available] was used instead of tert-butyl 3,3-dimethylpiperazine-1-carboxylate. LCMS (Method C): R T = 0.47 min, m / z = 338 [M+H] + .

[0391] Intermediate 22: 5-((9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1H)-one [ka] The title compound was prepared according to the method for 5-((2,2-dimethylpiperazine-1-yl)methyl)-2-phenylpyridine-4(1H)-one (intermediate 10), except that tert-butyl 9-oxa-1,4-diazaspiro[5.5]undecane-4-carboxylate [commercially available] was used instead of tert-butyl 3,3-dimethylpiperazine-1-carboxylate. LCMS (Method C): R T = 0.42 min, m / z = 340 [M+H] + .

[0392] Intermediate 23: 3-((4,7-diazaspiro[2.5]octan-4-yl)methyl)-6-phenylpyridine-2(1H)-one [ka] The title compound was prepared according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one (intermediate 3), except that tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate [commercially available] was used instead of tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate. LCMS (Method C): R T = 0.58 min, m / z = 296 [M+H] + .

[0393] Intermediate 24: 3-((5,8-diazaspiro[3,5]nonan-5-yl)methyl)-6-phenylpyridine-2(1H)-one [ka] The title compound was prepared according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one (intermediate 3), except that tert-butyl 5,8-diazaspiro[3.5]nonane-8-carboxylate [commercially available] was used instead of tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate. LCMS (Method C): R T = 0.50 min, m / z = 310 [M+H] + .

[0394] Intermediate 25: 3-((2-oxa-5,8-diazaspiro[3.5]nonan-5-yl)methyl)-6-phenylpyridine-2(1H)-one [ka] The title compound was prepared according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one (intermediate 3), except that tert-butyl 2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate [commercially available] was used instead of tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate. LCMS (Method C): R T = 0.55 min, m / z = 312 [M+H] + .

[0395] Intermediate 26: 3-((1,4-diazaspiro[5,5]undecane-1-yl)methyl)-6-phenylpyridine-2(1H)-one [ka] The title compound was prepared according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one (intermediate 3), except that 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. LCMS (Method C): R T = 0.55 min, m / z = 338 [M+H] + .

[0396] Intermediate 27: 3-((9-oxa-1,4-diazaspiro[5,5]undecane-1-yl)methyl)-6-phenylpyridine-2(1H)-one [ka] The title compound was prepared according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one (intermediate 3), except that tert-butyl 9-oxa-1,4-diazaspiro[5.5]undecane-4-carboxylate [commercially available] was used instead of tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate. LCMS (Method C): R T = 0.55 min, m / z = 340 [M+H] + .

[0397] Intermediate 28: (2S,4R)-2-(2,5-difluorophenyl)-4-(pyrrolidine-1-yl)piperidine hydrochloride [ka] Step 1: tert-butyl (2S)-2-(2,5-difluorophenyl)-4-(pyrrolidine-1-yl)piperidine-1-carboxylate: To a 10 mL solution of tert-butyl (S)-2-(2,5-difluorophenyl)-4-oxopiperidine-1-carboxylate (1.5 g, 4.82 mmol) [WO2022200523 Intermediate 19, prepared according to Step 5] in MeOH, 3 drops of acetic acid and 0.6 mL of pyrrolidine (7.23 mmol) were added at rt. After 2 hours, 0.9 g of NaBH3CN (14.5 mmol) was added. After a further 16 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography to obtain the title compound (1.6 g, 91%). LCMS (Method E): R T = 3.15 min, m / z = 367 [M+H] + .

[0398] Step 2: tert-butyl (2S,4R)-2-(2,5-difluorophenyl)-4-(pyrrolidine-1-yl)piperidine-1-carboxylate: 1.6 g of tert-butyl (2S)-2-(2,5-difluorophenyl)-4-(pyrrolidine-1-yl)piperidine-1-carboxylate was separated into single stereoisomers by reverse-phase preparative HPLC (C18 column) to obtain tert-butyl (2S,4S)-2-(2,5-difluorophenyl)-4-(pyrrolidine-1-yl)piperidine-1-carboxylate (first eluted isomer: 200 mg). LCMS (Method E): R T = 3.15 min, m / z = 367 [M+H] + ; and the title compound (second isomer eluted: 750 mg). LCMS (Method E): R T = 3.15 min, m / z = 367 [M+H] + I obtained it.

[0399] Step 3: (2S,4R)-2-(2,5-difluorophenyl)-4-(pyrrolidine-1-yl)piperidine hydrochloride: To a 10 mL solution of tert-butyl (2S,4R)-2-(2,5-difluorophenyl)-4-(pyrrolidine-1-yl)piperidine-1-carboxylate (890 mg 2.43 mmol) in DCM, a 6 mL solution of 1,4-dioxane in 4 M HCl was added at rt. After 3 hours, the solvent was evaporated under reduced pressure, the residue was ground with DCM and pentane, and subsequently lyophilized to obtain the title compound (770 mg, quantitative). LCMS (Method E): R T = 1.26 min, m / z = 267 [M+H] + .

[0400] Intermediate 29: 5-((6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1H)-one [ka] Step 1: To a solution of methyl 4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridine-3-carboxylate:(Z)-ethyl 2-(aminomethylene)-3-oxobutanoate (13.6 g, 87 mmol) in THF (400 mL), sodium hydride (55% in mineral oil, 10.0 g, 226 mmol) was added at 0°C under an argon atmosphere. After 1 hour, methyl thiophen-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 reduced pressure, and the residue was dissolved in anhydrous MeOH (300 mL), followed by the dropwise addition of thionyl chloride (31 g, 261 mmol). The reaction mixture was refluxed for 10 hours. The solvent was removed under reduced pressure, and the residue was dissolved in DCM and saturated NaHCO3. 3(水性) The mixture was partitioned. The resulting two-phase mixture was separated, the organic layer was dried (Na2SO4), the solvent was removed under reduced pressure, and the residue was purified by flash chromatography (0-10% toluene solution) to obtain the title compound (7.1 g, 34%). LCMS (Method D): R T = 0.70 min, m / z = 236 [M+H] + .

[0401] Step 2: 5-(hydroxymethyl)-2-(thiophen-3-yl)pyridine-4(1H)-one: Borane DMS complex (6.4 g, 84 mmol) was added at rt to a solution of methyl 4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridine-3-carboxylate (6.6 g, 28 mmol) in THF (250 mL) while stirring. After 30 hours, MeOH was slowly added until gas generation ceased, and the solvent was removed under reduced pressure using MeOH to aid co-evaporation to obtain the title compound (5.8 g, quantitative). LCMS (Method D): R T = 0.51 min, m / z = 208 [M+H] + .

[0402] Step 3: 5-(chloromethyl)-2-(thiophen-3-yl)pyridine-4(1H)-one: Thionyl chloride (40 mL, 0.55 mol) was added at 40°C to a solution of 5-(hydroxymethyl)-2-(thiophen-3-yl)pyridine-4(1H)-one (6.0 g, 29 mmol) in DCM (200 mL) while stirring. After 24 hours, the solvent was removed under reduced pressure using MeCN to aid co-evaporation to obtain the title compound (6.5 g, quantitative), which was used directly in the next step without further purification.

[0403] Step 4: To a solution of tert-butyl 6-((4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate:5-(chloromethyl)-2-(thiophen-3-yl)pyridine-4(1H)-one (2.1 g, 9.3 mmol) in MeCN (90 mL), DIPEA (3.6 g, 28 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (2.7 g, 11 mmol) were added, and the suspension was stirred at 80°C. After 24 hours, the solvent was removed under reduced pressure, the residue was partitioned into DCM and brine, separated, the organic phase was dried (Na2SO4), the solvent was removed under reduced pressure, and the residue was purified by flash chromatography (DCM solution in 0-5% MeOH) to obtain the title compound (1.9 g, 47%). LCMS (Method D): R T= 0.85 min, m / z = 430 [M+H] + .

[0404] Step 5: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1H)-one: The title compound (46.0 mg, quantitative) was prepared according to general procedure 1 using tert-butyl 6-((4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (60 mg, 140 μmol), TFA (0.3 mL), and DCM (1.5 mL). LC-MS (Method A): R T = 0.42 min, m / z = 330 [M+H] + .

[0405] Intermediate 30: 5-((6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(1-methyl-1H-pyrazole-5-yl)pyridine-4(1H)-one [ka] The title compound (via tert-butyl 6-((6-(1-methyl-1H-pyrazole-5-yl)-4-oxo-1,4-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate) was prepared in accordance with 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-3-yl)pyridine-4(1H)-one (intermediate 29), except that methyl 1-methyl-1H-pyrazole-5-yl) was used instead of methyl thiophene-3-carboxylate. LCMS (Method A): R T = 0.34 min, m / z = 328 [M+H] + .

[0406] Intermediate 31: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-methyl-5-phenylpyridine-2(1H)-one [ka] The title compound is described as 3-(hydroxymethyl)-6-phenylpyridine-2(1H)-one, except that 3-(hydroxymethyl)-6-methyl-5-phenylpyridine-2(1H)-one is used instead of 3-(hydroxymethyl)-6-phenylpyridine-2(1H)-one (commercially available 6-methyl-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxylic acid is used instead of 2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxylic acid). The title compound was obtained by preparing it according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one (intermediate 3), except for using the preparation method described below. LCMS (Method A): R T = 0.57 min, m / z = 338 [M+H] + .

[0407] Intermediate 32: 5-((6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(thiophen-2-yl)pyridine-4(1H)-one [ka] The title compound was prepared according to the method for 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-3-yl)pyridine-4(1H)-one (intermediate 29), except that methylthiophene-2-carboxylate was used instead of methylthiophene-3-carboxylate. LCMS (Method A): R T = 0.43 min, m / z = 330 [M+H] + .

[0408] Intermediate 33: 3-((6,9-diazaspiro[4,5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one [ka] Step 1: 3-Bromo-4H-pyrido[1,2-a]pyrimidine-4-one: To a 200 mL solution of commercially available 4H-pyrido[1,2-a]pyrimidine-4-one (6.00 g, 41 mmol) in DCM while stirring, NBS (8.05 g, 45 mmol, 1.1 equivalents) was gradually added at rt. After 10 hours, a 150 mL solution of 1 M aqueous sodium carbonate was added. After another 2 hours, the two-phase mixture was separated, the organic phase was dried (Na2SO4), and the solvent was removed under reduced pressure to obtain 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).

[0409] Step 2: 3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidine-4-one: Tributylstannylmethanol (9.25 g, 29 mmol) and XPhos-Pd-G2 (1.62 g, 2.0 mmol) were added to a solution of 3-bromo-4H-pyrido[1,2-a]pyrimidine-4-one (4.40 g, 19 mmol) in 1,4-dioxane (250 mL) while stirring. The reaction mixture was degassed and returned to the pack with argon, then heated at 100°C. After 48 hours, the solvent was removed under reduced pressure, the residue was ground with diethyl ether (150 mL), filtered, and the crude title compound (3.2 g, 68%) [contaminated with 4H-pyrido[1,2-a]pyrimidine-4-one] was obtained. LCMS (Method D): R T = 0.43 min, m / z = 177 [M+H] + .

[0410] Step 3: 3-(chloromethyl)-4H-pyrido[1,2-a]pyrimidine-4-one: 3.0 g, 17 mmol of 3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidine-4-one (200 mL) was stirred in a solution of DCM (40 mL, 0.55 mol) and added thionyl chloride (40 mL, 0.55 mol) at 40°C. After 24 hours, the solvent was removed under reduced pressure using MeCN to aid co-evaporation to obtain the title compound (3.2 g, quantitative), which was used directly in the next step without further purification.

[0411] Step 4: tert-butyl 6-((4-oxo-4H-pyrido[1,2-a]pyrimidine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate: DIPEA (6.2 g, 48 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (3.4 g, 16 mmol) were added at 80°C to a solution of 3-(chloromethyl)-4H-pyrido[1,2-a]pyrimidine-4-one (3.0 g, 16 mmol) in MeCN (150 mL) while stirring. After 18 hours, the solvent was removed under reduced pressure, and the residue was partitioned and separated into DCM and brine. The organic phase was dried (Na2SO4), the solvent was removed under reduced pressure, and the residue was purified by flash chromatography (DCM solution of 0-5% MeOH) to obtain the title compound (1.1 g, 27%). LCMS (Method D): R T = 0.81 min, m / z = 399 [M+H] + .

[0412] Step 5: 3-((6,9-diazaspiro[4,5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one: The title compound (85.0 mg, 95%) was prepared using tert-butyl 6-((4-oxo-4H-pyrido[1,2-a]pyrimidine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (120 mg, 300 μmol), TFA (0.7 mL), and DCM (1.5 mL) according to general procedure 1. LC-MS (Method A): R T = 0.41 min, m / z = 299 [M+H]+ .

[0413] Intermediate 34: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-fluorophenyl)pyridine-4(1H)-one hydrochloride [ka] The title compound was prepared in accordance with the method for 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-3-yl)pyridine-4(1H)-one (intermediate 29), except that in step 1, methyl 2-fluorobenzoate was used instead of methyl thiophene-3-carboxylate, 1,4-dioxane solution in 4M HCl / 1,4-dioxane was used instead of TFA / DCM, and SCX-2 purification was omitted in step 5. LCMS (Method A): R T = 0.43 min, m / z = 342 [M+H] + .

