Pharmaceutical compounds

Abstract

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

Description

[0001] PHARMACEUTICAL COMPOUNDS

[0002] FIELD OF INVENTION

[0003] The present invention concerns inhibitors of ubiquitin specific protease 19 (USP19) and methods of use thereof.

[0004] BACKGROUND

[0005] Over the past decade, protein ubiquitination has emerged as an important post- translational modification with roles in a plethora of cellular processes including amongst others proteolysis, gene expression, DNA repair, immune response, metabolism or cell cycle regulation. Dysregulation of the Ubiquitin Proteasome System (UPS) has also been implicated in the pathogenesis of multiple human diseases including but not limited to cancer (Hoeller D. etal., Nat. Rev. Cancer (2006), 6, 776-788), viral infection (Gao etal., Can. J. Physiol., Pharmacol. (2006), 84, 5-14), metabolic or neurodegenerative disorders (van Loosdregt J. etal., Immunity (2013), 39, 259-271 ; Rubinsztein D., etal., Nature (2006), 443, 780-786) as well as immune and inflammatory-related medical conditions (Wang J. etal., Cell Mol. Immunol. (2006), 3, 255-261 ; Corn J. etal., Nat. Struct. Mol. Biol. (2014), 21 , 297-300; Nicholson B. etal., Cell Biochem. Biophys. (2011), 60, 61-68).

[0006] The approval and clinical success of the proteasome inhibitors Velcade® (bortezomib) or Kyprolis® (carfilzomib) for the treatment of mantel cell lymphoma (MCL) and multiple myeloma (MM) have validated the UPS as a cancer target amenable for pharmacological intervention. Although effective, their clinical utility has however been severely limited due to poor selectivity and acute toxicity issues. By inhibiting the 26S proteasome, the current proteasome inhibitors indiscriminately impair proteolysis in both cancer and normal cells and are characterised by a low therapeutic index. To circumvent this issue, a promising alternative approach may be to target the UPS upstream of the proteasome. Interfering with the ubiquitin (Ub) conjugation I deconjugation machinery, for instance at the level of the Ubiquitin Specific Proteases (USPs), would allow for the development of improved therapeutics with enhanced specificity and reduced toxicity profiles.

[0007] USPs are the largest subfamily of the deubiquitinating enzymes (DUBs) family with over 60 family members reported to date (Komander D. etal., Nat. Rev. Mol. Cell Biol. (2009), 10, 550-563; Clague M. etal., Physiol. Rev. (2013), 93, 1289-1315). USPs are typically cysteine proteases that catalyse the removal of Ub from specific target substrates thus preventing their induced degradation by the proteasome, or regulating their activation and / or subcellular localization (Daviet L. etal., Biochimie (2008), 90, 270-283; Nicholson B. etal., Cell Biochem. Biophys. (2011), 60, 61-68). It is now well established that USPs regulate the stability and activation of numerous proteins involved in the pathogenesis of human diseases including both oncogenes and tumour suppressors. As such, USPs represent an emerging and attractive target class for pharmacological intervention.

[0008] Amongst all USPs, USP19 is an important member due to its association with a number of important pathways with implications for pathological conditions including but not restricted to cancer, neurodegeneration and degenerative diseases as well as antiviral immune response. USP19 expresses as multiple isoforms varying in length from 71.09 kDa (isoform 2) to 156.03 kDa (isoform 5) with the canonical sequence (isoform 1) of 145.65 kDa in size (uniprot.org). The cellular localisation of USP19 may be cytosolic or bound to the endoplasmic reticulum (Lee J. etal., J. Biol. Chem. (2014), 289, 3510-3517; Lee J. etal., Nat. Cell Biol. (2016), 18, 765-776). Localised to the endoplasmic reticulum, USP19 is a key component of the endoplasmic reticulum-associated degradation (ERAD) pathway (Hassink B. etal., EMBO Rep. (2009), 10, 755-761 ; Lee J. etal., J. Biol. Chem. (2014), 289, 3510-3517; Lee J. etal., Nat. Cell Biol. (2016), 18, 765-776). In particular, USP19 is involved in the latter steps of the protein quality-control machinery rescuing ERAD substrates that have been retro-translocated to the cytosol. USP19 has also been demonstrated to regulate the stability of the E3 ligases MARCH6 and HRD1 (Nakamura N. etal., Exp. Cell Res. (2014), 328, 207-216; Harada K. etal., Int. J. Mol. Sci. (2016), 17, 1829). In addition, USP19 has recently been implicated in the stabilisation of multiple and potentially important protein substrates. For instance, USP19 interacts with SIAH proteins to rescue HIF1a from degradation under hypoxic conditions (Altun M. etal., J. Biol. Chem. (2012), 287, 1962-1969; Velasco K. etal., Biochem. Biophys. Res. Commun. (2013), 433, 390-395). USP19 also stabilises the KPC1 ubiquitin ligase which is involved in the regulation of the p27Kip1cyclin-dependent kinase inhibitor (Lu Y. etal., Mol. Cell Biol. (2009), 29, 547-558). Knock-out of USP19 by RNAi leads to p27Kip1accumulation and inhibition of cell proliferation (Lu Y. etal., PLoS ONE (2011), 6, e15936). USP19 was also found to interact with the inhibitors of apoptosis (lAPs) including C-IAP1 and C-IAP2 (Mei Y. etal., J. Biol. Chem. (2011), 286, 35380-35387). Knockdown of USP19 decreases the total levels of these c-IAPs whilst overexpression increases the levels of both BIRC2 / clAP1 and BIRC3 / clAP2. Knockdown of USP19 also enhances TNFa-induced caspase activation and apoptosis in a BIRC2 / C-IAP1 and BIRC3 / C-IAP2 dependent manner. In addition to some direct involvement in regulating hypoxia response and ER stress, USP19 has also been implicated recently as a positive regulator of autophagy and negative regulator of type I interferon signalling (IFN, antiviral immune response) by deubiquitinating Beclin-1. USP19 was found to stabilise Beclin-1 at the post-translational level by removing the K11 -linked ubiquitin chains of Beclin-1 at Lysine 437 (Jin S. eta!., EMBOJ. (2016), 35, 866-880). USP19 negatively regulates type I IFN signalling pathway, by blocking RIG-I-MAVS interaction in a Beclin-1 dependent manner. Depletion of either USP19 or Beclin-1 inhibits autophagic flux and promotes type I IFN signalling as well as cellular antiviral immunity (Jin S. etal., EMBO J. (2016), 35, 866-880; Cui J. etal., Autophagy (2016), 12, 1210-1211). Recent findings also indicate USP19 may negatively affect the cellular antiviral type I IFN signalling by regulating the TRAF3 substrate (Gu Z. etal., Future Microbiol. (2017), 12, 767-779). USP19 has also been recently implicated in the Wnt signalling pathway by stabilising the coreceptor LRP6 (Perrody E. etal., eLife (2016), 5, e19083) and in the DNA repair processes, most particularly chromosomal stability and integrity, by regulating the HDAC1 and HDAC2 proteins (Wu M. etal., Oncotarget (2017), 8, 2197-2208).

[0009] In addition to cancer and associated conditions, USP19 has been linked in gene knock-out studies to muscle-wasting syndromes 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, 426-468; Wiles B. etal., Mol. Biol. Cell (2015), 26, 913-923; Combaret L. etal., 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 therapy, which increase morbidity and mortality of 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. etal., Mol. Biol. Ce / / (2015), 26, 913-923). Muscle wasting is also a prominent feature of aging.

[0010] Beyond the above pathological conditions, USP19 may also have implications in the pathogenesis of degenerative diseases including but not restricted to Parkinson’s disease and other prion-like transmission disorders by regulating important substrates such as a- synuclein or polyglutamine-containing proteins, Ataxin3, Huntington (He W. etal., PLoS ONE (2016), 11 , e0147515; Bieri G. etal., Neurobiol Dis. (2018), 109B, 219-225). The regulation of coronin 2A (C0R02A) through the activity of LISP19 has been shown to affect the transcriptional repression activity of the retinoic acid receptor (RAR), suggesting that USP19 may also be involved in the regulation of RAR-mediated adipogenesis (Lim K. et al., Oncotarget (2016), 7, 34759-34772).

[0011] WO 2022 / 200523 A1 discloses compounds that are useful as inhibitors of the activity of the ubiquitin specific protease USP19 and also relates to pharmaceutical compositions comprising these compounds and to methods of using these compounds in therapy.

[0012] The established connections between USP19 and numerous proteins involved in human pathologies indicate that small molecule inhibitors of USP19 may have broad therapeutic applications beneficial to human health. The identification of such inhibitors with drug-like potential is of prime importance and high priority.

[0013] SUMMARY OF INVENTION

[0014] In a first aspect is provided a compound of formula (I): wherein

[0015] R1is optionally substituted C1 -C6 alkyl, optionally substituted amino, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl;

[0016] R2and R3are each independently selected from H and C1 -C6 alkyl, or wherein R2and R3together form C3-C8 cycloalkyl, C3-C8 cycloalkenyl or 3 to 8 membered heterocycloalkyl together with the carbon to which they are attached; M is N or CRawherein Rais H, halo, optionally substituted C3-C8 cycloalkyl, or optionally substituted C1-C6 alkyl;

[0017] A, D, E and G are absent and

[0018] X is NR15or CH;

[0019] Y is CR4or N or absent;

[0020] Z is CR5, NR6or O;

[0021] R4is halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, 4 to 10 membered fused-ring heterocyclyl, optionally substituted C1 -C6 alkylsulfanyl, sulfoxide, sulfone, sulfoximine, optionally substituted amino, optionally substituted 3 to 8 membered heterocycloalkyl, or OR20; wherein R20is optionally substituted C1 -C6 alkyl;

[0022] R5is H, optionally substituted C1 -C6 alkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, optionally substituted 3 to 8 membered heterocycloalkyl, amido, sulfoximine, CN, halo, C(O)OR21, OR22, or NR23R24; wherein R21is selected from H and C1 -C6 alkyl;

[0023] R22is selected from H and C1-C6 alkyl;

[0024] R23and R24are independently selected from H and optionally substituted C1 -C6 alkyl;

[0025] R15is H or C1 -C6 alkyl; or R4and R5together form 3 to 8 membered heterocycloalkyl or aryl together with Y and Z to which they are attached; or R4and R15together form 5 membered cycloalkyl, heterocycloalkyl, or heteroaryl together with X and Y to which they are attached; R6is H, C1 -C6 alkyl, optionally substituted aryl, or C3-C8 cycloalkyl; or A is CR12or N, D is CR7or N, E is CR13or N and G is CR14or N and

[0026] X is N or C;

[0027] Y is C;

[0028] Z is CR20, N, NR11, or O, wherein R11is H, optionally substituted 01-06 alkyl, optionally substituted 03-08 cycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl; wherein R20is H, optionally substituted 01-06 alkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, optionally substituted 3 to 8 membered heterocycloalkyl, amido, sulfoximine, ON, halo, C(O)OR25, OR26, or NR27R28; wherein R25is selected from H and 01 -06 alkyl;

[0029] R26is selected from H and 01-06 alkyl;

[0030] R27and R28are independently selected from H and 01-06 alkyl;

[0031] R7is H, halo, 01 -06 alkyl, or OR19; wherein R19is optionally substituted 01 -06 alkyl;

[0032] R12is H, halo, or 01 -06 alkyl;

[0033] R13is H, halo, 01-06 alkyl, OR16; or NR17R18; wherein R16is optionally substituted 01 -06 alkyl,

[0034] R17and R18are independently selected from H and 01-06 alkyl or wherein R17and R18together form 5 to 6 membered heterocycloalkyl with the nitrogen atom to which they are attached; and

[0035] R14is H, halo, or C1 -C6 alkyl; or a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof.

[0036] In a second aspect the invention provides a pharmaceutical composition comprising a compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to the first aspect, and a pharmaceutically acceptable carrier or diluent.

[0037] In a further aspect the invention provides the compound, stereoisomer, tautomer, hydrate, M-oxide derivative or pharmaceutically acceptable salt according to the first aspect or the pharmaceutical composition according to the second aspect for use in therapy.

[0038] In a further aspect the invention provides the compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to the first aspect or the pharmaceutical composition according to the second aspect for use as a medicament.

[0039] In a further aspect the invention provides the compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to the first aspect or the pharmaceutical composition according to the second aspect for use in treating muscular atrophy, obesity, insulin resistance, or type II diabetes.

[0040] In a further aspect the invention provides the compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to the first aspect or the pharmaceutical composition according to the second aspect for use in treating muscular atrophy, cachexia or sarcopenia, wherein the muscular atrophy, cachexia and sarcopenia are associated with or induced by cancer.

[0041] In a further aspect the invention provides a method of treating obesity, insulin resistance, type II diabetes, or muscular 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 according to the first aspect or a pharmaceutical composition according to the second aspect. In a further aspect the invention provides a method of reducing loss of muscle mass in a subject comprising administering to a subject in need thereof an effective amount of a compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to the first aspect or a pharmaceutical composition according to the second aspect.

[0042] USP19 has been associated with a number of diseases and conditions including (but not limited to) cancer and neoplastic conditions. Knock-out of USP19 by RNAi leads to p27Kip1accumulation and inhibition of cell proliferation (Lu Y. eta!., PLoS ONE (2011), 6, e15936). USP19 was also found to interact with the inhibitors of apoptosis (lAPs) including C-IAP1 and C-IAP2 (Mei Y. etal., J. Biol. Chem. (2011), 286, 35380-35387). Knockdown of USP19 decreases the total levels of these c-IAPs whilst overexpression increases the levels of both BIRC2 / clAP1 and BIRC3 / clAP2. Knockdown of USP19 also enhances TNFa-induced caspase activation and apoptosis in a BIRC2 / C-IAP1 and BIRC3 / C-IAP2 dependent manner. USP19 has also been recently implicated in the Wnt signalling pathway by stabilising the coreceptor LRP6 (Perrody E. etal., eLife (2016), 5, e19083) and in the DNA repair processes, most particularly chromosomal stability and integrity, by regulating the HDAC1 and HDAC2 proteins (Wu M. etal., Oncotarget (2017), 8, 2197-2208).

[0043] It is further demonstrated herein that USP19 inhibitor compounds as described in relation to the first aspect exhibit cell permeability and potent target engagement in cancer cell lines. The cell permeability and target engagement in cancer cells is comparable to that observed in muscle cells. As demonstrated herein, USP19 inhibitors exhibit potent in vivo therapeutic effects on muscle wasting. Thus, by extension, since similar target engagement is seen in cancer cells, it is expected that pharmacological USP19 inhibitors will be effective at exerting therapeutic effects in cancer, due to the association of USP19 and oncogenic processes described above.

[0044] In vivo studies have also demonstrated that mice lacking the USP19 gene (USP19 KO mice) exhibited a decrease in fat mass when fed a high-fat diet (Coyne E. etal., Diabetologia (2019), 62, 136-146, which is incorporated herein by reference). USP19 KO mice also exhibited greater glucose tolerance and higher insulin sensitivity when fed a high-fat diet. These gene knock-out studies describe a connection between USP19 and obesity, as well as USP19 and insulin sensitivity. W02020 / 115500 and W02020 / 115501 describe in vivo studies demonstrating that pharmacological inhibitors of USP19 are an effective approach to the treatment of obesity and insulin resistance.

[0045] USP19 is also implicated in muscular atrophy, muscle-wasting syndromes and other skeletal muscle atrophy disorders (Wing S., Int. J. Biochem. Cell Biol. (2013), 45, 21 SO- 2135; Wing S., Int. J. Biochem. Cell Biol. (2016), 79, 462-468; Wiles B. eta!., Mol. Biol. Cell (2015), 26, 913-923; Combaret L. etal., Am. J. Physiol. Endocrinol. Metab. (2005), 288, E693-700). This was supported for instance by studies which demonstrated that USP19- silencing induced the expression of myofibrillar proteins and promoted myogenesis (Sundaram P. etal., Am. J. Physiol. Endocrinol. Metab. (2009), 297, E1283-E1290; Ogawa M. etal., J. Biol. Chem. (2011), 286, 41455-41465; Ogawa M. etal., J. Endocrinol. (2015), 225, 135-145).

[0046] Knock-out studies have demonstrated that mice lacking the USP19 gene were resistant to muscle wasting in response to both glucocorticoids, a common systemic cause of muscle atrophy, as well as in response to denervation, a model of disuse atrophy (Bedard N. etal., FASEB J. (2015), 29, 3889-3898, which is incorporated herein by reference).

[0047] As set out in the accompanying Examples, it is demonstrated herein that pharmacological treatment with a USP19 inhibitor can induce therapeutic effects in a wild-type in vivo model.

[0048] In particular, it is demonstrated that USP19 inhibitors reduce fat deposition in an in vivo model, indicating that USP19 inhibitors can be an effective treatment for obesity.

[0049] Similarly, it is demonstrated herein that USP19 inhibitors can reduce loss of muscle mass in an in vivo model of muscular atrophy.

[0050] Similarly, it is demonstrated herein that USP19 inhibitors can treat the symptoms of insulin resistance, as indicated by an improved response to glucose.

[0051] The compounds according to the invention are able to selectively inhibit USP19 activity.

[0052] The Examples further demonstrate that compounds which potently inhibit USP19 activity can be effective therapeutic compounds. The compounds of the invention are therefore suitable for use in methods of treatment. Indications suitable for treatment with compounds of the invention include: the treatment and prevention of cancer and neoplastic conditions; immunological and inflammatory conditions for example by promoting antiviral immune response; treatment and prevention of muscular atrophy, for example cachexia and sarcopenia; treatment and prevention of obesity; treatment and prevention of insulin resistance, for example diabetes; treatment and prevention of neurodegenerative diseases including Parkinson’s disease and other prion-based disorders.

[0053] Therefore, in a further aspect, is provided a compound, or a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof, according to the first aspect, or a pharmaceutical composition according to the second aspect, for use in therapy.

[0054] In a further aspect, is provided a compound, or a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof, according to the first aspect or a pharmaceutical composition according to the second aspect for use in a method of treating or preventing cancer. In certain preferred embodiments the cancer to be treated is breast cancer or neuroblastoma.

[0055] In a further aspect is provided a compound, or a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof, according to the first aspect, or a pharmaceutical composition according to the second aspect for use in a method of treating or preventing muscular atrophy, optionally cachexia or sarcopenia.

[0056] In a further aspect is provided a compound, or a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof, according to the first aspect, or a pharmaceutical composition according to the second aspect for use in a method of treating or preventing obesity.

[0057] In a further aspect is provided a compound, or a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof, according to the first aspect, or a pharmaceutical composition according to the second aspect for use in a method of treating or preventing insulin resistance. In a further aspect is provided a compound, or a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof, according to the first aspect, or a pharmaceutical composition according to the second aspect for use in a method of treating or preventing type II diabetes.

[0058] In a further aspect is provided a compound, or a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof, according to the first aspect, or a pharmaceutical composition according to the second aspect for use in a method of treating or preventing Parkinson’s Disease.

[0059] In a further aspect is provided a method of treating cancer comprising administering to a subject an effective amount of a compound, or a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof, according to the first aspect or a pharmaceutical composition according to the second aspect.

[0060] In a further aspect is provided a method of treating muscular atrophy comprising administering to a subject an effective amount of a compound, or a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof, according to the first aspect, or a pharmaceutical composition according to the second aspect.

[0061] In a further aspect is provided a method of treating Parkinson’s Disease comprising administering to a subject an effective amount of a compound, or a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof, according to the first aspect, or a pharmaceutical composition according to the second aspect.

[0062] The compounds, or stereoisomers, tautomers, hydrates, / V-oxide derivatives or pharmaceutically acceptable salts thereof, may be used as monotherapy or as combination therapy with radiation and / or additional therapeutic agents.

[0063] Without wishing to be bound by theory, it is thought that the compounds of the present invention tend to show the advantageous effects discussed above due, at least in part, to the presence of the carbon atom between position ‘M’ and the carbonyl group in formula (I).

[0064] As shown in Table 1 , compounds of the present invention exhibit improved in vitro physicochemical properties such as higher kinetic solubility (KSol) and improved in vitro ADME properties such as higher metabolic stability (demonstrated by lower estimated intrinsic clearance, CLnt, using human liver microsome data) and lower CYP3A4 inhibition compared to analogues having the presence of a nitrogen atom between position ‘M’ and the carbonyl group.

[0065] Table 1. Comparison of kinetic solubility (KSol), estimated intrinsic clearance (using human liver microsome data) and cytochrome P4503A4 inhibition data between matched pairs.

[0066] As shown in Table 2, compounds of the present invention exhibit improved in vitro physicochemical properties such as higher kinetic solubility (KSol) and improved in vitro ADME properties such as lower hERG inhibition and lower CYP3A4 inhibition compared to analogues having the presence of a nitrogen atom between position ‘M’ and the carbonyl group.

[0067] Table 2. Comparison of kinetic solubility (KSol), hERG inhibition and cytochrome P4503A4 inhibition data between matched pairs. As shown in Table 3, compounds of the present invention exhibit improved in vitro ADME properties such as higher metabolic stability (demonstrated by lower estimated intrinsic clearance, CLnt, using mouse or rat liver microsome data) and lower CYP3A4 inhibition compared to analogues having the presence of a nitrogen atom between position ‘M’ and the carbonyl group.

[0068] Table 3. Comparison of estimated intrinsic clearance (using mouse and rat liver microsome data) and cytochrome P4503A4 inhibition data between matched pairs.

[0069] Other preferred embodiments of the compounds provided herein appear throughout the specification and in particular in the examples. Particularly preferred are those named compounds having greater activity as tested. Compounds having higher activity are more preferred over those having lower activity.

[0070] Each aspect or embodiment as defined herein may be combined with any other aspect(s) or embodiment(s) unless clearly indicated to the contrary. In particular any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

[0071] FIGURES

[0072] Figure 1 : Effect of USP19 pharmacological inhibition on tibialis anterior mass. (A) Tibialis anterior mass (mg) from mice treated with vehicle or USP19 inhibitor compound ADC-141 . Mass is given for the muscle from limb that had undergone sciatic nerve denervation (DEN) and also from the innervated limb (INN). (B) Percentage loss of tibialis anterior muscle mass as a result of denervation in vehicle and USP19 inhibitor (ADC-141) treated mice. Percentage calculated as a proportion of the mass of the muscle from the innervated limb of the same mouse. (C) Loss of tibialis anterior muscle mass (in mg) as a result of denervation in vehicle treated and USP19 inhibitor (ADC-141) treated mice. P <0.025.

[0073] Figure 2: Effect of USP19 pharmacological inhibition on gastrocnemius muscle mass. (A) gastrocnemius muscle mass (mg) from mice treated with vehicle or USP19 inhibitor compound ADC-141. Mass is given for the muscle from limb that had undergone sciatic nerve denervation (DEN) and also from the innervated limb (INN). (B) Percentage loss of gastrocnemius muscle mass as a result of denervation in vehicle and USP19 inhibitor (ADC-141) treated mice. Percentage calculated as a proportion of the mass of the muscle from the innervated limb of the same mouse. (C) Loss of gastrocnemius muscle mass (in mg) as a result of denervation in vehicle treated and USP19 inhibitor (ADC-141) treated mice.

[0074] Figure 3: (A) Effect of USP19 pharmacological inhibition on fat mass. The epididymal fat pad was collected from vehicle and USP19 inhibitor (ADC-141) treated mice, with USP19 inhibitor treated mice showing a significant reduction in fat mass. (B) Effect of USP19 pharmacological inhibition on liver mass. The liver was collected from vehicle and USP19 inhibitor (ADC-141) treated mice. An increase in liver mass was observed, likely due to accumulation of drug compound in the liver. (C) Percentage change in overall body weight in vehicle-treated control DIO mice. USP19 inhibitor 5 mg / kg i.p. BID, USP19 inhibitor 25 mg / kg i.p. BID, or positive control liraglutide 0.1 mg / kg s.c. BID (left to right bars, respectively); (D) Percentage change in overall lean mass and (E) percentage change in overall fat mass in vehicle, USP19 inhibitor 5 mg / kg, USP19 inhibitor 25 mg / kg, and liraglutide treated mice (left to right, respectively). ***p<0.001 vs vehicle

[0075] Figure 4: Cellular target engagement of USP19 inhibitor compound in breast cancer, neuroblastoma and skeletal muscle cell lines. ECso was determined by densitometry.

[0076] Figure 5: Response to oral glucose tolerance test (OGTT) in obese mice. (A) Timeline of plasma glucose response in vehicle-treated control mice (circles), USP19 inhibitor 5 mg / kg i.p. BID (triangle), USP19 inhibitor 25 mg / kg i.p. BID (solid circle), or positive control liraglutide 0.1 mg / kg s.c. BID (diamond); (B) Glucose AUG (mM.h) and (C) insulin AUG (ng.h / mL) for vehicle, USP19 inhibitor 5 mg / kg, USP19 inhibitor 25 mg / kg, and liraglutide (left to right, respectively). ** p<0.01 vs vehicle; ***p<0.001 vs vehicle. DETAILED DESCRIPTION OF THE INVENTION

[0077] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear, however, in the event of any latent ambiguity, definitions provided herein take precedence over any dictionary or extrinsic definition.

[0078] As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated:

[0079] The term "alkyl group" (alone or in combination with another term(s)) means a straight-or branched-chain saturated hydrocarbon substituent typically containing 1 to 15 carbon atoms, such as 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. A “Cnalkyl” group refers to an aliphatic group containing n carbon atoms. For example, a C1-C10 alkyl group contains 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Attachment to the alkyl group occurs through a carbon atom. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl (branched or unbranched), hexyl (branched or unbranched), heptyl (branched or unbranched), octyl (branched or unbranched), nonyl (branched or unbranched), and decyl (branched or unbranched).

[0080] The term "alkenyl group" (alone or in combination with another term(s)) means a straight-or branched-chain hydrocarbon substituent containing one or more double bonds and typically 2 to 15 carbon atoms; such as 2 to 10, 2 to 8, 2 to 6 or 2 to 4 carbon atoms. Examples of such substituents include ethenyl (vinyl), 1 -propenyl, 3-propenyl, 1 ,4-pentadienyl, 1 ,4- butadienyl, 1 -butenyl, 2-butenyl, 3-butenyl, pentenyl and hexenyl.

[0081] The term "alkynyl group" (alone or in combination with another term(s)) means a straight-or branched-chain hydrocarbon substituent containing one or more triple bonds and typically 2 to 15 carbon atoms; such as 2 to 10, 2 to 8, 2 to 6 or 2 to 4 carbon atoms. Examples of such substituents include ethynyl, 1-propynyl, 3-propynyl, 1-butynyl, 3-butynyl and 4- butynyl.

[0082] The term "heteroalkyl group" (alone or in combination with another term(s)) means a straight-or branched-chain saturated hydrocarbyl substituent typically containing 1 to 15 atoms, such as 1 to 10, 1 to 8, 1 to 6, or 1 to 4 atoms, wherein at least one of the atoms is a heteroatom (i.e. oxygen, nitrogen, or sulfur), with the remaining atoms being carbon atoms. A “Cnheteroalkyl” group refers to an aliphatic group containing n carbon atoms and one or more heteroatoms, for example one heteroatom. For example, a C1-C10 heteroalkyl group contains 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in addition to one or more heteroatoms, for example one heteroatom. Attachment to the heteroalkyl group occurs through a carbon atom or through a heteroatom.

[0083] The term "heteroalkenyl group" (alone or in combination with another term(s)) means a straight-or branched-chain hydrocarbon substituent containing one or more carbon-carbon double bonds and typically 2 to 15 atoms; such as 2 to 10, 2 to 8, 2 to 6 or 2 to 4 atoms, wherein at least one of the atoms is a heteroatom (i.e. oxygen, nitrogen, or sulfur), with the remaining atoms being carbon atoms. A “Cnheteroalkenyl” group refers to an aliphatic group containing n carbon atoms and one or more heteroatoms, for example one heteroatom. For example, a C2-C10 heteroalkenyl group contains 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in addition to one or more heteroatoms, for example one heteroatom. Attachment to the heteroalkenyl group occurs through a carbon atom or through a heteroatom.

[0084] The term "heteroalkynyl group" (alone or in combination with another term(s)) means a straight-or branched-chain hydrocarbon substituent containing one or more carbon-carbon triple bonds and typically 2 to 15 carbon atoms; such as 2 to 10, 2 to 8, 2 to 6 or 2 to 4 carbon atoms, wherein at least one of the atoms is a heteroatom (i.e. oxygen, nitrogen, or sulfur), with the remaining atoms being carbon atoms. A “Cnheteroalkynyl” group refers to an aliphatic group containing n carbon atoms and one or more heteroatoms, for example one heteroatom. For example, a C2-C10 heteroalkynyl group contains 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in addition to one or more heteroatoms, for example one heteroatom. Attachment to the heteroalkynyl group occurs through a carbon atom or through a heteroatom.

[0085] The term "carbocyclyl group" (alone or in combination with another term(s)) means a saturated cyclic (i.e. "cycloalkyl"), partially saturated cyclic (i.e. "cycloalkenyl"), or completely unsaturated (i.e. "aryl") hydrocarbon substituent containing from 3 to 14 carbon ring atoms ("ring atoms" are the atoms bound together to form the ring or rings of a cyclic substituent). A carbocyclyl may be a single-ring (monocyclic) or polycyclic ring structure. A carbocyclyl may be a single ring structure, which typically contains 3 to 8 ring atoms, more typically 3 to 7 ring atoms, and more typically 5 to 6 ring atoms. Examples of such single-ring carbocyclyls include cyclopropyl (cyclopropanyl), cyclobutyl (cyclobutanyl), cyclopentyl (cyclopentanyl), cyclopentenyl, cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl, cyclohexadienyl, and phenyl. A carbocyclyl may alternatively be polycyclic (i.e. may contain more than one ring). Examples of polycyclic carbocyclyls include bridged, fused, and spirocyclic carbocyclyls. In a spirocyclic carbocyclyl, one atom is common to two different rings. An example of a spirocyclic carbocyclyl is spiropentanyl. In a bridged carbocyclyl, the rings share at least two common non-adjacent atoms. Examples of bridged carbocyclyls include bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl. For example, a bridged azepane may be 8-oxa-3-azabicyclo[3.2.1]octan-3-yl. In a fused- ring carbocyclyl system, two or more rings may be fused together, such that two rings share one common bond. Examples of two- or three-fused ring carbocyclyls include naphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.

[0086] The term "cycloalkyl group" (alone or in combination with another term(s)) means a saturated cyclic hydrocarbon substituent containing 3 to 14 carbon ring atoms. A cycloalkyl may be a single carbon ring, which typically contains 3 to 8 carbon ring atoms and more typically 3 to 6 ring atoms. It is understood that attachment to a cycloalkyl group is via a ring atom of the cycloalkyl group. Examples of single-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl may alternatively be polycyclic or contain more than one ring. Polycyclic cycloalkyls include bridged, fused, and spirocyclic cycloalkyls.

[0087] The term “alkylcycloalkyl” refers to a cycloalkyl substituent attached via an alkyl chain. Examples of an alkylcycloalkyl substitent include cyclohexylethane, where the cyclohexane is attached via an ethane linker. Other examples include cyclopropylethane, cyclobutylethane, cyclopentylethane, cycloheptylethane, cyclohexylmethane. In a “Cn” alkylcycloalkyl, Cnincludes the carbon atoms in the alkyl chain and in the cycloalkyl ring. For example, cyclohexylethane is a C8 alkylcycloalkyl.

[0088] The term "aryl group" (alone or in combination with another term(s)) means an aromatic carbocyclyl containing from 5 to 14 carbon ring atoms, optionally 5 to 8, 5 to 7, optionally 5 to 6 carbon ring atoms. A “Cnaryl” group refers to an aromatic group containing n carbon atoms. For example, a C6-C10 aryl group contains 6, 7, 8, 9 or 10 carbon atoms. Attachment to the aryl group occurs through a carbon atom. An aryl group may be monocyclic or polycyclic (i.e. may contain more than one ring). In the case of polycyclic aromatic rings, only one ring in the polycyclic system is required to be unsaturated while the remaining ring(s) may be saturated, partially saturated or unsaturated. Attachment to the aryl group occurs through a carbon atom contained in the ring. Examples of aryl groups include phenyl, naphthyl, acridinyl, indenyl, indanyl, and tetrahydronapthyl.

[0089] The term “arylalkyl” refers to an aryl substituent attached via an alkyl chain. Examples of an arylalkyl substitent include benzyl and phenylethane / ethylbenzene, where the ethane chain links to a phenyl group to the point of attachment. In a “Cn” arylalkyl, Cnincludes the carbon atoms in the alkyl chain and in the aryl group. For example, ethylbenzene is a 08 arylalkyl.

[0090] The term "heterocyclyl group" (alone or in combination with another term(s)) means 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, wherein at least one of the ring atoms is a heteroatom (e.g. oxygen, nitrogen, or sulfur), with the remaining ring atoms being carbon atoms. A heterocyclyl group may, for example, contain one, two, three, four or five heteroatoms. Attachment to the heterocyclyl group may occur through a carbon atom and / or one or more heteroatoms that are contained in the ring. A heterocyclyl may be a single-ring (monocyclic) or polycyclic ring structure.

[0091] A heterocyclyl group may be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples of single-ring heterocyclyls include furanyl, di hydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl, oxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxadiazolyl (including 1 ,2,3- oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl (furazanyl) or 1 ,3,4-oxadiazolyl), oxatriazolyl, dioxazolyl oxathiolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrothiopyranyl, pyridinyl (azinyl), piperidinyl, diazinyl (including pyridazinyl (1 ,2- diazinyl), pyrimidinyl (1 ,3-diazinyl) or pyrazinyl (1 ,4-diazinyl)), piperazinyl, triazinyl (including 1 ,3,5-triazinyl,1 ,2,4-triazinyl and 1 ,2,3-triazinyl)), oxazinyl (including 1 ,2-oxazinyl, 1 ,3-oxazinyl or 1 ,4-oxazinyl)), oxadiazinyl (including 1 ,2,3-oxadiazinyl, 1 ,2,4-oxadiazinyl, 1 ,4,2-oxadiazinyl or 1 ,3,5-oxadiazinyl)), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.

[0092] A heterocyclyl group may alternatively be polycyclic (i.e. may contain more than one ring). Examples of polycyclic heterocyclyl groups include bridged, fused, and spirocyclic heterocyclyl groups. In a spirocyclic heterocyclyl group, one atom is common to two different rings. In a bridged heterocyclyl group, the rings share at least two common non- adjacent atoms. In a fused-ring heterocyclyl group, two or more rings may be fused together, such that two rings share one common bond. Examples of fused ring heterocyclyl groups containing two or three rings include indolizinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, 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), indoleninyl (pseudoindolyl), isoindazolyl (benzpyrazolyl), benzazinyl (including quinolinyl (1-benzazinyl) or isoquinolinyl (2-benzazinyl)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (1 ,2-benzodiazinyl) or quinazolinyl (1 ,3-benzodiazinyl)), benzopyranyl (including chromanyl or isochromanyl), and benzisoxazinyl (including 1 ,2-benzisoxazinyl or 1 ,4-benzisoxazinyl).

[0093] The term "heterocycloalkyl group" (alone or in combination with another term(s)) means a saturated heterocyclyl. An “x to y membered heterocycloalkyl” group refers to a cyclic aliphatic group containing x to y ring atoms, including at least one heteroatom (e.g. nitrogen), with the remainder being carbon atoms. For example, a 3 to 8 membered heterocycloalkyl group contains a total of 3 to 8 ring atoms, wherein at least one of the ring atoms is a heteroatom (e.g. nitrogen, oxygen, sulfur) with the remaining atoms being carbon atoms. Attachment to the heterocycloalkyl group occurs through a carbon atom or one of the at least one heteroatoms.

[0094] The term "heteroaryl group" (alone or in combination with another term(s)) means an aromatic heterocyclyl containing from 5 to 14 ring atoms. An “x to y membered heteroaryl” group refers to an aromatic group containing x to y ring atoms, including at least one heteroatom (e.g. nitrogen), with the remainder being carbon atoms. For example, a 5 to 8 membered heteroaryl group contains a total of 5 to 8 ring atoms, wherein at least one of the ring atoms is a heteroatom (e.g. nitrogen, oxygen, sulfur) with the remaining atoms being carbon atoms. Attachment to the heteroaryl group occurs through a carbon atom or through a heteroatom. A heteroaryl group may be monocyclic or polycyclic. A heteroaryl may be a single ring or 2 or 3 fused rings. Examples of monocyclic heteroaryl groups include 6-membered rings such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and 1 ,3,5-, 1 ,2,4- or 1 ,2,3-triazinyl; 5-membered rings such as imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1 ,2,3-, 1 ,2,4-, 1 ,2,5-, or 1 ,3,4-oxadiazolyl and isothiazolyl. Polycyclic heteroaryl groups may be 2 or 3 fused rings. Examples of polycyclic heteroaryl groups include 6 / 5-membered fused ring groups such as benzothiofuranyl, benzisoxazolyl, benzoxazolyl, and purinyl; and 6 / 6-membered fused ring groups such as benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and benzoxazinyl. In the case of polycyclic heteroaryl groups, only one ring in the polycyclic system is required to be unsaturated while the remaining ring(s) may be saturated, partially saturated or unsaturated.

[0095] The term “amino group” refers to the -NR’R” group. The amino group can be optionally substituted. In an unsubstituted amino group, R’ and R” are hydrogen. In a substituted amino group R’ and R” each independently may be, but are not limited to, hydrogen, an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, sulfonyl, alkenyl, alkanoyl, aryl, arylalkyl, or a heteroaryl group, provided R’ and R” are not both hydrogen. In a substituted amino group R’ and R” may cyclise to form a cyclic amino group, e.g. a pyrrolidine group or a piperidine group. Such a cyclic amino group may incorporate other heteroatoms, for example to form a piperazine or morpholine group. Such a cyclic amino group may be optionally substituted, e.g. with an amino group, a hydroxyl group or an oxo group.

[0096] The term “alkylamino” group refers to the -RaNR’R” group, wherein Rais an alkyl chain as defined above and NR’R” is an optionally substituted amino group as defined above. “Cnalkylamino” group refers to a group containing n carbon atoms. For example, a C1-C10 alkylamino group contains 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. When the amino group of the alkylamino group is a substituted amino group, the number of carbon atoms includes any carbon atoms in the substituent groups. Attachment to the alkylamino group occurs through a carbon atom of the Raalkyl group. Examples of alkylamino substituents include methylamine, ethylamine, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, methylpyrrolidine, and ethylpyrrolidine The term “amido group” refers to the -C(=O)-NR- group. Attachment may be through the carbon or nitrogen atom. For example, the amido group may be attached as a substituent via the carbon atom only, in which case the nitrogen atom has two R groups attached (- C(=O)-NR2). The amido group may be attached by the nitrogen atom only, in which case the carbon atom has an R group attached (-NR-C(=O)R).

[0097] The term “alkylsulfanyl” refers to the -SRagroup, wherein Rais an alkyl chain as defined above. “Cnalkylsulfanyl” group refers to a group containing n carbon atoms. For example, a C1-C10 alkylsulfanyl group contains 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Attachment to the alkylsulfanyl group occurs through the sulfur atom of the SRagroup. The alkylsulfanyl group may be optionally substituted. Examples of the alkylsulfanyl substituents include SMe (a methylsulfanyl group), an ethylsulfanyl group, a propylsulfanyl group and a benzylsulfanyl group.

