Pharmaceutical compounds as ubiquitin-specific protease 19 inhibitors

Abstract

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

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to inhibitors of ubiquitin-specific protease 19 (USP19) and methods of use thereof. [Background technology]

[0002] background In the past few decades, protein ubiquitination has emerged as an important post-translational modification, with a role in a plethora of cellular processes, including protein degradation, gene expression, DNA repair, immune response, metabolism or cell cycle control, among others. Dysregulation of the ubiquitin-proteasome system (UPS) is a key factor in cancer (Hoeller D. et al., Nat. Rev. Cancer (2006), 6, 776-788), viral infection (Gao et al., J. Physiol., Pharmacol. (2006), 84, 5-14), metabolic or neurodegenerative disorders (Loosdregt J. et al., Immunity (2013), 39, 259-271; Rubinsztein D., et al., Nature (2006), 443, 780-786), and immune- and inflammatory-related pathologies (Wang J. et al., J. Cell Immunol. (2006), 3, 255-261; Corn J. et al., Nat. Struct. & Mol. Biol. (2014), 21, 297-300; It has been implicated in the pathogenesis of several human diseases, including, but not limited to, cerebrospinal fluid disorders (Nicholson B. et al., Cell Biochem. Biophys. (2013), 60, 61-68).

[0003] The approval and clinical success of the proteasome inhibitors Velcade® (bortezomib) and Kyprolis® (carfilzomib) for the treatment of mantle cell lymphoma (AML) and multiple myeloma (MM) has established the UPS as a cancer target amenable to pharmacological intervention. Although effective, their clinical utility is severely limited by poor selectivity and acute toxicity issues. By inhibiting the 26S proteasome, current proteasome inhibitors indiscriminately impair protein degradation in both cancer and normal cells and are characterized by a low therapeutic index. To circumvent this problem, another promising approach may be to target the UPS upstream of the proteasome. For example, ubiquitin (Ub) conjugation / deconjugation mechanisms at the level of ubiquitin-specific proteases (USPs) could enable the development of improved therapies with enhanced specificity and reduced toxicity profiles.

[0004] USPs are the largest subfamily of the deubiquitinating enzyme (DUB) family, with over 60 family members reported to date (Komander D. et al., Nat. Rev. Mol. (2009), 10, 550-563; Clague M. et al., Physiol. Rev. (2013), 93, 1289-1315). USPs are typically cysteine ​​proteases that catalyze the removal of Ub from specific target substrates, thereby preventing proteasomal degradation or controlling activation and / or subcellular localization (Colland F. et al., Biochimie (2008), 90, 270-283; Nicholson B. et al., Cell Biochem. Biophys. (2013), 60, 61-68). It is now well established that USPs regulate the stability and activity of numerous proteins involved in the pathogenesis of human disease, including both oncogenes and tumor suppressors, and thus represent an emerging and attractive target class for pharmacological intervention.

[0005] Among all USPs, USP19 is an important member due to its association with several important pathways involved in pathologies, including but not limited to cancer, neurodegenerative and degenerative diseases, and antiviral immune responses. USP19 is expressed as multiple isoforms, varying in length from 71.09 kDa (isoform 2) to 156.03 kDa (isoform 5), with a canonical sequence of 145.65 kDa (isoform 1) (uniprot.org). The cellular localization of USP19 can be cytoplasmic or endoplasmic reticulum-associated (Lee J. et al., J. Biol. Chem. (2014), 289, 3510-3507; Lee J. et al., Nat. Cell Biol. (2016), 18, 765-776). Localized to the endoplasmic reticulum, USP19 is a key component of the endoplasmic reticulum-associated degradation (ERAD) pathway (Hassink B. et al., EMBO J. (2009), 10, 755-761; Lee J. et al., J. Biol. Chem. (2014), 289, 3510-3507; Lee J. et al., Nat. Cell Biol. (2016), 18, 765-776). In particular, USP19 is involved in the late step of protein quality control, rescuing ERAD substrates that are retrogradely transported to the cytosol. USP19 has also been shown to regulate the stability of the E3 ligases MARCH6 and HRD1 (Nakamura N. et al., Exp. Cell Res. (2014), 328, 207-216; Harada K. et al., Int. J. Mol. Sci. (2016), 17, E1829). Furthermore, USP19 has recently been implicated in the stabilization of multiple, potentially important, protein substrates. For example, USP19 interacts with SIAH proteins and rescues HIF1α from degradation under hypoxic conditions (Altun M. et al., J. Biol. Chem. (2012), 287, 1962-1969; Velasco K. et al., Biochem. Biophys. Res. Commun. (2013), 433, 390-395).USP19 is also p27. Kip1 It also stabilizes KPC1 ubiquitin ligase, which is involved in the regulation of cyclin-dependent kinase inhibitors (Lu Y. et al., Mol. Cell Biol. (2009), 29, 547-558). Knockout of USP19 by RNAi reduces the expression of p27 Kip1This leads to the accumulation of USP19 and cell proliferation inhibition (Lu L. et al., PLoS ONE (2011), 6, e15936). USP19 has also been found to interact with inhibitors of apoptosis (IAPs), including c-IAP1 and c-IAP2 (Mei Y. et al., J. Biol. Chem. (2011), 286, 35380-35387). Knockdown of USP19 reduces the total levels of these c-IAPs, whereas overexpression increases the levels of both BIRC2 / cIAP1 and BIRC3 / cIAP2. Knockdown of USP19 also enhances TNFα-induced caspase activation and apoptosis in a BIRC2 / c-IAP1- and BIRC3 / c-IAP2-dependent manner. In addition to its direct involvement in hypoxia response and ER stress regulation to some extent, USP19 has also recently been implicated as a positive regulator of autophagy and a negative factor in type I interferon signaling (IFN, antiviral immune response) by deubiquitinating Beclin-1. USP19 was found to stabilize Beclin-1 at the post-translational level by removing the K11-linked ubiquitin chain from Beclin-1 at lysine 437 (Jin S. et al., EMBO J. (2016), 35, 866-880). USP19 negatively regulates the type I IFN signaling pathway by blocking the RIG-I-MAVS interaction in a Beclin-1-dependent manner. Depletion of USP19 or Beclin-1 inhibits autophagic flux and promotes type I IFN signaling and cellular antiviral immunity (Jin S. et al., EMBO J. (2016), 35, 866-880; Cui J. et al., Autophagy (2016), 12, 1210-1211). Recent findings also suggest that USP19 can negatively affect cellular antiviral type I IFN signaling by regulating TRAF3 substrates (Gu Z. et al., Future Microbiol. (2017), 12, 767-779).USP19 has also recently been linked to the Wnt signaling pathway by stabilizing its co-receptor LRP6 (Perrody E. et al., eLife (2016), 5, e19083) and to DNA repair processes, most specifically chromosomal stability and integrity, by regulating HDAC1 and HDAC2 proteins (Wu M. et al., Oncotarget (2017), 8, 2197-2208).

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

[0007] In addition to the above pathologies, USP19 has also been implicated in the pathogenesis of degenerative diseases, including but not limited to Parkinson's disease and other prion-like transmission disorders, through the regulation of key substrates such as α-synuclein or polyglutamine-containing proteins, ataxin 3, and huntingtin (He W. et al., PLoS ONE (2016), 11, e0147515; Bieri G. et al., Neurobiol Dis. (2018), 109B, 219-225). USP19-mediated regulation of coronin 2A (CORO2A) has been shown to affect the transcriptional repression activity of retinoic acid receptors (RARs), suggesting that USP19 may also be involved in RAR-mediated adipogenesis regulation (Lim K. et al., Oncotarget (2016), 7, 34759-34772). Summary of the Invention [Problem to be solved by the invention]

[0008] The established and growing association between USP19 and numerous proteins associated with human pathologies suggests that small molecule inhibitors of USP19 may have broad therapeutic applications beneficial to human health. However, to date, to our knowledge, no inhibitors targeting USP19 have been reported, and the identification of such inhibitors with drug-like potential remains of utmost importance and priority. [Means for solving the problem]

[0009] Summary of the Invention In a first embodiment, the compound of formula (I) [ka] [During the ceremony, R 0 is H, NH2, F or OCH3; R 1is optionally substituted C1-C6 alkyl, ethylcyclopropyl, ethylcyclobutyl, optionally substituted C5-C8 aryl, optionally substituted C3-C8 heteroaryl, optionally substituted C3-C8 heterocycloalkyl, NR a R b , N.R. a CH2R b , OR a or OCH2R a and where R a and R b are independently selected from H, C1-C6 alkyl, CF3, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C8 aryl, optionally substituted C6-C9 arylalkyl, and optionally substituted C2-C8 heteroaryl; R 1 NR a CH2R b wherein the methylene group is optionally substituted with CF3; or R 1 is NR a R b and R a and R b together with the N to which they are attached form an optionally substituted C2-C9 heterocycle; R 2 and R 3 are independently selected from H and C1-C6 alkyl, or together with the carbon to which they are attached form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl; X is absent, C, CR 4a , C.R. 4a R 4b , N, NR 4a or C=O, where R 4a and R 4b is independently selected from H, optionally substituted C1-C6 alkyl and halo; or R 4a and R 4bform a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl together with the carbon to which they are attached; Y is C, CR 5 , C.R. 5 R 6 , N, NR 5 or O, where R 5 and R 6 are independently selected from the group consisting of H, halo, optionally substituted C-C alkyl, C-C alkenyl, C-C alkynyl, optionally substituted C-C cycloalkyl, optionally substituted C-C heterocycloalkyl, optionally substituted C-C aryl, optionally substituted C-C arylalkyl, optionally substituted C-C heteroaryl, CHOH, NR'R", NS(O)R'R", SOR', C(O)R', COR', C(O)OR', C(O)NR'R", OR', where R' and R" are independently selected from H, C-C alkyl, C-C aryl, C-C arylalkyl and C-C heteroaryl, or R 5 is NR'R'', where R' and R'' are optionally substituted C 3-6 forming a heterocycloalkyl, or R 5 and R 6 together with the carbon to which they are attached form a C3-6 cycloalkyl or a C3-C6 heterocycloalkyl; Z is N, NR 7 , C, C.R. 7 , C.R. 7 R 8 or C=O, where R 7 and R 8 are independently H, halo, cyano, oxo, optionally substituted C1-C6 alkyl, C2-C6 alkene, C2-C6 alkyne, C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C3-C8 heteroaryl, CN, C(O)OR c,CONR c R d , N.R. c R d , NS(O)R c R d , S(O)(R c )NR d , SOR c , SO2R c and S.R. c wherein R c and R d are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C6 aryl, C6-C9 arylalkyl, C3-C6 heteroaryl, CN, COOH, or COCH3, or R c and R d together with the heteroatom to which they are attached form an optionally substituted C3-C7 heterocycle; or R 7 and R 8 together with the carbon to which they are attached form a C3-6 cycloalkyl or a C3-C6 heterocycloalkyl; M is absent, C, CR 13 or CR 13 R 14 where R 13 and R 14 are independently selected from H and C1-C6 alkyl or R 13 and R 14 together with the carbon to which they are attached form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl; and A is CR 9 , CHR 9 , N, NR 9 , S or O; D is CR 9 , CHR 9 , N or NR 9 and G is non-existent, CR 9 , CHR 9 or N, where R 9are independently H, halo, C1-C6 alkyl, CF3, and OR * where R * is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted C3-C6 heterocycloalkyl; E is CR 10 , CHR 10 , N, NR 10 , S or O, where R 10 is H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C4-C8 heteroaryl, SR x , OR x , N.R. x R y and NS(O)R x R y , S(O)(R x )NR y is selected from where R x and R y are independently selected from H, C1-C6 alkyl, CF3, C3-C6 cycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C4-C8 heteroaryl, COOH, amido, cyano, C2-C6 alkene, C2-C6 alkyne, or R x and R y together with the nitrogen to which they are attached form an optionally substituted C4-C6 heterocycloalkyl; Or A, D, E and G are all absent, optionally wherein X and M are absent, or optionally wherein Y and Z together form an optionally substituted C5-C6 aryl or C3-C6 heteroaryl fused ring, or Z and M together form an optionally substituted C5-C6 aryl or C5-C6 heteroaryl fused ring. or a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof, or [ka] Compounds are provided having a structure selected from:

[0010] In a second aspect, there is provided a pharmaceutical composition comprising a compound according to the first aspect or a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

[0011] USP19 has been associated with several diseases and conditions, including (but not limited to) cancer and neoplastic conditions. Knockout of USP19 by RNAi inhibits p27 Kip1 This leads to the accumulation of USP19 and cell proliferation inhibition (Lu L. et al., PLoS ONE (2011), 6, e15936). USP19 has also been found to interact with inhibitors of apoptosis (IAPs), including c-IAP1 and c-IAP2 (Mei Y. et al., J. Biol. Chem. (2011), 286, 35380-35387). Knockdown of USP19 reduces the total levels of these c-IAPs, whereas overexpression increases the levels of both BIRC2 / cIAP1 and BIRC3 / cIAP2. Knockdown of USP19 also enhances TNFα-induced caspase activation and apoptosis in a BIRC2 / c-IAP1- and BIRC3 / c-IAP2-dependent manner. USP19 has also recently been linked to the Wnt signaling pathway by stabilizing its co-receptor LRP6 (Perrody E. et al., eLife (2016), 5, e19083) and to DNA repair processes, most specifically chromosomal stability and integrity, by regulating HDAC1 and HDAC2 proteins (Wu M. et al., Oncotarget (2017), 8, 2197-2208).

[0012] Further, it has been shown herein that the USP19 inhibitor compounds described in connection with the first embodiment exhibit cell permeability and potent target binding in cancer cell lines. The cell permeability and target binding in cancer cells are comparable to those observed in muscle cells. As shown herein, USP19 inhibitors exhibit potent in vivo therapeutic effects on muscle wasting. Therefore, by extension, because similar target binding is observed in cancer cells, pharmacological USP19 inhibitors are expected to be effective in the treatment of cancer due to the above-mentioned association between USP19 and the oncogenic process.

[0013] In vivo studies have also shown that mice lacking the USP19 gene (USP19 KO mice) exhibit reduced fat mass when fed a high-fat diet (Coyne E, et al., Diabetologia (2019), 62, 136-146, which is incorporated herein by reference). USP19 KO mice also exhibit greater glucose tolerance and increased insulin sensitivity when fed a high-fat diet.

[0014] These gene knockout studies demonstrate an association between USP19 and obesity, as well as between USP19 and insulin sensitivity. However, prior to the data presented herein, no in vivo studies had demonstrated that pharmacological inhibitors of USP19 represented an effective approach for the treatment of obesity. Similarly, prior to the data presented herein, no in vivo studies had demonstrated that pharmacological inhibitors of USP19 could be effective in increasing insulin sensitivity.

[0015] USP19 has also been associated with muscle atrophy, muscle wasting syndromes and other skeletal muscle atrophy disorders (Wing S., Int. J. Biochem. Cell Biol. (2013), 45, 2130-2135; Wing S. et al., Int. J. Biochem. Cell Biol. (2016), 79, 426-468; Wiles B. et al., Mol. Biol. Cell (2015), 26, 913-923; Combaret L. et al., Am. J. Physiol. Endocrinol. Metab. (2005), 288, E693-700). For example, this is supported by studies showing that USP19 silencing induces myofibrillar protein expression and promotes myogenesis (Sundaram P. et al., Am. J. Physiol. Endocrinol. Metab. (2009), 297, E1283-90; Ogawa M. et al., J. Biol. Chem. (2011), 286, 41455-41465; Ogawa M. et al., J. Endocrinol. (2015), 225, 135-145).

[0016] Knockout studies have shown that mice lacking the USP19 gene are resistant to muscle wasting both in response to glucocorticoids, a common systemic cause of muscle atrophy, and in response to denervation, a model of disuse atrophy (Bedard N. et al., FASEB J. (2015), 29, 3889-3898, which is incorporated herein by reference).

[0017] As shown in the accompanying Examples, it has now been shown that pharmacological treatment with USP19 inhibitors can induce therapeutic effects in wild-type in vivo models.

[0018] In particular, USP19 inhibitors have been shown to reduce fat deposition in in vivo models, indicating that USP19 inhibitors may be an effective treatment for obesity.

[0019] Similarly, it has been shown here that USP19 inhibitors can reduce muscle mass loss in an in vivo model of muscle atrophy.

[0020] Similarly, it has now been shown that USP19 inhibitors can treat symptoms of insulin resistance, as evidenced by improved response to glucose.

[0021] The compounds of the present invention can selectively inhibit USP19 activity. The examples further demonstrate that compounds that may inhibit USP19 activity may be effective therapeutic compounds. The compounds of the present invention are therefore suitable for treatment methods. Indications suitable for treatment with the compounds of the present invention include the treatment and prevention of cancer and neoplastic conditions; immunological and inflammatory conditions, such as those caused by antiviral immune responses; muscle wasting, such as cachexia and sarcopenia; obesity; insulin resistance, such as diabetes; and neurodegenerative diseases, including Parkinson's disease and other prion-based disorders.

[0022] Thus, in a further aspect, there is provided a compound according to the first aspect or a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second aspect, for use in therapy.

[0023] In a further aspect, there is provided a compound according to the first aspect or a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second aspect, for use in a method for treating or preventing cancer. In certain preferred embodiments, the cancer to be treated is breast cancer or neuroblastoma.

[0024] In a further aspect, there is provided a compound according to the first aspect or a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second aspect, for use in a method for the treatment or prevention of muscle wasting, optionally cachexia or sarcopenia.

[0025] In a further aspect, there is provided a compound according to the first aspect or a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second aspect, for use in a method for the treatment or prevention of obesity.

[0026] In a further aspect, there is provided a compound according to the first aspect or a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second aspect, for use in a method for the treatment or prevention of insulin resistance.

[0027] In a further aspect, there is provided a compound according to the first aspect or a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second aspect, for use in a method for the treatment or prevention of type II diabetes.

[0028] In a further aspect, there is provided a compound according to the first aspect or a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second aspect, for use in a method for the treatment or prevention of Parkinson's disease.

[0029] In a further aspect, there is provided a method of treating cancer comprising administering to a subject an effective amount of a compound according to the first aspect or a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second aspect.

[0030] In a further aspect, there is provided a method of treating muscle atrophy comprising administering to a subject an effective amount of a compound according to the first aspect or a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second aspect.

[0031] In a further aspect, there is provided a method of treating Parkinson's disease comprising administering to a subject an effective amount of a compound according to the first aspect or a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second aspect.

[0032] The compounds or stereoisomers, tautomers, hydrates, N-oxide derivatives or pharmaceutically acceptable salts thereof can be used as monotherapy or in combination therapy with radiation and / or additional therapeutic agents.

[0033] Other preferred embodiments of the compounds provided herein can be found throughout the specification and particularly in the Examples. Particularly preferred are compounds listed as having greater activity in the tests. Compounds with greater activity are preferred over those with less activity.

[0034] Each aspect or embodiment defined herein may be combined with any other aspect or embodiment unless there is a clear contradiction. Any feature indicated as being particularly preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous. [Brief explanation of the drawings]

[0035] [Figure 1] Effect of USP19 pharmacological inhibition on tibialis anterior mass. (A) Tibialis anterior mass (mg) from mice treated with vehicle or the USP19 inhibitor compound ADC-141. Muscle mass from the limb that underwent sciatic nerve denervation (DEN) and also from the innervated limb (INN) is shown. (B) Percentage loss of tibialis anterior muscle mass as a result of denervation in vehicle- and USP19 inhibitor (ADC-141)-treated mice. Percentages were calculated as a proportion of muscle mass from the innervated limb of the same mouse. (C) Loss of tibialis anterior muscle mass (mg) as a result of denervation in vehicle- and USP19 inhibitor (ADC-141)-treated mice. *P<0.025.

[0036] [Figure 2]Effect of USP19 pharmacological inhibition on gastrocnemius muscle mass. (A) Gastrocnemius muscle mass (mg) from mice treated with vehicle or the USP19 inhibitor compound ADC-141. Muscle mass from the limb that underwent sciatic nerve denervation (DEN) and also from the innervated limb (INN) is shown. (B) Percentage loss of gastrocnemius muscle mass as a result of denervation in vehicle- and USP19 inhibitor (ADC-141)-treated mice. Percentages were calculated as a proportion of muscle mass from the innervated limb of the same mouse. (C) Loss of gastrocnemius muscle mass (mg) as a result of denervation in vehicle- and USP19 inhibitor (ADC-141)-treated mice.

[0037] [Figure 3] (A) Effect of USP19 pharmacological inhibition on fat mass. Epididymal fat pads were collected from vehicle- and USP19 inhibitor (ADC-141)-treated mice, and USP19 inhibitor-treated mice showed a significant decrease in fat mass. (B) Effect of USP19 pharmacological inhibition on liver mass. Livers were collected from vehicle- and USP19 inhibitor (ADC-141)-treated mice. Increased liver mass was observed, likely due to accumulation of drug compounds in the liver. (C) Percentage change in overall body weight in vehicle-treated control DIO mice. USP19 inhibitor 5 mg / kg ip BID, USP19 inhibitor 25 mg / kg ip BID, or positive control liraglutide 0.1 mg / kg sc BID (left to right bars, respectively); (D) Percentage change in total lean body mass and (E) Percentage change in total 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 [Figure 4] Cellular target binding of USP19 inhibitor compounds in breast cancer, neuroblastoma, and skeletal muscle cell lines. EC50 was determined by concentration measurement.

[0038] [Figure 5]Responses to the oral glucose tolerance test (OGTT) in obese mice. (A) Timeline of plasma glucose response for vehicle-treated control mice (circles), USP19 inhibitor 5 mg / kg ip BID (triangles), USP19 inhibitor 25 mg / kg ip BID (filled circles), or positive control liraglutide 0.1 mg / kg sc BID (diamonds); (B) Glucose AUC (mM.hr) and (C) insulin AUC (ng.hr / 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

[0039] Detailed Description of the Invention Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the same meaning as commonly understood by those skilled in the art. However, when the meaning and scope of a term must be clarified, the definitions provided herein take precedence over any dictionary or external definition in the event of any potential ambiguity.

[0040] As used in this specification and claims, unless specified to the contrary, the following terms have the meanings indicated: The term "alkyl group" (alone or in combination with other terms) means a straight-chain or branched-chain saturated hydrocarbon substituent, typically containing 1 to 15 carbon atoms, e.g., 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. n An "alkyl" group refers to an aliphatic group containing n carbon atoms. For example, C1-C 10The alkyl group may contain 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).

[0041] The term "alkenyl group" (alone or in combination with other terms) means a straight- or branched-chain hydrocarbon substituent containing one or more double bonds and typically 2 to 15 carbon atoms; for example, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. Examples of such substituents include ethenyl (vinyl), 1-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl, and hexenyl.

[0042] The term "alkynyl group" (alone or in combination with other terms) means a straight-chain or branched-chain hydrocarbon substituent containing one or more triple bonds and typically 2 to 15 carbon atoms; for example, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. Examples of such substituents include ethynyl, 1-propynyl, 3-propynyl, 1-butynyl, 3-butynyl, and 4-butynyl.

[0043] The term "heteroalkyl group" (alone or in combination with other terms) means a straight or branched chain saturated hydrocarbyl substituent that typically contains 1 to 15 atoms, e.g., 1 to 10, 1 to 8, 1 to 6, or 1 to 4 atoms, where at least one of the atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining atoms are carbon atoms. n A "heteroalkyl" group refers to an aliphatic group containing n carbon atoms and one or more heteroatoms, for example, one heteroatom. For example, C-C 10Heteroalkyl groups contain one or more heteroatoms, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms in addition to one heteroatom. Attachment to the heteroalkyl group can occur through a carbon atom or a heteroatom.

[0044] The term "heteroalkenyl group" (alone or in combination with other terms) means a straight or branched chain hydrocarbon substituent containing one or more carbon-carbon double bonds and typically 2 to 15 atoms; e.g., 2 to 10, 2 to 8, 2 to 6, or 2 to 4 atoms, where at least one of the atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining atoms are carbon atoms. n A "heteroalkenyl" group refers to an aliphatic group containing n carbon atoms and one or more heteroatoms, for example, one heteroatom. For example, C-C 10 Heteroalkenyl groups contain one or more heteroatoms, for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms in addition to one heteroatom. Bonding to the heteroalkenyl group can occur through a carbon atom or a heteroatom.

[0045] The term "heteroalkynyl group" (alone or in combination with other terms) means a straight or branched chain hydrocarbon substituent containing one or more carbon-carbon triple bonds and typically 2 to 15 carbon atoms; e.g., 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms, where at least one of the atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining atoms are carbon atoms. n A "heteroalkynyl" group refers to an aliphatic group containing n carbon atoms and one or more heteroatoms, for example, one heteroatom. For example, C-C 10 Heteroalkynyl groups contain one or more heteroatoms, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms in addition to one heteroatom. Bonding to a heteroalkynyl group can occur through a carbon atom or a heteroatom.

[0046] The term "carbocyclyl group" (alone or in combination with other terms) means a saturated cyclic (i.e., "cycloalkyl"), partially saturated cyclic (i.e., "cycloalkenyl"), or fully unsaturated (i.e., "aryl") hydrocarbon substituent containing 3 to 14 carbon ring atoms ("ring atoms" are the atoms that are bonded together to form one or more rings of the cyclic substituent). A carbocyclyl can be a single ring (monocyclic) or polycyclic ring structure.

[0047] A carbocyclyl can be a single ring structure, typically containing 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 can alternatively be polycyclic (i.e., contain more than one ring). Examples of polycyclic carbocyclyls include bridged, fused, and spirocyclic carbocyclyls. In spirocyclic carbocyclyls, one atom is common to two different rings. An example of a spirocyclic carbocyclyl is spiropentanyl. In a bridged carbocyclyl, the two rings share at least two non-adjacent atoms. Examples of bridged carbocyclyls include bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl. In fused-ring carbocyclyl systems, two or more rings may be fused together so 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.

[0048] The term "cycloalkyl group" (alone or in combination with other terms) means a saturated cyclic hydrocarbon substituent containing 3 to 14 carbon ring atoms. Cycloalkyls can be monocarbon rings, typically containing 3 to 8 carbon ring atoms and more typically 3 to 6 ring atoms. It is understood that attachment to a cycloalkyl group is through a ring atom of the cycloalkyl group. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyls may alternatively be polycyclic or contain more than one ring. Polycyclic cycloalkyls include bridged, fused, and spirocyclic cycloalkyls.

[0049] The term "alkylcycloalkyl" refers to a cycloalkyl substituent attached via an alkyl chain. Alkylcycloalkyl substituents include cyclohexylethane, where the alkylcycloalkyl substituent is attached via a cyclohexaneethane linker. Other examples include cyclopropylethane, cyclobutylethane, cyclopentylethane, cycloheptylethane, cyclohexylmethane. "C n " In alkylcycloalkyl, C n includes the carbon atoms in the alkyl chain and the cycloalkyl ring. For example, cyclohexylethane is a C alkylcycloalkyl.

[0050] The term "aryl group" (alone or in combination with other terms) refers to an aromatic carbocyclyl containing 5 to 14 carbon ring atoms, optionally 5 to 8, 5 to 7, and optionally 5 to 6 carbon ring atoms. n An "aryl" group refers to an aromatic group containing n carbon atoms. For example, C6-C 10The aryl group contains 6, 7, 8, 9, or 10 carbon atoms. Preferably, the aryl group is C6 aryl, i.e., phenyl. Bonding to the aryl group occurs through a carbon atom. The aryl group can be monocyclic or polycyclic (i.e., it can contain more than one ring). In the case of a polycyclic aromatic ring, only one ring in the polycyclic system need be unsaturated; the remaining rings can be saturated, partially saturated, or unsaturated. Bonding to the aryl group occurs through a carbon atom within the ring. Examples of aryl groups include phenyl, naphthyl, acridinyl, indenyl, indanyl, and tetrahydronaphthyl.

[0051] The term "arylalkyl" refers to an aryl substituent attached via an alkyl chain. Examples of arylalkyl substituents include benzyl and phenylethane / ethylbenzene, where the ethane chain is attached to the point of attachment of the phenyl group. n " In arylalkyl, C n contains the carbon atoms of the alkyl chain and the aryl group. For example, ethylbenzene is a C8 arylalkyl.

[0052] The term "heterocyclyl group" (alone or in combination with other terms) means a saturated (i.e., "heterocycloalkyl"), partially saturated (i.e., "heterocycloalkenyl"), or fully 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 (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms are carbon atoms. A heterocyclyl group can contain, for example, 1, 2, 3, 4, or 5 heteroatoms. Attachment to a heterocyclyl group can occur through a carbon atom and / or one or more heteroatoms contained in the ring. A heterocyclyl can be a monocyclic (monocyclic) or polycyclic ring structure.

[0053] Heterocyclyl groups may be monocyclic, typically containing from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically from 5 to 6 ring atoms. Examples of monocyclic heterocyclyls are furanyl, dihydrofuranyl, 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, dioxazolyloxathio including allyl, 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.

[0054] Heterocyclyl groups 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 spirocyclic heterocyclyl groups, one atom is common to two different rings. In bridged heterocyclyl groups, two rings share at least two non-adjacent atoms. In fused-ring heterocyclyl groups, two or more rings may be fused to each other so that two rings share one common bond. Examples of fused-ring heterocyclyl groups containing two or three rings include indolizinyl, pyranopyrrolyl, 4H-quinolidinyl, 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), indolininyl (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), benzofuranyl, dihydrobenzofuranyl and benzisoxazinyl (including 1,2-benzisoxazinyl or 1,4-benzisoxazinyl).

[0055] The term "heterocycloalkyl group" (alone or in combination with other terms) means a saturated heterocyclyl. n A "heterocycloalkyl" group refers to a cyclic aliphatic group containing n carbon atoms in addition to at least one heteroatom, e.g., nitrogen. For example, C1-C 10 Heterocycloalkyl groups contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon ring atoms in addition to at least one heteroatom. Attachment to the heterocycloalkyl group occurs through a carbon atom or through one of the at least one heteroatom.

[0056] The term "alkylheterocycloalkyl" refers to a heterocycloalkyl substituent attached via an alkyl chain. n " In alkylheterocycloalkyl, C n includes the carbon atoms of the alkyl chain and the heterocycloalkyl ring. For example, ethylpiperidine is a C7 alkylheterocycloalkyl.

[0057] The term "heteroaryl group" (alone or in combination with other terms) means an aromatic heterocyclyl containing 5 to 14 ring atoms. n A "heteroaryl" group refers to an aromatic group containing n carbon atoms and at least one heteroatom. For example, C-C 10 Aryl groups contain 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, in addition to at least one heteroatom. Bonding to the heteroaryl group occurs through a carbon atom or a heteroatom. Heteroaryl groups can be monocyclic or polycyclic. Heteroaryls can be monocyclic or have two or three condensed rings. Examples of monocyclic heteroaryl groups include six-membered rings such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and 1,3,5-, 1,2,4-, or 1,2,3-triazinyl; and five-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 can have two or three condensed 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 need be unsaturated; the remaining rings can be saturated, partially saturated, or unsaturated.

[0058] Nitrogen-containing heteroaryl groups are heteroaryl groups in which at least one of the one or more heteroatoms in the ring is nitrogen.

[0059] The term "heteroarylalkyl" refers to a heteroaryl substituent attached via an alkyl chain. An example of a heteroarylalkyl substituent includes ethylpyridine, where an ethane chain is attached to the point of attachment of the pyridine group.

[0060] The term "amino group" is -NR m R n The amino group may be optionally substituted. In an unsubstituted amino group, R m and R n is hydrogen. In a substituted amino group, R m and R n may each independently be, but is not limited to, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, sulfonyl, alkenyl, alkanoyl, aryl, arylalkyl, or heteroaryl group, with the proviso that R m and R n In a substituted amino group, R m and R n may cyclize to form a cyclic amino group, such as a pyrrolidine or piperidine group. Such cyclic amino groups may contain other heteroatoms, for example, to form piperazine or morpholine groups. Such cyclic amino groups may be optionally substituted, for example, with amino, hydroxyl, or oxo groups. For example, in a substituted amino group, R m and R n may be independently 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, with the proviso that R m and R n At least one of them is not H.

[0061] The term "aminoalkyl" refers to a group -R a NR m R n where R a is an alkyl chain as defined above, and NR m R n is an optionally substituted amino group as defined above. n An "aminoalkyl" group refers to a group containing n carbon atoms, e.g., C1-C 10 The aminoalkyl group may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. When the amino group of the aminoalkyl group is a substituted amino group, the number of carbon atoms includes all carbon atoms of the substituent. The bond to the aminoalkyl group occurs through a carbon atom of the R alkyl group. Examples of aminoalkyl substituents include methylamine, ethylamine, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, methylpyrrolidine, and ethylpyrrolidine.

[0062] The term "amide group" refers to the group -C(=O)-NR-. Attachment can be via a carbon or nitrogen atom. For example, an amide group can be attached solely through a carbon atom as a substituent, in which case the nitrogen atom has two attached R groups (-C(=O)-NR2). An amide group can be attached solely through a nitrogen atom, in which case the carbon atom has attached R groups (-NR-C(=O)R).