[0414] Intermediate 35: 5-((6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(o-tolyl)pyridine-4(1H)-one [ka] The title compound was prepared according to the method for 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-3-yl)pyridine-4(1H)-one (intermediate 29), except that methyl 2-methylbenzoate was used instead of methylthiophene-3-carboxylate. LCMS (Method A): R T = 0.45 min, m / z = 338 [M+H] + .

[0415] Intermediate 36: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-methoxyphenyl)pyridine-4(1H)-one hydrochloride [ka] The title compound was prepared in accordance with the method for 5-((6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(thiophene-3-yl)pyridine-4(1H)-one (intermediate 29), except that in step 1, methyl thiophene-3-carboxylate was replaced with methyl 2-methoxybenzoate, and 1,4-dioxane solution in 4M HCl was replaced with 1,4-dioxane instead of TFA / DCM, and SCX-2 purification was omitted in step 5. LCMS (Method A): R T = 0.55 min, m / z = 354 [M+H] + [Note: In step 4, a 2:1 mixture of tert-butyl 6-((6-(2-methoxyphenyl)-4-oxo-1,4-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate / tert-butyl 6-((6-(2-hydroxyphenyl)-4-oxo-1,4-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate was obtained, which required RP preparative HPLC purification.]

[0416] Intermediate 37: 3-((6,9-diazaspiro[4,5]decane-6-yl)methyl)-4H-chromen-4-one hydrochloride [ka] Step 1: 3-(hydroxymethyl)-4H-chromen-4-one: NaBH(OAc)3 (1.80 g, 8.61 mmol) was added at 0°C to a solution of 4-oxo-4H-chromen-3-carboaldehyde (500 mg, 2.87 mmol) [commercially available] in DCM (12 mL) while stirring, and the resulting mixture was warmed to rt. After 16 hours, the reaction mixture was diluted with water and extracted with DCM (2 × 100 mL). The combined organic phases were washed with brine (100 mL), dried (Na2SO4), the solvent was removed under reduced pressure, and the remaining residue was purified by flash chromatography (0-50% siRNA solution) to obtain the title compound (300 mg, 59%). LCMS (Method E): R T = 2.07 min, m / z = 177 [M+H] + .

[0417] Step 2: 3-(chloromethyl)-4H-chromen-4-one: To a solution of 3-(hydroxymethyl)-4H-chromen-4-one (1.00 g, 5.67 mmol) in DCM (20 mL) while stirring, SOCl2 (1.2 mL, 17.0 mmol) was added dropwise at 0°C, and the resulting mixture was warmed to rt. After 3 hours, the reaction mixture was diluted with water and extracted with DCM (2 × 200 mL). The combined organic phases were washed with brine (200 mL), dried (Na2SO4), and the solvent was removed under reduced pressure to obtain the title compound (640 mg, 58%), which was then purified in the next step without further purification. LCMS (Method E): R T = 2.93 minutes, m / z = 195 [M+H] + .

[0418] Step 3: tert-butyl 6-((4-oxo-4H-chromen-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate: To a MeCN (20 mL) solution of 3-(chloromethyl)-4H-chromen-4-one (640 mg, 3.28 mmol) while stirring, tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (869 mg, 3.61 mmol) was added, followed by the addition of Cs2CO3 (2.10 g, 6.57 mmol) at rt. The resulting mixture was heated to 90°C. After 3 hours, the reaction mixture was converted to Celite. (登録商標) The compound was filtered through a filter, the filtrate was evaporated under reduced pressure, and the remaining residue was purified by flash chromatography (0-30% hexane solution) to obtain the title compound (900 mg, 69%). LC-MS (Method E): R T = 10.22 minutes, m / z = 399 [M+H] + .

[0419] Step 4: Using 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-chromen-4-one hydrochloride:tert-butyl 6-((4-oxo-4H-chromen-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (60.0 mg, 151 μmol), a 1,4-dioxane solution in 4M HCl (0.38 mL), and 1,4-dioxane (1 mL), the product was prepared according to general procedure 1, omitting SCX-2 purification, to obtain the title compound (50 mg, 99%). LCMS (Method A): R T = 0.56 min, m / z = 299 [M+H] + .

[0420] Intermediate 38: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-4H-chromen-4-one hydrochloride [ka] The title compound was prepared according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-chromen-4-one hydrochloride (intermediate 37), except that 6-fluoro-4-oxo-4H-chromen-3-carboaldehyde was used instead of 4-oxo-4H-chromen-3-carboaldehyde. LCMS (Method A): R T = 0.62 min, m / z = 317 [M+H] + .

[0421] Intermediate 39: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2,3-dihydrobenzofuran-7-yl)pyridine-4(1H)-one hydrochloride [ka] The title compound was prepared in accordance with the method for 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-3-yl)pyridine-4(1H)-one (intermediate 29), except that in step 1, methyl 2,3-dihydrobenzofuran-7-carboxylate was used instead of methyl thiophene-3-carboxylate, 1,4-dioxane solution in 4M HCl / 1,4-dioxane was used instead of TFA / DCM, and SCX-2 purification was omitted in step 5. LCMS (Method A): R T= 0.59 min, m / z = 366 [M+H] + .

[0422] Intermediate 40: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(1-methyl-1H-pyrazole-3-yl)pyridine-4(1H)-one [ka] The title compound was prepared according to the method for 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-3-yl)pyridine-4(1H)-one (intermediate 29), except that methyl 1-methyl-1H-pyrazole-3-carboxylate was used instead of methyl thiophene-3-carboxylate. LCMS (Method A): R T = 0.38 min, m / z = 328 [M+H] + .

[0423] Intermediate 41: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-cyclopropyl-2-methylpyridine-4(1H)-one hydrochloride [ka] The title compound was obtained by preparing it according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one (intermediate 3), except that 1-cyclopropyl-5-(hydroxymethyl)-2-methylpyridine-4(1H)-one was used instead of 3-(hydroxymethyl)-6-phenylpyridine-2(1H)-one (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), 1,4-dioxane solution in 4M HCl / 1,4-dioxane instead of TFA / DCM, and SCX-2 purification was omitted in the final step. LCMS (Method A): R T = 0.34 min, m / z = 302 [M+H] + .

[0424] Intermediate 42: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-5,6-dimethylpyridine-2(1H)-one hydrochloride [ka] The title compound was obtained by preparing it according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one (intermediate 3), except that 3-(hydroxymethyl)-6-phenylpyridine-2(1H)-one was used instead of 3-(hydroxymethyl)-6-phenylpyridine-2(1H)-one (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), 1,4-dioxane solution in 4M HCl / 1,4-dioxane instead of TFA / DCM, and SCX-2 purification was omitted in the final step. LCMS (Method A): R T = 0.36 min, m / z = 276 [M+H] + .

[0425] Intermediate 43: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrimido[1,2-b]pyridazine-4-one hydrochloride [ka] The title compound was obtained by preparing it according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one (intermediate 3), except that 3-(hydroxymethyl)-6-phenylpyridine-2(1H)-one was used instead of 3-(hydroxymethyl)-6-phenylpyridine-2(1H)-one (using 4-oxo-4H-pyrido[1,2-b]pyridazin-3-carboxylic acid [commercially available] instead of 2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxylic acid), using a 1,4-dioxane solution in 4M HCl / DCM instead of TFA / DCM, and omitting SCX-2 purification in the final step. LCMS (Method A): R T = 0.35 min, m / z = 300 [M+H] + .

[0426] Intermediate 44: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoroquinoline-4(1H)-one hydrochloride

Chem.

[0427] Step 2: 3-(Chloromethyl)-6-fluoroquinolin-4(1H)-one: To a solution of 6-fluoro-3-(hydroxymethyl)quinolin-4(1H)-one (100 mg, 0.52 mmol) in DCM (6 mL) under stirring, SOCl2 (0.11 mL, 1.55 mmol) was added at 0 °C. The reaction mixture was heated to 50 °C. After 16 h, the solvent was removed under reduced pressure to give the title compound (101 mg, 92%). 1 1H NMR (400 MHz, DMSO-d6): 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).

[0428] Step 3: tert-butyl 6-((6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate: tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (647 mg, 2.96 mmol) and Cs2CO3 (1.17 g, 3.59 mmol) were added rt-to a solution of 3-(chloromethyl)-6-fluoroquinoline-4(1H)-one (380 mg, 1.79 mmol) in MeCN (76 mL) while stirring. After 2 hours, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (50 mL), dried (Na2SO4), and the solvent was removed under reduced pressure. The remaining residue was purified by flash chromatography (0-30% SiO2 hexane solution) followed by preparative HPLC to obtain the title compound (80 mg, 11%). LCMS (Method E): R T = 2.50 min, m / z = 416 [M+H]+.

[0429] Step 4: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoroquinoline-4(1H)-one hydrochloride: Except for the absence of SCX-2 purification, the title compound (49 mg, quantitative) was prepared according to general procedure 1 using tert-butyl 6-((6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (58 mg, 140 μmol), 1,4-dioxane solution in 4 M HCl (0.42 mL), and DCM (1.0 mL). LCMS (Method A): R T = 0.41 min, m / z = 316 [M+H] + .

[0430] Intermediate 45: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-hydroxyphenyl)pyridine-4(1H)-one hydrochloride [ka] tert-Butyl 6-((6-(2-hydroxyphenyl)-4-oxo-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (50 mg, 114 μmol) [obtained as a by-product in the production of tert-butyl 6-((6-(2-methoxyphenyl)-4-oxo-1,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate: step 4 in the synthetic procedure of 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-methoxyphenyl)pyridin-4(1H)-one hydrochloride (intermediate 36)] was deprotected with N-Boc according to General Procedure 1 using a 1,4-dioxane solution of 4M HCl (0.43 mL) and 1,4-dioxane (1 mL), except for omitting SCX-2 purification, to give the title compound (42 mg, 98%). LCMS (Method A): R T = 0.45 min, m / z = 340 [M+H] + .

[0431] Intermediate 46: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-methyl-2-propylpyridine-4(1H)-one

Chem.

[0432] Intermediate 47: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride

Chem.

[0433] Step 2: 3-Hydroxymethyl-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one: To a solution of 3-bromo-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one (4.40 g, 18 mmol) in 1,4-dioxane (250 mL) while stirring, (tributylstannyl)methanol (9.25 g, 29 mmol) and XPhos-Pd-G2 (1.62 g, 2.0 mmol) were added. The reaction mixture was degassed and returned to the pack with argon, then heated at 100°C. After 48 hours, the solvent was removed under reduced pressure, the residue was ground with diethyl ether (150 mL), filtered, and the crude title compound (3.2 g crude) was obtained. 1 ¹H NMR analysis determined the mixture to be 7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one (in a 1:2 ratio) and used in the next step without further purification. LCMS (Method D): R T = 0.51 min, m / z = 195 [M+H] + .

[0434] Step 3: 3-Chloromethyl-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one: Thionyl chloride (40 mL, 0.55 mol) was added at 40°C to a solution of 3-hydroxymethyl-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one [contaminated with 7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one] (3.2 g crude, estimated 6 mmol) in DCM (200 mL) while stirring. After 24 hours, the solvent was removed under reduced pressure using MeCN to aid co-evaporation to obtain the crude title compound (3.2 g crude), which was used directly in the next step without further purification.

[0435] Step 4: tert-butyl 6-((7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate: 3.0 g, estimated 6 mmol of 3-chloromethyl-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one (3.0 g, estimated 6 mmol) was added to a solution of MeCN (150 mL) at 80°C, along with DIPEA (2.3 g, 18 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (1.28 g, 6 mmol). After 18 hours, the solvent was removed under reduced pressure, and the residue was partitioned into DCM and brine to separate the resulting two-phase mixture. The organic phase was dried (Na2SO4), the solvent was removed under reduced pressure, and the remaining residue was purified by RP preparative HPLC to obtain the title compound (0.5 g, 7% over 3 steps). LCMS (Method D): R T = 0.81 min, m / z = 417 [M+H] + .

[0436] Step 5: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride: Except for the absence of SCX-2 purification, the title compound (51 mg, 97%) was prepared according to general procedure 1 using tert-butyl 6-((7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (60 mg, 144 μmol), a 1,4-dioxane solution in 4 M HCl (0.36 mL), and 1,4-dioxane (2 mL). LCMS (Method A): R T = 0.45 min, m / z = 317 [M+H] + .

[0437] Intermediate 48: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-5-(trifluoromethyl)pyridine-2(1H)-one hydrochloride [ka] The title compound was obtained by preparing it according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one (intermediate 3), except that 3-(hydroxymethyl)-6-phenylpyridine-2(1H)-one was used instead of 3-(hydroxymethyl)-6-phenylpyridine-2(1H)-one (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), 1,4-dioxane solution in 4M HCl / 1,4-dioxane instead of TFA / DCM, and SCX-2 purification was omitted in the final step. LCMS (Method A): R T = 0.50 min, m / z = 316 [M+H] + .