[0098] The term “sulfoximine” refers to sulfoximine substituents that are either S-linked or N-linked - that is, attachment may be through the sulfur or nitrogen atom. For example, the sulfoximine group may be attached as a substituent via the sulfur atom, in which case the sulfur has a single R group in addition to the oxo group and the sulfur-bound nitrogen atom has one R group attached -that is the group is -S(O)(R)NR’. By way of further example, the sulfoximine group may be attached as a substituent via the nitrogen atom, in which case the sulfur atom has two attached R groups in addition to the oxo group - that is, the group is -NS(O)RR’. In unsubstituted sulfoximine groups, each of R and R’ are H. Alternatively, the sulfoximine group may be substituted at one or both of R and R’, for example to form a dimethyl sulfoximine, where both R and R’ are methyl.

[0099] The term “ether” refers to an -O-alkyl group or an — alkyl-O-alkyl group, for example a methoxy group, a methoxymethyl group or an ethoxyethyl group. The alkyl chain(s) of an ether can be linear, branched or cyclic chains. The ether group can be optionally substituted (a "substituted ether") with one or more substituents. A Cnether refers to an ether group having n carbons in all alkyl chains of the ether group. For example, a CH(CH3)-O-C6H11 ether is a Cs ether group.

[0100] The term “alkoxy group” refers to an -O-alkyl group. The alkoxy group can refer to linear, branched, or cyclic, saturated or unsaturated oxy-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, t-butoxyl and pentoxyl. The alkoxy group can be optionally substituted (a "substituted alkoxy") with one or more alkoxy group substituents.

[0101] The term “aryloxy group” refers to an -O-aryl group, for example a phenoxy group. An aryloxy substituent may itself be optionally substituted, for example with a halogen.

[0102] The term “alkylester” refers to a -C(O)OR group, where R is an alkyl group as defined herein. An example of an alkylester is ethyl methanoate - i.e. R is an ethyl group.

[0103] The term "hydroxyl" refers to an -OH group.

[0104] The term “oxo group” refers to the (=0) group, i.e. a substituent oxygen atom connected to another atom by a double bond. For example, a carbonyl group (-C(=O)-) is a carbon atom connected by a double bond to an oxygen atom, i.e. an oxo group attached to a carbon atom. Examples of carbonyl substituents include aldehydes (-C(=O)H), acetyl (-C(=O)CH3) and carboxyl / carboxylic acid groups (-C(=O)OH).

[0105] 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.

[0106] An alkyl, alkenyl, alkynyl, carbocyclyl (including cycloalkyl, cycloalkenyl and aryl), heterocyclyl (including heterocycloalkyl, heterocyloalkenyl, heteroaryl, nitrogen-containing heterocyclyl), amino, amido, ester, ether, alkoxy, or sulfonamide group can be optionally substituted with one or more substituents, which can be the same or different. A substituent can be attached through a carbon atom and / or a heteroatom in the alkyl, alkenyl, alkynyl, carbocyclyl (including cycloalkyl, cycloalkenyl and aryl), heterocyclyl (including heterocycloalkyl, heterocyloalkenyl, heteroaryl, nitrogen-containing heterocyclyl, nitrogen- containing heteroaryl), amino, amido, ester, ether, alkoxy, or sulfonamide group. 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, amido, alkylamino, arylamino, carbocyclyl, 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 sulfoximinyl.

[0107] In certain aspects, the substituent is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halo, hydroxyl, cyano, amino, amido, alkylamino, arylamino, carbocyclyl, 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.

[0108] If a group, for example an alkyl group, is “optionally substituted”, it is understood that the group has one or more substituents attached (substituted) or does not have any substituents attached (unsubstituted).

[0109] If a group is substituted with a further optionally substituted group, it is understood that the first substituent may itself be either unsubstituted or substituted.

[0110] For completeness, it is also noted that certain chemical formulae used herein define delocalized systems. This definition is known in the art as a definition of aromaticity and may indicate the presence of, for example, a planar mono-, di- or tri-cyclic system that contains (4n+2) electrons where n is an integer. In other words, these systems may display Huckel aromaticity.

[0111] In whatever aspect, the compounds of the present invention may possess some aspect of stereochemistry. For example, the compounds may possess chiral centres and / or planes and / or axes of symmetry. As such, the compounds may be provided as single stereoisomers, single diastereomers, mixtures of stereoisomers or as racemic mixtures, unless otherwise specified. Stereoisomers are known in the art to be molecules that have the same molecular formula and sequence of bonded atoms, but which differ in their spatial orientations of their atoms and / or groups.

[0112] In addition, the compounds of the present invention may exhibit tautomerism. Each tautomeric form is intended to fall within the scope of the invention. In addition, the compounds of the present invention may be provided as a pro-drug. Pro- drugs are transformed, generally in vivo, from one form to the active forms of the drugs described herein.

[0113] In addition, it will be understood that the elements described herein may be the common isotope or an isotope other than the common isotope. For example, a hydrogen atom may be1H,2H (deuterium) or3H (tritium).

[0114] In addition, the compounds of the present invention may be provided in the form of their pharmaceutically acceptable salts or as co-crystals.

[0115] The term “pharmaceutically acceptable salt” refers to ionic compounds formed by the addition of an acid to a base. The term refers to such salts that are considered in the art as being suitable for use in contact with a patient, for example in vivo and pharmaceutically acceptable salts are generally chosen for their non-toxic, non-irritant characteristics.

[0116] The term “co-crystal” refers to a multi- component molecular crystal, which may comprise non-ionic interactions.

[0117] Pharmaceutically acceptable salts and co-crystals may be prepared by ion exchange chromatography or by reacting the free base or acidic form of a compound with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in one or more suitable solvents, or by mixing the compound with another pharmaceutically acceptable compound capable of forming a co-crystal.

[0118] Salts known in the art to be generally suitable for use in contact with a patient include salts derived from inorganic and / or organic acids, including the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate and tartrate. These may include cations based on the alkali and alkaline earth metals, such as sodium, potassium, calcium and magnesium, as well as ammonium, tetramethylammonium, tetraethylammonium. Further reference is made to the number of literature sources that survey suitable pharmaceutically acceptable salts, for example the handbook of pharmaceutical salts published by IUPAC. In addition, the compounds of the present invention may sometimes exist as zwitterions, which are considered as part of the invention.

[0119] As used herein, a USP19 inhibitor refers to a compound which acts on USP19 so as to decrease the activity of the enzyme. Examples of USP19 inhibitors are exemplified compounds herein. Preferably a USP19 inhibitor exhibits an IC50 of less than 5 μM, preferably less than 0.5 μM.

[0120] As used herein, “obesity” refers to the medical condition characterised by excess body fat. Obesity can be characterised by, for example, a body mass index (BMI) of greater than 30. Treatment of obesity may be indicated by, for example, the reduction of body fat, in percentage and / or absolute mass terms. Treatment of obesity may also be exemplified by a reduction in the rate of body fat accumulation by a subject compared to before treatment.

[0121] As used herein, “insulin resistance” refers to the medical condition characterised by an abnormally weak response to insulin. Since insulin resistance is typically not treated by exogenous insulin treatment, the resistance is typically to insulin produced by the body of the subject, though the subject may also be resistant to exogenous insulin. “Insulin resistance” encompasses the conditions “prediabetes” and Type II diabetes. Insulin resistance may be indicated, for example, by a glucose tolerance test (GTT) glycaemia of 7.8 mmol / L or greater. Type II diabetes is typically diagnosed following a glucose tolerance test (GTT) glycaemia of 11 .1 mmol / L or greater.

[0122] Treatment of insulin resistance may be indicated by an improvement (i.e. reduction) in the subject’s GTT glycaemia compared to before treatment. Treatment may also be indicated by a reduction in the subject’s blood sugar concentration under normal conditions compared to before treatment.

[0123] As used herein, “muscular atrophy” and “muscle-wasting” are used interchangeably to refer to decrease in muscle mass in a subject, including in the context of cachexia or sarcopenia, for example. Muscular atrophy can be as a result of temporary or permanent disability, temporary or permanent immobilisation of a limb, extended bedrest, cachexia (for example as a result of cancer, heart failure, or COPD), or sarcopenia. Treatment of muscular atrophy may be characterised as the slowing of the rate of atrophy - that is, treatment results in less muscle mass lost over a given period of time. Preferably, successful treatment results in no loss of muscle mass.

[0124] Accordingly, in a first aspect is provided a compound of formula (I): wherein

[0125] R1is optionally substituted C1 -C6 alkyl, optionally substituted amino, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl;

[0126] R2and R3are each independently selected from H and C1 -C6 alkyl, or wherein R2and R3together form C3-C8 cycloalkyl, C3-C8 cycloalkenyl or 3 to 8 membered heterocycloalkyl together with the carbon to which they are attached;

[0127] M is N or CRawherein Rais H, halo, optionally substituted C3-C8 cycloalkyl, or optionally substituted C1-C6 alkyl;

[0128] A, D, E and G are absent and

[0129] X is NR15or CH;

[0130] Y is CR4or N or absent;

[0131] Z is CR5, NR6or O;

[0132] R4is halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, 4 to 10 membered fused-ring heterocyclyl, optionally substituted C1-C6 alkylsulfanyl (optionally SMe), sulfoxide, sulfone, sulfoximine, optionally substituted amino, optionally substituted 3 to 8 membered heterocycloalkyl, or OR20; wherein R20is optionally substituted C1-C6 alkyl;

[0133] R5is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, optionally substituted 3 to 8 membered heterocycloalkyl, amido, sulfoximine, CN, halo, C(O)OR21, OR22, or NR23R24; wherein R21is selected from H and C1-C6 alkyl;

[0134] R22is selected from H and C1-C6 alkyl;

[0135] R23and R24are independently selected from H and optionally substituted C1-C6 alkyl;

[0136] R15is H or C1-C6 alkyl; or R4and R5together form 3 to 8 membered heterocycloalkyl or aryl together with Y and Z to which they are attached; or R4and R15together form 5 membered cycloalkyl, heterocycloalkyl, or heteroaryl together with X and Y to which they are attached;

[0137] R6is H, C1-C6 alkyl, optionally substituted aryl or C3-C8 cycloalkyl; or A is CR12or N, D is CR7or N, E is CR13or N and G is OR14or N and

[0138] X is N or C;

[0139] Y is C;

[0140] Z is CR20, N, NR11, or O, wherein R11is H, optionally substituted 01-06 alkyl, optionally substituted 03-08 cycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl; wherein R20is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, optionally substituted 3 to 8 membered heterocycloalkyl, amido, sulfoximine, CN, halo, C(O)OR25, OR26, or NR27R28; wherein R25is selected from H and C1 -C6 alkyl;

[0141] R26is selected from H and C1-C6 alkyl;

[0142] R27and R28are independently selected from H and C1-C6 alkyl;

[0143] R7is H, halo, C1 -C6 alkyl, or OR19; wherein R19is optionally substituted C1 -C6 alkyl;

[0144] R12is H, halo, or C1 -C6 alkyl;

[0145] R13is H, halo, C1-C6 alkyl, OR16; or NR17R18; wherein R16is optionally substituted C1 -C6 alkyl,

[0146] R17and R18are independently selected from H and C1-C6 alkyl or wherein R17and R18together form 5 to 6 membered heterocycloalkyl with the nitrogen atom to which they are attached; and

[0147] R14is H, halo, or C1 -C6 alkyl; or a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof.

[0148] Dotted lines in formula (I) indicate optional bonds. That is, the dotted lines indicate the ring including positions X, Y, Z, M can be aliphatic (for example saturated or partially unsaturated) or aromatic. Similarly, in formula (I) dotted lines indicate that, when present, the ring including positions A, D, E and G can be aliphatic (for example saturated or partially unsaturated) or aromatic.

[0149] For the avoidance of doubt, when A, D, E and G are absent and Y is absent, X is bonded directly to Z. Put another way, when A, D, E and G are absent and Y is absent, the ring containing X, Z and M is five-membered. For the compounds of formula (I), for each group that is optionally substituted, there is one or more independently selected optional substituent. In certain embodiments, each of the one or more optional substituents is independently selected from alkyl, alkoxy, oxo, halo, cycloalkyl, heterocycloalkyl, aryl, aryl substituted by one or more halo, aryl substituted by halo and alkyl, aryl substituted by halo and alkoxy, heteroaryl, hydroxyl, CR8R9R10, NR8, NR8R9, NHC(O)R8, NHCR8R9R10, NHCH2CR8R9R10and NHCH2C(O)R8, wherein R8, R9and R10are each independently selected from H, halo, hydroxyl, alkyl, cycloalkyl, cycloalkyl substituted by one or more halo or alkyl, heterocycloalkyl substituted by one or more alkyl or oxo, heteroaryl, alkoxy, CH2OH and CH2CH2OH.

[0150] In certain embodiments, R1is optionally substituted C1 -C6 alkyl, optionally substituted amino, optionally substituted 3 to 8 membered heterocycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl.

[0151] In certain preferred embodiments R1is optionally substituted 3 to 11 membered heterocycloalkyl. More preferably, R1is optionally substituted 3 to 8 membered heterocycloalkyl. More preferably, R1is optionally substituted 5 to 8 membered heterocycloalkyl. More preferably still R1is optionally substituted 5 to 6 membered heterocycloalkyl.

[0152] In certain preferred embodiments R1is optionally substituted morpholine, bridged azepane, diazepane, thiomorpholine, pyrrolidine, piperazine, or piperidine. In preferred such embodiments R1is optionally substituted morpholine, thiomorpholine, pyrrolidine, piperazine, or piperidine. Preferably R1is optionally substituted piperidine.

[0153] In certain preferred embodiments R1is substituted by one or more alkyl, oxo, cycloalkyl, heterocycloalkyl, aryl, aryl substituted by one or more halo, heteroaryl, NR8, NR8R9, NHC(O)R8, NHCR8R9R10, NHCH2CR8R9R10and NHCH2C(O)R8, wherein R8, R9and R10are each independently selected from H, halo, hydroxyl, alkyl, cycloalkyl, cycloalkyl substituted by one or more halo or alkyl, heterocycloalkyl substituted by one or more alkyl or oxo, heteroaryl, and alkoxy.

[0154] In certain preferred embodiments R1is substituted by NR8R9, NHC(O)R8, or NHCH2CR8R9R10, wherein R8, R9and R10are each independently selected from H, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, CH2OH, CH2CH2OH, and optionally substituted C3-C6 cycloalkyl.

[0155] In certain preferred embodiments R1is substituted by NR8R9, NHC(O)R8, or NHCH2CR8R9R10, wherein R8, R9and R10are each independently selected from H, C1-C6 alkyl, fluoro-substituted C1-C6 alkyl, C1-C6 alkoxy, CH2OH, CH2CH2OH, fluoro- substituted C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by C1 -C6 alkyl, and pyridine- substituted C1 -C6 alkyl.

[0156] In certain preferred embodiments R1is substituted by phenyl or phenyl substituted by one or more halo, and wherein R1is optionally substituted with one or more further substituents.

[0157] In certain preferred embodiments R1is substituted by phenyl or phenyl substituted by one or more fluoro, wherein R1is optionally substituted with one or more further substituents. In certain preferred embodiments R1is substituted by difluoro-phenyl.

[0158] In certain preferred embodiments R1is substituted by phenyl substituted by halo and C1- C6 alkyl, wherein R1is optionally substituted with one or more further substituents. In certain preferred embodiments R1is substituted by phenyl substituted by halo and C1 -C6 alkoxy, wherein R1is optionally substituted with one or more further substituents. In certain preferred embodiments R1is substituted by phenyl substituted by fluoro and methyl, wherein R1is optionally substituted with one or more further substituents. In certain preferred embodiments R1is substituted by phenyl substituted by fluoro and methoxy, wherein R1is optionally substituted with one or more further substituents.

[0159] In certain preferred embodiments R1is substituted by NR8R9, NHC(O)R8, or NHCH2CR8R9R10, and wherein R1is optionally substituted with one or more further substituents. In certain preferred embodiments R1is further substituted by phenyl or phenyl substituted by one or more halo. In certain preferred embodiments R1is further substituted by phenyl or phenyl substituted by one or more fluoro. In certain preferred embodiments R1is further substituted by difluoro-phenyl.

[0160] In certain preferred embodiments R1is optionally substituted C1 -C6 alkyl. Preferably, each optional substituent is selected from halo, alkoxy, cycloalkyl, and hydroxyl. In certain preferred embodiments R1is optionally substituted 6 membered heteroaryl, preferably pyridinyl substituted by phenyl.

[0161] In certain preferred embodiments R1is optionally substituted amino. More preferably, R1is amino substituted with phenyl substituted by one or more halo or benzyl substituted by one or more halo.

[0162] In certain preferred embodiments of the compound of formula (I) R1is NRbRcor NRbCH2Rc, wherein Rband Rcare 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, benzodioxol, optionally substituted oxadiazole, thiazole, and thiophene, wherein each of the one or more optional substituents are independently selected from halo, methyl, cyclopropyl and CN, optionally wherein R1is NRaCH2Rband the methylene group is substituted with CF3.

[0163] In certain embodiments R1is NRbRcand Rband Rctogether form an optionally substituted C3-C9 heterocycle together with the N to which they are attached.

[0164] In certain embodiments, R1is NRbRcand Rband Rctogether form an optionally substituted C3-C9 heterocycle together with the N to which they are attached, wherein each of the one or more optional substituents is selected from OH, oxo, C1-C3 alkyl optionally substituted with OH and / or halo, optionally substituted phenyl, optionally substituted benzyl, C1-C3 alkoxy, NRmRn, NHC(O)Rm, and NHCH2Rn, wherein Rmand R" are independently selected from H; C1 -C3 alkyl optionally substituted with OH, methoxy or halo; C3-C4 cycloalkyl optionally substituted with methyl and / or halo; C3-C4 heterocycloalkyl optionally substituted with oxo, methyl or fluoro-methyl; C3-C5 heteroaryl optionally substituted with methyl; and Boc; and / or wherein Rnis further selected from CH2OCH3, COOH and COOCH3, or wherein Rmand Rnform a C3-C5 heterocyclyl group together with the N to which they are attached, optionally wherein Rmand Rnform a morpholinyl group together with the N to which they are attached.

[0165] In certain embodiments, R1is NRbRcand Rband Rctogether form an optionally substituted

[0166] C3-C9 heterocycle together with the N to which they are attached, wherein each of the one or more optional substituents is selected from optionally halo-substituted phenyl, NRmRn, NHC(O)Rm, and NHCH2Rn, wherein Rmand Rnare independently selected from H; C1 -C3 alkyl optionally substituted with OH, methoxy or halo; C3-C4 cycloalkyl optionally substituted with methyl and / or halo; C3-C4 heterocycloalkyl optionally substituted with oxo, methyl or fluoro-methyl; C3-C5 heteroaryl optionally substituted with methyl; and Boc; and / or wherein Rnis further selected from CH2OCH3, COOH and COOCH3, or wherein Rmand Rnform a C3-C5 heterocyclyl group together with the N to which they are attached, optionally wherein Rmand R" form a morpholinyl group together with the N to which they are attached.

[0167] In certain embodiments, R1is NRbRcand Rband Rctogether form a substituted C3-C9 heterocycle together with the N to which they are attached, wherein each of the one or more substituents is selected from OH, CH2OH, CH2OCH3, oxo, NH2, C1-C3 aminoalkyl, amino-thietane dioxide, methyl, ethyl, propyl, CF3, phenyl, substituted phenyl, and benzyl.

[0168] In certain embodiments, R1is NRbRcand Rband Rcform an optionally substituted heterocycle together with the N to which they are attached, wherein the heterocycle is selected from pyrrolidinyl, pyrimidinyl, piperidinyl, morpholino, piperazinyl, and thiomorpholino. In certain such embodiments, the heterocycle is optionally substituted with one or more substituents independently selected from methyl, spiro-cyclopropyl, C1-C3 aminoalkyl, NH2, CH2OH, CH2CF3, oxo, thiophene, phenyl optionally substituted with F or CF3, and OH provided the same ring carbon is not also substituted with methyl.

[0169] In certain embodiments, R1is NRbRcand Rband Rcform a heterocycle together with the N to which they are attached, wherein the heterocycle is selected from pyrrolidinyl, piperidinyl, morpholino, piperazinyl, and thiomorpholino, wherein the heterocycle is optionally substituted with one or more substituents independently selected from methyl, NH2, C1 or C2 aminoalkyl, CH2CF3, oxo, thiophene, phenyl optionally substituted with F or CF3, and OH provided the same ring carbon is not also substituted with methyl.

[0170] In certain embodiments, R1is NRbRcand Rband Rcform a heterocycle together with the N to which they are attached, wherein the heterocycle is selected from piperidinyl and piperazinyl, wherein the heterocycle is optionally substituted with one or more substituents independently selected from methyl, NH2, C1 or C2 aminoalkyl, CH2CF3, oxo, thiophene, phenyl optionally substituted with F or CF3, and OH provided the same ring carbon is not also substituted with methyl.

[0171] In certain embodiments, R1is NRbRcand Rband Rcform an optionally substituted heterocycle together with the N to which they are attached, wherein the heterocycle is selected from piperidinyl and piperazinyl.

[0172] Preferably R1forms a piperazinyl group substituted with fluoro-phenyl or difluorophenyl.

[0173] In certain embodiments, the piperazinyl group is optionally further substituted with methyl.

[0174] In certain embodiments, the piperazinyl group is optionally further substituted with CH2OH or spiro-cyclopropyl.

[0175] In certain embodiments, R1is NRbRcand Rband Rcform an optionally substituted heterocycle, wherein the heterocycle is a piperidinyl group substituted with phenyl, wherein the phenyl is optionally substituted with one or more halo (e.g. fluoro) substituents. In certain preferred such embodiments the piperidinyl group is optionally further substituted with NH2 or NHCH3.

[0176] In certain embodiments, R1is NRbRcand Rband Rctogether with the N to which they are attached form a piperidinyl group optionally substituted with phenyl, fluoro-phenyl, or difluoro-phenyl, and wherein the piperidinyl group is optionally further substituted with NRmRn, NHC(O)Rm, or NHCH2Rn, wherein Rmand Rnare independently selected from H; C1 -C3 alkyl optionally substituted with OH, methoxy or halo; C3-C4 cycloalkyl optionally substituted with methyl and / or halo; C3-C4 heterocycloalkyl optionally substituted with oxo, methyl or fluoro-methyl; C3-C5 heteroaryl optionally substituted with methyl; and Boc; and / or wherein Rnis further selected from CH2OCH3, COOH and COOCH3, or wherein Rmand Rnform a C3-C5 heterocyclyl group together with the N to which they are attached, optionally wherein Rmand Rnform a morpholinyl group together with the N to which they are attached. In certain embodiments R1is NRbRcand Rband Rctogether with the N to which they are attached form a piperidinyl group optionally substituted with phenyl, fluoro-phenyl, or difluoro-phenyl, and wherein the piperidinyl group is optionally further substituted with NRmRn, NHC(O)Rm, or NHCH2Rn, wherein Rmis selected from H; C1 -C3 alkyl optionally substituted with OH or halo; C3-C4 cycloalkyl optionally substituted with methyl and / or halo; C3-C4 heterocycloalkyl optionally substituted with oxo, methyl or fluoro-methyl; C3-C5 heteroaryl optionally substituted with methyl; and Boc; and wherein Rnis selected from H; C1 -C3 alkyl optionally substituted with OH or halo; C3-C4 cycloalkyl optionally substituted with methyl and / or halo; C3-C4 heterocycloalkyl optionally substituted with oxo, methyl or fluoro-methyl; C3-C5 heteroaryl optionally substituted with methyl; Boc; COOH and COOCH3.

[0177] In certain preferred embodiments, the piperidinyl ring formed by R1is substituted with NRmRn, wherein Rmand Rnare independently selected from H; C1-C3 alkyl optionally substituted with OH or halo (preferably F); C3-C4 cycloalkyl optionally substituted with methyl and / or halo (preferably F); C3-C4 heterocycloalkyl optionally substituted with oxo, methyl or fluoro-methyl; C3-C5 heteroaryl optionally substituted with methyl; and Boc.

[0178] In certain preferred embodiments where R1is substituted with NRmRn, Rmis H.

[0179] In certain preferred embodiments, Rmis H and Rnis selected from: H; methyl; ethyl 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 fluoro-methyl.

[0180] In certain preferred embodiments, the piperidinyl ring formed by R1is substituted with NHC(O)Rm, wherein Rmis selected from H; C1-C3 alkyl optionally substituted with OH or halo (preferably F); C3-C4 cycloalkyl optionally substituted with methyl and / or halo (preferably F); C3-C4 heterocycloalkyl optionally substituted with oxo, methyl or fluoro- methyl; C3-C5 heteroaryl optionally substituted with methyl; and Boc.

[0181] In certain preferred embodiments wherein R1is substituted with NHC(O)Rm, Rmis selected from C1 -C3 alkyl, C3-C4 cycloalkyl, and C4-C5 heteroaryl, for example pyridine. In certain embodiments, R1is NRbRcand Rband Rctogether with the N to which they are attached form a piperidinyl group optionally substituted with phenyl, fluoro-phenyl, or difluoro-phenyl, and wherein the piperidinyl group is optionally further substituted with NRmRn, wherein Rmand R" form a C3-C5 heterocyclyl group together with the N to which they are attached. In certain such embodiments Rmand Rnform a morpholinyl group together with the N to which they are attached.

[0182] In certain embodiments, R1is NRbRcand Rband Rctogether with the N to which they are attached form a piperidinyl group optionally substituted with phenyl, fluoro-phenyl, or difluoro-phenyl, and wherein the piperidinyl group is optionally further substituted with NH2, NHCH3 or NHCH2CH3.

[0183] In certain embodiments wherein the heterocycle formed by R1is substituted, it is substituted at the para position (4 position).

[0184] In certain embodiments wherein the heterocycle formed by R1is substituted, it is substituted at the ortho position (2 position).

[0185] In certain such embodiments the heterocycle formed by R1is substituted at the ortho position and the para position (2,4 position).

[0186] In certain embodiments, the heterocycle formed by R1is substituted at the meta position (3 position). In certain such embodiments, the heterocycle formed by R1is substituted at the ortho position and the meta position (2,3 position).

[0187] In certain embodiments, the heterocycle formed by R1is substituted at the 3,5 position.

[0188] In certain preferred embodiments, R1is NRbRcand Rband Rctogether with the N to which they are attached form a piperidinyl group, wherein the piperidinyl group is substituted at the 4 position with NRmRn, NHC(O)Rm, and NHCH2Rn, and is further substituted at the 2 position with phenyl, fluoro-phenyl, or difluoro-phenyl. In such embodiments, Rmand Rnare as defined above and elsewhere herein. In preferred such embodiments where R1is a heterocycle substituted (e.g. by phenyl) at the ortho or 2 position and is chiral, the compound is the (Reconfiguration at this position.

[0189] In preferred embodiments where R1is substituted (e.g. by phenyl) at the ortho or 2 position and is chiral, the compound is the (^-configuration at this position.

[0190] In certain preferred embodiments where R1is a heterocycle substituted at the ortho or 2 position and at the meta or 3 position and is chiral, the compound is the (^-configuration at the ortho position and the (^-configuration at the meta position. In certain preferred embodiments where R1is substituted at the ortho or 2 position and at the meta or 3 position and is chiral, the compound is the (^-configuration at the ortho position and the (Reconfiguration at the meta position.

[0191] In certain preferred embodiments, R1is a heterocycle substituted at the 3,4 position. In preferred such embodiments, and where R1is chiral, the compound is the ( / ^-configuration at the 3 position and the ( / ^-configuration at the 4 position.

[0192] In certain preferred embodiments, R1is a heterocycle substituted at the 3,5 position. In preferred such embodiments, and where R1is chiral, the compound is the ( / ^-configuration at the 3 position and the (^-configuration at the 5 position.

[0193] In certain preferred embodiments, R1is a heterocycle substituted at the 1 ,2,5 position. In preferred such embodiments, and where R1is chiral, the compound is the (^-configuration at the 1 position, the (Reconfiguration at the 2 position and the (Reconfiguration at the 5 position.

[0194] In preferred such embodiments where R1is a heterocycle substituted (e.g. by NH2 or C1- C2 alkylamino) at the ortho or 2 position and at the para or 4-position and is chiral, the compound is the (Reconfiguration at the para position and the (^-configuration at the ortho position. In preferred such embodiments where R1is substituted (e.g. by NH2 or C1 - C2 alkylamino) at the ortho or 2 position and at the para or 4-position and is chiral, the compound is the (S)-configuration at the para position and the (Reconfiguration at the ortho position.

[0195] In certain preferred embodiments, R1forms a piperazinyl group substituted with phenyl, fluoro-phenyl, difluoro-phenyl, or thiophenyl. In certain preferred embodiments, R1forms a 4-aminopiperidinyl group substituted with phenyl, fluoro-phenyl, difluoro-phenyl, or thiophenyl. Preferably R1forms a piperazinyl or 4-aminopiperidinyl group substituted with phenyl. Preferably R1forms a piperazinyl or 4-aminopiperidinyl group substituted with fluoro-phenyl. Preferably R1forms a piperazinyl or 4-aminopiperidinyl group substituted with difluoro-phenyl.

[0196] In preferred embodiments where R1is substituted with difluoro-phenyl, the substituent is 2,5 difluoro-phenyl or 3,5 difluoro-phenyl.

[0197] In certain embodiments, the piperazinyl or 4-aminopiperidinyl group is optionally further substituted with one or two, preferably one, / V-alkyl groups, such as methyl or ethyl.

[0198] In certain preferred embodiments, R1is:

[0199] In certain preferred embodiments, R1is:

[0200] In certain preferred embodiments, R1is: In certain preferred embodiments, R1is:

[0201] In certain preferred such embodiments, the phenyl ring is mono- or di-substituted with fluoro.

[0202] In certain preferred embodiments, R1is selected from:

[0203]

[0204] In certain preferred embodiments of the compound of formula (I), R1is NRbRcor NRbCH2Rc, wherein Rband Rcare independently selected from H, methyl, ethyl, propyl, CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, pyridinyl, pyrazole, imidazole, or wherein Rband Rctogether form a C3-C5 heterocycle together with the N to which they are attached, optionally substituted with OH, CH2OH, CH2OCH3, methyl, ethyl, propyl, CF3, phenyl, or benzyl.

[0205] In certain preferred embodiments, R1is NRbCH2R°, wherein Rbis H or methyl and Rcis selected from cyclobutyl optionally substituted with F, cyclohexyl, phenyl optionally substituted with F, furan and thiophene, optionally wherein the methylene group is substituted with CF3.

[0206] In certain preferred such embodiments, Rcis phenyl or fluoro-substituted phenyl.

[0207] In certain preferred embodiments R2and R3are each independently H or methyl, or R2and R3together form C3-C6 cycloalkyl, cyclopentenyl or 4 to 6 membered heterocycloalkyl together with the carbon to which they are attached. In certain such embodiments, R2and R3together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, oxetanyl or oxanyl together with the carbon to which they are attached. More preferably, R2and R3are each independently H or methyl, or R2and R3together form cyclopentyl. More preferably, R2and R3together form cyclopentyl together with the carbon to which they are attached.

[0208] In certain preferred embodiments M is N or CRawherein Rais H, halo, cyclopropyl, or optionally substituted C1-C6 alkyl.

[0209] In certain preferred embodiments M is N or CRawherein Rais H, fluoro, chloro, cyclopropyl, or C1 -C6 alkyl optionally substituted with one or more halo groups.

[0210] In certain preferred embodiments M is N or CRawherein Rais H, fluoro, chloro, cyclopropyl, CF3or C1 -C6 alkyl.

[0211] In certain preferred embodiments M is N or CRawherein Rais H, or optionally substituted C1 -C6 alkyl. More preferably, M is N or CRawherein Rais H, or C1-C6 alkyl.

[0212] In certain preferred embodiments M is CRa. In certain such embodiments, Rais H, cyclopropyl, CF3or methyl.

[0213] In certain preferred embodiments Rais H or methyl. More preferably, Rais H.

[0214] In certain preferred embodiments M is N.

[0215] In certain preferred embodiments R15is H or methyl.

[0216] In certain preferred embodiments:

[0217] A, D, E and G are absent and

[0218] X is NR15or CH;

[0219] Y is CR4, N or absent;

[0220] Z is CR5, NR6or O; R4is halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, 4 to 10 membered fused-ring heterocyclyl or C1-C6 alkylsulfanyl;

[0221] R5is H, optionally substituted C1 -C6 alkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, optionally substituted 3 to 8 membered heterocycloalkyl, amido, sulfoximine, CN or halo; or R4and R5together form 3 to 8 membered heterocycloalkyl or aryl together with Y and Z to which they are attached;

[0222] R6is H, C1 -C6 alkyl, aryl or C3-C8 cycloalkyl;

[0223] R15is H or C1 -C6 alkyl; or R4and R15together form 5 membered heterocycloalkyl, or heteroaryl together with X and Y to which they are attached, optionally wherein R4and R15together form dihydrothiazole with X and Y to which they are attached; or A is CR12or N, D is CR7or N, E is CR13or N and G is OR14or N and

[0224] X is N or C;

[0225] Y is C;

[0226] Z is CH, N, NR11, or O, wherein R11is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl;

[0227] R7is H, halo, C1 -C6 alkyl;

[0228] R12is H, halo, or C1 -C6 alkyl;

[0229] R13is H, halo, C1-C6 alkoxy, or C1-C6 alkyl; and R14is H, halo, or C1 -C6 alkyl; or a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof.

[0230] In certain preferred embodiments:

[0231] A, D, E and G are absent and

[0232] X is NH or CH;

[0233] Y is CR4or N.

[0234] In certain preferred embodiments:

[0235] A, D, E and G are absent and

[0236] X is NH or CH;

[0237] Y is CR4or N;

[0238] Z is CR5, NR6or O;

[0239] R4is halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, 4 to 10 membered fused-ring heterocyclyl, C1-C6 alkylsulfanyl (optionally SMe), sulfoxide, sulfone, sulfoximine, optionally substituted amino, or optionally substituted 3 to 8 membered heterocycloalkyl;

[0240] R5is H, optionally substituted C1 -C6 alkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, optionally substituted 3 to 8 membered heterocycloalkyl, amido, sulfoximine, CN, or halo; or R4and R5together form 3 to 8 membered heterocycloalkyl or aryl together with Y and Z to which they are attached; and

[0241] R6is H, C1 -C6 alkyl, or C3-C8 cycloalkyl.

[0242] In certain preferred embodiments, when A, D, E and G are absent, Z is CR5or NR6.

[0243] In certain preferred embodiments, when A, D, E and G are absent, R6is H or 01-06 alkyl.

[0244] In certain preferred embodiments, when A, D, E and G are absent, R4is halo, optionally substituted 01 -06 alkyl, optionally substituted 03-08 cycloalkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, 4 to 10 membered fused-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, R4is halo, optionally substituted C1 -C6 alkyl, optionally substituted 03-08 cycloalkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, or 4 to 10 membered fused-ring heterocyclyl.

[0245] In certain preferred embodiments, when A, D, E and G are absent, R5is H.

[0246] In certain preferred embodiments, when A, D, E and G are absent, Y is OR4.

[0247] In certain preferred embodiments, when A, D, E and G are absent, Y is N.

[0248] In certain preferred embodiments, when A, D, E and G are absent, X is NH.

[0249] In certain preferred embodiments, when A, D, E and G are absent, X is CH.

[0250] In certain preferred embodiments, when A, D, E and G are absent, R4is 01 -06 alkyl, 01- 06 alkyl substituted by one or more halo groups, halo, cycloalkyl, cycloalkyl substituted by one or more 01-06 alkyl, heteroaryl, heteroaryl substituted by 01 -06 alkyl, dihydrobenzofuran, phenyl, or phenyl substituted by one or more 01 -06 alkyl, alkoxy (optionally 01 -06 alkoxy), or halo. More preferably, when A, D, E and G are absent, R4is methyl, CF3, CHF2, chloro, cyclopropyl, methyl substituted cyclopropyl, thiophene, methyl substituted pyrazole, 2,3-dihydrobenzofuran, phenyl, or phenyl substituted by methyl, methoxy, or fluoro.

[0251] In certain preferred embodiments, when A, D, E and G are absent, R4is phenyl or phenyl substituted by methyl, methoxy, or fluoro.

[0252] In certain preferred embodiments, when A, D, E and G are absent, R4and R5together form

[0253] 6 membered heterocycloalkyl or aryl together with Y and Z to which they are attached.

[0254] In certain preferred embodiments, when A, D, E and G are absent, Z is CH.

[0255] In certain preferred embodiments, when A, D, E and G are absent, Z is NR6.

[0256] In certain preferred embodiments, when A, D, E and G are absent, R6is H, methyl or cyclopropyl. More preferably, when A, D, E and G are absent, R6is H or methyl.

[0257] In certain preferred embodiments, Y is CR4wherein R4is C1-C6 alkylsulfanyl, preferably SMe, and Z is CR5wherein R5is CN.

[0258] In certain preferred embodiments M is N, X is CH, Y is CR4and Z is NH. In preferred such embodiments, R4is phenyl.

[0259] In certain preferred embodiments:

[0260] A, D, E and G are absent;

[0261] X is CH;

[0262] Y is CR4;

[0263] Z is NR6; and

[0264] M is CRaor N, wherein Ra, R4and R6are as defined herein above.

[0265] In certain preferred embodiments:

[0266] A, D, E and G are absent;

[0267] X is NH;

[0268] Y is CR4;

[0269] Z is CR5; and M is CRa, wherein Ra, R4and R5are as defined herein above.

[0270] In certain preferred embodiments:

[0271] A, D, E and G are absent;

[0272] X is NH;

[0273] Y is OR4;

[0274] M is CRa; and

[0275] Z is N, wherein Raand R4are as defined herein above.

[0276] In certain preferred embodiments:

[0277] A is OR12or N, D is CR7or N, E is CR13or N and G is OR14or N and

[0278] X is N or C;

[0279] Y is C;

[0280] Z is CH, N, NR11, or O, wherein R11is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl;

[0281] R7is H, halo, or C1-C6 alkyl;

[0282] R12is H, halo, or C1 -C6 alkyl;

[0283] R13is H, halo, C1-C6 alkoxy, or C1-C6 alkyl; and

[0284] R14is H, halo, or C1 -C6 alkyl.

[0285] In certain preferred embodiments, when A is CR12or N, D is CR7or N, E is CR13or N and G is CR14or N, Z is CH, N, or NR11. In certain preferred embodiments, when A is OR12or N, D is OR7or N, E is OR13or N and G is CR14or N, Z is CH, N, or O.

[0286] In certain preferred embodiments, when A is OR12or N, D is OR7or N, E is OR13or N and G is OR14or N, Z is CH or N.

[0287] In certain preferred embodiments, when A is CR12or N, D is CR7or N, E is CR13or N and G is CR14or N, R7is H, methyl or halo.

[0288] In certain preferred embodiments, when A is CR12or N, D is CR7or N, E is CR13or N and G is CR14or N, R12is H.

[0289] In certain preferred embodiments, A is CR12or N, D is CR7, E is CR13or N and G is CR14or N.

[0290] In certain preferred embodiments, when A is CR12or N, D is CR7or N, E is CR13and G is CR14or N.

[0291] In certain preferred embodiments, when A is CR12or N, D is CR7or N, E is CR13or N and G is CR14or N, R13is H.