[0063] The term sulfoximine refers to a sulfoximine substituent that is S-linked or N-linked—i.e., attachment can be through the sulfur or the nitrogen atom. For example, a sulfoximine group can be attached through a sulfur atom as a substituent, in which case the sulfur has one R group in addition to the oxo group, and the sulfur-linked nitrogen atom has one attached R group—i.e., the group is —S(O)(R)NR′. As a further example, a sulfoximine group can be attached through a nitrogen atom as a substituent, in which case the sulfur atom has two attached R groups in addition to the oxo group—i.e., the group is —NS(O)RR′. In an unsubstituted sulfoximine group, each of R and R′ is H. Alternatively, a sulfoximine group can be substituted at one or both of R and R′, R and R′, to form, for example, dimethyl sulfoximine, where both R and R′ are methyl.

[0064] The term "ether" refers to an -O-alkyl group or an -alkyl-O-alkyl group, such as a methoxy group, a methoxymethyl group, or an ethoxyethyl group. The alkyl chain of the ether can be a straight chain, a branched chain, or a cyclic chain. The ether group can optionally be substituted with one or more substituents ("substituted ethers"). n Ether refers to an ether group having n carbon atoms in the entire alkyl chain of the ether group. For example, CH(CH3)-O-CH 11 The ether is a C8 ether group.

[0065] The term "alkoxy group" refers to an -O-alkyl group. An alkoxy group refers to a straight, branched, or cyclic, saturated or unsaturated oxy-hydrocarbon chain, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, t-butoxyl, and pentoxyl. An alkoxy group can optionally be substituted with one or more alkoxy group substituents ("substituted alkoxy").

[0066] The term "aryloxy group" refers to an -O-aryl group, such as a phenoxy group. The aryloxy substituent may itself be optionally substituted, for example with halogen.

[0067] The term "alkyl ester" refers to a -C(O)OR group, where R is an alkyl group, as defined herein. An example of an alkyl ester is ethyl formate - i.e., R is an ethyl group.

[0068] The term "hydroxyl" refers to the group --OH.

[0069] The term "oxo group" refers to a (=O) group, i.e., a substituent oxygen atom attached to another atom by a double bond. For example, a carbonyl group (-C(=O)-) is a carbon atom attached to an oxygen atom by a double bond, i.e., an oxo group attached to a carbon atom. Examples of carbonyl substituents include aldehyde (-C(=O)H), acetyl (-C(=O)CH3), and carboxyl / carboxylic acid groups (-C(=O)OH).

[0070] The term "halo" refers to a substituent selected from chlorine, fluorine, bromine and iodine. Preferably, halo substituents are selected from chlorine and fluorine.

[0071] An alkyl, alkenyl, alkynyl, carbocyclyl (including cycloalkyl, cycloalkenyl, and aryl), heterocyclyl (including heterocycloalkyl, heterocycloalkenyl, heteroaryl, and nitrogen-containing heterocyclyl), amino, amido, ester, ether, alkoxy, or sulfonamido group can be optionally substituted with one or more substituents, which can be the same or different. The substituents can be attached via carbon atoms and / or heteroatoms in the alkyl, alkenyl, alkynyl, carbocyclyl (including cycloalkyl, cycloalkenyl, and aryl), heterocyclyl (heterocycloalkyl, heterocycloalkenyl, heteroaryl, and nitrogen-containing heteroaryl, including nitrogen-containing heterocyclyl), amino, amido, ester, ether, alkoxy, or sulfonamido 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.

[0072] In certain embodiments, the substituents are 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.

[0073] If a group, for example, an alkyl group, is "optionally substituted," it is understood that the group may have one or more substituents attached (substituted) or may have no substituents attached (unsubstituted).

[0074] It is understood that if a group is substituted with a further optionally substituted group, the first substituent may itself be unsubstituted or substituted.

[0075] For the sake of completeness, it should also be noted that certain chemical formulas used herein define delocalized systems. This definition is known in the art as the definition of aromaticity and may refer, for example, to the presence of planar mono-, bi-, or tricyclic ring systems containing (4n+2) electrons, where n is an integer. In other words, these systems exhibit Hückel aromaticity.

[0076] In any embodiment, the compounds of the present invention may have certain stereochemical aspects. For example, the compounds may have chiral centers and / or planes and / or axes of symmetry. That is, the compounds may be provided as single stereoisomers, single diastereomers, mixtures of stereoisomers, or 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 differ in the spatial orientation of the atoms and / or groups.

[0077] Additionally, compounds of the invention may exhibit tautomerism, and each tautomeric form is intended to be within the scope of the invention.

[0078] Additionally, the compounds of the present invention may be provided as prodrugs, which are converted, generally in vivo, from one form of the drug described herein to an active form.

[0079] Additionally, it is understood that the elements described herein may be common isotopes or isotopes other than common isotopes. For example, hydrogen atoms are 1 H, 2 H (deuterium) or 3 H (tritium).

[0080] Additionally, the compounds of the present invention may be provided as their pharmaceutically acceptable salts or co-crystals.

[0081] The term "pharmaceutically acceptable salt" refers to an ionic compound formed by the addition of an acid to a base. This term refers to salts that are considered in the art to be suitable for contact with a patient, e.g., in vivo; pharmaceutically acceptable salts are generally chosen for their non-toxic, non-irritating characteristics.

[0082] The term "co-crystal" refers to a multi-component molecular crystal that may involve non-ionic interactions.

[0083] Pharmaceutically acceptable salts and co-crystals can be prepared by ion exchange chromatography or by reacting the free base or acid form of a compound with a stoichiometric amount or an excess of the desired salt-forming inorganic or organic acid or base in one or more suitable solvents, or by mixing other pharmaceutically acceptable compounds that can form co-crystals with the compound.

[0084] Salts generally known in the art to be suitable for contact with patients include salts derived from inorganic and / or organic acids, including 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 alkali and alkaline earth metals such as sodium, potassium, calcium, and magnesium, as well as ammonium, tetramethylammonium, and tetraethylammonium. Further references examining suitable pharmaceutically acceptable salts are available, for example, in the Handbook of Pharmaceutical Salts published by IUPAC.

[0085] Additionally, compounds of the present invention may exist as zwitterions and are considered as part of this invention.

[0086] As used herein, a USP19 inhibitor refers to a compound that reduces the activity of the enzyme USP19. Examples of USP19 inhibitors are the compounds exemplified herein. Preferably, USP19 inhibitors have an IC of less than 5 μM, preferably less than 0.5 μM. 50 Shows.

[0087] As used herein, " obesity " refers to a medical condition characterized by excess body fat. Obesity can be characterized, for example, by a body mass index (BMI) greater than 30. Treatment of obesity can be indicated, for example, by the reduction of body fat in terms of percentage and / or absolute mass. Treatment of obesity can also be exemplified by the reduction of the rate of body fat accumulation by the subject compared to before treatment.

[0088] As used herein, "insulin resistance" refers to a condition characterized by an abnormally weak response to insulin. Insulin resistance is typically not treated with exogenous insulin treatment, so the resistance is typically to insulin produced by the subject's body, although a subject may also be resistant to exogenous insulin. "Insulin resistance" includes the condition "prediabetes" and type II diabetes. Insulin resistance can be indicated, for example, by a glucose tolerance test (GTT) glycemia of 7.8 mmol / L or higher. Type II diabetes is typically diagnosed after a glucose tolerance test (GTT) glycemia of 11.1 mmol / L or higher.

[0089] Treatment of insulin resistance can be indicated by an improvement (i.e., a decrease) in the subject's GTT glycemia compared to before treatment. Treatment can also be indicated by a decrease in the subject's blood glucose level to normal compared to before treatment.

[0090] As used herein, " muscle atrophy " and " muscle wasting " are used interchangeably and refer to the loss of muscle mass in a subject, including, for example, cachexia or sarcopenia.Muscle atrophy can be the result of temporary or persistent disability, temporary or persistent limb immobility, prolonged bed rest, cachexia (for example, as a result of cancer, heart failure or COPD) or sarcopenia.

[0091] Treatment of muscle atrophy can be characterized as slowing the rate of atrophy - i.e., the treatment reduces muscle mass loss over a period of time. Preferably, successful treatment does not result in muscle mass loss.

[0092] Thus, in a first embodiment, a compound of formula (I) [ka] [During the ceremony, R 0 is H, F, NH2 or OCH3; R 1is optionally substituted C1-C6 alkyl, ethylcyclopropyl, ethylcyclobutyl, optionally substituted C5-C8 aryl, optionally substituted C3-C8 heteroaryl, optionally substituted C3-C8 heterocycloalkyl, NR a R b , N.R. a CH2R b , OR a or OCH2R a where R a and R b are independently selected from H, C1-C6 alkyl, CF3, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C8 aryl, optionally substituted C6-C9 arylalkyl, and optionally substituted C2-C8 heteroaryl (optionally C4-C8 heteroaryl), where R 1 NR a CH2R b wherein the methylene group is optionally substituted with CF3; or R 1 is NR a R b and R a and R b together with the N to which they are attached form an optionally substituted C2-C9 heterocycle, and optionally together with the N to which they are attached form a C3-C5 heterocycle; R 2 and R 3 are independently selected from H and C1-C6 alkyl, or together with the carbon to which they are attached form a C3-C6 cycloalkyl or heterocycloalkyl; X is non-existent, C, CR 4a , C.R. 4a R 4b , N, NR 4a or C=O, where R 4a and R 4b is independently selected from H, optionally substituted C1-C6 alkyl or halo; or R 4aand R 4b form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl together with the carbon to which they are attached; Y is C, CR 5 , C.R. 5 R 6 , N, NR 5 or O, where R 5 and R 6 are independently selected from the group consisting of H, halo, optionally substituted C-C alkyl, C-C alkenyl, C-C alkynyl, optionally substituted C-C cycloalkyl, optionally substituted C-C heterocycloalkyl, optionally substituted C-C aryl, optionally substituted C-C arylalkyl, optionally substituted C-C heteroaryl, CHOH, NR'R", NS(O)R'R", SOR', C(O)R', COR', C(O)OR', C(O)NR'R', OR', where R' and R" are independently selected from H, C-C alkyl, C-C aryl, C-C arylalkyl and C-C heteroaryl, or R 5 is NR'R'', and R' and R'' form an optionally substituted C3-6 heterocycloalkyl containing the nitrogen to which they are attached. or R 5 and R 6 together with the carbon to which they are attached form a C3-6 cycloalkyl or a C3-C6 heterocycloalkyl; Z is N, NR 7 , C, C.R. 7 , C.R. 7 R 8 or C=O, where R 7 and R 8 are independently H, halo, cyano, oxo, optionally substituted C1-C6 alkyl, C2-C6 alkene, C2-C6 alkyne, C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C3-C8 heteroaryl, CN, C(O)ORc ,CONR c R d , N.R. c R d , NS(O)R c R d , S(O)(R c )NR d , SOR c , SO2R c and S.R. c wherein R c and R d are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C6 aryl, C6-C9 arylalkyl, C3-C6 heteroaryl, CN, COOH, or COCH3, or R c and R d together with the heteroatom to which they are attached form an optionally substituted C3-C7 heterocycle; or R 7 and R 8 together with the carbon to which they are attached form a C3-6 cycloalkyl or a C3-C6 heterocycloalkyl; M is absent, C, CR 13 or CR 13 R 14 where R 13 and R 14 are independently selected from H and C1-C6 alkyl or R 13 and R 14 together with the carbons to which they are attached form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl; and A is CR 9 , CHR 9 , N, NR 9 , S or O, D is CR 9 , CHR 9 , N or NR 9 and G is non-existent, CR 9 , CHR 9 or N, where R 9are independently H, halo, C1-C6 alkyl, CF3, and OR * where R * is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl or optionally substituted heterocycloalkyl; E is CR 10 , CHR 10 , N, NR 10 , S or O, where R 10 is H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C4-C8 heteroaryl, SR x , OR x , N.R. x R y and NS(O)R x R y , S(O)(R x )NR y where R x and R y are independently selected from H, C1-C6 alkyl, CF3, C3-C6 cycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C4-C8 heteroaryl, COOH, amido, cyano, C2-C6 alkene, C2-C6 alkyne, or R x and R y together with the nitrogen to which they are attached form an optionally substituted C4-C6 heterocycloalkyl; or A, D, E and G are all absent, X, Y, Z and M are as defined above, and Optionally, both X and M are absent or Optionally, Y and Z are joined together to form an optionally substituted C5-C6 aryl or C3-C6 heteroaryl fused ring, or Z and M are joined together to form an optionally substituted C5-C6 aryl or C5-C6 heteroaryl fused ring. or a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof, or [ka] Compounds are provided having a structure selected from:

[0093] For the avoidance of doubt, in formula (I), when any of positions A, D, E or G is present, each of the other positions A, D and E (and optionally G) may also be present to form a fused ring system.

[0094] For the avoidance of doubt, when one of positions X, M, or G is absent, the remaining ring members form a five-membered ring. In embodiments where X and M are absent, the remaining members form a four-membered ring. For example, when M is absent, the atom at ring position Z is bonded to the ring nitrogen.

[0095] The dotted lines in formula (I) indicate optional bonds. That is, the dotted lines indicate that the ring comprising positions X, Y, Z, and M can be aliphatic (e.g., saturated or partially unsaturated) or aromatic. Similarly, in formula (I), the dotted lines, when present, indicate that the ring comprising positions A, D, E, and optionally G can be aliphatic (e.g., saturated or partially unsaturated) or aromatic.

[0096] For compounds of Formula (I), for each optionally substituted group, there are one or more independently selected optional substituents. In some embodiments, each of the one or more optional substituents is independently selected from C-C alkyl, C-C cycloalkyl, halo, CHF, CF, hydroxyl, NH, substituted amino, NO, CHOH, CHOCH, methoxy, OCHF, OCF, cyclopropyloxy, phenyl, fluoro-substituted phenyl (e.g., difluoro-substituted phenyl), benzyl, and oxo.

[0097] In certain embodiments, each of the one or more optional substituents is independently selected from C1-C4 alkyl, C3-C4 cycloalkyl, halo, CHF2, CF3, hydroxyl, NH2, NHCH3, NHCH2CH3, NO2, CH2OH, CHOCH3, methoxy, OCHF2, OCF3, cyclopropyloxy, phenyl, fluoro-substituted phenyl (e.g., difluoro-substituted phenyl), benzyl, and oxo.

[0098] R 0 is H and R 2 and / or R 3 In embodiments where R is not H, 0 The ring carbon to which R is attached is chiral. 0 For compounds where R is H and the ring carbon is chiral, assign the (R)-configuration of the ring carbon for the more active stereoisomer for the example compound. 0 is F, NH2 or OMe, and R 0 When the ring carbon to which is attached is chiral, in the example compound, the conformation in which that stereocenter is more active is assigned the (S)-configuration.

[0099] The compound of formula (I) is R 0 In embodiments of the invention where is chiral at the stereocenter of the ring carbon to which is attached, the more active configuration is preferred.

[0100] R 0 In embodiments where is H, preferably this stereocenter is in the (R)-configuration.

[0101] R 0 In embodiments where is not H, preferably this stereocenter is in the (S)-configuration.

[0102] Nevertheless, R 0位It should be noted that any or all of the configurations of R may be inaccurately assigned, for example, due to errors in the original X-ray crystallography data determination or in the strategy of inferring stereochemistry from other compounds. Thus, it is possible that these compounds have the opposite configuration at this position. As already mentioned, the more active configuration is preferred. Therefore, R 0 In embodiments where R is H, preferably the ring carbon stereocenter is in the (R)-configuration. 0 In embodiments where is not H, preferably this stereocenter is in the (S)-configuration.

[0103] [Table 1]

[0104] In certain embodiments of compounds of Formula (I), R 0 is H. As shown in Table 1, R 0 The compound where is H is R 0 Compared to direct analogs where R is OH (some of which have been previously reported in WO2019150119 or WO2020115501), they show improved cell target binding ability (HTRF assay in HEK293T cells) and improved in vitro ADME properties such as Caco-2 permeability (AB: apical vs. basal data shown) and thermodynamic solubility (TSol). Furthermore, R 0 Compounds where is H are R 0 Compared to the direct analog where is OH, it shows improved in vivo mouse PK data with respect to extended IV half-life (t1 / 2 IV 1 mg / kg), reduced IV clearance (CL IV 1 mg / kg) and highly superior oral exposure (area under the curve, AUC PO 30 mg / kg) and oral bioavailability (F PO 30 mg / kg).

[0105] [Table 2]

[0106] In certain preferred embodiments of compounds of Formula (I), R 0 is H.

[0107] In certain embodiments of compounds of Formula (I), R 0 is NH2. Position R 0 Compounds with NH2 at position R 0 Compared to analogs with an OH at the 5' end, they exhibit improved kinetic solubility (KSol) and / or metabolic stability (as evidenced by lower predicted hepatic clearance, CLhep, using mouse liver microsome data), as shown in Table 3.

[0108] [Table 3]

[0109] Thus, in one preferred such embodiment, R 0 is NH2.

[0110] In one preferred embodiment, R 0 is F.

[0111] In one preferred embodiment, R 0 is OCH3.

[0112] In one preferred embodiment, R 1 is an optionally substituted C1-C6 alkyl. In certain embodiments, the optional substituents are chosen from halo, C1-C6 alkyl, C1-C6 alkoxy, and OH.

[0113] In certain preferred embodiments of compounds of Formula (I), R 1 is optionally substituted trifluoropropyl. In certain preferred such embodiments, each optional substituent is selected from methyl, CH2OCH3, and CH2OH.

[0114] In one preferred embodiment, R 1 teeth: [ka] is.

[0115] In one preferred embodiment, R 1 teeth: [ka] is.

[0116] R 1 In certain preferred embodiments, R is optionally substituted trifluoropropyl. 0 is H.

[0117] R 1 In certain preferred embodiments, R is optionally substituted trifluoropropyl. 0 is NH2.

[0118] In certain preferred embodiments of compounds of Formula (I), R 1 is NR a R b or NR a CH2R b where R a and R b are independently selected from the group consisting of 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, benzodioxole, optionally substituted oxadiazole, thiazole, and thiophene, wherein each of the one or more optional substituents is independently selected from halo, methyl, cyclopropyl, and CN; In some cases, R 1 is NR a CH2R b where the methylene group is replaced by CF3.

[0119] or In some embodiments, R 1 is NR a R b and R a and R b taken together with the N to which they are attached form an optionally substituted C3-C9 heterocycle.

[0120] In some embodiments, R 1 is NR a R b and R a and R b taken together with the N to which they are attached form an optionally substituted C3-C9 heterocycle, wherein each of the one or more optional substituents is OH, oxo, C1-C3 alkyl optionally substituted with OH and / or halo, optionally substituted phenyl, optionally substituted benzyl, C1-C3 alkoxy, NR m R n , NHC(O)R m and NHCH2R n is selected from where R m and R n is 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 R n is further selected from CH2OCH3, COOH and COOCH3; or R m and R n together with the N to which they are attached form a C3-C5 heterocyclyl group, and optionally R m and R n together with the N to which they are attached to form a morpholinyl group.

[0121] In some embodiments, R 1 is NR a R b and R a and R b taken together with the N to which they are attached form an optionally substituted C3-C9 heterocycle, wherein each of the one or more optional substituents is optionally halo-substituted phenyl, NR m R n , NHC(O)R m and NHCH2R n is selected from where R m and R n is 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 R n is further selected from CH2OCH3, COOH and COOCH3; or R m and R n together with the N to which they are attached form a C3-C5 heterocyclyl group, and optionally R m and R n together with the N to which they are attached to form a morpholinyl group.

[0122] In some embodiments, R 1 is NR a R b and R a and R b taken together with the N to which they are attached form a substituted C3-C9 heterocycle, wherein each of the one or more substituents is selected from OH, CH2OH, CHOCH3, oxo, NH2, C1-C3 aminoalkyl, amino-thietane dioxide, methyl, ethyl, propyl, CF3, phenyl, substituted phenyl, and benzyl.

[0123] In some embodiments, R 1 is NR a R b and R a and R b taken together with the N to which they are attached form an optionally substituted heterocycle, where the heterocycle is selected from pyrrolidinyl, pyrimidinyl, piperidinyl, morpholino, piperazinyl, and thiomorpholino. In some such embodiments, the heterocycle is optionally substituted with one or more substituents independently selected from methyl, spiro-cyclopropyl, C-C aminoalkyl, NH, CHOH, CHCF, oxo, thiophene, phenyl optionally substituted with F or CF, and OH, provided that the same ring carbon is not also substituted with methyl.

[0124] In some embodiments, R 1 is NR a R b and R a and R b together with the N to which they are attached form a heterocycle, 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, NH, C or C aminoalkyl, CHCF, oxo, thiophene, phenyl optionally substituted with F or CF, and OH, provided that the same ring carbon is not also substituted with methyl.

[0125] In some embodiments, R 1 is NR a R b and R a and R b together with the N to which they are attached form a heterocycle, wherein the heterocycle is selected from piperidinyl and piperazinyl; wherein the heterocycle is optionally substituted with one or more substituents independently selected from methyl, NH, C or C aminoalkyl, CHCF, oxo, thiophene, phenyl optionally substituted with F or CF, and OH, provided that the same ring carbon is not also substituted with methyl.

[0126] In some embodiments, R 1 is NR a R b and R a and R b taken together with the N to which they are attached form an optionally substituted heterocycle, wherein the heterocycle is selected from piperidinyl and piperazinyl.

[0127] Preferably, R 1 forms a fluoro-phenyl or difluorophenyl substituted piperazinyl group.

[0128] In certain embodiments, the piperazinyl group is optionally further substituted with methyl.

[0129] In certain embodiments, the piperazinyl group is optionally further substituted with CH2OH or spiro-cyclopropyl.

[0130] In some embodiments, R 1 is NR a R b and R a and R b forms an optionally substituted heterocycle, wherein the heterocycle is a piperidinyl group substituted with phenyl. In some preferred such embodiments, the piperidinyl group is optionally further substituted with NH or NHCH.

[0131] In some embodiments, R 1 is NR a R b and R a and R btogether with the N to which they are attached form a piperidinyl group optionally substituted with phenyl, fluoro-phenyl or difluoro-phenyl, wherein the piperidinyl group is optionally NR m R n , NHC(O)R m or NHCH2R n is further substituted with where R m and R n is 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 R n is further selected from CH2OCH3, COOH and COOCH3; or R m and R n together with the N to which they are attached form a C3-C5 heterocyclyl group, and optionally R m and R n together with the N to which they are attached to form a morpholinyl group.

[0132] In some embodiments, R 1 is NR a R b and R a and R b together with the N to which they are attached form a piperidinyl group optionally substituted with phenyl, fluoro-phenyl or difluoro-phenyl, wherein the piperidinyl group is optionally NR m R n , NHC(O)R m or NHCH2R n is further substituted with where R mis 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 where R n is 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.

[0133] In one preferred embodiment, R 1 The piperidinyl ring formed by NR m R n where R m and R n are independently selected from H; C1-C3 alkyl (preferably F) optionally substituted with OH or halo; C3-C4 cycloalkyl (preferably F) 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.

[0134] R 1 NR m R n In certain preferred embodiments, R m is H.

[0135] In one preferred embodiment, R m is H and R nis 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 oxetane optionally substituted with methyl or fluoro-methyl.

[0136] In one preferred embodiment, R 1 The piperidinyl ring formed by NHC(O)R m where R m is selected from H; C1-C3 alkyl (preferably F) optionally substituted with OH or halo; C3-C4 cycloalkyl (preferably F) 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.

[0137] R 1 NHC(O)R m In certain preferred embodiments, R m is selected from C1-C3 alkyl, C3-C4 cycloalkyl, and C4-C5 heteroaryl, such as pyridine.

[0138] In some embodiments, R 1 is NR a R b and R a and R b together with the N to which they are attached form a piperidinyl group optionally substituted with phenyl, fluoro-phenyl or difluoro-phenyl, wherein the piperidinyl group is optionally NR m R n is further substituted with where R m and R n together with the N to which they are attached form a C3-C5 heterocyclyl group. In some such embodiments, R m and Rn together with the N to which they are attached to form a morpholinyl group.

[0139] In some embodiments, R 1 is NR a R b and R a and R b together with the N to which they are attached form a piperidinyl group optionally substituted with phenyl, fluoro-phenyl, or difluoro-phenyl, wherein the piperidinyl group is optionally further substituted with NH, NHCH, or NHCHCH.

[0140] R 1 In certain embodiments where the heterocycle formed by is substituted, the substitution is at the para position (position 4).

[0141] R 1 In certain embodiments where the heterocycle formed by is substituted, the substitution is at the ortho position (position 2).

[0142] In some such embodiments, R 1 The heterocycle formed by is substituted at the ortho and para positions (2,4 positions).

[0143] In some embodiments, R 1 is NR a R b and R a and R b together with the N to which they are attached to form a piperidinyl group, where the piperidinyl group has the 4-position as NR m R n , NHC(O)R m and NHCH2R n and further substituted at the 2-position with phenyl, fluoro-phenyl, or difluoro-phenyl. m and R n is as defined above and elsewhere herein.

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

[0145] R 1 In preferred such embodiments, where R is a heterocycle substituted at the ortho or 2-position and the para or 4-position (e.g., with NH or C-C alkylamino) and is chiral, the compound is in the (R)-configuration at the para position and the (S)-configuration at the ortho position. 1 is substituted at the ortho or 2-position and the para or 4-position (e.g., with NH or C-C alkylamino) and is chiral. In preferred such embodiments, the compound is in the (S)-configuration at the para position and the (R)-configuration at the ortho position.

[0146] In one preferred embodiment, R 1 forms a piperazinyl group substituted with phenyl, fluoro-phenyl, difluoro-phenyl or thiophenyl. In one preferred embodiment, R 1 forms a 4-aminopiperidinyl group substituted with phenyl, fluoro-phenyl, difluoro-phenyl or thiophenyl. Preferably, R 1 forms a phenyl-substituted piperazinyl or 4-aminopiperidinyl group. Preferably, R 1 forms a fluoro-phenyl substituted piperazinyl or 4-aminopiperidinyl group. Preferably, R 1 forms a difluoro-phenyl substituted piperazinyl or 4-aminopiperidinyl group.

[0147] R 1 In preferred embodiments where is substituted with difluoro-phenyl, the substituent is 2,5-difluoro-phenyl or 3,5-difluoro-phenyl.

[0148] In certain embodiments, the piperazinyl or 4-aminopiperidinyl group is optionally further substituted with one or two, preferably one, N-alkyl groups such as methyl or ethyl.

[0149] In one preferred embodiment, R 1 teeth [ka] is.

[0150] In one preferred embodiment, R 1 teeth [ka] is.

[0151] In one preferred embodiment, R 1 teeth [ka] is.

[0152] In one preferred embodiment, R 1 teeth [ka] is.

[0153] In certain preferred such embodiments, the phenyl ring is mono- or di-substituted with fluoro.

[0154] In one preferred embodiment, R 1 teeth [ka] is selected from.

[0155] In certain preferred embodiments of compounds of Formula (I), R 1 is NR a R bor NR a CH2R b where R a and R b are independently selected from H, methyl, ethyl, propyl, CF, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, pyridinyl, pyrazole, imidazole, or R a and R b taken together with the N to which they are attached form a C3-C5 heterocycle optionally substituted with OH, CH2OH, CH2OCH3, methyl, ethyl, propyl, CF3, phenyl or benzyl.

[0156] In one preferred embodiment, R 1 is NR a CH2R b where R a is H or methyl, and R b is selected from cyclobutyl, cyclohexyl optionally substituted with F, phenyl optionally substituted with F, furan and thiophene, and optionally the methylene group is replaced with CF3.

[0157] In one preferred such embodiment, R b is phenyl or fluoro-substituted phenyl.

[0158] In one preferred embodiment, R 1 forms an optionally substituted C or C heterocycloalkyl ring attached to the carbonyl of Formula (I) through a carbon ring atom, where the optional substituent is phenyl. In some such embodiments, the heteroatom in the heterocycloalkyl ring is N.

[0159] In certain preferred embodiments of compounds of Formula (I), R 2 and R 3are independently selected from H, methyl, and ethyl, or taken together with the carbon to which they are attached form optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted pyrrolidine, optionally substituted tetrahydropyran, or optionally substituted tetrahydrofuran.

[0160] In some such embodiments, R 2 and R 3 is independently selected from H and methyl. In some embodiments, R 2 and R 3 and R are both methyl. 2 and R 3 are both H.

[0161] In one preferred embodiment, R 2 and R 3 taken together with the carbons to which they are attached form cyclohexyl, cyclopentyl or cyclobutyl. Preferably, R 2 and R 3 together form cyclopentyl. Alternatively, preferably, R 2 and R 3 together form cyclohexyl.

[0162] In certain embodiments, a compound of Formula (I) is provided, wherein: X is CR 4a where R 4a are independently selected from H, optionally substituted C1-C6 alkyl or halo, preferably H or C1-C6 alkyl; Y is N; Z is CR 7 where R 7is H, halo, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkyne, C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C3-C8 heteroaryl, CN, COOR c ,CONR c R d , N.R. c R d , NS(O)R c R d , S(O)(R c )NR d , SOR c , SO2R c and S.R. c where R c and R d are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C6 aryl, C6-C9 arylalkyl, C3-C6 heteroaryl, CN, COOH, or COCH3, or R c and R d together with the heteroatom to which they are attached form an optionally substituted C3-C7 heterocycle; M is CH or C-CH3; and the ring containing X, Y and Z is aromatic, and A, D, E and G are all absent.

[0163] In one preferred such embodiment, Z is CR 7 and R 7 are H, methyl, cyclopropyl, phenyl, pyridine, pyrazole, indazole, imidazole, Cl, Br, COOH, COOCH3, C(O)NR c R d , N.R. c R d where R c R d is selected from methyl or R c and R d taken together with the N to which they are attached form an optionally substituted piperazine, morpholine or an optionally substituted pyrrolidine.

[0164] In one preferred embodiment, R 7 is Cl, Br or C(O)OCH3 or R 7 CONR c R d and R c and R d is each methyl or R c and R d together with the N to which they are attached to form a piperazinyl ring.

[0165] In one embodiment, X is CR 4a where R 4a is selected from H, optionally substituted C-C alkyl and halo, and optionally R 4a is H or C1-C6 alkyl; Y is CR 5 and; Z is N or CR 7 and; M is CH or C-CH3; wherein the ring containing X, Y, and Z is aromatic, A, D, E, and G are all absent, and R 5 is selected from H, halo, optionally substituted C-C alkyl, C-C alkenyl, C-C alkynyl, optionally substituted C-C cycloalkyl, optionally substituted C-C aryl, optionally substituted C-C arylalkyl, optionally substituted C-C heteroaryl, CHOH, NR'R", NS(O)R'R", SOR', C(O)R', COR', C(O)OR', C(O)NR'R", OR', and SR', where R' and R" are independently selected from H, C-C alkyl, C-C aryl, C-C arylalkyl, and C-C heteroaryl; and R 7is H, halo, cyano, oxo, optionally substituted C1-C6 alkyl, C2-C6 alkene, C2-C6 alkyne, C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C3-C8 heteroaryl, CN, C(O)OR c ,CONR c R d , N.R. c R d , NS(O)R c R d , S(O)(R c )NR d , SOR c , SO2R c and S.R. c where R c and R d are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C6 aryl, C6-C9 arylalkyl, C3-C6 heteroaryl, CN, COOH, or COCH3, or R c and R d taken together with the heteroatom to which they are attached form an optionally substituted C3-C7 heterocycle.

[0166] In one preferred embodiment, Z is N or CR 7 where R 7 is H, C1-C6 alkyl, NR'R", C(O)NR'R", cyano, carboxyl, halo, C1-C6 alkylamine, C3-C6 alkylester, optionally substituted C6-C 10 aryl or optionally substituted C2-C6 heteroaryl, wherein one or more heteroatoms are selected from N and O, and one or more optional substituents on the aryl or heteroaryl are selected from C1-C6 alkyl, C1-C6 alkylamine, amido, and cyano; wherein R' and R" are independently selected from H, C1-C6 alkyl optionally substituted with OH, C3-C7 cycloalkyl, C1-C7 heterocycloalkyl, C4-C7 alkylcycloalkyl, C3-C7 alkylheterocycloalkyl, benzyl, phenyl, and methoxy, or R' and R" taken together form a C2-C7 heterocycle containing the N to which they are attached, wherein the heterocycle is optionally hydroxyl-, oxo-, methyl-, CH2OH-, or acetyl-substituted.

[0167] In one preferred embodiment, Z is N or CR 7 where R 7 is selected from phenyl optionally substituted with amido, cyano or methylamine; pyridine; oxazole; pyrazole; carboxyl; C(O)NR'R"; or NR'R"; wherein R' and R" are independently selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl (wherein the heteroatom is N or O); or R' and R" taken together form a C2-C7 heterocycloalkyl containing the N to which they are attached, wherein the heterocycloalkyl is optionally hydroxyl-, oxo-, methyl-, CH2OH-, or acetyl-substituted.