[0438] Intermediate 49: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(4-fluorophenyl)pyridine-4(1H)-one hydrochloride [ka] The title compound was prepared in accordance with the method for 5-((6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(thiophene-3-yl)pyridine-4(1H)-one (intermediate 29), except that in step 1, methyl 4-fluorobenzoate was used instead of methyl thiophene-3-carboxylate, 1,4-dioxane solution in 4M HCl / 1,4-dioxane was used instead of TFA / DCM, and SCX-2 purification was omitted in step 5. LCMS (Method A): R T = 0.45 min, m / z = 342 [M+H] + .

[0439] Intermediate 50: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(3-fluorophenyl)pyridine-4(1H)-one hydrochloride [ka] The title compound was prepared in accordance with the method for 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-3-yl)pyridine-4(1H)-one (intermediate 29), except that in step 1, methyl 3-fluorobenzoate was used instead of methyl thiophene-3-carboxylate, 1,4-dioxane solution in 4M HCl / 1,4-dioxane was used instead of TFA / DCM, and SCX-2 purification was omitted in step 5. LCMS (Method A): R T = 0.45 min, m / z = 342 [M+H] + .

[0440] Intermediate 51: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(m-tolyl)pyridine-4(1H)-one hydrochloride [ka] The title compound was prepared in accordance with the method for 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophene-3-yl)pyridine-4(1H)-one (intermediate 29), except that in step 1, methylthiophene-3-carboxylate was replaced with methyl 3-methylbenzoate, and 1,4-dioxane solution in 4M HCl was replaced with 1,4-dioxane instead of TFA / DCM, and SCX-2 purification was omitted in step 5. LCMS (Method A): RT = 0.49 min, m / z = 338 [M+H] + .

[0441] Intermediate 52: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(m-tolyl)pyridine-2(1H)-one hydrochloride [ka] Step 1: 2-Oxo-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, returned to the cell with argon, and then heated under reflux. After 24 hours, the solvent was evaporated. The remaining residue was dissolved in hot water (200 mL), filtered, and HCl was removed. (水性) The solution was acidified to approximately pH 3. The resulting precipitate was filtered, washed with water, and dried under vacuum to obtain the title compound (3.0 g, 86%) as a gray solid. LC-MS (Method D): R T = 0.87 min, m / z = 230 [M+H] + .

[0442] Step 2: 3-(hydroxymethyl)-6-(m-tolyl)pyridine-2(1H)-one: To a solution of 2-oxo-6-(m-tolyl)-1,2-dihydropyridine-3-carboxylic acid (2.9 g, 12.6 mmol) in THF (120 mL) while stirring, a solution of 1 M borane DMS complex in THF (39 mL, 39 mmol) was added at rt. After 18 hours, MeOH was slowly added until gas generation ceased. The resulting solution was partitioned into ELISA and brine, separated, the organic phase was dried (Na2SO4), and the solvent was removed under reduced pressure. The remaining residue was purified by flash chromatography (DCM solution of 0-5% MeOH) to obtain 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] +.

[0443] Step 3: 3-(chloromethyl)-6-(m-tolyl)pyridine-2(1H)-one: 2.5 g, 11.6 mmol of 3-(hydroxymethyl)-6-(m-tolyl)pyridine-2(1H)-one (100 mL) was dissolved in DCM (100 mL), to which thionyl chloride (20 mL, 0.278 mol) 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 obtain the title compound (2.5 g, 92%) as a brown solid, which was used directly in the next step without further purification.

[0444] Step 4: tert-butyl 6-((2-oxo-6-(m-tolyl)-1,2-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate: 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 solution of 3-(chloromethyl)-6-(m-tolyl)pyridine-2(1H)-one (2.4 g, 10 mmol) in MeCN (100 mL). The resulting suspension was stirred at 80°C. After 18 hours, the reaction mixture was evaporated, partitioned into DCM and brine, separated, the organic phase was dried (Na2SO4), and the solvent was removed under reduced pressure. The residual residue was purified by flash chromatography (0-5% MeOH DCM solution) to obtain the title compound (1.2 g, 27%) as a pale yellow solid. LC-MS (Method D): R T = 1.00 min, m / z = 438 [M+H] + .

[0445] Step 5: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(m-tolyl)pyridine-2(1H)-one hydrochloride: Except for the absence of SCX-2 purification, the title compound (51 mg, 99%) was prepared according to general procedure 1 using tert-butyl 6-((2-oxo-6-(m-tolyl)-1,2-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (60 mg, 137 μmol), 1,4-dioxane solution in 4 M HCl (0.411 mL), and DCM (1.0 mL). LCMS (Method A): R T = 0.59 min, m / z = 338 [M+H] + .

[0446] Intermediate 53: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(3-fluorophenyl)pyridine-2(1H)-one hydrochloride [ka] The title compound was prepared according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(m-tolyl)pyridine-2(1H)-one hydrochloride (intermediate 52), except that 3-fluorophenylboronic acid was used instead of m-tolylboronic acid in step 1. LCMS (Method A): R T = 0.54 min, m / z = 342 [M+H] + .

[0447] Intermediate 54: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(4-fluorophenyl)pyridine-2(1H)-one hydrochloride [ka] The title compound was prepared according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(m-tolyl)pyridine-2(1H)-one hydrochloride (intermediate 52), except that 4-fluorophenylboronic acid was used instead of m-tolylboronic acid in step 1. LCMS (Method A): R T = 0.53 min, m / z = 342 [M+H] + .

[0448] Intermediate 55: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(methylthio)-6-oxo-1,6-dihydropyridine-3-carbonilicate hydrochloride [ka] The title compound was prepared using 5-(hydroxymethyl)-2-(methylthio)-6-oxo-1,6-dihydropyridine-3-carbonitride (prepared in accordance with 3-(hydroxymethyl)-6-phenylpyridine-2(1H)-one, except that 5-cyano-6-(methylthio)-2-oxo-1,2-dihydropyridine-3-carboxylic acid [commercially available] was used instead of 2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxylic acid) instead of 3-(hydroxymethyl)-6-phenylpyridine-2(1H)-one, and 4M instead of TFA / DCM. The title compound was obtained by preparing 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one (intermediate 3) using a 1,4-dioxane solution in HCl / 1,4-dioxane, except that the SCX-2 purification in the final step was omitted. LCMS (Method A): R T = 0.54 min, m / z = 319 [M+H] + .

[0449] Intermediate 56: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyrimidine-4(3H)-one hydrochloride [ka] The title compound was obtained by preparing it according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one (intermediate 3), except that 5-(hydroxymethyl)-2-phenylpyrimidine-4(3H)-one was used instead of 3-(hydroxymethyl)-6-phenylpyridine-2(1H)-one (using 6-oxo-2-phenyl-1,6-dihydropyrimidine-5-carboxylic acid [commercially available] instead of 2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxylic acid), 1,4-dioxane solution in 4M HCl / DCM was used instead of TFA / DCM, and SCX-2 purification was omitted in the final step. LCMS (Method A): R T= 0.49 min, m / z = 325 [M+H] + .

[0450] Intermediate 57: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1,7-naphthirizine-4(1H)-one hydrochloride [ka] The title compound was prepared in the same manner as for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one (intermediate 33), except that in step 1, 1,7-naphthyridine-4(1H)-one [commercially available] was used instead of 4H-pyrido[1,2-a]pyrimidine-4-one, 1,4-dioxane solution in 4M HCl / 1,4-dioxane was used instead of TFA / DCM, and SCX-2 purification was omitted in the final step. LCMS (Method C): R T = 0.32 min, m / z = 299 [M+H] + .

[0451] Intermediate 58: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2,6-dimethylpyridine-4(1H)-one hydrochloride [ka] The title compound was prepared in the same manner as for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one (intermediate 33), except that in step 1, 2,6-dimethylpyridine-4(1H)-one [commercially available] was used instead of 4H-pyrido[1,2-a]pyrimidine-4-one, 1,4-dioxane solution in 4M HCl / DCM was used instead of TFA / DCM, and SCX-2 purification was omitted in the final step. LCMS (Method A): R T = 0.24 min, m / z = 276 [M+H] + .

[0452] Intermediate 59: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(thiophen-3-yl)pyridine-4(1H)-one hydrochloride [ka] Step 1: To a solution of tert-butyl 6-((1-methyl-4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (429 mg, 1 mmol) in DMF (2 mL), 55% sodium hydride (56 mg, 1.3 mmol) in mineral oil was added under argon. After 1 hour, iodomethane (184 mg, 1.3 mmol) was added, and the solution was stirred at rt. After 14 hours, the solvent was removed under reduced pressure, the remaining residue was partitioned into DCM and brine, separated, and the organic phase was dried (Na2SO4). The solvent was removed under reduced pressure, and the remaining residue was purified by preparative HPLC to obtain the title compound (0.2 g, 48%) as a white solid. LCMS (Method D): R T = 1.05 min, m / z = 444 [M+H] + .

[0453] Step 2: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(thiophen-3-yl)pyridine-4(1H)-one hydrochloride: Except for the absence of SCX-2 purification, the title compound (42 mg, 98%) was prepared according to general procedure 1 using tert-butyl 6-((1-methyl-4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (50 mg, 113 μmol), 1,4-dioxane solution in 4 M HCl (0.338 mL), and DCM (1.0 mL). LCMS (Method A): R T = 0.42 min, m / z = 344 [M+H] + .

[0454] Intermediate 60: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(2-methoxyphenyl)pyridine-2(1H)-one hydrochloride [ka] The title compound was obtained by preparing it in accordance with the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(m-tolyl)pyridine-2(1H)-one hydrochloride (intermediate 52), except that in step 1, 2-methoxyphenylboronic acid [commercially available] was used instead of m-tolylboronic acid, 1,4-dioxane solution in 4M HCl / 1,4-dioxane was used instead of TFA / DCM, and SCX-2 purification was omitted in step 5. LCMS (Method A): R T = 0.55 min, m / z = 354 [M+H] + .

[0455] Intermediate 61: 3-((2,2-dimethylpiperazine-1-yl)methyl)-6-(1-methyl-1H-pyrazole-5-yl)pyridine-2(1H)-one hydrochloride [ka] Step 1: tert-butyl 4-((6-chloro-2-(2-(trimethylsilyl)ethoxy)pyridine-3-yl)methyl)-3,3-dimethylpiperazine-1-carboxylate: Triethylamine (167 μL, 1.20 mmol) and methanesulfonyl chloride (85.7 μL, 1.10 mmol) were successively added to a 10 mL solution of (6-chloro-2-(2-(trimethylsilyl)ethoxy)pyridine-3-yl)methanol (260 mg, 1.00 mmol) [prepared according to WO2018195321] in DCM (10 mL) under an N2 atmosphere at 0°C. After stirring at 0°C for 30 minutes, the ice bath was removed and the reaction mixture was stirred at rt for 3 hours. 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 rt for 19 hours. 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 rt for 3 hours, and then the reaction mixture was separated using a phase separator with water (10 mL) and 1 M NaOH. (水性)The mixture was washed sequentially 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. The resulting suspension was stirred at rt for 4 days, then the temperature was raised to 40°C to obtain a solution, which was stirred at 40°C for a further 2 days. After cooling to rt, water (15 mL) was added, and the resulting mixture was extracted using a phase separator with DCM (3 × 10 mL). The combined organic phase was concentrated under reduced pressure, and the residue was purified by flash chromatography to obtain the title compound (322 mg, 70%) as a colorless oil. LCMS (Method A): R T = 1.26 min, m / z = 456, 457 [M+H] + .

[0456] Step 2: tert-butyl 3,3-dimethyl-4-((6-(1-methyl-1H-pyrazole-5-yl)-2-(2-(trimethylsilyl)ethoxy)pyridine-3-yl)methyl)piperazine-1-carboxylate: tert-butyl 4-((6-chloro-2-(2-(trimethylsilyl)ethoxy)pyridine-3-yl)methyl)-3,3-dimethyl A sealed 2-5 mL microwave vial containing piperazine-1-carboxylate (96.6 mg, 0.212 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-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) was degassed by "exhausting," and the container was filled by returning it to its original state three times with N2. The reaction mixture was heated under microwave irradiation at 120 °C for 30 minutes. After cooling to rt, the reaction mixture was poured into a mixture of brine (20 mL) and water (40 mL), and the resulting mixture was extracted with ELISA (3 × 20 mL). The combined organic phases were dried (using a phase separator) and concentrated under reduced pressure. The residue was purified by flash chromatography to obtain the title compound (91.3 mg, 85%). LC-MS (Method A): R T = 1.15 min, m / z = 502 [M+H] + .

[0457] Step 3: 3-((2,2-dimethylpiperazine-1-yl)methyl)-6-(1-methyl-1H-pyrazole-5-yl)pyridine-2(1H)-one hydrochloride:tert-butyl 3,3-dimethyl-4-((6-(1-methyl-1H-pyrazole-5-yl)-2-(2-(trimethylsilyl)ethoxy)pyridine-3-yl)methyl)piperazine-1-carboxylate (91.3 mg, 0.182 mmol), a 1,4-dioxane solution in 4M HCl (908 μL, 3.63 mmol), and DCM (1.8 mL) were mixed and stirred at rt for 16 hours. The resulting suspension was filtered, the solid was washed with DCM (3 × 2 mL), and dried in a vacuum oven at 50°C to obtain the title compound (56 mg, 82%) as a yellow solid. LCMS (Method A): R T = 0.33 min, m / z = 302 [M+H] + .