[0292] In certain preferred embodiments, when A is CR12or N, D is CR7or N, E is CR13or N and G is CR14.

[0293] In certain preferred embodiments, when A is CR12or N, D is CR7or N, E is CR13or N and G is CR14or N, R14is H.

[0294] In certain preferred embodiments, when A is CR12or N, D is CR7or N, E is CR13or N and G is CR14or N, X is N.

[0295] In certain preferred embodiments, A is CH, D is CR7or N, E is CR13or N and G is CR14or N.

[0296] In certain preferred embodiments, A is N, D is CR7or N, E is CR13or N and G is CR14or N. In certain preferred embodiments, when A is CR12or N, D is CR7or N, E is CR13or N and G is OR14or N, R7is H or halo, optionally fluoro.

[0297] In certain preferred embodiments, when A is OR12or N, D is OR7or N, E is CR13or N and G is OR14or N, Z is CH.

[0298] In certain preferred embodiments, when A is CR12or N, D is CR7or N, E is CR13or N and G is CR14or N, Z is N.

[0299] In certain preferred embodiments, when A is CR12or N, D is CR7or N, E is CR13or N and G is CR14or N, Z is O.

[0300] In certain preferred embodiments, when A is CR12or N, D is CR7or N, E is CR13or N and G is CR14or N, Z is NR11.

[0301] In certain preferred embodiments, when A is CR12or N, D is CR7or N, E is CR13or N, G is CR14or N, and Z is NR11, R11is H, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, or 5 to 7 membered heteroaryl. More preferably, when A is CR12or N, D is CR7or N, E is CR13or N, G is CR14or N, and Z is NR11, R11is methyl. More preferably, when A is CR12or N, D is CR7or N, E is CR13or N, G is CR14or N, and Z is NR11, R11is H.

[0302] In certain preferred embodiments, X is N; Y is C; Z is N; M is CRa; A and G are each CH; D is CR7; and E is CR13, wherein Ra, R7and R11are as defined herein above.

[0303] In certain preferred embodiments, X and Y are each C; Z is O; A, E, G and M are each CH; and D is CR7, wherein R7is as defined herein above.

[0304] In certain preferred embodiments, X and Y are each C; Z is NR11; A, E, G and M are each CH; and D is N, wherein R11is as defined herein above.

[0305] In certain preferred embodiments, X and Y are each C; Z is NH; E is N; and A, D, G and M are each CH.

[0306] In certain preferred embodiments, A, D, E and G are absent; X is NR15; Y is CR4; Z is N; M is CH; and R4and R15together form 5 membered heterocycloalkyl with X and Y to which they are attached. In certain preferred embodiments, R4and R15together form dihydrothiazole with X and Y to which they are attached.

[0307] In certain preferred embodiments:

[0308] A, D, E and G are absent,

[0309] X is NH or CH;

[0310] Y is CR4;

[0311] Z is CR5or NR6;

[0312] R1is optionally substituted piperidine or piperazine,

[0313] R2and R3together form cyclopentyl together with the carbon to which they are attached,

[0314] R4is phenyl,

[0315] R5is H, and

[0316] R6is H or methyl, wherein each optional substituent is selected from phenyl, difluoro-phenyl, NHCH3, NHCH2CH3, NHCH(CH3)2, NHC(O)CH3, N(CH3)2, NHCH2CHF2, NHCH2CH2F, NHCH2CH2OH and NHCH2CH2OCH3.

[0317] In certain preferred embodiments:

[0318] A, D, E and G are absent;

[0319] X is NH or CH;

[0320] Y is CR4;

[0321] Z is CR5or NR6;

[0322] R1is piperidine or piperazine each substituted by difluoro-phenyl and further substituted by amino optionally substituted by one or more C1-C3 alkyl, oxo- substituted C1 -C3 alkyl, fluoro-substituted C1-C3 alkyl, CH2CH2OH, C1-C3 alkoxy, fluoro-substituted C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by C1-C3 alkyl, or pyridine-substituted C1-C3 alkyl;

[0323] R2and R3are each methyl, or together form cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, oxetanyl or oxanyl together with the carbon to which they are attached;

[0324] R4is methyl, dihydrobenzofuran, phenyl, phenyl substituted by methyl, phenyl substituted by F, phenyl substituted by OMe, phenyl substituted by SMe, phenyl substituted by OH, or thiophene;

[0325] R5is H, methyl or CN; and R6is H or methyl.

[0326] In certain preferred embodiments:

[0327] X is N or C;

[0328] Y is C;

[0329] Z is N, NR11or O, wherein R11is H or methyl;

[0330] M is CRawherein Rais H, methyl or cyclopropyl;

[0331] A is C;

[0332] D is CR7, wherein R7is H, methyl, F, Cl, Br;

[0333] E is N or CR13, wherein R13is H, Cl or OMe;

[0334] G is C;

[0335] R1is piperidine or piperazine each substituted by difluoro-phenyl and further substituted by amino optionally substituted by one or more C1-C3 alkyl, fluoro- substituted C1-C3 alkyl, CH2CH2OH, C1-C3 alkoxy; and

[0336] R2and R3are each methyl, or together form cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, oxetanyl or oxanyl together with the carbon to which they are attached.

[0337] In certain preferred embodiments there is provided a compound selected from:

[0338] (R)-6-Phenyl-3-((4-(3-phenylmorpholine-4-carbonyl)piperazin-1-yl)methyl)pyridin- 2(1 H)-one;

[0339] (F?)-3-((2,2-Dimethyl-4-(3-phenylmorpholine-4-carbonyl)piperazin-1-yl)methyl)-6- phenylpyridin-2(1 H)-one;

[0340] 3-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0341] 3-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)quinolin-2(1 H)-one;

[0342] / V-((2S,4F?)-2-(2,5-Difluorophenyl)-1-(6-((2-oxo-6-phenyl-1 ,2-dihydropyridin-3- yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidin-4-yl)acetamide;

[0343] 3-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1 ,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-2-one; A / -(2,4-Difluorobenzyl)-6-((2-oxo-6-phenyl-1 ,2-dihydropyridin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxamide; (f?)-6-Phenyl-3-((9-(4,4,4-trifluoro-2-methylbutanoyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)pyridin-2(1 H)-one;

[0344] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0345] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1-methyl-2-phenylpyridin-4(1 H)-one;

[0346] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0347] 3-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0348] 3-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0349] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0350] 3-((9-((2S,4fi)-4-(Methylamino)-2-phenylpiperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0351] 3-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0352] 3-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0353] (fl)-3-((9-(2-(2,5-Difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0354] 6-Phenyl-3-((9-((3fl,4H)-3-phenylpiperidine-4-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)pyridin-2(1 H)-one;

[0355] 3-((9-((2S,4fi)-4-((3,3-Difluorocyclobutyl)amino)-2-(2,5-difluorophenyl)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0356] (S)-6-Phenyl-3-((9-(4,4,4-trifluoro-2-(methoxymethyl)butanoyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)pyridin-2(1 H)-one;

[0357] (fl)-3-((9-(3-Cyclohexyl-2-methylpropanoyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- phenylpyridin-2(1 H)-one;

[0358] 6-Phenyl-3-((9-(3-phenylisonicotinoyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)pyridin- 2(1 H)-one;

[0359] 3-((9-((2S,4 / 7)-4-((2-Hydroxyethyl)amino)-2-phenylpiperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one; 5-((4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2,2- dimethylpiperazin-1 -yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0360] 5-((7-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-4,7- diazaspiro[2.5]octan-4-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0361] 6-Phenyl-3-((9-((2S,4fl)-2-phenyl-4-((pyridin-2-ylmethyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)pyridin-2(1 H)-one;

[0362] 5-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0363] 5-((9-((2S,4fi)-2-(3,4-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0364] (fl)-3-((9-(2-Methyl-2-phenylpiperazine-1-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0365] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0366] (fl)-5-((9-(3-(2,5-Difluorophenyl)morpholine-4-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0367] (S)-5-((9-(3-(2,5-Difluorophenyl)morpholine-4-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0368] 5-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0369] 5-((9-((2S,4R)-2-(2,3-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0370] 5-((9-((2S,4fi)-4-(Methylamino)-2-phenylpiperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0371] 5-((9-((2S,4fi)-4-(Cyclopropylamino)-2-phenylpiperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0372] (fl)-5-((9-(2-(2,5-Difluorophenyl)-1 ,4-diazepane-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0373] (S)-5-((9-(2-(2,5-Difluorophenyl)-1 ,4-diazepane-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0374] 5-((9-((2S,4 / 7)-2-(3,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0375] (fl)-5-((9-(3-(2,5-Difluorophenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carbonyl)- 6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one; (S)-5-((9-(3-(2,5-Difluorophenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carbonyl)-

[0376] 6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0377] 5-((9-((2S,4fi)-2-(2,6-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0378] 5-((9-((2S,4fi)-2-(2,4-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0379] 3-((9-((3fl,5S)-3-(2,5-Difluorophenyl)-5-methylmorpholine-4-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0380] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0381] 5-((8-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-5,8- diazaspiro[3.5]nonan-5-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0382] 5-((8-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2-oxa-

[0383] 5.8-diazaspiro[3.5]nonan-5-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0384] 5-((4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-1 ,4- diazaspiro[5.5]undecan-1 -yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0385] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0386] 3-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0387] 5-((4-((2S,4R)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-9-oxa-

[0388] 1 ,4-diazaspiro[5.5]undecan-1 -yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0389] 3-((4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2,2- dimethylpiperazin-1 -yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0390] 3-((7-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-4,7- diazaspiro[2.5]octan-4-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0391] 3-((9-((2S,4fi)-4-Amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0392] 3-((8-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-5,8- diazaspiro[3.5]nonan-5-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0393] 3-((8-((2S,4R)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2-oxa-

[0394] 5.8-diazaspiro[3.5]nonan-5-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0395] 3-((4-((2S,4R)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-1 ,4- diazaspiro[5.5]undecan-1 -yl)methyl)-6-phenylpyridin-2(1 H)-one; 3-((4-((2SJ4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-9-oxa- 1 ,4-diazaspiro[5.5]undecan-1 -yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0396] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(pyrrolidin-1-yl)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0397] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(thiophen-3-yl)pyridin-4(1 H)-one;

[0398] 5-((9-((2S,4f?)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(1 -methyl-1 H-pyrazol-5-yl)pyridin-4(1 H)-one;

[0399] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-methyl-5-phenylpyridin-2(1 H)-one;

[0400] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(thiophen-2-yl)pyridin-4(1 H)-one;

[0401] (fl)-3-((9-(3-Cyclohexyl-2-methylpropanoyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)- 4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0402] 5-((9-((2S,4fi)-4-((2,2-Difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0403] 5-((9-((2S,4fi)-4-Morpholino-2-phenylpiperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0404] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2-fluorophenyl)pyridin-4(1 H)-one;

[0405] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(o-tolyl)pyridin-4(1 H)-one;

[0406] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2-methoxyphenyl)pyridin-4(1 H)-one;

[0407] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-4H-chromen-4-one;

[0408] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-fluoro-4H-chromen-4-one;

[0409] (fl)-3-((9-(3-Cyclohexyl-2-methylpropanoyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)- 4H-chromen-4-one;

[0410] (fl)-3-((9-(3-Cyclohexyl-2-methylpropanoyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- fluoro-4H-chromen-4-one;

[0411] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2,3-dihydrobenzofuran-7-yl)pyridin-4(1 H)-one; (fl)-3-((9-(2-(2,5-Difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-6-fluoro-4H-chromen-4-one;

[0412] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(1 -methyl-1 H-pyrazol-3-yl)pyridin-4(1 H)-one;

[0413] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0414] 3-((4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2,2- dimethylpiperazin-1 -yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0415] 1-Cyclopropyl-5-((9-((2S,4fl)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-methylpyridin-4(1 H)-one;

[0416] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-5,6-dimethylpyridin-2(1 H)-one;

[0417] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrimido[1 ,2-b]pyridazin-4-one;

[0418] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-fluoroquinolin-4(1 H)-one;

[0419] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2-hydroxyphenyl)pyridin-4(1 H)-one;

[0420] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-methyl-2-propylpyridin-4(1 H)-one;

[0421] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0422] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-5-(trifluoromethyl)pyridin-2(1 H)-one;

[0423] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(o-tolyl)pyridin-4(1 H)-one;

[0424] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2,3-dihydrobenzofuran-7-yl)pyridin-4(1 H)-one;

[0425] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2-methoxyphenyl)pyridin-4(1 H)-one;

[0426] (fl)-5-((9-(2-(2,5-Difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0427] (fl)-3-((9-(2-(2,5-Difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one; 3-((9-((2S,4fi)-2-(2J5-Difluorophenyl)-4-(isopropylamino)piperidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0428] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(4-fluorophenyl)pyridin-4(1 H)-one;

[0429] 3-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(isopropylamino)piperidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0430] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(3-fluorophenyl)pyridin-4(1 H)-one;

[0431] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(m-tolyl)pyridin-4(1 H)-one;

[0432] 5-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2-methoxyphenyl)pyridin-4(1 H)-one;

[0433] 5-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(isopropylamino)piperidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2,3-dihydrobenzofuran-7-yl)pyridin-4(1 / - / )-one; 5-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(isopropylamino)piperidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(o-tolyl)pyridin-4(1 H)-one;

[0434] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-(m-tolyl)pyridin-2(1 H)-one;

[0435] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-(3-fluorophenyl)pyridin-2(1 H)-one;

[0436] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-(4-fluorophenyl)pyridin-2(1 H)-one;

[0437] 5-((9-((2S,4fi)-2-(3-Fluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0438] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(methylthio)-6-oxo-1 ,6-dihydropyridine-3- carbonitrile;

[0439] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyrimidin-4(3 / - / )-one;

[0440] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1 ,7-naphthyridin-4(1 H)-one;

[0441] 5-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyrimidin-4(3H)-one;

[0442] 5-((4-((2S,4fl)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1 -carbonyl)-1 ,4- diazaspiro[5.5]undecan-1 -yl)methyl)-2-phenylpyridin-4(1 A7)-one; 5-((9-((2S,4fi)-2-(2J5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(thiophen-2-yl)pyridin-4(1 H)-one;

[0443] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(thiophen-2-yl)pyridin-4(1 H)-one;

[0444] 5-((4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-1 ,4- diazaspiro[5.5]undecan-1 -yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0445] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2,6-dimethylpyridin-4(1 H)-one;

[0446] 3-((9-((2S,4fi)-4-((2,2-Difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-

[0447] 4-one;

[0448] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-

[0449] 4-one;

[0450] 3-((4-((2S,5R)-5-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazin-1- yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0451] (fl)-6-Phenyl-3-((4-(3-phenylmorpholine-4-carbonyl)-9-oxa-1 ,4- diazaspiro[5.5]undecan-1 -yl) methyl)pyridin-2(1 H)-one;

[0452] (fl)-3-((4-(3-(4-Fluorophenyl)morpholine-4-carbonyl)-9-oxa-1 ,4- diazaspiro[5.5]undecan-1 -yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0453] 3-((4-((2fl,5R)-5-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazin-1- yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0454] 5-((9-((2S,4fi)-2-(2-Fluoro-5-methylphenyl)-4-(isopropylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0455] 5-((9-((2S,4fi)-2-(2-Fluoro-5-methoxyphenyl)-4-(isopropylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0456] 5-((9-((2S,5fi)-5-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0457] 5-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyrimidin-4(3H)-one;

[0458] 3-((9-((2S,4 / 7)-2-(2,5-Difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0459] 5-((9-((2S,4 / 7)-2-(2,5-Difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one; A / -((2S,4f?)-2-(2,5-Difluorophenyl)-1 -(6-((7-fluoro-4-oxo-4H-pyrido[1 ,2-a]pyrimidin-3- yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidin-4-yl)acetamide;

[0460] A / -((2S,4f?)-2-(2,5-Difluorophenyl)-1 -(6-((7-fluoro-4-oxo-4H-pyrido[1 ,2-a]pyrimidin-3- yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidin-4- y l)cyclopropanecarboxam ide ;

[0461] 3-((9-((2S,4fi)-4-((1 ,1-Dioxidothietan-3-yl)amino)-2-phenylpiperidine-1 -carbonyl)-

[0462] 6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0463] 3-((9-((2S,4fi)-4-((2,2-Difluoroethyl)amino)-2-(3,5-difluorophenyl)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0464] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(dimethylamino)piperidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1-methyl-2-(thiophen-3-yl)pyridin-4(1 H)-one;

[0465] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(dimethylamino)piperidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0466] (S)-6-(2-Methoxyphenyl)-3-((9-(2-phenylpyrrolidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)pyridin-2(1 H)-one;

[0467] (S)-6-Phenyl-3-((7-(2-phenylpyrrolidine-1-carbonyl)-4,7-diazaspiro[2.5]octan-4- yl)methyl)pyridin-2(1 H)-one;

[0468] (S)-6-Phenyl-3-((4-(2-phenylpyrrolidine-1 -carbonyl)-9-oxa-1 ,4- diazaspiro[5.5]undecan-1 -yl) methyl)pyridin-2(1 H)-one;

[0469] 5-((9-((2fl,5R)-5-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0470] (S)-3-((4-(2-(2,5-Difluorophenyl)pyrrolidine-1 -carbonyl)-2,2-dimethylpiperazin-1 - yl)methyl)-6-(1-methyl-1 H-pyrazol-5-yl)pyridin-2(1 H)-one;

[0471] (S)-3-((2,2-Dimethyl-4-(2-phenylpyrrolidine-1 -carbonyl)piperazin-1-yl)methyl)-6- phenylpyridin-2(1 H)-one;

[0472] (S)-6-Phenyl-3-((8-(2-phenylpyrrolidine-1-carbonyl)-2-oxa-5,8-diazaspiro[3.5]nonan-

[0473] 5-yl)methyl)pyridin-2(1 H)-one;

[0474] 3-((4-((1 S,2fl,5fl)-2-(2,5-Difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane-3- carbonyl)piperazin-1 -yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0475] 3-((9-((1 S,2fl,5fl)-2-(2,5-Difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane-3- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0476] 5-((9-((1 S,2H,5H)-2-(2,5-Difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane-3- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0477] 5-((9-((2S,4H)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2-fluorophenyl)pyridin-4(1 H)-one; 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-fluoro-1-methylquinolin-4(1 H)-one;

[0478] 3-((9-((2fl,3 / 3)-3-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0479] 3-((9-((2S,3S)-3-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0480] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1 -methyl-2-(1 -methyl-1 H-pyrazol-5-yl)pyridin- 4(1 H)-one;

[0481] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-(trifluoromethyl)pyridin-2(1 H)-one;

[0482] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(trifluoromethyl)pyridin-4(1 H)-one;

[0483] 3-((4-((2fl,3R)-3-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazin-1- yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0484] 3-((4-((2S,3S)-3-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazin-1- yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0485] 5-((9-((2fl,3R)-3-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0486] 5-((9-((2S,3S)-3-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0487] 3-((9-((2fl,4H)-4-Amino-2-ethylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0488] 3-((9-((2fl,4H)-2-Ethyl-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0489] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-((2-hydroxyethyl)(methyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0490] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1 -methyl-2-(1 -methyl-1 H-pyrazol-3-yl)pyridin- 4(1 H)-one;

[0491] 5-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(thiophen-3-yl)pyridin-4(1 H)-one;

[0492] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one; 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-hydroxypiperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0493] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(dimethylamino)piperidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1 -methyl-2-(1 -methyl-1 H-pyrazol-3-yl)pyridin- 4(1 H)-one;

[0494] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropyl(methyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-

[0495] 4-one;

[0496] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-((2-methoxyethyl)(methyl)amino)piperidine-

[0497] 1 -carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2- a]pyrimidin-4-one;

[0498] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-hydroxypiperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0499] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(thiophen-3-yl)pyridin-4(1 H)-one;

[0500] 3-(((S)-4-((2S,4fl)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1 -carbonyl)-

[0501] 2-methylpiperazin-1 -yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0502] 7-Chloro-3-((9-((2S,4fl)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0503] 3-((4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1 -carbonyl)-1 ,4- diazaspiro[5.5]undecan-1-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0504] 3-((4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1 -carbonyl)-2,2- dimethylpiperazin-1-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0505] 3-(((H)-4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-

[0506] 2-methylpiperazin-1-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0507] 5-((9-((2S,4fi)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1-methyl-2-(thiophen-3-yl)pyridin-4(1 H)-one;

[0508] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-

[0509] 4-one;

[0510] 3-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-((2-hydroxyethyl)(methyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-

[0511] 4-one;

[0512] 3-((9-((2S,4H)-2-(2,5-Difluorophenyl)-4-(ethyl(methyl)amino)piperidine-1 -carbonyl)- 6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one; 3-((9-((2S,4fi)-2-(2J5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0513] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-8-methoxy-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0514] 5-((9-((2S,4S)-4-Amino-2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0515] 5-((9-((2S,4S)-4-(lsopropylamino)-2-phenylpyrrolidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0516] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7,8-dihydropyrrolo[1 ,2-a]pyrimidin-4(6H)-one;

[0517] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7,8-dihydropyrrolo[1 ,2-a]pyrimidin-4(6H)-one;

[0518] 3-((9-(5-Amino-2',5'-difluoro-[1 ,1'-biphenyl]-2-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-6-phenylpyridin-2(1 H)-one;

[0519] 3-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4- one;

[0520] 3-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-((2-fluoroethyl)amino)piperidine-1-carbonyl)-

[0521] 6.9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0522] 5-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-((2-fluoroethyl)amino)piperidine-1-carbonyl)-

[0523] 6.9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;

[0524] 7-Fluoro-3-((9-((2S,4S)-4-(isopropylamino)-2-phenylpyrrolidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0525] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0526] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4- one;

[0527] 4-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1-phenyl-1 ,2-dihydro-3H-pyrazol-3-one;

[0528] 4-((9-((2S,4 / 7)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-methyl-1-phenyl-1 ,2-dihydro-3H-pyrazol-3-one;

[0529] 7-Chloro-3-((9-((2S,4H)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one; 3-((4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-1 ,4- diazaspiro[5.5]undecan-1-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0530] 3-((4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-1 ,4- diazaspiro[5.5]undecan-1-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0531] 7-Chloro-3-((9-((2S,4fl)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)- 6,9-diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0532] 6-((9-((2S,4f?)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;

[0533] 6-((9-((2S,4f?)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;

[0534] 7-Fluoro-3-((9-((2S,4fi)-4-((3-methyloxetan-3-yl)amino)-2-phenylpiperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0535] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0536] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4- one;

[0537] 2-Cyclopropyl-3-((9-((2S,4fl)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-

[0538] 4-one;

[0539] 2-Cyclopropyl-3-((9-((2S,4fl)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin- 4-one;

[0540] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridazin-4(1 H)-one;

[0541] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridazin-4(1 H)-one;

[0542] 3-((9-((2S,4fi)-4-Amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0543] 3-((9-((2S,4fi)-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]pyrimidin-4-one;

[0544] 7-Bromo-3-((9-((2S,4H)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one;

[0545] 8-Chloro-3-((9-((2S,4H)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one; 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-2-(trifluoromethyl)-4H-pyrido[1 ,2- a]pyrimidin-4-one;

[0546] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-2-(trifluoromethyl)-4H-pyrido[1 ,2- a]pyrimidin-4-one;

[0547] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1 -methyl-1 ,6-naphthyridin-4(1 H)-one;

[0548] 3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-((1-methylcyclopropyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-

[0549] 4-one; and

[0550] 5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(1-methylcyclopropyl)pyridin-4(1 H)-one; or a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof.

[0551] In certain embodiments there is provided a compound, stereoisomer, tautomer, hydrate, N- oxide derivative or pharmaceutically acceptable salt as described above that is an inhibitor of USP19, preferably human USP19.

[0552] In a second aspect the invention provides a pharmaceutical composition comprising a compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to the first aspect, and a pharmaceutically acceptable carrier or diluent.

[0553] Pharmaceutical compositions may be formulated according to their particular use and purpose by mixing, for example, excipient, binding agent, lubricant, disintegrating agent, coating material, emulsifier, suspending agent, solvent, stabilizer, absorption enhancer and / or ointment base. The composition may be suitable for oral, injectable, rectal or topical administration.

[0554] Suitable pharmaceutically acceptable excipients would be known by the person skilled in the art, for example: fats, water, physiological saline, alcohol (e.g. ethanol), glycerol, polyols, aqueous glucose solution, extending agent, disintegrating agent, binder, lubricant, wetting agent, stabilizer, emulsifier, dispersant, preservative, sweetener, colorant, seasoning agent or aromatizer, concentrating agent, diluent, buffer substance, solvent or solubilizing agent, chemical for achieving storage effect, salt for modifying osmotic pressure, coating agent or antioxidant, saccharides such as lactose or glucose; starch of corn, wheat or rice; fatty acids such as stearic acid; inorganic salts such as magnesium metasilicate aluminate 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, plant oil and gum arable.

[0555] For example, the pharmaceutical composition may be administered orally, such as in the form of tablets, coated tablets, hard or soft gelatine capsules, solutions, emulsions, or suspensions. Administration can also be carried out rectally, for example using suppositories, locally or percutaneously, for example using ointments, creams, gels or solution, or parenterally, for example using injectable solutions.

[0556] For the preparation of tablets, coated tablets or hard gelatine capsules, the compounds of the present invention may be admixed with pharmaceutically inert, inorganic or organic excipients. Examples of suitable excipients include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof. Suitable excipients for use with soft gelatine capsules include, for example, vegetable oils, waxes, fats and semi-solid or liquid polyols.

[0557] For the preparation of solutions and syrups, excipients include, for example, water, polyols, saccharose, invert sugar and glucose.

[0558] For injectable solutions, excipients include, for example, water, alcohols, polyols, glycerine and vegetable oil.

[0559] For suppositories and for local and percutaneous application, excipients include, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols.

[0560] The pharmaceutical compositions may also contain preserving agents, solublizing agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, buffers, coating agents and / or antioxidants. For combination therapies, the second drug may be provided in pharmaceutical composition with the present invention or may be provided separately.

[0561] Thus, a pharmaceutical formulation for oral administration may, for example, be granule, tablet, sugar-coated tablet, capsule, pill, suspension or emulsion. For parenteral injection for, for example, intravenous, intramuscular or subcutaneous use, a sterile aqueous solution may be provided that may contain other substances including, for example, salts and / or glucose to make to solution isotonic. The anti-cancer agent may also be administered in the form of a suppository or pessary, or may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.

[0562] In a further aspect the invention provides a compound according to the first aspect, including a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof, for use in therapy.

[0563] In a further aspect the invention provides a pharmaceutical composition according to the second aspect for use in therapy.

[0564] In a further aspect the invention provides a compound according to any embodiment of the first aspect, or a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer.

[0565] In a further aspect the invention provides a pharmaceutical composition according to the second aspect for use in the treatment and / or prevention of cancer.

[0566] In a further aspect the invention provides a method of treating or preventing cancer comprising administering to a subject a compound, including a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof, according to any embodiment of the first aspect of the invention or a pharmaceutical composition according to any embodiment of the second aspect of the invention.

[0567] In a further aspect the invention provides a use of a compound, including a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof, according to any embodiment of the first aspect in the manufacture of a medicament for treating or preventing cancer. Cancers or neoplastic conditions suitable to be treated with the compounds or compositions according to the invention include, for example: prostate cancer, colon cancer, breast cancer, lung cancer, kidney cancer, CNS cancers (e.g. neuroblastomas, glioblastomas), osteosarcoma, haematological malignancies (e.g. leukaemia, multiple myeloma and mantle cell lymphoma). In certain preferred embodiments the cancer is associated with p53 dysregulation. In certain preferred embodiments, the cancer is selected from a haematological malignancy (e.g. mantle cell lymphoma, multiple myeloma), prostate cancer, a neuroblastoma, or a glioblastoma. In certain preferred embodiments, the cancer is neuroblastoma or breast cancer.

[0568] It is demonstrated herein that the potent USP19 inhibitory compounds effectively reduce fat accumulation in vivo. Gene knockout studies have described a possible association between USP19 and fat accumulation (Coyne et al., Diabetologia, 2019, 62, 136-146, incorporated herein by reference). However, the effects seen in these studies need to be considered alongside the possible confounding factors inherent in knockout studies such as altered developmental or underlying physiological processes. For these reasons, acute or chronic pharmacological inhibition of an enzyme does not always result in similar physiological outcomes to genetic ablation.

[0569] The data provided herein demonstrates that pharmacological inhibition of USP19 can reduce fat accumulation in a wild-type background. Taken together, the in vitro and in vivo data demonstrate that compounds which potently inhibit USP19 activity can effectively treat obesity.

[0570] In a further aspect is provided a compound according to the first aspect, or a pharmaceutically acceptable salt, tautomer, stereoisomer or / V-oxide derivative thereof, for use in a method of treating obesity.

[0571] In a further aspect is provided a pharmaceutical composition according to the second aspect for use in a method of treating obesity.

[0572] Also provided in accordance with the invention is a method of treating obesity comprising administering to a subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative according to the first aspect, or an effective amount of a pharmaceutical composition according to the second aspect.

[0573] It is further demonstrated herein that the potent USP19 inhibitory compounds provided herein can effectively treat insulin resistance. Gene knockout studies have described an association between USP19 and insulin sensitivity (Coyne etal., supra). Coyne etal. describe an improvement in insulin sensitivity in USP19 knockout mice but, as noted above, it could not be assumed that the effects would translate to pharmacological inhibition of USP19 in wild-type subjects.

[0574] The data provided herein demonstrates that pharmacological inhibition of USP19 can effectively treat insulin resistance (e.g. type II diabetes).

[0575] In a further aspect is provided a compound as defined in relation to the first aspect of the invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer or / V-oxide derivative thereof, for use in a method of treating insulin resistance.

[0576] In a further aspect of the invention is provided a compound as defined in relation to the first aspect of the invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer or N- oxide derivative thereof, for use in a method of treating type II diabetes.

[0577] In a further aspect of the invention is provided a pharmaceutical composition according to the second aspect for use in a method of treating insulin resistance.

[0578] In a further aspect of the invention is provided a pharmaceutical composition according to the second aspect for use in a method of treating type II diabetes.

[0579] Also provided in accordance with the invention is a method of treating insulin resistance comprising administering to a subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or / V-oxide derivative as defined in relation to the first aspect of the invention, or an effective amount of a pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or / V-oxide derivative as defined in relation to the first aspect of the invention. Also provided in accordance with the invention is a method of treating type II diabetes comprising administering to a subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative as defined in relation to the first aspect of the invention, or an effective amount of a pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or / V-oxide derivative as defined in relation to the first aspect of the invention.

[0580] It is demonstrated in the accompanying Examples that compounds provided herein are potent USP19 inhibitors and further that potent USP19 inhibitory compounds effectively treat muscle loss in an in vivo disease model. Taken together, the in vitro and in vivo data demonstrate that compounds which potently inhibit USP19 activity can effectively treat muscular atrophy.

[0581] In a further aspect is provided a compound as defined in relation to the first aspect of the invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof, for use in a method of treating muscular atrophy.

[0582] In a further aspect the invention provides a compound as defined in relation to the first aspect, or a pharmaceutically acceptable salt, tautomer, stereoisomer or / V-oxide derivative thereof, for use in a method of treating cachexia or sarcopenia.

[0583] In a further aspect of the invention is provided a pharmaceutical composition according to the second aspect for use in a method of treating muscular atrophy.

[0584] In a further aspect of the invention is provided a pharmaceutical composition according to the second aspect for use in a method of treating cachexia or sarcopenia.

[0585] Also provided in accordance with the invention is a method of treating muscular atrophy comprising administering to a subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or / V-oxide derivative as defined in relation to the first aspect of the invention, or an effective amount of a pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or / V-oxide derivative as defined in relation to the first aspect of the invention. Also provided in accordance with the invention is a method of treating cachexia or sarcopenia comprising administering to a subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative as defined in relation to the first aspect of the invention, or an effective amount of a pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or / V-oxide derivative as defined in relation to the first aspect of the invention.

[0586] 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 disease (MND), Parkinson’s disease, dementia, or cancer.

[0587] In a further aspect, the invention provides a compound or composition according to any embodiment of the first aspect or second aspect for use in the treatment and / or prevention of Parkinson’s Disease. In a further aspect, the invention provides a method of treating or preventing Parkinson’s Disease comprising administering an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof, or pharmaceutical composition according to the invention to a subject. In a further aspect, the invention provides the use of a compound according to the invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof, in the manufacture of a medicament for the treatment of Parkinson’s Disease.

[0588] The compound or composition of the invention may be used in monotherapy and / or a combination modality. Suitable agents to be used in such combination modalities with compounds or compositions according to the invention include one or more of anti-cancer agents, anti-inflammatory agents, immuno-modulatory agents, for example immuno- suppressive agents, neurological agents, anti-diabetic agents, anti-viral agents, anti- bacterial agents and / or radiation therapy.

[0589] Agents used in combination with the compounds of the present invention may target the same or a similar biological pathway to that targeted by the compounds of the present invention or may act on a different or unrelated pathway. Depending on the disease to be treated, a variety of combination partners may be coadministered with the compounds of the present invention. The second active ingredient may include, but is not restricted to: alkylating agents, including cyclophosphamide, ifosfamide, thiotepa, melphalan, chloroethylnitrosourea and bendamustine; platinum derivatives, including cisplatin, oxaliplatin, carboplatin and satraplatin; antimitotic agents, including vinca alkaloids (vincristine, vinorelbine and vinblastine), taxanes (paclitaxel, docetaxel), epothilones and inhibitors of mitotic kinases including aurora and polo kinases; topoisomerase inhibitors, including anthracyclines, epipodophyllotoxins, camptothecin and analogues of camptothecin; antimetabolites, including 5-fluorouracil, capecitabine, cytarabine, gemcitabine, 6-mercaptopurine, 6-thioguanine, fludarabine, methotrexate and premetrexed; protein kinase inhibitors, including imatinib, gefitinib, sorafenib, sunitinib, erlotinib, dasatinib, and lapatinib; proteosome inhibitors, including bortezomib; histone deacetylase inhibitors, including valproate and SAHA; antiangiogenic drugs, including bevacizumab; monoclonal antibodies, including trastuzumab, rituximab, alemtuzumab, tositumomab, cetuximab, panitumumab; conjugates of myoclonal antibodies, including Gemtuzumab ozogamicin, Ibritumomab tiuxetan; hormonal therapies, including antiestrogens (tamoxifen, raloxifen, anastrazole, letrozole, examestane) antiandrogens (Flutamide, Biclutamide) and Luteinisng Hormone Analogues or antagonists.

[0590] In regard to aspects of the invention relating to therapeutic use of compounds according to the invention, the compounds may be administered to the subject in need of treatment in an “effective amount”. The term “effective amount” refers to the amount or dose of a compound which, upon single or multiple dose administration to a subject, provides therapeutic efficacy in the treatment of disease. Therapeutically effective amounts of a compound according to the invention can comprise an amount in the range of from about 0.1 mg / kg to about 20 mg / kg per single dose. A therapeutic effective amount for any individual patient can be determined by the healthcare professional by methods understood by the skilled person. The amount of compound administered at any given time point may be varied so that optimal amounts of the compound, whether employed alone or in combination with any other therapeutic agent, are administered during the course of treatment. It is also contemplated to administer compounds according to the invention, or pharmaceutical compositions comprising such compounds, in combination with any other cancer treatment, as a combination therapy. For combination therapies, the second drug may be provided in pharmaceutical composition with the present invention or may be provided separately.

[0591] Routes of administration

[0592] In certain preferred embodiments, treatment according to the invention comprises administering the therapeutic agent (that is, the compound, pharmaceutically acceptable salt, tautomer, stereoisomer or / V-oxide derivative, or pharmaceutical composition for use according to the invention) parenterally.

[0593] In certain preferred embodiments, the therapeutic agent is administered orally.

[0594] In certain preferred embodiments the therapeutic agent is administered intravenously. In certain preferred embodiments, the therapeutic agent is administered intraperitoneally. In certain preferred embodiments, the therapeutic agent is administered subcutaneously.

[0595] Dosage regimen

[0596] In certain preferred embodiments of the invention, treatment comprises administering the therapeutic agent (that is, the compound, pharmaceutically acceptable salt, tautomer, stereoisomer or / V-oxide derivative, or pharmaceutical composition for use according to the invention) at a dose in the range of 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 administration.

[0597] In certain preferred embodiments, treatment comprises administering the therapeutic agent at a dose in the range of from 25 to 125 mg / kg. In certain preferred embodiments, treatment comprises administering the therapeutic agent at a dose in the range of from 50 to 100 mg / kg.

[0598] In certain preferred embodiments, the method comprises administering the therapeutic agent at a dose of 75 mg / kg.

[0599] In certain preferred embodiments, treatment comprises administering the therapeutic agent (that is, the compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N- oxide derivative, or pharmaceutical composition for use according to the invention) 1 , 2, 3 or 4 times daily. In certain preferred embodiments, the therapeutic agent is administered once or twice daily, most preferably twice daily.

[0600] In certain preferred embodiments, the therapeutic agent is administered at a daily dosage in the range of from 10 to 300 mg / kg. That is, the total amount of active agent administered to the subject in one day is in the range of from 10-300 mg / kg. In such embodiments, the therapeutic agent may be administered once or multiple times per day as described herein, provided the total daily dosage is in the indicated range.

[0601] In certain preferred embodiments, the therapeutic agent is administered at a daily dosage in the range of from 50 to 250 mg / kg. In certain preferred embodiments, the therapeutic agent is administered at a daily dosage in the range of from 75 to 250 mg / kg. In certain preferred embodiments, the therapeutic agent is administered at a daily dosage in the range of from 100 to 200 mg / kg. In certain preferred embodiments, the therapeutic agent is administered at a daily dosage of 150 mg / kg.

[0602] In certain preferred embodiments, the therapeutic agent (for example a compound as provided herein) is administered at a dose of 75 mg / kg twice daily.

[0603] In regard to aspects of the invention relating to therapeutic use of compounds according to the invention, in preferred embodiments the subject to be treated is human.

[0604] In a further aspect the invention provides the compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to the first aspect or the pharmaceutical composition according the second aspect for use as a medicament.

[0605] In a further aspect the invention provides the compound, stereoisomer, tautomer, hydrate, M-oxide derivative or pharmaceutically acceptable salt according to the first aspect or the pharmaceutical composition according to the second aspect for use in treating muscular atrophy, obesity, insulin resistance, or type II diabetes.

[0606] In a further aspect the invention provides a method of treating obesity, insulin resistance, type II diabetes, or muscular 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 according to the first aspect or a pharmaceutical composition according to the second aspect.

[0607] In a further aspect the invention provides a method of reducing loss of muscle mass in a subject comprising administering to a subject in need thereof an effective amount of a compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to according to the first aspect or a pharmaceutical composition according to the second aspect.

[0608] When introducing elements of the present disclosure or the preferred embodiments(s) thereof, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0609] The foregoing detailed description has been provided by way of explanation and illustration, and is not intended to limit the scope of the appended claims. Many variations in the presently preferred embodiments illustrated herein will be apparent to one of ordinary skill in the art, and remain within the scope of the appended claims and their equivalents.

[0610] EXAMPLES

[0611] The present invention will now be described in relation to several examples.