[0168] In one preferred embodiment, Z is CR 7 where R 7 is C(O)NR'R", where R' and R" taken together form an optionally substituted pyrrolidine, piperidine, piperazine or morpholine containing the N to which it is attached, wherein the piperidine, pyrrolidine, piperazine or morpholine is optionally hydroxyl-, oxo-, methyl-, hydroxymethyl- or acetyl-substituted.

[0169] In one preferred embodiment, R 5is phenyl optionally substituted with one or more substituents independently selected from methyl, halo (e.g., fluoro), and OCH. In certain preferred embodiments, R 5 is halo, e.g., Cl. In one preferred embodiment, R 5 is cyclopropyl optionally substituted with methyl. In one preferred embodiment, R 5 is methyl optionally substituted with 2 or 3 fluoro. In one preferred embodiment, R 5 is SCH3.

[0170] In one preferred such embodiment, R 4a is H and R 5 is Cl or phenyl optionally substituted with fluoro, methyl or OCH3, and Z is N or CR 7 is.

[0171] In one preferred embodiment, Z is CR 7 where R 7 is Cl, Br or C(O)OCH3 or R 7 CONR c R d and R c and R d is each methyl or R c and R d are taken together with the N to which they are attached to form a piperazinyl ring. In one preferred such embodiment, R 7 is a di-methylamide.

[0172] In one preferred embodiment, Z is CR 7 where R 7 is H.

[0173] In certain preferred embodiments, Z is N.

[0174] In certain embodiments, compounds of Formula (I) are provided, wherein the ring comprising X, Y, and Z is aromatic; A, D, E, and G are all absent; X is CR 4a where R 4a is selected from H, optionally substituted C1-C6 alkyl and halo, preferably H or C1-C6 alkyl; Y is CR 5 and; Z is N or CR 7 and; M is CH or C-CH3; In some such embodiments, R 4a is H and R 5 is Cl or phenyl optionally substituted with fluoro, and Z is N or CR 7 is.

[0175] In one embodiment: X is CH, Z is N or CH; M is CH, Y is CR 5 where R 5 is selected from halo, optionally substituted C-C alkyl, optionally substituted C-C cycloalkyl, optionally substituted C-C heterocycloalkyl, optionally substituted C-C aryl, optionally substituted C-C heteroaryl, and NR'R", where R' and R" together form an optionally substituted C-C heterocycloalkyl containing the nitrogen to which they are attached.

[0176] In one preferred such embodiment, R 5is selected from halo, optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted thiophenyl, optionally substituted piperidinyl, optionally substituted pyrazolyl, optionally substituted pyrrolidinyl, optionally substituted dihydrobenzofuranyl, optionally substituted azabicyclohexyl and optionally substituted azetidinyl. Preferably, R 5 is optionally substituted phenyl.

[0177] In a preferred such embodiment, R 5 wherein each of the one or more substituents is selected from the group consisting of Cl, F, methyl, CHF2, CF3, methoxy, OCHF2, OCF3, and cyclopropyloxy.

[0178] In some embodiments, R 5 is selected from the group consisting of halo; phenyl optionally substituted with fluoro, methoxy or methyl; methyl optionally substituted with fluoro, difluoro or trifluoro; cyclopropyl optionally substituted with methyl.

[0179] In one preferred embodiment, R 5 is phenyl, OCH3, or methyl, optionally substituted with F. In one preferred embodiment, R 5 is methyl optionally substituted with fluoro. In one preferred embodiment, R 5 is CHF2 or CF3.

[0180] In one preferred embodiment, R 5 is Cl.

[0181] Preferably, in some such embodiments, Z is N. Alternatively, preferably, in some such embodiments, Z is CH.

[0182] In some embodiments, X is CR 4a and Y is CR5 Z is N or CH; M is CH or C-CH3, where R 4a is H and R 5 is Cl or phenyl or methoxy optionally substituted with fluoro.

[0183] In certain embodiments, a compound of Formula (I) is provided, wherein the ring comprising X, Y, and Z is aliphatic, and wherein A, D, E, and G are all absent; X is non-existent, CR 4a R 4b , N.R. 4a or C=O, where R 4a and R 4b is H, optionally substituted C1-C6 alkyl or halo, or R 4a and R 4b form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl together with the carbon to which they are attached; Y is O, CR 5 R 6 or NR 5 where R 5 and R 6 are independently selected from the group consisting of H, halo, optionally substituted C-C alkyl, optionally substituted C-C cycloalkyl, optionally substituted C-C aryl, optionally substituted C-C arylalkyl, optionally substituted C-C heteroaryl, CHOH, NR'R", NS(O)R'R", COR', COOR', C(O)NR'R", OR', where R' and R" are independently selected from C-C alkyl, C-C aryl, C-C arylalkyl, and C-C heteroaryl; or R 5 and R 6 together with the carbon to which they are attached form a C3-6 cycloalkyl or a C3-C6 heterocycloalkyl; Z is CR 7 R 8 where R 7 and R 8are independently H, halo, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkyne, C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C3-C8 heteroaryl, CN, COOR c ,CONR c R d , N.R. c R d wherein R c and R d are independently selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, C5-C6 aryl, C6-C9 arylalkyl, C3-C6 heteroaryl, CN, COOH, or COCH3; or R c and R d together with the heteroatom to which they are attached form an optionally substituted C3-C7 heterocycle; or R 7 and R 8 together with the carbon to which they are attached form a C3-6 cycloalkyl or a C3-C6 heterocycloalkyl; M is absent, CH2, or Z and M together form part of an optionally substituted phenyl or pyridine ring; or M is absent and Y and Z together form a fused phenyl or heteroaryl ring; or M and X are both absent and Z is CHR 7 where R 7 is H, halo, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkyne, C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C3-C8 heteroaryl, CN, COOR c ,CONR c R d , N.R. c R d where R c and R d are independently H, C1-C6 alkyl, or cand R d taken together with the heteroatom to which they are attached form an optionally substituted C3-C7 heterocycle.

[0184] In one preferred such embodiment: R 4a is selected from H, C1-C6 alkyl or halo, and R 4b is H, preferably where X is CR 4a R 4b and R 4a is selected from H and C1-C6 alkyl, and R 4b is H; R 5 and R 6 are independently selected from the group consisting of H, halo, optionally substituted C-C alkyl, optionally substituted phenyl, benzyl, pyridinyl, CHOH, C(O)R', COR', C(O)OR', C(O)NR'R" and SO2R', where R' and R" are independently selected from methyl, ethyl, propyl, butyl, phenyl and benzyl, or R 5 and R 6 together form a cyclohexyl including the carbon to which they are attached, preferably where Y is O or CR 5 R 6 and R 5 and R 6 are independently selected from H, halo, optionally substituted C-C alkyl, optionally substituted phenyl, benzyl, pyridinyl, CHOH, C(O)R', COR', C(O)OR', C(O)NR'R" and SO2R', where R' and R" are independently selected from methyl, ethyl, propyl, butyl, phenyl and benzyl, or R 5 and R 6 together form a cyclohexyl with the carbon to which they are attached; R 7 is H, C1-C6 alkyl, phenyl and CONR c R d where R c and Rd are independently H, methyl, or R c and R d taken together with the nitrogen to which they are attached form an optionally substituted pyrrolidine, and R 8 is H, preferably where Z is CR 7 R 8 and R 7 is H, C1-C6 alkyl, phenyl and CONR c R d where R c and R d are independently H, methyl, or R c and R d taken together with the nitrogen to which they are attached form an optionally substituted pyrrolidine, and R 8 is H.

[0185] In some embodiments, Z is CH2 and Y is NR 5 In some such embodiments, R 5 is C(O)CH3.

[0186] In one preferred embodiment: X is CR 4a R 4b and R 4a and R 4b are both H; Y is O or CR 5 R 6 where R 5 is phenyl or C(O)NR'R" where R' and R" are both methyl, and R 6 is H; and Z is CR 7 R 8 where R 7 is phenyl or C(O)NR c R d where R c and R d and R are both methyl. In some such embodiments, R 8 is H.

[0187] In one preferred such embodiment: X is CR 4a R 4b and R 4a and R 4b are both H; Y is O; and Z is CR 7 R 8 where R 7 and R 8 are both H.

[0188] In one preferred embodiment, X is CR 4a R 4b and R 4a and R 4b are both H; Y is N and Z is C, and Y and Z are taken together to form a fused heteroaryl ring and optionally together to form a fused imidazolyl ring.

[0189] In some embodiments, Z is CR 7 R 8 and Y is NR 5 In one preferred such embodiment, R 5 is phenyl, pyridinyl, butylcarboxylate or C(O)CH3, preferably where R 5 is phenyl. In certain preferred such embodiments, Z is CH2.

[0190] In certain preferred embodiments of compounds of Formula (I), the ring comprising X, Y and Z is aliphatic, and A, D, E and G are each C or N and form a fused aryl or heteroaryl ring with the aliphatic ring that includes X, Y and Z in the case of a 5-membered ring (wherein M is absent) and X, Y, Z and M in the case of a 6-membered ring; X is C, Y is C, Z is NR 7 , C.R. 7 R 8 or C=O, where R 7 and R8 are independently H, halo, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkyne, C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C3-C8 heteroaryl, CN, COOR c ,CONR c R d , N.R. c R d , NS(O)R c R d , S(O)(R c )NR d , SOR c , SO2R c and S.R. c wherein R c and R d are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C6 aryl, C6-C9 arylalkyl, C3-C6 heteroaryl, CN, COOH, or COCH3, or R c and R d together with the heteroatom to which they are attached form an optionally substituted C3-C7 heterocycle; or R 7 and R 8 form a C3-6 cycloalkyl or a C3-C6 heterocycloalkyl together with the carbon to which they are attached; and M is absent or CR 13 R 14 where R 13 and R 14 are independently selected from H and C1-C6 alkyl or R 13 and R 14 taken together with the carbon to which they are attached form a C3-C6 cycloalkyl.

[0191] In certain preferred such embodiments, M is absent and Z is CR 7 R 8 where R 7 and R 8 is H.

[0192] In one preferred such embodiment, A, D and E are C and G is C or N.

[0193] In certain preferred embodiments of compounds of formula (I): X is C or N, Y is C or N; Z is N or CR 7 where R 7 is H, halo, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkyne, C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C3-C8 heteroaryl, CN, COOR c ,CONR c R d , N.R. c R d , NS(O)R c R d , S(O)(R c )NR d , SOR c , SO2R c and S.R. c where R c and R d are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C6 aryl, C6-C9 arylalkyl, C3-C6 heteroaryl, CN, COOH, or COCH3, or R c and R d together with the heteroatom to which they are attached form an optionally substituted C3-C7 heterocycle; M is absent, CH or C-CH; A is CR 9 , CHR 9 , N, NR 9 , S or O, D is CR 9 , CHR 9 , N or NR 9 and G is non-existent, CR 9 , CHR 9or N, where R 9 are independently H, halo, C1-C6 alkyl, CF3, and OR * where R * is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 cycloalkyl or optionally substituted heterocycloalkyl, and E is CR 10 , CHR 10 , N, NR 10 , S or O, where R 10 is H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C4-C8 heteroaryl, SR x , OR x , N.R. x R y and NS(O)R x R y , S(O)(R x )NR y where R x and R y are independently selected from H, C1-C6 alkyl, CF3, C3-C6 cycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C4-C8 heteroaryl, COOH, amido, cyano, C2-C6 alkene, C2-C6 alkyne, or R x and R y taken together with the nitrogen to which they are attached form an optionally substituted C4-C6 heterocycloalkyl.

[0194] In certain preferred such embodiments, Z is N or CR 7 where R 7 is H, C1-C6 alkyl, CN or C(O)NR c R d where R c and R dare independently H, methyl, or taken together with the nitrogen to which they are attached form an optionally substituted piperidine, piperazine, or morpholine ring.

[0195] In certain preferred such embodiments, Z is N or CR 7 where R 7 is H, C1-C6 alkyl, CN or C(O)NR c R d where R c and R d are independently H, methyl, or taken together with the nitrogen to which they are attached form an optionally substituted piperidine, piperazine, or morpholine ring.

[0196] In one preferred such embodiment: E is CR 10 , CHR 10 , N, NR 10 , S or O, where R 10 is H, F, Cl, Br, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, SR x , OR x , N.R. x R y and NS(O)(CH), where R x and R y are independently selected from H, methyl, ethyl, CF, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, COOH, amido, cyano, or R x and R y taken together with the nitrogen to which they are attached form piperidine, piperazine or morpholine, optionally substituted with methyl.

[0197] In one preferred embodiment: A, M, X and Y are C and E is CR 10 and D is N, G is C or N, and Z is C or N, As a result, the ring comprising A, D, E, G, X, Y, Z and M forms a fused aromatic ring system. In one preferred such embodiment, G is C and Z is C.

[0198] In one preferred embodiment: M is non-existence, A, X and Y are C, D and G are N, E is CR 10 and Z is NR 7 and and the ring containing A, D, E, G, X, and Y forms a condensed aromatic ring with the ring containing X, Y, and Z; where R 7 is H or C1-C6 alkyl, and optionally R 7 is methyl.

[0199] In one preferred embodiment: M, A, X, Y and Z are C; D and G are N; E is CR 10 and and the ring containing A, D, E, G, X, and Y forms a fused aromatic ring with the ring containing X, Y, M, and Z.

[0200] In one preferred embodiment, E is CR 10 where R 10 is H or SR x where R x is C1-C6 alkyl. Preferably, R x is methyl.

[0201] In one preferred embodiment: X, Y, M, A and G are C; Z is N and D is CR 9 and E is CR 10 and As a result, the rings containing A, D, E, G, X, Y, Z and M form a fused aromatic ring system, where R9 is halo, preferably F or Cl, and R 10 is H or halo, optionally F or Cl.

[0202] In one preferred embodiment: G is absent, A is C, D and Z are N, and E is NR 10 and As a result, the rings containing A, D, E, X, Y, Z and M form a fused aromatic ring system, where R 10 is selected from H, ethyl, cyclopropyl, phenyl and benzyl. In a preferred embodiment, R 10 is cyclopropyl.

[0203] In a preferred such embodiment, R 2 R, not H 3 is not H. This embodiment is particularly advantageous because it improves the selectivity of USP19 inhibition relative to other USPs. In one preferred such embodiment, R 2 and R 3 are both CH or together with the carbon to which they are attached form a C-C cycloalkyl. In certain preferred embodiments, R 2 and R 3 together with the carbon to which they are attached to form cyclopentyl.

[0204] In certain preferred embodiments of compounds of formula (I): X is CR 4 where R 4 is independently selected from H, C1-C6 alkyl, or halo; Y is CR 5 where R 5is selected from H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, optionally halo-substituted phenyl, optionally halo-substituted benzyl, pyridinyl, pyrazole, imidazole, CH2OH, NR'R", COR', C(O)OR', C(O)NR'R", OR', where R' and R" are independently selected from C1-C6 alkyl and phenyl, benzyl, pyridinyl, pyrazole, imidazole; Z is CR 7 where R 7 is H, halo, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkyne, C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C3-C8 heteroaryl, CN, COOR c ,CONR c R d , N.R. c R d , NS(O)R c R d , S(O)(R c )NR d , SOR c , SO2R c and S.R. c where R c and R d are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C6 aryl, C6-C9 arylalkyl, C3-C6 heteroaryl, CN, COOH, or COCH3, or R c and R d together with the heteroatom to which they are attached form an optionally substituted C3-C7 heterocycle; M is CH; and the ring containing X, Y, and Z is aromatic, and A, D, E, and G are all absent.

[0205] In certain preferred embodiments, Z is CH.

[0206] In one preferred embodiment, R 5is phenyl, OCH3, or methyl, optionally substituted with F. In one preferred embodiment, R 5 is methyl optionally substituted with fluoro. In one preferred embodiment, R 5 is CHF2 or CF3.

[0207] In some embodiments of the compounds provided herein, the compounds are chiral at the tertiary alcohol position of Formula (I). In a preferred embodiment, the compounds are in the (R)-configuration. In another preferred embodiment, the compounds are in the (S)-configuration.

[0208] In one preferred embodiment: X is CR 4a R 4b where R 4a and R 4b are independently selected from H, optionally substituted C-C alkyl and halo; or R 4a and R 4b form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl together with the carbon to which they are attached; Y is O, Z is CR 7 R 8 where R 7 and R 8 are independently H, halo, cyano, oxo, optionally substituted C1-C6 alkyl, C2-C6 alkene, C2-C6 alkyne, C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, C5-C8 aryl, C6-C9 arylalkyl, C3-C8 heteroaryl, CN, C(O)OR c ,CONR c R d , N.R. c R d , NS(O)R c R d , S(O)(R c )NR d , SOR c , SO2R c and S.R. cwherein R c and R d are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C6 aryl, C6-C9 arylalkyl, C3-C6 heteroaryl, CN, COOH, or COCH3, or R c and R d together with the heteroatom to which they are attached form an optionally substituted C3-C7 heterocycle; or wherein R 7 and R 8 together with the carbon to which they are attached form a C3-6 cycloalkyl or a C3-C6 heterocycloalkyl; M is CR 13 R 14 where R 13 and R 14 are independently selected from H and C1-C6 alkyl or R 13 and R 14 together with the carbon to which they are attached form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl; where the ring containing XYZM is aliphatic.

[0209] In certain preferred such embodiments, X, Z, and M are CH2 and Y is O.

[0210] In one embodiment, (R)-6-phenyl-3-((1-(2-phenylpiperazine-1-carbonyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one; (R)-6-phenyl-3-((7-(2-phenylpiperazine-1-carbonyl)-7-azaspiro[4.5]dec-9-en-10-yl)methyl)pyrimidin-4(3H)-one; (R,Z)-6-phenyl-3-((7-(2-phenylpiperazine-1-carbonyl)-7-azaspiro[4.5]decan-10-ylidene)methyl)pyrimidin-4(3H)-one; 6-phenyl-3-((7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one; 4-phenyl-1-((7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one; (R)-4-phenyl-1-((1-(2-phenylpiperazine-1-carbonyl)piperidin-4-yl)methyl)pyridin-2(1H)-one; 6-phenyl-3-((7-((S)-4,4,4-trifluoro-2-(methoxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one; 6-phenyl-3-((7-((S)-2-phenylpyrrolidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one; 3-((1-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4(3H)-one; N-benzyl-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxamide; 3-((7-((R)-2-(3,5-difluorophenyl)piperazine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-((7-((3R,4R)-1-imino-1-oxide-4-phenyltetrahydro-1H-1λ 6 -thiophene-3-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-((7-((3S,4S)-1-Imino-1-oxide-4-phenyltetrahydro-1H-1λ 6-thiophene-3-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 6-phenyl-3-(((S)-7-((R)-2-phenylpiperazine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one; 6-phenyl-3-(((R)-7-((R)-2-phenylpiperazine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one; 4-phenyl-1-(((S)-7-((R)-2-phenylpiperazine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one; 4-phenyl-1-(((R)-7-((R)-2-phenylpiperazine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one; 1-((1-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one; 3-((3,3-dimethyl-1-((R)-2-phenylpiperazine-1-carbonyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-((1-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-3,3-dimethylpiperidin-4-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 1-((3,3-dimethyl-1-((R)-2-phenylpiperazine-1-carbonyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one; 1-((1-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-3,3-dimethylpiperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one; (R)-1-((1-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 1-(((S)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 3-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((S)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one; 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(difluoromethyl)pyrimidin-4(3H)-one; 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-cyclopropylpyrimidin-4(3H)-one; 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one; 1-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrazin-2(1H)-one; 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-methylpyrimidin-4(3H)-one; 2-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-2,7-naphthyridin-1(2H)-one; 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one; 5-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-1-cyclopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(1-methylcyclopropyl)pyrimidin-4(3H)-one; 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6,7-difluoroquinazolin-4(3H)-one; 1-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(difluoromethyl)pyridin-2(1H)-one; 1-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-methylpyridin-2(1H)-one; 6-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one; 4-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)morpholin-3-one; 7-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-7,8-dihydroimidazo[1,2-a]pyrazin-6(5H)-one; 1-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(trifluoromethyl)pyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-4-hydroxy-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-4-(ethylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-4-(dimethylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 1-((1-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 3-((10-amino-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 1-(((R)-7-((2S,4R)-4-((1,1-dioxidothietan-3-yl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 1-(((R)-7-((2S,4S)-4-((1,1-dioxidothietan-3-yl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-4-hydroxy-4-methyl-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 4-(2-methoxyphenyl)-1-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(o-tolyl)pyridin-2(1H)-one; 4-(2-fluorophenyl)-1-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one; 3-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-10-fluoro-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 1-(((S)-10-methoxy-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)pyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(o-tolyl)pyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl)pyridin-2(1H)-one; 3-(((R)-7-((2S,4R)-4-(ethylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(3-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 1-(((R)-7-((2S,4R)-2-(3-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-4-amino-2-(3-fluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 3-(((R)-7-((2S,4R)-4-amino-2-(3-fluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 1-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-chloropyridin-2(1H)-one; 1-(((R)-7-((2R,4R)-4-amino-2-ethylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 1-(((R)-1-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-3,3-dimethylpiperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one; 3-(((R)-7-((2S,4S)-4-amino-2-phenylpyrrolidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-((2,2-difluoroethyl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 1-(((R)-3,3-dimethyl-1-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one; 1-(((S)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-10-methoxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 3-((1-((2S,4R)-2-(3-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-((1-((2S,4R)-4-(ethylamino)-2-phenylpiperidine-1-carbonyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4(3H)-one; Methyl (2S,4R)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)-2-phenylpiperidine-4-carboxylate; 3-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-(cyclopropylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-amino-2-(2,4-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-amino-2-(3-fluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one; 4-chloro-1-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one; 3-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one; 1-(((R)-7-((2S,4S,5R)-4-amino-5-fluoro-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 1-(((R)-7-((2S,4S,5S)-4-amino-5-fluoro-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 3-(((R)-7-((2S,4R)-4-amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 1-(((R)-7-((2S,4R)-4-amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-4-amino-2-(3-fluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)pyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-4-amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)pyridin-2(1H)-one; 3-(((R)-7-((2S,4S)-4-(methylamino)-2-phenylpyrrolidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 1-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 3-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one; N-((2S,4R)-1-((R)-10-((2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)-2-phenylpiperidin-4-yl)acetamide; 3-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 1-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; N-((2S,4R)-1-((R)-10-((2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)-2-phenylpiperidin-4-yl)cyclopropanecarboxamide; 6-(2-methoxyphenyl)-3-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one; 1-((1-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one; 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one; 6-fluoro-3-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)quinazolin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(3-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(2-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(4-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one; Methyl ((2S,4R)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)-2-phenylpiperidin-4-yl)glycinate; Sodium ((2S,4R)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)-2-phenylpiperidin-4-yl)glycinate; 3-(((R)-7-((2S,4R)-4-amino-2-(3,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 1-(((R)-7-((2S,4R)-4-amino-2-(3,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 6-(2-fluorophenyl)-3-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one; 6-(2-Methoxyphenyl)-3-(((R)-7-((2S,4R)-4-morpholino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one; 1-(((R)-7-((2S,4R)-4-((3-methyloxetan-3-yl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-4-((3-(fluoromethyl)oxetan-3-yl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)pyridin-2(1H)-one; 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one; 3-(((R)-7-((R)-2-(3-fluorophenyl)piperazine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one; 3-(((R)-7-((R)-2-(2,5-difluorophenyl)piperazine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one; 1-(((R)-7-((2S,4R)-2-(2-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)pyridin-2(1H)-one; 3-(((R)-7-((2S,4R)-2-(3-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one; 1-(((R)-7-((2S,4R)-2-(4-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)pyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 3-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 4-chloro-1-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one; 3-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one; 1-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)pyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)-5,6-dihydropyridin-2(1H)-one; 1-(((S)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)-5,6-dihydropyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-2(1H)-one; 2-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridazin-3(2H)-one; 6-(difluoromethyl)-3-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one; 1-(((R)-7-((2S,4R)-2-(2,3-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)pyridin-2(1H)-one; 3-(((R)-7-((2S,4R)-2-(2,3-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(3,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-((3,3-difluorocyclobutyl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(2,3-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(3,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(3,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(2,3-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(3,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one; 6-phenyl-3-(((R)-7-((2S,4R)-2-phenyl-4-((pyridin-2-ylmethyl)amino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-((1-methyl-1H-pyrazol-3-yl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-(((5-fluoropyridin-2-yl)methyl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(2,3-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one; 6-phenyl-3-(((R)-7-((2S,4R)-2-phenyl-4-(phenylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-((1-methylcyclopropyl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(difluoromethyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one; tert-butyl ((2S,4R)-2-(2,5-difluorophenyl)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)piperidin-4-yl)glycinate; N-((2S,4R)-2-(2,5-difluorophenyl)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)piperidin-4-yl)acetamide; 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one; ((2S,4R)-2-(2,5-difluorophenyl)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)piperidin-4-yl)glycine; 4-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)morpholin-3-one; 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-((2-hydroxyethyl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one; 6-cyclopropyl-3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one; N-((2S,4R)-2-(2,5-difluorophenyl)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)piperidin-4-yl)cyclopropanecarboxamide; N-((2S,4R)-2-(2,5-difluorophenyl)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)piperidin-4-yl)picolinamide; 3-(((R)-7-((2S,4R)-2-(2,3-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one; 6-fluoro-3-(((R)-7-((2S,4R)-2-(3-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)quinazolin-4(3H)-one; 1-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl-5,6-dihydropyridin-2(1H)-one; 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-((pyrimidin-2-ylmethyl)amino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-((pyrimidin-4-ylmethyl)amino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 6-fluoro-3-(((R)-7-((2S,4R)-4-morpholino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)quinazolin-4(3H)-one hydrochloride; N-((2S,4R)-2-(2,5-difluorophenyl)-1-((R)-10-((6-fluoro-4-oxoquinazolin-3(4H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)piperidin-4-yl)acetamide; N-((2S,4R)-2-(2,5-difluorophenyl)-1-((R)-10-((6-fluoro-4-oxoquinazolin-3(4H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)piperidin-4-yl)cyclopropanecarboxamide; 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one; (2S,4R)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)-2-phenylpiperidine-4-carboxylic acid; (2S,4R)-N-methyl-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)-2-phenylpiperidine-4-carboxamide; (2S,4R)-N,N-dimethyl-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)-2-phenylpiperidine-4-carboxamide; 1-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl-1,5-dihydro-2H-pyrrol-2-one; 4-chloro-1-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one; 1-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one; 3-(((R)-7-((2S,4R)-4-amino-2-(3,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one hydrochloride; 6-cyclopropyl-3-(((R)-7-((2S,4R)-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-((3,3-difluorocyclobutyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(difluoromethyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one hydrochloride; 4-chloro-1-(((R)-7-((2S,4R)-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one; 4-chloro-1-(((R)-7-((2S,4R)-4-((3,3-difluorocyclobutyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one; 3-(((S)-7-((R)-2-(2,5-difluorophenyl)piperazine-1-carbonyl)-10-methoxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,5R)-5-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2R,5S)-5-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one; 3-(((S)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-10-methoxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-(((3-methylpyridin-2-yl)methyl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-(((4,6-dimethylpyrimidin-2-yl)methyl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(3-fluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-(((R)-7-((2S,4R)-4-((2-fluoroethyl)amino)-2-(3-fluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one; 3-((2S,4R)-2-(3-fluorophenyl)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)piperidin-4-yl)oxazolidin-2-one; 6-chloro-3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)quinazolin-4(3H)-one; 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)quinazolin-4(3H)-one; 3-(((R)-7-((2S,5R)-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one; 3-(((R)-7-((2S,5R)-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one or a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof.

[0211] In certain embodiments, there is provided the above compounds, stereoisomers, tautomers, hydrates, N-oxide derivatives or pharmaceutically acceptable salts thereof, which are inhibitors of USP19, preferably human USP19.

[0212] USP19 inhibitor compounds are also described in WO2018 / 020242, WO2020 / 115500, WO2019 / 150119, and WO2020 / 115501, each of which is expressly incorporated herein by reference. Analogs of the compounds disclosed in WO2018 / 020242, WO2020 / 115500, WO2019 / 150119, and WO2020 / 115501 according to formula (I) - i.e., R 0 is H, F, NH or OCH - are expressly included herein and can be obtained by one skilled in the art by following the synthesis protocols provided herein and in WO2018 / 020242, WO2020 / 115500, WO2019 / 150119 and WO2020 / 115501.

[0213] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of any embodiment of the first aspect, or a stereoisomer, tautomer, hydrate, N-oxide derivative, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0214] Pharmaceutical compositions may be formulated depending on the particular use and purpose, for example, by mixing additives, binders, lubricants, disintegrating agents, coating materials, emulsifiers, suspending agents, solvents, stabilizers, absorption enhancers, and / or ointment bases. The compositions may be suitable for oral, injectable, rectal, or topical administration.

[0215] Suitable pharmaceutically acceptable additives are known to those skilled in the art and include, for example, fats, water, saline, alcohols (e.g., ethanol), glycerol, polyols, aqueous glucose solutions, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavors or fragrances, thickeners, diluents, buffer substances, solvents or solubilizers, chemicals for achieving a preservative effect, salts for modifying osmotic pressure, coating agents or antioxidants, sugars such as lactose or glucose; corn, wheat or rice starch; fatty acids such as stearic acid; inorganic salts such as magnesium aluminometasilicate or anhydrous calcium phosphate; synthetic polymers such as polyvinylpyrrolidone or polyalkylene glycols; alcohols such as stearyl alcohol or benzyl alcohol; synthetic cellulose derivatives such as methylcellulose, carboxymethylcellulose, ethylcellulose or hydroxypropylmethylcellulose; and other commonly used additives such as gelatin, talc, vegetable oils and gum arabic.

[0216] For example, the pharmaceutical compositions may be administered orally in the form of tablets, coated tablets, hard or soft gelatin capsules, solutions, emulsions or suspensions, etc. Administration can also be carried out rectally, e.g., using suppositories, topically or transdermally, e.g., using ointments, creams, gels or solutions, or parenterally, e.g., using injectable solutions.

[0217] For the preparation of tablets, coated tablets or hard gelatin capsules, the compounds of the present invention can be mixed with pharmaceutically inert, inorganic or organic additives.Suitable additives include lactose, maize starch or its derivatives, talc or stearic acid or its salts.Suitable additives for use in soft gelatin capsules include, for example, vegetable oils, waxes, fats and semi-solid or liquid polyols.

[0218] For the preparation of solutions and syrups, additives include, for example, water, polyols, sucrose, invert sugar and glucose.

[0219] For injectable solutions, additives include, for example, water, alcohols, polyols, glycerin and vegetable oils.

[0220] For suppositories and topical and transdermal applications, excipients include, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols.

[0221] The pharmaceutical compositions may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, odorants, buffers, coating agents, and / or antioxidants.

[0222] For combination therapy, the second drug may be provided in a pharmaceutical composition with the present invention or may be provided separately.

[0223] Thus, pharmaceutical preparations for oral administration may be, for example, granules, tablets, sugar-coated tablets, capsules, pills, suspensions, or emulsions.For parenteral injection, for example, for intravenous, intramuscular, or subcutaneous use, a sterile aqueous solution may be provided, which may contain other substances, for example, salts and / or glucose to make the solution isotonic.Anticancer agents may also be administered in the form of suppositories or pessaries, or may be applied topically in the form of lotions, solutions, creams, ointments, or dusting powders.

[0224] In a further aspect, the present invention provides a compound according to the first aspect, including a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof, for use in therapy.

[0225] In a further aspect, the present invention provides a pharmaceutical composition according to the second aspect for use in therapy.

[0226] In a further aspect, the present invention provides a compound of any embodiment of the first aspect or a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof for use in the treatment and / or prophylaxis of cancer.

[0227] In a further aspect, the present invention provides a pharmaceutical composition according to the second aspect for use in the treatment and / or prevention of cancer.

[0228] In a further aspect, the present invention provides a method of treating and / or preventing cancer comprising administering to a subject a compound according to any embodiment of the first aspect of the invention, including a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any embodiment of the second aspect of the invention.

[0229] In a further aspect, the present invention provides the use of a compound, including a stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt thereof, according to any embodiment of the first aspect in the manufacture of a medicament for the treatment or prevention of cancer.

[0230] Cancer or neoplastic conditions suitable for treatment with the compound or composition of the present invention include, for example, prostate cancer, colon cancer, breast cancer, lung cancer, kidney cancer, CNS cancer (e.g., neuroblastoma, glioblastoma), osteosarcoma, hematological malignancies (e.g., leukemia, multiple myeloma and mantle cell lymphoma).In some preferred embodiments, cancer is associated with p53 dysregulation.In some preferred embodiments, cancer is selected from hematological malignancies (e.g., mantle cell lymphoma, multiple myeloma), prostate cancer, neuroblastoma or glioblastoma.In some preferred embodiments, cancer is neuroblastoma or breast cancer.

[0231] We have now demonstrated that potent USP19 inhibitory compounds effectively reduce adiposity in vivo. Gene knockout studies have documented a possible link between USP19 and adiposity (Coyne et al., Diabetologia, 2019, 62, 136-146, incorporated herein by reference). However, the effects seen in these studies must be considered alongside potential confounding factors inherent in knockout studies, such as alterations in developmental or underlying physiological processes. For these reasons, acute or chronic pharmacological inhibition of the enzyme does not always result in physiological outcomes similar to those of gene ablation.