[0458] Intermediate 62: (1S,2R,5R)-2-(2,5-difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane [ka] Step 1: (R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)dihydrofuran-2(3H)-one: To a solution of (R)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (1.00 g, 8.61 mmol) and imidazole (1.17 g, 17.2 mmol) in DMF (10 mL) while stirring, tert-butylchlorodiphenylsilane (2.91 mL, 11.2 mmol) was added at 0°C. The reaction mixture was warmed to rt. After 16 hours, SiO (50 mL) was added, and the resulting mixture was washed with 1:1 brine / water (3 × 50 mL), the organic phase was dried in (MgSO4), and concentrated under reduced pressure. The remaining residue was purified by flash chromatography to obtain the title compound (2.74 g, 89%). LCMS (Method A): R T = 1.70 min, m / z = 277 [M - Ph] + . 1H 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).

[0459] Step 2: (5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-ol: To a solution of (R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)dihydrofuran-2(3H)-one (2.74 g, 7.72 mmol) in diethyl ether (40 mL) while stirring, a 1 M solution of diisobutylaluminum hydride in DCM (11.6 mL, 11.6 mmol) was added at -78 °C under nitrogen. After 5 hours at -78 °C, the reaction mixture was quenched by adding MeOH (5 mL). After a further 15 minutes at -78 °C, the reaction mixture was warmed to rt, diluted with diethyl ether (150 mL), and 0.2 M sodium tartrate was added. (水性) The solution (3 × 100 mL) and saline solution were used for washing. The organic phase was dried (MgSO4), filtered, and concentrated under reduced pressure to obtain the title compound (2.75 g, quantitative). LC-MS (Method A): R T = 1.69 min, m / z = 339 [M - OH] + .

[0460] Step 3: (R)-tert-butyl((2,3-dihydrofuran-2-yl)methoxy)diphenylsilane: Methanesulfonyl chloride (748 μL, 9.64 mmol) was added to a 50 mL DCM solution of (5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-ol (2.75 g, 7.71 mmol) and triethylamine (4.09 mL, 29.3 mmol) under nitrogen at -50°C. After 3 hours at -50°C, the reaction mixture was warmed to rt and then stirred at reflux temperature for a further 18 hours. After cooling to rt, the reaction mixture was concentrated under reduced pressure, and the remaining residue was purified by flash chromatography to obtain 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).

[0461] Step 4: (R)-(2,3-dihydrofuran-2-yl)methyl 4-methylbenzenesulfonate: (R)-tert-butyl((2,3-dihydrofuran-2-yl)methoxy)diphenylsilane (1.37 g, 4.05 mmol) was mixed with a 1 M TBAF THF solution (4.05 mL, 4.05 mmol), and the resulting mixture was stirred at rt for 1 hour. The reaction mixture was diluted with DCM (25 mL), 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 then warmed at rt. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in Depositphotos (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 flash chromatography to obtain the title compound (858 mg, 83%). LC-MS (Method B): R T= 1.40 min, m / z = 255 [M+H] + .

[0462] Step 5: (R)-2-((2,3-dihydrofuran-2-yl)methyl)isoindoline-1,3-dione: The mixture of (R)-(2,3-dihydrofuran-2-yl)methyl 4-methylbenzenesulfonate (858 mg, 3.74 mmol) and potassium 1,3-dioxoisoindoline-2-oid (937 mg, 5.06 mmol) in DMF (13 mL) was stirred under nitrogen at 75°C for 19 hours. After cooling to rt, the reaction mixture was diluted with ELISA (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 residual residue was purified by flash chromatography to obtain the title compound (623 mg, 80%). LCMS (Method A): R T = 1.10 min, m / z = 230 [M+H] + .

[0463] Step 6: To a solution of (R)-(2,3-dihydrofuran-2-yl)methaneamine:(R)-2-((2,3-dihydrofuran-2-yl)methyl)isoindoline-1,3-dione (310 mg, 1.35 mmol) in MeOH (5.5 mL), hydrazine monohydrate (250 μL, 8.1 mmol) was added, and the resulting mixture was heated at 60°C for 2 hours. After cooling to rt, 2M sodium hydroxide was added. (水性) The solution (10 mL) was added, and the resulting mixture was extracted using DCM (3 × 20 mL). The combined phase was washed with brine (50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure (41 °C, 220 mbar) to obtain the title compound (140 mg, crude), which was used in the next step without purification.

[0464] Step 7: (1S,2R,5R)-2-(2,5-Difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane: 3 Å molecular sieves (300 mg) were added to a solution of crude (R)-(2,3-dihydrofuran-2-yl)methanamine (134 mg, 1.35 mmol) and 2,5-difluorobenzaldehyde (192 mg, 1.35 mmol) in DCM (1.4 mL) at rt. After 16 h, the reaction mixture was filtered (syringe filter) and the volatiles were evaporated under reduced pressure (40 °C, 210 mbar). The resulting crude imine was transferred to a 20 mL MW vial and dissolved in 2-propanol (13 mL). Mn(dpm)3 (40.9 mg, 0.068 mmol) was added and the vial was capped. PhSiH3 (0.33 mL, 2.71 mmol) was added and the reaction was heated at 85 °C for 5 h. Since the reaction was incomplete, additional PhSiH3 (0.33 mL, 2.71 mmol) was added and the reaction was continued at 85 °C for 16 h. 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 h. The reaction mixture was cooled to rt and evaporated under reduced pressure. The residual residue was purified by flash chromatography (cyclohexane solution of 20 - 100% EtOAc) to afford the title compound (57 mg, 19%). LCMS (Method C): R T = 0.50 min, m / z = 226 [M+H] + .

[0465] Intermediate 63: 3-((6,9-diazaspiro[4,5]decane-6-yl)methyl)-6-fluoro-1-methylquinoline-4(1H)-one [Chemical Structure] Step 1: 6-Fluoro-3-(hydroxymethyl)-1-methylquinolin-4(1H)-one: NaOH (260 mg, 6.49 mmol) and then dimethyl sulfate (1.40 mL, 19.0 mmol) were added to a stirred solution of 6-fluoro-3-(hydroxymethyl)quinolin-4(1H)-one (965 mg, 5.00 mmol) in water (40 mL) at rt. After 3 h, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (0.79 g, 76%) as an off-white solid. LCMS (Method E): RT = 1.80 min, m / z = 208 [M+H] + .

[0466] Step 2: 3-(chloromethyl)-6-fluoro-1-methylquinoline-4(1H)-one: 6-fluoro-3-(hydroxymethyl)-1-methylquinoline-4(1H)-one (300 mg, 1.45 mmol) was added to a 10 mL solution of DCM (10 mL) while stirring, with SOCl2 (0.31 mL, 4.34 mmol) added at 50°C. After 16 hours, the solvent was evaporated under reduced pressure to obtain the title compound (0.32 g, 98%), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6): 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).

[0467] Step 3: tert-butyl 6-((6-fluoro-1-methyl-4-oxo-1,4-dihydroquinoline-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate: To a solution of 3-(chloromethyl)-6-fluoro-1-methylquinoline-4(1H)-one (0.32 g, 1.42 mmol) in MeCN (40 mL) while stirring, tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (0.511 g, 2.13 mmol) and DIPEA (0.74 mL, 4.25 mmol) were added at rt. After 2 hours, the reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by preparative HPLC to obtain 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] + .

[0468] 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 tert-butyl 6-((6-fluoro-1-methyl-4-oxo-1,4-dihydroquinoline-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (50 mg, 116 μmol), TFA (0.5 mL), and DCM (1.0 mL). LC-MS (Method C): R T = 0.46 min, m / z = 330 [M+H] + .

[0469] Intermediate 64: rac-(2R,3R)-3-(2,5-difluorophenyl)-2-methylmorpholine [ka] 300 mg of 3 Å molecular sieves were added at rt to a 1.4 mL solution of 2-vinyloxyethanamine (100 mg, 1.15 mmol) and 2,5-difluorobenzaldehyde (163 mg, 1.15 mmol) in DCM (1.4 mL). After 16 hours, the reaction mixture was filtered (syringe filter) and evaporated under reduced pressure (40°C, 210 mbar). The resulting crude imine was transferred to a 20 mL MW vial and dissolved in 2-propanol (12 mL). Mn(dpm)3 (34.8 mg, 0.0575 mmol) was added, and the vial was capped. PhSiH3 (0.28 mL, 2.30 mmol) was added, and the reaction mixture was heated at 85°C for 5 hours. Because the reaction was incomplete, more PhSiH3 (0.28 mL, 2.30 mmol) was added, and the reaction was continued at 85°C for 16 hours. Because the reaction was incomplete, 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 rt and evaporated under reduced pressure. The remaining residue was purified by flash chromatography (20-100% HCl cyclohexane solution) to obtain the title compound (22 mg, 9%). LCMS (Method C): R T = 0.52 min, m / z = 214 [M+H] + .

[0470] Intermediate 65: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(1-methyl-1H-pyrazole-5-yl)pyridine-4(1H)-one [ka] In step 1, the title compound was prepared by using tert-butyl 6-((6-(1-methyl-1H-pyrazole-5-yl)-4-oxo-1,4-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate instead of tert-butyl 6-((6-(1-methyl-1H-pyrazole-5-yl)-4-oxo-1,4-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate, 4M The title compound was obtained by preparing it according to the method for 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(thiophene-3-yl)pyridine-4(1H)-one hydrochloride (intermediate 59), except that TFA / DCM was used instead of HCl 1,4-dioxane solution / DCM, and SCX-2 purification was included in the final step. LCMS (Method C): R T = 0.38 min, m / z = 342 [M+H] + .

[0471] Intermediate 66: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(trifluoromethyl)pyridine-2(1H)-one hydrochloride [ka] The title compound was obtained by following the procedure for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one (intermediate 33), except that step 1 was omitted, 3-bromo-6-(trifluoromethyl)pyridine-2(1H)-one [commercially available] was used instead of 3-bromo-4H-pyrido[1,2-a]pyrimidine-4-one in step 2, 1,4-dioxane solution in 4M HCl / 1,4-dioxane was used instead of TFA / DCM, and SCX-2 purification was omitted in the final step. LCMS (Method A): R T = 0.51 min, m / z = 316 [M+H] + .

[0472] Intermediate 67: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(trifluoromethyl)pyridine-4(1H)-one hydrochloride [ka] The title compound was obtained by following the procedure for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one (intermediate 33), except that step 1 was omitted, 5-bromo-2-(trifluoromethyl)pyridine-4(1H)-one [commercially available] was used instead of 3-bromo-4H-pyrido[1,2-a]pyrimidine-4-one in step 2, 1,4-dioxane solution in 4M HCl / 1,4-dioxane was used instead of TFA / DCM, and SCX-2 purification was omitted in the final step. LCMS (Method A): R T = 0.55 min, m / z = 316 [M+H] + .

[0473] Intermediate 68: 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(1-methyl-1H-pyrazole-3-yl)pyridine-4(1H)-one hydrochloride [ka] The title compound was obtained by preparing it according to the method for 5-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(thiophene-3-yl)pyridine-4(1H)-one hydrochloride (intermediate 59), except that tert-butyl 6-((6-(1-methyl-1H-pyrazole-3-yl)-4-oxo-1,4-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate was used in step 1 instead of tert-butyl 6-((6-(1-methyl-1H-pyrazole-3-yl)-4-oxo-1,4-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate. LCMS (Method A): R T = 0.37 min, m / z = 342 [M+H] + .

[0474] Intermediate 69: (S)-7-fluoro-3-((2-methylpiperazin-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride [ka] The title compound was prepared according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride (intermediate 47), except that tert-butyl (S)-3-methylpiperazine-1-carboxylate [commercially available] was used instead of tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate in step 4. LCMS (Method A): R T = 0.31 min, m / z = 277 [M+H] + .

[0475] Intermediate 70: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-chloro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride [ka] The title compound was prepared according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride (intermediate 47), except that 7-chloro-4H-pyrido[1,2-a]pyrimidine-4-one [commercially available] was used instead of 7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one in step 1. LCMS (Method A): R T = 0.53 min, m / z = 333 [M+H] + .

[0476] Intermediate 71: 3-((1,4-diazaspiro[5,5]undecane-1-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride [ka] The title compound was prepared according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride (intermediate 47), except that 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 in step 4. LCMS (Method A): R T = 0.48 min, m / z = 331 [M+H]+ .

[0477] Intermediate 72: 3-((2,2-dimethylpiperazine-1-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride [ka] The title compound was prepared according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride (intermediate 47), except that tert-butyl 3,3-dimethylpiperazine-1-carboxylate [commercially available] was used instead of tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate in step 4. LCMS (Method A): R T = 0.36 min, m / z = 291 [M+H] + .

[0478] Intermediate 73: (R)-7-fluoro-3-((2-methylpiperazin-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride [ka] The title compound was prepared according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride (intermediate 47), except that tert-butyl (R)-3-methylpiperazine-1-carboxylate [commercially available] was used instead of tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate in step 4. LCMS (Method A): R T = 0.26 min, m / z = 277 [M+H] + .