[0612] The examples indicated below were synthesised according to the methods described subsequently. IC50 values were determined as described below and are represented in the following table:

[0613] Table 4. USP19 inhibition by exemplified compounds. The USP19 inhibitory activities are classified as the following:

[0614] USP19 activity was determined in a fluorescence polarisation (FP) homogeneous assay using the isopeptide Ubiquitin-Lys-TAMRA substrate (either AIIB-101 , Almac Sciences Scotland Limited, or U-558, Boston Biochem, both of which gave identical results). Full- length USP19 was purchased from Boston Biochem (E-576). Unless otherwise stated, all other reagents were purchased from Sigma. Enzymatic reactions were conducted in black flat bottom polystyrene 384-well plates (Nunc) and 30 pL total volume. USP19 (2.5 nM, 10 pL) was incubated in assay buffer (50 mM HEPES (pH 7.4), 150 mM NaCI, 5 mM DTT, 0.05% BSA (w / v), 0.05% CHAPS) in the presence or absence of inhibitor (10 pL). Inhibitors were stored as 10 mM DMSO stocks in an inert environment (low humidity, dark, low oxygen, rt) using the StoragePod® system (Roylan Developments) and serial dilutions were prepared in buffer just prior to the assay (from 200 μM to 2 pM, 8-18 data point curve). Following incubation at rt for 30 min, the enzymatic reactions were initiated by dispensing the Ub substrate (500 nM, 10 μL). FP was measured every 15 min over a period of 90 min (within the linear range of the assay) using a Synergy 4 plate reader (BioTek) exciting at 530 nm and measuring the amount of parallel and perpendicular light at 575 nm. The FP signal was subsequently normalised to the no compound control. Data were plotted and fitted, and the concentrations resulting in 50% inhibition (ICso) were calculated using the non-linear regression curve fitting model using Prism (GraphPad). ICso values for the inhibitors of the invention are compiled in Table 4 and represent the average of at least two duplicate experiments.

[0615] Cellular target engagement using western blotting

[0616] Cells from a breast cancer cell line, a neuroblastoma cell line and a mouse skeletal muscle cell line were treated with a USP19 inhibitor compound (ADC-141) for 2 h, lysed (lysis buffer: 50 mM Tris pH 7.4; 150 mM NaCI; 5 mM MgCI2; 0.5 mM EDTA; 0.5% NP-40; 10% glycerol; 2 mM DTT) and ubiquitin-propargylamine (Ub-PA; UbiQ) or ubiquitin-vinyl methyl ester (Ub-VME; Almac Sciences Scotland Limited) was then added. Samples were analysed by western blotting probing for USP19 (ECso determined by densitometry). In each cell line, the USP19 inhibitor compound showed good cell permeability and exhibited a low nanomolar ECso. The results for each cell line are shown in Figure 4.

[0617] Kinetic solubility (KSol) assay

[0618] Test compounds (5 pL of 10 mM DMSO stock) were added to 245 pL of phosphate- buffered saline (PBS) buffer solution at pH 7.4 (Dulbecco A) in a MultiScreen® Solubility filter plate (Millipore) and mixed at 300 rpm at rt on a plate shaker for 90 min. Meanwhile 5- point calibration curves for each compound were established in a mixture of acetonitrile / PBS buffer (top concentration 200 pM). After filtration and matrix match, the calibration and assay plates were analysed on a BioTek Synergy 4 plate reader (240-400 nm). Final concentration of the test compound in the filtrate was calculated using the slope of the calibration curve. Determination of intrinsic clearance in human / mouse / rat liver microsomes (HLM / MLM / RLM) Test compounds (final concentration = 1 pM; final DMSO concentration = 0.1%v / v) were incubated in 0.1 M PBS buffer solution at pH 7.4 (Dulbecco A) with human, mouse or rat liver microsomes (0.5 mg of protein / mL), as required, at 37 °C. Reactions were started by addition of NADPH in 0.1 M PBS buffer solution at pH 7.4 (Dulbecco A) (final concentration = 1 mM). 40 pL aliquots were removed at 2, 5, 10, 15, 20, 30, 40, and 50 min time points. Reactions were quenched with 80 pL of ice-cold methanol. Samples were subsequently frozen overnight, then centrifuged at 3500 rpm for 20 min at 4 °C. The supernatants were removed and transferred into analytical plates and analysed by LC / MS / MS.

[0619] LC / MS / MS method:

[0620] All samples were analysed on a Waters ACQUITY l-Class UPLC coupled to a Waters Xevo TQD mass spectrometer. A Waters BEH C18 column (2.1 x 50 mm, 1.7 pm) was used and the mobile phases were water and methanol containing 0.1%v / v formic acid as a modifier. Analysis was by multiple reaction monitoring and conditions were optimised for each test compound.

[0621] Data analyses:

[0622] From a plot of In peak area against time, the gradient of the line was determined. Subsequently, half-life and intrinsic clearance are calculated using the equations below: Eliminated rate constant (k) = (- gradient) where V = Incubation volume (pL) / number of cells

[0623] Cytochrome P450 (CYP) inhibition assay

[0624] CYP inhibition was assessed simultaneously for 5 major isoforms (CYP1 A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) using a commercially available mixture of the isoforms heterogeneously expressed in E. coll (Cypex). The method was adapted from Weaver R. et al., Drug Metab. Dispos. (2003), 31 , 955-966. Activity of each isoform was assessed by measuring the appearance of an isoform-specific metabolite using a selective and FDA accepted substrate for each isoform at a concentration around its published Km. Test compounds were assayed over a range of 8 concentrations (half-log dilutions) typically in the range of 50 pM to 0.023 pM final concentration. Test compounds at 4x the desired final concentration in 0.1 M PBS buffer solution at pH 7.4 (Dulbecco A) were incubated at 37 °C for 3 min with a 2x mixture of GYP isoforms and substrate mix. 4 mM NADPH solution in 0.1 M PBS buffer solution at pH 7.4 (Dulbecco A) was then added to start the reaction.

[0625] After 10 min incubation, the reaction was stopped by the addition of methanol containing an internal standard and 0.1%v / v formic acid. Metabolites for each GYP substrate were quantified by LC / MS / MS using a Waters ACQUITY l-Class coupled to a Waters Xevo TQD mass spectrometer. A Waters BEH C18 column (2.1 x 50 mm, 1 .7 pm) was used and mobile phases were water and methanol containing 0.1%v / v formic acid as a modifier.

[0626] Analysis was by multiple reaction monitoring and conditions were optimised for each metabolite.

[0627] Data analyses:

[0628] The GYP activities for test compounds at each concentration were converted to % of control activity (GA) and the log (concentration) vs activity was plotted and used to generate a pseudo-Hill plot. The slope and y axis intercept were used to calculate the IC5ovalues for test compounds against each GYP isoform according to the following equation: hERG ion channel inhibition assay

[0629] Test compounds were assayed at an external provider for human Ether-a-go-go- Related Gene (hERG) inhibition using the QPatch II (Sophion Bioscience) automated patch-clamp. Six-point concentration-response curves were generated with serial dilutions from a 100 pM maximum concentration of test compound to allow for IC5ovalue determination after curve fitting. Each data point is plotted from a minimum of n = 3 cells.

[0630] In vivo activity

[0631] The following data from an in vivo model demonstrates that a USP19 inhibitor can be used to treat muscle loss, to reduce fat deposition and to improve insulin sensitivity. These data demonstrate that compounds which potently inhibit USP19 activity can effectively treat muscular atrophy, obesity and / or insulin resistance.

[0632] Methods:

[0633] To induce muscle wasting, a 1 cm segment of the sciatic nerve in the thigh was removed from mice (male C57bl / 6 mice at 8-10 weeks of age; n=10 per group) under isoflurane anaesthesia and analgesia with carprofen. A sham operation was carried out in the opposite leg as a control.

[0634] Mice were randomised into Vehicle or Test groups, with all animals weighed to ensure a similar mean weight in each group. ADC-141 , a USP19 inhibitory compound at 75 mg / kg or Vehicle was administered i.p. twice daily starting from the evening post-operation.

[0635] Mice were sacrificed 14 days later. Fat pads, liver, gastrocnemius and tibialis anterior muscles were harvested. Tissue masses were measured in both groups.

[0636] To assess obesity and insulin resistance, a diet-induced obesity mouse model was used. The diet-induced obese (DIO) mouse is a well characterised model of obesity which exhibits increased adiposity, insulin resistance and glucose intolerance.

[0637] Male C57BL6 / J mice were continuously provided with high-fat diet (D12451 , 45% kcal as fat; Research Diets, New Jersey, USA) and filtered tap water ad libitum for the duration of the study. From day 0, mice were administered vehicle i.p. BID, USP19 inhibitor (ADC-141) i.p. BID at 5 mg / kg or 25 mg / kg, or positive control liraglutide 0.1 mg / kg s.c. BID.

[0638] Body weight was measured daily. On Day 13, body composition was be assessed by DEXA. On Day 15, fasting glucose and insulin levels were measured before and during an oral glucose tolerance test (OGTT) to assess improvements in glucose control. The OGTT was performed following an overnight fast. Hence, on Day 14 food (but not water) was removed beginning at approximately 16:45, immediately after the PM dose. An OGTT was performed the following morning (~16 h post fast). Mice were dosed with vehicle or test compound (starting at 08.45) to a timed schedule 30 min prior to the administration of the glucose challenge (2.0 g / kg p.o.). Blood samples were taken immediately prior to dosing (B1), immediately prior to glucose administration (B2) and 15, 30, 60 and 120 min after glucose administration.

[0639] ADC-141 is 1 -(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7- azaspiro[4.5]decan-10-yl)methyl)-4-phenyl-5-(piperazine-1 -carbonyl)pyridin-2(1 H)-one, corresponding to exemplary compound 212 provided in WO2018 / 020242. Both ADC-141 and the compounds provided herein are shown to have USP19 inhibitory activity using the fluorescence polarisation assay described above. It is therefore expected that the USP19 inhibitor compounds provided herein will show levels of efficacy similar to that described below for ADC-141 .

[0640] Results:

[0641] Muscular atrophy

[0642] As shown in Figure 1 , mice receiving a USP19 inhibitor had a significantly lower loss of muscle mass in the tibialis anterior muscle compared to mice receiving vehicle only. The sparing of muscle atrophy was evident both in terms of percentage mass (Figure 1 B) and absolute muscle mass (Figure 1C).

[0643] Muscle wasting was also reduced in the gastrocnemius muscle (Figure 2), though the trend did not reach significance. Again, mice receiving a USP19 inhibitor exhibited less muscle wasting both in terms of percentage mass (Figure 2B) and absolute muscle mass (Figure 2C).

[0644] These data demonstrate the pharmacological inhibition of USP19 in vivo can reduce muscular atrophy. The data indicate that pharmacological inhibition of USP19 will be especially effective at reducing muscle wasting as a result of inactivity, immobilisation or other disuse. On the basis of the results provided herein, pharmacological USP19 inhibition is also expected to be effective in treating muscular atrophy as a result of cachexia or sarcopenia.

[0645] Obesity

[0646] Figure 3A shows the mass of the epididymal fat pad in mice following 2 weeks of receiving a USP19 inhibitor or vehicle alone. As shown in Figure 3, mice which received the USP19 inhibitor had significantly smaller fat pads compared to vehicle treated mice.

[0647] Figure 3B shows an increase in liver mass in mice treated with a USP19 inhibitor. This is thought to be as a result of drug accumulation in the liver.

[0648] Figure 3C shows that mice receiving USP19 inhibitor exhibited a reduction in overall body weight gain when on a high-fat diet. Figures 3D and 3E show that this is due to a reduction in fat mass, but that lean body mass is preserved. DIO mice treated with USP19 inhibitor also exhibited a reduction in cumulative food intake compared to vehicle control mice. The data shown in Figure 3 demonstrates that pharmacological inhibition of USP19 can reduce fat accumulation in a wild-type background. Gene knockout studies have described a possible association between USP19 and fat accumulation (Coyne E. etal., Diabetologia (2019), 62, 136-146, incorporated herein by reference). However, acute or chronic pharmacological inhibition of an enzyme does not always result in similar physiological outcomes to genetic ablation.

[0649] The in vivo pharmacological inhibition data provided herein demonstrate that compounds which potently inhibit USP19 activity can effectively treat obesity.

[0650] Insulin resistance

[0651] Figure 5 shows the results of an oral glucose tolerance test (OGTT) in mice with diet- induced obesity. Untreated mice exhibit the symptoms of insulin-resistance characterised by elevated plasma glucose and plasma insulin levels. Mice treated with a USP19 inhibitor exhibit a dose-dependent improvement in OGTT response characterised by decreased plasma glucose and decreased plasma insulin.

[0652] The data shown in Figure 5 demonstrates that pharmacological inhibition of USP19 can reduce insulin resistance in a wild-type background. Gene knockout studies have also described an association between USP19 and insulin sensitivity (Coyne E. etal., supra). Coyne etal. describe an improvement in insulin sensitivity in USP19 knockout mice but, as noted above, it could not be assumed that the effects would translate to pharmacological inhibition of USP19 in wild-type subjects.

[0653] The data provided herein demonstrates that pharmacological inhibition of USP19 effectively treats insulin resistance.

[0654] The data presented herein demonstrates the therapeutic effects of pharmacological inhibition of USP19. Accordingly, the USP19 inhibitor compounds provided herein can effectively treat muscular atrophy, obesity and / or insulin resistance. EXPERIMENTAL SECTION

[0655] Abbreviations and Acronyms

[0656] AcOH: acetic acid; aq: aqueous; atm: atmosphere(s); Boc: tert-butyloxycarbonyl; br: broad; Cbz: carboxybenzyl; d: doublet (spectral); DCM: dichloromethane; Dess-Martin periodinane: 1 ,1 ,1 -tris(acetyloxy)-1 ,1 -dihydro- 1 ,2-benziodoxol-3-(1 H)-one; DIPEA: diisopropylethylamine; DMF: / V, / V-dimethylformamide; DMS: dimethylsulfide; DMSO: dimethylsulfoxide; dpm: dipivaloylmethanato; dppf: 1 ,1'-bis(diphenylphosphino)ferrocene; EDA: ethane-1 ,2-diamine; equiv.: equivalents; EtOAc: ethyl acetate; EtOH: ethanol; ESI: electrospray ionisation; h: hour(s); HATU: / V-[(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5- b]pyridin-1-ylmethylene]- / V-methylmethanaminium hexafluorophosphate / V-oxide; hept: heptet (spectral); HPLC: high pressure liquid chromatography; IPA: 2-propanol; LC: liquid chromatography; LCMS: liquid chromatography mass spectrometry; M: molar; m / z\ mass- to-charge ratio; MeCN: acetonitrile; MeOH: methanol; min: minute(s); mmol: millimole(s); MS: mass spectrometry; MTBE: methyl fert-butyl ether; m: multiplet (spectral); NBS: N- bromosuccinimide; NMR: nuclear magnetic resonance; pent: pentet (spectral); ppm: parts per million; q: quartet (spectral); RT: retention time; rt: room temperature; s: singlet; SCX: strong cation exchange; sept: septet (spectral); SFC: supercritical fluid chromatography; TBAF: tetra-n-butylammonium fluoride; TBDMS: tert-butyldimethylsilyl; Teoc: 2- (trimethylsilyl)ethoxycarbonyl; TFA: trifluoroacetic acid; THF: tetrahydrofuran; t: triplet; UV: ultraviolet; v / v: volume per unit volume; wt%: weight percent; w / v: weight per unit volume; w / w: weight per unit weight; XPhos-Pd-G2: chloro(2-dicyclohexylphosphino-2',4',6'- triisopropyl- 1 ,1 '-biphenyl)[2-(2'-amino-1 ,1 '-biphenyl)]palladium(l I).

[0657] General Experimental Conditions

[0658] Solvents and reagents

[0659] Common organic solvents that were used in reactions (e.g. THF, DMF, DCM, and MeOH) were purchased anhydrous from Sigma-Aldrich® in Sure / Seal™ bottles and were handled appropriately under nitrogen. Water was deionised using an Elga PURELAB Option-Q. All other solvents used (i.e. for work-up procedures and purification) were generally HPLC grade and were used as supplied from various commercial sources. Unless otherwise stated, all starting materials used were purchased from commercial suppliers and used as supplied. Automated synthesis

[0660] Automated experiments were carried out using a Synple 2 instrument. The system uses reagent cartridges that allow for the appropriate reactant(s) to be subjected to various synthetic reaction procedures (including / V-heterocycle formation, reductive amination, Mitsunobu, amide formation, deoxyfluorination, Suzuki, among others) in an automated manner that includes reaction, work-up and purification steps to give the desired reaction products. The system gives good reproducibility and allows for modification of some reaction parameters (e.g. time and temperature).

[0661] Microwave synthesis

[0662] Microwave experiments were carried out using a Biotage Initiator™ Eight instrument. The system gives good reproducibility and control at temperature ranges from 60-250 °C and pressures of up to a maximum of 20 bar.

[0663] Flash chromatography

[0664] Purification of compounds by flash chromatography was achieved using a Biotage Isolera Four system. Unless otherwise stated, Biotage Star Silica D cartridge columns (10-340 g) or Grace GraceResolv cartridge columns (4-330 g) were used along with the stated solvent system and an appropriate solvent gradient depending on compound polarity. In the case of some more polar and basic compounds, Biotage Star KP-Amino D cartridge columns (11-28 g) were used.

[0665] NMR spectroscopy

[0666] 1H NMR spectra were recorded at ambient temperature using a Bruker Avance III (400 MHz) or Bruker Ascend (500 MHz) spectrometer. All chemical shifts (5) are expressed in ppm. Residual solvent signals were used as an internal standard and the characteristic solvent peaks were corrected to the reference data outlined in J. Org. Chem., 1997, 62, p7512-7515; in other cases, NMR solvents contained tetramethylsilane, which was used as an internal standard.

[0667] Liquid Chromatography Mass Spectrometry (LCMS)

[0668] Liquid Chromatography Mass Spectrometry (LCMS) experiments to determine retention times (RT) and associated mass ions were performed using the following methods: Method A: The system consisted of an Agilent Technologies 6140 single quadrupole mass spectrometer linked to an Agilent Technologies 1290 Infinity LG system with UV diode array detector and autosampler. The spectrometer consisted of a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. LCMS experiments were performed on each sample submitted using the following conditions: LC Column: Zorbax Eclipse Plus C18 RRHD, 1.8 μm, 50 x 2.1 mm maintained at 40 °C. Mobile phases: A) 0.1% (v / v) formic acid in water; B) 0.1% (v / v) formic acid in MeCN.

[0669] Gradient Time (min) Flow (mL / min) %A %B 0.00 1.0 95 5

[0670] 1.80 1.0 0 100

[0671] 2.20 1.0 0 100

[0672] 2.21 1.0 95 5

[0673] 2.50 1.0 95 5

[0674] Method B The system consisted of an Agilent Technologies 6130 quadrupole mass spectrometer linked to an Agilent Technologies 1290 Infinity LC system with UV diode array detector and autosampler. The spectrometer consisted of an electrospray ionization source operating in positive and negative ion mode. LCMS experiments were performed on each sample submitted using the following conditions: LC Column: Agilent Eclipse Plus C18 RRHD, 1 .8 μm, 50 x 2.1 mm maintained at 40 °C. Mobile phases: A) 0.1% (v / v) formic acid in water; B) 0.1% (v / v) formic acid in MeCN.

[0675] Gradient Time (min) Flow (mL / min) %A %B

[0676] 0.00 0.5 80 20

[0677] 1.80 0.5 0 100

[0678] 2.20 0.5 0 100

[0679] 2.50 0.5 80 20

[0680] 3.00 0.5 80 20

[0681] Method C: The system consisted of a Waters ACQUITY QDa mass spectrometer linked to a Waters ACQUITY l-Class UPLC system with TUV detector. The spectrometer consisted of an electrospray ionization source operating in positive and negative ion mode. LCMS experiments were performed on each sample submitted using the following conditions: LC Column: Zorbax Eclipse Plus C18 RRHD, 1.8 μm, 50 x 2.1 mm maintained at 40 °C. Mobile phases: A) 0.1% (v / v) formic acid in water; B) 0.1% (v / v) formic acid in MeCN.

[0682] Gradient Time (min) Flow (mL / min) %A %B

[0683] 0.00 0.8 95 5

[0684] 1.80 0.8 0 95

[0685] 2.20 0.8 0 95

[0686] 2.30 0.8 95 5

[0687] 2.50 0.8 95 5

[0688] The system consisted of either an Agilent Technologies 1100 Series LC / MSD system with UV diode array detector and evaporative light scattering detector (DAD / ELSD) and Agilent LC / MSD VL (G1956A), SL (G1956B) mass spectrometer or an Agilent 1200 Series LC / MSD system with DAD / ELSD and Agilent LC / MSD SL (G6130A), SL (G6140A) mass spectrometer. All of the LCMS data were obtained using the atmospheric pressure chemical ionization mode with positive and negative ion mode switching with a scan range of mlz 80-1000. LCMS experiments were performed on each sample submitted using the following conditions: LC Column: Zorbax SB-C18 RRHD, 1 .8 μm, 4.6 x 15 mm. Mobile phases: A) 0.1% (v / v) formic acid in water; B) 0.1% (v / v) formic acid in MeCN.

[0689] Gradient Time (min) Flow (mL / min) %A %B

[0690] 0.00 3.0 100 0

[0691] 1.50 3.0 0 100

[0692] 1.80 3.0 0 100

[0693] 1.81 3.0 100 0

[0694] Method E The system consisted of Shimadzu Prominence HPLC / Applied Biosystem

[0695] LCMS / MS API 2000 instruments. Spectrometer ionization technique: ESI using API source operating in positive ion mode. LCMS experiments were performed on each sample submitted using the following conditions: LC Column: XBridge C18, 5 μm, 4.6 x 50 mm maintained at 25 °C. Mobile phases: A) 10 mM ammonium acetate (aq); B) MeCN.

[0696] Gradient Time (min) Flow (mL / min) %A %B

[0697] 0.01 1.2 90 10

[0698] 1.50 1.2 70 30 3.00 1.2 10 90

[0699] 4.00 1.2 10 90

[0700] 5.00 1.2 90 10

[0701] Method F: The system consisted of a Waters ACQUITY SQD 2 mass spectrometer linked to a Waters ACQUITY H-Class UPLC system with TUV detector. The spectrometer consisted of an electrospray ionization source operating in positive and negative ion mode. LCMS experiments were performed on each sample submitted using the following conditions: LC Column: XBridge C18, 3.5 μm, 3.0 x 50 mm maintained at 50 °C. Mobile phases: A) 5 mM ammonium acetate (aq); B) 5 mM ammonium acetate in 9:1 MeCN / water.

[0702] Gradient Time (min) Flow (mL / min) %A %B 0.00 1.2 95 5

[0703] 0.75 1.2 95 5

[0704] 1 .00 1.2 70 30

[0705] 2.00 1.2 2 98

[0706] 2.50 1.2 2 98

[0707] 2.75 1.2 95 5

[0708] 3.00 1.2 95 5

[0709] Preparative High Pressure Liquid Chromatography

[0710] The system consisted of an Agilent Technologies 6120 single quadrupole mass spectrometer linked to an Agilent Technologies 1200 Preparative LG system with multiple wavelength detector and autosampler. The mass spectrometer used a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. Fraction collection was mass-triggered (multimode positive and negative ion). Purification experiments, unless otherwise stated, were performed under basic conditions at an appropriate solvent gradient that was typically determined by the retention time found using an appropriate LCMS method. In cases where the basic conditions were unsuccessful, acidic conditions were employed.

[0711] Basic conditions: LC Column: Waters XBridge™ Prep C18 5 pm OBD™ 30 x 100 mm column at rt. Mobile phase: A) 0.1% (v / v) ammonium hydroxide in water; B) 0.1% (v / v) ammonium hydroxide in 95:5, MeCN / water. Total experiment time was ca. 10 min and a generic method is shown: Gradient Time (min) Flow (mL / min) %A %B

[0712] 0.00 20.0 50 50

[0713] 3.00 20.0 12 88

[0714] 5.00 20.0 12 88

[0715] 7.00 20.0 0 100

[0716] 8.0 20.0 0 100

[0717] 8.20 20.0 50 50

[0718] Chiral separation of stereoisomers by supercritical fluid chromatography (SFC)

[0719] The separation of mixtures of stereoisomers was performed using the following general procedure. The mixture of stereoisomers was dissolved to 50 mg / mL in MeOH and purified by SFC under the stated conditions. Combined fractions of each of stereoisomer were evaporated to near dryness using a rotary evaporator, transferred into final vessels using DCM, which was removed under a stream of compressed air at 40 °C, before being stored in a vacuum oven at 40 °C and 5 mbar for 16 h.

[0720] Chiral separation of stereoisomers by HPLC

[0721] The separation of mixtures of stereoisomers was performed using the following general procedure. The mixture of stereoisomers was dissolved to 66 mg / mL in MeOH and purified by HPLC under the stated conditions. Combined fractions of each of stereoisomer were evaporated to near dryness using a rotary evaporator, transferred into final vessels using MeOH, which was removed under a stream of compressed air at 35 °C, before being stored in a vacuum oven at 35 °C and 5 mbar for 16 h.

[0722] Chiral purity analysis

[0723] After chiral separation of mixtures of stereoisomers, each stereoisomer was analysed to determine chiral purity using appropriate analytical SFC or HPLC methods under the stated conditions.

[0724] Nomenclature

[0725] Unless otherwise indicated, the nomenclature of structures was determined using the ‘Convert Structure to Name’ function of ChemDraw Professional 21 .0 (CambridgeSoft / PerkinElmer). Stereochemical configuration for the Examples was determined by inferring from the intermediate precursors used to prepare them for which either the absolute stereochemistry was already known (i.e. commercial reagents) or it was inferred from previous work (e.g. WO 2022 / 200523 intermediates). In the cases where new intermediates were used, the relative potency of the enantiomeric pairs allowed for assignment by comparing with similar analogues from previous work. However, it should be noted that for some or all of the Examples herein, it may be the case that they have been assigned with the incorrect configuration due to an error in this process and therefore, it is possible that these compounds have the opposite configuration to that stated. In any case, the most potent stereoisomers are preferred and expressly included herein.

[0726] General procedures

[0727] General Procedure 1: Boc deprotection to free base

[0728] The Boc protected amine (1 equiv.) was dissolved in DOM. TFA or 4 M HOI in 1 ,4-dioxane was added (as stated). The reaction was stirred at rt for 1-24 h. The mixture was loaded onto 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 / 7 M NH3 in MeOH. The ammoniacal fractions were concentrated in vacuo to give the desired product that was used directly in the next step or repurified under the stated conditions, as necessary.

[0729] General Procedure 2: Automated synthesis using Synple 2 for N-heterocycle formation This procedure utilised the Synple 2 integrated console for “capsule-based automated organic synthesis” (Chem. Sci., 2021 , 12, 6977-6982) for the purpose of / V-heterocycle formation using the Sn amine protocol (SnAP) chemistry (Org. Lett., 2014, 16, 1236-1239). The appropriate aldehyde and a stirring bar were placed in the reaction vial and the line cap was attached. The appropriate reagent cartridge was scanned to load the reaction procedure and conditions, placed into the cartridge holder and locked into place. The solvents used for the procedure were attached to the appropriate solvent lines: DCM (S1), hexafluoroisopropanol (S2), MeOH (S3), 35:65 diisopropylamine / THF (S4). Nitrogen flow was applied. The reaction procedure was started using the standard conditions (unless otherwise stated) by pressing “Start”. At the end of the sequence, the resultant product solution was analysed by LCMS to determine if further purification (i.e. flash chromatography or preparative HPLC) was required. The solvents were removed in vacuo to give the desired product that was used directly in the next step or repurified under the stated conditions, as necessary. General Procedure 3: Urea formation via a carbamoyl chloride intermediate

[0730] To a solution of triphosgene (0.3-0.6 equiv.) in MeCN at 0 °C was added pyridine or DIPEA (2-5 equiv.) and the solution stirred for 10 min. A solution of the appropriate first amine (1 equiv.) in MeCN was added and the reaction stirred while warming to rt for 1 -24 h. The mixture was added to the appropriate second amine (1 equiv.) followed by addition of DIPEA (2-5 equiv.) and stirred for a further 1-24 h. Saturated NaHCO3(aq) was added. The resulting mixture was extracted with DCM (x 3) using a phase separator, the combined organic phase was concentrated under reduced pressure, and the residue was purified by flash chromatography to give the desired product.

[0731] General Procedure 4: Trifluoroacetamide deprotection to free base

[0732] The appropriate trifluoroacetamide (1 equiv.) was dissolved in a 10:1 mixture of MeOH / water and potassium carbonate (5-10 equiv.) was added. The resulting mixture was stirred at rt or up to 50 °C for 1-18 h, as required. The solvents were removed in vacuo and the remaining residue was partitioned between DCM and water or DCM and saturated NaHCO3(aq) solution, the resultant biphasic mixture was separated, the aqueous phase was extracted using further DCM (x 2), and the combined organic phase was concentrated in vacuo. [Alternatively, the reaction mixture was diluted with DCM and loaded onto 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 / 7 M NH3in MeOH. The ammoniacal fractions were concentrated in vacuo]. The residue was purified by flash chromatography to give the desired product.

[0733] General Procedure 5: HATU coupling

[0734] The appropriate amine (1 equiv.), carboxylic acid (1.0-1 .5 equiv.) and HATU (1 -1.5 equiv.) were dissolved in DCM and DIPEA (1-4 equiv.) was added. The reaction was stirred for 1 - 24 h, as required, before being quenched by the addition of saturated NaHCO3(aq). The resulting mixture was extracted with DCM (x 3) using a phase separator. The combined organic extracts were concentrated under reduced pressure and the remaining residue was purified by flash chromatography to give the desired product.

[0735] General Procedure 6: Carbamoyl chloride formation

[0736] To a stirred solution of triphosgene (1 equiv.) in DCM was added pyridine (10 equiv.) dropwise at 0 °C. After 30 min, a solution of the appropriate amine (1 equiv.) in DCM, or amine salt (1 equiv.) and DI PEA (1.5 equiv.) in DCM, was added dropwise at 0 °C. The temperature was allowed to increase to rt and stirred for 1-18 h, as required. The reaction mixture was quenched by addition of 1 M HCI(aq) and the resultant mixture was extracted with DCM (x 3) using a phase separator. The combined organic phase was concentrated in vacuo to give the desired product that was typically used in the next step without further purification.

[0737] General Procedure 7: Urea formation using a carbamoyl chloride intermediate The appropriate carbamoyl chloride (1-2 equiv.), amine or amine.HCI salt (1-3 equiv.) and DIPEA (2-6 equiv.) were stirred in the stated solvent at rt for 1-18 h, as required, before quenching with 0.5 M HCI(aq) and extracted with DCM (x 3) using a phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography to give the desired product.

[0738] General Procedure 8: Reductive alkylation of amine

[0739] A solution of the amine (1 equiv.) and appropriate aldehyde or ketone (5 equiv.) in MeOH was stirred at rt. After 2 h, sodium triacetoxyborohydride (10 equiv.) was added. After a further 1 h, reaction progression was checked by LCMS. Depending on reaction progression, further portion(s) of aldehyde / ketone and sodium triacetoxyborohydride may be added until reaction completion. The reaction mixture was diluted with MeOH and loaded onto 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 / 7 M NH3 in MeOH. The ammoniacal fractions were concentrated in vacuo and further purified by flash chromatography (typically 0-20% MeOH in DCM or 0-20% MeOH in EtOAc) to give the desired product.

[0740] General Procedure 9: Cbz deprotection to free base using H-Cube® Pro

[0741] The Cbz protected amine (e.g. 1 .0 mmol) was dissolved in EtOAc (20 mL) / EtOH (20 mL) and the solution was passed through an H-Cube® Pro hydrogenation flow reactor containing a 10%w / w Pd / C cartridge with a flow rate of 1 mL / min at 60 °C and using the “controlled mode” setting for 1 bar of hydrogen. Reaction completion was determined by LCMS and the material was passed through the system again, if necessary, until complete reaction. The solvents were removed in vacuo and the remaining residue was purified by flash chromatography to give the desired product.

[0742] Step 1: 3-(Hydroxymethyl)-6-phenylpyridin-2(1H)-one: To a solution of 2-oxo-6-phenyl-1 ,2- dihydropyridine-3-carboxylic acid (53.3 g, 248 mmol) [commercially available] in THF (1200 mL) was added 1 M borane. DMS complex in THF solution (991 ml_, 991 mmol), and the suspension was stirred at rt. After 18 h, MeOH was slowly added until gas evolution ceased. The reaction mixture was partitioned between EtOAc and brine, separated, the organic phase was dried (Na2SO4), filtered, and evaporated to dryness and purified by flash chromatography (0-5% MeOH in DCM) to give the title compound (33.1 g, 66%). LCMS (Method D): RT= 0.69 min, m / z = 202 [M+H]+.

[0743] Step 2: 2-Oxo-6-phenyl-1 ,2-dihydropyridine-3-carbaldehyde: To a stirred solution of 3- (hydroxymethyl)-6-phenylpyridin-2(1 H)-one (8.0 g, 40 mmol) in DCM (250 mL) at 0 °C was added Dess-Martin periodinane (22.0 g, 52 mmol). After 10 h, 2 M Na2CO3(aq> (300 mL) was added. After 2 h, the resultant precipitate was filtered and dried under vacuum to give the title compound (7.2 g, 90%).1H NMR (400 MHz, DMSO-ofe): δ 12.61 (s, 1 H), 10.14 (s, 1 H), 8.05 - 7.96 (m, 4H), 7.70 (m, 1 H), 7.55 (m, 1 H), 6.80 (m, 1 H).

[0744] Step 3: tert-Butyl 4-((2-oxo-6-phenyl-1,2-dihydropyridin-3-yl)methyl)piperazine-1- carboxylate: To a stirred solution of 2-oxo-6-phenyl-1 ,2-dihydropyridine-3-carbaldehyde (1.5 g, 7.5 mmol) in DCM (50 mL) was added tert-butyl piperazine-1 -carboxylate (2.1 g, 11 .2 mmol) followed by sodium triacetoxyborohydride (4.8 g, 22.5 mmol). After 3 h, the reaction mixture was heated to 55 °C. After a further 10 h, saturated NaHCO3(aq) (150 mL) was added with care and stirred for an additional 30 min. The resultant biphasic mixture was separated, the organic phase was dried (Na2SO4), filtered, evaporated to dryness, and purified by flash chromatography (0-5% MeOH in DCM) to give the title compound (1 .6 g, 58%). LCMS (Method D): RT= 0.85 min, m / z = 370 [M+H]+.

[0745] Step 4: 6-Phenyl-3-(piperazin-1 -ylmethyl)pyridin-2(1 H)-one dihydrochloride: Prepared according to General Procedure 1 using tert-butyl 4-((2-oxo-6-phenyl-1 ,2-dihydropyridin-3- yl)methyl)piperazine-1-carboxylate (50.0 mg, 0.14 mmol), 4 M HCI in 1 ,4-dioxane (3 mL) and DCM (4 mL) but without SCX-2 purification to give the title compound (46.3 mg, quantitative) [assumed dihydrochloride salt]. LCMS (Method A): RT = 0.41 min, m / z = 270 [M+H]+.

[0746] Intermediate 2: 3-((2,2-DimethylDiDerazin-1-yl)methyl)-6-DhenylDyridin-2(1 H)-one

[0747] The title compound was prepared similarly to 6-phenyl-3-(piperazin-1 -ylmethyl)pyridin- 2(1 H)-one (Intermediate 1 ) except using fert-butyl 3, 3-dimethylpiperazine-1 -carboxylate [commercially available] instead of fert-butyl piperazine-1 -carboxylate (Step 3) and using TFA instead of 4 M HCI in 1 ,4-dioxane and including SCX-2 purification (Step 4) to give the title compound as the free base. LCMS (Method A): RT = 0.44 min, m!z = 298 [M+H]+.

[0748] Intermediate 3: 3-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-6-DhenylDyridin-2(1 H)-one

[0749] Step 1: 3-(Chloromethyl)-6-phenylpyridin-2(1H)-one: To a stirred solution of 3- (hydroxymethyl)-6-phenylpyridin-2(1 H)-one (33.0 g, 165 mmol) in DCM (1200 mL) was added thionyl chloride (200 mL, 2.78 mol). The reaction mixture was heated to 40 °C. After 24 h, the volatiles were removed in vacuo using MeCN to assist with coevaporation to give the title compound (36.2 g, quantitative) that was used directly in the next step without purification.

[0750] Step 2: tert-Butyl 6-((2-oxo-6-phenyl-1,2-dihydropyridin-3-yl)-methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate: To a solution of 3-(chloromethyl)-6-phenylpyridin- 2(1 H)-one (8.5 g, 39 mmol) in MeCN (300 mL) was added DIPEA (15 g, 116 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (9.3 g, 39 mmol) [commercially available] and the suspension was stirred at 80 °C for 18 h. The reaction mixture was concentrated and partitioned between DCM and brine, separated, the organic phase was dried (Na2SO4), filtered, evaporated to dryness, and purified by flash chromatography (0- 5% MeOH in DCM) to give the title compound (10.1 g, 61%). LCMS (Method D): RT = 0.64 min, m / z = 424 [M+H]+. Step 3: 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1H)-one: Prepared according to General Procedure 1 using fert-butyl 6-((2-oxo-6-phenyl-1 ,2-dihydropyridin-3- yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (100.0 mg, 0.24 mmol), TFA (1.1 mL) and anhydrous DOM (1 mL) to give the title compound (75.5 mg, 99%). LCMS (Method A): RT = 0.50 min, m / z = 324 [M+H]+.

[0751] Intermediate 4: 3- ,9-Di -one

[0752] Step 1: tert-Butyl 6-((2-oxo-1,2-dihydroquinolin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9- carboxylate: To a solution of 2-oxo-1 ,2-dihydroquinoline-3-carbaldehyde [commercially available] (1 .50 g, 8.7 mmol) in 1 ,2-dichloroethane (50 mL) was added tert-butyl 6,9- diazaspiro[4.5]decane-9-carboxylate (3.10 g, 13.5 mmol) followed by portionwise addition of sodium triacetoxyborohydride (5.50 g, 26.1 mmol) and the suspension was stirred at 60 °C. After 18 h, the solvents were removed in vacuo and the remaining residue was partitioned between EtOAc and brine, and separated. The organic phase was washed using saturated NaHCO3(aq), dried (Na2SO4), filtered, evaporated to dryness, and purified by flash chromatography (0-5% MeOH in DOM) to give the title compound (0.50 g, 14%). LCMS (Method D): RT= 0.75 min, m / z = 398 [M+H]+.

[0753] Step 2: 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)quinolin-2(1H)-one: Prepared according to General Procedure 1 using tert-butyl 6-((2-oxo-1 ,2-dihydroquinolin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate (100.0 mg, 0.25 mmol), TFA (0.5 mL) and anhydrous DCM (1 mL) to give the title compound (75.1 mg, quantitative). LCMS (Method A): RT = 0.47 min, m / z = 298 [M+H]+.