[0232] The data provided herein demonstrate that pharmacological inhibition of USP19 can reduce adiposity in a wild-type background. Collectively, the in vitro and in vivo data demonstrate that compounds that potently inhibit USP19 activity can effectively treat obesity.

[0233] In a further aspect, there is provided a compound according to the first aspect, or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof, for use in a method of treating obesity.

[0234] In a further aspect, there is provided a pharmaceutical composition according to the second aspect for use in a method for treating obesity.

[0235] Also provided herein 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 of the first aspect, or an effective amount of a pharmaceutical composition according to the second aspect.

[0236] Furthermore, it has been shown herein that the potent USP19 inhibitory compounds provided herein can effectively treat insulin resistance. Gene knockout studies have documented an association between USP19 and insulin sensitivity (Coyne et al., supra). Coyne et al. described improved insulin sensitivity in USP19 knockout mice, but as noted above, it cannot be inferred that this effect translates to pharmacological inhibition of USP19 in wild-type subjects.

[0237] The data provided herein demonstrate that pharmacological inhibition of USP19 can effectively treat insulin resistance (eg, type II diabetes).

[0238] In a further aspect, there 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 insulin resistance.

[0239] In a further aspect of the invention, there 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.

[0240] In a further aspect of the invention there is provided a pharmaceutical composition according to the second aspect for use in a method of treating insulin resistance.

[0241] In a further aspect of the invention there is provided a pharmaceutical composition according to the second aspect for use in a method of treating type II diabetes.

[0242] Also provided by the present invention is a method of treating insulin resistance, comprising administering to a subject in need thereof an effective amount of a compound as defined in connection with the first aspect of the invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof, or a pharmaceutical composition comprising an effective amount of a compound as defined in connection with the first aspect of the invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof.

[0243] Also provided by the present invention is a method of treating type II diabetes, comprising administering to a subject in need thereof an effective amount of a compound as defined in connection with the first aspect of the invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative, or a pharmaceutical composition comprising an effective amount of a compound as defined in connection with the first aspect of the invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative.

[0244] In the accompanying examples, it is shown that the compounds provided herein are potent USP19 inhibitors, and furthermore, potent USP19 inhibitory compounds can effectively treat muscle weakness in in vivo disease models. Collectively, the in vitro and in vivo data demonstrate that compounds that potently inhibit USP19 activity can effectively treat muscle atrophy.

[0245] In a further aspect, there 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 muscle atrophy.

[0246] In a further aspect, the present invention provides a compound as defined in relation to the first aspect, or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof, for use in a method of treating cachexia or sarcopenia.

[0247] In a further aspect of the invention there is provided a pharmaceutical composition according to the second aspect for use in a method of treating muscle wasting.

[0248] In a further aspect of the invention there is provided a pharmaceutical composition according to the second aspect for use in a method of treating cachexia or sarcopenia.

[0249] Also provided herein is a method of treating muscle atrophy, comprising administering to a subject in need thereof an effective amount of a compound as defined in connection with the first aspect of the invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof, or a pharmaceutical composition comprising an effective amount of a compound as defined in connection with the first aspect of the invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof.

[0250] Also provided herein is a method of treating cachexia or sarcopenia, comprising administering to a subject in need thereof an effective amount of a compound as defined in connection with the first aspect of the invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof, or a pharmaceutical composition comprising an effective amount of a compound as defined in connection with the first aspect of the invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof.

[0251] Muscle atrophy, cachexia or sarcopenia may be associated with or caused 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.

[0252] In a further aspect, the present invention provides a compound or composition of any of the embodiments of the first or second aspect for use in the treatment and / or prevention of Parkinson's disease. In a further aspect, the present invention provides a method of treating or preventing Parkinson's disease, comprising administering to a subject an effective amount of a compound of the present invention, a pharmaceutically acceptable salt, tautomer, stereoisomer, or N-oxide derivative thereof, or a pharmaceutical composition thereof. In a further aspect, the present invention provides the use of a compound of the present 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.

[0253] The compounds or compositions of the present invention may be used in monotherapy and / or combination modalities. Suitable agents for use in such combination modalities with the compounds or compositions of the present invention include one or more of anti-cancer agents, anti-inflammatory agents, immunomodulatory agents, such as immunosuppressants, neurological agents, antidiabetic agents, antiviral agents, antibacterial agents, and / or radiation therapy.

[0254] Agents used in combination with the compounds of the present invention may target the same or similar biological pathways targeted by the compounds of the present invention or may act on different or unrelated pathways.

[0255] Depending on the disease being treated, various combination partners may be co-administered with the compounds of the present invention. The second active ingredient may be an alkylating agent, including cyclophosphamide, ifosfamide, thiotepa, melphalan, chloroethylnitrosourea, and bendamustine; a platinum derivative, including cisplatin, oxaliplatin, carboplatin, and satraplatin; a mitotic inhibitor, including vinca alkaloids (vincristine, vinorelbine, and vinblastine), taxanes (paclitaxel, docetaxel), epothilones, and inhibitors of mitotic kinases, including aurora and polo kinases; a topoisomerase inhibitor, including anthracyclines, epipodophyllotoxins, camptothecin, and camptothecin analogs; -Antimetabolites including fluorouracil, capecitabine, cytarabine, gemcitabine, 6-mercaptopurine, 6-thioguanine, fludarabine, methotrexate, and pemetrexed; 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, and panitumumab; and gemtuzumab Hormone therapies including, but not limited to, ozogamicin, monoclonal antibody conjugates including ibritumomab tiuxetan; antiestrogens (tamoxifen, raloxifene, anastrozole, letrozole, exemestane), antiandrogens (flutamide, bicalutamide) and luteinizing hormone analogs or antagonists.

[0256] With respect to aspects of the present invention relating to the therapeutic use of the compounds of the present invention, the compounds may be administered to a subject in need of treatment in an "effective amount." The term "effective amount" refers to an amount or dose of a compound that, upon single or multiple administration to a subject, provides therapeutic efficacy in treating a disease. A therapeutically effective amount of a compound of the present invention may include an amount ranging from about 0.1 mg / kg to about 20 mg / kg per administration. The therapeutically effective amount for any individual patient can be determined by a medical professional by methods understood by those skilled in the art. The amount of compound administered at any given time may vary, whether used alone or in combination with any other therapeutic agent, such that an optimal amount of compound is administered over the course of treatment. The compounds of the present invention or pharmaceutical compositions containing such compounds are also contemplated for administration in combination with any other cancer treatment as a combination therapy.

[0257] For combination therapy, the second drug may be provided in a pharmaceutical composition with the present invention or may be provided separately.

[0258] Administration route In certain preferred embodiments, the treatment of the present invention comprises parenterally administering a therapeutic agent (i.e., a compound, pharmaceutically acceptable salt, tautomer, stereoisomer, or N-oxide derivative, or pharmaceutical composition for use in accordance with the present invention).

[0259] In certain preferred embodiments, the therapeutic agent is administered orally.

[0260] In some preferred embodiments, the therapeutic agent is administered intravenously. In some preferred embodiments, the therapeutic agent is administered intraperitoneally. In some preferred embodiments, the therapeutic agent is administered subcutaneously.

[0261] Dosing regimen In certain preferred embodiments of the invention, treatment comprises administering a therapeutic agent (i.e., a compound, pharmaceutically acceptable salt, tautomer, stereoisomer, or N-oxide derivative, or pharmaceutical composition for use in accordance with the invention) at a dose ranging from 10 to 150 mg / kg. In such embodiments, dose refers to the amount of active ingredient administered to a subject per administration.

[0262] In one preferred embodiment, treatment involves administration of a therapeutic agent at a dose ranging from 25 to 125 mg / kg, hi one preferred embodiment, treatment involves administration of a therapeutic agent at a dose ranging from 50 to 100 mg / kg.

[0263] In one preferred embodiment, the method comprises administering the therapeutic agent at a dose of 75 mg / kg.

[0264] In certain preferred embodiments, treatment involves administration of a therapeutic agent (i.e., a compound, pharmaceutically acceptable salt, tautomer, stereoisomer, or N-oxide derivative, or pharmaceutical composition for use according to the invention) once, twice, three times, or four times daily. In certain preferred embodiments, the therapeutic agent is administered once or twice daily, most preferably twice daily.

[0265] In certain preferred embodiments, the Therapeutic Agent is administered at a daily dosage in the range of 10-300 mg / kg. That is, the total amount of active agent administered to a subject per day is in the range of 10-300 mg / kg. In such embodiments, the Therapeutic Agent may be administered one or more times daily, as described above, so long as the total daily dosage falls within the indicated range.

[0266] In a preferred embodiment, the therapeutic agent is administered at a daily dose ranging from 50 to 250 mg / kg. In a preferred embodiment, the therapeutic agent is administered at a daily dose ranging from 75 to 250 mg / kg. In a preferred embodiment, the therapeutic agent is administered at a daily dose ranging from 100 to 200 mg / kg. In a preferred embodiment, the therapeutic agent is administered at a daily dose of 150 mg / kg.

[0267] In certain preferred embodiments, a therapeutic agent (eg, a compound provided herein) is administered at a dose of 75 mg / kg, twice daily.

[0268] With respect to aspects of the invention relating to therapeutic uses of the compounds of the invention, in preferred embodiments the subject treated is a human being.

[0269] When introducing elements of the invention or preferred embodiments thereof, the words "a," "the," and "the" are intended to mean that there are one or more elements. The terms "comprise," "include," and "have" are intended to be inclusive, meaning that there may be additional elements other than the listed elements.

[0270] The above detailed description has been provided for purposes of illustration and description and is not intended to limit the scope of the appended claims. Many variations of the presently preferred embodiments described herein will be apparent to those of ordinary skill in the art and remain within the scope of the appended claims and their equivalents. [Example]

[0271] The invention will now be described in connection with several examples.

[0272] The following example compounds were synthesized by the methods described below. 50 The values ​​were determined as follows and are shown in the following table: [Table 4] [Table 5]

[0273] Table 3. USP19 inhibition by exemplary compounds. USP19 inhibitory activity is classified as follows: [Table 6]

[0274] USP19 activity was determined by a fluorescence polarization (FP) homogeneous assay using the isopeptide ubiquitin-Lys-TAMRA substrate (either AUB-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). All other reagents were purchased from Sigma unless otherwise noted. Enzyme reactions were performed in black flat-bottom polystyrene 384-well plates (Nunc) in a total volume of 30 μL. USP19 (2.5 nM, 10 μL) was incubated in assay buffer (50 mM HEPES (pH 7.4), 150 mM NaCl, 5 mM DTT, 0.05% BSA (w / v), 0.05% CHAPS) with or without inhibitor (10 μL). Inhibitors were added to the StoragePod (登録商標) Ub was stored as a 10 mM DMSO stock solution in an inert environment (low humidity, dark, hypoxic, rt) using a system (Roylan Developments), and serial dilutions were prepared in buffer immediately prior to the assay (200 μM to 2 pM, 8 to 18 data point curves). After a 30-minute incubation at RT, the enzymatic reaction was initiated by the dispensing of Ub substrate (500 nM, 10 μL). FP was measured every 15 minutes over a 90-minute period (within the linear range of the assay) using a Synergy 4 plate reader (BioTek) with excitation at 530 nm and the amount of parallel and perpendicular light at 575 nm measured. FP signal was then normalized to a compound-free control. Data were plotted and fitted to determine the concentration resulting in 50% inhibition (IC). 50 ) was calculated using a nonlinear regression curve fitting model using GraphPad (Prism). 50 The values ​​are compiled in Tables 1 and 3 and represent the average of at least two duplicate experiments.

[0275] Cellular target binding using Western blotting Cells from breast cancer, neuroblastoma, and mouse skeletal muscle cell lines were treated with the USP19 inhibitor compound (ADC-141) for 2 hours, lysed (lysis buffer: 50 mM Tris pH 7.4; 150 mM NaCl; 5 mM MgCl; 0.5 mM EDTA; 0.5% NP40; 10% glycerol; 2 mM DTT), and ubiquitin-propargylamine (Ub-PA; UbiQ) or ubiquitin-vinylmethyl ester (Ub-VME; Almac Sciences Scotland Limited) were then added. Samples were analyzed by Western blotting probing for USP19 (EC determined by densitometry). 50 ). In each cell line, the USP19 inhibitor compounds exhibited good cell permeability and low nanomolar EC 50 The results for each cell line are shown in Figure 4.

[0276] Cellular target binding using HTRF assay USP19 cellular target binding was determined in a homogeneous time-resolved fluorescence (HTRF) assay using an HA-tagged ubiquitin vinylpentynyl sulfone (VPS) probe (UbiQ-193, UbiQ Bio) and a USP19-Flag overexpression construct. (登録商標)Compounds were stored as 10 mM DMSO stock solutions in an inert environment (low humidity, dark, hypoxic, rt) using a system (Roylan Developments). USP19-Flag transfected cells were incubated with serially diluted compounds for 2 hours using an 11-point dose-response curve (50 μM to 0.01 nM), then washed with PBS and lysed. Unless otherwise noted, all HTRF reagents were purchased from CisBio. HTRF assays using cell lysates were completed in a 384-well plate (Greiner) in a total volume of 20 μL. Cell lysates were incubated with an HA-tagged ubiquitin VPS probe for 40 minutes in PPI detection buffer, followed by the addition of anti-HA and anti-FLAG HTRF detection reagents. HTRF was measured every hour for 18 hours using a Pherastar FSX plate reader (excitation 337 nm, emission 620 / 665 nm). Data were normalized to DMSO (no compound control) and nonlinear regression curve fitting was used to derive IC using Prism (GraphPad). 50 The values ​​were used for fitting.

[0277] Caco-2 permeability assay Caco-2 cells are commonly used as an in vitro model for predicting human intestinal absorption of test compounds. When cultured, Caco-2 cells (derived from a human colorectal carcinoma) spontaneously differentiate into a monolayer of polarized enterocytes. Cells are seeded into multi-well insert plates and allowed to form a confluent monolayer for 20 days prior to assay. On day 20, compounds were added to the apical side of the membrane, and the flux of compound across the monolayer was monitored for 2 hours. Absorption of test compounds in the apical-to-basal direction (P app Only the permeability coefficient data for A:B) are shown in Table 1. All data were generated using Cyptotex.

[0278] Thermodynamic solubility assay Test compounds (approximately 0.5 mg, accurately weighed) were suspended in duplicate in high-recovery glass vials in PBS buffer pH 7.4 (Dulbecco A) to a concentration of 1 mg / mL. The suspension was shaken at 300 rpm at room temperature for 64 hours. Approximately 250 μL of the suspension was then transferred to a MultiScreen (登録商標) The filtrates were transferred in duplicate to Solubility filter plates (Millipore). The concentrations of the filtrates were then quantified against a five-point calibration curve of acetonitrile / PBS buffer mixtures (maximum concentration 500 μM). After filtration and matrix matching, the calibration and assay plates were analyzed on a Bioteck Synergy 4 plate reader (240-400 nm). The final concentration of test compound in the filtrate was calculated using the slope of the calibration curve.

[0279] In vivo activity The following data from in vivo models demonstrate for the first time that USP19 inhibitors can be used to treat muscle wasting, reduce fat deposition, and improve insulin sensitivity. These data indicate that compounds that potently inhibit USP19 activity can effectively treat muscle wasting, obesity, and / or insulin resistance.

[0280] method: To induce muscle wasting, a 1 cm segment of the femoral sciatic nerve was removed from mice (male C57bl / 6 mice, 8–10 weeks old; n = 10 per group) under isoflurane anesthesia and carprofen analgesia. A sham operation was performed on the opposite leg as a control. Mice were randomized into vehicle or test groups, and all animals were weighed to ensure similar mean body weights in each group. ADC-141, a USP19 inhibitory compound, 75 mg / kg, or vehicle was administered IP twice daily, starting the evening after surgery. Mice were sacrificed 14 days later. Fat pads, livers, gastrocnemius muscles, and tibialis anterior muscles were collected. Tissue masses were measured in both groups. To assess obesity and insulin resistance, a diet-induced obese mouse model was used. Diet-induced obese (DIO) mice are a well-characterized model of obesity that exhibits increased adiposity, insulin resistance, and glucose intolerance. Male C57BL6 / J mice were continuously fed a high-fat diet (D12451, 45% kcal as fat; Research Diets, New Jersey, USA) and filtered tap water ad libitum throughout the study. From day 0, mice received vehicle ip BID, a USP19 inhibitor (ADC-141) ip BID at 5 mg / kg or 25 mg / kg, or the positive control liraglutide 0.1 mg / kg sc BID. Body weight was measured daily. On day 13, body composition was measured by DEXA. On day 15, fasting glucose and insulin levels were measured before and during an oral glucose tolerance test (OGTT) to assess improvement in glucose control. The OGTT was performed after an overnight fast. Therefore, on day 14, food (but not water) was removed starting at approximately 16:45, immediately after PM dosing. The OGTT was performed the following morning (after approximately 16 hours of fasting). Mice were administered vehicle or test compound 30 minutes prior to the scheduled administration of a glucose load (2.0 g / kg po) (starting at 08:45). Blood samples were taken immediately before dosing (B1), immediately before glucose administration (B2), and 15, 30, 60, and 120 minutes after glucose administration. 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(1H)-one, which corresponds to exemplary compound 212 provided in WO2018 / 020242. Both ADC-141 and the compounds provided herein have been shown to have USP19 inhibitory activity using the above-described fluorescence polarization assay. Accordingly, the USP19 inhibitor compounds provided herein are expected to exhibit levels of potency similar to those described below for ADC-141.

[0281] result: muscle atrophy As shown in Figure 1, mice receiving the USP19 inhibitor experienced significantly less muscle mass loss in the tibialis anterior muscle compared to mice receiving vehicle alone. Avoidance of muscle atrophy was evident in terms of both percentage mass (Figure 1B) and absolute muscle mass (Figure 1C). Muscle wasting was also reduced in gastrocnemius muscle (Figure 2), although the trend did not reach significance. Similarly, mice receiving the USP19 inhibitor showed less muscle wasting, both in terms of percentage mass (Figure 2B) and absolute muscle mass (Figure 2C). These data indicate that pharmacological inhibition of USP19 in vivo can reduce muscle atrophy. The data suggest that pharmacological inhibition of USP19 is particularly effective in reducing muscle wasting as a result of inactivity, immobility, or other disuse. Based on the results provided herein, pharmacological USP19 inhibition is also expected to be effective in treating muscle atrophy as a result of cachexia or sarcopenia.

[0282] obesity Figure 3A shows the epididymal fat pad mass in mice after 2 weeks of receiving the USP19 inhibitor or vehicle alone. As shown in Figure 3, mice receiving the USP19 inhibitor had significantly smaller fat pads compared to vehicle-treated mice. Figure 3B shows increased liver mass in mice treated with USP19 inhibitors, likely a result of drug accumulation in the liver. Figure 3C shows that mice receiving the USP19 inhibitor gained less overall weight when fed a high-fat diet. Figures 3D and 3E show that this is due to a reduction in fat mass, while lean body mass is preserved. DIO mice treated with USP19 inhibitors also show a decrease in cumulative food intake compared to vehicle control mice. The data shown in Figure 3 demonstrate for the first time that pharmacological inhibition of USP19 can reduce fat accumulation in a wild-type background. Gene knockout studies have documented a possible link between USP19 and fat accumulation (Coyne et al., Diabetologia. 2018 Nov 1. doi: 10.1007 / s00125-018-4754-4., incorporated herein by reference). However, acute or chronic pharmacological inhibition of the enzyme does not always result in physiological outcomes similar to those of gene ablation. The in vivo pharmacological inhibition data provided herein demonstrate that compounds that potently inhibit USP19 activity can effectively treat obesity.

[0283] Insulin resistance Figure 5 shows the results of an oral glucose tolerance test (OGTT) in diet-induced obese mice. Untreated mice exhibit symptoms of insulin resistance characterized by elevated plasma glucose and plasma insulin levels. Mice treated with USP19 inhibitors show a dose-dependent improvement in OGTT response characterized by decreased plasma glucose and decreased plasma insulin. The data shown in Figure 5 demonstrate for the first time that pharmacological inhibition of USP19 can reduce insulin resistance in a wild-type background. Gene knockout studies have documented an association between USP19 and insulin sensitivity (Coyne et al., supra). Although Coyne et al. described improved insulin sensitivity in USP19 knockout mice, as noted above, it cannot be inferred that this effect translates to pharmacological inhibition of USP19 in wild-type subjects. The data provided here demonstrate for the first time that pharmacological inhibition of USP19 can effectively treat insulin resistance. The data presented herein demonstrate for the first time the therapeutic efficacy of pharmacological inhibition of USP19. Thus, USP19 inhibitor compounds provided herein can effectively treat muscle wasting, obesity, and / or insulin resistance.

[0284] Experimental Section Abbreviations and Acronyms AcOH: acetic acid; aq: aqueous; atm: atmosphere; dba: dibenzylideneacetone; Bn: benzyl; Boc: tert-butyloxycarbonyl; br: broad; CAN: ceric ammonium nitrate; Cbz: carboxybenzyl; CDI: carbonyldiimidazole; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM: dichloromethane; d: doublet (spectral); de: diastereomeric excess; DIPEA: diisopropylethylamine; DMA: N,N-dimethylacetamide; DMAP: 4-dimethylaminopyridinone Lysine; DME: dimethoxyethane; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; dppf: 1,1'-bis(diphenylphosphino)ferrocene; Eaton's reagent: phosphorus pentoxide, 7.7 wt% in methanesulfonic acid; EDC: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; ee: enantiomeric excess; equiv.: equivalent; EtOAc: ethyl acetate; EtOH: ethanol; Ex.: example; PE: petroleum ether 40 / 60; ESI: electrospray ionization; h: hour; GCMS: Gas chromatography mass spectrometry; HATU: N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; hept: sevent peak (spectrum); HPLC: high-performance liquid chromatography; IPA: 2-propanol; LC: liquid chromatography; LCMS: liquid chromatography mass spectrometry; LiHMDS: lithium bis(trimethylsilyl)amide; M: molar concentration; m / z: mass-to-charge ratio; mC PBA: 3-chloroperbenzoic acid; MeCN: acetonitrile; MeOH: methanol; min: minute; mmol: millimole; MS: mass spectrometry; MTBE: methyl tert-butyl ether; m: multiplet (spectrum); NaHMDS: sodium bis(trimethylsilyl)amide; NMP: N-methyl-2-pyrrolidone; NMR: nuclear magnetic resonance; p: quintet (spectrum); Ph: phenyl; PMB: p-methoxybenzyl; ppm: parts per million; q: quartet (spectrum); quint: quintet (spectrum); RBF: round-bottom flask; R T: retention time; rt: room temperature; s: singlet; SCX: strong cation exchange; SFC: supercritical fluid chromatography; SM: starting material; 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; Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0285] General experimental conditions Solvents and Reagents Common organic solvents used in the reactions (e.g., THF, DMF, DCM, and MeOH) were anhydrous and obtained from Sigma-Aldrich (登録商標) From Sure / Seal TM Bottles were purchased and handled appropriately under nitrogen. Water was deionized using an Elga PURELAB Option-Q. All other solvents used (i.e., workup steps and purification) were generally HPLC grade and were used as received from various commercial sources. Unless otherwise noted, all starting materials used were purchased from commercial sources and used as received.

[0286] Microwave synthesis Microwave experiments are performed using the Biotage Initiator TM The experiment was carried out using an Eight apparatus. The system has good reproducibility and controls the temperature range from 60 to 250 °C and pressures up to 20 bar.

[0287] Flash chromatography Purification of compounds by flash chromatography was carried out using a Biotage Isolera Four system. Unless otherwise noted, Biotage KP-Sil SNAP cartridge columns (10-340 g) or Grace GraceResolv cartridge columns (4-330 g) were used with the solvent system and appropriate solvent gradients indicated depending on compound polarity. For more polar and basic compounds, Biotage KP-NH SNAP cartridge columns (11 g) were used.

[0288] NMR spectroscopy 1 H NMR spectra were recorded at ambient temperature using a Bruker Avance (300 MHz), Bruker Avance III (400 MHz), or Bruker Ascend (500 MHz) spectrometer. All chemical shifts (δ) are expressed in ppm. The residual solvent signal was used as an internal standard, and characteristic solvent peaks were corrected against the reference data outlined in J. Org. Chem., 1997, 62, pp. 7512-7515; otherwise, the NMR solvent included tetramethylsilane, which was used as an internal standard.

[0289] Liquid Chromatography Mass Spectrometry (LCMS) Retention time (R T Liquid chromatography mass spectrometry (LCMS) experiments to determine ) and related mass ions were carried out using the following method: Method AThe system consisted of an Agilent Technologies 1290 Infinity LC system and an Agilent Technologies 6130 quadrupole mass spectrometer coupled to a UV diode array detector and autosampler. The spectrometer consisted of an electrospray ionization source operated in positive and negative ion mode. LCMS experiments were performed on each provided sample using the following conditions: LC column: Agilent Eclipse Plus C18 RRHD, 1.8 μm, 50 × 2.1 mm, maintained at 40 °C. Mobile phase: A) 0.1% (v / v) formic acid in water; B) 0.1% (v / v) formic acid in acetonitrile. [Table 7]

[0290] Method B The system consisted of an Agilent Technologies 1290 Infinity LC system and an Agilent Technologies 6140 single quadrupole mass spectrometer coupled to a UV diode array detector and autosampler. The spectrometer consisted of a multimode ionization source (electrospray and atmospheric pressure chemical ionization) operated in positive and negative ion modes. LCMS experiments were performed on each provided sample using the following conditions: LC column: Zorbax Eclipse Plus C18 RRHD, 1.8 μm, 50 × 2.1 mm, maintained at 40 °C. Mobile phase: A) 0.1% (v / v) formic acid in water; B) 0.1% (v / v) formic acid in acetonitrile. [Table 8]

[0291] Method CThe system consisted of a Shimadzu Prominence HPLC / Applied Biosystem LCMS / MS API 2000 instrument. Spectrometer ionization technique: ESI with the API source operating in positive ion mode. LCMS experiments were performed on each provided sample using the following conditions: LC column: XBridge C18, 5 μm, 4.6 × 50 mm, maintained at 25 °C. Mobile phase: A) 10 mM ammonium acetate (aqueous); B) acetonitrile. [Table 9]

[0292] Method D The system consisted of a Shimadzu Prominence HPLC / Applied Biosystem LCMS / MS API 2000 instrument. Spectrometer ionization technique: ESI with the API source operating in positive ion mode. LCMS experiments were performed on each provided sample using the following conditions: LC column: Zorbax Extend C18, 5 μm, 4.6 × 50 mm, maintained at 25 °C. Mobile phase: A) 10 mM ammonium acetate (aqueous); B) acetonitrile. [Table 10]

[0293] Method E The system consisted of a Waters ACQUITY UPLC / Waters ACQUITY SQD mass spectrometer instrument. Spectrometer ionization technique: ESI operated in positive ion mode. LCMS experiments were performed on each provided sample using the following conditions: LC column: YMC Triart C18, 3 μm, 2.1 × 33 mm, maintained at 50 °C. Mobile phase: A) 0.05% (v / v) formic acid in water; B) acetonitrile. [Table 11]

[0294] Method FThe system consisted of an Agilent Technologies 1100 Series LC / MSD system with a UV diode array detector and evaporative light scattering detector (DAD / ELSD) and an Agilent LC / MSD VL (G1956A) or SL (G1956B) mass spectrometer or an Agilent 1200 Series LC / MSD system with a DAD / ELSD and an Agilent LC / MSD SL (G6130A) or SL (G6140A) mass spectrometer. All LC / MS data were obtained using atmospheric pressure chemical ionization (ACI) with positive and negative ion mode switching in the m / z range of 80–1000. LC / MS experiments were performed on each provided sample using the following conditions: LC column: Zorbax SB-C18 RRHD, 1.8 μm, 4.6 × 15 mm. Mobile phase: A) 0.1% (v / v) formic acid in water; B) 0.1% (v / v) formic acid in acetonitrile. [Table 12]

[0295] Method G The system consisted of a Waters ACQUITY UPLC / Waters ACQUITY SQD mass spectrometer instrument. Spectrometer ionization technique: ESI operated in positive ion mode. LCMS experiments were performed on each provided sample using the following conditions: LC column: Luna Omega, 3 μm, 4.6 × 100 mm, maintained at 50 °C. Mobile phase: A) 0.05% (v / v) TFA in water; B) acetonitrile. [Table 13]

[0296] Method HThe system consisted of a Waters ACQUITY H Class UPLC / Waters ACQUITY SQD 2 mass spectrometer instrument. Spectrometer ionization technique: ESI operated in positive ion mode. LCMS experiments were performed on each provided sample using the following conditions: LC column: XBridge C18, 3.5 μm, 3 × 50 mm, maintained at 50 °C. Mobile phase: A) 5 mM ammonium acetate (aqueous); B) 9:1 5 mM ammonium acetate in acetonitrile / water. [Table 14]

[0297] Method I The system consisted of a Waters ACQUITY H Class UPLC / Waters ACQUITY SQD 2 mass spectrometer instrument. Spectrometer ionization technique: ESI operated in positive ion mode. LCMS experiments were performed on each provided sample using the following conditions: LC column: Waters Acquity UPLC BEH C8, 1.7 μm, 2.1 × 50 mm, maintained at 50 °C. Mobile phase: A) 0.05% (v / v) formic acid in water; B) 9:1 0.05% (v / v) formic acid in acetonitrile / water. [Table 15]

[0298] Method J The system consisted of a Waters ACQUITY H Class UPLC / Waters ACQUITY SQD 2 mass spectrometer instrument. Spectrometer ionization technique: ESI operated in positive ion mode. LCMS experiments were performed on each provided sample using the following conditions: LC column: Waters Acquity UPLC BEH C8, 1.7 μm, 2.1 × 30 mm, maintained at 50 °C. Mobile phase: A) 5 mM ammonium acetate (aqueous); B) 9:1 5 mM ammonium acetate in acetonitrile / water. [Table 16]

[0299] Method K The system consisted of a Waters ACQUITY H Class Plus UPLC / Waters ACQUITY QDa mass spectrometer with a UV detector and autosampler. Spectrometer ionization technique: ESI operated in positive ion mode and negative. LCMS experiments were performed on each provided sample using the following conditions: LC column: Agilent Extend-C18 RRHD, 1.8 μm, 2.1 × 50 mm, maintained at 40 °C. Mobile phase: A) 0.1% (v / v) formic acid in water; B) 0.1% (v / v) formic acid in acetonitrile. [Table 17]

[0300] Gas Chromatography Mass Spectrometry (GCMS) Method A The system consisted of an Agilent 7890B GC and an Agilent 5977B GC / MSD instrument. GCMS experiments were performed on each provided sample using the following conditions: GC column: HP-5ms (30 m x 0.25 mm, 0.25 μm). Carrier gas: Helium. Inlet temperature: 250°C. Split ratio: 20:1. Carrier gas flow: 1.0 mL / min. Ramping profile: oven temperature initially held at 60°C for 2 min, increased to 100°C over 2 min (20°C / min) and held for 2 min, then increased to 310°C over 5.25 min (40°C / min) and held for 4 min (total run time: 15.25 min).

[0301] Preparative high-performance liquid chromatography The system consisted of an Agilent Technologies 1200 preparative LC system and an Agilent Technologies 6120 single quadrupole mass spectrometer coupled to a multi-wavelength detector and autosampler. The mass spectrometer used a multimode ionization source (electrospray and atmospheric pressure chemical ionization) operated in positive and negative ion modes. Fraction collection was mass-triggered (multimode positive and negative ion). Purification experiments were performed under basic conditions, unless otherwise noted, with appropriate solvent gradients determined by retention times determined using LCMS methods. When basic conditions were unsuccessful, acidic conditions were used.

[0302] Basic conditions :LC column:Waters XBridge TM Prep C18 5μm OBD TM 30 x 100 mm column, rt. Mobile phase: A) 0.1% (v / v) ammonium hydroxide in water; B) 0.1% (v / v) ammonium hydroxide in 95:5 acetonitrile / water. Total run time is approximately 10 minutes and represents a general method. [Table 18]

[0303] Chiral separation of stereoisomers by supercritical fluid chromatography (SFC) Separation of stereoisomeric mixtures was carried out using the following general method: The stereoisomeric mixture was dissolved in methanol to 50 mg / mL and purified by SFC under the conditions described. The combined fractions of each stereoisomer were evaporated to near dryness using a rotary evaporator and transferred to a final vessel using DCM, which was stripped under a stream of compressed air at 40°C, and then stored in a vacuum oven at 40°C and 5 mbar for 16 hours.

[0304] Chiral separation of stereoisomers by HPLC Separation of the stereoisomeric mixture was carried out using the following general method: The stereoisomeric mixture was dissolved in methanol to 66 mg / mL and purified by HPLC under the conditions described. The combined fractions of each stereoisomer were evaporated to near dryness using a rotary evaporator and transferred to a final container using MeOH, which was stripped under a compressed air stream at 35°C, and then stored in a vacuum oven at 35°C and 5 mbar for 16 hours.