[0479] Intermediate 74: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-methyl-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride [ka] The title compound was prepared according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride (intermediate 47), except that 7-methyl-4H-pyrido[1,2-a]pyrimidine-4-one [commercially available] was used instead of 7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one in step 1. LCMS (Method A): R T = 0.46 min, m / z = 313 [M+H] + .

[0480] Intermediate 75: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride [ka] To a 300 mL EtOH (340 mL) solution of 4-methoxy-2-aminopyridine (15.8 g, 127 mmol) while stirring, 2,2-dimethyl-1,3-dioxan-4,6-dione (20.1 g, 140 mmol) and triethyl orthoformate (20.7 g, 140 mmol) were added at rt. The reaction mixture was stirred at reflux temperature for 24 hours, evaporated to dryness, and the residue was dissolved in diphenyl ether (100 mL) and heated at 240 °C for 3 hours. After cooling to rt, the reaction mixture was added to hexane (1.5 L), the resulting precipitate was filtered, washed with hexane, and 8-methoxy-4H-pyrido[1,2-a]pyrimidine-4-one (11.1 g, 50%) was obtained. LCMS (Method D): R T = 0.72 min, m / z = 177 [M+H] + .

[0481] Subsequently, the title compound was prepared in accordance with the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride (intermediate 47), except that 8-methoxy-4H-pyrido[1,2-a]pyrimidine-4-one was used instead of 7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one in step 1, to obtain the title compound. LCMS (Method A): R T = 0.44 min, m / z = 329 [M+H] + .

[0482] Intermediate 76: 3-((6,9-diazaspiro[4,5]decane-6-yl)methyl)-7,8-dihydropyrrolo[1,2-a]pyrimidine-4(6H)-one [ka] The title compound was obtained by preparing it in accordance with the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride (intermediate 47), except that in step 1, 7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one was replaced with 7,8-dihydropyrrolo[1,2-a]pyrimidine-4(6H)-one [commercially available] instead of 7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one, TFA / DCM was used instead of 1,4-dioxane solution in 4M HCl / 1,4-dioxane, and SCX-2 purification was included in the final step. LCMS (Method C): R T = 0.42 min, m / z = 289 [M+H] + .

[0483] Intermediate 77: 5-((tert-butoxycarbonyl)amino)-2',5'-difluoro-[1,1'-biphenyl]-2-carboxylic acid [ka] Step 1: Dissolve 5-amino-2',5'-difluoro-[1,1'-biphenyl]-2-carboxylic acid (0.1g, 0.35 mmol) [commercially available] in MeOH (3mL), and fill the H-Cube containing a 10% w / w Pd / C cartridge with the solution. (登録商標) The mixture was passed through a Pro hydrogenation flow reactor at a flow rate of 1 mL / min at 30°C. After one cycle, the solvent was removed under reduced pressure to obtain the title compound (0.09 g, 98%). LC-MS (Method A): R T = 0.90 min, m / z = 250 [M+H] + .

[0484] 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 1,4-dioxane (4 mL) / water (2 mL) 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) while stirring. The reaction mixture was stirred at rt for 24 hours. The solvent was removed under reduced pressure and 3 M HCl was added. (水性) The solution (10 mL) was added dropwise to the remaining residue. The resulting precipitate was filtered, washed with water, and dried under vacuum to obtain the title compound (0.076 g, 61%). LC-MS (Method A): R T = 1.31 minutes, m / z = 348 [MHz] - .

[0485] Intermediate 78: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride [ka] To a 200 mL EtOH (EtOH) solution of 5-fluoro-2-aminopyridine (10.0 g, 89 mmol) while stirring, 2,2-dimethyl-1,3-dioxan-4,6-dione (14.1 g, 98 mmol) and triethyl orthoacetate (15.9 g, 98 mmol) were added at rt. The reaction mixture was stirred at reflux temperature for 24 hours, evaporated to dryness, and the residue was dissolved in diphenyl ether (90 mL) and heated at 240 °C for 3 hours. After cooling to rt, the reaction mixture was added to hexane (1.0 L), the resulting precipitate was filtered, washed with hexane, and 7-fluoro-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one (6.2 g, 39%) was obtained. Subsequently, the title compound was prepared in accordance with the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride (intermediate 47), except that 7-fluoro-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one was used instead of 7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one in step 1, to obtain the title compound. LCMS (Method A): R T= 0.47 min, m / z = 331 [M+H] + .

[0486] Intermediate 79: tert-butyl ((2S,4R)-2-(2,5-difluorophenyl)piperidine-4-yl)(2-fluoroethyl)carbamate [ka] Step 1: Benzyl (2S,4R)-4-((tert-butoxycarbonyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate: Benzyl (2,5-difluorophenyl)-4-piperidyl]carbamate (0.3 g, 0.96 mmol) in THF (2 mL) was mixed with 0.28 g, 1.15 mmol of benzyl (2,5-dioxopyrrolidine-1-yl) carbonate, followed by a 2 mL aqueous solution of sodium bicarbonate (0.16 g, 192 mmol). After 24 hours, the reaction mixture was separated by partitioning into ELISA (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 reduced pressure, and the remaining residue was purified by flash chromatography (0-60% alkyl cyclohexane solution) to obtain the title compound (0.31 g, 59%). LC-MS (Method A): R T = 1.56 min, m / z = 347 [M-Boc+H] + .

[0487] Step 2: Benzyl (2S,4R)-4-((tert-butoxycarbonyl)(2-fluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate: 0.3 g, 0.67 mmol of benzyl (2S,4R)-4-((tert-butoxycarbonyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate (0.3 g, 0.67 mmol) was added to a 3 mL solution of DMF at 0°C, containing 55% sodium hydride dispersion in mineral oil. After 30 minutes, 0.07 mL, 0.80 mmol of 1-fluoro-2-iodoethane was added. After 24 hours, 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 to the reaction mixture. After another 24 hours, toluene (30 mL) and 15% NH4Cl were added to the reaction mixture. (水性) The solution (10 mL) was partitioned, separated, and the organic phase was washed with water (10 mL) followed by brine (10 mL) and dried (Mg2SO4). The solvent was removed under reduced pressure, and the remaining residue was purified by flash chromatography (0-40% HCl cyclohexane solution) to obtain the title compound (0.1 g, 30%). LC-MS (Method A): R T = 1.68 min, m / z = 393 [M-Boc+H] + .

[0488] Step 3: Dissolve tert-butyl ((2S,4R)-2-(2,5-difluorophenyl)piperidine-4-yl)(2-fluoroethyl)carbamate:benzyl (2S,4R)-4-((tert-butoxycarbonyl)(2-fluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate (0.08 g, 0.16 mmol) in MeOH (3 mL), and add the solution to an H-Cube containing a 10% w / w Pd / C cartridge. (登録商標) The mixture was passed through a Pro hydrogenation flow reactor at a flow rate of 1 mL / min at 50°C. After one cycle, the solvent was removed under reduced pressure to obtain the title compound (0.05 g, 85%). LC-MS (Method A): R T = 0.778 min, m / z = 359 [M+H]+ .

[0489] Intermediate 80: 4-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-phenyl-1,2-dihydro-3H-pyrazole-3-one [ka] Step 1: Diethyl 2-(ethoxymethylene)malonate (14.8 g, 73.2 mmol) was added at rt to a solution of ethyl 3-oxo-1-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate:N'-phenylacetohydrazide (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 water. The resulting precipitate was filtered and washed with water. The remaining solid was dissolved in SiO2 (200 mL), washed with brine (100 mL), dried, and the solvent was removed under reduced pressure to obtain the title compound (15.4 g, 16%). LCMS (Method E): R T = 3.02 min, m / z = 233 [M+H] + .

[0490] Step 2: Ethyl 3-methoxy-1-phenyl-1H-pyrazole-4-carboxylate: To a solution of ethyl 3-oxo-1-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (300 mg, 1.29 mmol) and K2CO3 (250 mg, 1.80 mmol) in DMF (5 mL) while stirring, iodomethane (96.5 μL, 1.55 mmol) was added at rt. After 4 hours, the reaction mixture was diluted with ice-cold water and extracted with siRNA (50 mL). The organic phase was washed with brine (20 mL), dried (Na2SO4), the solvent was removed under reduced pressure, and the remaining residue was purified by flash chromatography (0-20% siRNA solution in hexane) to obtain the title compound (220 mg, 69.1%). LCMS (Method E): R T = 3.48 min, m / z = 247 [M+H] + .

[0491] Step 3: (3-Methoxy-1-phenyl-1H-pyrazole-4-yl)methanol: To a solution of ethyl 3-methoxy-1-phenyl-1H-pyrazole-4-carboxylate (100 mg, 0.41 mmol) in diethyl ether (2 mL) while stirring, a 1 M toluene solution of DIBAL-H (0.046 mL, 1.22 mmol) was added at -78°C. The temperature of the reaction mixture was raised to -10°C and maintained at this temperature. After 4 hours, the reaction mixture was saturated with NH4Cl (水性) The solution was quenched and extracted with ethyl acetate (20 mL). The organic phase was washed with brine (20 mL), dried (Na₂SO₄), the solvent was removed under reduced pressure, and the remaining residue was purified by flash chromatography (0-50% ethyl acetate in hexane solution) to obtain the title compound (60 mg, 72%). LC-MS (Method E): R T = 2.78 min, m / z = 205 [M+H] + .

[0492] Step 4: 4-(bromomethyl)-3-methoxy-1-phenyl-1H-pyrazole: Triphenylphosphine (806 mg, 3.07 mmol) and CBr4 (1.0 g, 3.07 mmol) were added at rt to a solution of (3-methoxy-1-phenyl-1H-pyrazole-4-yl)methanol (570 mg, 2.79 mmol) in DCM (85 mL) while stirring. After 16 hours, the reaction mixture was concentrated under reduced pressure to obtain the title compound (crude, 570 mg), which was used in the next step without further purification.

[0493] Step 5: tert-butyl 6-((3-methoxy-1-phenyl-1H-pyrazole-4-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate: Cs2CO3 (1.39 g, 4.26 mmol) was added rt-to a solution of 4-(bromomethyl)-3-methoxy-1-phenyl-1H-pyrazole (570 mg, 2.13 mmol) in MeCN (45 mL) while stirring. 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 reduced pressure, diluted with siRNA (100 mL), washed with brine (50 mL), and dried (Na2SO4). The solvent was removed under reduced pressure, and the remaining residue was purified by flash chromatography (0-5% MeOH DCM solution) to obtain the title compound (700 mg, 59% over two steps). LC-MS (Method E): R T = 4.18 min, m / z = 427 [M+H] + .

[0494] Step 6: A slurry of 6-((3-methoxy-1-phenyl-1H-pyrazole-4-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (670 mg, 1.57 mmol) in 33% HBr 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 obtain the crude product (800 mg). 150 mg of this product was purified by preparative HPLC to obtain the title compound (52 mg, 35% recovery), and the remaining material (650 mg) was used in the subsequent reaction without further purification. LCMS (Method E): R T = 1.97 min, m / z = 313 [M+H] + .

[0495] Intermediate 81: 4-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-methyl-1-phenyl-1,2-dihydro-3H-pyrazole-3-one hydrochloride [ka] Step 1: tert-butyl 6-((3-oxo-1-phenyl-2,3-dihydro-1H-pyrazole-4-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate: Triethylamine (0.4 mL, 2.29 mmol) was added rt-to a solution of 4-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-phenyl-1,2-dihydro-3H-pyrazole-3-one (180 mg, 0.46 mmol) in DCM (4 mL) while stirring, followed by the addition of Boc2O (0.09 mL, 0.41 mmol). After 2 hours, the reaction mixture was diluted with water and extracted using 9:1 DCM / MeOH (3 × 20 mL). The combined organic phase was washed with water (10 mL) followed by brine (10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure, and the remaining residue was purified by flash chromatography (0-5% MeOH DCM solution) to obtain the title compound (90 mg, 47%). LC-MS (Method E): R T = 1.90 min, m / z = 413 [M+H] + .

[0496] Step 2: tert-butyl 6-((2-methyl-3-oxo-1-phenyl-2,3-dihydro-1H-pyrazole-4-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate: Trimethylsilyldiazomethane (0.12 mL, 1.09 mmol) was added at rt to a 1:1 DCM / MeOH (5 mL) solution of tert-butyl 6-((3-oxo-1-phenyl-2,3-dihydro-1H-pyrazole-4-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (150 mg, 0.36 mmol) while stirring. After 5 hours, the reaction mixture was diluted with water (20 mL) and extracted using 9:1 DCM / MeOH (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SO4), the solvent was removed under reduced pressure, and the remaining residue was eluted by flash chromatography (0-15% ethyl acetate in hexane solution, followed by 10% MeOH in DCM solution) to extract tert-butyl 6-((3-methoxy-1-phenyl-1H-pyrazole-4-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (25 mg, 16.8%, first eluate): LCMS (Method E): R T = 3.56 min, m / z = 427 [M+H] + ; and title compound (35 mg, 21%, second eluate): LCMS (Method E): R T = 2.60 min, m / z = 427 [M+H] + I obtained it.