[0754] Intermediate 5: 3-((6,9-Diazaspiro[4.5ldecan-6-yl)methyl)-1 ,5,7,8-tetrahydro-2H-pyrano[4,3- idin-2-one Step 1: tert-Butyl 6-((2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate:To a solution of 2-oxo-2,5,7,8-tetrahydro-1 H- pyrano[4,3-b]pyridine-3-carbaldehyde [commercially available] (0.50 g, 2.8 mmol) in 1 ,2- dichloroethane (30 mL) was added tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (1.00 g, 4.2 mmol) followed by portionwise addition of sodium triacetoxyborohydride (1.80 g, 8.4 mmol) and the suspension was stirred at 60 °C. After 18 h, the solvents were removed in vacuo and the remaining residue was partitioned between EtOAc and brine, and separated. The organic phase was washed using saturated NaHCO3(aq), dried (Na2SO4), filtered, evaporated to dryness, and purified by flash chromatography (0-10% MeOH in DCM) to give the title compound (0.10 g, 9%). LCMS (Method D): RT = 1.01 min, m / z = 404 [M+H]+.

[0755] Step 2: 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)- 1,5, 7,8-tetrahydro-2H-pyrano[4,3- b]pyridin-2-one: Prepared according to General Procedure 1 using terf-butyl 6-((2-oxo- 1 ,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9- carboxylate (100 mg, 0.25 mmol), TFA (0.5 mL) and DCM (1 mL) to give the title compound (30 mg, 40%). LCMS (Method B): RT = 0.27 min (solvent front), m / z = 304 [M+H]+.

[0756] Intermediate 6: tert- Butyl ((2S,4fl)-2-(2,5-difluoroDhenyl)DiDeridin-4-yl)(methyl)carbamate

[0757] Step 1 : 2-(2,5-Difluorophenyl)isonicotinic acid: To a solution of 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) was added Pd(dppf)Cl2 (47.5 g, 5 mol%) and potassium phosphate tribasic (735 g, 3.46 mol). The reaction mixture was refluxed for 16 h and evaporated to dryness. The residue was dissolved in hot water (4 L) and filtered. The pH of the filtrate was adjusted to pH 3 using HCI(aq), the precipitate was filtered, washed with water (2 L), and dried in a vacuum oven to give the title compound (260 g, 95%). LCMS (Method D): RT = 1.15 min, m / z = 236 [M+H]+.

[0758] 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) was added 10% w / w Pd / C (6.0 g, 10%w / w) and the resultant mixture was reacted with hydrogen (50 atm) at 50 °C in an autoclave. After the reaction was complete (determined by1H NMR sampling of the reaction mixture to monitor for starting material consumption), the solvent was evaporated to dryness to give crude title compound (65.3 g, assumed 0.255 mol, contaminated with residual Pd / C catalyst) that was used in the next step without further purification.

[0759] Step 3: rac-(2S,4R)-1-((Benzyloxy)carbonyl)-2-(2,5-difluorophenyl)piperidine-4-carboxylic acid: To a suspension of rac-(2S,4F?)-2-(2,5-difluorophenyl)piperidine-4-carboxylic acid (284 g, assumed 1.11 mol, contaminated with Pd / C) in 1 ,4-dioxane (5.0 L) and water (2.5 L) added NaOH (221 g, 5.54 mol). The reaction mixture was cooled to 0 °C followed by dropwise addition of benzyl chloroformate (282 g, 1.66 mol). After 16 h, the resultant mixture was evaporated to dryness, the residue dissolved in water (5 L) and extracted using MTBE (2 L). The aqueous phase was made acidic (pH = 3) using HCI(aq) and extracted with ethyl acetate (3 L). The organic phase was dried (Na2SO4), filtered, and evaporated to dryness to give the title compound (313 g, 75.3%) as white solid. LCMS (Method D): RT= 1 .27 min, m / z = 374 [M-H]\

[0760] Step 4: rac-Benzyl (2S,4R)-2-(2,5-difluorophenyl)-4-(((2- (trimethylsilyl)ethoxy)carbonyl)amino)piperidine-1-carboxylate:To a suspension of rac- (2S,4R)-1 -((benzyloxy)carbonyl)-2-(2,5-difluorophenyl)piperidine-4-carboxylic acid (313 g, 0.834 mol) in toluene (4.0 L) was added triethylamine (253 g, 2.50 mol), followed by DPPA (298 g, 1 .08 mol). The reaction mixture heated at 75 °C for 4 h until gas evolution ceased, followed by addition of 2-(trimethylsilyl)ethanol (296 g, 2.50 mol). The reaction mixture was heated at 110 °C for 24 h. The reaction mixture was extracted using 15% w / v NaOH(aq) (2 x 2 L), the organic phase was dried (Na2SO4), filtered, and evaporated to dryness to give the title compound (375 g, 92%).1H NMR (400 MHz, CDCI3): δ 7.31 - 7.16 (m, 5H), 6.99 - 6.84 (m, 3H), 5.28 (m, 1 H), 5.08 (m, 2H), 4.46 (m, 1 H), 4.16 - 4.07 (m, 3H), 3.90 (m, 1 H), 3.50 (m, 1 H), 2.29 - 2.09 (m, 3H), 1 .64 (m, 1 H), 0.90 (m, 1 H), 0.04 (s, 9H).

[0761] 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) was added 1 M TBAF in THF solution (2292 mL, 2.29 mol) and the resultant mixture was heated at 55 °C for 48 h. The reaction mixture was concentrated in vacuo, the remaining residue was partitioned between EtOAc (3 L) and 15% w / v NH4CI(aq) (2 L) and separated. The organic phase was washed using water (1 L) followed by brine (1 L), dried (NaaSO^, filtered, and the solvent was concentrated to dryness. The resultant crude rac- benzyl (2S,4fi)-4-amino-2-(2,5-difluorophenyl)piperidine-1 -carboxylate material 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 h, the solvent was evaporated and the remaining residue was purified by flash chromatography (0-20% EtOAc in hexane) to give the title compound (250 g, 74%). LCMS (Method D): RT = 1.32 min, mlz= 347 [M-Boc+H]+.

[0762] Step 6: rac-(2S,4R)-Benzyl 4-((tert-butoxycarbonyl)(methyl)amino)-2-(2,5- difluorophenyl)piperidine-1 -carboxylate: To a stirred 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_) at 0 °C was added NaH (55% in mineral oil, 2.7 g, 61.7 mmol). After 3 h, iodomethane (9.6 g, 67.3 mmol) was added and the temperature was allowed to increase to rt. After a further 24 h, the reaction mixture was partitioned between EtOAc (400 mL) and 15% w / v NH4CI(aq) (500 mL), separated, the organic phase was washed with water (500 mL) and brine (500 mL), dried (Na2SO4), and the solvents were removed in vacuo. The remaining residue was purified by flash chromatography (0-20% EtOAc in hexane) to give the title compound (22.1 g, 86%). LCMS (Method D): RT = 1.61 min, m / z = 361 [M-Boc+H]+.

[0763] Step 7: Benzyl (2S,4R)-4-((tert-butoxycarbonyl)(methyl)amino)-2-(2,5- difluorophenyl)piperidine- 1 -carboxylate: rao-(2S,4R)-benzyl 4-((tert- butoxycarbonyl)(methyl)amino)-2-(2,5-difluorophenyl)piperidine-1 -carboxylate (18.0 g) was resolved into the single stereoisomers by chiral HPLC using a CHIRALCEL® OJ-H (20 mm x 250 mm, 5 pm) column with isocratic solvent conditions: 90:5:5 hexane / IPA / MeOH. The first eluted material (RT = 16.12 min) afforded the title compound (6.95 g). LCMS (Method D): RT = 1.61 min, m / z= 361 [M-Boc+H]+; and the second eluted material (RT = 24.90 min) afforded benzyl (2R,4S)-4-((tert-butoxycarbonyl)(methyl)amino)-2-(2,5- difluorophenyl)piperidine-1 -carboxylate (7.74 g). LCMS (Method D): RT = 1.61 min, mlz = 361 [M-Boc+H]+.

[0764] Step 8: tert-Butyl ((2S,4R)-2-(2,5-difluorophenyl)piperidin-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 to this solution was added 10%w / w Pd / C (0.7 g) and the reaction mixture was hydrogenated (~1 atm, balloon) at rt. After 24 h, the reaction mixture was filtered through a pad of silica and evaporated to dryness to give the title compound (4.59 g, 93%). Chiral HPLC (CHIRALCEL® OJ-H (4.6 mm x 250 mm, 5 pm) column with isocratic solvent conditions: 95:2.5:2.5 hexane / IPA / MeOH): RT = 9.05 min. LCMS (Method D): RT = 1.04 min, mlz = 327 [M+H]+. [a]D21= +34.6 (c 0.25 in CHCI3).

[0765] Intermediate 7: 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-1 -methyl-2-DhenylDyridin-4(1 H)- one

[0766] Step 1: 5-(Hydroxymethyl)-2-phenylpyridin-4(1H)-one: To a solution of ethyl 4-oxo-6- phenyl-1 ,4-dihydropyridine-3-carboxylate (30.4 g, 125 mmol) [prepared according to Chem.Pharm.Bull., 1995, 43, p450-460] in THF (1100 mL) was added 1.0 M borane.DMS complex in THF solution (485 mL, 485 mmol), and the suspension was stirred at rt. After 18 h, MeOH was slowly added until gas evolution ceased. The resulting mixture was partitioned between EtOAc and brine, and the organic layer was dried (NaaSCU). The solvents were removed under vacuum and the residue was purified by flash chromatography (0-10% EtOAc in hexane) to give the title compound (16.5 g, 66%). LCMS (Method D): RT= 0.59 min, m / z = 202 [M+H]+.

[0767] Step 2: 5-(Chloromethyl)-2-phenylpyridin-4(1H)-one: To a solution of 5-(hydroxymethyl)-2- phenylpyridin-4(1 Hj-one (16.3 g, 82 mmol) in DCM (600 mL) was added thionyl chloride (100 mL, 1 .39 mol) and the suspension was stirred at 40 °C. After 24 h, the volatiles were removed in vacuo using MeCN to assist with coevaporation to give the title compound (18.0 g, quantitative) that was used directly in the next step without purification.

[0768] Step 3: tert-Butyl 6-((4-oxo-6-phenyl-1,4-dihydropyridin-3-yl)-methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate: To a solution of 5-(chloromethyl)-2-phenylpyridin- 4(1 H)-one (8.5 g, 39 mmol) in MeCN (300 mL) was added DIPEA (15 g, 116 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (9.3 g, 39 mmol), and the resulting suspension was stirred at 80 °C. After 24 h, the solvents were removed in vacuo and the remaining residue was partitioned between DCM and brine, separated, and the organic phase was dried (Na2SO4). The solvents were removed in vacuo and the residue was purified by flash chromatography (0-5% MeOH in DCM) to give the title compound (11 .4 g, 69%). LCMS (Method D): RT= 0.93 min, m / z = 424 [M+H]+.

[0769] Step 4: tert-Butyl 6-((1-methyl-4-oxo-6-phenyl-1,4-dihydropyridin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate:To a solution of tert-butyl 6-((4-oxo-6-phenyl-1 ,4- dihydropyridin-3-yl)-methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (0.212 mg, 0.5 mmol) in DMF (2 mL) under argon was added sodium hydride (55% in mineral oil, 28 mg, 0.65 mmol). After 1 h, iodomethane (92 mg, 0.65 mmol) was added. After 4 h, the solvents were removed in vacuo and the residue was partitioned between DCM and brine, separated, and the organic phase was dried (Na2SO4). The solvents were removed in vacuo and the remaining residue was purified by reversed phase preparative HPLC (C18 column) to give the title compound (11.4 g, 69%). LCMS (Method D): RT = 1.09 min, m / z = 438 [M+H]+.

[0770] Step 5: 5-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-1-methyl-2-phenylpyridin-4(1H)-one: Prepared according to General Procedure 1 using tert-butyl 6-((1-methyl-4-oxo-6-phenyl- 1 ,4-dihydropyridin-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) to give the title compound (49.5 mg, quantitative). LCMS (Method A): RT = 0.44 min, m / z= 338 [M+H]+.

[0771] Intermediate 8: 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-2-DhenylDyridin-4(1 H)-one

[0772] Prepared according to General Procedure 1 using tert-butyl 6-((4-oxo-6-phenyl-1 ,4- dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (30 mg, 70.8 pmol), TFA (0.5 mL) and DCM (1 mL) to give the title compound (20 mg, 87%). LCMS (Method C): RT = 0.43 min, m / z = 324 [M+H]+.

[0773]

[0774] Step 1: rac-Benzyl (2S,4R)-4-((tert-butoxycarbonyl)(2-methoxyethyl)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 (4.50 g, 10.2 mmol) in DMF (120 mL) at 0 °C was added sodium hydride (55% in mineral oil, 0.78 g, 13.3 mmol). After 3 h, 1 -iodo-2-methoxyethane (4.20 g, 22.4 mmol) was added. After a further 24 h, the reaction mixture was partitioned between EtOAc (200 mL) and 15% NH4CI(aq) (300 mL), and separated. The organic phase was washed using water (300 mL), followed by brine (300 mL) and was dried (Na2SO4). The solvents were removed in vacuo and the residue was purified by flash chromatography (0-40% CHCh in hexane) to give the title compound (3.01 g, 59%). LCMS (Method D): RT = 1.58 min, m!z = 405 [M-Boc+H]+.

[0775] Step 2: Benzyl (2S,4R)-4-((tert-butoxycarbonyl)(2-methoxyethyl)amino)-2-(2,5- difluorophenyl)piperidine- 1 -carboxylate: rao-Benzyl (2S,4R)-4-((tert-butoxycarbonyl) (2- methoxyethyl)amino)-2-(2,5-difluorophenyl)piperidine-1 -carboxylate (2.98 g) was resolved into the single stereoisomers by chiral HPLC using a CHIRALPAK® AD-H (4.6 mm x 250 mm, 5 pm) column with isocratic solvent conditions: 95:2.5:2.5 hexane / IPA / MeOH. The first eluted material (RT = 19.25 min) afforded the title compound (1 .21 g). LCMS (Method D): RT = 1 .58 min, m / z = 405 [M-Boc+H]+; and the second eluted material (RT = 25.65 min) afforded benzyl (2R,4S)-4-((tert-butoxycarbonyl)(2-methoxyethyl)amino)-2-(2,5- difluorophenyl)piperidine-1 -carboxylate (1.16 g). LCMS (Method D): RT= 1.58 min, m / z = 405 [M-Boc+H]+.

[0776] Step 3: tert-Butyl ((2S,4R)-2-(2,5-difluorophenyl)piperidin-4-yl)(2-methoxyethyl)carbamate: Benzyl (2S,4R)-4-((ferf-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 (~1 atm, balloon) at rt. After 24 h, the reaction mixture was filtered through a pad of silica and evaporated to dryness to give the title compound (0.88 g, 99%). Chiral HPLC (CHIRALPAK® IC, 4.6 mm x 250 mm, 5 pm) column with isocratic solvent conditions: 98:1 :1 hexane (0.1% EDA) / IPA / MeOH): RT= 7.12 min. LCMS (Method D): RT= 1.12 min, m!z = 371 [M+H]+.

[0777] Intermediate 10: 5- -one

[0778] Step 1: tert-Butyl 3,3-dimethyl-4-((4-oxo-6-phenyl-1,4-dihydropyridin-3- yl)methyl)piperazine-1 -carboxylate: The title compound was prepared similarly to tert-butyl 6-((4-oxo-6-phenyl-1 ,4-dihydropyridin-3-yl)-methyl)-6,9-diazaspiro[4.5]decane-9- carboxylate (Intermediate 7, Steps 1 to 3) except using tert-butyl 3,3-dimethylpiperazine-1 - carboxylate instead of tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate. LCMS (Method D): RT= 1.01 min, m / z = 398 [M+H]+.

[0779] Step 2: 5-((2,2-Dimethylpiperazin-1-yl)methyl)-2-phenylpyridin-4(1H)-one: Prepared according to General Procedure 1 using tert-butyl 3,3-dimethyl-4-((4-oxo-6-phenyl-1 ,4- dihydropyridin-3-yl)methyl)piperazine-1 -carboxylate (60.0 mg, 151 pmol), TFA (0.13 mL) and DCM (2 mL) to give the title compound (44.0 mg, 98%). LCMS (Method A): RT= 0.38 min, m / z = 298 [M+H]+.

[0780] Intermediate 11 : 5-((4,7-Diazaspiro[2.5loctan-4-yl)methyl)-2-phenylpyridin-4(1 H)-one

[0781] The title compound was prepared similarly to 5-((2,2-dimethylpiperazin-1-yl)methyl)-2- phenylpyridin-4(1 H)-one (Intermediate 10) except using tert-butyl 4,7- diazaspiro[2.5]octane-7-carboxylate [commercially available] instead of tert-butyl 3,3- dimethylpiperazine-1 -carboxylate to give the title compound. LCMS (Method A): RT= 0.44 min, m!z = 296 [M+H]+.

[0782] Intermediate 12: tert-Butyl ((2S,4fl)-2-(3,4-difluoroDhenyl)DiDeridin-4-yl)(methyl)carbamate

[0783]

[0784] The title compound was prepared similarly to tert-butyl ((2S,4R)-2-(2,5- difluorophenyl)piperidin-4-yl)(methyl)carbamate (Intermediate 6) except using (3,4- difluorophenyl)boronic acid instead of (2,5-difluorophenyl)boronic acid (Step 1) and a CHIRALPAK® AD-H (4.6 mm x 250 mm, 5 pm) column with isocratic solvent conditions: 70:15:15 hexane / IPA / MeOH for the chiral HPLC separation of enantiomers (Step 7) to give the title compound. Chiral HPLC (CHIRALPAK® AD-H (4.6 mm x 250 mm, 5 pm) column with isocratic solvent conditions: 5:5:90 hexane with 0.1%v / v EDA / IPA / MeOH): RT = 6.19 min. LCMS (Method D): RT = 0.80 min, m / z = 327 [M+H]+. [Q]D21= +25.3 (c 0.50 in CHCh).

[0785] Intermediate 13: 3-(2,5-difluoroDhenyl)morDholine

[0786] 2,5-Difluorobenzaldehyde (0.05 mL, 0.50 mmol) was reacted using SnAP chemistry according to General Procedure 2 using the / V-heterocycle formation “Morpholine” cartridge (H101) under the full sequence conditions (11 h) to afford material that required further purification by flash chromatography to give the title compound (35 mg, 35%) [assumed racemate, 1 :1 mixture of enantiomers]. LCMS (Method A): RT = 0.42 min, mlz = 200 [M+H]+.

[0787] Intermediate 14: tert-Butyl 3-(2,5-difluoroDhenyl)-1 ,4-diazeDane-1 -carboxylate

[0788] 2,5-Difluorobenzaldehyde (0.05 mL, 0.50 mmol) was reacted using SnAP chemistry according to General Procedure 2 using the / V-heterocycle formation “Diazepane” cartridge (H106) under the full sequence conditions (11 h) to afford material that required further purification by flash chromatography to give the title compound (18 mg, 12%) [assumed racemate, 1 :1 mixture of enantiomers]. LCMS (Method A): RT = 0.77 min, mlz = 257 [M- butene+H]+.

[0789] ;-9-

[0790] 2,5-Difluorobenzaldehyde (0.05 mL, 0.50 mmol) was reacted using SnAP chemistry according to General Procedure 2 using the A / -heterocycle formation “Morpholine-2-spiro- (4-Pip)” cartridge (H111) under the full sequence conditions (11 h) to afford material that required further purification by flash chromatography to give the title compound (66 mg, 33%) [assumed racemate, 1 :1 mixture of enantiomers]. LCMS (Method A): RT = 0.91 min, m!z = 403 [M+H]+.

[0791] Intermediate 16: tert-Butvl ((2S,4R

[0792] The title compound was prepared similarly to tert-butyl ((2S,4R)-2-(2,5- difluorophenyl)piperidin-4-yl)(methyl)carbamate (Intermediate 6) except using (2,6- difluorophenyl)boronic acid instead of (2,5-difluorophenyl)boronic acid (Step 1) and a CHIRALCEL® AD-H (4.6 mm x 250 mm, 5 pm) column with isocratic solvent conditions: 70:15:15 hexane / IPA / MeOH for the chiral HPLC separation of enantiomers (Step 7) to give the title compound. Chiral HPLC (CHIRALCEL® OJ-H (4.6 mm x 250 mm, 5 pm) column with isocratic solvent conditions: 90:5:5 hexane / IPA / MeOH): RT = 7.80 min. LCMS (Method D): RT = 0.76 min, m!z = 327 [M+H]+. [a]D21= +42.9 (c 0.20 in CHCI3). Intermediate 17: tert-Butvl ((2S,4R) idin-4-’

[0793] The title compound was prepared similarly to tert-butyl ((2S,4R)-2-(2,5- difluorophenyl)piperidin-4-yl)(methyl)carbamate (Intermediate 6) except using (2,4- difluorophenyl)boronic acid instead of (2,5-difluorophenyl)boronic acid (Step 1) and a CHIRALPAK® IJ (4.6 mm x 250 mm, 5 pm) column with isocratic solvent conditions: 80:10:10 hexane / IPA / MeOH for the chiral HPLC separation of enantiomers (Step 7) to give the title compound. Chiral HPLC (CHIRALCEL® OD-H (4.6 mm x 250 mm, 5 pm) column with isocratic solvent conditions: 98:1 :1 hexane / IPA / MeOH): RT = 6.39 min. LCMS (Method D): RT = 1.07 min, m!z = 327 [M+H]+. [a]D21= +24.9 (c 0.25 in CHCI3).

[0794] Intermediate 18: rac-(3R,5S)-

[0795] 2,5-Difluorobenzaldehyde (0.05 mL, 0.50 mmol) was reacted using SnAP chemistry according to General Procedure 2 using the M-heterocycle formation “3-Methylmorpholine” cartridge (H107) under the full sequence conditions (11 h) to give the title compound (35 mg, 33%) that was used in the next step without further purification. LCMS (Method A): RT = 0.379 min, mlz = 214 [M+H]+.1H NMR (500 MHz, CDCI3): δ 7.31 (ddd, 1 H), 6.97 (td, 1 H), 6.93 - 6.87 (m, 1 H), 4.37 - 4.30 (m, 1 H), 3.89 (dd, 1 H), 3.83 - 3.74 (m, 1 H), 3.20 (t, 1 H), 3.16 - 3.10 (m, 2H), 1 .06 - 1 .01 (m, 3H). [Note: NMR data suggested only cis stereoisomers present, i.e. no trans stereoisomers observed].

[0796] Intermediate 19: 5-((5.8-DiazasDiro[3.51nonan-5-yl)methyl)-2-DhenylDvndin-4(1 H)-one

[0797] The title compound was prepared similarly to 5-((2,2-dimethylpiperazin-1-yl)methyl)-2- phenylpyridin-4(1 H)-one (Intermediate 10) except using tert-butyl 5,8- diazaspiro[3.5]nonane-8-carboxylate [commercially available] instead of tert-butyl 3,3- dimethylpiperazine-1 -carboxylate to give the title compound. LCMS (Method C): RT = 0.41 min, mlz = 310 [M+H]+.

[0798] Intermediate 20: 5-((2-Oxa-5,8-diazasDiro[3.51nonan-5-yl)methyl)-2-DhenylDyridin-4(1 H)- one

[0799] The title compound was prepared similarly to 5-((2,2-dimethylpiperazin-1-yl)methyl)-2- phenylpyridin-4(1 H)-one (Intermediate 10) except using tert-butyl 2-oxa-5,8- diazaspiro[3.5]nonane-8-carboxylate [commercially available] instead of tert-butyl 3,3- dimethylpiperazine-1 -carboxylate to give the title compound. LCMS (Method C): RT = 0.42 min, mlz = 312 [M+H]+.

[0800] Intermediate 21 : 5-((1 ,4-DiazasDiro[5.51undecan-1 -yl)methyl)-2-Dhenyloyridin-4(1 H)-one

[0801] The title compound was prepared similarly to 5-((2,2-dimethylpiperazin-1-yl)methyl)-2- phenylpyridin-4(1 H)-one (Intermediate 10) except using tert-butyl 1 ,4- diazaspiro[5.5]undecane-4-carboxylate [commercially available] instead of tert-butyl 3,3- dimethylpiperazine-1 -carboxylate to give the title compound. LCMS (Method C): RT = 0.47 min, m / z = 338 [M+H]+.

[0802] Intermediate 22: 5-((9-Oxa-1 ,4-diazasDiro[5.51undecan-1 -yl)methyl)-2-DhenylDyridin-4(1 H)- one

[0803] The title compound was prepared similarly to 5-((2,2-dimethylpiperazin-1-yl)methyl)-2- phenylpyridin-4(1 H)-one (Intermediate 10) except using tert-butyl 9-oxa-1 ,4- diazaspiro[5.5]undecane-4-carboxylate [commercially available] instead of tert-butyl 3,3- dimethylpiperazine-1 -carboxylate to give the title compound. LCMS (Method C): RT = 0.42 min, m / z = 340 [M+H]+.

[0804] Intermediate 23: 3-((4,7-DiazasDiro[2.51octan-4-yl)methyl)-6-DhenylDyridin-2(1 H)-one

[0805] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- phenylpyridin-2(1 H)-one (Intermediate 3) except using tert-butyl 4,7-diazaspiro[2.5]octane- 7-carboxylate [commercially available] instead of tert-butyl 6,9-diazaspiro[4.5]decane-9- carboxylate to give the title compound. LCMS (Method C): RT = 0.58 min, m / z = 296 [M+H]+.

[0806] Intermediate 24: 3-((5,8-DiazasDiro[3.51nonan-5-yl)methyl)-6-DhenylDyridin-2(1 H)-one

[0807] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- phenylpyridin-2(1 H)-one (Intermediate 3) except using tert-butyl 5,8-diazaspiro[3.5]nonane- 8-carboxylate [commercially available] instead of tert-butyl 6,9-diazaspiro[4.5]decane-9- carboxylate to give the title compound. LCMS (Method C): RT = 0.50 min, m / z = 310 [M+H]+.

[0808] Intermediate 25: 3-((2-Oxa-5,8-diazasDiro[3.51nonan-5-yl)methyl)-6-DhenylDyridin-2(1 H}- one

[0809] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- phenylpyridin-2(1 H)-one (Intermediate 3) except using tert-butyl 2-oxa-5,8- diazaspiro[3.5]nonane-8-carboxylate [commercially available] instead of tert-butyl 6,9- diazaspiro[4.5]decane-9-carboxylate to give the title compound. LCMS (Method C): RT = 0.55 min, m!z = 312 [M+H]+.

[0810] Intermediate 26: 3-((1 ,4-Diazaspiro[5.51undecan-1 -yl)methyl)-6-phenylpyridin-2(1 H)-one

[0811] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- phenylpyridin-2(1 H)-one (Intermediate 3) except using tert-butyl 1 ,4- diazaspiro[5.5]undecane-4-carboxylate [commercially available] instead of tert-butyl 6,9- diazaspiro[4.5]decane-9-carboxylate to give the title compound. LCMS (Method C): RT = 0.55 min, m!z = 338 [M+H]+.

[0812] Intermediate 27: 3-((9-Oxa-1 ,4-diazaspiro[5.51undecan-1 -yl)methyl)-6-phenylpyridin-2(1 H\- one

[0813] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- phenylpyridin-2(1 H)-one (Intermediate 3) except using tert-butyl 9-oxa-1 ,4- diazaspiro[5.5]undecane-4-carboxylate [commercially available] instead of tert-butyl 6,9- diazaspiro[4.5]decane-9-carboxylate to give the title compound. LCMS (Method C): RT = 0.55 min, m!z = 340 [M+H]+.

[0814] Intermediate 28: (2S,4fi)-2-(2,5-Difluorophenyl)-4-(pyrrolidin-1-yl)piperidine hydrochloride

[0815]

[0816] Step 1: tert-Butyl (2S)-2-(2,5-difluorophenyl)-4-(pyrrolidin-1-yl)piperidine-1 -carboxylate: To a stirred solution of tert-butyl (S)-2-(2,5-difluorophenyl)-4-oxopiperidine-1 -carboxylate (1.5 g, 4.82 mmol) [prepared according to W02022200523 Intermediate 19, Step 5] in MeOH (10 mL) were added acetic acid (3 drops) and pyrrolidine (0.6 mL, 7.23 mmol) at rt. After 2 h, NaBH3CN (0.9 g, 14.5 mmol) was added. After a further 16 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography to give the title compound (1 .6 g, 91%). LCMS (Method E): RT= 3.15 min, m / z = 367 [M+H]+.

[0817] Step 2: tert-Butyl (2S,4R)-2-(2,5-difluorophenyl)-4-(pyrrolidin- 1 -yl)piperidine- 1 -carboxylate: tert-Butyl (2S)-2-(2,5-difluorophenyl)-4-(pyrrolidin-1-yl)piperidine-1 -carboxylate (1.6 g) was separated into the single stereoisomers by reversed phase preparative HPLC (C18 column) to give tert-butyl (2S,4S)-2-(2,5-difluorophenyl)-4-(pyrrolidin-1-yl)piperidine-1- carboxylate (first eluting isomer: 200 mg). LCMS (Method E): RT = 3.15 min, mlz = 367 [M+H]+; and the title compound (second eluting isomer: 750 mg). LCMS (Method E): RT= 3.15 min, m / z = 367 [M+H]+.

[0818] Step 3: (2S,4Fl)-2-(2,5-Difluorophenyl)-4-(pyrrolidin-1-yl)piperidine hydrochloride: To a stirred solution of tert-butyl (2S,4R)-2-(2,5-difluorophenyl)-4-(pyrrolidin-1-yl)piperidine-1- carboxylate (890 mg 2.43 mmol) in DCM (10 mL) was added 4 M HCI in 1 ,4-dioxane (6 mL) at rt. After 3 h, the solvent was evaporated under reduced pressure and residue was triturated with DCM and pentane followed by lyophilization to yield the title compound (770 mg, quantitative). LCMS (Method E): RT = 1.26 min, mlz = 267 [M+H]+.

[0819] Intermediate 29: 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-2-(thioDhen-3-yl)Dyridin-4(1 H)- one Step 1: Methyl 4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridine-3-carboxylate: To a solution of (Z)-ethyl 2-(aminomethylene)-3-oxobutanoate (13.6 g, 87 mmol) in THF (400 ml_) was added sodium hydride (55% in mineral oil, 10.0 g, 226 mmol) at 0 °C under argon atmosphere. After 1 h, methyl thiophene-3-carboxylate (25.0 g, 174 mmol) was slowly added and the resultant mixture was stirred at 60 °C. After 4 h, the solvents were removed in vacuo and the residue was dissolved in anhydrous MeOH (300 mL) followed by dropwise addition of thionyl chloride (31 g, 261 mmol). The reaction mixture was refluxed for 10 h. The solvents were removed in vacuo and the residue was partitioned between DCM and saturated NaHCO3(aq). The resultant biphasic mixture was separated, the organic layer was dried (Na2SO4), the solvents were removed in vacuo, and the residue was purified by flash chromatography (0-10% EtOAc in hexane) to gave the title compound (7.1 g, 34%). LCMS (Method D): RT = 0.70 min, m / z = 236 [M+H]+.

[0820] Step 2: 5-(Hydroxymethyl)-2-(thiophen-3-yl)pyridin-4(1H)-one: To a stirred solution of methyl 4-oxo-6-(thiophen-3-yl)-1 ,4-dihydropyridine-3-carboxylate (6.6 g, 28 mmol) in THF (250 mL) was added borane.DMS complex (6.4 g, 84 mmol) at rt. After 30 h, MeOH was slowly added until gas evolution ceased, the solvents were removed in vacuo using further MeOH to assist with coevaporation to give the title compound (5.8 g, quantitative). LCMS (Method D): RT= 0.51 min, m / z = 208 [M+H]+.

[0821] Step 3: 5-(Chloromethyl)-2-(thiophen-3-yl)pyridin-4(1H)-one: To a stirred solution of 5- (hydroxymethyl)-2-(thiophen-3-yl)pyridin-4(1 H)-one (6.0 g, 29 mmol) in DCM (200 mL) was added thionyl chloride (40 mL, 0.55 mol) at 40 °C. After 24 h, the solvents were removed in vacuo using MeCN to assist with coevaporation to give the title compound (6.5 g, quantitative) that was used directly in the next step without further purification.

[0822] Step 4: tert-Butyl 6-((4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate: To a solution of 5-(chloromethyl)-2-(thiophen-3- yl)pyridin-4(1 H)-one (2.1 g, 9.3 mmol) in MeCN (90 mL) was added DIPEA (3.6 g, 28 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (2.7 g, 11 mmol) and the suspension was stirred at 80 °C. After 24 h, the solvents were removed in vacuo and the residue was partitioned between DCM and brine, separated, the organic phase was dried (Na2SO4), the solvents were removed in vacuo, and the residue was purified by flash chromatography (0-5% MeOH in DCM) to give the title compound (1 .9 g, 47%). LCMS (Method D): RT= 0.85 min, m / z = 430 [M+H]+. Step 5: 5-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-2-(thiophen-3-yl)pyridin-4( 1H)-one:

[0823] Prepared according to General Procedure 1 using tert-butyl 6-((4-oxo-6-(thiophen-3-yl)-1 ,4- dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (60 mg, 140 pmol), TFA (0.3 mL) and DOM (1 .5 mL) to give the title compound (46.0 mg, quantitative). LCMS (Method A): RT = 0.42 min, m!z = 330 [M+H]+.

[0824] Intermediate 30: 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-2-(1 -methyl-1 H-pyrazol-5- yl)pyridin-4(1 / 7)-one

[0825] The title compound was prepared similarly to 5-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-2- (thiophen-3-yl)pyridin-4(1 H)-one (Intermediate 29) except using methyl 1-methyl-1 H- pyrazole-5-carboxylate instead of methyl thiophene-3-carboxylate to give the title compound (via tert-butyl 6-((6-(1-methyl-1 H-pyrazol-5-yl)-4-oxo-1 ,4-dihydropyridin-3- yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate). LCMS (Method A): RT= 0.34 min, m / z = 328 [M+H]+.

[0826] Intermediate 31 : 3-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-6-methyl-5-DhenylDyridin-2(1 H)- one

[0827] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- phenylpyridin-2(1 H)-one (Intermediate 3) except using 3-(hydroxymethyl)-6-methyl-5- phenylpyridin-2(1 H)-one (prepared similarly to 3-(hydroxymethyl)-6-phenylpyridin-2(1 / - / )- one except using 6-methyl-2-oxo-5-phenyl-1 ,2-dihydropyridine-3-carboxylic acid [commercially available] instead of 2-oxo-6-phenyl-1 ,2-dihydropyridine-3-carboxylic acid) instead of 3-(hydroxymethyl)-6-phenylpyridin-2(1 H)-one to give the title compound. LCMS (Method A): RT= 0.57 min, m!z = 338 [M+H]+. Intermediate 32: 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-2-(thioDhen-2-yl)Dyridin-4(1 / - / )- one

[0828] The title compound was prepared similarly to 5-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-2- (thiophen-3-yl)pyridin-4(1 H)-one (Intermediate 29) except using methyl thiophene-2- carboxylate instead of methyl thiophene-3-carboxylate to give the title compound. LCMS (Method A): RT= 0.43 min, m!z = 330 [M+H]+.

[0829] Intermediate 33: 3-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-4H-Dyrido[1 ,2-alDyrimidin-4-one

[0830] Step 1: 3-Bromo-4H-pyrido[1,2-a]pyrimidin-4-one: To a stirred solution of 4 / 7-pyrido[1 ,2- a]pyrimidin-4-one (6.00 g, 41 mmol) [commercially available] in DCM (200 mL) was added NBS (8.05 g, 45 mmol, 1.1 eq.) portionwise at rt. After 10 h, 1 M sodium carbonate (aq) solution (150 mL) was added. After a further 2 h, the biphasic mixture was separated, the organic phase was dried (Na2SO4), and the solvents were removed in vacuo to give the title compound (6.2 g, 69%).1H NMR (400 MHz, CDCI3): δ 9.07 (d, 1 H), 8.55 (s, 1 H), 7.78 (t, 1 H), 7.67 (d, 1 H), 7.22 (t, 1 H).

[0831] Step 2: 3-(Hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one: To a stirred solution of 3- bromo-4H-pyrido[1 ,2-a]pyrimidin-4-one (4.40 g, 19 mmol) in 1 ,4-dioxane (250 mL) was added tributylstannylmethanol (9.25 g, 29 mmol) and XPhos-Pd-G2 (1.62 g, 2.0 mmol).

[0832] The reaction mixture degassed and back-filled with argon and then heated at 100 °C. After 48 h, the solvents were removed in vacuo and the residue was triturated using diethyl ether (150 mL) and filtered to give the crude title compound (3.2 g, 68%) [contaminated with 4H- pyrido[1 ,2-a]pyrimidin-4-one]. LCMS (Method D): RT = 0.43 min, m!z = 177 [M+H]+.

[0833] Step 3: 3-(Chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one: To a stirred solution of 3- (hydroxymethyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one (3.0 g, 17 mmol) in DCM (200 mL) was added thionyl chloride (40 mL, 0.55 mol) at 40 °C. After 24 h, the solvents were removed in vacuo using MeCN to assist with coevaporation to give the title compound (3.2 g, quantitative) that was used directly in the next step without further purification.

[0834] Step 4: tert-Butyl 6-((4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate: To a stirred solution of 3-(chloromethyl)-4H- pyrido[1 ,2-a]pyrimidin-4-one (3.0 g, 16 mmol) in MeCN (150 mL) was added DIPEA (6.2 g, 48 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (3.4 g, 16 mmol) at 80 °C. After 18 h, solvents were removed in vacuo and the residue partitioned between DCM and brine, and separated. The organic phase was dried (Na2SO4), the solvents were removed in vacuo and the residue was purified by flash chromatography (0-5% MeOH in DCM) to give the title compound (1.1 g, 27%). LCMS (Method D): RT = 0.81 min, m / z = 399 [M+H]+.

[0835] Step 5: 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[ 1 ,2-a]pyrimidin-4-one: Prepared according to General Procedure 1 using tert-butyl 6-((4-oxo-4H-pyrido[1 ,2- a]pyrimidin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (120 mg, 300 pmol), TFA (0.7 mL) and DCM (1 .5 mL) to give the title compound (85.0 mg, 95%). LCMS (Method A): RT = 0.41 min, m / z = 299 [M+H]+.

[0836] Intermediate 34: 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-2-(2-fluoroDhenyl)Dyridin-4(1 Hi- one hydrochloride

[0837] The title compound was prepared similarly to 5-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-2- (thiophen-3-yl)pyridin-4(1 H)-one (Intermediate 29) except using methyl 2-fluorobenzoate instead of methyl thiophene-3-carboxylate in Step 1 and using 4M HCI in 1 ,4-dioxane / 1 ,4- dioxane instead of TFA / DCM and omitting the SCX-2 purification in Step 5 to give the title compound. LCMS (Method A): RT= 0.43 min, m / z = 342 [M+H]+.

[0838] Intermediate 35: 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-2-(o-tolyl)Dyridin-4(1 H)-one Ill

[0839] The title compound was prepared similarly to 5-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-2- (thiophen-3-yl)pyridin-4(1 H)-one (Intermediate 29) except using methyl 2-methylbenzoate instead of methyl thiophene-3-carboxylate to give the title compound. LCMS (Method A): RT= 0.45 min, m!z = 338 [M+H]+.

[0840] Intermediate 36: 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-2-(2-methoxyDhenyl)Dyridin-

[0841] 4(1 H)-one hydrochloride

[0842] The title compound was prepared similarly to 5-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-2- (thiophen-3-yl)pyridin-4(1 H)-one (Intermediate 29) except using methyl 2-methoxybenzoate instead of methyl thiophene-3-carboxylate in Step 1 and using 4M HCI in 1 ,4-dioxane / 1 ,4- dioxane instead of TFA / DCM and omitting the SCX-2 purification in Step 5 to give the title compound. LCMS (Method A): RT= 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-dihydropyridin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate / tert-butyl 6-((6-(2-hydroxyphenyl)-4-oxo-1 ,4- dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate was obtained that required RP preparative HPLC purification].