[0305] Chiral Purity Analysis After chiral separation of the stereoisomeric mixture, each stereoisomer was analyzed to determine chiral purity using the following analytical SFC or HPLC method under the conditions described. [Table 19]

[0306] [Table 20]

[0307] [Table 21]

[0308] [Table 22]

[0309] [Table 23]

[0310] nomenclature Unless otherwise stated, structure nomenclature was determined using the 'Convert Structure to Name' function in ChemDraw Professional 17.1 for Examples 1-58 and ChemDraw Professional 20.1 for Examples 59-201 (CambridgeSoft / PerkinElmer). 2 and R 3 But it's not H, it's R 0 is chiral, the active stereostructure can be determined by the following equation: 0 The bond is assigned to be on the "top" surface. 0 This has been shown to be the case when R =OH, and is inferred from previous observations using confirmatory X-ray crystallography data (WO2018020242). 0 In the following examples where R is chiral, 0 When =H, the active conformation at that stereocenter is assigned the (R)-configuration, and R 0 When =F, NH, or OMe, the active stereocenter was assigned the (S)-configuration. However, it should be noted that for all of these examples, the configuration at the tertiary alcohol position may not have been correctly assigned due to errors in the original X-ray crystallography data or in the strategy for inferring stereochemistry from other compounds. Therefore, it is possible that these compounds have the opposite configuration at this position. Both the (R)- and (S)-enantiomers are disclosed herein, with the most potent being preferred.

[0311] General method General Method 1: Boc Deprotection to the Free Base The Boc-protected amine (1 equiv.) was dissolved in DCM and TFA or 4M HCl in 1,4-dioxane was added. 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 compounds were eluted using a 4:1 mixture of DCM / 7M NH3 in MeOH. The ammonia fraction was concentrated under reduced pressure to give the desired product.

[0312] General Method 2: Urea Formation via a Carbamoyl Chloride Intermediate To a solution of triphosgene (0.3-0.6 equiv.) in MeCN was added pyridine or DIPEA (2-5 equiv.) at 0°C and the solution was stirred for 10 min. A solution of the appropriate primary amine (1 equiv.) in MeCN was added and the reaction was stirred for 1-24 h while warming to rt. The mixture was added to the appropriate secondary amine (1 equiv.), followed by DIPEA (2-5 equiv.) and stirred for an additional 1-24 h. Saturated NaHCO 3(水性) The resulting mixture was extracted with DCM (x3) using a phase separator, the combined organic phases were concentrated under reduced pressure and the residue was purified by flash chromatography to give the desired product.

[0313] General Method 3: HATU Coupling 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, after which saturated NaHCO 3(水性) The mixture was quenched by the addition of HCl. The resulting mixture was extracted with DCM (x3) 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 product.

[0314] General Method 4: Alkylation of Nucleophiles Using Alkyl Halides To a solution of the appropriate nucleophile (1 equivalent) in 1,4-dioxane was added the appropriate alkyl halide (1.1 equivalents) and cesium carbonate (2.0 equivalents). The reaction mixture was heated at 100°C for 40 hours. After cooling, the reaction mixture was filtered and evaporated to dryness. The remaining residue was purified by flash chromatography to give the desired product.

[0315] General Method 5: Suzuki Coupling A reaction vial was charged with a mixture of the appropriate halide (1 equiv.), organoboron reagent (1-3 equiv.), Pd catalyst (0.05-0.1 equiv.), and inorganic base (2-5 equiv.) in a mixture of water and 1,4-dioxane or toluene, as indicated. The mixture was degassed by evacuating and refilling with N2 three times or bubbling N2 for 5-15 min, then the reaction tube was sealed. The reaction was heated under the indicated conditions for the indicated time and cooled to rt. Water or saturated NH4Cl (水性) was added and the resulting mixture was extracted using DCM (x3). The combined organic extracts were dried (phase separator) and concentrated under reduced pressure and the remaining residue was purified by flash chromatography to give the desired product.

[0316] General Method 6: Trifluoroacetamide Deprotection to the Free Base The appropriate trifluoroacetamide (1 equiv.) was dissolved in MeOH and water (10:1) and potassium carbonate (5 equiv.) was added. The resulting mixture was stirred at room temperature or up to 50 °C for 1–18 h. 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 basic compounds were eluted using a 4:1 mixture of DCM / 7M NH3 in MeOH. The ammonia fraction was concentrated under reduced pressure and further purified by flash chromatography (typically 0–20% MeOH in DCM or 0–20% MeOH in EtOAc) to give the desired product.

[0317] General Method 7: Urea Formation Using a Carbamoyl Chloride Intermediate The appropriate carbamoyl chloride (1-2 equiv.), amine or amine HCl salt (1-3 equiv.), and DIPEA (2-6 equiv.) are stirred in the indicated solvent at rt for 1-18 h, followed by 0.5 M HCl. (水性) The mixture was quenched with HCl and extracted with DCM (x3) 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.

[0318] General Method 8: Carbamoyl Chloride Formation 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 an amine salt (1 equiv.) and DIPEA (1.5 equiv.) in DCM was added dropwise at 0° C. The temperature was allowed to rise to rt over 1-18 h. The reaction mixture was diluted with 1 M HCl (水性) The mixture was quenched by the addition of HCl and the resulting mixture was extracted with DCM (x3) using a phase separator. The combined organic phases were concentrated under reduced pressure to give the desired product without further purification.

[0319] General Method 9: PMB Deprotection to the Free Base The PMB-protected amine (1 equiv.) was dissolved in MeCN, and aqueous ceric ammonium nitrate (4 equiv.) was added dropwise to the stirring solution at 0 °C. The temperature was allowed to rise to rt. After 18 h, the volatiles were removed under reduced pressure, and the remaining aqueous solution was basified with excess KCO and extracted with MTBE. The solvent was removed under reduced pressure, and the remaining residue was purified by flash chromatography or preparative HPLC to give the desired product.

[0320] General Method 10: Teoc Deprotection to the Free Base The Teoc-protected amine (1 equiv.) was dissolved in DCM and TFA was added (typically 2:1 by volume, DCM / TFA). The reaction was stirred at rt for 0.5-24 h and then loaded onto a pre-equilibrated SCX-2 cartridge. The column was washed with a 3:1 mixture of DCM / MeOH, and basic compounds were eluted using a 3:1 mixture of DCM / 7M NH3 in MeOH. The ammonia fraction was concentrated under reduced pressure and further purified by flash chromatography to give the desired product.

[0321] Intermediate 1: tert-butyl ((2S,4R)-2-phenylpiperidin-4-yl)carbamate [ka] Step 1: Methyl (S)-3-amino-3-phenylpropanoate hydrochloride: To a stirred solution of (S)-3-amino-3-phenylpropanoic acid (144 g, 873 mmol) in MeOH (1.44 L) was added SOCl (76 mL, 1047 mmol) dropwise at 0 °C and stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with pentane and dried under reduced pressure to give the title compound (156 g, 87%). LCMS (Method C): R T = 2.23 minutes, m / z = 180 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.75 (br s, 3H), 7.54 (d, 2H), 7.43 - 7.35 (m, 3H), 4.57 (br s, 1H), 3.54 (s, 3H), 3.24 - 31.6 (m, 1H), 3.03 - 2.97 (m, 1H)

[0322] Step 2: Methyl (S)-3-((3-methoxy-3-oxopropyl)amino)-3-phenylpropanoate: Methyl (S)-3-amino-3-phenylpropanoate hydrochloride (165 g, 766 mmol) was dissolved in MeOH (1.65 L). A solution of triethylamine (160 mL, 1149 mmol) in MeOH (1.48 L) was added, followed by the dropwise addition of a solution of methyl acrylate (104 mL, 1149 mmol) in MeOH (1.48 L) at rt. The reaction was diluted with water (3 L) and extracted with EtOAc (3 x 5 L). The organic layer was dried (NaSO) and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (0-50% EtOAc in hexanes) to give the title compound (180 g, 88.6%). LCMS (Method C): R T = 3.02 min, m / z = 266 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.31 - 7.23 (m, 5H), 4.07 - 4.04 (m, 1H), 3.64 (s, 3H), 3.62 (s, 3H), 2.69 - 2.55 (m, 4H), 2.49 - 2.37 (m, 2H)

[0323] Step 3: Methyl (S)-3-((tert-butoxycarbonyl)(3-methoxy-3-oxopropyl)amino)-3-phenylpropanoate: Methyl (S)-3-((3-methoxy-3-oxopropyl)amino)-3-phenylpropanoate (184 g, 694 mmol) was suspended in MeOH (1.84 L) and BocO (191 mL, 833 mmol) was added dropwise. The reaction mixture was stirred at rt for 32 h. The reaction mixture was diluted with water (3 L) and extracted with ethyl acetate (3 × 5 L). The organic layer was dried (NaSO) and concentrated under reduced pressure. The residue was purified by flash chromatography (0–20% EtOAc in hexanes) to give the title compound (220 g, 87%). LCMS (Method D): R T = 3.44 minutes, m / z = 366 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.33 - 7.24 (m, 5H), 5.69 - 5.52 (m, 1H), 3.65 (s, 3H), 3.58 (s, 3H), 3.32 (br s, 2H), 3.03 - 2.97 (m, 2H), 2.47 (br s, 1H), 2.16 - 2.02 (m, 1H), 1.45 (s, 9H)

[0324] Step 4: 1-tert-butyl 3-methyl(6S)-4-hydroxy-6-phenyl-1,2,5,6-tetrahydropyridine-1,3-dicarboxylate and 1-tert-butyl 3-methyl(2S)-4-hydroxy-2-phenyl-1,2,3,6-tetrahydropyridine-1,3-dicarboxylate: Methyl (S)-3-((tert-butoxycarbonyl)(3-methoxy-3-oxopropyl)amino)-3-phenylpropanoate (55 g, 151 mmol) was dissolved in toluene (1.1 L) and cooled to −78° C. A 1 M solution of LiHMDS in THF (181 mL, 180 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at −78° C. for 2 hours. The reaction was quenched with water (1 L) and extracted using ethyl acetate (3×2 L). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (0-10% EtOAc in hexanes) to give the mixture of title compounds (25 g, 50%). LCMS (Method D): T = 3.40, 3.69 min (2 compounds), m / z = 334 [M+H] +

[0325] Step 5: tert-Butyl (S)-4-oxo-2-phenylpiperidine-1-carboxylate: A mixture of 1-tert-butyl 3-methyl(6S)-4-hydroxy-6-phenyl-1,2,5,6-tetrahydropyridine-1,3-dicarboxylate and 1-tert-butyl 3-methyl(2S)-4-hydroxy-2-phenyl-1,2,3,6-tetrahydropyridine-1,3-dicarboxylate (40 g, 120 mmol) was dissolved in DMSO (200 mL). NaCl (21 g, 360 mmol) and water (7.5 mL) were added, and the reaction mixture was heated at 145° C. for 6 hours. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (2×2 L). The organic layer was dried (NaSO) and concentrated under reduced pressure. The crude compound was purified by flash chromatography (0-20% EtOAc in hexanes) to give the title compound (20 g, 60%). LCMS (Method C): T = 1.59 min, m / z = 276 [M+H]+ . 1 H NMR (400 MHz, CDCl3): δ 7.33 - 7.22 (m, 5H), 5.70 (br s, 1H), 4.19 (br s, 1H), 3.18 - 3.11 (m, 1H), 2.97 - 2.92 (dd, 1H), 2.85 - 2.80 (dd, 1H), 2.53 - 2.47 (m, 1H), 2.37 - 2.31 (m, 1H), 1.46 (s, 9H)

[0326] Step 6: (S)-2-Phenylpiperidin-4-one hydrochloride: To a solution of tert-butyl (S)-4-oxo-2-phenylpiperidine-1-carboxylate (5 g, 18.2 mmol) in DCM (4 mL) was added 4 M HCl in 1,4-dioxane (20 mL) at 0° C., and the reaction mixture was stirred at rt for 16 h. The reaction was concentrated under reduced pressure to give the crude title compound (3.18 g, 82%), which was used in the next step without further purification. LCMS (Method C): R T = 2.13 min, m / z = 176 [M+H] +

[0327] Step 7: (S)-2-Phenyl-1-(2,2,2-trifluoroacetyl)piperidin-4-one: (S)-2-Phenylpiperidin-4-one hydrochloride (3.8 g, 18.1 mmol) was suspended in DCM (100 mL). EtN (5.54 mL, 39.7 mmol) and trifluoroacetic anhydride (5.52 mL, 39.7 mmol) were added to the reaction mixture at 0 °C and stirred at rt for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 × 250 mL). The organic layer was dried (NaSO) and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (0–30% EtOAc in hexanes) to give the title compound (3.5 g, 71%). GCMS (Method A): m / z = 271 M + .

[0328] Step 8: 2,2,2-Trifluoro-1-((2S)-4-((4-methoxybenzyl)amino)-2-phenylpiperidin-1-yl)ethan-1-one: To a solution of (S)-2-phenyl-1-(2,2,2-trifluoroacetyl)piperidin-4-one (1.0 g, 3.63 mmol) in MeOH (10 mL) was added 4-methoxybenzylamine (1.42 g, 10.9 mmol) and catalytic AcOH (1-2 drops) at rt. The reaction mixture was stirred for 1 h. NaBHCN (0.69 g, 10.9 mmol) was added to the reaction mixture and stirred at rt for 16 h. The reaction mixture was diluted with water (50 mL) and extracted using ethyl acetate (2 x 100 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give the crude material which was purified by flash chromatography (0-10% MeOH in DCM) to give the title compound (750 mg, 52%). LCMS (Method D): R T = 3.45 minutes, m / z = 393 [M+H] +

[0329] Step 9: 1-((2S)-4-amino-2-phenylpiperidin-1-yl)-2,2,2-trifluoroethan-1-one: To a solution of 2,2,2-trifluoro-1-((2S)-4-((4-methoxybenzyl)amino)-2-phenylpiperidin-1-yl)ethan-1-one (1.9 g, 4.85 mmol) in 1:1 MeCN / water (20 mL) was added CAN (7.97 g, 14.5 mmol) and the reaction mixture was stirred at rt for 5 h. The reaction mixture was cooled to rt with saturated NaHCO 3 3(水性) The reaction mixture was quenched with 25 mL of ethyl acetate, diluted with water (50 mL), and extracted using ethyl acetate (3 x 100 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (0-5% MeOH in DCM) to give the title compound (950 mg, 72%). LCMS (Method C): T = 2.54 min, m / z = 273 [M+H] +

[0330] Step 10: tert-Butyl ((2S,4R)-2-phenyl-1-(2,2,2-trifluoroacetyl)piperidin-4-yl)carbamate: To a solution of 1-((2S)-4-amino-2-phenylpiperidin-1-yl)-2,2,2-trifluoroethan-1-one (950 mg, 3.5 mmol) in DCM (5 mL) was added EtN (1.46 mL, 10.5 mmol) and BocO (0.96 mL, 4.19 mmol) at 0 °C. After the addition, the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (50 mL) and extracted using ethyl acetate (100 mL). The organic layer was washed with saturated NaHCO 3(水性) The resulting solution (50 mL) was washed with water (50 mL) and dried (NaSO). The solvent was evaporated under reduced pressure to give crude tert-butyl ((2S)-2-phenyl-1-(2,2,2-trifluoroacetyl)piperidin-4-yl)carbamate (mixture of diastereoisomers), which was purified and separated by flash chromatography (0-30% EtOAc in hexanes) to give tert-butyl ((2S,4S)-2-phenyl-1-(2,2,2-trifluoroacetyl)piperidin-4-yl)carbamate) (first eluting diastereoisomer: 400 mg, 30%). LCMS (Method C): R T = 3.65 min, m / z = 273 [M-Boc+H] + [α] D 25 = +5.2 (c 0.25 in MeOH); and the title compound (second eluting diastereoisomer: 300 mg, 23%). LCMS (Method C): R T = 3.58 min, m / z = 373 [M+H] + [α] D 25 = +36.1 (c 0.25 in MeOH). [Note: The stereochemistry of the title compound was assigned based on comparison of the optical rotation data of the same compound prepared by another method outlined in WO2020115501, p. 317: [α] D 21 = +49.82 (c 0.25 in MeOH), previously unpublished].

[0331] Step 11: tert-Butyl ((2S,4R)-2-phenylpiperidin-4-yl)carbamate: To a solution of tert-butyl ((2S,4R)-2-phenyl-1-(2,2,2-trifluoroacetyl)piperidin-4-yl)carbamate (300 mg, 0.8 mmol) in 4:1 MeOH / HO (10 mL) was added KCO (168 mg, 0.2 mmol) and stirred at rt for 16 h. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2 x 50 mL). The organic phase was dried (NaSO) and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (0-30% EtOAc in hexanes) to give the title compound (150 mg, 67%, de = 100%). LCMS (Method E): R T = 1.34 min, m / z = 277 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.34 - 7.19 (m, 5H), 6.79 (d, 1H), 3.54 (d, 1H), 3.40 (br s, 1H), 3.03 (d, 1H), 2.65 - 2.59 (m, 1H), 1.82 - 1.69 (m, 2H), 1.36 (s, 9H), 1.30 - 1.05 (m, 3H). [α] D 20 = +36.11 (c 0.25 in MeOH)

[0332] Intermediate 2: tert-butyl (R)-3-(3,5-difluorophenyl)piperazine-1-carboxylate [ka] tert-Butyl 3-(3,5-difluorophenyl)piperazine-1-carboxylate (10.2 g) [commercially available] was resolved into single stereoisomers by chiral FC using a Chiralpak IG (20 mm x 250 mm, 5 μm) column with isocratic solvent conditions: 20:80 MeOH / CO (0.2% v / v NH). The first eluted material yielded tert-butyl (S)-3-(3,5-difluorophenyl)piperazine-1-carboxylate (4.75 g). Chiral purity (Method A): RT = 1.07 min, 99.9% ee. The second eluting material gave the title compound (4.83 g). Chiral purity (Method A): R T = 1.55 min, 99.7% ee. [Note: Stereochemistry was assigned based on the relative potency of the derivatives - the (R)-stereoisomer is known to be significantly more potent, see WO2020115501].

[0333] Intermediate 3: tert-butyl (R)-3-(2,5-difluorophenyl)piperazine-1-carboxylate [ka] tert-Butyl 3-(2,5-difluorophenyl)piperazine-1-carboxylate (9.88 g) [commercially available] was resolved into single stereoisomers by chiral HPLC using a Lux A2 (21.2 mm x 250 mm, 5 μm) column with isocratic solvent conditions: 50:50 heptane / IPA (0.2% v / v NH). The first eluted material yielded the title compound (4.55 g). Chiral purity (Method B): R T = 4.05 min, 100% ee. The second eluting material gave tert-butyl (S)-3-(2,5-difluorophenyl)piperazine-1-carboxylate (4.47 g). Chiral purity (Method B): R T = 6.29 min, 100% ee. [Note: Stereochemistry was assigned based on the relative potency of the derivatives - the (R)-stereoisomer is known to be significantly more potent, see WO2020115501].

[0334] Intermediate 4: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-phenylpiperidine [ka] Step 1: tert-Butyl (2S)-4-hydroxy-2-phenylpiperidine-1-carboxylate: To a solution of tert-butyl (S)-4-oxo-2-phenylpiperidine-1-carboxylate (2.5 g, 9.08 mmol) in THF (100 mL) was added 1 M LiAlH in THF (10.9 mL, 10.9 mmol) at 0 °C under nitrogen, and the reaction mixture was stirred at 0 °C for 40 min. The reaction mixture was diluted with NaSO4(水性) The reaction mixture was quenched by dropwise addition of the solution and diluted with water (50 mL) and ethyl acetate (100 mL). The organic layer was separated, washed with brine (75 mL), and dried (Na2SO4). The solvent was evaporated under reduced pressure to give the crude material, which was purified by flash chromatography (0-20% EtOAc in hexanes) to give the title compound (1.85 g, 73%). LCMS (Method D): R T = 3.07 min, m / z = 278 [M+H] +

[0335] Step 2: (2S,4R)-2-Phenylpiperidin-4-ol: To a solution of tert-butyl (2S)-4-hydroxy-2-phenylpiperidine-1-carboxylate (1.3 g, 4.69 mmol) in DCM (58.5 mL) was added TFA (6.5 mL), and the reaction mixture was stirred at rt for 4 h. The solvent was evaporated under reduced pressure. The residue was diluted with water (50 mL), basified with NaHCO solution to approximately pH 9-10, and extracted with ethyl acetate (2 × 100 mL). The organic layer was washed with brine (80 mL), dried (NaSO), and the solvent was evaporated under reduced pressure to give (2S)-2-phenylpiperidin-4-ol (690 mg, 83%). This material was resolved into single stereoisomers by chiral HPLC using a Chiralpak IG (21 mm x 250 mm, 5 μm) column under isocratic solvent conditions: 90:10 hexane / EtOH (0.1% v / v isopropylamine) to give the title compound (150 mg). GCMS (Method A): m / z = 177 M + . 1H NMR (400 MHz, DMSO-d): δ 7.36–7.29 (m, 4H), 7.26–7.23 (m, 1H, overlapping CDCl signals), 3.82–3.74 (m, 1H), 3.64–3.61 (m, 1H), 3.25–3.20 (m, 1H), 2.82–2.75 (m, 1H), 2.15–2.11 (m, 1H), 2.03–1.99 (m, 1H), 1.54–1.44 (m, 2H). [Note: Literature data from Tetrahedron: Asymmetry, 1999, 10, 4231–4237 was used to confirm the structure assignment.]

[0336] Step 3: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-phenylpiperidine: To a stirring solution of (2S,4R)-2-phenylpiperidin-4-ol (60 mg, 0.339 mmol) and TBDMSCl (128 mg, 0.846 mmol) in DCM (2 mL) was added imidazole (92 mg, 1.35 mmol) and the resulting mixture was stirred at rt for 18 h. The reaction was purified with saturated NaHCO 3(水性) The mixture was quenched with HCl and extracted with DCM (x3) using a phase separator. The combined organic phases were concentrated under reduced pressure and the crude material was purified by flash chromatography using a Biotage Sfar Amino D column (0-50% DCM in cyclohexane) to give the title compound (77 mg, 78%). LCMS (Method B): T = 1.04 min, m / z = 292 [M+H] +

[0337] Intermediate 5: tert-butyl ethyl ((2S,4R)-2-phenylpiperidin-4-yl)carbamate [ka] Step 1: 1-((2S)-4-(ethylamino)-2-phenylpiperidin-1-yl)-2,2,2-trifluoroethan-1-one: To a solution of (S)-2-phenyl-1-(2,2,2-trifluoroacetyl)piperidin-4-one (1.6 g, 5.81 mmol) in MeOH (5 mL) was added a 2 M solution of EtNH in EtOH (8.22 mL, 17.4 mmol) and catalytic AcOH (1-2 drops) at rt and stirred for 1 h. NaBHCN (1.09 g, 17.4 mmol) was added to the reaction mixture and stirred at rt for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 150 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give the crude material which was purified by flash chromatography (0-10% MeOH / DCM) to give the title compound (1.0 g, 57%). LCMS (Method D): T = 2.61 min, m / z = 301 [M+H] +

[0338] Step 2: tert-Butyl ethyl ((2S)-2-phenyl-1-(2,2,2-trifluoroacetyl)piperidin-4-yl)carbamate: To a solution of 1-((2S)-4-(ethylamino)-2-phenylpiperidin-1-yl)-2,2,2-trifluoroethan-1-one (1 g, 3.33 mmol) in DCM (10 mL) was added EtN (1.4 mL, 10 mmol) and BocO (0.920 mL, 4 mmol) at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The organic layer was washed with saturated NaHCO 3(水性) The solution (80 mL) was washed with water (80 mL) and dried (Na2SO4). The solvent was evaporated under reduced pressure to give the crude material, which was purified by flash chromatography (0-20% EtOAc in hexanes) to give the title compound (1 g, 75%). LCMS (Method D): R T = 3.81, 3.89min, m / z = 401 [M+H] +

[0339] Step 3: tert-Butyl ethyl ((2S,4R)-2-phenylpiperidin-4-yl)carbamate: To a solution of tert-butyl ethyl ((2S)-2-phenyl-1-(2,2,2-trifluoroacetyl)piperidin-4-yl)carbamate (1 g, 2.5 mmol) in 4:1 MeOH / HO (10 mL) was added KCO (518 mg, 3.75 mmol) at rt and stirred for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The organic layer was dried (NaSO) and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (0–30% EtOAc in hexanes) to give tert-butyl ethyl ((2S)-2-phenylpiperidin-4-yl)carbamate (600 mg, 79%). This material was resolved into single stereoisomers by chiral HPLC using a Chiralpak AY-H (21 mm x 250 mm, 5 μm) column under isocratic solvent conditions: 90:10 hexane / EtOH containing 0.1% v / v isopropylamine, to give tert-Butyl ethyl ((2S,4S)-2-phenylpiperidin-4-yl)carbamate (first eluting: 130 mg, de=100%). LCMS (Method D): R T = 3.07 min, m / z = 305 [M+H]+. 1 H NMR (400 MHz, CDCl3): δ 7.48 (d, 2H), 7.35 (t, 2H), 7.23 - 7.20 (m, 1H), 4.34 (d, 1H), 4.11 - 4.08 (m, 1H), 3.26 - 3.12 (m, 2H), 2.90 - 2.85 (m, 1H), 2.75 - 2.69 (m, 1H), 2.33 - 2.29 (m, 1H), 2.07 - 1.99 (m, 1H), 1.73 - 1.70(m, 1H), 1.68 (1H), 1.44 (s, 9H), 1.12 9t, 3H); and Title compound (second eluting: 330 mg, de=100%). LCMS (Method D): T = 3.14 min, m / z = 305 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.36 - 7.29 (m, 4H), 7.23 - 7.22 (m, 1H), 4.22 (bs, 1H), 3.68 (d, 1H), 3.27 - 3.22 (m, 1H), 3.14 (br s, 2H), 2.88 - 2.82 (m, 1H), 1.88 - 1.85 (m, 1H), 1.75 - 1.72 (m, 2H), 1.63 (br s, 1H), 1.45 (s, 9H), 1.07 (t, 3H) obtained. [Note: Stereoisomers 1 confirmed by comparison with H NMR nOe data]

[0340] Intermediate 6: 2,2,2-trifluoro-N-methyl-N-((2S,4R)-2-phenylpiperidin-4-yl)acetamide hydrochloride [ka] Step 1: tert-Butyl (2S)-4-(methylamino)-2-phenylpiperidine-1-carboxylate: To a solution of tert-butyl (S)-4-oxo-2-phenylpiperidine-1-carboxylate (5.00 g, 18.2 mmol) in MeOH (20 mL) was added 40% MeNH in MeOH (1.69 g, 54.5 mmol) and catalytic AcOH (1-2 drops) at rt and stirred for 1 h. NaBHCN (3.44 g, 54.5 mmol) was added to the reaction mixture and stirred at rt for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 250 mL). The organic layer was dried (NaSO) and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (0-10% MeOH in DCM) to give the title compound (3.3 g, 62%). LCMS (Method C): R T = 2.77 min, m / z = 291 [M+H] +

[0341] Step 2: tert-Butyl (2S)-2-phenyl-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate: To a solution of tert-butyl (2S)-4-(methylamino)-2-phenylpiperidine-1-carboxylate (3.3 g, 11.4 mmol) in DCM (30 mL) was added EtN (3.5 mL, 25.0 mmol) followed by trifluoroacetic anhydride (3.48 mL, 25.0 mmol) at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The organic layer was dried (NaSO) and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (0–30% EtOAc in hexanes) to give the title compound (2.5 g, 57%).

[0342] Step 3: tert-Butyl (2S,4R)-2-phenyl-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate: tert-Butyl (2S)-2-phenyl-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate (3.2 g) was resolved into single stereoisomers by chiral HPLC using a Chiralpak IC (20 mm x 250 mm, 5 μm) column under isocratic solvent conditions: 95:5 hexane / EtOH to give tert-Butyl (2S,4S)-2-phenyl-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate (first eluting isomer, 0.8 g). LCMS (Method C): R T = 3.81 min, m / z = 387 [M+H] + . 1H NMR at 100 ℃(400 MHz, DMSO-d6): δ 7.39 (t, 2H), 7.29 - 7.25 (m, 3H), 5.53 (br s, 1H), 4.28 - 4.10 (m, 3H), 2.97 - 2.92 (m, 2H), 2.87 - 2.81 (m, 1H), 2.39 - 2.35 (m, 1H), 2.16 (br s, 1H), 1.82 (br s, 1H), 1.63 - 1.60 (m, 1H), 1.45 (s, 9H); and Title compound (second eluting isomer: 1.2 g). LCMS (Method C): T = 3.77 min, m / z = 387 [M+H] + . 1 H NMR at 100 ℃(400 MHz, DMSO-d6): δ 7.34 - 7.21 (m, 5H), 4.85 - 4.81 (m, 1H), 4.40 (br s, 1H), 3.97 - 3.91 (m, 1H), 3.53 - 3.46 (m, 1H), 2.15 - 2.10 (m, 3H), 1.79 (br s, 1H), 1.41 (s, 9H) obtained. [Note: Stereoisomers 1 This was confirmed by comparison with H NMR nOe data].

[0343] Step 4: 2,2,2-Trifluoro-N-methyl-N-((2S,4R)-2-phenylpiperidin-4-yl)acetamide hydrochloride: tert-Butyl (2S,4R)-2-phenyl-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate (1.20 g, 3.11 mmol) was suspended in DCM (3 mL) followed by the addition of 4 M HCl in 1,4-dioxane (10 mL). The reaction mixture was stirred at rt for 3 h. The solvent was evaporated under reduced pressure and the residue was triturated with DCM and pentane to give the title compound (890 mg, 89%, de=100%). LCMS (Method C): R T = 2.39 min, m / z = 287 [M+H] + 1 H NMR at 100 ℃(400 MHz, DMSO-d6): δ 9.39 (br s, 2H), 7.64 (d, 2H), 7.46 - 7.39 (m, 3H), 4.61 (br s, 1H), 4.45 (d, 1H), 3.40 - 3.44 (m, 1H), 3.27 - 3.21 (m, 1H), 3.0 (3H, overlapped with HDO signal), 2.44 (m, 1H), 1.99 (d, 1H),1.87 (d, 1H)

[0344] Intermediate 7: 3-(((2S,4R)-2-phenylpiperidin-4-yl)amino)thietane 1,1-dioxide hydrochloride [ka] Step 1: tert-Butyl (2S)-4-((1,1-dioxidothietan-3-yl)amino)-2-phenylpiperidine-1-carboxylate: To a solution of tert-butyl (S)-4-oxo-2-phenylpiperidine-1-carboxylate (500 mg, 1.82 mmol) in MeOH (10 mL) was added 3-aminothietane 1,1-dioxide (264 mg, 2.18 mmol) and catalytic AcOH (1 drop) at rt. The reaction mixture was stirred for 1 h. NaBHCN (344 mg, 5.45 mmol) was added to the reaction mixture and stirred at rt for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (0-10% MeOH in DCM) to give the title compound (500 mg, 72%), which was used in the next step.

[0345] Step 2: tert-Butyl (2S,4R)-4-((1,1-dioxidothietan-3-yl)amino)-2-phenylpiperidine-1-carboxylate: tert-Butyl (2S)-4-((1,1-dioxidothietan-3-yl)amino)-2-phenylpiperidine-1-carboxylate (1.2 g) was resolved into single stereoisomers by chiral HPLC using a Chiralpak AY-H (21 mm x 250 mm, 5 μm) column in isocratic solvent conditions: 80:20 hexane / EtOH containing 0.1% v / v isopropylamine to give tert-Butyl (2S,4S)-4-((1,1-dioxidothietan-3-yl)amino)-2-phenylpiperidine-1-carboxylate (first eluting diastereoisomer: 125 mg). LCMS (Method D): R T = 3.21 min, m / z = 381 [M+H] + ; and Title compound (second eluting diastereoisomer: 292 mg). LCMS (Method C): R T = 3.39 min, m / z = 381 [M+H] + obtained.