[0497] Step 3: 4-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-methyl-1-phenyl-1,2-dihydro-3H-pyrazole-3-one hydrochloride:tert-butyl 6-((2-methyl-3-oxo-1-phenyl-2,3-dihydro-1H-pyrazole-4-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (32 mg, 75.0 μmol), 1,4-dioxane solution in 4 M HCl (0.375 mL), and 1,4-dioxane (3.0 mL) were used to prepare the title compound (28.0 mg, quantitative) according to general procedure 1. LCMS (Method A): RT = 0.42 min, m / z = 327 [M+H] + .

[0498] Intermediate 82: 6-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-5H-thiazolo[3,2-a]pyrimidine-5-one hydrochloride [ka] The title compound was prepared according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride (intermediate 47), except that 5H-thiazolo[3,2-a]pyrimidine-5-one [commercially available] was used instead of 7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one in step 1. LCMS (Method A): R T = 0.39 min, m / z = 305 [M+H] + .

[0499] Intermediate 83: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-cyclopropyl-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one [ka] 5-Fluoro-2-aminopyridine (5.0 g, 45 mmol), ethyl 3-cyclopropyl-3-oxopropanoate (16.4 g, 90 mmol), and bismuth(III) chloride (0.7 g, 2.2 mmol) were stirred under reflux temperature for 24 hours. The reaction mixture was evaporated to dryness, dissolved in diphenyl ether (100 mL), and heated at 100°C for 24 hours. After cooling to rt, the reaction mixture was purified by flash chromatography to obtain 2-cyclopropyl-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one (4.1 g, 43%). LCMS (Method D): R T = 0.87 min, m / z = 205 [M+H] + Subsequently, in step 1, the title compound was dissolved using 2-cyclopropyl-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one instead of 7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one, and the HCl salt in the final step was dissolved in saturated sodium bicarbonate. (水性)Except for washing with , the product was prepared according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride (intermediate 47) to obtain the title compound as a free base. LCMS (Method A): R T = 0.59 min, m / z = 357 [M+H] + .

[0500] Intermediate 84: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridazine-4(1H)-one hydrochloride [ka] Step 1: 4-Methoxy-6-phenylpyridazine-3(2H)-one: Phenylboronic 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 1,4-dioxane (130 mL) / water (45 mL) solution of 4-methoxy-6-chloropyridazine-3(2H)-one (6.0 g, 37.5 mmol) [commercially available] while stirring. The reaction mixture was degassed, backfilled using argon, and heated under reflux. After 24 hours, the solvent was removed under reduced pressure, the remaining residue was dissolved in hot water (200 mL), filtered, and HCl was removed. (水性) The solution was acidified to approximately pH 3 using [method name]. The resulting precipitate was filtered, washed with water, and dried under vacuum to obtain the title compound (7.1 g, 94%). LC-MS (Method D): R T = 0.98 min, m / z = 203 [M+H] + .

[0501] Step 2: 3-Chloro-4-methoxy-6-phenylpyridazine: 4-methoxy-6-phenylpyridazine-3(2H)-one (6.5 g, 62 mmol) was suspended in POCl3 (80 mL) and stirred at reflux temperature for 4 hours. After evaporation of excess POCl3, ice water was added to the remaining residue. After 1 hour, the aqueous mixture was extracted using DCM. The combined organic phase was concentrated under reduced pressure, and the resulting residue was dissolved in MeCN and re-evaporated to obtain the title compound (4.4 g, 98%). LCMS (Method D): R T = 1.16 min, m / z = 221 [M+H] + .

[0502] Step 3: (4-Methoxy-6-phenylpyridazin-3-yl)methanol: Tributylstannylmethanol (6.94 g, 24 mmol) and XPhos Pd G4 (0.9 g, 10 mol%) were added to a 1,4-dioxane (90 mL) solution of 3-chloro-4-methoxy-6-phenylpyridazine (3.6 g, 16 mmol) while stirring. The reaction mixture was degassed, purged with argon, and heated to 60°C. After 48 hours, the solvent was removed under reduced pressure, the remaining residue was ground with diethyl ether (70 mL), filtered, and purified by flash chromatography to obtain the title compound (0.4 g, 43%). LCMS (Method D): R T = 0.60 min, m / z = 251 [M+Cl] - .

[0503] Step 4: tert-butyl 6-((4-oxo-6-phenyl-1,4-dihydropyridazin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate: Thionyl chloride (3.0 mL) was added at rt to a solution of (4-methoxy-6-phenylpyridazin-3-yl)methanol (0.38 g, 1.8 mmol) in DCM (20 mL) while stirring. After 4 hours, the solvent was removed under reduced pressure, 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, the remaining residue was partitioned into DCM and brine, separated, and the organic phase was dried (Na2SO4). The solvent was removed under reduced pressure, and the remaining residue was left in 40% HBr (水性) The compound was dissolved in (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 reduced pressure, the remaining residue was washed with water, and the mixture was purified by preparative HPLC to obtain the title compound (0.10 g, 22%). LCMS (Method D): R T= 0.86 min, m / z = 425 [M+H] + .

[0504] Step 5: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridazine-4(1H)-one hydrochloride: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 solution in 4 M HCl (1.28 mL), and 1,4-dioxane (4.0 mL) were used to prepare the title compound (71 mg, 77%) according to general procedure 1, using 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (109 mg, 257 μmol), 1,4-dioxane solution in 4 M HCl (1.28 mL), and 1,4-dioxane (4.0 mL). LCMS (Method A): R T = 0.51 min, m / z = 325 [M+H] + .

[0505] Intermediate 85: 3-((6,9-diazaspiro[4.5]dec-2-en-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride [ka] Step 1: tert-butyl 3,3-diallylpiperazine-1-carboxylate: Triallylborane (16.4 g, 90 mmol) was added to a solution of tert-butyl 3-oxopiperazine-1-carboxylate (6.0 g, 30 mmol) in THF (80 mL) while stirring. The reaction mixture was stirred at 70°C. After 14 hours, the solvent was removed under reduced pressure, and the remaining residue was collected in DCM (100 mL) and 2M NaOH. (水性) The mixture was divided into 100 mL. The resulting two-phase mixture was separated, extracted (3 × DCM), dried (Na₂SO₄), the solvent was removed under reduced pressure, and the remaining residue was purified by flash chromatography to obtain the title compound (5.1 g, 49%). 1 H NMR (500 MHz, CDCl3): δ 5.78 (m, 2H), 5.11 (m, 4H), 3.37 (m, 2H), 3.20 (s, 2H), 2.79 (m, 2H), 2.16 (m, 4H), 1.45 (s, 9H).

[0506] Step 2: tert-butyl 3,3-diallyl-4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylate: Triethylamine (2.4 g, 23 mmol) was added at 0°C to a solution of tert-butyl 3,3-diallylpiperazine-1-carboxylate (5.50 g, 19 mmol) in DCM (100 mL) while stirring, followed by dropwise addition of triethylamine (2.4 g, 23 mmol) and then trifluoroacetic anhydride (4.3 g, 20.5 mmol). After 24 hours, the reaction mixture was partitioned into DCM and water, separated, and the organic phase was washed several times with water, dried (Na2SO4), and the solvent was removed under reduced pressure to obtain the title compound (6.9 g, 99%). 1 H NMR (500 MHz, CDCl3): δ 5.67 (m, 2H), 5.12 (m, 4H), 3.64 (m, 4H), 3.45 (m, 2H), 2.94 (m, 2H), 2.43 (m, 2H), 1.45 (d, 9H).

[0507] Step 3: tert-butyl 6,9-diazaspiro[4.5]dec-2-ene-9-carboxylate: Degassed beforehand (bubbling with argon for 15 minutes), tert-butyl 3,3-diallyl-4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylate (6.90 g, 19 mmol) is added to a DCM (200 mL) solution with a Grubbs catalyst. (登録商標) M204 (0.6g, 5mol%) was added at rt. After 48 hours, 2M NaOH (水性) The solution was added, and the resulting mixture was heated at 40°C. After a further 24 hours, the organic phase was decanted and dried (Na2SO4), the solvent was removed under reduced pressure, and the remaining residue was purified by flash chromatography to obtain the title compound (3.2 g, 71%). 1 H NMR (500 MHz, CDCl3): δ 5.68 (m, 2H), 3.42 (m, 2H), 3.27 (s, 2H), 2.85 (m, 2H), 2.40 (m, 2H), 2.25 (m, 2H), 1.81 (br s, 1H), 1.46 (s, 9H).

[0508] Step 4: tert-butyl 6-((7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-yl)methyl)-6,9-diazaspiro[4.5]dec-2-ene-9-carboxylate: tert-butyl 6,9-diazaspiro[4.5]dec-2-ene-9-carboxylate (0.94 g, 4 mmol) was added to a MeCN (30 mL) solution of 3-chloromethyl-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one (0.70 g, 3.3 mmol) and DIPEA (1.7 g, 13.2 mmol) while stirring. The resulting suspension was stirred at 80°C. After 18 hours, the solvent was removed under reduced pressure, and the remaining residue was partitioned into DCM and brine, separated, and extracted using DCM. The combined organic phase was dried (Na2SO4), the solvent was removed under reduced pressure, and the remaining residue was purified by flash chromatography to obtain the title compound (0.53 g, 39%). LC-MS (Method D): R T = 0.67 min, m / z = 415 [M+H] + .

[0509] Step 5: 3-((6,9-diazaspiro[4.5]dec-2-en-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride:tert-butyl 6-((7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-yl)methyl)-6,9-diazaspiro[4.5]dec-2-en-9-carboxylate (50 mg, 121 μmol), 1,4-dioxane solution in 4 M HCl (0.25 mL), and DCM (0.25 mL) were used to prepare the title compound (42.2 mg, quantitative) according to general procedure 1 to obtain the title compound (42.2 mg, quantitative). LCMS (Method C): R T = 0.49 min, m / z = 315 [M+H] + .

[0510] Intermediate 86: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-bromo-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride [ka] The title compound was prepared according to the method for 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one hydrochloride (intermediate 47), except that 7-bromo-4H-pyrido[1,2-a]pyrimidine-4-one [commercially available] was used instead of 7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one in step 1. LCMS (Method C): R T = 0.57 min, m / z = 377 [M+H] + .

[0511] Intermediate 87: 3-((6,9-diazaspiro[4.5]decane-6-yl)methyl)-8-chloro-4H-pyrido[1,2-a]pyrimidi...

Claims

1. Equation (I) 【Chemistry 1】 [During the ceremony, R １ C is replaced as desired. １ -C ６ The alkyl, optionally substituted amino, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted aryl, or optionally substituted 5- to 8-membered heteroaryl; R ２ and R ３ are each independently selected from the group consisting of H and C １ -C ６ alkyl, or R ２ and R ３ together with the carbon to which they are attached form C ３ -C ８ cycloalkyl, C ３ -C ８ cycloalkenyl or 3- to 8-membered heterocycloalkyl; M is N or CR ａ And here, R ａ H, halo, and C as desired are substituted. ３ -C ８ Cycloalkyl or optionally substituted C １ -C ６ It is alkyl; A, D, E and G do not exist and X is NR １５ or CH; Y is CR ４ or N or not present; Z is CR ５ , NR ６ or O; R ４ C is replaced by Halo as desired. １ -C ６ Alkyl, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, 4- to 10-membered condensed ring heterocyclyl, optionally substituted C １ -C ６ Alkyl sulfanyl, sulfoxide, sulfone, sulfoximine, optionally substituted amino, optionally substituted 3- to 8-membered heterocycloalkyl, or OR ２０ And; Here, R ２０ C is replaced as desired. １ -C ６ It is alkyl; R ５ H is replaced by C as desired. １ -C ６ Alkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, optionally substituted 3- to 8-membered heterocycloalkyl, amide, sulfoxymine, CN, halo, C(O)OR ２１ , OR ２２ , or NR ２３ R ２４ And; Here, R ２１ H and C １ -C ６ Selected from alkyl groups; R ２２ H and C １ -C ６ Selected from alkyl groups; R ２３ and R ２４ H and optionally C are independently substituted. １ -C ６ Selected from alkyl groups; R １５ is H or C １ -C ６ It is alkyl; or R ４ and R ５ They, together with the Y and Z to which they are bound, form a 3- to 8-membered heterocycloalkyl or aryl group; or R ４ and R １５ They, together with X and Y to which they are bound, form a five-membered cycloalkyl, heterocycloalkyl, or heteroaryl; R ６ H, C １ -C ６ Alkyl, optionally substituted aryl, or C ３ -C ８ It is cycloalkyl; Or A is CR １２ Or N, and D is CR ７ Or N, and E is CR １３ Or N, and G is CR １４ or N and X is either N or C; Y is C; Z is CR ２０ , N, NR １１ , or O, Here, R １１ H is replaced by C as desired. １ -C ６ Alkyl, optionally substituted C ３ -C ８ A cycloalkyl, optionally substituted aryl, or optionally substituted 5- to 8-membered heteroaryl; Here, R ２０ H is replaced by C as desired. １ -C ６ Alkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, optionally substituted 3- to 8-membered heterocycloalkyl, amide, sulfoxymine, CN, halo, C(O)OR ２５ , OR ２６ , or NR ２７ R ２８ And; Here, R ２５ H and C １ -C ６ Selected from alkyl groups; R ２６ H and C １ -C ６ Selected from alkyl groups; R ２７ and R ２８ are independently selected from H and C １ -C ６ alkyl; R ７ H, Haro, C １ -C ６ Alkyl, or OR １９ And; Here, R １９ is optionally substituted C １ -C ６ alkyl; R １２ is H, halo, or C １ -C ６ It is alkyl; R １３ H, Haro, C １ -C ６ Alkyl, OR １６ ; or NR １７ R １８ And; Here, R １６ C is replaced as desired. １ -C ６ It is alkyl, R １７ and R １８ H and C are independent of each other. １ -C ６ Selected from alkyl or R １７ and R １８ They combine with the nitrogen atom to which they are bonded to form a 5-6 member heterocycloalkyl group; and R １４ is H, halo, or C １ -C ６ It is alkyl. Compounds thereof or their stereoisomers, tautomers, hydrates, N-oxide derivatives, or pharmaceutically acceptable salts.