[0843] Intermediate 37: 3-((6,9-Di i-6-vl)methyl)-4H-chromen-4-one hydrochloride

[0844] Step 1: 3-(Hydroxymethyl)-4H-chromen-4-one: To a stirred solution of 4-oxo-4H-chromene- 3-carbaldehyde (500 mg, 2.87 mmol) [commercially available] in DCM (12 mL) was added NaBH(OAc)3 (1 .80 g, 8.61 mmol) at 0 °C and the resultant mixture was allowed to warm to rt. After 16 h, the reaction mixture was diluted with water and extracted with DCM (2 x 100 mL). The combined organic phase was washed with brine (100 ml_), dried (NaaSCU), solvents were removed in vacuo, and the remaining residue was purified by flash chromatography (0-50% EtOAc in hexane) to give the title compound (300 mg, 59%). LCMS (Method E): RT = 2.07 min, m / z = 177 [M+H]+.

[0845] Step 2: 3-(Chloromethyl)-4H-chromen-4-one: To a stirred solution of 3-(hydroxymethyl)-4H- chromen-4-one (1 .00 g, 5.67 mmol) in DCM (20 mL) was added dropwise SOCI2 (1 .2 mL, 17.0 mmol) at 0 °C and the resultant mixture was allowed to warm to rt. After 3 h, the reaction mixture was diluted with water and extracted with DCM (2 x 200 mL). The combined organic phase was washed with brine (200 mL), dried (NaaSCU) and the solvents were removed in vacuo to give the title compound (640 mg, 58%) which was used next step without further purification. LCMS (Method E): RT = 2.93 min, m / z = 195 [M+H]+.

[0846] Step 3: tert-Butyl 6-((4-oxo-4H-chromen-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9- carboxylate: To a stirred of 3-(chloromethyl)-4H-chromen-4-one (640 mg, 3.28 mmol) in MeCN (20 mL) were added tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (869 mg, 3.61 mmol) followed by addition of CS2CO3 (2.10 g, 6.57 mmol) at rt. The resultant mixture was heated to 90 °C. After 3 h, the reaction mixture was filtered through Celite®, the filtrate was evaporated under reduced pressure and the remaining residue was purified by flash chromatography (0-30% EtOAc in hexane) to give the title compound (900 mg, 69%). LCMS (Method E): RT= 10.22 min, m / z = 399 [M+H]+.

[0847] Step 4: 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-4H-chromen-4-one hydrochloride: Prepared according to General Procedure 1 using tert-butyl 6-((4-oxo-4H-chromen-3- yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (60.0 mg, 151 nmol), 4M HCI in 1 ,4- dioxane (0.38 mL) and 1 ,4-dioxane (1 mL) and omitting the SCX-2 purification to give the title compound (50 mg, 99%). LCMS (Method A): RT = 0.56 min, m / z = 299 [M+H]+.

[0848] Intermediate 38: 3-((6,9-DiazasDirof4.51decan-6-yl)methyl)-6-fluoro-4H-chromen-4-one hydrochloride The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-4 / - / - chromen-4-one hydrochloride (Intermediate 37) except using 6-fluoro-4-oxo-4H-chromene- 3-carbaldehyde instead of 4-oxo-4 / - / -chromene-3-carbaldehyde to give the title compound. LCMS (Method A): RT= 0.62 min, mlz = 317 [M+H]+.

[0849] Intermediate 39: 5-((6,9-DiazasDirof4.51decan-6-yl)methyl)-2-(2,3-dihvdrobenzofuran-7- yl)Dyridin-4(1 H)-one hydrochloride

[0850] The title compound was prepared similarly to 5-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-2- (thiophen-3-yl)pyridin-4(1 H)-one (Intermediate 29) except using methyl 2,3- dihydrobenzofuran-7-carboxylate instead of methyl thiophene-3-carboxylate in Step 1 and using 4M HCI in 1 ,4-dioxane / 1 ,4-dioxane instead of TFA / DCM and omitting the SCX-2 purification in Step 5 to give the title compound. LCMS (Method A): RT= 0.59 min, m / z = 366 [M+H]+.

[0851] Intermediate 40: 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-2-(1 -methyl-1 H-pyrazol-3- yl)pyridin-4(1 H)-one

[0852] The title compound was prepared similarly to 5-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-2- (thiophen-3-yl)pyridin-4(1 H)-one (Intermediate 29) except using methyl 1-methyl-1 H- pyrazole-3-carboxylate instead of methyl thiophene-3-carboxylate to give the title compound. LCMS (Method A): RT= 0.38 min, m / z = 328 [M+H]+.

[0853] Intermediate 41 : 5-((6,9-Diazaspiro[4.51decan-6-yl)methyl)-1-cvclopropyl-2-methylpyridin- 4(1 H)-one hydrochloride

[0854] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- phenylpyridin-2(1 Hj-one (Intermediate 3) except using 1 -cyclopropyl-5-(hydroxymethyl)-2- methylpyridin-4(1 Hj-one (prepared similarly to 3-(hydroxymethyl)-6-phenylpyridin-2(1 Hj- one except using 1 -cyclopropyl-6-methyl-4-oxo-1 ,4-dihydropyridine-3-carboxylic acid [commercially available] instead of 2-oxo-6-phenyl-1 ,2-dihydropyridine-3-carboxylic acid) instead of 3-(hydroxymethyl)-6-phenylpyridin-2(1 Hj-one and using 4M HCI in 1 ,4- dioxane / 1 ,4-dioxane instead of TFA / DCM and omitting the SCX-2 purification in the final step to give the title compound. LCMS (Method A): RT= 0.34 min, m / z = 302 [M+H]+.

[0855] Intermediate 42: 3-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-5,6-dimethylDyridin-2(1 H)-one hydrochloride

[0856] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- phenylpyridin-2(1 F / )-one (Intermediate 3) except using 3-(hydroxymethyl)-5,6- dimethylpyridin-2(1 H)-one (prepared similarly to 3-(hydroxymethyl)-6-phenylpyridin-2(1 H)- one except using 5,6-dimethyl-2-oxo-1 ,2-dihydropyridine-3-carboxylic acid [commercially available] instead of 2-oxo-6-phenyl-1 ,2-dihydropyridine-3-carboxylic acid) instead of 3- (hydroxymethyl)-6-phenylpyridin-2(1 H)-one and using 4M HCI in 1 ,4-dioxane / 1 ,4-dioxane instead of TFA / DCM and omitting the SCX-2 purification in the final step to give the title compound. LCMS (Method A): RT= 0.36 min, m / z = 276 [M+H]+.

[0857] Intermediate 43: 3-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-4 / - / -pyrimido[1 ,2-blpyridazin-4- one hydrochloride The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- phenylpyridin-2(1 Hj-one (Intermediate 3) except using 3-(hydroxymethyl)-4H-pyrimido[1 ,2- b]pyridazin-4-one (prepared similarly to 3-(hydroxymethyl)-6-phenylpyridin-2(1 Hj-one except using 4-oxo-4H-pyrimido[1 ,2-b]pyridazine-3-carboxylic acid [commercially available] instead of 2-oxo-6-phenyl-1 ,2-dihydropyridine-3-carboxylic acid) instead of 3- (hydroxymethyl)-6-phenylpyridin-2(1 H)-one and using 4M HCI in 1 ,4-dioxane / DCM instead of TFA / DCM and omitting the SCX-2 purification in the final step to give the title compound. LCMS (Method A): RT= 0.35 min, m!z = 300 [M+H]+.

[0858] Intermediate 44: 3-((6,9-DiazasDiro[4.5ldecan-6-yl)methyl)-6-fluoroguinolin-4(1 H)-one hydrochloride

[0859] Step 1: 6-Fluoro-3-(hydroxymethyl)quinolin-4(1H)-one: To a stirred solution of ethyl 6- fluoro-4-oxo-1 ,4-dihydroquinoline-3-carboxylate (1.5 g, 6.38 mmol) [commercially available] in dimethoxyethane (45 mL) was added a 2M solution of UAIH4 in THF (3.2 mL, 6.4 mmol) at rt. The reaction mixture was heated to 75 °C. After 2 h, the reaction mixture was cooled, quenched with saturated Na2SO4(aq) solution (50 mL) and filtered using Celite®. The filtrate was extracted with 3:2 EtOAc / THF (2 x 50 mL). The combined organic phase was dried (Na2SO4) and the solvents were removed in vacuo to give title compound (640 mg, 52%). LCMS (Method E): RT= 1.52 min, m / z = 194 [M+H]+.

[0860] Step 2: 3-(Chloromethyl)-6-fluoroquinolin-4(1H)-one: To a stirred solution of 6-fluoro-3- (hydroxymethyl)quinolin-4(1 H)-one (100 mg, 0.52 mmol) in DCM (6 mL) was added SOCI2 (0.11 mL, 1 .55 mmol) at 0 °C. The reaction mixture was heated to 50 °C. After 16 h, the solvents were removed in vacuo to give title compound (101 mg, 92%).1H NMR (400 MHz, DMSO-ofe): δ 12.21 (s, 1 H), 8.29 - 8.27 (m, 1 H), 7.79 - 7.76 (m, 1 H), 7.64 - 7.59 (m, 2H), 4.66 (s, 2H).

[0861] Step 3: tert-Butyl 6-((6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate: To a stirred solution of 3-(chloromethyl)-6- fluoroquinolin-4(1 H)-one (380 mg, 1 .79 mmol) in MeCN (76 mL) were added tert-butyl 6,9- diazaspiro[4.5]decane-9-carboxylate (647 mg, 2.96 mmol) and CS2CO3 (1 .17 g, 3.59 mmol) at rt. After 2 h, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with brine (50 mL), dried (Na2SO4), the solvents were removed in vacuo, and the remaining residue was purified by flash chromatography (0-30% EtOAc in hexane), followed by RP preparative HPLC to give the title compound (80 mg, 11%). LCMS (Method E): RT = 2.50 min, m / z = 416 [M+H]+.

[0862] Step 4: 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-6-fluoroquinolin-4(1H)-one hydrochloride: Prepared according to General Procedure 1 using tert-butyl 6-((6-fluoro-4-oxo-1 ,4- dihydroquinolin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (58 mg, 140 nmol), 4M HCI in 1 ,4-dioxane (0.42 mL) and DCM (1 .0 mL) but without SCX-2 purification to give the title compound (49 mg, quantitative). LCMS (Method A): RT= 0.41 min, m / z = 316 [M+H]+.

[0863] Intermediate 45: 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-2-(2-hvdroxyDhenyl)Dyridin- 4(1 H)-one hydrochloride 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 pmol) [obtained as a byproduct in the preparation 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 for 5-((6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2-methoxyphenyl)pyridin-4(1 H)-one hydrochloride (Intermediate 36)] was / V-Boc deprotected according to General Procedure 1 using 4M HCI in 1 ,4-dioxane (0.43 mL) and 1 ,4-dioxane (1 mL) but without SCX-2 purification to give the title compound (42 mg, 98%). LCMS (Method A): RT= 0.45 min, m / z = 340 [M+H]+.

[0864] Intermediate 46: 3-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-6-methyl-2-DroDylDyridin-4(1 H)- one

[0865] The title compound was prepared similarly to 5-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-2- (thiophen-3-yl)pyridin-4(1 Hj-one (Intermediate 29) except omitting Step 1 and using methyl 6-methyl-4-oxo-2-propyl-1 ,4-dihydropyridine-3-carboxylate [commercially available] instead of methyl 4-oxo-6-(thiophen-3-yl)-1 ,4-dihydropyridine-3-carboxylate in Step 2 to give the title compound. LCMS (Method A): RT= 0.40 min, m!z = 304 [M+H]+.

[0866] Intermediate 47: 3-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-7-fluoro-4H-Dyrido[1 ,2-

[0867] -4-one

[0868] Step 1: 3-Bromo-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one: To a stirred solution of 7-fluoro- 4H-pyrido[1 ,2-a]pyrimidin-4-one (4.50 g, 27 mmol) [commercially available] in DCM (120 mL) was added NBS (5.37 g, 30 mmol) portionwise at rt. After 10 h, 1 M sodium carbonate (aq) solution (150 mL) was added. After a further 2 h, the biphasic mixture was separated, the organic phase was dried (Na2SO4), and the solvents were removed in vacuo to give the title compound (4.9 g, 75%).1H NMR (400 MHz, CDCI3): δ 8.98 (m, 1 H), 8.67 (s, 1 H), 8.15 (m, 1 H), 7.86 (m, 1 H).

[0869] Step 2: 3-Hydroxymethyl-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one: To a stirred solution of 3-bromo-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one (4.40 g, 18 mmol) in 1 ,4-dioxane (250 mL) was added (tributylstannyl)methanol (9.25 g, 29 mmol) and XPhos-Pd-G2 (1.62 g, 2.0 mmol). The reaction mixture was degassed and back-filled with argon and then heated at 100 °C. After 48 h, the solvents were removed in vacuo and the residue was triturated using diethyl ether (150 mL) and filtered to give the crude title compound (3.2 g crude, 1 :2 mixture with 7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one determined by1H NMR analysis) that was used in the next step without further purification. LCMS (Method D): RT = 0.51 min, m / z = 195 [M+H]+. Step 3: 3-Chloromethyl-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one: To a stirred solution of 3- hydroxymethyl-7-fluoro-4A / -pyrido[1 ,2-a]pyrimidin-4-one [contaminated with 7-fluoro-4A / - pyrido[1 ,2-a]pyrimidin-4-one] (3.2 g crude, assumed 6 mmol) in DCM (200 ml_) was added thionyl chloride (40 mL, 0.55 mol) at 40 °C. After 24 h, the solvents were removed in vacuo using MeCN to assist with coevaporation to give the crude title compound (3.2 g crude) that was used directly in the next step without further purification.

[0870] Step 4: tert-Butyl 6-((7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate: To a stirred solution of 3-chloromethyl-7-fluoro-4A / - pyrido[1 ,2-a]pyrimidin-4-one (3.0 g, assumed 6 mmol) in MeCN (150 mL) was added DIPEA (2.3 g, 18 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (1.28 g, 6 mmol) at 80 °C. After 18 h, the solvents were removed in vacuo, the residue was partitioned between DCM and brine, and the resulting biphasic mixture was separated. The organic phase was dried (Na2SO4), the solvents were removed in vacuo and the remaining residue was purified by RP preparative HPLC to give the title compound (0.5 g, 7% over 3 steps). LCMS (Method D): RT= 0.81 min, m / z = 417 [M+H]+.

[0871] Step 5: 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[ 1 ,2-a]pyrimidin-4-one hydrochloride: Prepared according to General Procedure 1 using tert-butyl 6-((7-fluoro-4- oxo-4A / -pyrido[1 ,2-a]pyrimidin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (60 mg, 144 pmol), 4M HCI in 1 ,4-dioxane (0.36 mL) and 1 ,4-dioxane (2 mL) but without SCX-2 purification to give the title compound (51 mg, 97%). LCMS (Method A): RT = 0.45 min, m / z = 317 [M+H]+.

[0872] Intermediate 48: 3-((6,9-Diazaspiro[4.51decan-6-yl)methyl)-5-(trifluoromethyl)pyridin-2(1 Aft- one hydrochloride

[0873] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- phenylpyridin-2(1 Aft-one (Intermediate 3) except using 3-(hydroxymethyl)-5- (trifluoromethyl)pyridin-2(1 Aft-one (prepared similarly to 3-(hydroxymethyl)-6-phenylpyridin- 2(1 Aft-one except using 2-oxo-5-(trifluoromethyl)-1 ,2-dihydropyridine-3-carboxylic acid [commercially available] instead of 2-oxo-6-phenyl-1 ,2-dihydropyridine-3-carboxylic acid) instead of 3-(hydroxymethyl)-6-phenylpyridin-2(1 H)-one and using 4M HCI in 1 ,4- dioxane / 1 ,4-dioxane instead of TFA / DCM and omitting the SCX-2 purification in the final step to give the title compound. LCMS (Method A): RT= 0.50 min, m / z = 316 [M+H]+.

[0874] Intermediate 49: 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-2-(4-fluoroDhenyl)oyridin-4(1 H)- one

[0875] The title compound was prepared similarly to 5-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-2- (thiophen-3-yl)pyridin-4(1 H)-one (Intermediate 29) except using methyl 4-fluorobenzoate instead of methyl thiophene-3-carboxylate in Step 1 and using 4M HCI in 1 ,4-dioxane / 1 ,4- dioxane instead of TFA / DCM and omitting the SCX-2 purification in Step 5 to give the title compound. LCMS (Method A): RT= 0.45 min, m / z = 342 [M+H]+.

[0876] Intermediate 50: 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-2-(3-fluoroDhenyl)Dyridin-4(1 H}- one hydrochloride

[0877] The title compound was prepared similarly to 5-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-2- (thiophen-3-yl)pyridin-4(1 H)-one (Intermediate 29) except using methyl 3-fluorobenzoate instead of methyl thiophene-3-carboxylate in Step 1 and using 4M HCI in 1 ,4-dioxane / 1 ,4- dioxane instead of TFA / DCM and omitting the SCX-2 purification in Step 5 to give the title compound. LCMS (Method A): RT= 0.45 min, m / z = 342 [M+H]+.

[0878] Intermediate 51 : 5-((6,9-DiazasDiro[4.51decan-6-yl)rnethyl)-2-(m-tolyl)oyridin-4(1 H)-one hydrochloride The title compound was prepared similarly to 5-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-2- (thiophen-3-yl)pyridin-4(1 Hj-one (Intermediate 29) except using methyl 3-methylbenzoate instead of methyl thiophene-3-carboxylate in Step 1 and using 4M HCI in 1 ,4-dioxane / 1 ,4- dioxane instead of TFA / DCM and omitting the SCX-2 purification in Step 5 to give the title compound. LCMS (Method A): RT= 0.49 min, mlz = 338 [M+H]+.

[0879] Intermediate 52: 3-((6,9-DiazasDirof4.51decan-6-yl)methyl)-6- tolyl)Dyridin-2(1 H)-one hydrochloride

[0880] 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) was added 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). The reaction mixture was degassed and backfilled with argon before heating to reflux. After 24 h, the solvents were evaporated. The remaining residue was dissolved in hot water (200 mL), filtered and acidified with HCI(aq) to -pH 3. The resulting precipitate was filtered, washed with water and dried under vacuum to give the title compound (3.0 g, 86%) as a grey solid. LCMS (Method D): RT= 0.87 min, m / z = 230 [M+H]+.

[0881] Step 2: 3-(Hydroxymethyl)-6-(m-tolyl)pyridin-2(1H)-one: To a stirred solution of 2-oxo-6-(m- tolyl)-1 ,2-dihydropyridine-3-carboxylic acid (2.9 g, 12.6 mmol) in THF (120 mL) was added 1 M borane.DMS complex in THF solution (39 mL, 39 mmol) at rt. After 18 h, MeOH was slowly added until gas evolution ceased. The resulting solution was partitioned between EtOAc and brine, separated, the organic phase was dried (Na2SO4), and the solvents were removed in vacuo. The remaining residue was purified by flash chromatography (0-5% MeOH in DCM) to give the title compound (2.6 g, 96%) as pale yellow solid that was used directly in the next step. LCMS (Method D): RT= 1.03 min, m / z = 216 [M+H]+.

[0882] Step 3: 3-(Chloromethyl)-6-(m-tolyl)pyridin-2(1H)-one: To a solution of 3-(hydroxymethyl)-6- (m-tolyl)pyridi n-2( 1 H)-one (2.5 g, 11 .6 mmol) in DCM (100 mL) was added thionyl chloride (20 mL, 0.278 mol), and the suspension was stirred at 40 °C. After 24 h, the solvents were removed under vacuum, the reside was dissolved in MeCN and reevaporated to give the title compound (2.5 g, 92%) as a brown solid that was used directly in the next step without further purification.

[0883] Step 4: tert-Butyl 6-((2-oxo-6-(m-tolyl)-1,2-dihydropyridin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate: To a solution of 3-(chloromethyl)-6-(m-tolyl)pyridin- 2(1 H)-one (2.4 g, 10 mmol) in MeCN (100 mL) was added DIPEA (3.9 g, 30 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (2.4 g, 10 mmol). The resultant suspension was stirred at 80 °C. After 18 h, reaction mixture was evaporated, partitioned between DCM and brine, separated, the organic phase was dried (Na2SO4), and the solvents were removed in vacuo. The remaining residue was purified by flash chromatography (0-5% MeOH in DCM) to give the title compound (1 .2 g, 27%) as pale yellow solid. LCMS (Method D): RT= 1 .00 min, m / z = 438 [M+H]+.

[0884] Step 5: 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-6-(m-tolyl)pyridin-2(1H)-one hydrochloride: Prepared according to General Procedure 1 using tert-butyl 6-((2-oxo-6-(m- tolyl)-1 ,2-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (60 mg, 137 pmol), 4M HCI in 1 ,4-dioxane (0.411 mL) and DCM (1 .0 mL) but without SCX-2 purification to give the title compound (51 mg, 99%). LCMS (Method A): RT= 0.59 min, m / z = 338 [M+H]+.

[0885] Intermediate 53: 3-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-6-(3-fluoroDhenyl)Dyridin-2(1 Hi- one hydrochloride

[0886] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- (m-tolyl)pyridin-2(1 H)-one hydrochloride (Intermediate 52) except using 3- fluorophenylboronic acid instead of m-tolylboronic acid in Step 1 to give the title compound. LCMS (Method A): RT= 0.54 min, m / z = 342 [M+H]+.

[0887] Intermediate 54: 3- ,9-Di i-6-vl)methvl)-6-(4-1 one

[0888] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- (m-tolyl)pyridin-2(1 H)-one hydrochloride (Intermediate 52) except using 4- fluorophenylboronic acid instead of m-tolylboronic acid in Step 1 to give the title compound. LCMS (Method A): RT= 0.53 min, m!z = 342 [M+H]+.

[0889] Intermediate 55: 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-2-(methylthio)-6-oxo-1 ,6- dihvdroDyridine-3-carbonitrile hydrochloride

[0890] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- phenylpyridin-2(1 H)-one (Intermediate 3) except using 5-(hydroxymethyl)-2-(methylthio)-6- oxo-1 ,6-dihydropyridine-3-carbonitrile (prepared similarly to 3-(hydroxymethyl)-6- phenylpyridin-2(1 A7)-one except using 5-cyano-6-(methylthio)-2-oxo-1 ,2-dihydropyridine-3- carboxylic acid [commercially available] instead of 2-oxo-6-phenyl-1 ,2-dihydropyridine-3- carboxylic acid) instead of 3-(hydroxymethyl)-6-phenylpyridin-2(1 H)-one and using 4M HCI in 1 ,4-dioxane / 1 ,4-dioxane instead of TFA / DCM and omitting the SCX-2 purification in the final step to give the title compound. LCMS (Method A): RT = 0.54 min, m / z = 319 [M+H]+.

[0891] Intermediate 56: 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-2-DhenylDyrimidin-4 -one hydrochloride

[0892] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- phenylpyridin-2(1 H)-one (Intermediate 3) except using 5-(hydroxymethyl)-2- phenylpyrimidin-4(3H)-one (prepared similarly to 3-(hydroxymethyl)-6-phenylpyridin-2(1 H)- one except 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) instead of 3- (hydroxymethyl)-6-phenylpyridin-2(1 H)-one and using 4M HCI in 1 ,4-dioxane / DCM instead of TFA / DCM and omitting the SCX-2 purification in the final step to give the title compound. LCMS (Method A): RT = 0.49 min, m!z = 325 [M+H]+.

[0893] Intermediate 57: 3-((6,9-Diazaspiro[4.51decan-6-yl)methyl)-1 ,7-naDhthyridin-4(1 H)-one hydrochloride

[0894] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-4H- pyrido[1 ,2-a]pyrimidin-4-one (Intermediate 33) except using 1 ,7-naphthyridin-4(1 H)-one [commercially available] instead of 4H-pyrido[1 ,2-a]pyrimidin-4-one in Step 1 and using 4M HCI in 1 ,4-dioxane / 1 ,4-dioxane instead of TFA / DCM and omitting the SCX-2 purification in the final step to give the title compound. LCMS (Method C): RT = 0.32 min, mlz = 299 [M+H]+.

[0895] Intermediate 58: 3-((6,9-Diazaspiro[4.51decan-6-yl)methyl)-2,6-dimethylpyridin-4(1 / - / bone

[0896] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-4H- pyrido[1 ,2-a]pyrimidin-4-one (Intermediate 33) except using 2,6-dimethylpyridin-4(1 H)-one [commercially available] instead of 4H-pyrido[1 ,2-a]pyrimidin-4-one in Step 1 and using 4M HCI in 1 ,4-dioxane / DCM instead of TFA / DCM and omitting the SCX-2 purification in the final step to give the title compound. LCMS (Method A): RT = 0.24 min, m / z = 276 [M+H]+.

[0897] Intermediate 59: 5-((6,9-Diazaspiro[4.51decan-6-yl)methyl)-1 -methyl-2-(thiophen-3- yl)pyridin-4(1 H)-one hydrochloride

[0898] Step 1: tert-Butyl 6-((1-methyl-4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate:To a solution of tert-butyl 6-((4-oxo-6-(thiophen-3-yl)- 1 ,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (429 mg, 1 mmol) in DMF (2 mL) under argon was added 55% sodium hydride in mineral oil (56 mg, 1.3 mmol). After 1 h, iodomethane (184 mg, 1.3 mmol) was added and the solution was stirred at rt. After 14 h, the solvents were removed in vacuo, the remaining residue was partitioned between DCM and brine, separated, the organic phase was dried (NagSO^. The solvents were removed in vacuo and the remaining residue was purified by preparative HPLC to give the title compound (0.2 g, 48%) as white solid. LCMS (Method D): RT = 1.05 min, m / z = 444 [M+H]+.

[0899] Step 2: 5-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-1-methyl-2-(thiophen-3-yl)pyridin-4(1H)- one hydrochloride: Prepared according to General Procedure 1 using tert-butyl 6-((1- methyl-4-oxo-6-(thiophen-3-yl)-1 ,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9- carboxylate (50 mg, 113 pmol), 4M HOI in 1 ,4-dioxane (0.338 mL) and DCM (1 .0 mL) but without SCX-2 purification to give the title compound (42 mg, 98%). LCMS (Method A): RT= 0.42 min, m / z = 344 [M+H]+.

[0900] Intermediate 60: 3-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-6-(2-methoxyohenyl)Dyridin- 2(1 H)-one hydrochloride

[0901] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- (m-tolyl)pyridin-2(1 H)-one hydrochloride (Intermediate 52) except using 2- methoxyphenylboronic acid [commercially available] instead of m-tolylboronic acid in Step

[0902] 1 and using 4M HCI in 1 ,4-dioxane / 1 ,4-dioxane instead of TFA / DCM and omitting the SCX-

[0903] 2 purification in Step 5 to give the title compound. LCMS (Method A): RT = 0.55 min, m / z = 354 [M+H]+. -methvl-1 H-ovrazol-5-'

[0904] Step 1: tert-Butyl 4-((6-chloro-2-(2-(trimethylsilyl)ethoxy)pyridin-3-yl)methyl)-3,3- dimethylpiperazine-1 -carboxylate: To a stirred solution of (6-chloro-2-(2- (trimethylsilyl)ethoxy)pyridin-3-yl)methanol (260 mg, 1.00 mmol) [prepared according to WO2018195321] in DCM (10 mL) under an atmosphere of N2at 0 °C were sequentially added triethylamine (167 μL, 1.20 mmol) and methanesulfonyl chloride (85.7 μL, 1.10 mmol). After stirring at 0 °C for 30 min, the ice-bath was removed and the reaction was stirred at rt for 3 h. The reaction was cooled to 0 °C before further triethylamine (167 μL, 1.20 mmol) and methanesulfonyl chloride (85.7 μL, 1.10 mmol) were sequentially added. After stirring at 0 °C for 30 min the ice-bath was removed and the reaction was stirred at rt for 19 h. The reaction was cooled to 0 °C before further triethylamine (167 μL, 1 .20 mmol) and methanesulfonyl chloride (85.7 μL, 1.10 mmol) were sequentially added. After stirring at 0 °C for 30 min, the ice-bath was removed and the reaction was stirred at rt for 3 h before the reaction mixture was washed sequentially with water (10 mL), 1 M NaOH(aq) solution (10 mL) and brine (10 mL) using a phase separator. The organic layer was concentrated under reduced pressure before MeCN (1 mL), tert-butyl 3,3- dimethylpiperazine-1 -carboxylate (236 mg, 1.10 mmol) and DIPEA (227 μL, 1.30 mmol) were added. After stirring the resulting suspension at rt for 4 days, the temperature was increased to 40 °C to give a solution which was stirred for a further 2 days at 40 °C. Upon cooling to rt, water (15 mL) was added, and the resulting mixture was extracted with DCM (3 x 10 mL) using a phase separator. The combined organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography to give the title compound (322 mg, 70%) as a colourless oil. LCMS (Method A): RT = 1.26 min, m / z = 456, 457 [M+H]+.

[0905] Step 2: tert-Butyl 3,3-dimethyl-4-((6-(1-methyl-1H-pyrazol-5-yl)-2-(2- (trimethylsilyl)ethoxy)pyridin-3-yl)methyl)piperazine-1 -carboxylate'. A sealed 2-5 mL microwave vial charged with tert-butyl 4-((6-chloro-2-(2-(trimethylsilyl)ethoxy)pyridin-3- yl)methyl)-3,3-dimethylpiperazine-1 -carboxylate (96.6 mg, 0.212 mmol), 1-methyl-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (88.1 mg, 0.424 mmol), potassium phosphate (135 mg, 0.635 mmol), Pd(dppf)Cl2.DCM (9 mg, 0.0106 mmol), 1 ,4- dioxane (1 .5 mL) and water (0.5 ml_) was 'degassed' by evacuating and refilling the vessel three times with N2. The reaction was heated under microwave irradiation at 120 °C for 30 min. Upon 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 EtOAc (3 x 20 mL). The combined organic phase was dried (phase separator) and concentrated under reduced pressure. The residue was purified by flash chromatography to give the title compound (91.3 mg, 85%). LCMS (Method A): RT = 1.15 min, m / z = 502 [M+H]+.

[0906] Step 3: 3-((2,2-Dimethylpiperazin- 1 -yl)methyl)-6-(1 -methyl- 1 H-pyrazol-5-yl)pyridin-2( 1 H)- one hydrochloride'. A mixture of tert-butyl 3,3-dimethyl-4-((6-(1-methyl-1 H-pyrazol-5-yl)-2- (2-(trimethylsilyl)ethoxy)pyridin-3-yl)methyl)piperazine-1 -carboxylate (91.3 mg, 0.182 mmol), 4 M HCI in 1 ,4-dioxane (908 μL, 3.63 mmol) and DCM (1.8 mL) was stirred at rt for 16 h. The resulting suspension was filtered, the solids were washed with DCM (3 x 2 mL) and dried in a vacuum oven at 50 °C to give title compound (56 mg, 82%) as yellow solid. LCMS (Method A): RT= 0.33 min, m / z= 302 [M+H]+.

[0907] Intermediate 62: (1 S,2fl,5fl)-2-(2,5-DifluoroDhenyl)-8-oxa-3-azabicvclof3.2.1loctane

[0908] Step 1: (R)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)dihydrofuran-2(3H)-one:To a stirred 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) at 0 °C was added tert-butylchlorodiphenylsilane (2.91 mL, 11 .2 mmol). The reaction mixture was allowed to warm to rt. After 16 h, EtOAc (50 mL) was added, the resulting mixture was washed with 1 :1 brine / water (3 x 50 mL), the organic phase was dried (MgSO4), and concentrated under reduced pressure. The remaining residue was purified by flash chromatography to give title compound (2.74 g, 89%). LCMS (Method A): RT = 1.70 min, m / z = 277 [M-Ph]+.1H NMR (500 MHz, CDCI3): δ 7.70 - 7.61 (m, 4H), 7.48 - 7.34 (m, 6H), 4.66 - 4.56 (m, 1 H), 3.88 (dd, 1 H), 3.69 (dd, 1 H), 2.67 (ddd, 1 H), 2.51 (ddd, 1 H), 2.37 - 2.15 (m, 2H), 1.06 (s, 9H). Step 2: (5R)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-ol: To a stirred solution of (fl)-5-(((tert-butyldiphenylsilyl)oxy)methyl)dihydrofuran-2(3H)-one (2.74 g, 7.72 mmol) in diethyl ether (40 mL) at -78 °C under nitrogen and was added a 1 M solution of diisobutylaluminium hydride in DCM (11.6 mL, 11.6 mmol). After 5 h at -78 °C, the reaction mixture was quenched by the addition of MeOH (5 mL). After a further 15 min at -78 °C, the reaction mixture was warmed to rt, diluted with diethyl ether (150 mL) and washed using 0.2 M sodium tartrate^) solution (3 x 100 mL) and brine. The organic phase was dried (MgSO-O, filtered, and concentrated under reduced pressure to give the title compound (2.75 g, quantitative). LCMS (Method A): RT= 1.69 min, m / z = 339 [M-OH]+.

[0909] Step 3: (R)-tert-Butyl((2,3-dihydrofuran-2-yl)methoxy)diphenylsilane:To a stirred 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) in DCM (50 mL) at -50 °C under nitrogen was added methanesulfonyl chloride (748 μL, 9.64 mmol). After 3 h at -50 °C, the reaction mixture was warmed to rt and subsequently stirred at reflux for a further 18 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure and the remaining residue was purified by flash chromatography to give title compound (1.37 g, 52%).1H NMR (500 MHz, CDCI3): δ 7.74 - 7.65 (m, 4H), 7.45 - 7.34 (m, 6H), 6.27 (q, 1 H), 4.85 (q, 1 H), 4.71 - 4.58 (m, 1 H), 3.75 (dd, 1 H), 3.68 (dd, 1 H), 2.64 (ddt, 1 H), 2.47 (ddt, 1 H), 1.06 (s, 9H).

[0910] Step 4: (R)-(2,3-Dihydrofuran-2-yl)methyl 4-methylbenzenesulfonate:To (R)-tert-butyl((2,3- dihydrofuran-2-yl)methoxy)diphenylsilane (1.37 g, 4.05 mmol) was added a 1 M TBAF in THF solution (4.05 mL, 4.05 mmol) and the resulting mixture was stirred at rt for 1 h. The reaction mixture was diluted with DCM (25 mL) and cooled to 0 °C before 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 h and allowed to warm to rt. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in EtOAc (50 mL) and washed with 1 :1 brine / water (2 x 50 mL). The organic layer was dried (MgSCU), filtered, concentrated under reduced pressure, and the remaining residue was purified by flash chromatography to give title compound (858 mg, 83%). LCMS (Method B): RT = 1 .40 min, m!z= 255 [M+H]+.

[0911] Step 5: (R)-2-((2,3-Dihydrofuran-2-yl)methyl)isoindoline-1 ,3-dione: A mixture of (F?)-(2,3- dihydrofuran-2-yl)methyl 4-methylbenzenesulfonate (858 mg, 3.74 mmol) and potassium 1 ,3-dioxoisoindolin-2-ide (937 mg, 5.06 mmol) in DMF (13 mL) under nitrogen was stirred at 75 °C for 19 h. Upon cooling to rt, the reaction mixture was diluted with EtOAc (50 ml_) and washed with 1 :1 brine / water (3 x 50 mL). The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The remaining residue was purified by flash chromatography to give title compound (623 mg, 80%). LCMS (Method A): RT= 1 .10 min, mlz= 230 [M+H]+.

[0912] Step 6: (R)-(2,3-Dihydrofuran-2-yl)methanamine:To (R)-2-((2,3-dihydrofuran-2- yl)methyl)isoindoline-1 , 3-dione (310 mg, 1.35 mmol) in MeOH (5.5 mL) was added hydrazine monohydrate (250 μL, 8.1 mmol) and the resulting mixture was heated at 60 °C for 2 h. Upon cooling to rt, a 2M sodium hydroxide^) solution (10 mL) was added and the resulting mixture was extracted using DCM (3 x 20 mL). The combined phase was washed using brine (50 mL), dried (MgSCM, filtered, and concentrated at reduced pressure (41 °C, 220 mbar) to give the title compound (140 mg, crude) that was used in the next step without purification.

[0913] Step 7: (1S,2R,5R)-2-(2,5-Difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane:To 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) was added 3A molecular sieves (300 mg) 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 resultant 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. Due to incomplete reaction, further PhSiH3(0.33 mL, 2.71 mmol) was added and the reaction was continued at 85 °C for 16 h. Due to incomplete reaction, further 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 remaining residue was purified by flash chromatography (20-100% EtOAc in cyclohexane) to give the title compound (57 mg, 19%). LCMS (Method C): RT = 0.50 min, m / z = 226 [M+H]+.

[0914] Intermediate 63: 3-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-6-fluoro-1-methylguinolin-4(1 H}- one

[0915] Step 1: 6-Fluoro-3-(hydroxymethyl)-1-methylquinolin-4(1H)-one:To a stirred solution of 6- fluoro-3-(hydroxymethyl)quinolin-4(1 / - / )-one (965 mg, 5.00 mmol) in water (40 mL) were added NaOH (260 mg, 6.49 mmol), followed by dimethyl sulfate (1.40 ml_,19.0 mmol) at rt. After 3 h, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (0.79 g, 76%) as an off-white solid. LCMS (Method E): RT = 1.80 min, m / z = 208 [M+H]+.

[0916] Step 2: 3-(Chloromethyl)-6-fluoro-1-methylquinolin-4(1H)-one: To a stirred solution of 6- fluoro-3-(hydroxymethyl)-1-methylquinolin-4(1 H)-one (300 mg 1.45 mmol) in DCM (10 mL) was added SOCI2(0.31 mL, 4.34 mmol) at 50 °C. After 16 h, the solvents were evaporated under reduced pressure to yield the title compound (0.32 g, 98%) that was used in the next step without further purification.1H NMR (400 MHz, DMSO-cfe): 58.38 (s, 1 H), 7.97 -7.85 (m, 1 H), 7.82 - 7.79 (m, 1 H), 7.72 - 7.68 (m, 1 H), 4.64 (s, 2H), 3.87 (s, 3H).

[0917] Step 3: tert-Butyl 6-((6-fluoro-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate:To a stirred solution of 3-(chloromethyl)-6-fluoro-1- methylquinolin-4(1 F / )-one (0.32 g, 1.42 mmol) in MeCN (40 mL) were added tert-butyl 6,9- diazaspiro[4.5]decane-9-carboxylate (0.511 g, 2.13 mmol) and DIPEA (0.74 mL, 4.25 mmol) at rt. After 2 h, the reaction mixture was concentrated under reduced pressure to get crude product which was purified by preparative HPLC to give the title compound (0.1 g, 16%) as an off-white solid. LCMS (Method F): RT = 2.68 min, mlz= 430 [M+H]+.

[0918] Step 4: 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-6-fluoro-1-methylquinolin-4(1H)-one: Prepared according to General Procedure 1 using tert-butyl 6-((6-fluoro-1-methyl-4-oxo- 1 ,4-dihydroquinolin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (50 mg, 116 pmol), TFA (0.5 mL) and DCM (1.0 mL) to give the title compound (35.7 mg, 93%). LCMS (Method C): RT = 0.46 min, m / z = 330 [M+H]+.