[0346] Step 3: 3-(((2S,4R)-2-phenylpiperidin-4-yl)amino)thietane 1,1-dioxide hydrochloride: To a suspension of tert-butyl (2S,4R)-4-((1,1-dioxidethietan-3-yl)amino)-2-phenylpiperidine-1-carboxylate (700 mg, 1.84 mmol) in DCM (2 mL) was added 4M HCl in 1,4-dioxane (10 mL) at 0° C. and stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure to give the crude material which was triturated with DCM and pentane to give the title compound (575 mg, 98%, de=100%). LCMS (Method G): R T = 2.83 min, m / z = 281 [M+H] + . 1H NMR (400 MHz, methanol-d4): δ 7.57 - 7.47 (m, 5H), 4.65 - 4.60 (m, 2H), 4.53 - 4.50 (m, 4H), 3.74 (t, 1H), 3.66 - 3.63 (m, 1H), 3.35 (d, 1H), 2.57 - 2.54 (m, 2H), 2.32 - 2.11 (m, 2H). [Note: Stereoisomers of intermediate 8 were identified.] 1 confirmed by comparison with H NMR nOe data]

[0347] Intermediate 8: 3-(((2S,4S)-2-phenylpiperidin-4-yl)amino)thietane 1,1-dioxide hydrochloride [ka] To a suspension of tert-butyl (2S,4S)-4-((1,1-dioxidothietan-3-yl)amino)-2-phenylpiperidine-1-carboxylate (300 mg, 0.79 mmol) in DCM (2 mL) was added 4M HCl in 1,4-dioxane (7 mL) at 0° C. and stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure to give the crude material, which was triturated with DCM and pentane to give the title compound (245 mg, 98%, de=100%). LCMS (Method G): R T = 3.34 min, m / z = 281 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 7.54 - 7.46 (m, 5H), 4.98 (d, 1H), 4.59 - 4.45 (m, 4H), 4.35 - 4.33 (m 1H), 3.80 - 3.71 (m, 2H), 3.44 - 3.41 (m, 1H), 2.49 - 2.36 (m, 2H), 2.29 - 2.27 (m, 2H). [Note: Stereoisomers were identified in the intermediate 7 1 confirmed by comparison with H NMR nOe data]

[0348] Intermediate 9: (2S,4R)-4-methyl-2-phenylpiperidin-4-ol hydrochloride [ka] Step 1: (2S,4R)-4-Hydroxy-4-methyl-2-phenyl-piperidine-1-carboxylic acid tert-butyl ester: To a stirred solution of tert-butyl (S)-4-oxo-2-phenylpiperidine-1-carboxylate (1 g, 3.36 mmol) in THF (50 mL) was added dropwise a 3 M solution of MeMgBr in diethyl ether (2.42 mL, 7.26 mmol) at −10° C. and stirred at rt for 16 h. The reaction mixture was added with saturated ammonium chloride. (水性) The mixture was quenched by dropwise addition of HCl, diluted with water (50 mL), and extracted using ethyl acetate (3 x 50 mL). The organic layer was washed with brine (60 mL), dried (NaSO), and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (0-75% EtOAc in hexanes) to give the title compound (0.5 g, 47%). LCMS (Method D): T = 3.34 min, m / z = 292 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.29 - 7.25 (m, 2H), 7.19 - 7.14 (m, 3H), 5.11 - 5.10 (d, 1H), 3.21 - 3.12 (m, 1H), 2.22 - 2.28 (dd, 1H), 1.82 - 1.76 (dd, 1H), 1.47 - 1.44 (m, 2H), 1.32 (s, 9H), 1.13 (s, 3H)

[0349] Step 2: (2S,4R)-4-Methyl-2-phenylpiperidin-4-ol hydrochloride: (2S,4R)-4-Hydroxy-4-methyl-2-phenyl-piperidine-1-carboxylic acid tert-butyl ester (425 mg, 1.46 mmol) was dissolved in DCM (50 mL). 4M HCl in 1,4-dioxane (12.5 mL) was added dropwise at 0° C. and stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure to give the crude material, which was triturated with diethyl ether to give the title compound (190 mg, 68%). LCMS (Method C): R T = 1.72 min, m / z = 192 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 9.27 (br s, 1H), 7.58 - 7.56 (d, 2H), 7.46 - 7.38 (m, 3H), 5.01 (s, 1H), 4.31 - 4.28 (d, 1H), 3.31 - 3.26 (m, 1H), 3.09 - 3.03 (m, 1H), 2.07 - 1.91 (m, 2H), 1.80 - 1.73 (m, 2H), 1.34 (s, 3H). [Note: stereoisomers (only formed) are 1 confirmed by analysis of H NMR nOe data]

[0350] Intermediate 10: 2,2,2-trifluoro-N-((2S,4R)-2-(3-fluorophenyl)piperidin-4-yl)-N-methylacetamide hydrochloride [ka] Step 1: tert-butyl (S)-2-(3-fluorophenyl)-4-oxopiperidine-1-carboxylate: The title compound was prepared analogously to tert-butyl (S)-4-oxo-2-phenylpiperidine-1-carboxylate (Intermediate 1, steps 1-5), except using (S)-3-amino-3-(3-fluorophenyl)propanoic acid instead of (S)-3-amino-3-phenylpropanoic acid as the starting material. LCMS (Method C): R T = 3.47 minutes, m / z = 294 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.31 - 7.27 (m, 1H), 57.01 (d, 1H), 6.97 - 6.93 (m, 2H), 5.66 (br s, 1H), 4.20 (br s, 1H), 3.18 (dt, 1H), 2.93 - 2.81 (m, 2H), 2.56 - 2.47 (m, 1H), 2.38 - 2.33 (m, 1H), 1.46 (s, 9H)

[0351] Step 2: tert-Butyl (2S)-2-(3-fluorophenyl)-4-(methylamino)piperidine-1-carboxylate: To a stirring solution of tert-butyl (S)-2-(3-fluorophenyl)-4-oxopiperidine-1-carboxylate (2.5 g, 8.52 mmol) in MeOH (100 mL) was added MeNH (10 mL) and stirred at rt for 1 h. NaBHCN (2.4 g, 38.4 mmol) was added portionwise at rt. After 24 h, the reaction mixture was quenched with water (25 mL) and concentrated under reduced pressure to remove volatiles. The remaining mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic phases were dried (NaSO) and concentrated to give the crude product, which was purified by flash chromatography (70–80% EtOAc in hexanes) to give the title compound (2.5 g, 95%). LCMS (Method E): R T = 1.53 min, m / z = 309 [M+H] +

[0352] Step 3: tert-Butyl (2S)-2-(3-fluorophenyl)-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate: To a stirring solution of tert-butyl (2S)-2-(3-fluorophenyl)-4-(methylamino)piperidine-1-carboxylate (2.5 g, 8.11 mmol) in DCM (50 mL) was added triethylamine (4.5 mL, 32.4 mmol) followed by trifluoroacetic anhydride (2.5 mL, 17.8 mmol) at 0 °C, and the reaction mixture was stirred at rt. After 16 h, the reaction mixture was diluted with water (70 mL) and extracted with DCM (2 × 150 mL). The combined organic phases were dried (NaSO) and concentrated to give the crude product, which was purified by flash chromatography (30% EtOAc in hexanes) to give the title compound (1.2 g, 40%).

[0353] Step 4: tert-Butyl (2S,4R)-2-(3-fluorophenyl)-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate: tert-Butyl (2S)-2-(3-fluorophenyl)-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate (1.2 g) was resolved into single stereoisomers by chiral HPLC using a Chiralpak IC (20 mm x 250 mm, 5 μm) column under isocratic solvent conditions: 95:5 hexane / EtOH. tert-Butyl (2S,4S)-2-(3-fluorophenyl)-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate (first eluting isomer: 0.25 g, de=100%). LCMS (Method D): R T = 3.58 min, m / z = 405 [M+H] + . 1 H NMR (400 MHz, CDCl): δ 7.33 (br s, 1H), 7.12 - 7.85 (m, 3H), 5.71 - 5.53 (br s, 2 peaks, 1H), 4.53 - 4.11 (m, 2H), 2.99 - 2.92 (s, 2 peaks, 3H), 2.85 - 2.71 (m, 1H), 2.35 (d, 1H), 2.21 - 2.00 (m, 1H), 1.78 - 1.60 (m, 2H), 1.52 (s, 2 peaks, 9H); and Title compound (second eluting isomer: 0.45 g, de=100%). LCMS (Method D): T = 3.58 min, m / z = 405 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 7.28 - 7.23 (m, 1H), 6.98 - 6.88 (m, 3H), 4.79 (t, 1H), 4.77 - 4.58 (m, 1H), 4.12 - 4.06 (m, 1H), 3.51 - 3.45 (m, 1H), 2.97 - 2.88 (m, 3H), 2.21 - 2.15 (m, 1H), 2.07 - 1.97 (m, 2H), 1.71 - 1.69 (m, 1H), 1.25 (s, 9H) obtained. [Note: Stereoisomers 1 This was confirmed by comparison with H NMR nOe data].

[0354] Step 5: 2,2,2-Trifluoro-N-((2S,4R)-2-(3-fluorophenyl)piperidin-4-yl)-N-methylacetamide hydrochloride: To a stirring solution of tert-butyl (2S,4R)-2-(3-fluorophenyl)-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate (650 mg, 1.61 mmol) in DCM (10 mL) was added 4 M HCl in 1,4-dioxane (10 mL) at 0° C. The reaction mixture was stirred for 3 h at 0° C. and then concentrated under reduced pressure. The remaining crude product was triturated with diethyl ether and pentane to give the title compound (445 mg, 81%, de=100%). LCMS (Method C): R T = 2.71 min, m / z = 305 [M+H] + . 1 H NMR at 100 ℃(400 MHz, DMSO-d6): δ 9.60 (br s, 2H), 7.58 - 7.43 (m, 3H), 7.28 - 7.24 (m, 1H), 4.67 - 4.52 (m, 2H), 3.46 - 3.43 (m, 1H), 3.24 - 3.21 (m, 1H), 3.01 - 2.92 (s, 2 peaks, 3H), 2.36 - 2.27 (m, 2H), 1.98 - 1.82 (m, 2H)

[0355] Intermediate 11: 2,2,2-trifluoro-N-((2S,4R)-2-(3-fluorophenyl)piperidin-4-yl)acetamide hydrochloride [ka] Step 1: tert-Butyl (2S)-4-amino-2-(3-fluorophenyl)piperidine-1-carboxylate: To a stirring solution of tert-butyl (S)-2-(3-fluorophenyl)-4-oxopiperidine-1-carboxylate (6.0 g, 20.5 mmol) in MeOH (10 mL) was added 7 M NH in MeOH (30 mL), followed by catalytic AcOH (1-2 drops) and stirred at rt for 1 h. NaBHCN (3.86 g, 61.4 mmol) was added portionwise at rt and stirred at rt. After 16 h, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic phases were dried (NaSO) and concentrated to give the crude material, which was purified by flash chromatography (10% MeOH in DCM) to give the title compound (2.6 g, 43%). LCMS (Method C): R T = 2.81 min, m / z = 295 [M+H] +

[0356] Step 2: tert-Butyl (2S)-2-(3-fluorophenyl)-4-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate: To a stirring solution of tert-butyl (2S)-4-amino-2-(3-fluorophenyl)piperidine-1-carboxylate (2.4 g, 8.16 mmol) in DCM (25 mL) was added TEA (3.66 mL, 26.1 mmol) followed by trifluoroacetic anhydride (2.50 mL, 18.0 mmol) at 0 °C, and the reaction mixture was stirred at rt. After 16 h, the reaction mixture was diluted with water (70 mL) and extracted with DCM (2 × 150 mL). The organic phase was dried (NaSO) and concentrated to give the crude material, which was purified by flash chromatography (30% EtOAc in hexanes) to give the title compound (2.0 g, 62%).

[0357] Step 3: tert-Butyl (2S,4R)-2-(3-fluorophenyl)-4-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate: tert-Butyl (2S)-2-(3-fluorophenyl)-4-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate (2.0 g) was resolved into single stereoisomers by chiral HPLC using a Chiralpak IC (20 mm x 250 mm, 5 μm) column under isocratic solvent conditions: 95:5 hexane / EtOH to give tert-Butyl (2S,4S)-2-(3-fluorophenyl)-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate (first eluting isomer: 0.45 g, de=100%). LCMS (Method C): T = 3.71 min, m / z = 391 [M+H] + ; and Title compound (second eluting isomer: 0.65 g, de=100%). LCMS (Method C): T = 3.63 min, m / z = 391 [M+H] + obtained. [Note: Stereoisomers 1 This was confirmed by comparison with H NMR nOe data].

[0358] Step 4: 2,2,2-Trifluoro-N-((2S,4R)-2-(3-fluorophenyl)piperidin-4-yl)acetamide hydrochloride: To a stirring solution of tert-butyl (2S,4R)-2-(3-fluorophenyl)-4-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate (650 mg, 1.67 mmol) in DCM (5 mL) was added 4 M HCl in dioxane (10 mL) at 0° C. and the reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure and lyophilized to give the title compound (480 mg, 99%). LCMS (Method C): R T = 2.87 min, m / z = 291 [M+H] + . 1H NMR at 100 ℃(400 MHz, DMSO-d6): δ 9.59 (br s, 2H), 9.37 (br s, 1H), 7.52 - 7.43 (m, 3H), 7.21 (t, 1H), 4.46 - 4.43 (m, 1H), 4.17 - 4.12 (m, 1H), 3.43 (d, 1H), 3.21 - 3.14 (m, 1H), 2.18 - 2.02 (m, 4H)

[0359] Intermediate 12: (R)-1-((7-azaspiro[4.5]decan-10-yl)methyl)-4-chloropyridin-2(1H)-one hydrochloride [ka] A solution of tert-butyl (R)-10-((4-chloro-2-oxopyridin-1(2H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (300 mg, 0.788 mmol) [Example 44, Step 2] in 4 M HCl (2 mL) in 1,4-dioxane was stirred at rt for 18 h. The reaction was then concentrated under reduced pressure to give the title compound (249 mg, quantitative). LCMS (Method B): R T = 0.62 min, m / z = 281, 283 [M+H] +

[0360] Intermediate 13: 2-(trimethylsilyl)ethyl ((2R,4R)-2-ethylpiperidin-4-yl)carbamate [ka] Step 1: rac-(2R,4R)-2-ethylpiperidine-4-carboxylic acid: To a solution of 2-ethylpyridine-4-carboxylic acid (5.00 g, 33 mmol) in methanol (150 mL) was added 10% (w / w) Pd / C (2.00 g) and stirred under hydrogen (100 atm) at 50° C. After 48 h, the reaction mixture was filtered and evaporated to dryness to give the title compound (4.72 g, 90%). 1H NMR (400 MHz, DMSO-d6): δ 9.21 (br s, 1H), 3.22 (m, 1H), 2.93 (m, 1H), 2.84 (m, 1H), 2.53 (m, 1H), 2.03 (m, 1H), 1.93 (m, 1H), 1.69 (m, 2H), 1.2 (m, 1H), 1.40 (m, 1H), 0.90 (t, 3H)

[0361] Step 2: rac-Benzyl (2R,4R)-2-ethyl-4-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)piperidine-1-carboxylate: To a solution of rac-(2R,4R)-2-ethylpiperidine-4-carboxylic acid (4.72 g, 30.0 mmol) in 1,4-dioxane (200 mL) and water (100 mL) was added sodium hydroxide (4.80 g, 120 mmol). The reaction mixture was cooled to 0° C. and CbzCl (7.70 g, 45.0 mmol) was added dropwise. After 24 h, the volatiles were evaporated and the remaining aqueous phase was washed with MTBE and saturated sodium hydrogen sulfate. (水性) The mixture was acidified to pH 4 using hexanes solution, which gave an oil that was extracted using EtOAc. Evaporation of the solvent gave crude rac-(2R,4R)-1-((benzyloxy)carbonyl)-2-ethylpiperidine-4-carboxylic acid (7.8 g), which was dissolved in toluene (200 mL) followed by the addition of diphenylphosphoryl azide (11.1 g, 40.0 mmol) and triethylamine (4.06 g, 40.0 mmol). The reaction mixture was heated at 75° C. for 4 hours, followed by the addition of trimethylsilylethanol (9.50 g, 80.0 mmol). The reaction mixture was heated to 100° C. After 24 hours, the solvent was removed under reduced pressure, and the remaining residue was purified by flash chromatography to give the title compound (5.40 g, 44%). 1H NMR (400 MHz, DMSO-d6): δ 7.30 (m, 5H), 7.09 (br s, 1H), 5.02 (m, 2H), 4.00 (m, 2H), 3.81 (m, 1H), 3.64 (m, 1H), 3.53 (m, 1H), 3.22 (m, 1H), 1.71 - 1.63 (m, 4H), 1.47 (m, 2H), 0.88 (m, 2H), 0.71 (t, 3H), - 0.02 (s, 9H)

[0362] Step 3: rac-2-(trimethylsilyl)ethyl ((2R,4R)-2-ethylpiperidin-4-yl)carbamate: rac-benzyl (2R,4R)-2-ethyl-4-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)piperidine-1-carboxylate (5.40 g, 13.3 mmol) was dissolved in methanol (70 mL), 10% (w / w) Pd / C (0.5 g) was added and stirred under hydrogen (1 atm) at rt. After 24 h, the reaction mixture was filtered, the solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the title compound (1.72 g, 47%). LCMS (Method F): R T = 0.92 min, m / z = 273 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.01 (m, 1H), 4.00 (m, 2H), 3.25 (m, 1H), 2.91 (m, 1H), 2.27 (m, 1H), 1.75 - 1.61 (m, 2H), 1.30 - 1.11 (m, 3H), 0.88 (m, 2H), 0.83 (t, 3H), - 0.01 (s, 9H)

[0363] Step 4: 2-(Trimethylsilyl)ethyl ((2R,4R)-2-ethylpiperidin-4-yl)carbamate: rac-2-(trimethylsilyl)ethyl ((2R,4R)-2-ethylpiperidin-4-yl)carbamate (1.4 g) was resolved into single stereoisomers by chiral HPLC using a Chiralpak AD-H (20 mm x 250 mm, 5 μm) column with isocratic solvent conditions: 80:10:10 hexane / IPA / MeOH. The first-eluting material (R T = 9.48 min) is 2-(trimethylsilyl)ethyl ((2S,4S)-2-ethylpiperidin-4-yl)carbamate (0.65 g). [α] D 25 = - 9.88 (c 0.25 in CHCl3); and the second eluting material (R T =13.27 min) was obtained from the title compound (0.62 g). [α] D 25 = +11.42 (c 0.25 in CHCl3).

[0364] Intermediate 14: tert-butyl (R)-3,3-dimethyl-4-((2-oxo-4-chloropyridin-1(2H)-yl)methyl)piperidine-1-carboxylate [ka] Step 1: tert-Butyl 4-(iodomethyl)-3,3-dimethylpiperidine-1-carboxylate: To a stirring mixture of tert-butyl 4-(hydroxymethyl)-3,3-dimethyl-piperidine-1-carboxylate (15.3 g, 63.0 mmol), imidazole (5.14 g, 75.6 mmol), and triphenylphosphine (19.8 g, 75.6 mmol) in THF (153 mL) was added dropwise a solution of iodine (19.2 g, 75.6 mmol) in THF (150 mL) at 0° C. The reaction mixture was stirred overnight at rt and then added saturated NaSO 3(水性)The mixture was quenched with ethyl acetate (3×500 mL) until complete discoloration, followed by extraction with ethyl acetate (3×500 mL). The combined organic phases were washed successively with brine (300 mL), water (300 mL), and brine (300 mL), dried (NaSO), and the solvent was removed under reduced pressure. The remaining residue was purified by flash chromatography (10% MTBE in hexanes) to afford the title compound (18 g, 81%) as a viscous, colorless oil. 1 H NMR (500 MHz, CDCl3): δ 4.20 (s, 1H), 3.54 (m, 2H), 2.78 (t, 1H), 2.66 (s, 1H), 2.43 (s, 1H), 1.98 (m, 1H), 1.54 (m, 1H), 1.44 (s, 9H), 1.25 (m, 1H), 0.97 (s, 3H), 0.78 (s, 3H)

[0365] Step 2: tert-Butyl 3,3-dimethyl-4-((2-oxo-4-chloropyridin-1(2H)-yl)methyl)piperidine-1-carboxylate: A mixture of 4-chloropyridin-2(1H)-one (2.70 g, 20.8 mmol), tert-butyl 4-(iodomethyl)-3,3-dimethylpiperidine-1-carboxylate (8.83 g, 25 mmol), CsCO (8.15 g, 25 mmol) and 1,4-dioxane (106 mL) was placed in a sealed tube and heated at 120° C. for 48 h. After cooling to rt, the solvent was evaporated. The residue was dissolved in DCM, filtered and the solvent was evaporated. The remaining residue was purified by flash chromatography to give the title compound (2.3 g, 26%). LCMS (Method F): R T = 1.34 min, m / z = 299 [M-butene + H] +

[0366] Step 3: tert-Butyl (R)-3,3-dimethyl-4-((2-oxo-4-chloropyridin-1(2H)-yl)methyl)piperidine-1-carboxylate: tert-Butyl 3,3-dimethyl-4-((2-oxo-4-chloropyridin-1(2H)-yl)methyl)piperidine-1-carboxylate (1.62 g) was resolved into single stereoisomers by chiral HPLC using a Chiralcel OD-H (4.6 mm x 250 mm, 5 μm) column with isocratic solvent conditions: 80:10:10 hexane / IPA / MeOH. The first-eluting material (R T = 7.79 min) was tert-butyl (S)-3,3-dimethyl-4-((2-oxo-4-phenylpyridin-1(2H)-yl)methyl)piperidine-1-carboxylate (674 mg). LCMS (Method F): R T = 1.30 min, m / z = 299 [M-butene + H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.72 (d, 1H), 6.51 (s, 1H), 6.35 (d, 1H), 4.12 (d, 1H), 3.90 (m, 1H), 3.50 (m, 2H), 2.60 (m, 1H), 2.42 (m, 1H), 1.68 (m, 1H), 1.38 (s, 9H), 1.27 (m, 1H), 0.97 (s, 3H), 0.81 (s, 3H). [α] D 25 = +85.58 (c 0.4 in MeOH); and the second eluting material (R T = 9.44 min) gave the title compound (692 mg). LCMS (Method F): T = 1.30 min, m / z = 299 [M-butene + H] + . 1H NMR (400 MHz, DMSO-d6): δ 7.72 (d, 1H), 6.51 (s, 1H), 6.35 (d, 1H), 4.12 (d, 1H), 3.90 (m, 1H), 3.50 (m, 2H), 2.60 (m, 1H), 2.42 (m, 1H), 1.68 (m, 1H), 1.38 (s, 9H), 1.27 (m, 1H), 0.97 (s, 3H), 0.81 (s, 3H). [α] D 25 = - 78.98 (c 0.4 in MeOH) was provided.

[0367] Intermediate 15: tert-butyl ((3S,5S)-5-phenylpyrrolidin-3-yl)carbamate [ka] Step 1: rac-tert-butyl ((3S,5S)-5-phenyl-1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)carbamate: To a solution of rac-tert-butyl ((3S,5S)-5-phenylpyrrolidin-3-yl)carbamate (2.52 g, 9.6 mmol) in DCM (100 mL) was added triethylamine (2.92 g, 28.8 mmol) at 0° C., followed by the dropwise addition of trifluoroacetic anhydride (2.22 g, 10.6 mmol). After 24 h, the reaction mixture was washed several times with water, the combined organic phases were dried (NaSO), and the solvent was removed under reduced pressure to give the title compound (3.41 g, 99%). LCMS (Method F): T = 1.23 min, m / z = 303 [M-butene + H] +

[0368] Step 2: tert-Butyl ((3S,5S)-5-phenyl-1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)carbamate: rac-tert-butyl ((3S,5S)-5-phenyl-1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)carbamate (2.80 g) was resolved into single stereoisomers by chiral HPLC using a Chiralpak IB (20 mm x 250 mm, 5 μm) column with isocratic solvent conditions: 90:5:5 hexane / IPA / MeOH (flow rate: 12 mL / min). The first-eluting material (R T =12.12 min) was obtained from the title compound (1.49 g). [α] D 25 = - 9.76 (c 0.25 in CHCl3); and the second-eluting material (R T = 25.22 min) is tert-butyl ((3R,5R)-5-phenyl-1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)carbamate (0.95 g). [α] D 25 = +10.44 (c 0.25 in CHCl3).

[0369] Step 3: tert-Butyl ((3S,5S)-5-phenylpyrrolidin-3-yl)carbamate: To a stirring solution of tert-butyl ((3S,5S)-5-phenyl-1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)carbamate (1.49 g, 4.16 mmol) in DCM (70 mL) was added 2 M KCO 3(水性) Solution (20 mL) was added at rt. After 24 h, stirring was stopped and the resulting biphasic mixture was separated and further extracted with DCM (x3). The combined organic phases were dried (Na2SO4) and the solvent removed under reduced pressure to give the title compound (0.89 g, 82%). LCMS (Method F): R T = 0.76 min, m / z = 263 [M+H] + . 1H NMR (500 MHz, CDCl3): δ 7.38 - 7.24 (m, 5H), 4.83 (m, 1H), 4.24 (m, 1H), 4.14 (m, 1H), 3.24 (m, 1H), 3.01 (m, 1H), 2.64 (m, 1H), 2.22 (m, 1H), 1.51 (m, 1H), 1.44 (s, 9H). [α] D 21 = - 19.76 (c 0.25 in MeOH)

[0370] Intermediate 16: (2S,4R)-N-(2,2-difluoroethyl)-2-phenylpiperidin-4-amine hydrochloride [ka] Step 1: tert-Butyl (2S)-4-((2,2-difluoroethyl)amino)-2-phenylpiperidine-1-carboxylate: To a stirring solution of tert-butyl (S)-4-oxo-2-phenylpiperidine-1-carboxylate (1.0 g, 3.63 mmol) in MeOH (10 mL) was added 2,2-difluoroethan-1-amine (0.512 mL, 7.26 mmol) and catalytic AcOH (1-2 drops) at rt. After 1 h, NaBHCN (0.69 g, 10.9 mmol) was added. After 16 h, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were dried (NaSO) and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (0-10% MeOH in DCM) to give the title compound (1.0 g, 80%).

[0371] Step 2: tert-butyl (2S,4R)-4-((2,2-difluoroethyl)amino)-2-phenylpiperidine-1-carboxylate: tert-Butyl (2S)-4-((2,2-difluoroethyl)amino)-2-phenylpiperidine-1-carboxylate (1.1 g) was resolved into single stereoisomers by chiral HPLC using a Chiralcel OD-H (20 mm x 250 mm, 5 μm) column with isocratic solvent conditions: 95:5 hexane / EtOH + 0.1% triethylamine to give tert-butyl (2S,4S)-4-((2,2-difluoroethyl)amino)-2-phenylpiperidine-1-carboxylate (first eluting isomer: 300 mg, de = 100%). LCMS (Method D): R T = 3.48 min, m / z = 341 [M+H] + and the title compound (second eluting isomer: 600 mg, de=100%). LCMS (Method D): T = 3.48 min, m / z = 341 [M+H] + [Note: stereoisomers were 1 confirmed by comparison with H NMR nOe data]

[0372] Step 3: (2S,4R)-N-(2,2-difluoroethyl)-2-phenylpiperidin-4-amine hydrochloride: To a solution of tert-butyl (2S,4R)-4-((2,2-difluoroethyl)amino)-2-phenylpiperidine-1-carboxylate (600 mg, 1.77 mmol) in DCM (5 mL) was added 4 M HCl solution in 1,4-dioxane (5 mL) and the reaction mixture was stirred at rt. After 16 h, the solvent was removed under reduced pressure and the remaining residue was triturated with pentane to give the title compound (412 mg, 97%). LCMS (Method C): R T = 1.82 min, m / z = 241 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 10.01 (br s, 2H), 9.82 (br s, 1H), 9.46 (br s, 1H), 7.64 - 7.58 (m, 2H), 7.48 - 7.42 (m, 3H), 6.47 (t, 1H), 4.37 (t, 1H), 3.56 - 3.40 (m, 4H), 3.16 - 3.12 (m, 1H), 2.49 (m, 1H, duplicate DMSO signal), 2.34 - 2.31 (m, 1H), 2.18 - 2.10 (m, 2H)

[0373] Intermediate 17: Methyl (2S,4R)-2-phenylpiperidine-4-carboxylate [ka] Step 1: 2-Phenylisonicotinic acid: The title compound was prepared by general method 5 using methyl 2-bromoisonicotinate (10.8 g, 50 mmol) [commercially available], phenylboronic acid (9.15 g, 75 mmol), potassium phosphate tripotassium (31.8 g, 150 mmol), and Pd(dppf)Cl.DCM (1.22 g, 1.5 mmol) in 3:1 1,4-dioxane / water (400 mL) to give the title compound (9.5 g, 95%). LCMS (Method F): R T = 1.01 min, m / z = 200 [M+H] +

[0374] Step 2: Methyl 2-phenylisonicotinate: To a solution of 2-phenylisonicotinic acid (9.5 g, 47.7 mmol) in methanol (285 mL) was added thionyl chloride (17.0 g, 143 mmol) dropwise at 0° C. The reaction mixture was refluxed and after 16 h the solvent was removed under reduced pressure and the resulting material was dried under reduced pressure at 60° C. to give the title compound (10.0 g, 98%). 1 H NMR (500 MHz, CDCl3): δ 9.11 (d, 1H), 8.62 (s, 1H), 8.26 (m, 3H), 7.65 (m, 3H), 4.08 (s, 3H)

[0375] Step 3: rac-methyl (2S,4R)-2-phenylpiperidine-4-carboxylate: To a solution of methyl 2-phenylisonicotinate (10.0 g, 47.0 mmol) [commercially available] in methanol (400 mL) was added 10% (w / w) Pd / C (2.0 g), and the reaction mixture was placed in an autoclave and hydrogenated (100 atm) at 60 °C. After 48 h, the reaction mixture was filtered and evaporated to dryness to give the title compound (10 g, 97%). LCMS (Method F): T = 0.60 min, m / z = 220 [M+H] + .1H NMR (500 MHz, DMSO-d6): δ 9.55 (s, 1H), 7.58 (d, 2H), 7.41 (m, 3H), 4.29 (t, 1H), 3.61 (s, 3H), 3.37 (m, 1H), 3.09 (t, 1H), 2.88 (t, 1H), 2.11 (d, 1H), 2.00 (m, 3H)

[0376] Step 4: Methyl (2S,4R)-2-phenylpiperidine-4-carboxylate: rac-Methyl (2S,4R)-2-phenylpiperidine-4-carboxylate (0.80 g) was resolved into single stereoisomers by chiral HPLC using a Chiralpak OD-H (4.6 mm x 250 mm, 5 μm) column with isocratic solvent conditions: 80:10:10 hexane / IPA / MeOH (flow rate: 0.6 mL / min). The first-eluting material (R T = 10.93 min) is methyl (2R,4S)-2-phenylpiperidine-4-carboxylate (281 mg). [α] D 25 = - 37.86 (c 0.4 in MeOH); and the second eluting material (R T =12.87 min) was obtained from the title compound (275 mg). [α] D 25 = +36.57 (c 0.4 in MeOH).

[0377] Intermediate 18: tert-butyl (R)-10-((6-oxo-4-(o-tolyl)pyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate [ka] Step 1: tert-butyl 10-((6-oxo-4-(o-tolyl)pyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate: To a solution of 6-(o-tolyl)pyrimidin-4(3H)-one (7.00 g, 37.6 mmol) [commercially available] in 1,4-dioxane (400 mL) was added tert-butyl 10-(iodomethyl)-7-azaspiro[4.5]decane-7-carboxylate (20.0 g, 52.6 mmol) and 2 equivalents of cesium carbonate (24.5 g, 75.2 mmol). The reaction mixture was heated and stirred at 100° C. After 40 h, the reaction mixture was filtered and the solvent was removed under reduced pressure. The remaining residue was purified by flash chromatography to give the title compound (6.40 g, 39%). LCMS (Method F): R T = 1.68 min, m / z = 382 [M-butene + H] +

[0378] Step 2: tert-Butyl (R)-10-((6-oxo-4-(o-tolyl)pyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate: tert-Butyl 10-((6-oxo-4-(o-tolyl)pyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (7.30 g) was resolved into single stereoisomers by chiral HPLC using a Chiralpak IA-III (20 mm x 250 mm, 5 μm) column with isocratic solvent conditions: 90:5:5 hexane / IPA / MeOH (flow rate: 15 mL / min). The first-eluting material (R T = 17.25 min) is tert-butyl (S)-10-((6-oxo-4-(o-tolyl)pyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (2.33 g). [α] D 25 = +77.60 (c 0.1 in CHCl3); and the second-eluting material (R T =23.76 min) was obtained from the title compound (2.26 g). [α] D 25= - 77.50 (c 0.1 in CHCl3) was provided.