2. For each of the optionally substituted groups, one or more optional substituents are independently alkyl, alkoxy, oxo, halo, cycloalkyl, heterocycloalkyl, aryl, aryl substituted with one or more halos, aryl substituted with halo and alkyl, aryl substituted with halo 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 , NHCH ２ CR ８ R ９ R １０ and NHCH ２ C(O)R ８ Selected from, Here, R ８ , R ９ and R １０ Each of these is independently H, halo, hydroxyl, alkyl, cycloalkyl, cycloalkyl substituted with one or more halo or alkyl groups, heterocycloalkyl substituted with one or more alkyl or oxo groups, heteroaryl, alkoxy, CH ２ OH, and CH ２ CH ２ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to claim 1, selected from OH.

3. R １ The compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to claim 1 or 2, wherein the compound is optionally substituted with a 3- to 11-membered heterocycloalkyl group.

4. R １ R is a 5- to 8-membered heterocycloalkyl group which is optionally substituted, and optionally R １ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein the compound is a 5-6 member heterocycloalkyl which is optionally substituted.

5. R １ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein the compound is optionally substituted with morpholine, cross-linked azepane, diazepane, thiomorpholine, pyrrolidine, piperazine, or piperidine.

6. R １ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein piperidine is optionally substituted.

7. R １ substituted with one or more alkyl, oxo, cycloalkyl, heterocycloalkyl, aryl, aryl, heteroaryl, or NR ８ , NR ８ R ９ NHC(O)R ８ NHCR ８ R ９ R １０ , NHCH ２ CR ８ R ９ R １０ and NHCH ２ C(O)R ８ It is replaced with, here, R ８ , R ９ and R １０ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 3 to 6, wherein each is independently selected from H, halo, hydroxyl, alkyl, cycloalkyl, cycloalkyl substituted with one or more halo or alkyl, heterocycloalkyl substituted with one or more alkyl or oxo, heteroaryl, and alkoxy.

8. R １ R is substituted with phenyl or phenyl substituted with one or more halos, where R １ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 3 to 7, wherein the compound is optionally substituted with one or more further substituents.

9. R １ R is substituted with phenyl or phenyl which is substituted with one or more fluorocarbons, where R １ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 3 to 8, wherein the compound is optionally substituted with one or more further substituents.

10. R １ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 3 to 9, wherein is substituted with difluorophenyl.

11. R １ NR ８ R ９ NHC(O)R ８ , or NHCH ２ CR ８ R ９ R １０ It is replaced with, here, R １ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 3 to 10, wherein the compound is optionally substituted with one or more further substituents.

12. R ８ , R ９ , and R １０ H and C are independent of each other. １ -C ６ Alkyl and fluorosubstituted C １ -C ６ Alkyl, C １ -C ６ Alkoxy, CH ２ OH, CH ２ CH ２ OH, fluorosubstituted C ３ -C ６ Cycloalkyl, C １ -C ６ C substituted with alkyl ３ -C ６ Cycloalkyl and pyridine-substituted C １ -C ６ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt selected from alkyl groups according to any one of claims 2 to 11.

13. R １ C is replaced as desired. １ -C ６ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to claim 1 or 2, which is alkyl.

14. Each optional substituent is a halo, C １ -C ６ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to claim 13, selected from alkoxy, cycloalkyl, and hydroxyl.

15. R １ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein the amino acid is optionally substituted.

16. R １ The compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to claim 15, wherein is an amino substituted with one or more phenyls substituted with one or more halos, or a benzyl substituted with one or more halos.

17. R ２ and R ３ Each is independently either H or methyl, or R ２ and R ３ They become one with the carbon to which they are bonded, C ３ -C ６ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 16, forming a cycloalkyl, cyclopentenyl, or 4- to 6-membered heterocycloalkyl.

18. R ２ and R ３ Each is independently either H or methyl, or R ２ and R ３ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 17, wherein the compounds form a cyclopentyl compound together.

19. R ２ and R ３ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 1 to 18, wherein these atoms combine with the carbon to which they are bonded to form oxetanyl or oxanyl.

20. M is CR ａ The compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 19.

21. R ａ H, cyclopropyl, CF ３ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 1 to 20, or methyl.

22. R ａ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 22, wherein is H.

23. A, D, E, and G do not exist and X is NR １５ or CH; Y is CR ４ , N or not present; Z is CR ５ , NR ６ or O; R ４ C is replaced by Halo as desired. １ -C ６ Alkyl, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, 4- to 10-membered condensed ring heterocyclyl, or C １ -C ６ It is an alkylsulfanyl; R ５ H is replaced by C as desired. １ -C ６ Alkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, optionally substituted 3- to 8-membered heterocycloalkyl, amide, sulfoxymine, CN, or halo; or R ４ and R ５ These, together with the Y and Z to which they are bound, form a 3- to 8-membered heterocycloalkyl or aryl group; R ６ H, C １ -C ６ Alkyl, aryl, or C ３ -C ８ It is cycloalkyl; R １５ is H or C １ -C ６ It is alkyl; or R ４ and R １５ These, together with X and Y to which they are bonded, form a five-membered heterocycloalkyl or heteroaryl group, and optionally, R ４ and R １５ They combine with X and Y to form a dihydrothiazole; Or A is CR １２ Or N, and D is CR ７ Or N, and E is CR １３ Or N, and G is CR １４ or N and X is N or C; Y is C; Z is CH, N, NR １１ , or O, Here, R １１ H is replaced by C as desired. １ -C ６ Alkyl, optionally substituted C ３ -C ８ A cycloalkyl, optionally substituted aryl, or optionally substituted 5- to 8-membered heteroaryl; R ７ H, Haro, C １ -C ６ It is alkyl; R １２ is H, halo, or C １ -C ６ It is alkyl; R １３ H, Haro, C １ -C ６ Alkoxy, or C １ -C ６ It is alkyl; and R １４ is H, halo, or C １ -C ６ It is alkyl; The compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 22, or a stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt thereof.

24. A, D, E, and G do not exist and X is NH or CH; Y is CR ４ or N A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 23.

25. 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 C is replaced by Halo as desired. １ -C ６ Alkyl, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, 4- to 10-membered condensed ring heterocyclyl, C １ -C ６ Alkylsulfanyl, sulfoxide, sulfone, sulfoximine, optionally substituted amino, or optionally substituted 3- to 8-membered heterocycloalkyl; R ５ H is replaced by C as desired. １ -C ６ Alkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, optionally substituted 3- to 8-membered heterocycloalkyl, amide, sulfoxymine, CN, or halo; or R ４ and R ５ They combine with Y and Z, to which they are bound, to form a 3- to 8-membered heterocycloalkyl or aryl group; and R ６ H, C １ -C ６ Alkyl, or C ３ -C ８ It is a cycloalkyl, A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 24.

26. Z is CR ５ Or NR ６ The compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to claim 25.

27. R ６ is H or C １ -C ６ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to claim 25 or 26, which is alkyl.

28. R ４ C is replaced by Halo as desired. １ -C ６ Alkyl, optionally substituted C ３ -C ８ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 25 to 27, which is a cycloalkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, 4- to 10-membered condensed ring heterocyclyl, SMe, sulfoxide, sulfone, sulfoximine, optionally substituted amino, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted morpholine, or optionally substituted piperazine.

29. R ４ C is replaced by Halo as desired. １ -C ６ Alkyl, optionally substituted C ３ -C ８ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 25 to 28, which is a cycloalkyl, optionally substituted aryl, optionally substituted 5- to 8-membered heteroaryl, or 4- to 10-membered condensed ring heterocyclil.

30. R ５ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 25 to 29, wherein is H.

31. Y is CR ４ The compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 25 to 30.

32. A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 25 to 31, wherein Y is N.

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

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

35. R ４ C １ -C ６ Alkyl, C substituted with one or more halo groups １ -C ６ Alkyl, halo, cycloalkyl, one or more C １ -C ６ Alkyl-substituted cycloalkyl, heteroaryl, C １ -C ６ Alkyl-substituted heteroaryls, dihydrobenzofurans, phenyls, or one or more C atoms １ -C ６ Alkyl, C １ -C ６ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 25 to 34, wherein the phenyl is substituted with an alkoxy or halo.

36. R ４ methyl, CF ３ CHF ２ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 25 to 35, which is chloro, cyclopropyl, methyl-substituted cyclopropyl, thiophene, methyl-substituted pyrazole, 2,3-dihydrobenzofuran, phenyl, or phenyl substituted with methyl, methoxy, or fluoro.

37. R ４ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 25 to 36, wherein is phenyl or phenyl substituted with methyl, methoxy, or fluoro.

38. R ４ and R ５ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 25, 26, 31, 33 or 34, wherein the Y and Z to which they are bound together form a six-membered heterocycloalkyl or aryl compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt.

39. A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 25, 26, or 28-38, wherein Z is CH.

40. Z is NR ６ The compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 25 to 38.

41. R ６ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 25 to 37 or 40, wherein is H or methyl.

42. Y is CR ４ And here, R ４ C １ -C ６ Alkyl sulfanyl, preferably SMe, where Z is CR ５ And here, R ５ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 25, 33, or 34, wherein is CN.

43. M is N, X is CH, and Y is CR ４ And Z is NH, here R as desired. ４ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 25, 28, 29, 35, 36 or 37, wherein is phenyl.

44. A is CR １２ Or N, and D is CR ７ Or N, and E is CR １３ Or N, and G is CR １４ or N and X is N or C; Y is C; Z is CH, N, NR １１ , or O, where R １１ H is replaced by C as desired. １ -C ６ Alkyl, optionally substituted C ３ -C ８ A cycloalkyl, optionally substituted aryl, or optionally substituted 5- to 8-membered heteroaryl; R ７ is H, halo, or C １ -C ６ It is alkyl; R １２ is H, halo, or C １ -C ６ It is alkyl; R １３ H, Haro, C １ -C ６ Alkoxy, or C １ -C ６ It is alkyl; and R １４ is H, halo, or C １ -C ６ It is alkyl. A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 23.

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

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

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

48. R ７ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 44 to 47, wherein is H, methyl or halo.

49. R １２ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 44 to 48, wherein is H.

50. D is CR ７ The compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 44 to 49.

51. E is CR １３ The compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 44 to 50.

52. R １３ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 44 to 51, wherein is H.

53. G is CR １４ The compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 44 to 52.

54. R １４ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 44 to 53, wherein is H.

55. A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 44 to 54, wherein X is N.

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

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

58. R ７ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 44 to 57, wherein is a halo.

59. R ７ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 44 to 58, wherein is fluoro.

60. R ７ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 44 to 57, wherein is H.

61. A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 44 to 60, wherein Z is CH.

62. A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 44 to 60, wherein Z is N.

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

64. Z is NR １１ The compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 44, 45, or 48-60.

65. R １１ H, C １ -C ６ Alkyl, C ３ -C ６ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 44, 45, 48-60 or 64, which is cycloalkyl, phenyl, or a 5- to 7-membered heteroaryl.

66. R １１ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 44, 45, 48-60, 64 or 65, wherein is H.

67. R １１ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 44, 45, 48-60, 64 or 65, wherein is methyl.

68. A, D, E, and G are not present; M is CR ａ or N; X is CH; Y is CR ４ and Z is NR ６ That is, A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 25, 27 to 29, 35 to 37, or 41.

69. A, D, E, and G are not present; M is CR ａ And; X is NH; Y is CR ４ and Z is CR ５ That is, A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 25, 28 to 30, 35 to 39, or 42.

70. A, D, E, and G are not present; M is CR ａ And; X is NH; Y is CR ４ and Z is N, A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 25, 28, 29, 35, 36, or 37.

71. X is N; Y is C; Z is N; M is CR ａ And; A and G are CH respectively; D is CR ７ and E is CR １３ That is, A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 23, 44, 48, 52, 58, 59, or 60.

72. X and Y are each C; Z is O; A, E, G, and M are each CH; and D is CR ７ That is, A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 23, 44, 48, 58, 59, or 60.

73. X and Y are each C; Z is NR １１ And; A, E, G, and M are each CH; and D is N, A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 23, 44, 65, 66, or 67.

74. X and Y are each C; Z is NH; E is N; and A, D, G, and M are each CH. A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 23 or 44.

75. C １ -C ６ Alkyl is C １ -C ３ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 74, wherein the compound is alkyl, and preferably methyl.