[0919] Intermediate 64: rac-(2fl,3fl)-3-(2,5-difluoroDhenyl)-2-methylmorDholine

[0920] To 2-vinyloxyethanamine (100 mg, 1.15 mmol) and 2,5-difluorobenzaldehyde (163 mg, 1.15 mmol) in DCM (1.4 mL) was added 3A molecular sieves (300 mg) at rt. After 16 h, the reaction mixture was filtered (syringe filter) and evaporated under reduced pressure (40 °C, 210 mbar). The resultant 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 was heated at 85 °C for 5 h. Due to incomplete reaction, further PhSiH3(0.28 mL, 2.30 mmol) was added and the reaction was continued at 85 °C for 16 h. Due to incomplete reaction, further PhSiH3(0.28 mL, 2.30 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 remaining residue was purified by flash chromatography (20-100% EtOAc in cyclohexane) to give the title compound (22 mg, 9%). LCMS (Method C): RT = 0.52 min, m!z = 214 [M+H]+.

[0921] Intermediate 65: 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-1-methyl-2-(1 -methyl-1 / 7-

[0922] -one

[0923] The title compound was prepared similarly to 5-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-1- methyl-2-(thiophen-3-yl)pyridin-4(1 Aft-one hydrochloride (Intermediate 59) except using tert-butyl 6-((6-( 1 -methyl-1 A / -pyrazol-5-yl)-4-oxo-1 ,4-dihydropyridin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate instead of tert-butyl 6-((1 -methyl-4-oxo-6-(thiophen-3- yl)-1 ,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate in Step 1 and using TFA / DCM instead of 4M HCI in 1 ,4-dioxane / DCM and including the SCX-2 purification in the final step to give the title compound. LCMS (Method C): RT = 0.38 min, m!z = 342 [M+H]+.

[0924] Intermediate 66: 3-((6,9-DiazasDiro[4.5ldecan-6-yl)methyl)-6-(trifluoromethyl)Dyridin-2(1 Aft- one hydrochloride

[0925] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-4H- pyrido[1 ,2-a]pyrimidin-4-one (Intermediate 33) except omitting Step 1 and using 3-bromo-6- (trifluoromethyl)pyridin-2(1 H)-one [commercially available] instead of 3-bromo-4H- pyrido[1 ,2-a]pyrimidin-4-one in Step 2 and using 4M HCI in 1 ,4-dioxane / 1 ,4-dioxane instead of TFA / DCM and omitting the SCX-2 purification in the final step to give the title compound. LCMS (Method A): RT = 0.51 min, m / z = 316 [M+H]+.

[0926] Intermediate 67: 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-2-(trifluoromethyl)Dyridin-4(1 H}- one hydrochloride

[0927] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-4H- pyrido[1 ,2-a]pyrimidin-4-one (Intermediate 33) except omitting Step 1 and using 5-bromo-2- (trifluoromethyl)pyridin-4(1 Hj-one [commercially available] instead of 3-bromo-4H- pyrido[1 ,2-a]pyrimidin-4-one in Step 2 and using 4M HCI in 1 ,4-dioxane / 1 ,4-dioxane instead of TFA / DCM and omitting the SCX-2 purification in the final step to give the title compound. LCMS (Method A): RT = 0.55 min, m / z = 316 [M+H]+.

[0928] Intermediate 68: 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-1-methyl-2-(1 -methyl-1 H-

[0929] Dyrazol-3-yl)Dyridin-4(1 F / )-one hydrochloride

[0930] The title compound was prepared similarly to 5-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-1- methyl-2-(thiophen-3-yl)pyridin-4(1 H)-one hydrochloride (Intermediate 59) except using tert-butyl 6-((6-(1 -methyl-1 H-pyrazol-3-yl)-4-oxo-1 ,4-dihydropyridin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate instead of tert-butyl 6-((1 -methyl-4-oxo-6-(thiophen-3- yl)-1 ,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate in Step 1 to give the title compound. LCMS (Method A): RT = 0.37 min, m!z = 342 [M+H]+.

[0931] Intermediate 69: (S)-7-Fluoro-3-((2-methylpiperazin-1 -yl)methyl)-4 / - / -pyrido[1 ,2-aloyrimidin- 4-one hydrochloride

[0932] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-7- fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one hydrochloride (Intermediate 47) except using tert- butyl (S)-3-methylpiperazine-1 -carboxylate [commercially available] instead of te / t-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate in Step 4 to give the title compound. LCMS (Method A): RT= 0.31 min, m!z = 277 [M+H]+.

[0933] Intermediate 70: 3-((6,9-Diazaspiro[4.51decan-6-yl)methyl)-7-chloro-4H-pyrido[1 ,2-

[0934] -4-one

[0935] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-7- fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one hydrochloride (Intermediate 47) except using 7- chloro-4H-pyrido[1 ,2-a]pyrimidin-4-one [commercially available] instead of 7-fluoro-4H- pyrido[1 ,2-a]pyrimidin-4-one in Step 1 to give the title compound. LCMS (Method A): RT= 0.53 min, m / z = 333 [M+H]+.

[0936] Intermediate 71 : 3-((1 ,4-Diazaspiro[5.51undecan-1 -yl)methyl)-7-fluoro-4 / - / -pyrido[1 ,2-

[0937] -4-one

[0938] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-7- fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one hydrochloride (Intermediate 47) except using tert- butyl 1 ,4-diazaspiro[5.5]undecane-4-carboxylate [commercially available] instead of tert- butyl 6,9-diazaspiro[4.5]decane-9-carboxylate in Step 4 to give the title compound. LCMS (Method A): RT= 0.48 min, m / z = 331 [M+H]+.

[0939] Intermediate 72: 3-((2,2-Dimethylpiperazin-1 -yl)methyl)-7-fluoro-4H-pyrido[1 ,2-aloyrimidin- 4-one hydrochloride

[0940] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-7- fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one hydrochloride (Intermediate 47) except using tert- butyl 3, 3-dimethylpiperazine-1 -carboxylate [commercially available] instead of tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate in Step 4 to give the title compound. LCMS (Method A): RT= 0.36 min, m!z = 291 [M+H]+.

[0941] Intermediate 73: (R)-7-Fluoro-3-((2-methyloiperazin-1-yl)methyl)-4 / 7-pyrido[1 ,2-alpyrimidin- 4-one hydrochloride

[0942] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-7- fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one hydrochloride (Intermediate 47) except using tert- butyl (R)-3-methylpiperazine-1 -carboxylate [commercially available] instead of tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate in Step 4 to give the title compound. LCMS (Method A): RT= 0.26 min, m / z = 277 [M+H]+.

[0943] Intermediate 74: 3-((6,9-Diazaspiro[4.51decan-6-yl)methyl)-7-methyl-4 / - / -pyrido[1 ,2-

[0944] -4-one

[0945] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-7- fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one hydrochloride (Intermediate 47) except using 7- methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one [commercially available] instead of 7-fluoro-4H- pyrido[1 ,2-a]pyrimidin-4-one in Step 1 to give the title compound. LCMS (Method A): RT = 0.46 min, m!z= 313 [M+H]+.

[0946] Intermediate 75: 3-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-8-methoxy-4 / - / -oyrido[1 ,2-

[0947] -4-one

[0948] To a stirred solution of 4-methoxy-2-aminopyridine (15.8 g, 127 mmol) in EtOH (300 mL) was added 2, 2-dimethyl-1 ,3-dioxane-4, 6-dione (20.1 g, 140 mmol) and triethyl orthoformate (20.7 g, 140 mmol) at rt. The reaction mixture was stirred at reflux for 24 h, evaporated to dryness, the residue was dissolved in diphenylether (100 mL) and heated to 240 °C for 3 h. After cooling to rt, the reaction mixture was poured into hexane (1 .5 L), the resultant precipitate was filtered and washed with hexane to give 8-methoxy-4H-pyrido[1 ,2- a]pyrimidin-4-one (11 .1 g, 50%). LCMS (Method D): RT = 0.72 min, mlz = 177 [M+H]+. Subsequently, the title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6- yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one hydrochloride (Intermediate 47) except using 8-methoxy-4H-pyrido[1 ,2-a]pyrimidin-4-one instead of 7-fluoro-4H-pyrido[1 ,2- a]pyrimidin-4-one in Step 1 to give the title compound. LCMS (Method A): RT = 0.44 min, m!z = 329 [M+H]+.

[0949] Intermediate 76: 3-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-7,8-dihvdroDyrrolo[1 ,2-

[0950] -one

[0951] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-7- fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one hydrochloride (Intermediate 47) except using 7,8- dihydropyrrolo[1 ,2-a]pyrimidin-4(6H)-one [commercially available] instead of 7-fluoro-4H- pyrido[1 ,2-a]pyrimidin-4-one in Step 1 and using TFA / DCM instead of 4M HCI in 1 ,4- dioxane / 1 ,4-dioxane and including SCX-2 purification in the final step to give the title compound. LCMS (Method C): RT = 0.42 min, m / z = 289 [M+H]+. Intermediate 77: 5-((tert-Butoxycarbonyl)amino)-2',5'-difluoro-[1 ,r-biDhenyl1-2-carboxylic acid

[0952] Step 1: 5-amino-2',5'-difluoro-[ 1, 1 '-biphenyl]-2-carboxylic acid: 2',5'-Difluoro-5-nitro-[1 ,1 biphenyl]-2-carboxylic acid (0.1 g, 0.35 mmol) [commercially available] was dissolved in MeOH (3 mL) and the solution was passed through an H-Cube® Pro hydrogenation flow reactor containing a 10%w / w Pd / C cartridge with a flow rate of 1 mL / min at 30 °C. After one cycle, the solvents were removed in vacuo to give the title compound (0.09 g, 98%). LCMS (Method A): RT = 0.90 min, m!z = 250 [M+H]+.

[0953] Step 2: 5-((tert-Butoxycarbonyl)amino)-2',5'-difluoro-[1, r-biphenyl]-2-carboxylic acid: To a stirred solution 5-amino-2',5'-difluoro-[1 ,1 '-biphenyl]-2-carboxylic acid (0.09 g, 0.35 mmol) and triethylamine (0.15 mL, 1 .06 mmol) in 1 ,4-dioxane (4 mL) / water (2 mL) was added BOC2O (0.16 mL, 0.71 mmol). The reaction mixture was stirred at rt for 24 h. The solvents were removed in vacuo and a 3 M HCI(aq) solution (10 mL) was added dropwise to the remaining residue. The resultant precipitate was filtered, washed using water and dried under vacuum to give the title compound (0.076 g, 61%). LCMS (Method A): RT= 1 .31 min, mlz = 348 [M-H]-.

[0954] Intermediate 78: 3-((6,9-DiazasDiro[4.5ldecan-6-yl)methyl)-7-fluoro-2-methyl-4H-Dyridof1 ,2- alDyrimidin-4-one hydrochloride

[0955] To a stirred solution of 5-fluoro-2-aminopyridine (10.0 g, 89 mmol) in EtOH (200 mL) was added 2, 2-dimethyl-1 ,3-dioxane-4, 6-dione (14.1 g, 98 mmol) and triethyl orthoacetate (15.9 g, 98 mmol) at rt. The reaction mixture was stirred at reflux for 24 h, evaporated to dryness, the residue was dissolved in diphenylether (90 mL) and heated to 240 °C for 3 h. After cooling to rt, the reaction mixture was poured into hexane (1 .0 L), the resultant precipitate was filtered and washed with hexane to give 7-fluoro-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4- one (6.2 g, 39%). Subsequently, the title compound was prepared similarly to 3-((6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one hydrochloride (Intermediate 47) except using 7-fluoro-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one instead of 7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one in Step 1 to give the title compound. LCMS (Method A): RT = 0.47 min, m!z = 331 [M+H]+. idin-4-’

[0956] Step 1: Benzyl (2S,4R)-4-((tert-butoxycarbonyl)amino)-2-(2,5-difluorophenyl)piperidine-1- carboxylate: To a stirred solution of tert-butyl A / -[(2S,4R)-2-(2,5-difluorophenyl)-4- piperidyl]carbamate (0.3 g, 0.96 mmol) in THF (2 mL) was added benzyl (2,5- dioxopyrrolidin-1 -yl) carbonate (0.28 g, 1 .15 mmol) followed by a solution of sodium bicarbonate (0.16 g, 192 mmol) in water (2 mL). After 24 h, the reaction mixture was partitioned between EtOAc (10 mL) and brine (10 mL) and separated. The organic phase was washed using water (10 mL), followed by brine (10 mL). The solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-60% EtOAc in cyclohexane) to give the title compound (0.31 g, 59%). LCMS (Method A): RT= 1 .56 min, m / z = 347 [M-Boc+H]+.

[0957] Step 2: Benzyl (2S,4R)-4-((tert-butoxycarbonyl)(2-fluoroethyl)amino)-2-(2,5- difluorophenyl)piperidine-1 -carboxylate: To a stirred solution of benzyl (2S,4R)-4-((tert- butoxycarbonyl)amino)-2-(2,5-difluorophenyl)piperidine-1 -carboxylate (0.3 g, 0.67 mmol) in DMF (3 mL) was added 55% sodium hydride dispersion in mineral oil (0.035 g, 0.87 mmol) at 0 °C. After 30 min, 1 -fluoro-2-iodoethane (0.07 mL, 0.80 mmol) was added. After 24 h, further 1 -fluoro-2-iodoethane (0.07 mL, 0.80 mmol) and sodium hydride (55% in mineral oil, 0.035 g, 0.87 mmol) were added. After a further 24 h, the reaction mixture was partitioned between EtOAc (30 mL) and 15% NFLCIfaq) solution (10 mL), separated, the organic phase was washed using water (10 mL), followed by brine (10 mL), and dried (Mg2SO4). The solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-40% EtOAc in cyclohexane) to give the title compound (0.1 g, 30%). LCMS (Method A): RT= 1.68 min, m / z = 393 [M-Boc+H]+. Step 3: tert-Butyl ((2S,4R)-2-(2,5-difluorophenyl)piperidin-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) was dissolved in MeOH (3 mL) and the solution was passed through an H-Cube® Pro hydrogenation flow reactor containing a 10%w / w Pd / C cartridge with a flow rate of 1 mL / min at 50 °C. After one cycle, the solvents were removed in vacuo to give the title compound (0.05 g, 85%). LCMS (Method A): RT = 0.778 min, m / z = 359 [M+H]+. i-6-yl) methyl)- 1 -phenvl-1 ,2-dihvdro-3H-

[0958] Step 1: Ethyl 3-oxo-1 -phenyl-2,3-dihydro-1 H-pyrazole-4-carboxylate: To a solution of N- phenylacetohydrazide (10.0 g, 66.6 mmol) in POCI3 (37.4 mL, 400 mmol) was added diethyl 2-(ethoxymethylene)malonate (14.8 g, 73.2 mmol) at rt and the resultant reaction mixture was heated at 70 °C. After 3 h, the reaction mixture was cooled and quenched using ice cold water. The resultant precipitate was filtered and washed using water. The residual solid was dissolved in EtOAc (200 mL), washed with brine (100 mL), dried (Na2SO4) and the solvents were removed in vacuo to give the title compound (15.4 g, 16%). LCMS (Method E): RT= 3.02 min, m / z = 233 [M+H]+.

[0959] Step 2: Ethyl 3-methoxy-1-phenyl-1H-pyrazole-4-carboxylate: To a stirred solution of ethyl 3-oxo-1-phenyl-2,3-dihydro-1 H-pyrazole-4-carboxylate (300 mg, 1.29 mmol) and K2CO3 (250 mg, 1 .80 mmol) in DMF (5 mL) was added iodomethane (96.5 μL, 1 .55 mmol) at rt. After 4 h, the reaction mixture was diluted with ice cold water and extracted using EtOAc (50 mL). The organic phase was washed using brine (20 mL), dried (Na2SO4), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-20% EtOAc in hexane) to give title compound (220 mg, 69.1%). LCMS (Method E): RT = 3.48 min, m / z = 247 [M+H]+. Step 3: (3-Methoxy-1 -phenyl-1 H-pyrazol-4-y I) methanol: To a stirred solution of ethyl 3- methoxy-1 -phenyl-1 H-pyrazole-4-carboxy late (100 mg, 0.41 mmol) in diethyl ether (2 ml_) was added 1 M DIBAL-H in toluene (0.046 mL, 1 .22 mmol) at -78 °C. The temperature of the reaction mixture was allowed to increase to -10 °C and held at this temperature. After 4 h, the reaction mixture was quenched using saturated NH4CI(aq) solution, and extracted using EtOAc (20 mL). The organic phase was washed using brine (20 mL), dried (Na2SO4), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-50% EtOAc in hexane) to give the title compound (60 mg, 72%). LCMS (Method E): RT = 2.78 min, mlz = 205 [M+H]+.

[0960] Step 4: 4-(Bromomethyl)-3-methoxy-1 -phenyl-1 H-pyrazole: To a stirred solution of (3- methoxy-1 -phenyl-1 H-pyrazol-4-yl)methanol (570 mg, 2.79 mmol) in DCM (85 mL) was added triphenylphosphine (806 mg, 3.07 mmol) and CBr4(1.0 g, 3.07 mmol) at rt. After 16 h, the reaction mixture was concentrated in vacuo to give the title compound (crude, 570 mg) that was used in the next step without further purification.

[0961] Step 5: tert-Butyl 6-((3-methoxy-1 -phenyl-1 H-pyrazol-4-yl)methyl)-6, 9- diazaspiro[4.5]decane-9-carboxylate: To a stirred solution of 4-(bromomethyl)-3-methoxy-1- phenyl-1 H-pyrazole (570 mg, 2.13 mmol) in MeCN (45 mL) was added CS2CO3 (1.39 g, 4.26 mmol) at rt. After 30 min, tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (1 .02 g, 4.26 mmol) was added. After 16 h, the reaction mixture was concentrated in vacuo, diluted with EtOAc (100 mL), washed using brine (50 mL), dried (Na2SO4). The solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-5% MeOH in DCM) to give the title compound (700 mg, 59% over 2 steps). LCMS (Method E): RT = 4.18 min, m / z = 427 [M+H]+.

[0962] Step 6: 4-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-1 -phenyl-1, 2-dihydro-3H-pyrazol-3-one: A slurry of tert-butyl 6-((3-methoxy-1 -phenyl-1 H-pyrazol-4-yl)methyl)-6, 9- diazaspiro[4.5]decane-9-carboxylate (670 mg, 1 .57 mmol) in 33% HBr in AcOH (4 mL) was heated at 100 °C. After 2 h, the reaction mixture was concentrated under reduced pressure and the remaining residue was triturated with diethyl ether (3 x 20 mL) to give crude product material (800 mg) of which 150 mg was purified by preparative HPLC to give the title compound (52 mg, 35% recovery) and the rest of the material (650 mg) was held for use in a subsequent reaction without further purification. LCMS (Method E): RT = 1 .97 min, m / z = 313 [M+H]+. Intermediate 81 : 4-((6,9-Diazaspiro[4.5ldecan-6-vl)methvl)-2-methyl-1 -phenyl-1 ,2-dihvdro-

[0963] 3H-pyrazol-3-one hydrochloride

[0964] 0

[0965] Step 1: tert-Butyl 6-((3-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-4-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate: To a stirred solution of 4-((6,9-diazaspiro[4.5]decan- 6-yl)methyl)-1 -phenyl-1 ,2-dihydro-3H-pyrazol-3-one (180 mg, 0.46 mmol) in DCM (4 mL) was added triethylamine (0.4 mL, 2.29 mmol) at rt, followed by BOC2O (0.09 mL, 0.41 mmol). After 2 h, the reaction mixture was diluted with water and was extracted using 9:1 DCM / MeOH (3 x 20 mL). The combined organic phase was washed using water (10 mL), followed by brine (10 mL) and dried (Na2SO4). The solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-5% MeOH in DCM) to give the title compound (90 mg, 47%). LCMS (Method E): RT = 1.90 min, m!z= 413 [M+H]+.

[0966] Step 2: tert-Butyl 6-((2-methyl-3-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-4-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate:To a stirred solution of tert-butyl 6-((3-oxo-1-phenyl- 2,3-dihydro-1 H-pyrazol-4-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (150 mg, 0.36 mmol) in 1 :1 DCM / MeOH (5 mL) was added trimethylsilyldiazomethane (0.12 mL, 1 .09 mmol) at rt. After 5 h, the reaction mixture was diluted with water (20 mL) and was extracted using 9:1 DCM / MeOH (3 x 20 mL). The combined organic phase was washed using brine (20 mL), dried (Na2SO4), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-15% EtOAc in hexane, then 10% MeOH in DCM) to give tert-butyl 6-((3-methoxy-1 -phenyl-1 H-pyrazol-4-yl)methyl)-6, 9- diazaspiro[4.5]decane-9-carboxylate (25 mg, 16.8%, first eluting): LCMS (Method E): RT= 3.56 min, m!z = 427 [M+H]+; and the title compound (35 mg, 21%, second eluting): LCMS (Method E): RT= 2.60 min, m / z= 427 [M+H]+.

[0967] Step 3: 4-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-2-methyl-1-phenyl- 1 ,2-dihydro-3H- pyrazol-3-one hydrochloride: Prepared according to General Procedure 1 using tert-butyl 6- ((2-methyl-3-oxo-1-phenyl-2,3-dihydro-1 / 7-pyrazol-4-yl)methyl)-6,9-diazaspiro[4.5]decane- 9-carboxylate (32 mg, 75.0 pmol), 4M HCI in 1 ,4-dioxane (0.375 mL) and 1 ,4-dioxane (3.0 mL) to give the title compound (28.0 mg, quantitative). LCMS (Method A): RT = 0.42 min, m / z= 327 [M+H]+.

[0968] Intermediate 82: 6-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-5 / - / -thiazolo[3,2-alDyrimidin-5- one hydrochloride

[0969] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-7- fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one hydrochloride (Intermediate 47) except using 5H- thiazolo[3,2-a]pyrimidin-5-one [commercially available] instead of 7-fluoro-4H-pyrido[1 ,2- a]pyrimidin-4-one in Step 1 to give the title compound. LCMS (Method A): RT = 0.39 min, m!z = 305 [M+H]+.

[0970] Intermediate 83: 3-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-2-cvcloDroDyl-7-fluoro-4H- pyrido[1 ,2-alDyrimidin-4-one

[0971] 5-Fluoro-2-aminopyridine (5.0 g, 45 mmol), ethyl 3-cyclopropyl-3-oxopropanoate (16.4 g, 90 mmol) and bismuth(lll) chloride (0.7 g, 2.2 mmol) were stirred at reflux for 24 h. The reaction mixture was evaporated to dryness, dissolved in diphenylether (100 mL) and heated to 100 °C for 24 h. After cooling to rt, the reaction mixture was purified by flash chromatography to give 2-cyclopropyl-7-fluoro-4 / 7-pyrido[1 ,2-a]pyrimidin-4-one (4.1 g, 43%). LCMS (Method D): RT = 0.87 min, m / z = 205 [M+H]+. Subsequently, the title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4 / 7- pyrido[1 ,2-a]pyrimidin-4-one hydrochloride (Intermediate 47) except using 2-cyclopropyl-7- fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one instead of 7-fluoro-4 / 7-pyrido[1 ,2-a]pyrimidin-4-one in Step 1 and dissolving the HCI salt in the final step and washing with saturated sodium bicarbonate<aq) to give the title compound as the free base. LCMS (Method A): RT= 0.59 min, m!z = 357 [M+H]+.

[0972] Intermediate 84: 3- i,9-Di> i-6-vl)methvD-6-phenvlovridazin-4(1 H)-one

[0973] Step 1: 4-Methoxy-6-phenylpyridazin-3(2H)-one:To a stirred solution of 4-methoxy-6- chloropyridazin-3(2H)-one (6.0 g, 37.5 mmol) [commercially available] in 1 ,4-dioxane (130 mL) / water (45 mL) were added phenylboronic acid (5.0 g, 41 mmol), Pd(dppf)Cl2 (1.5 g, 5 mol%) and potassium phosphate tribasic (24.0 g, 112 mmol). The reaction mixture was degassed and backfilled using argon and heated to reflux. After 24 h, the solvents were removed in vacuo and the remaining residue was dissolved in hot water (200 mL), filtered, and acidified using HCI(aq) to -pH 3. The resultant precipitate was filtered, washed with water, and dried under vacuum to give the title compound (7.1 g, 94%). LCMS (Method D): RT = 0.98 min, m / z= 203 [M+H]+.

[0974] Step 2: 3-Chloro-4-methoxy-6-phenylpyridazine: 4-Methoxy-6-phenylpyridazin-3(2 / - / )-one (6.5 g, 62 mmol) was suspended in POCI3 (80 mL) and stirred at reflux for 4 h. After evaporation of excess POCI3, iced water was added to the remaining residue. After 1 h, the aqueous mixture was extracted using DCM. The combined organic phase was concentrated under reduced pressure and the resultant residue was dissolved in MeCN and reevaporated to give the title compound (4.4 g, 98%). LCMS (Method D): RT= 1.16 min, mlz= 221 [M+H]+.

[0975] Step 3: (4-Methoxy-6-phenylpyridazin-3-yl)methanol:To a stirred solution of 3-chloro-4- methoxy-6-phenylpy ridazine (3.6 g, 16 mmol) in 1 ,4-dioxane (90 mL) were added tributylstannylmethanol (6.94 g, 24 mmol) and XPhos Pd G4 (0.9 g, 10 mol%). The reaction mixture was degassed and purged with argon and heated to 60 °C. After 48 h, the solvents were removed in vacuo, the remaining residue was triturated in diethyl ether (70 mL), filtered, and purified by flash chromatography to give the title compound (0.4 g, 43%). LCMS (Method D): RT= 0.60 min, m / z = 251 [M+CI]’.

[0976] Step 4: tert-Butyl 6-((4-oxo-6-phenyl-1,4-dihydropyridazin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate:To a stirred solution of (4-methoxy-6-phenylpyridazin- 3-yl)methanol (0.38 g, 1 .8 mmol) in DCM (20 mL) was added thionyl chloride (3.0 mL) at rt. After 4 h, the solvents were removed in vacuo 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 resultant suspension was stirred at 80 °C for 24 h. The reaction mixture was concentrated under reduced pressure and the remaining residue was partitioned between DCM and brine, separated, and the organic phase was dried (Na2SO4). The solvents were removed in vacuo and the remaining residue was dissolved in 40% HBr(aq) (15 mL) and heated at 80 °C. After 48 h, 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 solvents were removed in vacuo and the remaining residue was washed using water and purified by preparative HPLC to give the title compound (0.10 g, 22%). LCMS (Method D): RT = 0.86 min, mlz = 425 [M+H]+.

[0977] Step 5: 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridazin-4(1H)-one hydrochloride: Prepared according to General Procedure 1 using tert-butyl 6-((4-oxo-6- phenyl-1 ,4-dihydropyridazin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (109 mg, 257 pmol), 4M HCI in 1 ,4-dioxane (1 .28 mL) and 1 ,4-dioxane (4.0 mL) to give the title compound (71 mg, 77%). LCMS (Method A): RT = 0.51 min, m!z = 325 [M+H]+.

[0978] Intermediate 85: 3-((6,9-DiazasDiro[4.51dec-2-en-6-yl)methyl)-7-fluoro-4 / - / -Dyrido[1 ,2-

[0979] -4-one

[0980] Step 1: tert-Butyl 3, 3-diallylpiperazine-1 -carboxylate: To a stirred solution of tert-butyl 3- oxopiperazine-1 -carboxylate (6.0 g, 30 mmol) in THF (80 mL) was added triallylborane (16.4 g, 90 mmol). The reaction mixture was stirred at 70 °C. After 14 h, the solvents were removed in vacuo and the remaining residue was partitioned between DCM (100 mL) and 2M NaOH(aq) (100 mL). The resultant biphasic mixture was separated, extracted (3 x DCM), dried (Na2SO4), the solvents were removed in vacuo, and the remaining residue was purified by flash chromatography to give the title compound (5.1 g, 49%).1H NMR (500 MHz, CDCh): 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). Step 2: tert-Butyl 3,3-diallyl-4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylate: To a stirred solution of tert-butyl 3, 3-diallylpiperazine-1 -carboxylate (5.50 g, 19 mmol) in DCM (100 ml_) at 0 °C was added triethylamine (2.4 g, 23 mmol), followed by dropwise addition of trifluoroacetic anhydride (4.3 g, 20.5 mmol). After 24 h, the reaction mixture was partitioned between DCM and water, separated, the organic phase was washed several times using water, dried (Na2SO4), and the solvents were removed in vacuo to give the title compound (6.9 g, 99%).1H NMR (500 MHz, CDCI3): 55.67 (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).

[0981] Step 3: tert-Butyl 6, 9-diazaspiro[4.5]dec-2-ene-9-carboxylate: To a pre-degassed (bubbling argon for 15 min) and stirred solution of tert-butyl 3,3-diallyl-4-(2,2,2- trifluoroacetyl)piperazine-1 -carboxylate (6.90 g, 19 mmol) in DCM (200 mL) was added Grubbs Catalyst® M204 (0.6 g, 5 mol%) at rt. After 48 h, 2M NaOH(aq) solution was added and the resultant mixture was heated at 40 °C. After a further 24 h, the organic phase was decanted, dried (Na2SO4), the solvents were removed in vacuo, and the remaining residue was purified by flash chromatography to give the title compound (3.2 g, 71%).1H NMR (500 MHz, CDCI3): 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, 1 H), 1 .46 (s, 9H).

[0982] Step 4: tert-Butyl 6-((7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)methyl)-6,9- diazaspiro[4.5]dec-2-ene-9-carboxylate: To a stirred solution of 3-chloromethyl-7-fluoro-4 / - / - pyrido[1 ,2-a]pyrimidin-4-one (0.70 g, 3.3 mmol) and DIPEA (1.7 g, 13.2 mmol) in MeCN (30 mL) was added tert-butyl 6,9-diazaspiro[4.5]dec-2-ene-9-carboxylate (0.94 g, 4 mmol). The resultant suspension was stirred at 80 °C. After 18 h, the solvents were removed in vacuo, and the remaining residue was partitioned between DCM and brine, separated, and extracted using DCM. The combined organic phase was dried (Na2SO 4), the solvents were removed in vacuo, and the remaining residue was purified by flash chromatography to give the title compound (0.53 g, 39%). LCMS (Method D): RT = 0.67 min, m / z = 415 [M+H]+.

[0983] Step 5: 3-((6,9-Diazaspiro[4.5]dec-2-en-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4- one hydrochloride: Prepared according to General Procedure 1 using tert-butyl 6-((7-fluoro- 4-oxo-4H-pyrido[1 ,2-a]pyrimidin-3-yl)methyl)-6,9-diazaspiro[4.5]dec-2-ene-9-carboxylate (50 mg, 121 pmol), 4M HCI in 1 ,4-dioxane (0.25 mL) and DCM (0.25 mL) to give the title compound (42.2 mg, quantitative). LCMS (Method C): RT = 0.49 min, m!z = 315 [M+H]+. Intermediate 86: 3-((6,9-Diazaspiro[4.5ldecan-6-vl)methvl)-7-bromo-4H-pvridof1 ,2- alovrimidin-4-one hydrochloride

[0984] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-7- fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one hydrochloride (Intermediate 47) except using 7- bromo-4H-pyrido[1 ,2-a]pyrimidin-4-one [commercially available] instead of 7-fluoro-4H- pyrido[1 ,2-a]pyrimidin-4-one in Step 1 to give the title compound. LCMS (Method C): RT = 0.57 min, m!z = 377 [M+H]+.

[0985] Intermediate 87: 3T(6.9-Diazaspiro[4.51decan-6-vl)methvl)-8-chloro-4F / -pyridon ,2- alovrimidin-4-one hydrochloride

[0986] The title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-7- fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one hydrochloride (Intermediate 47) except using 8- chloro-4H-pyrido[1 ,2-a]pyrimidin-4-one [commercially available] instead of 7-fluoro-4H- pyrido[1 ,2-a]pyrimidin-4-one in Step 1 to give the title compound. LCMS (Method C): RT = 0.52 min, m / z = 333 [M+H]+.

[0987] Intermediate 88: 3-((6.9-Diazaspiro[4.51decan-6-vl)methyl)-7-fluoro-2-(trifluoromethvO-4 / - / - ovridoH ,2-alpyrimidin-4-one hydrochloride

[0988] 5-Fluoro-2-aminopyridine (5.0 g, 45 mmol), ethyl 4,4,4-trifluoro-3-oxobutanoate (16.4 g, 90 mmol) and bismuth(lll) chloride (0.7 g, 2.2 mmol) were stirred at reflux for 24 h. The reaction mixture was evaporated to dryness, dissolved in diphenylether (100 mL), and heated to 100 °C for 24 h. After cooling to rt, the reaction mixture was purified by flash chromatography to give 7-fluoro-2-(trifluoromethyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one (5.1 g, 49%). LCMS (Method D): RT = 1 .13 min, m / z = 233 [M+H]+. Subsequently, the title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4 / - / - pyrido[1 ,2-a]pyrimidin-4-one hydrochloride (Intermediate 47) except using 7-fluoro-2- (trifluoromethyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one instead of 7-fluoro-4H-pyrido[1 ,2- a]pyrimidin-4-one in Step 1 to give the title compound. LCMS (Method C): RT = 0.78 min, m / z = 385 [M+H]+.

[0989] Intermediate 89: 3-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-1-methyl-1 ,6-naphthyridin- 4(1 H)-one

[0990] Step 1: Ethyl 1 -methyl-4-oxo-1 ,4-dihydro-1 ,6-naphthyridine-3-carboxylate: To a stirred solution ethyl 4-oxo-1 ,4-dihydro-1 ,6-naphthyridine-3-carboxylate (1.50 g, 6.87 mmol) [commercially available] in DMF (20 mL) was added K2CO3 (1.90 g, 13.8 mmol) and iodomethane (0.26 mL, 3.43 mmol) at rt. After 16 h, the reaction mixture was concentrated in vacuo, the remaining residue was diluted with 9:1 DCM / MeOH (75 mL) and washed using water (30 mL) and brine (30 mL). The organic phase was dried (Na2SO4), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (10% MeOH in DCM) to give the title compound (720 mg, 45%). LCMS (Method E): RT= 1.59 min, m / z = 233 [M+H]+.

[0991] Step 2: 1-Methyl-4-oxo-1 ,4-dihydro-1 ,6-naphthyridine-3-carboxylic acid: To a stirred solution of ethyl 1 -methyl-4-oxo-1 ,4-dihydro-1 ,6-naphthyridine-3-carboxylate (0.4 g, 1.72 mmol) in 4:1 THF / water (10 mL) was added LiOH.FfeO (0.18 g, 4.31 mmol) at 0 °C. The reaction mixture was stirred at rt for 16 h. The solvents were removed in vacuo and the remaining residue was diluted with water (30 mL) and acidified with glacial acetic acid to ~pH 2. The resultant precipitate was filtered and dried under vacuum to give the title compound (200 mg, 57%). LCMS (Method E): RT = 0.59 min, mlz = 205 [M+H]+.

[0992] Step 3: 3-Bromo-1 -methyl-1 ,6-naphthyridin-4(1 H)-one:To a stirred solution of 1 -methyl-4- oxo-1 ,4-dihydro-1 ,6-naphthyridine-3-carboxylic acid (0.2 g, 0.98 mmol) in 5:1 DMF / water (6 mL) were added lithium acetate (0.078 g, 1.17 mmol) and NBS (0.74 g, 4.11 mmol). The reaction mixture was heated under microwave irradiation at 85 °C for 10 min. The reaction mixture was diluted with water (10 mL), 5M sodium carbonate<aq) solution (20 mL) was added, and stirred for 30 min. The resultant biphasic mixture was separated, the aqueous phase was extracted using EtOAc (50 ml_) and the combined organic phase was dried (NaaSO^. The solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-80% EtOAc in hexane) to give the title compound (100 mg, 43%). LCMS (Method E): RT = 1.49 min, m / z = 239 [M+H]+.

[0993] Step 4: 3-(((tert-Butyldimethylsilyl)oxy)methyl)-1 -methyl-1 ,6-naphthyridin-4(1 H)-one: A stirred solution of 3-bromo-1 -methyl-1 , 6-naphthyridin-4(1 H)-one (0.14 g, 0.58 mmol) in 1 ,4- dioxane (5 mL) was degassed by bubbling argon for 20 min. tert- butyldimethyl[(tributylstannyl)methoxy]silane (0.25 g, 0.58 mmol) and XPhos Pd G2 (0.046 g, 0.06 mmol) were added and the reaction mixture was stirred at 80 °C for 24 h. The reaction mixture was filtered through Celite®, the filtrate was concentrated in vacuo and the remaining residue was purified by flash chromatography (0-30% EtOAc in hexane) to give the title compound (80 mg, 45%). LCMS (Method E): RT = 1.28 min, mlz = 305 [M+H]+.

[0994] Step 5: 3-(Hydroxymethyl)- 1 -methyl- 1,6-naphthyridin-4(1H)-one: To a stirred solution of 3- (((tert-butyldimethylsilyl)oxy)methyl)-1 -methyl-1 ,6-naphthyridin-4(1 H)-one (0.07 g, 0.23 mmol) in THF (3 mL) was added TBAF (0.09 mL, 0.35 mmol) at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with water (10 mL) and washed using EtOAc (20 mL). The aqueous phase was concentrated in vacuo and dried under vacuum to give the title compound (40 mg, crude) and used in the next step without further purification. LCMS (Method F): RT = 0.66 min, m / z = 191 [M+H]+.

[0995] Step 6: 3-(Chloromethyl)-1 -methyl-1 ,6-naphthyridin-4(1 H)-one: To a stirred solution of 3- (hydroxymethyl)-l -methyl-1 , 6-naphthyridin-4(1 H)-one (100 mg, 0.52 mmol) in DCM (5 mL) was added SOCh (0.11 mL, 1 .55 mmol) at 0 °C. The reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was concentrated in vacuo to give the title compound (100 mg, crude) that was used in the next step without further purification.

[0996] Step 7: tert-Butyl 6-((1-methyl-4-oxo-1,4-dihydro-1,6-naphthyridin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate: To a stirred solution of 3-(chloromethyl)-1 -methyl-1 ,6- naphthyridin-4(1 H)-one (100 mg, assumed 0.48 mmol) in MeCN (5 mL) were added tert- butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (0.14 g, 0.57 mmol) and CS2CO3 (0.31 g, 0.96 mmol) at rt. After 2 h, the reaction mixture was diluted with water (25 mL) and extracted using EtOAc (3 x 30 mL). The combined organic phase was washed using brine (30 mL), dried (NagSO^, the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-5% MeOH in DCM) to give the title compound (15 mg, 7% over 2 steps). LCMS (Method E): RT = 2.43 min, m / z = 413 [M+H]+.

[0997] Step 8: 3-((6, 9-Diazaspiro[4.5]decan-6-yl)methyl)- 1 -methyl- 1 ,6-naphthyridin-4( 1 H)-one: Prepared according to General Procedure 1 using tert-butyl 6-((1 -methyl-4-oxo-1 ,4-dihydro- 1 ,6-naphthyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (10.5 mg, 121 pmol), TFA (0.1 mL) and DOM (0.4 mL) to give the title compound (4.0 mg, 50%). LCMS (Method C): RT = 0.36 min, m!z = 313 [M+H]+.