[0379] Intermediate 19: N-((2S,4R)-2-(2,5-difluorophenyl)piperidin-4-yl)-2,2,2-trifluoro-N-methylacetamide hydrochloride [ka] Step 1: Methyl (S)-3-amino-3-(2,5-difluorophenyl)propanoate hydrochloride: To a stirring solution of (S)-3-amino-3-(2,5-difluorophenyl)propanoic acid (10 g, 49.7 mmol) in MeOH (80 mL) was added SOCl (4.33 mL, 59.7 mmol) dropwise at 0 °C and then stirred at rt. After 16 h, the reaction mixture was concentrated under reduced pressure, and the residue was triturated with pentane and dried under reduced pressure to give the title compound (10 g, 83%). LCMS (Method C): R T = 2.72 min, m / z = 216 [M+H] +

[0380] Step 2: Methyl (S)-3-((1-(2,5-difluorophenyl)-3-(methylperoxy)-3λ 2 (S)-3-amino-3-(2,5-difluorophenyl)propanoate: Methyl (S)-3-amino-3-(2,5-difluorophenyl)propanoate hydrochloride (15.6 g, 62.0 mmol) was dissolved in MeOH (130 mL) and stirred at rt. TEA (12.7 mL, 93.0 mmol) was added, followed by the dropwise addition of a solution of methyl acrylate (8.43 mL, 93.0 mmol) in MeOH (5 mL). After 16 h, the reaction mixture was concentrated under reduced pressure, diluted with water (500 mL), and extracted with EtOAc (2 x 750 mL). The organic layer was dried (NaSO) and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (0-10% EtOAc in hexanes) to give the title compound (12 g, 64%). LCMS (Method C): R T = 1.72 min, m / z = 302 [M+H] +

[0381] Step 3: Methyl (S)-3-((tert-butoxycarbonyl)(3-methoxy-3-oxopropyl)amino)-3-(2,5-difluorophenyl)propanoate: Methyl (S)-3-((1-(2,5-difluorophenyl)-3-(methylperoxy)-3λ 2 (-propyl)amino)propanoate (10.6 g, 35.2 mmol) was suspended in MeOH (90 mL) and BocO (14.6 mL, 63.3 mmol) was added dropwise with stirring at rt. After 16 h, the reaction mixture was diluted with water (750 mL) and extracted with ethyl acetate (2 x 1 L). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The remaining residue was purified by flash chromatography (0-20% EtOAc in hexanes) to give the title compound (12 g, 84%). LCMS (Method C): R T = 3.67 min, m / z = 402 [M+H] +

[0382] Step 4: 1-tert-butyl 3-methyl(6S)-4-hydroxy-6-(2,5-difluorophenyl)-1,2,5,6-tetrahydropyridine-1,3-dicarboxylate and 1-(tert-butyl)3-methyl(2S)-2-(2,5-difluorophenyl)-4-hydroxy-3,6-dihydropyridine-1,3(2H)-dicarboxylate: Methyl (S)-3-((tert-butoxycarbonyl)(3-methoxy-3-oxopropyl)amino)-3-(2,5-difluorophenyl)propanoate (15.0 g, 37.4 mmol) was dissolved in toluene (300 mL) and cooled to −78° C. A 1 M solution of LiHMDS in THF (9.38 mL, 56.0 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at -78 °C for 4 h, after which the reaction was quenched with water (500 mL) and extracted using ethyl acetate (2 x 750 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (0-20% EtOAc in hexanes) to give the isomeric mixture of the title compound (8.0 g, 57%). LCMS (Method D): R T= 3.49, 3.77 min (2 peaks), m / z = 370 [M+H] +

[0383] Step 5: tert-Butyl (S)-2-(2,5-difluorophenyl)-4-oxopiperidine-1-carboxylate: A mixture of 1-tert-butyl 3-methyl(6S)-4-hydroxy-6-(2,5-difluorophenyl)-1,2,5,6-tetrahydropyridine-1,3-dicarboxylate and 1-(tert-butyl)3-methyl(2S)-2-(2,5-difluorophenyl)-4-hydroxy-3,6-dihydropyridine-1,3(2H)-dicarboxylate (12.5 g, 33.8 mmol) was dissolved in DMSO (62 mL). NaCl (5.93 g, 102 mmol) and water (4 mL) were added to the reaction mixture and heated to 145 °C. After 4 h, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (0-20% EtOAc in hexanes) to give the title compound (8 g, 75%). LCMS (Method C): T = 3.49 min, m / z = 312 [M+H] +

[0384] Step 6: tert-Butyl (2S)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carboxylate: To a stirring solution of tert-butyl (S)-2-(2,5-difluorophenyl)-4-oxopiperidine-1-carboxylate (2.1 g, 6.43 mmol) in MeOH (20 mL) was added 33% (w / w) MeNH in EtOH (7.94 mL, 64.34 mmol) and catalytic AcOH (1-2 drops) at rt. After 2 h, NaBHCN (1.21 g, 19.3 mmol) was added. After an additional 16 h, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 × 250 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (0-10% MeOH in DCM) to give the title compound (1.8 g, 81%). LCMS (Method C): T = 2.9 min, m / z = 327 [M+H] +

[0385] Step 7: tert-Butyl (2S)-2-(2,5-difluorophenyl)-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate: To a stirring solution of tert-butyl (2S)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carboxylate (2.5 g, 7.66 mmol) in DCM (25 mL) was added pyridine (6.17 mL, 76.6 mmol) followed by trifluoroacetic anhydride (1.59 mL, 11.5 mmol) at 0° C. The reaction mixture was stirred at rt for 16 h, then diluted with water (100 mL) and extracted using ethyl acetate (2×100 mL). The combined organic phase was dried (Na2SO4) and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (0-30% EtOAc in hexanes) to give the title compound (2.8 g, 86%).

[0386] Step 8: tert-Butyl (2S,4R)-2-(2,5-difluorophenyl)-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate: tert-Butyl (2S)-2-(2,5-difluorophenyl)-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate (2.8 g) was resolved into single stereoisomers by chiral HPLC using a Chiralpak IC (20 mm x 250 mm, 5 μm) column under isocratic solvent conditions: 95:2.5 / 2.5 hexane / DCM / EtOH (flow rate: 18 mL / min) to give the title compound (first eluting isomer: 1.3 g). LCMS (Method C): T = 3.68 min, m / z = 423 [M+H] + . 1 H NMR at 100 ℃(400 MHz, DMSO-d6): δ 7.17 - 7.08 (m, 3H), 4.97 - 4.93 (m, 1H), 4.39 (br s, 1H), 3.92 - 3.88 (m, 1H), 3.66 - 3.59 (m, 1H), 2.96 (d, 3H), 2.24 - 2.12 (m, 1H), 2.06 - 2.02 (m, 1H), 1.98 - 1.95 (m, 1H), 1.83 (br s, 1H), 1.24 (s, 9H); and tert-butyl (2S,4S)-2-(2,5-difluorophenyl)-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate (second eluting isomer: 0.65 g). LCMS (Method C): R T = 3.77 min, m / z = 423 [M+H] + . 1H NMR at 100 °C (400 MHz, DMSO-d6): δ 7.26 - 7.15 (m, 2H), 7.04 (br s, 1H), 5.62 - 5.61 (d, 1H), 4.32 (br s, 1H), 4.21 - 4.17 (d, 1H), 3.91 - 3.88 (br s, 1H), 3.18 - 3.07 (br s, 1H), 2.67 (s, 3H), 2.32 - 2.24 (m, 1H), 2.13 - 2.10 (m, 1H), 1.98 - 1.17 (m, 2H), 1.38 (s, 9H). [Note: Stereoisomers are the same as those of closely related analogs.] 1 This was confirmed by comparison with H NMR data.

[0387] Step 9: N-((2S,4R)-2-(2,5-difluorophenyl)piperidin-4-yl)-2,2,2-trifluoro-N-methylacetamide hydrochloride: tert-Butyl (2S,4R)-2-(2,5-difluorophenyl)-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate (1.6 g, 3.78 mmol) was suspended in DCM (5 mL) and a 4 M solution of HCl in 1,4-dioxane (20 mL) was added. The reaction mixture was stirred at rt for 3 h. The solvent was evaporated under reduced pressure and the residue was triturated with DCM and pentane followed by lyophilization to give the title compound (1.2 g, 99%). LCMS (Method C): R T = 2.52 min, m / z = 323 [M+H] + . 1 H NMR at 100 ℃(400 MHz, DMSO-d6): δ 9.76 (br s, 2H), 7.93 (s, 1H), 7.32 - 7.29 (m, 2H), 4.75 - 4.72 (m, 2H), 3.50 - 3.32 (m, 2H), 3.02 (s, 3H, overlapping water signal), 2.49 (m, 2H, overlapping DMSO signal), 2.00 - 1.86 (m, 2H)

[0388] Intermediate 20: tert-butyl cyclopropyl ((2S,4R)-2-phenylpiperidin-4-yl)carbamate [ka] Step 1: 1-((2S)-4-(cyclopropylamino)-2-phenylpiperidin-1-yl)-2,2,2-trifluoroethan-1-one: To a stirring solution of (S)-2-phenyl-1-(2,2,2-trifluoroacetyl)piperidin-4-one (2.0 g, 7.26 mmol) in MeOH (10 mL) was added cyclopropylamine (1.5 mL, 21.8 mmol) and catalytic AcOH (1-2 drops) at rt. After 1 h, NaBHCN (1.4 g, 21.8 mmol) was added. After an additional 16 h, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 × 150 mL). The combined organic phases were dried (NaSO) and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (0-30% EtOAc in hexanes) to give the title compound (1.6 g, 70%). LCMS (Method C): R T = 3.33 minutes, m / z = 313 [M+H] +

[0389] Step 2: tert-Butyl cyclopropyl((2S)-2-phenyl-1-(2,2,2-trifluoroacetyl)piperidin-4-yl)carbamate: To a stirring solution of 1-((2S)-4-(cyclopropylamino)-2-phenylpiperidin-1-yl)-2,2,2-trifluoroethan-1-one (1.6 g, 5.13 mmol) in DCM (10 mL) was added TEA (2.15 mL, 15.4 mmol) and BocO (1.4 mL, 6.15 mmol) at rt. After 16 h, the reaction mixture was cooled to 100° C. with saturated NaHCO 3 3(水性) The reaction mixture was quenched with 10 mL of hexanes (100 mL), diluted with water (100 mL), and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (30% EtOAc in hexanes) to give the title compound (1.5 g, 70%). LCMS (Method D): T = 3.94 min, m / z = 413 [M+H] +

[0390] Step 3: tert-Butyl cyclopropyl ((2S)-2-phenylpiperidin-4-yl)carbamate: To a stirring solution of tert-butyl cyclopropyl ((2S)-2-phenyl-1-(2,2,2-trifluoroacetyl)piperidin-4-yl)carbamate (1.5 g, 4.80 mmol) in 4:1 MeOH / water (20 mL) was added K2CO3 (0.997 g, 7.21 mmol) at rt. After 16 h, the reaction mixture was diluted with water (50 mL) and extracted using ethyl acetate (2 x 100 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (0-30% EtOAc in hexanes) to give the title compound (900 mg, 59%).

[0391] Step 4: tert-Butyl cyclopropyl ((2S,4R)-2-phenylpiperidin-4-yl)carbamate: tert-Butyl cyclopropyl ((2S)-2-phenylpiperidin-4-yl)carbamate (900 mg) was separated into single stereoisomers by chiral HPLC using a Chiralpak IC (20 mm x 250 mm, 5 μm) column under isocratic solvent conditions: 95:5 hexane / EtOH (flow rate: 21 mL / min) to give the title compound (first eluting isomer: 400 mg). LCMS (Method D): R T = 3.06 min, m / z = 317 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.37 - 7.24 (m, 5H), 3.92 - 3.89 (m, 1H), 3.68 - 3.65 (m, 1H), 3.27 - 3.24 (m, 1H), 2.83 (t, 1H), 2.31 (br s, 1H), 2.02 - 1.91 (m, 3H), 1.79 - 1.76 (m, 1H), 2.45 (s, 9H), 0.74 - 0.67 (m, 4H); and tert-butyl cyclopropyl((2S,4S)-2-phenylpiperidin-4-yl)carbamate (second-eluting isomer: 300 mg). LCMS (Method D): R T= 3.19 min, m / z = 317 [M+H] + . 1 H NMR (400 MHz, CDCl): δ 7.49 (d, 2H), 7.34 (t, 2H), 7.21 (t, 1H), 4.35 (s, 1H), 3.87–3.85 (m, 1H), 2.91 (d, 1H), 2.77–2.71 (m, 1H), 2.36–2.32 (m, 3H), 2.12–2.02 (m, 1H), 1.44 (s, 9H), 0.77–0.68 (m, 4H).

[0392] Intermediate 21: N-((2S,4R)-2-(2,4-difluorophenyl)piperidin-4-yl)-2,2,2-trifluoroacetamide hydrochloride [ka] Step 1: tert-butyl (S)-2-(2,4-difluorophenyl)-4-oxopiperidine-1-carboxylate: The title compound was prepared analogously to tert-butyl (S)-4-oxo-2-phenylpiperidine-1-carboxylate (Intermediate 1, steps 1-5), except using (S)-3-amino-3-(2,4-difluorophenyl)propanoic acid instead of (S)-3-amino-3-phenylpropanoic acid as the starting material. LCMS (Method C): R T = 3.45 minutes, m / z = 312 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.37 - 7.31 (m, 1H), 7.26 - 7.20 (m, 1H), 7.08 (t, 1H), 5.42 (br s, 1H), 4.07 - 3.99 (m, 1H), 3.69 - 3.62 (m, 1H), 2.92 - 2.86 (m, 1H), 2.75 - 2.70 (m, 1H), 2.48 - 2.40 (m, 2H), 1.26 (s, 9H)

[0393] Step 2: N-((2S,4R)-2-(2,4-difluorophenyl)piperidin-4-yl)-2,2,2-trifluoroacetamide hydrochloride: The title compound was prepared analogously to 2,2,2-trifluoro-N-((2S,4R)-2-(3-fluorophenyl)piperidin-4-yl)acetamide hydrochloride (Intermediate 11, steps 1-4), except that tert-butyl (S)-2-(2,4-difluorophenyl)-4-oxopiperidine-1-carboxylate was used instead of tert-butyl (S)-2-(3-fluorophenyl)-4-oxopiperidine-1-carboxylate; separation of the diastereoisomers was possible using flash chromatography. LCMS (Method E): R T = 1.81 min, m / z = 309 [M+H] + . 1 H NMR at 100 ℃(400 MHz, DMSO-d6): δ 9.48 (br s, 1H), 9.36 (br s, 1H), 7.93 - 7.87 (m, 1H), 7.27 - 7.17 (m, 2H), 4.66 - 4.62 (m, 1H), 4.20 - 4.17 (m, 1H), 3.43 (d, 1H), 3.30 - 3.14 (m, 1H), 2.19 - 2.05 (m, 4H)

[0394] Intermediate 22: N-((2S,4R)-2-(2,5-difluorophenyl)piperidin-4-yl)-2,2,2-trifluoroacetamide hydrochloride [ka] The title compound was prepared analogously to 2,2,2-trifluoro-N-((2S,4R)-2-(3-fluorophenyl)piperidin-4-yl)acetamide hydrochloride (Intermediate 11, steps 1-4), except that tert-butyl (S)-2-(2,5-difluorophenyl)-4-oxopiperidine-1-carboxylate was used instead of tert-butyl (S)-2-(3-fluorophenyl)-4-oxopiperidine-1-carboxylate and the following conditions for separation of diastereoisomers were used: isocratic solvent conditions: 95:5 hexane / EtOH (flow rate: 21 mL / min) with a Chiralcel OJ-H (20 mm x 250 mm, 5 μm) column. LCMS (Method C): T = 2.97 min, m / z = 309 [M+H] + . 1 H NMR at 100 ℃(400 MHz, DMSO-d6): δ 10.03 (br s, 1H), 9.70 (d, 1H), 7.80 (s, 1H), 7.41 - 7.34 (m, 2H), 4.71 (br s, 1H), 4.20 (br s, 1H), 3.43 (d, 1H), 2.07 - 1.96 (m, 4H)

[0395] Intermediate 23: tert-butyl (2S,4S)-4-azido-5-fluoro-2-phenylpiperidine-1-carboxylate [ka] To a stirred solution of tert-butyl (2S,4S,5S)-4-azido-5-hydroxy-2-phenylpiperidine-1-carboxylate (1.02 g, 3.3 mmol) [according to Angew. Chem. Int. Ed., 2011, 50, 2734-2737, but using commercially available (S)-1-phenylbut-3-en-1-amine in subsequent steps to use tert-butyl (S)-2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate as the desired single stereoisomer] in DCM (30 mL) at −10° C. was added sodium bicarbonate (1.62 g, 19.2 mmol), followed by the dropwise addition of 4-morpholinylsulfur trifluoride (0.72 g, 5.2 mmol). After 24 h, the reaction mixture was washed with water (x3), the organic phase was dried (Na2SO4), the solvent was removed under reduced pressure and the remaining residue was purified by preparative HPLC to give the title compound (0.361 g, 35%). LCMS (Method F): T = 2.86 min, m / z = 265 [M-butene + H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.38 - 7.19 (m, 5H), 5.31 - 5.24 (m, 1H), 4.85 - 4.29 (m, 2H), 4.10 - 3.87 (m, 1H), 3.49 - 3.32 (m, 1H), 2.66 - 2.38 (m, 1H), 2.24 - 2.05 (m, 1H), 1.43 - 1.38 (d, 9H)

[0396] Intermediate 24: tert-butyl methyl ((3S,5S)-5-phenylpyrrolidin-3-yl)carbamate [ka] Step 1: rac-tert-butyl ((3S,5S)-1-(4-methoxybenzyl)-5-phenylpyrrolidin-3-yl)carbamate: To a stirring solution of rac-tert-butyl ((3S,5S)-5-phenylpyrrolidin-3-yl)carbamate (2.0 g, 7.63 mmol, 1 equiv.) [commercially available] in DCE (60 mL) was added p-methoxybenzaldehyde (1.14 g, 8.40 mmol), acetic acid (0.458 g, 7.63 mmol), and sodium triacetoxyborohydride (4.85 g, 22.9 mmol) at rt. After 48 h, the reaction mixture was diluted with DCM (200 mL) and saturated KCO 3(水性) The solution was washed with water and brine. The volatiles were removed under reduced pressure and the remaining residue was purified by flash chromatography (0-100%, EtOAc in hexanes) to give the title compound (2.65 g, 91%). LCMS (Method F): T = 1.01 min, m / z = 383 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 1.28 - 1.37 (m, 10H), 1.52 - 1.66 (m, 1H), 2.39 (t, J = 9.9 Hz, 2H), 2.72 (d, J = 9.9 Hz, 1H), 2.92 (d, J = 13.2 Hz, 1H), 3.54 (d, J = 13.2 Hz, 1H), 3.71 (s, 3H), 3.89 - 3.99 (m, 1H), 6.84 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 6.8 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.25 (t, J = 6.8 Hz, 1H), 7.35 (t, J = 7.4 Hz, 2H), 7.49 (d, J = 7.4 Hz, 2H)

[0397] Step 2: tert-Butyl ((3S,5S)-1-(4-methoxybenzyl)-5-phenylpyrrolidin-3-yl)carbamate: rac-tert-butyl ((3S,5S)-1-(4-methoxybenzyl)-5-phenylpyrrolidin-3-yl)carbamate (2.5 g) was resolved into single stereoisomers by chiral FC using a Chiralcel OJ-H (20 mm x 250 mm, 5 μm) column with isocratic solvent conditions: 90:10 CO2 / MeOH (flow rate: 50 mL / min). The first-eluting material (R T =11.63 min) provided the title compound (1.20 g). A sample (40 mg) of this material was subjected to N-PMB deprotection under the conditions of General Method 9, and the optical rotation of the product was measured and confirmed to be consistent with tert-butyl ((3S,5S)-5-phenylpyrrolidin-3-yl)carbamate (Intermediate 15). The first eluting material was therefore confirmed as the title compound and used in the next step. The second eluting material (R T =13.79 min) provided tert-butyl ((3R,5R)-1-(4-methoxybenzyl)-5-phenylpyrrolidin-3-yl)carbamate (501 mg).

[0398] Step 3: (3S,5S)-1-(4-Methoxybenzyl)-N-methyl-5-phenylpyrrolidin-3-amine: To a stirring solution of tert-butyl ((3S,5S)-1-(4-methoxybenzyl)-5-phenylpyrrolidin-3-yl)carbamate (0.76 g, 1.99 mmol) in THF (20 mL) was added LiAlH (0.2 g, 5.26 mmol) in portions, and the resulting mixture was refluxed. After 5 h, the reaction mixture was cooled to 0 °C and diluted with 35% NaOH. (水性) The resulting suspension was filtered, washed with hot THF, and the solvent removed under reduced pressure to give the title compound (0.47 g, 79%) as a yellow oil. LCMS (Method F): T = 0.86 min, m / z = 297 [M+H] +

[0399] Step 4: tert-Butyl ((3S,5S)-1-(4-methoxybenzyl)-5-phenylpyrrolidin-3-yl)(methyl)carbamate: To a stirring solution of (3S,5S)-1-(4-methoxybenzyl)-N-methyl-5-phenylpyrrolidin-3-amine (0.51 g, 1.72 mmol) in methanol (15 mL) was added BocO (0.417 g, 1.91 mmol) at rt. After 16 h, the volatiles were removed under reduced pressure to give the crude title compound (0.68 g, quantitative) as a yellow oil, which was used in the next step without purification. LCMS (Method F): R T = 1.11 min, m / z = 397 [M+H] +

[0400] Step 5: tert-Butyl methyl ((3S,5S)-5-phenylpyrrolidin-3-yl)carbamate: Stirring tert-butyl ((3S,5S)-1-(4-methoxybenzyl)-5-phenylpyrrolidin-3-yl)(methyl)carbamate (0.68 g, 1.72 mmol) was dissolved in acetonitrile (13.5 mL) and a solution of ceric ammonium nitrate (3.76 g, 6.67 mmol) in water (13.5 mL) was added dropwise at 0° C. After 18 h, the volatiles were removed under reduced pressure and the remaining mixture was basified using excess K2CO3 and extracted with MTBE. The solvent was removed under reduced pressure and the crude material (0.37 g, 52% purity) was purified by preparative HPLC to give the title compound (11.5 mg, 2.4%). LCMS (Method F): R T = 0.98 min, m / z = 277 [M+H] +

[0401] Intermediate 25: tert-butyl (R)-10-((4-(2-methoxyphenyl)-6-oxopyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate [ka] The title compound was prepared in a similar manner to tert-butyl (R)-10-((6-oxo-4-(o-tolyl)pyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (Intermediate 18), except that 6-(2-methoxyphenyl)pyrimidin-4(3H)-one (commercially available) was used instead of 6-(o-tolyl)pyrimidin-4(3H)-one in the first step. tert-Butyl 10-((4-(2-methoxyphenyl)-6-oxopyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (3.75 g) was resolved into single stereoisomers by chiral HPLC using a Chiralpak IG (20 mm x 250 mm, 5 μm) column with isocratic solvent conditions: 60:20:20 hexane / IPA / MeOH (flow rate: 12 mL / min). The first-eluting material (R T = 26.2 min) is tert-butyl (S)-10-((4-(2-methoxyphenyl)-6-oxopyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (1.77 g). [α] D 25 = +7.28 (c 0.1 in CHCl3); and the second eluting material (R T =32.0 min) was the title compound (1.82 g). LCMS (Method F): T = 1.63 min, m / z = 454 [M+H] + [α] D 25 = - 9.76 (c 0.1 in CHCl3).

[0402] Intermediate 26: N-((2S,4R)-2-(2,4-difluorophenyl)piperidin-4-yl)-2,2,2-trifluoro-N-methylacetamide hydrochloride [ka] The title compound was prepared in a manner similar to that of N-((2S,4R)-2-(2,5-difluorophenyl)piperidin-4-yl)-2,2,2-trifluoro-N-methylacetamide hydrochloride (Intermediate 19), except using (S)-3-amino-3-(2,4-difluorophenyl)propanoic acid instead of (S)-3-amino-3-(2,5-difluorophenyl)propanoic acid as the starting material. tert-Butyl (2S)-2-(2,4-difluorophenyl)-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate (2.0 g) was separated by reverse-phase preparative HPLC (C18 column) to give tert-butyl (2S,4R)-2-(2,4-difluorophenyl)-4-(2,2,2-trifluoro-N-methylacetamido)piperidine-1-carboxylate (first-eluting isomer: 1.0 g, de=100%). [Note: cis and trans stereochemistry was assigned by nOe data]. LCMS (Method C): R T = 3.73 min, m / z = 423 [M+H] + This material was deprotected to give the title compound (610 mg). LCMS (Method E): T = 1.81 min, m / z = 323 [M+H] + . 1 H NMR at 100℃(400MHz, DMSO-d6): δ 9.72 (br s, 2H), 8.11 - 8.05 (m, 1H), 7.26 - 7.16 (m, 2H), 4.72 - 4.69 (m, 2H), 3.48 - 3.40 (m, 2H), 3.02 (s, 3H, overlapping water signal), 2.49 (m, 1H, overlapping DMSO signal), 2.00 - 1.85 (m, 2H)

[0403] Intermediate 27: tert-butyl (R)-10-((6-fluoro-4-oxoquinazolin-3(4H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate [ka] The title compound was prepared in a similar manner to tert-butyl (R)-10-((6-oxo-4-(o-tolyl)pyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (Intermediate 18), except that 6-fluoroquinazolin-4(3H)-one (commercially available) was used instead of 6-(o-tolyl)pyrimidin-4(3H)-one in the first step. tert-Butyl 10-((6-fluoro-4-oxoquinazolin-3(4H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (2.46 g) was resolved into single stereoisomers by chiral HPLC using a Chiral ART Cellulose-SC (20 mm x 250 mm, 5 μm) column in isocratic solvent conditions: 80:10:10 hexane / IPA / MeOH (flow rate: 13 mL / min). The first-eluting material (R T = 12.9 min) is tert-butyl (S)-10-((6-fluoro-4-oxoquinazolin-3(4H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (1.11 g). [α] D 25 = +77.96 (c 0.25 in CHCl3); and the second-eluting material (R T =16.9 min) was the title compound (1.09 g). LCMS (Method F): T = 4.13 min, m / z = 360 [M-butene + H] + . 1 H NMR (DMSO-d6) δ: 8.37 (s, 1H), 7.83 - 7.71 (m, 3H), 4.18 (m, 1H), 3.80 (m, 1H), 3.67 (m, 1H), 3.52 (m, 1H), 2.82 - 2.55 (m, 2H), 1.79 (m, 2H), 1.65 (m, 2H), 1.53 (m, 2H), 1.38 (s, 9H), 1.40 - 1.14 (m, 5H). [α] D 25 = - 77.36 (c 0.25 in CHCl3) was provided.

[0404] Intermediate 28: tert-butyl ((2S,4R)-2-(2-fluorophenyl)piperidin-4-yl)(methyl)carbamate [ka] Step 1: rac-(2S,4R)-1-((benzyloxy)carbonyl)-2-(2-fluorophenyl)piperidine-4-carboxylic acid: To a stirring 2:1 1,4-dioxane / water solution of rac-methyl (2S,4R)-2-(2-fluorophenyl)piperidine-4-carboxylate [prepared according to the method of Intermediate 17, Steps 1-3, except that (2-fluorophenyl)boronic acid (21 g, 150 mmol) was used instead of phenylboronic acid to react with methyl 2-bromoisonicotinate (21.6 g, 100 mmol)] was added sodium hydroxide (4 equiv.) at 0 °C, followed by the dropwise addition of a 1,4-dioxane solution of CbzCl (1.5 equiv.). After 16 h, the solvent was removed under reduced pressure, the remaining residue was diluted with water, and the aqueous mixture was washed with MTBE (×2) and then saturated NaHSO. 4(水性) The mixture was acidified to about pH 2 with hexanes solution and extracted with EtOAc. The solvent was removed under reduced pressure to give the title compound (12.1 g, 33.9 mmol), which was used in the next step without further purification.

[0405] Step 2: rac-Benzyl (2S,4R)-4-((tert-butoxycarbonyl)(methyl)amino)-2-(2-fluorophenyl)piperidine-1-carboxylate: rac-(2S,4R)-1-((benzyloxy)carbonyl)-2-(2-fluorophenyl)piperidine-4-carboxylic acid (12.1 g, 33.9 mmol) was dissolved in toluene (242 mL) and treated with diphenylphosphoryl azide (11.2 g, 40.7 mmol) and triethylamine (4.11 g, 40.7 mmol). The reaction mixture was heated at 75° C. for 4 hours, followed by the addition of trimethylsilylethanol (12.0 g, 102 mmol). The reaction mixture was heated to 100° C. After 24 h, the solvent was removed under reduced pressure and the crude material was purified by flash chromatography to give rac-benzyl (2S,4R)-2-(2-fluorophenyl)-4-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)piperidine-1-carboxylate (9.80 g, 61%), which was dissolved in THF (98 mL) and a 1 M solution of TBAF in THF (35.3 mL, 35.3 mmol, 1.7 equiv) was added and the reaction mixture was heated to 50° C. After 18 h, the solvent was removed under reduced pressure and the remaining residue was dissolved in EtOAc (320 mL) and washed successively with water, brine and dried (NaSO). The solvent was removed under reduced pressure to give crude rac-benzyl (2S,4R)-4-amino-2-(2-fluorophenyl)piperidine-1-carboxylate (6.13 g, 90%), which was subsequently treated with a solution of BocO (5.0 g, 23.4 mmol, 1.25 equiv) in methanol (125 mL) and stirred at rt. After 16 h, the solvent was removed under reduced pressure, and the remaining residue was purified by flash chromatography to give rac-benzyl (2S,4R)-4-((tert-butoxycarbonyl)amino)-2-(2-fluorophenyl)piperidine-1-carboxylate (2.2 g, 28%), which was subsequently dissolved in DMF (22 mL) and cooled to 0 °C. Sodium hydride (60% in mineral oil, 0.26 g, 5.92 mmol, 1.15 equiv.) and iodomethane (0.95 g, 6.68 mmol, 1.3 equiv.) were added and the reaction mixture was stirred at rt. After 18 h, the reaction mixture was diluted with water (85 mL) and saturated NH4Cl (水性)The resulting mixture was extracted with MTBE (x3), the combined organic phases were concentrated, and the remaining residue was purified by flash chromatography to give the title compound (1.9 g, 84%). LCMS (Method F): T = 1.49 min, m / z = 443 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.28 (m, 5H), 7.16 (m, 2H), 7.05 (m, 2H), 4.97 (m, 3H), 4.00 (m, 1H), 3.57 (m, 1H), 3.31 (m, 1H), 2.66 (s, 3H), 2.04 (m, 2H), 1.85 (m, 1H), 1.67 (m, 1H), 1.37 (s, 9H)

[0406] Step 3: Benzyl (2S,4R)-4-((tert-butoxycarbonyl)(methyl)amino)-2-(2-fluorophenyl)piperidine-1-carboxylate: rac-Benzyl (2S,4R)-4-((tert-butoxycarbonyl)(methyl)amino)-2-(2-fluorophenyl)piperidine-1-carboxylate (1.9 g) was resolved into single stereoisomers by chiral HPLC using a Chiralpak AD-H (20 mm x 250 mm, 5 μm) column with isocratic solvent conditions: 80:10:10 hexane / IPA / MeOH (flow rate: 12 mL / min). The first-eluting material (R T = 12.32 min) was obtained from benzyl (2R,4S)-4-((tert-butoxycarbonyl)(methyl)amino)-2-(2-fluorophenyl)piperidine-1-carboxylate (0.85 g) and the second-eluting material (R T =15.35 min) to provide the title compound (0.84 g).