76. C １ -C ６ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 12, 14, 23, 35 or 44, wherein the alkoxy is methoxy or 2-methoxyethyl.

77. C １ -C ６ A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 76, wherein the alkylsulfanil is SMe.

78. A, D, E, and G do not exist. X is NH or CH; Y is CR ４ And; Z is CR ５ Or NR ６ And; R １ A piperidine or piperazine in which is optionally substituted, R ２ and R ３ These then combine with the carbon atoms to which they bond to form cyclopentyl, R ４ It is phenyl, R ５ H is and R ６ is H or methyl, Here, each optional substituent is phenyl, difluorophenyl, NHCH ３ , NHCH ２ CH ３ NHCH(CH ３ ) ２ NHC(O)CH ３ , N(CH ３ ) ２ , NHCH ２ CHF ２ , NHCH ２ CH ２ F, NHCH ２ CH ２ OH, and NHCH ２ CH ２ OCH ３ Selected from, The compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt of claim 1.

79. A, D, E, and G are not present; X is NH or CH; Y is CR ４ And; Z is CR ５ Or NR ６ And; R １ is piperidine or piperazine, each substituted with difluorophenyl, and optionally one or more C １ -C ３ Alkyl-substituted amino and oxo-substituted C １ -C ３ Alkyl and fluorosubstituted C １ -C ３ XML, CH2CH2OH, C １ -C ３ Alkoxy and fluorosubstituted C ３ -C ６ Cycloalkyl, C １ -C ３ C substituted with alkyl ３ -C ６ Cycloalkyl or pyridine-substituted C １ -C ３ Substituted with alkyl; R ２ and R ３ Each of these is methyl, or together with the carbon to which they are bonded, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, oxetanyl, or oxanyl; R ４ is methyl, dihydrobenzofuran, phenyl, methyl-substituted phenyl, F-substituted phenyl, OMe-substituted phenyl, SMe-substituted phenyl, OH-substituted phenyl, or thiophene; R ５ is H, methyl or CN; and R ６ is H or methyl, The compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt of claim 1.

80. X is N or C; Y is C; Z is N, NR １１ Or O, where R １１ is H or methyl; M is CR ａ And here, R ａ is H, methyl, or cyclopropyl; A is C; D is CR ７ And here, R ７ These are H, methyl, F, Cl, and Br; E is N or CR １３ And here, R １３ is H, Cl, or OMe; G is C; R １ is piperidine or piperazine, each substituted with difluorophenyl, and optionally one or more C １ -C ３ Alkyl-substituted amino and fluoro-substituted C １ -C ３ Alkyl, CH ２ CH ２ OH, C １ -C ３ It is substituted with alkoxy; and R ２ and R ３ Each of these is methyl, or together with the carbon to which they are bonded, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, oxetanyl, or oxanyl. The compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt of claim 1.

81. The following compounds can be selected: (R)-6-phenyl-3-((4-(3-phenylmorpholine-4-carbonyl)piperazine-1-yl)methyl)pyridine-2(1H)-one; (R)-3-((2,2-dimethyl-4-(3-phenylmorpholine-4-carbonyl)piperazine-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)quinoline-2(1H)-one; N-((2S,4R)-2-(2,5-difluorophenyl)-1-(6-((2-oxo-6-phenyl-1,2-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidine-4-yl)acetamide; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridine-2-one; N-(2,4-difluorobenzyl)-6-((2-oxo-6-phenyl-1,2-dihydropyridine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxamide; (R)-6-phenyl-3-((9-(4,4,4-trifluoro-2-methylbutanoyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 3-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; (R)-3-((9-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 6-phenyl-3-((9-((3R,4R)-3-phenylpiperidine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1H)-one; 3-((9-((2S,4R)-4-((3,3-difluorocyclobutyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; (S)-6-phenyl-3-((9-(4,4,4-trifluoro-2-(methoxymethyl)butanoyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1H)-one; (R)-3-((9-(3-cyclohexyl-2-methylpropanoyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 6-phenyl-3-((9-(3-phenylisonicotinoyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1H)-one; 3-((9-((2S,4R)-4-((2-hydroxyethyl)amino)-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2,2-dimethylpiperazine-1-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-4,7-diazaspiro[2.5]octan-4-yl)methyl)-2-phenylpyridine-4(1H)-one; 6-phenyl-3-((9-((2S,4R)-2-phenyl-4-((pyridine-2-ylmethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1H)-one; 5-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(3,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; (R)-3-((9-(2-methyl-2-phenylpiperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; (R)-5-((9-(3-(2,5-difluorophenyl)morpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; (S)-5-((9-(3-(2,5-difluorophenyl)morpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,3-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-4-(cyclopropylamino)-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; (R)-5-((9-(2-(2,5-difluorophenyl)-1,4-diazepan-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; (S)-5-((9-(2-(2,5-difluorophenyl)-1,4-diazepan-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; (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(1H)-one; (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(1H)-one; 5-((9-((2S,4R)-2-(2,6-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 3-((9-((3R,5S)-3-(2,5-difluorophenyl)-5-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((8-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-5,8-diazaspiro[3.5]nonanane-5-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((8-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2-oxa-5,8-diazaspiro[3.5]nonanane-5-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1H)-one; 3-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2,2-dimethylpiperazine-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-4,7-diazaspiro[2.5]octan-4-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-4-amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((8-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-5,8-diazaspiro[3.5]nonanane-5-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((8-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2-oxa-5,8-diazaspiro[3.5]nonanane-5-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(pyrrolidine-1-yl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(1-methyl-1H-pyrazole-5-yl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-methyl-5-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-2-yl)pyridine-4(1H)-one; (R)-3-((9-(3-cyclohexyl-2-methylpropanoyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4one; 5-((9-((2S,4R)-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-4-morpholino-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-fluorophenyl)pyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(o-tolyl)pyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-methoxyphenyl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-chromen-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-4H-chromen-4-one; (R)-3-((9-(3-cyclohexyl-2-methylpropanoyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-chromen-4-one; (R)-3-((9-(3-cyclohexyl-2-methylpropanoyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-4H-chromen-4-one; 5-((9-((2S,4R)-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(1H)-one; (R)-3-((9-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-4H-chromen-4-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(1-methyl-1H-pyrazole-3-yl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 1-Cyclopropyl-5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-methylpyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-5,6-dimethylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoroquinoline-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-hydroxyphenyl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-methyl-2-propylpyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-5-(trifluoromethyl)pyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(o-tolyl)pyridine-4(1H)-one; 5-((9-((2S,4R)-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(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-methoxyphenyl)pyridine-4(1H)-one; (R)-5-((9-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; (R)-3-((9-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(4-fluorophenyl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-2-(3-fluorophenyl)pyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(m-tolyl)pyridine-4(1H)-one; 5-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-methoxyphenyl)pyridine-4(1H)-one; 5-((9-((2S,4R)-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(1H)-one; 5-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(o-tolyl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(m-tolyl)pyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(3-fluorophenyl)pyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-6-(4-fluorophenyl)pyridine-2(1H)-one; 5-((9-((2S,4R)-2-(3-fluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-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-carbonitrile; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyrimidine-4(3H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-1,7-naphthyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyrimidine-4(3H)-one; 5-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-2-yl)pyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-2-yl)pyridine-4(1H)-one; 5-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-2-phenylpyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2,6-dimethylpyridine-4(1H)-one; 3-((9-((2S,4R)-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((4-((2S,5R)-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazine-1-yl)methyl)-6-phenylpyridine-2(1H)-one; (R)-6-phenyl-3-((4-(3-phenylmorpholine-4-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)pyridine-2(1H)-one; (R)-3-((4-(3(4-fluorophenyl)morpholine-4-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((4-((2R,5R)-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazine-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2-fluoro-5-methylphenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2-fluoro-5-methoxyphenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,5R)-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyrimidine-4(3H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; N-((2S,4R)-2-(2,5-difluorophenyl)-1-(6-((7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidine-4-yl)acetamide; N-((2S,4R)-2-(2,5-difluorophenyl)-1-(6-((7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidine-4-yl)cyclopropanecarboxamide; 3-((9-((2S,4R)-4-((1,1-dioxidethietan-3-yl)amino)-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-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)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(thiophen-3-yl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; (S)-6-(2-methoxyphenyl)-3-((9-(2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)pyridine-2(1H)-one; (S)-6-phenyl-3-((7-(2-phenylpyrrolidine-1-carbonyl)-4,7-diazaspiro[2.5]octan-4-yl)methyl)pyridine-2(1H)-one; (S)-6-phenyl-3-((4-(2-phenylpyrrolidine-1-carbonyl)-9-oxa-1,4-diazaspiro[5.5]undecane-1-yl)methyl)pyridine-2(1H)-one; 5-((9-((2R,5R)-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; (S)-3-((4-(2-(2,5-difluorophenyl)pyrrolin-1-carbonyl)-2,2-dimethylpiperazine-1-yl)methyl)-6-(1-methyl-1H-pyrazole-5-yl)pyridine-2(1H)-one; (S)-3-((2,2-dimethyl-4-(2-phenylpyrrolidine-1-carbonyl)piperazine-1-yl)methyl)-6-phenylpyridine-2(1H)-one; (S)-6-phenyl-3-((8-(2-phenylpyrrolidine-1-carbonyl)-2-oxa-5,8-diazaspiro[3.5]nonanane-5-yl)methyl)pyridine-2(1H)-one; 3-((4-((1S,2R,5R)-2-(2,5-difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)piperazine-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((1S,2R,5R)-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(1H)-one; 5-((9-((1S,2R,5R)-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(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(2-fluorophenyl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-fluoro-1-methylquinoline-4(1H)-one; 3-((9-((2R,3R)-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,3S)-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(1-methyl-1H-pyrazole-5-yl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-(trifluoromethyl)pyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(trifluoromethyl)pyridine-4(1H)-one; 3-((4-((2R,3R)-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazine-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((4-((2S,3S)-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazine-1-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2R,3R)-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,3S)-3-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 3-((9-((2R,4R)-4-amino-2-ethylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2R,4R)-2-ethyl-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)(methyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(1-methyl-1H-pyrazole-3-yl)pyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-hydroxypiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-2-(1-methyl-1H-pyrazole-3-yl)pyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropyl(methyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-methoxyethyl)(methyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-hydroxypiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(thiophen-3-yl)pyridine-4(1H)-one; 3-(((S)-4-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-2-methylpiperazine-1-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 7-Chloro-3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-2,2-dimethylpiperazine-1-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-(((R)-4-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-2-methylpiperazine-1-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 5-((9-((2S,4R)-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(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-hydroxyethyl)(methyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethyl(methyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-methyl-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidine-4-one; 5-((9-((2S,4S)-4-amino-2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 5-((9-((2S,4S)-4-(isopropylamino)-2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 3-((9-((2S,4R)-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(6H)-one; 3-((9-((2S,4R)-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(6H)-one; 3-((9-(5-amino-2',5'-difluoro-[1,1'-biphenyl]-2-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridine-2(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-fluoroethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((2-fluoroethyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-phenylpyridine-4(1H)-one; 7-Fluoro-3-((9-((2S,4S)-4-(isopropylamino)-2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-methyl-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one; 4-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-phenyl-1,2-dihydro-3H-pyrazole-3-one; 4-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-methyl-1-phenyl-1,2-dihydro-3H-pyrazole-3-one; 7-Chloro-3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((4-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-1,4-diazaspiro[5.5]undecane-1-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 7-Chloro-3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 6-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-5H-thiazolo[3,2-a]pyrimidine-5-one; 6-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-5H-thiazolo[3,2-a]pyrimidine-5-one; 7-Fluoro-3-((9-((2S,4R)-4-((3-methyloxetan-3-yl)amino)-2-phenylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-methyl-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one; 2-Cyclopropyl-3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 2-Cyclopropyl-3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridazine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-6-phenylpyridazine-4(1H)-one; 3-((9-((2S,4R)-4-amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9-diazaspiro[4,5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]dec-2-en-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; 7-bromo-3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 8-Chloro-3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-4-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-1-methyl-1,6-naphthyridine-4(1H)-one; 3-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-((1-methylcyclopropyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidine-4-one; and 5-((9-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decane-6-yl)methyl)-2-(1-methylcyclopropyl)pyridine-4(1H)-one; or its stereoisomers, tautomers, hydrates, N-oxide derivatives, or pharmaceutically acceptable salts.

82. A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 81, which is an inhibitor of USP19, preferably human USP19.

83. A pharmaceutical composition comprising a compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 1 to 82, and a pharmaceutically acceptable carrier or diluent.

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

85. A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 1 to 82, or a pharmaceutical composition according to claim 83, for use as a pharmaceutical.

86. A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to any one of claims 1 to 82 or a pharmaceutical composition according to claim 83, for use in the treatment of muscle atrophy, obesity, insulin resistance or type 2 diabetes.

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

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

89. A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt or pharmaceutical composition according to any one of claims 1 to 82 for use according to claim 88, wherein the use includes muscle atrophy, cachexy and / or sarcopenia.

90. A method for treating obesity, insulin resistance, type 2 diabetes, or muscle atrophy, comprising administering to a subject in need thereof an effective amount of a compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt or a pharmaceutical composition according to any one of claims 1 to 82 or claim 83.

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

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