[0998] Intermediate 90: (2S,4R)-2-(2,5-DifluoroDhenyl)- / V-(1 -methylcvclooroDyl)DiDeridin-4-amine bis(2,2,2-trifluoroacetate)

[0999] Step 1: tert-Butyl (2S)-2-(2,5-difluorophenyl)-4-((1-methylcyclopropyl)amino)piperidine-1- carboxylate: To a stirred solution of tert-butyl (S)-2-(2,5-difluorophenyl)-4-oxopiperidine-1 - carboxylate (1 g, 3.21 mmol) [prepared according to W02022200523 Intermediate 19, Step 5] in MeOH (20 mL) was added 1 -methylcyclopropan-1 -amine.HCI (0.52 g, 4.82 mmol) at rt. After 2 h, NaBHsCN (0.61 g, 9.64 mmol) was added portionwise. After 16 h, the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-50% EtOAc in hexane) to give the title compound (0.7 g, 59%). LCMS (Method E): RT= 1 .73 min, m / z = 367 [M+H]+.

[1000] Step 2: tert-Butyl (2S,4R)-2-(2,5-difluorophenyl)-4-(2,2,2-trifluoro-N-(1- methylcyclopropyl)acetamido)piperidine-1 -carboxylate: To a stirred solution of tert-butyl (2S)-2-(2,5-difluorophenyl)-4-((1 -methylcyclopropyl)amino)piperidine-1 -carboxylate (0.6 g, 1.63 mmol) and triethylamine (1.14 mL, 8.19 mmol) in DCM (10 mL) was added trifluoroacetic anhydride (0.43 mL, 3.11 mmol) at 0 °C. The reaction mixture was stirred at rt for 16 h. The solvents were removed in vacuo and the remaining crude mixture of diastereoisomers was purified and separated by flash chromatography (0-20% EtOAc in hexane) to give tert-butyl (2S,4S)-2-(2,5-difluorophenyl)-4-(2,2,2-trifluoro- / V-(1 - methylcyclopropyl)acetamido)piperidine-1 -carboxylate (140 mg, 18%, de = 99%) as first eluting trans diastereoisomer. LCMS (Method E): RT = 4.01 min, m / z= 463 [M+H]+.1H NMR (400 MHz, DMSO-dfe @ 100 °C): 57.25 - 7.16 (m, 2 H), 7.01 (s, 1 H), 5.55 (s, 1 H), 4.10 - 4.07 (m, 1 H), 3.67 (br s, 1 H), 3.25 - 3.19 (m, 1 H), 2.66 (br s, 1 H), 2.31 - 2.16 (m, 2H), 1.90 - 1.87 (m, 1 H), 1.36 - 1.32 (m, 12H), 1.19 - 0.75 (m, 4H); and the title compound (130 mg, 17%, de = 98%) as the second eluting cis diastereoisomer. LCMS (Method E): RT = 4.01 min, mlz= 463 [M+H]+.1H NMR (400 MHz, DMSO-d6 @ 100 °C): 57.16 - 7.15 (m, 1 H), 7.07 - 7.05 (m, 2 H), 4.93 - 4.90 (m, 1 H), 3.93 (br s, 2H), 3.62 - 3.57 (t, 1 H), 2.66 - 2.57 (m, 1 H), 2.16 (br s, 1 H), 1.95 - 1.87 (m, 2H), 1.41 (s, 3H), 1.23 (s, 9H), 1.12 - 1.07 (m, 2H), 0.84 (br s, 2H). [Note: cis and trans stereochemistry was assigned by comparison of NMR data with closely related analogues].

[1001] Step 3: tert-Butyl (2S,4R)-2-(2,5-difluorophenyl)-4-((1-methylcyclopropyl)amino)piperidine- 1 -carboxylate: To a stirred solution of tert-butyl (2S,4R)-2-(2,5-difluorophenyl)-4-[(1- methylcyclopropyl)-(2, 2, 2-trifluoroacetyl)amino]piperidine-1 -carboxylate (30 mg, 0.065 mmol) in MeOH (0.50 mL) were added K2CO3 (72 mg, 0.52 mmol) and water (0.10 mL). The reaction mixture was heated under microwave irradiation at 100 °C for 3 h. The solvents were removed in vacuo and the remaining residue was partitioned between water and DCM, separated, the aqueous phase was extracted (2 x DCM), and the combined organic phase was dried (phase separator). The solvents were removed in vacuo and the remaining residue was dissolved in DCM and loaded onto 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 ammoniacal fractions were concentrated in vacuo to give the title compound (12 mg, 50%) that was used directly in the next step without further purification. LCMS (Method A): RT = 0.90 min, m / z= 311 [M-butene+H]+.

[1002] Step 4: (2S,4R)-2-(2,5-Difluorophenyl)-N-(1-methylcyclopropyl)pipendin-4-amine bis(2,2,2- trifluoroacetate):To a stirred solution of tert-butyl (2S,4R)-2-(2,5-difluorophenyl)-4-((1- methylcyclopropyl)amino)piperidine-1 -carboxylate (12 mg, 0.033 mmmol) in DCM (0.5 mL) was added TFA (0.13 mL, 1.64 mmol) at rt. After 4 h, the solvents were removed in vacuo to give the title compound (16 mg, 98%) that was used directly in the next step without further purification. LCMS (Method A): RT = 0.17 min, m!z= 267 [M+H]+. Intermediate 91 : 5-((6,9-DiazasDiro[4.51decan-6-yl)methyl)-2-(1 -methylcvcloDroDyl)Dyridin- 4(1 H)-one

[1003] Step 1: 4-Methoxy-6-(prop-1-en-2-yl)nicotinic acid: To a stirred solution of 6-chloro-4- methoxynicotinic acid (15.3 g, 80 mmol) in 1 ,4-dioxane (350 ml_) / water (120 ml_) were added potassium trifluoro(prop-1-en-2-yl)borate (13.3 g, 88 mmol), Pd(dppf)Cl2 (3.06 g, 5 mol%) and potassium phosphate tribasic (52.0 g, 240 mmol) at rt. The resultant mixture was degassed and backfilled using argon and heated to reflux. After 24 h, the solvents were removed in vacuo, the remaining residue was dissolved in hot water (200 mL), filtered, and acidified using HCI(aq) to -pH 3. The resultant precipitate was filtered, washed using water and dried under vacuum to give the title compound (14.0 g, 91%). LCMS (Method D): RT = 0.59 min, m / z = 194 [M+H]+.

[1004] Step 2: (4-Methoxy-6-(1-methylcyclopropyl)pyridin-3-yl)methanol: To a stirred solution of 4- methoxy-6-(prop-1 -en-2-yl)nicotinic acid (12 g, 62 mmol) in MTBE (300 mL) was added a 2M solution of diazomethane in diethyl ether (300 mL). The reaction mixture was stirred at reflux for 24 h. After cooling, th...

Claims

CLAIMS:

1. A compound of formula (I):whereinR1is optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl;R2and R3are each independently selected from H and C1-C6 alkyl, or wherein R2and R3together form C3-C8 cycloalkyl, C3-C8 cycloalkenyl or 3 to 8 membered heterocycloalkyl together with the carbon to which they are attached;M is N or CRawherein Rais H, halo, optionally substituted C3-C8 cycloalkyl, or optionally substituted C1-C6 alkyl;A, D, E and G are absent andX is NR15or CH;Y is CR4or N or absent;Z is CR5, NR6or O;R4is halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, 4 to 10 membered fused-ring heterocyclyl, optionally substituted C1-C6 alkylsulfanyl, sulfoxide, sulfone, sulfoximine, optionally substituted amino, optionally substituted 3 to 8 membered heterocycloalkyl, or OR20;wherein R20is optionally substituted C1-C6 alkyl;R5is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, optionally substituted 3 to 8 membered heterocycloalkyl, amido, sulfoximine, CN, halo, C(O)OR21, OR22, or NR23R24; wherein R21is selected from H and C1-C6 alkyl;R22is selected from H and C1-C6 alkyl;R23and R24are independently selected from H and optionally substituted C1-C6 alkyl;R15is H or C1-C6 alkyl; or R4and R5together form 3 to 8 membered heterocycloalkyl or aryl together with Y and Z to which they are attached; or R4and R15together form 5 membered cycloalkyl, heterocycloalkyl, or heteroaryl together with X and Y to which they are attached;R6is H, C1-C6 alkyl, optionally substituted aryl, or C3-C8 cycloalkyl; or A is CR12or N, D is CR7or N, E is CR13or N and G is OR14or N andX is N or C;Y is C;Z is OR20, N, NR11, or O, wherein R11is H, optionally substituted 01-06 alkyl, optionally substituted 03-08 cycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl; wherein R20is H, optionally substituted 01-06 alkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, optionally substituted 3 to 8 membered heterocycloalkyl, amido, sulfoximine, CN, halo, C(O)OR25, OR26, or NR27R28;wherein R25is selected from H and C1 -C6 alkyl;R26is selected from H and C1-C6 alkyl;R27and R28are independently selected from H and C1-C6 alkyl;R7is H, halo, C1 -C6 alkyl, or OR19; wherein R19is optionally substituted C1 -C6 alkyl;R12is H, halo, or C1 -C6 alkyl;R13is H, halo, C1-C6 alkyl, OR16; or NR17R18; wherein R16is optionally substituted C1 -C6 alkyl, R17and R18are independently selected from H and C1-C6 alkyl or wherein R17and R18together form 5 to 6 membered heterocycloalkyl with the nitrogen atom to which they are attached; andR14is H, halo, or C1 -C6 alkyl; or a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof.

2. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to claim 1 , wherein for each optionally substituted group, each one or more optional substituent is independently selected from alkyl, alkoxy, oxo, halo, cycloalkyl, heterocycloalkyl, aryl, aryl substituted by one or more halo, aryl substituted by halo and alkyl, aryl substituted by halo and alkoxy, heteroaryl, hydroxyl, CR8R9R10, NR8, NR8R9, NHC(O)R8, NHCR8R9R10, NHCH2CR8R9R10and NHCH2C(O)R8, wherein R8, R9and R10are each independently selected from H, halo, hydroxyl, alkyl, cycloalkyl, cycloalkyl substituted by one or more halo or alkyl, heterocycloalkyl substituted by one or more alkyl or oxo, heteroaryl, alkoxy, CH2OH, and CH2CH2OH.

3. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein R1is optionally substituted 3 to 11 membered heterocycloalkyl.

4. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any preceding claim, wherein R1is optionally substituted 5 to 8 membered heterocycloalkyl, optionally wherein R1is optionally substituted 5 to 6 membered heterocycloalkyl.

5. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any preceding claim, wherein R1is optionally substituted morpholine, bridged azepane, diazepane, thiomorpholine, pyrrolidine, piperazine, or piperidine.

6. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any preceding claim, wherein R1is optionally substituted piperidine.

7. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 3 to 6, wherein R1is substituted by one or more alkyl, oxo, cycloalkyl, heterocycloalkyl, aryl, aryl substituted by one or more halo, heteroaryl, NR8, NR8R9, NHC(O)R8, NHCR8R9R10, NHCH2CR8R9R10and NHCH2C(O)R8, wherein R8, R9and R10are each independently selected from H, halo, hydroxyl, alkyl, cycloalkyl, cycloalkyl substituted by one or more halo or alkyl, heterocycloalkyl substituted by one or more alkyl or oxo, heteroaryl, and alkoxy.

8. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 3 to 7, wherein R1is substituted by phenyl or phenyl substituted by one or more halo, and wherein R1is optionally substituted with one or more further substituents.

9. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 3 to 8, wherein R1issubstituted by phenyl or phenyl substituted by one or more fluoro, and wherein R1is optionally substituted with one or more further substituents.

10. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 3 to 9, wherein R1is substituted by difluoro-phenyl.11 . The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 3 to 10, wherein R1is substituted by NR8R9, NHC(O)R8, or NHCH2CR8R9R10, and wherein R1is optionally substituted with one or more further substituents.

12. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 2 to 11 , wherein R8, R9, and R10are each independently selected from H, C1-C6 alkyl, fluoro-substituted C1- C6 alkyl, C1 -C6 alkoxy, CH2OH, CH2CH2OH, fluoro-substituted C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by C1 -C6 alkyl, and pyridine-substituted C1 -C6 alkyl.

13. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein R1is optionally substituted C1-C6 alkyl.

14. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to claim 13, wherein each optional substituent is selected from halo, C1-C6 alkoxy, cycloalkyl, and hydroxyl.

15. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 1 -4, wherein R1is optionally substituted amino.

16. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to claim 15, wherein R1is amino substituted with phenyl substituted by one or more halo, or benzyl substituted by one or more halo.

17. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any preceding claim, wherein R2and R3are each independently H or methyl, or wherein R2and R3together form C3-C6 cycloalkyl, cyclopentenyl or 4 to 6 membered heterocycloalkyl together with the carbon to which they are attached.

18. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any preceding claim, wherein R2and R3are each independently H or methyl, or wherein R2and R3together form cyclopentyl.

19. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any preceding claim, wherein R2and R3together form oxetanyl or oxanyl together with the carbon to which they are attached.

20. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any preceding claim, wherein M is CRa.21 . The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any preceding claim, wherein Rais H, cyclopropyl, CF3or methyl.

22. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any preceding claim, wherein Rais H.

23. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any preceding claim, wherein:A, D, E and G are absent andX is NR15or CH;Y is CR4, N or absent;Z is CR5, NR6or O;R4is halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, 4 to 10 membered fused-ring heterocyclyl, or C1-C6 alkylsulfanyl;R5is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, optionally substituted 3 to 8 membered heterocycloalkyl, amido, sulfoximine, CN, or halo; or R4and R5together form 3 to 8 membered heterocycloalkyl or aryl together with Y and Z to which they are attached;R6is H, C1-C6 alkyl, aryl, or C3-C8 cycloalkyl;R15is H or C1-C6 alkyl; or R4and R15together form 5 membered heterocycloalkyl, or heteroaryl together with X and Y to which they are attached, optionally wherein R4and R15together form dihydrothiazole with X and Y to which they are attached; or A is CR12or N, D is CR7or N, E is CR13or N and G is OR14or N andX is N or C;Y is C;Z is CH, N, NR11, or O, wherein R11is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl;R7is H, halo, C1-C6 alkyl;R12is H, halo, or C1-C6 alkyl;R13is H, halo, C1-C6 alkoxy, or C1-C6 alkyl; andR14is H, halo, or C1-C6 alkyl; or a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof.

24. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any preceding claim, wherein:A, D, E and G are absent andX is NH or CH;Y is CR4or N.

25. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any preceding claim, wherein:A, D, E and G are absent andX is NH or CH;Y is CR4or N;Z is CR5, NR6or O;R4is halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, 4 to 10 membered fused-ring heterocyclyl, C1-C6 alkylsulfanyl, sulfoxide, sulfone, sulfoximine, optionally substituted amino, or optionally substituted 3 to 8 membered heterocycloalkyl;R5is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, optionally substituted 3 to 8 membered heterocycloalkyl, amido, sulfoximine, CN, or halo; or R4and R5together form 3 to 8 membered heterocycloalkyl or aryl together with Y and Z to which they are attached; andR6is H, C1-C6 alkyl, or C3-C8 cycloalkyl.

26. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to claim 25, wherein Z is CR5or NR6.

27. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to claim 25 or claim 26, wherein R6is H or C1- C6 alkyl.

28. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 25 to 27, wherein R4is halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, 4 to 10 membered fused-ring heterocyclyl, SMe, sulfoxide, sulfone, sulfoximine, optionally substituted amino, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted morpholine, or optionally substituted piperazine.

29. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 25 to 28, wherein R4is halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, or 4 to 10 membered fused-ring heterocyclyl.

30. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 25 to 29, wherein R5is H.

31. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 25 to 30, wherein Y is CR4.

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

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

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

35. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 25 to 34, wherein R4is C1-C6 alkyl, C1-C6 alkyl substituted by one or more halo groups, halo, cycloalkyl, cycloalkyl substituted by one or more C1-C6 alkyl, heteroaryl, heteroaryl substituted by C1-C6 alkyl, dihydrobenzofuran, phenyl, or phenyl substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, or halo.

36. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 25 to 35, wherein R4is methyl, CF3, CHF2, chloro, cyclopropyl, methyl substituted cyclopropyl, thiophene, methyl substituted pyrazole, 2,3-dihydrobenzofuran, phenyl, or phenyl substituted by methyl, methoxy, or fluoro.

37. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 25 to 36, wherein R4is phenyl or phenyl substituted by methyl, methoxy, or fluoro.

38. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 25, 26, 31 , 33 or 34, wherein R4and R5together form 6 membered heterocycloalkyl or aryl together with Y and Z to which they are attached.

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

40. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 25 to 38, wherein Z is NR6.41 . The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 25 to 37 or 40, wherein R6is H or methyl.

42. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 25, 33 or 34, wherein Y is CR4wherein R4is C1 -C6 alkylsulfanyl, optionally SMe, and wherein Z is CR5wherein R5is CN.

43. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 25, 28, 29, 35, 36 or 37, wherein M is N, X is CH, Y is CR4and Z is NH, optionally wherein R4is phenyl.

44. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 1 to 23, wherein:A is CR12or N, D is CR7or N, E is CR13or N and G is CR14or N andX is N or C;Y is C;Z is CH, N, NR11, or O, wherein R11is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl;R7is H, halo, or C1-C6 alkyl;R12is H, halo, or C1 -C6 alkyl;R13is H, halo, C1-C6 alkoxy, or C1-C6 alkyl; andR14is H, halo, or C1 -C6 alkyl.

45. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to claim 44, wherein Z is CH, N, or NR11.

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

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

48. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 44 to 47, wherein R7is H, methyl or halo.

49. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 44 to 48, wherein R12is H.

50. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 44 to 49, wherein D is CR7.51 . The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 44 to 50, wherein E is CR13.

52. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 44 to 51 , wherein R13is H.

53. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 44 to 52, wherein G is CR14.

54. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 44 to 53, wherein R14is H.

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

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

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

58. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 44 to 57, wherein R7is halo.

59. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 44 to 58, wherein R7is fluoro.

60. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 44 to 57, wherein R7is H.

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

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

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

64. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 44, 45 or 48 to 60, wherein Z is NR11.

65. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 44, 45, 48 to 60 or 64, wherein R11is H, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, or 5 to 7 membered heteroaryl.

66. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 44, 45, 48 to 60, 64 or 65, wherein R11is H.

67. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 44, 45, 48 to 60, 64 or 65, wherein R11is methyl.

68. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 1 to 25, 27 to 29, 35 to 37 or41 , wherein:A, D, E and G are absent;M is CRaor N;X is CH;Y is CR4; and Z is NR6.

69. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 1 to 25, 28 to 30, 35 to 39 or42, wherein:A, D, E and G are absent;M is CRa;X is NH;Y is CR4; and Z is CR5.

70. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 1 to 25, 28, 29, 35, 36 or 37, wherein:A, D, E and G are absent;M is CRa;X is NH;Y is CR4; andZ is N.

71. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 1 to 23, 44, 48, 52, 58, 59 or 60, wherein:X is N;Y is C;Z is N;M is CRa;A and G are each CH;D is CR7; andE is CR13.

72. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 1 to 23, 44, 48, 58, 59 or 60, wherein:X and Y are each C;Z is O;A, E, G and M are each CH; and D is CR7.73 The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 1 to 23, 44, 65, 66 or 67, wherein:X and Y are each C;Z is NR11;A, E, G and M are each CH; and D is N.

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

75. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any preceding claim, wherein the C1-C6 alkyl is C1-C3 alkyl, optionally methyl.

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

77. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any preceding claim, wherein the 01-06 alkylsulfanyl is SMe.

78. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to claim 1 , wherein:A, D, E and G are absent,X is NH or CH;Y is OR4;Z is OR5or NR6;R1is optionally substituted piperidine or piperazine,R2and R3together form cyclopentyl together with the carbon to which they are attached,R4is phenyl,R5is H, andR6is H or methyl, wherein each optional substituent is selected from phenyl, difluoro-phenyl, NHCH3, NHCH2CH3, NHCH(CH3)2, NHC(0)CH3, N(CH3)2, NHCH2CHF2, NHCH2CH2F, NHCH2CH2OH, and NHCH2CH2OCH3.

79. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to claim 1 , whereinA, D, E and G are absent;X is NH or CH;Y is CR4;Z is CR5or NR6;R1is piperidine or piperazine each substituted by difluoro-phenyl and further substituted by amino optionally substituted by one or more C1-C3 alkyl, oxo- substituted C1-C3 alkyl, fluoro-substituted C1-C3 alkyl, CH2CH2OH, C1-C3 alkoxy, fluoro-substituted C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by C1-C3 alkyl, or pyridine-substituted C1-C3 alkyl;R2and R3are each methyl, or together form cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, oxetanyl or oxanyl together with the carbon to which they are attached;R4is methyl, dihydrobenzofuran, phenyl, phenyl substituted by methyl, phenyl substituted by F, phenyl substituted by OMe, phenyl substituted by SMe, phenyl substituted by OH, or thiophene;R5is H, methyl or CN; andR6is H or methyl.

80. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to claim 1 , wherein X is N or C;Y is C;Z is N, NR11or O, wherein R11is H or methyl;M is CRawherein Rais H, methyl or cyclopropyl;A is C;D is CR7, wherein R7is H, methyl, F, Cl, Br;E is N or CR13, wherein R13is H, Cl or OMe;G is C;R1is piperidine or piperazine each substituted by difluoro-phenyl and further substituted by amino optionally substituted by one or more C1-C3 alkyl, fluoro- substituted C1-C3 alkyl, CH2CH2OH, C1-C3 alkoxy; andR2and R3are each methyl, or together form cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, oxetanyl or oxanyl together with the carbon to which they are attached.

81. A compound selected from:(fl)-6-Phenyl-3-((4-(3-phenylmorpholine-4-carbonyl)piperazin-1-yl)methyl)pyridin- 2(1 H)-one;(fl)-3-((2,2-Dimethyl-4-(3-phenylmorpholine-4-carbonyl)piperazin-1-yl)methyl)-6- phenylpyridin-2(1 H)-one;3-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)quinolin-2(1 H)-one; / V-((2S,4fl)-2-(2,5-Difluorophenyl)-1-(6-((2-oxo-6-phenyl-1 ,2-dihydropyridin-3- yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidin-4-yl)acetamide;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1 ,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-2-one;A / -(2,4-Difluorobenzyl)-6-((2-oxo-6-phenyl-1 ,2-dihydropyridin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxamide;(fl)-6-Phenyl-3-((9-(4,4,4-trifluoro-2-methylbutanoyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)pyridin-2(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1-methyl-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;3-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((9-((2S,4fi)-4-(Methylamino)-2-phenylpiperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((9-((2S,4 / 7)-2-(2,5-Difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;(fl)-3-((9-(2-(2,5-Difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-6-phenylpyridin-2(1 H)-one;6-Phenyl-3-((9-((3f?,4 / 3)-3-phenylpiperidine-4-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)pyridin-2(1 H)-one',3-((9-((2S,4fi)-4-((3,3-Difluorocyclobutyl)amino)-2-(2,5-difluorophenyl)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;(S)-6-Phenyl-3-((9-(4,4,4-trifluoro-2-(methoxymethyl)butanoyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)pyridin-2(1 H)-one;(fl)-3-((9-(3-Cyclohexyl-2-methylpropanoyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- phenylpyridin-2(1 H)-one;6-Phenyl-3-((9-(3-phenylisonicotinoyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)pyridin- 2(1 H)-one;3-((9-((2S,4fi)-4-((2-Hydroxyethyl)amino)-2-phenylpiperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;5-((4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2,2- dimethylpiperazin-1 -yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((7-((2S,4R)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-4,7- diazaspiro[2.5]octan-4-yl)methyl)-2-phenylpyridin-4(1 H)-one;6-Phenyl-3-((9-((2S,4fl)-2-phenyl-4-((pyridin-2-ylmethyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)pyridin-2(1 H)-one;5-((9-((2S,4R)-2-(3,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4fi)-2-(3,4-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;(fl)-3-((9-(2-Methyl-2-phenylpiperazine-1-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-6-phenylpyridin-2(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;(fl)-5-((9-(3-(2,5-Difluorophenyl)morpholine-4-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-2-phenylpyridin-4(1 H)-one;(S)-5-((9-(3-(2,5-Difluorophenyl)morpholine-4-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4 / 7)-2-(2,5-Difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2SJ4fi)-2-(2,3-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4fi)-4-(Methylamino)-2-phenylpiperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4fi)-4-(Cyclopropylamino)-2-phenylpiperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;(fl)-5-((9-(2-(2,5-Difluorophenyl)-1 ,4-diazepane-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;(S)-5-((9-(2-(2,5-Difluorophenyl)-1 ,4-diazepane-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;(fl)-5-((9-(3-(2,5-Difluorophenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;(S)-5-((9-(3-(2,5-Difluorophenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4R)-2-(2,6-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4R)-2-(2,4-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;3-((9-((3 / ?,5S)-3-(2,5-Difluorophenyl)-5-methylmorpholine-4-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((8-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-5,8- diazaspiro[3.5]nonan-5-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((8-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2-oxa-5,8-diazaspiro[3.5]nonan-5-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-1 ,4- diazaspiro[5.5]undecan-1 -yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4 / 7)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;3-((9-((2S,4 / 7)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;5-((4-((2SJ4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-9-oxa- 1 ,4-diazaspiro[5.5]undecan-1 -yl)methyl)-2-phenylpyridin-4(1 H)-one;3-((4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2,2- dimethylpiperazin-1 -yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((7-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-4,7- diazaspiro[2.5]octan-4-yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((9-((2S,4f?)-4-Amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((8-((2S,4f?)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-5,8- diazaspiro[3.5]nonan-5-yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((8-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-2-oxa- 5,8-diazaspiro[3.5]nonan-5-yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-1 ,4- diazaspiro[5.5]undecan-1 -yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-9-oxa- 1 ,4-diazaspiro[5.5]undecan-1 -yl)methyl)-6-phenylpyridin-2(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(pyrrolidin-1-yl)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(thiophen-3-yl)pyridin-4(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(1 -methyl-1 H-pyrazol-5-yl)pyridin-4(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-methyl-5-phenylpyridin-2(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(thiophen-2-yl)pyridin-4(1 H)-one;(fl)-3-((9-(3-Cyclohexyl-2-methylpropanoyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)- 4H-pyrido[1 ,2-a]pyrimidin-4-one;5-((9-((2S,4fi)-4-((2,2-Difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4fi)-4-Morpholino-2-phenylpiperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2-fluorophenyl)pyridin-4(1 H)-one;5-((9-((2SJ4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(o-tolyl)pyridin-4(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2-methoxyphenyl)pyridin-4(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-4H-chromen-4-one;3-((9-((2S,4f?)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-fluoro-4H-chromen-4-one;(fl)-3-((9-(3-Cyclohexyl-2-methylpropanoyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-4H-chromen-4-one;(fl)-3-((9-(3-Cyclohexyl-2-methylpropanoyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- fluoro-4H-chromen-4-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2,3-dihydrobenzofuran-7-yl)pyridin-4(1 H)-one;(fl)-3-((9-(2-(2,5-Difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-6-fluoro-4H-chromen-4-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(1 -methyl-1 H-pyrazol-3-yl)pyridin-4(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one;1-Cyclopropyl-5-((9-((2S,4fl)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-methylpyridin-4(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-5,6-dimethylpyridin-2(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrimido[1 ,2-b]pyridazin-4-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-fluoroquinolin-4(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2-hydroxyphenyl)pyridin-4(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-methyl-2-propylpyridin-4(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((9-((2SJ4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-5-(trifluoromethyl)pyridin-2(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(o-tolyl)pyridin-4(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2,3-dihydrobenzofuran-7-yl)pyridin-4(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2-methoxyphenyl)pyridin-4(1 H)-one;(fl)-5-((9-(2-(2,5-Difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-2-phenylpyridin-4(1 H)-one;(fl)-3-((9-(2-(2,5-Difluorophenyl)piperazine-1-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;5-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(4-fluorophenyl)pyridin-4(1 H)-one;3-((9-((2S,4R)-2-(3,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;5-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(3-fluorophenyl)pyridin-4(1 H)-one;5-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(m-tolyl)pyridin-4(1 H)-one;5-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2-methoxyphenyl)pyridin-4(1 H)-one;5-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2,3-dihydrobenzofuran-7-yl)pyridin-4(1 H)-one;5-((9-((2S,4fi)-2-(3,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(o-tolyl)pyridin-4(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-(m-tolyl)pyridin-2(1 H)-one;3-((9-((2S,4 / 7)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-(3-fluorophenyl)pyridin-2(1 H)-one;3-((9-((2S,4 / 7)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-(4-fluorophenyl)pyridin-2(1 H)-one;5-((9-((2S,4fi)-2-(3-Fluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(methylthio)-6-oxo-1 ,6-dihydropyridine-3- carbonitrile;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyrimidin-4(3H)-one;3-((9-((2S,4F?)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1 ,7-naphthyridin-4(1 H)-one;5-((9-((2S,4F?)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyrimidin-4(3H)-one;5-((4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1 -carbonyl)-1 ,4- diazaspiro[5.5]undecan-1 -yl)methyl)-2-phenylpyridin-4(1 A7)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(thiophen-2-yl)pyridin-4(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(dimethylamino)piperidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(thiophen-2-yl)pyridin-4(1 H)-one;5-((4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(dimethylamino)piperidine-1 -carbonyl)-1 ,4- diazaspiro[5.5]undecan-1 -yl)methyl)-2-phenylpyridin-4(1 H)-one;3-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2,6-dimethylpyridin-4(1 H)-one;3-((9-((2S,4fi)-4-((2,2-Difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4 / - / -pyrido[1 ,2-a]pyrimidin-4-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1 - carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4 / - / -pyrido[1 ,2-a]pyrimidin-4-one;3-((4-((2S,5fi)-5-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazin-1- yl)methyl)-6-phenylpyridin-2(1 / - / )-one;(fl)-6-Phenyl-3-((4-(3-phenylmorpholine-4-carbonyl)-9-oxa-1 ,4- diazaspiro[5.5]undecan-1 -yl) methyl)pyridin-2( 1 H)-one;(fl)-3-((4-(3-(4-Fluorophenyl)morpholine-4-carbonyl)-9-oxa-1 ,4- diazaspiro[5.5]undecan-1 -yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((4-((2fl,5R)-5-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazin-1 - yl)methyl)-6-phenylpyridin-2(1 H)-one;5-((9-((2S,4fi)-2-(2-Fluoro-5-methylphenyl)-4-(isopropylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4fi)-2-(2-Fluoro-5-methoxyphenyl)-4-(isopropylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,5F?)-5-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4F?)-2-(3,5-Difluorophenyl)-4-(isopropylamino)piperidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyrimidin-4(3H)-one;3-((9-((2S,4F?)-2-(2,5-Difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;5-((9-((2S,4F?)-2-(2,5-Difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;A / -((2S,4 / 7)-2-(2,5-Difluorophenyl)-1 -(6-((7-fluoro-4-oxo-4H-pyrido[1 ,2-a]pyrimidin-3- yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidin-4-yl)acetamide;A / -((2S,4fl)-2-(2,5-Difluorophenyl)-1 -(6-((7-fluoro-4-oxo-4H-pyrido[1 ,2-a]pyrimidin-3- yl)methyl)-6,9-diazaspiro[4.5]decane-9-carbonyl)piperidin-4- y l)cyclopropanecarboxam ide ;3-((9-((2S,4R)-4-((1 ,1-Dioxidothietan-3-yl)amino)-2-phenylpiperidine-1 -carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((9-((2S,4R)-4-((2,2-Difluoroethyl)amino)-2-(3,5-difluorophenyl)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(dimethylamino)piperidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1-methyl-2-(thiophen-3-yl)pyridin-4(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(dimethylamino)piperidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;(S)-6-(2-Methoxyphenyl)-3-((9-(2-phenylpyrrolidine-1 -carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)pyridin-2(1 H)-one;(S)-6-Phenyl-3-((7-(2-phenylpyrrolidine-1-carbonyl)-47-diazaspiro[2.5]octan-4- yl)methyl)pyridin-2(1 H)-one;(S)-6-Phenyl-3-((4-(2-phenylpyrrolidine-1 -carbonyl)-9-oxa-1 ,4- diazaspiro[5.5]undecan-1 -yl) methyl)pyridin-2(1 H)-one;5-((9-((2H,5R)-5-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;(S)-3-((4-(2-(2,5-Difluorophenyl)pyrrolidine-1 -carbonyl)-2,2-dimethylpiperazin-1 - yl)methyl)-6-(1-methyl-1 H-pyrazol-5-yl)pyridin-2(1 H)-one;(S)-3-((2,2-Dimethyl-4-(2-phenylpyrrolidine-1-carbonyl)piperazin-1-yl)methyl)-6- phenylpyridin-2(1 H)-one;(S)-6-Phenyl-3-((8-(2-phenylpyrrolidine-1-carbonyl)-2-oxa-5,8-diazaspiro[3.5]nonan- 5-yl)methyl)pyridin-2(1 H)-one', 3-((4-((1 S,2fl,5fl)-2-(2,5-Difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane-3- carbonyl)piperazin-1 -yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((9-((1 S,2fl,5fl)-2-(2,5-Difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane-3- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;5-((9-((1 S,2fl,5fl)-2-(2,5-Difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane-3- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(2-fluorophenyl)pyridin-4(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-fluoro-1-methylquinolin-4(1 H)-one;3-((9-((2fl,3R)-3-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((9-((2S,3S)-3-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1 -methyl-2-(1 -methyl-1 H-pyrazol-5-yl)pyridin- 4(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-(trifluoromethyl)pyridin-2(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(trifluoromethyl)pyridin-4(1 H)-one;3-((4-((2fl,3H)-3-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazin-1- yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((4-((2S,3S)-3-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)piperazin-1- yl)methyl)-6-phenylpyridin-2(1 H)-one;5-((9-((2fl,3H)-3-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,3S)-3-(2,5-Difluorophenyl)-2-methylmorpholine-4-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;3-((9-((2fl,4R)-4-Amino-2-ethylpiperidine-1-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((9-((2f?,4 / ^-2-Ethyl-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-((2-hydroxyethyl)(methyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1 -methyl-2-(1 -methyl-1 H-pyrazol-3-yl)pyridin- 4(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(thiophen-3-yl)pyridin-4(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-hydroxypiperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1 -methyl-2-(1 -methyl-1 H-pyrazol-3-yl)pyridin- 4(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropyl(methyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-((2-methoxyethyl)(methyl)amino)piperidine-1-carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2- a]pyrimidin-4-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-hydroxypiperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(thiophen-3-yl)pyridin-4(1 H)-one;3-(((S)-4-((2S,4fl)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-2-methylpiperazin-1-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;7-Chloro-3-((9-((2S,4fl)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((4-((2S,4R)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-1 ,4- diazaspiro[5.5]undecan-1-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((4-((2S,4 / 7)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-2,2- dimethylpiperazin-1-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((( / ^-4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-2-methylpiperazin-1-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;5-((9-((2S,4fi)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1-methyl-2-(thiophen-3-yl)pyridin-4(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-((2-hydroxyethyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-((2-hydroxyethyl)(methyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((9-((2S,4 / ?)-2-(2,5-Difluorophenyl)-4-(ethyl(methyl)amino)piperidine-1 -carbonyl)-6.9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4 / - / -pyrido[1 ,2-a]pyrimidin-4-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-8-methoxy-4H-pyrido[1 ,2-a]pyrimidin-4-one;5-((9-((2S,4S)-4-Amino-2-phenylpyrrolidine-1-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-2-phenylpyridin-4(1 H)-one;5-((9-((2S,4S)-4-(lsopropylamino)-2-phenylpyrrolidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;3-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7,8-dihydropyrrolo[1 ,2-a]pyrimidin-4(6H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7,8-dihydropyrrolo[1 ,2-a]pyrimidin-4(6H)-one;3-((9-(5-Amino-2',5'-difluoro-[1 ,1'-biphenyl]-2-carbonyl)-6,9-diazaspiro[4.5]decan-6- yl)methyl)-6-phenylpyridin-2(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-2-methyl-4 / - / -pyrido[1 ,2-a]pyrimidin-4- one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-((2-fluoroethyl)amino)piperidine-1-carbonyl)-6.9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;5-((9-((2S,4 / 7)-2-(2,5-Difluorophenyl)-4-((2-fluoroethyl)amino)piperidine-1-carbonyl)-6.9-diazaspiro[4.5]decan-6-yl)methyl)-2-phenylpyridin-4(1 H)-one;7-Fluoro-3-((9-((2S,4S)-4-(isopropylamino)-2-phenylpyrrolidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((9-((2SJ4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4- one;4-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1-phenyl-1 ,2-dihydro-3H-pyrazol-3-one;4-((9-((2S,4f?)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-methyl-1-phenyl-1 ,2-dihydro-3H-pyrazol-3-one;7-Chloro-3-((9-((2S,4fl)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((4-((2S,4f?)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-1 ,4- diazaspiro[5.5]undecan-1-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((4-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-1 ,4- diazaspiro[5.5]undecan-1-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;7-Chloro-3-((9-((2S,4fl)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)- 6,9-diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one;6-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;6-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-Fluoro-3-((9-((2S,4fi)-4-((3-methyloxetan-3-yl)amino)-2-phenylpiperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4- one;2-Cyclopropyl-3-((9-((2S,4fl)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;2-Cyclopropyl-3-((9-((2S,4H)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin- 4-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridazin-4(1 H)-one;3-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridazin-4(1 H)-one;3-((9-((2S,4fi)-4-Amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((9-((2S,4fi)-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]pyrimidin-4-one;7-Bromo-3-((9-((2S,4fl)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one;8-Chloro-3-((9-((2S,4fl)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one;3-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-2-(trifluoromethyl)-4H-pyrido[1 ,2- a]pyrimidin-4-one;3-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-2-(trifluoromethyl)-4H-pyrido[1 ,2- a]pyrimidin-4-one;3-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-1 -methyl-1 ,6-naphthyridin-4(1 H)-one;3-((9-((2S,4R)-2-(2,5-Difluorophenyl)-4-((1-methylcyclopropyl)amino)piperidine-1- carbonyl)-6,9-diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one; and5-((9-((2S,4fi)-2-(2,5-Difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-6,9- diazaspiro[4.5]decan-6-yl)methyl)-2-(1-methylcyclopropyl)pyridin-4(1 H)-one; or a stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt thereof.

82. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any preceding claim that is an inhibitor of USP19, preferably human USP19.

83. A pharmaceutical composition comprising a compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any preceding claim, and a pharmaceutically acceptable carrier or diluent.

84. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 1-82 or the pharmaceutical composition according to claim 83 for use in therapy.

85. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any of claims 1-82 or the pharmaceutical composition according to claim 83 for use as a medicament.

86. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any one of claims 1-82 or the pharmaceutical composition according to claim 83 for use in treating muscular atrophy, obesity, insulin resistance, or type II diabetes.

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

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

89. The compound, stereoisomer, tautomer, hydrate, / V-oxide derivative or pharmaceutically acceptable salt according to any one of claims 1-82 or the pharmaceutical composition according to claim 83 for use according to claim 88, wherein the use comprises treating muscular atrophy, cachexia and / or sarcopenia.

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

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

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