[0407] Step 4: tert-butyl ((2S,4R)-2-(2-fluorophenyl)piperidin-4-yl)(methyl)carbamate: To a stirred solution of benzyl (2S,4R)-4-((tert-butoxycarbonyl)(methyl)amino)-2-(2-fluorophenyl)piperidine-1-carboxylate (0.84 g, 1.90 mmol) in methanol (30 mL) was added 10% (w / w) Pd / C (80 mg, 40 mol%) and the reaction mixture was hydrogenated at rt (ca. 1 atm, balloon). After 24 h, the reaction mixture was filtered and evaporated to dryness to give the title compound (0.43 g, 74%). LCMS (Method F): T = 1.00 min, m / z = 309 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.50 (m, 1H), 7.20 (m, 1H), 7.10 (m, 1H), 6.98 (m, 1H), 4.05 (m, 2H), 3.25 (m, 1H), 2.85 (m, 1H), 2.72 (s, 3H), 2.08 (m, 1H), 1.85 (dd, 1H), 1.70 (m, 3H), 1.45 (s, 9H). [α] D 25 = +44.6 (c 0.35 in MeOH)

[0408] Intermediate 29: tert-butyl ((2S,4R)-2-(4-fluorophenyl)piperidin-4-yl)(methyl)carbamate [ka] The title compound was prepared according to the procedure for preparing rac-benzyl (2S,4R)-4-((tert-butoxycarbonyl)(methyl)amino)-2-(4-fluorophenyl)piperidine-1-carboxylate (2.2 g) following the procedure for Intermediate 28, except using (4-fluorophenyl)boronic acid instead of (2-fluorophenyl)boronic acid, which was resolved into single stereoisomers by chiral HPLC using a Chiralpak AD-H (20 mm x 250 mm, 5 μm) column under isocratic solvent conditions: 80:10:10 hexane / IPA / MeOH (flow rate: 12 mL / min). The first-eluting material (R T= 15.85 min) was benzyl (2S,4R)-4-((tert-butoxycarbonyl)(methyl)amino)-2-(4-fluorophenyl)piperidine-1-carboxylate (996 mg) and the second eluting material (R T = 33.58 min) provided benzyl (2R,4S)-4-((tert-butoxycarbonyl)(methyl)amino)-2-(4-fluorophenyl)piperidine-1-carboxylate (1.08 g). Benzyl (2S,4R)-4-((tert-butoxycarbonyl)(methyl)amino)-2-(4-fluorophenyl)piperidine-1-carboxylate (996 mg) was used in the final step (Cbz deprotection) to give the title compound (0.58 g, 84%). LCMS (Method F): T = 0.82 min, m / z = 309 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.66 (m, 2H), 7.24 (t, 2H), 4.30 (m, 2H), 3.31 (m, 1H), 3.05 (m, 1H), 2.67 (s, 3H), 2.12 (q, 2H), 1.70 (dd, 2H), 1.38 (s, 9H). [α] D 25 = +46.5 (c 0.25 in MeOH)

[0409] Intermediate 30: N-((2S,4R)-2-(3,5-difluorophenyl)piperidin-4-yl)-2,2,2-trifluoroacetamide hydrochloride [ka] tert-Butyl (S)-2-(3,5-difluorophenyl)-4-oxopiperidine-1-carboxylate was prepared in a similar manner to tert-butyl (S)-2-(2,5-difluorophenyl)-4-oxopiperidine-1-carboxylate (Intermediate 19, steps 1-5), except that (S)-3-amino-3-(3,5-difluorophenyl)propanoic acid was used instead of (S)-3-amino-3-(2,5-difluorophenyl)propanoic acid. The title compound was prepared analogously to 2,2,2-trifluoro-N-((2S,4R)-2-(3-fluorophenyl)piperidin-4-yl)acetamide hydrochloride (Intermediate 11, steps 1-4), except that tert-butyl (S)-2-(3,5-difluorophenyl)-4-oxopiperidine-1-carboxylate was used instead of tert-butyl (S)-2-(3-fluorophenyl)-4-oxopiperidine-1-carboxylate, and the diastereoisomers in analogy to step 3 were resolved using reverse-phase preparative HPLC (C18 column) instead of chiral preparative HPLC methods. LCMS (Method C): T = 1.82 min, m / z = 309 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 9.71 (br s, 1H), 9.38 (d, 1H), 7.41 (t, 2H), 7.21 - 7.16 (m, 1H), 4.48 - 4.45 (m, 1H), 4.16 - 4.08 (m, 1H), 3.58 - 3.42 (m, 1H), 3.19 - 3.12 (m, 1H), 2.19 - 2.01 (m, 4H)

[0410] Intermediate 31: tert-butyl (R)-10-((4-(2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate [ka] The title compound was prepared in a similar manner to tert-butyl (R)-10-((6-oxo-4-(o-tolyl)pyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (Intermediate 18), except that in the first step, 6-(2-fluorophenyl)pyrimidin-4(3H)-one (commercially available) was used instead of 6-(o-tolyl)pyrimidin-4(3H)-one. tert-Butyl 10-((4-(2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (0.53 g) was resolved into single stereoisomers by chiral HPLC using a Chiralpak IB (20 mm x 250 mm, 5 μm) column with isocratic solvent conditions: 75:15:15 hexane / IPA / MeOH (flow rate: 15 mL / min). The first-eluting material (R T = 6.70 min) is tert-butyl (S)-10-((4-(2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (0.18 g). [α] D 25 = +70.15 (c 0.25 in CHCl3); and the second-eluting material (R T =7.98 min) was the title compound (0.17 g). LCMS (Method F): T = 3.66 min, m / z = 386 [M-butene + H] + [α] D 25 = - 60.15 (c 0.25 in CHCl3)

[0411] Intermediate 32: 4-((2S,4R)-2-Penylpiperidin-4-yl)morpholine hydrochloride [ka] Step 1: tert-Butyl (2S)-4-morpholino-2-phenylpiperidine-1-carboxylate: To a stirring solution of tert-butyl (S)-4-oxo-2-phenylpiperidine-1-carboxylate (800 mg, 2.9 mmol) in MeOH (10 mL) was added morpholine (0.75 mL, 8.72 mmol) and a catalytic amount of AcOH (1-2 drops) at rt. After 1 h, NaBHCN (550 mg, 8.72 mmol) was added. After an additional 16 h, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were dried (NaSO) and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (0-10% MeOH in DCM) to give the title compound (800 mg, 80%). LCMS (Method D): R T = 3.29 minutes, m / z = 347 [M+H] +

[0412] Step 2: tert-Butyl (2S,4R)-4-morpholino-2-phenylpiperidine-1-carboxylate: tert-Butyl (2S)-4-morpholino-2-phenylpiperidine-1-carboxylate (900 mg) was separated into single stereoisomers by chiral HPLC using a Chiralpak IC (20 mm x 250 mm, 5 μm) column under isocratic solvent conditions: 85 / 15 hexane / EtOH + 0.1% isopropylamine (flow rate: 18 mL / min) to give tert-butyl (2S,4S)-4-morpholino-2-phenylpiperidine-1-carboxylate (first eluting isomer: 90 mg). LCMS (Method D): R T = 3.33 minutes, m / z = 347 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 7.37 (t, 2H), 2.23 (t, 1H), 7.17 (t, 2H), 5.41 (br s, 1H), 4.05 - 4.01 (m, 1H), 3.54 (t, 4H), 2.71 (br s, 1H), 2.45 - 2.38 (m, 4H), 2.18 - 2.15 (m, 1H), 1.73 - 1.65 (m, 2H), 1.39 (s, 9H), 1.32 - 1.28 (m, 1H); and the title compound (second-eluting isomer: 450 mg). LCMS (Method D): R T = 3.29 minutes, m / z = 347 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.29 (t, 2H), 7.22 - 7.17 (m, 3H), 4.73 - 4.69 (m, 1H), 3.91 - 3.86 (m, 1H), 3.46 - 3.34 (m, 4H), 2.35 - 2.32 (m, 4H), 2.05 - 1.99 (m, 1H), 1.85 - 1.71 (m, 2H), 1.66 - 1.63 (m, 1H), 1.21 (s, 9H). [Note: cis and trans stereochemistry assigned from nOe data]

[0413] Step 3: 4-((2S,4R)-2-phenylpiperidin-4-yl)morpholine hydrochloride: To a stirring solution of tert-butyl (2S,4R)-4-morpholino-2-phenylpiperidine-1-carboxylate (450 mg, 1.30 mmol) in DCM (3 mL) was added 4M HCl in 1,4-dioxane (10 mL) at rt for 16 h. The solvent was evaporated under reduced pressure and the residue was triturated with pentane to give the title compound (320 mg, 87%). LCMS (Method E): R T = 0.14 min, m / z = 247 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 11.64 (br s, 1H), 9.75 (d, 1H), 9.51 (d, 1H), 7.62 (d, 2H), 7.50 - 7.42 (m, 3H), 4.35 (t, 1H), 3.99 - 3.84 (m, 4H), 3.61 (br s, 1H), 3.52 (br s, 2H), 3.12 - 3.10 (m, 3H), 2.53 (br s, 1H, fused with DMSO), 2.38 - 2.16 (m, 3H)

[0414] Intermediate 33: (2S,4R)-N-(3-methyloxetan-3-yl)-2-phenylpiperidin-4-amine 2,2,2-trifluoroacetate [ka] Step 1: tert-Butyl (2S)-4-((3-methyloxetan-3-yl)amino)-2-phenylpiperidine-1-carboxylate: To a stirring solution of tert-butyl-4-oxo-2-phenylpiperidine-1-carboxylate (600 mg, 2.18 mmol) in MeOH (20 mL) was added 3-methyloxetan-3-amine (569 mg, 6.54 mmol) followed by a catalytic amount of AcOH (1-2 drops) at rt. After 3 h, NaBHCN (412 mg, 6.54 mmol) was added portionwise at 0 °C and the temperature was allowed to rise to rt. After 16 h, the reaction mixture was diluted with DCM (500 mL), washed with water (100 mL), brine (150 mL), and dried (NaSO). The solvent was evaporated under reduced pressure to give the crude product, which was purified by flash chromatography (0-50% EtOAc in hexanes) to give the title compound (520 mg, 69%). LCMS (Method C): T = 3.17 min, m / z = 347 [M+H] +

[0415] Step 2: tert-butyl (2S,4R)-4-((3-methyloxetan-3-yl)amino)-2-phenylpiperidine-1-carboxylate: tert-Butyl (2S)-4-((3-methyloxetan-3-yl)amino)-2-phenylpiperidine-1-carboxylate (600 mg) was separated into single stereoisomers by chiral HPLC using a Lux i-Amylose-3 (21.2 mm x 250 mm, 5 μm) column in isocratic solvent conditions: 80:20 CO2 / MeOH + 0.3% isopropylamine (flow rate: 30 g / min) to give the title compound (second-eluting isomer: 140 mg). LCMS (Method D): R T = 3.17 min, m / z = 347 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.33 - 7.12 (m, 5H), 4.99 (t, 1H, J = 6.8Hz), 4.25 - 4.28 (m, 4H), 4.02 - 3.98 (m, 1H), 3.40 - 3.33 (m, 1H), 3.08 (bs, 1H), 3.09 - 1.88 (m, 4H), 1.46 (s, 3H), 1.30 (s, 9H); and tert-butyl (2S,4S)-4-((3-methyloxetan-3-yl)amino)-2-phenylpiperidine-1-carboxylate (first-eluting isomer: 140 mg). LCMS (Method D): R T = 3.17 min, m / z = 347 [M+H] + . 1 H NMR (400 MHz, CDCl): δ 7.36 - 7.29 (m, 2H), 7.19 - 7.17 (m, 3H), 5.54 - 5.51 (m, 1H), 4.49 - 4.44 (m, 2H), 4.40 - 4.34 (m, 2H), 4.17 - 4.11 (m, 1H), 2.80 - 2.74 (m, 2H), 2.43 - 2.39 (m, 1H), 1.62 (m, 2H), 1.45 (s, 12H), 1.32 - 1.29 (m, 1H). [Note: Stereochemistry confirmed by nOe data]

[0416] Step 3: (2S,4R)-N-(3-methyloxetan-3-yl)-2-phenylpiperidin-4-amine 2,2,2-trifluoroacetate: To a stirring solution of tert-butyl (2S,4R)-4-((3-methyloxetan-3-yl)amino)-2-phenylpiperidine-1-carboxylate (130 mg, 0.36 mmol) in DCM (10 mL) was added TFA (0.5 mL) dropwise at 0° C. The temperature was raised to rt and after 5 h the reaction mixture was concentrated under reduced pressure at low temperature (i.e., ≦35° C.) followed by trituration with pentane / diethyl ether to give the title compound (135 mg, 76%). LCMS (Method G): R T = 1.38 min, m / z = 247 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 9.94 (br s, 1H), 9.32 (br s, 1H), 9.22 (br s, 1H), 7.51 - 7.42 (m, 5H), 4.77 - 4.73 (m, 2H), 4.41 - 4.38 (m, 3H), 3.52 - 3.45 (m, 2H), 3.22 - 3.16 (m, 1H), 2.10 - 2.02 (m, 3H), 1.95 - 1.89 (m, 1H), 1.71 (s, 3H)

[0417] Intermediate 34: (2S,4R)-N-(3-(fluoromethyl)oxetan-3-yl)-2-phenylpiperidin-4-amine [ka] The title compound was prepared according to the procedure for (2S,4R)-N-(3-methyloxetan-3-yl)-2-phenylpiperidin-4-amine TFA salt (Intermediate 33), except that instead of 3-methyloxetan-3-amine, 3-(fluoromethyl)oxetan-3-amine (801 mg, 7.64 mmol) was reacted with tert-butyl-4-oxo-2-phenylpiperidine-1-carboxylate (700 mg, 2.55 mmol) and the following conditions for separation of diastereoisomers were used: isocratic solvent conditions: 70:30 hexane / EtOH (flow rate: 21 mL / min) on a Chiralpak IG (21 mm x 250 mm, 5 μm) column. LCMS (Method I):T = 0.33 min, m / z = 265 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 9.06 (br s, 1H), 8.90 (br s, 1H), 7.51 - 7.42 (m, 5H), 5.00 - 4.88 (m, 2H), 4.59 (br s, 2H), 4.49 - 4.44 (m, 2H), 4.36 - 4.34 (m, 1H), 3.47 - 3.40 (m, 2H), 3.15 - 3.12 (m, 1H), 2.05 - 1.96 (m, 2H), 1.86 - 1.73 (m, 2H)

[0418] Intermediate 35: N-((2S,4R)-2-(3,5-difluorophenyl)piperidin-4-yl)-2,2,2-trifluoro-N-methylacetamide hydrochloride [ka] The title compound was prepared analogously to N-((2S,4R)-2-(2,5-difluorophenyl)piperidin-4-yl)-2,2,2-trifluoro-N-methylacetamide hydrochloride (Intermediate 19), except that (S)-3-amino-3-(3,5-difluorophenyl)propanoic acid was used instead of (S)-3-amino-3-(2,5-difluorophenyl)propanoic acid, and the diastereoisomers in analogy step 8 were resolved using reverse-phase preparative HPLC (C18 column) instead of chiral preparative HPLC methods. LCMS (Method H): R T = 1.86 min, m / z = 323 [M+H] + . 1 H NMR at 100 ℃(400 MHz, DMSO-d6): δ 9.74 (br s, 1H), 7.48 (t, 2H), 7.21 - 7.17 (m, 1H), 4.62 - 4.52 (m, 2H), 3.50 - 3.46 (m, 1H), 3.25 - 3.18 (m, 2H), 3.05 (s, 3H), 2.5 - 2.49 (m, 2H), 2.03 (d, 1H), 1.87 (d, 1H)

[0419] Intermediate 36: tert-butyl 10-((4-(2-methoxyphenyl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate [ka] Step 1: tert-Butyl 10-((6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridin-1(2H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate: To a stirring solution of tert-butyl 10-(aminomethyl)-7-azaspiro[4.5]decane-7-carboxylate (5.00 g, 18.6 mmol) [commercially available] in methanol (150 mL) was added methyl acrylate (1.60 g, 18.6 mmol) dropwise at 0° C. After 24 h, the volatiles were removed under reduced pressure and the remaining residue was dissolved in DCM (150 mL) and triethylamine (2.07 g, 20.5 mmol) was added, followed by the dropwise addition of methyl 3-chloro-3-oxopropanoate (2.80 g, 20.5 mmol) at 0° C. After 24 hours, the reaction mixture was washed with water (×3) and dried (NaSO). The solvent was removed under reduced pressure, and the crude product was dissolved in a solution of sodium methoxide (4.02 g, 74.4 mmol) in methanol (100 mL) and heated to reflux. After 48 hours, the reaction mixture was concentrated and carefully acidified using acetic acid. The crude product was extracted using DCM (×3), the solvent was removed under reduced pressure, and the remaining residue was dissolved in 1:1 acetonitrile / water and heated to reflux. After a further 48 hours, the reaction mixture was evaporated to dryness, and the crude product was dissolved in dry THF (150 mL), followed by the addition of potassium tert-butoxide (2.03 g, 18 mmol) and N-phenyl-bis(trifluoromethanesulfonimide) (6.47 g, 18 mmol). After 24 hours, the solvent was evaporated, and the remaining residue was dissolved in DCM and saturated NH4Cl. (水性) The organic phase was dried (Na2SO4), the solvent was removed under reduced pressure and the crude product was purified by flash chromatography to give the title compound (3.40 g, 45% over 5 steps). LCMS (Method F): T = 1.40 min, m / z = 396 [M-Boc+H] + 1H NMR (400 MHz, CDCl3): δ 7.97 (s, 1H), 6.26 (s, 1H), 4.25 (m, 1H), 4.00 (m, 1H), 3.66 (m, 1H), 3.48 (m, 1H), 2.78 - 2.60 (m, 2H), 1.78 (m, 3H), 1.75 - 1.53 (m, 6H), 1.38 (s, 9H), 1.40 - 1.22 (m, 5H)

[0420] Step 2: tert-butyl 10-((4-(2-methoxyphenyl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate: A 3:1 reaction of tert-butyl 10-((6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridin-1(2H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (0.50 g, 1.00 mmol) under argon atmosphere with stirring. To a solution of 1,4-dioxane / water (40 mL) was added (2-methoxyphenyl)boronic acid (0.141 g, 1.10 mmol), Pd(dppf)Cl.DCM (0.041 g, 0.05 mmol), and sodium carbonate (0.32 g, 3.00 mmol). The reaction mixture was heated to reflux. After 24 h, the organic phase was separated and evaporated to dryness. The crude product was purified by reverse-phase preparative HPLC (C18 column) to give the title compound (0.22 g, 57%). LCMS (Method F): R T = 1.60 min, m / z = 355 [M-Boc+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.28 (t, 1H), 7.22 (d, 1H), 6.99 (t, 1H), 6.87 (d, 1H), 6.12 (s, 1H), 4.00 - 3.48 (m, 5H), 3.78 (s, 3H), 2.90 - 2.61 (m, 4H), 1.75 - 1.48 (m, 8H), 1.42 (s, 9H), 1.38 - 1.21 (m, 3H)

[0421] Intermediate 37: tert-butyl (R)-10-((2-oxopyrimidin-1(2H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate [ka] The title compound was prepared in a similar manner to tert-butyl (R)-10-((6-oxo-4-(o-tolyl)pyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (Intermediate 18), except that in the first step, pyrimidin-2(1H)-one (1.25 g, 13 mmol) [commercially available] was used instead of 6-(o-tolyl)pyrimidin-4(3H)-one. tert-Butyl 10-((2-oxopyrimidin-1(2H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (0.41 g) was resolved into single stereoisomers by chiral HPLC using a Chiralpak IA-3 (20 mm x 250 mm, 5 μm) column under isocratic solvent conditions: 80:10:10 hexane / IPA / MeOH (flow rate: 15 mL / min). The first-eluting material (R T = 18.84 min) is tert-butyl (S)-10-((2-oxopyrimidin-1(2H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (143 mg). [α] D 25 = +142.56 (c 0.25 in CHCl3); and the second eluting material (R T =25.30 min) gave the title compound (147 mg). LCMS (Method F): T = 1.26 min, m / z = 292 [M-butene + H] + . 1 H NMR (400 MHz, CDCl3): δ 8.60 (m, 1H), 7.61 (m, 1H), 6.32 (m, 1H), 4.25 (m, 1H), 4.12 (m, 1H), 4.02 (m, 1H), 3.72 (m, 1H), 2.82 - 2.65 (m, 2H), 2.01 (m, 2H), 1.65 (m, 3H), 1.53 (m, 2H), 1.38 (s, 9H), 1.40 - 1.15 (m, 5H). [α] D 25= - 130.68 (c 0.25 in CHCl3).

[0422] Intermediate 38: tert-butyl (R)-10-((6-oxopyridazin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate [ka] The title compound was prepared in a similar manner to tert-butyl (R)-10-((6-oxo-4-(o-tolyl)pyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (Intermediate 18), except that in the first step, pyridazin-3(2H)-one (2.5 g, 26 mmol) [commercially available] was used instead of 6-(o-tolyl)pyrimidin-4(3H)-one. tert-Butyl 10-((6-oxopyridazin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (2.60 g) was resolved into single stereoisomers by chiral HPLC using a Chiralpak IC (4.6 mm x 250 mm, 5 μm) column with isocratic solvent conditions: 70:15:15 hexane / IPA / MeOH (flow rate: 0.6 mL / min). The first-eluting material (R T =20.28 min) was the title compound (1.22 g). LCMS (Method F): T = 1.46 min, m / z = 248 [M-Boc+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.75 (d, 1H), 7.16 (m, 1H), 6.92 (d, 1H), 4.07 (m, 1H), 3.79 (m, 1H), 3.67 (m, 1H), 3.52 (m, 1H), 2.82 - 2.65 (m, 2H), 2.01 (m, 1H), 1.65 (m, 3H), 1.53 (m, 2H), 1.38 (s, 9H), 1.40 - 1.15 (m, 5H). [α] D 25 = - 26.2 (c 0.25 in CHCl3); and the second eluting material (R T= 24.17 min) is tert-butyl (S)-10-((6-oxopyridazin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (1.32 g). [α] D 25 = +26.5 (c 0.25 in CHCl3).

[0423] Intermediate 39: tert-butyl (R)-10-((4-(difluoromethyl)-6-oxopyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate [ka] The title compound was prepared in a similar manner to tert-butyl (R)-10-((6-oxo-4-(o-tolyl)pyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (Intermediate 18), except that in the first step, 6-(difluoromethyl)pyrimidin-4(3H)-one (0.38 g, 2.6 mmol) [commercially available] was used instead of 6-(o-tolyl)pyrimidin-4(3H)-one. tert-Butyl 10-((4-(difluoromethyl)-6-oxopyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (0.9 g) was resolved into single stereoisomers by chiral HPLC using a Chiralpak IC (20 mm x 250 mm, 5 μm) column with isocratic solvent conditions: 70:15:15 hexane / IPA / MeOH (flow rate: 12 mL / min). The first-eluting material (R T = 15.03 min) is tert-butyl (S)-10-((4-(difluoromethyl)-6-oxopyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (0.396 g). [α] D 25 = +65.16 (c 0.25 in CHCl3); and the second-eluting material (R T =25.28 min) was the title compound (0.379 g). LCMS (Method F): T = 4.04 min, m / z = 342 [M-butene + H] + . 1H NMR (400 MHz, DMSO-d6) δ: 8.59 (s, 1H), 6.75 (m, 1H), 6.67 (s, 1H), 4.07 (m, 1H), 3.79 (m, 1H), 3.67 (m, 1H), 3.52 (m, 1H), 2.82 - 2.55 (m, 2H), 1.80 (m, 2H), 1.65 (m, 2H), 1.53 (m, 2H), 1.38 (s, 9H), 1.40 - 1.15 (m, 5H). [α] D 25 = - 67.52 (c 0.25 in CHCl3)

[0424] Intermediate 40: N-((2S,4R)-2-(2,3-difluorophenyl)piperidin-4-yl)-2,2,2-trifluoro-N-methylacetamide hydrochloride [ka] The title compound was prepared analogously to N-((2S,4R)-2-(2,5-difluorophenyl)piperidin-4-yl)-2,2,2-trifluoro-N-methylacetamide hydrochloride (Intermediate 19), except that (S)-3-amino-3-(2,3-difluorophenyl)propanoic acid was used instead of (S)-3-amino-3-(2,5-difluorophenyl)propanoic acid, and the diastereoisomers in analogy to step 8 were resolved using flash chromatography instead of chiral preparative HPLC methods. LCMS (Method H): R T = 1.82 min, m / z = 323 [M+H] + . 1 H NMR at 100 ℃(400 MHz, DMSO-d6): δ 9.63 (br s, 1H), 7.77(s, 1H), 7.49 - 7.42 (m, 1H), 7.33 - 7.32 (m, 1H), 4.80 - 4.77 (d, 1H), 4.69 (m, 1H), 3.50 - 3.47 (m, 1H), 3.39 - 3.33 (t, 1H), 3.03 (s, 3H), 2.50 - 2.46 (m, 2H), 2.03 - 2.00 (d, 1H), 1.90 - 1.87 (d, 1H),1.27 (1H), 0.87 (m, 1H)

[0425] Intermediate 41: N-((2S,4R)-2-(3,4-difluorophenyl)piperidin-4-yl)-2,2,2-trifluoro-N-methylacetamide hydrochloride [ka] The title compound was prepared analogously to N-((2S,4R)-2-(2,5-difluorophenyl)piperidin-4-yl)-2,2,2-trifluoro-N-methylacetamide hydrochloride (Intermediate 19), except that (S)-3-amino-3-(3,4-difluorophenyl)propanoic acid was used instead of (S)-3-amino-3-(2,5-difluorophenyl)propanoic acid, and the diastereoisomers in analogy to step 8 were resolved on a Chiralpak IG (21 mm x 250 mm, 5 μm) column under the following conditions: isocratic solvent conditions: 90:10 hexane / EtOH + 0.1% isopropylamine (flow rate: 21 mL / min). LCMS (Method C): T = 1.75 min, m / z = 323 [M+H] + . 1 H NMR at 100 ℃(400 MHz, DMSO-d6): δ 9.49 (br s, 2H), 7.83 - 7.78 (m, 1H), 7.50 - 7.43 (m, 2H), 4.60 (br s, 1H), 4.50 (d, 1H), 3.47 (d, 1H), 3.21 (t, 1H), 3.01 (d, 3H), 2.44 (m, 2H), 2.0 (d, 1H), 1.88 (d, 1H)

[0426] Intermediate 42: N-(2,2-difluoroethyl)-N-((2S,4R)-2-(2,5-difluorophenyl)piperidin-4-yl)-2,2,2-trifluoroacetamide hydrochloride [ka] Step 1: tert-Butyl (2S)-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate: To a stirring solution of tert-butyl (S)-2-(2,5-difluorophenyl)-4-oxopiperidine-1-carboxylate (1.0 g, 3.21 mmol) in MeOH (10 mL) was added 2,2-difluoroethan-1-amine (0.312 mL, 3.85 mmol) at rt. After 8 h, NaBHCN (0.606 g, 9.63 mmol) was added. After an additional 16 h, the reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (0-10% MeOH in DCM) to give the title compound (700 mg, 58%). LCMS (Method C): R T = 3.55 min, m / z = 377 [M+H] +

[0427] Step 2: tert-Butyl (2S)-4-(N-(2,2-difluoroethyl)-2,2,2-trifluoroacetamido)-2-(2,5-difluorophenyl)piperidine-1-carboxylate: tert-Butyl (2S)-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carboxylate (3.0 g, 7.97 mmol) was suspended in DCM (25 mL) and stirred at 0 °C. Triethylamine (1.65 mL, 12.0 mmol) and trifluoroacetic anhydride (1.66 mL, 12.0 mmol) were added and the temperature was raised to rt. After 16 h, the reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (0 to 30% EtOAc in hexanes) to give the title compound (2.4 g, 64%). LCMS (Method C): R T = 3.78 min, m / z = 473 [M+H] +

[0428] Step 3: tert-Butyl (2S,4R)-4-(N-(2,2-difluoroethyl)-2,2,2-trifluoroacetamido)-2-(2,5-difluorophenyl)piperidine-1-carboxylate: tert-Butyl (2S)-4-(N-(2,2-difluoroethyl)-2,2,2-trifluoroacetamido)-2-(2,5-difluorophenyl)piperidine-1-carboxylate was resolved into single stereoisomers by reverse-phase preparative HPLC (C18 column) to give the title compound (first eluting isomer: 840 mg). LCMS (Method C): R T = 3.75 min, m / z = 473 [M+H] + . 1 H NMR at 100 ℃(400 MHz, DMSO-d6): δ 7.21 - 7.06 (m, 3H), 6.31 (t, 1H), 4.96 - 4.92 (m, 1H), 4.04 (br s, 1H), 3.93 - 3.85 (m, 3H), 3.69 - 3.61 (m, 1H), 2.31 - 2.32 (m, 1H), 2.16 - 2.13 (m, 1H), 2.11 - 2.08 (m, 1H), 1.21 (s, 9H); and tert-butyl (2S,4S)-4-(N-(2,2-difluoroethyl)-2,2,2-trifluoroacetamido)-2-(2,5-difluorophenyl)piperidine-1-carboxylate (second eluting isomer: 300 mg). LCMS (Method C): R T = 3.81 min, m / z = 473 [M+H] + . 1H NMR at 100 ℃(400 MHz, DMSO-d6): δ 7.26 - 7.12 (m, 2H), 6.97 (br s, 1H), 6.33 - 6.03 (dt, 1H), 5.61 (d, 1H), 4.17 (d, 1H), 3.92 - 3.81 (m, 3H), 3.68 (br s, 1H), 3.25 - 3.21 (m, 2H), 2.41 - 2.33 (m, 1H), 2.20 - 2.16 (m, 1H), 2.02 - 1.92 (m, 1H), 1.84 - 1.81 (m, 1H), 1.37 (s, 9H) were obtained. [Note: Stereoisomers are closely related analogs. 1 This was confirmed by comparison with H NMR data.

[0429] Step 4: N-(2,2-Difluoroethyl)-N-((2S,4R)-2-(2,5-difluorophenyl)piperidin-4-yl)-2,2,2-trifluoroacetamide hydrochloride: To a stirring suspension of tert-butyl (2S,4R)-4-(N-(2,2-difluoroethyl)-2,2,2-trifluoroacetamido)-2-(2,5-difluorophenyl)piperidine-1-carboxylate (1.8 g, 3.81 mmol) in DCM (25 mL) was added 4 M HCl in 1,4-dioxane (10 mL) at rt. After 3 h, the solvent was removed under reduced pressure and the remaining residue was triturated with DCM and pentane followed by lyophilization to give the title compound (1.4 g, 90%). LCMS (Method H): R T = 2.77 min, m / z = 373 [M+H] + . 1 H NMR at 100 ℃(400 MHz, DMSO-d6): δ 9.4 (br s, 2H), 7.77 (s, 1H), 7.31 (s, 2H), 6.28 (t, 1H), 4.74 (br s, 1H), 4.35 (br s, 1H), 3.92 - 3.86 (m, 2H), 3.51 - 3.48 (m, 1H), 3.37 - 3.28 (m, 1H), 2.01 (dd, 2H)

[0430] Intermediate 43: N-(3,3-difluorocyclobutyl)-2,2,2-trifluoro-N-((2S,4R)-2-phenylpiperidin-4-yl)acetamide hydrochloride [ka] Step 1: tert-Butyl (2S)-4-((3,3-difluorocyclobutyl)amino)-2-phenylpiperidine-1-carboxylate: To a stirring solution of tert-butyl (S)-4-oxo-2-phenylpiperidine-1-carboxylate (1.0 g, 3.63 mmol) in MeOH (10 mL) was added 3,3-difluorocyclobutan-1-amine (1.16 mL, 10.9 mmol) at rt. After 8 h, NaBHCN (1.14 g, 18.2 mmol) was added. After an additional 16 h, the reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (0-10% MeOH in DCM) to give the title compound (970 mg, 73%). LCMS (Method C): R T = 3.67 min, m / z = 367 [M+H] +

[0431] Step 2: tert-Butyl (2S)-4-(N-(3,3-difluorocyclobutyl)-2,2,2-trifluoroacetamido)-2-phenylpiperidine-1-carboxylate: tert-Butyl (2S)-4-((3,3-difluorocyclobutyl)amino)-2-phenylpiperidine-1-carboxylate (1.0 g, 2.73 mmol) was suspended in DCM (25 mL) and stirred at 0 °C. Triethylamine (2.30 g, 16.4 mmol) and trifluoroacetic anhydride (0.80 mL, 5.74 mmol) were added and the temperature was raised to rt. After 16 h, the reaction mixture was diluted with water (100 mL) and extracted using DCM (2 x 100 mL). The organic layer was washed with saturated NaHCO 3(水性) The solution (50 mL) was washed with water (50 mL) and dried (NaSO). The solvent was evaporated under reduced pressure to give the crude product, which was purified by flash chromatography (0-30% EtOAc in hexanes) to give the title compound (980 mg, 77%). LCMS (Method C): T = 3.96 min, m / z = 463 [M+H] +

[0432] Step 3: tert-Butyl (2S,4R)-4-(N-(3,3-difluorocyclobutyl)-2,2,2-trifluoroacetamido)-2-phenylpiperidine-1-carboxylate: tert-Butyl (2S)-4-(N-(3,3-difluorocyclobutyl)-2,2,2-trifluoroacetamido)-2-phenylpiperidine-1-carboxylate was resolved into single stereoisomers by reverse-phase preparative HPLC (C18 column) to give the title compound (first eluting isomer: 200 mg). LCMS (Method C): R T = 3.94 min, m / z = 463 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.35 - 7.22 (m, 5H), 4.78 - 4.73 (m, 1H), 4.20 - 4.17 (m, 1H), 3.96 - 3.91 (m, 2H), 3.59 - 3.51 (m, 1H), 3.47 - 3.37 (m, 1H), 3.29 - 2.93 (m, 1H), 2.91 - 2.68 (m, 2H), 2.35 - 2.28 (m, 1H), 2.25 - 2.08 (m, 1H), 1.96 - 1.93 (m, 1H), 1.83 - 1.71 (m, 1H), 1.23 - 1.14 (m, 9H); and tert-butyl (2S,4S)-4-(N-(3,3-difluorocyclobutyl)-2,2,2-trifluoroacetamido)-2-phenylpiperidine-1-carboxylate (second eluting isomer: 65 mg). LCMS (Method C): R T = 3.99 min, m / z = 463 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 7.4 - 7.37 (m, 2H), 7.29 - 7.27 (m, 1H), 7.25 - 7.18 (m, 2H), 5.56 - 5.47 (m, 1H), 4.23 - 4.05 (m, 2H), 3.64 - 3.55 (m, 1H), 3.51 - 3.43 (m, 2H), 2.75 - 2.65 (m, 3H), 2.44 - 2.32 (m, 2H), 1.93 - 1.91 (m, 1H), 1.56 - 1.54 (m, 1H), 1.38 (s, 9H). [Note: Stereochemistry confirmed by nOe data]

[0433] Step 3: N-(3,3-Difluorocyclobutyl)-2,2,2-trifluoro-N-((2S,4R)-2-phenylpiperidin-4-yl)acetamide hydrochloride: To a stirring solution of tert-butyl (2S,4R)-4-(N-(3,3-difluorocyclobutyl)-2,2,2-trifluoroacetamido)-2-phenylpiperidine-1-carboxylate (200 mg 0.432 mmol) in DCM (5 mL) was added 4M HCl in 1,4-dioxane (1 mL) at rt. After 3 h, the solvent was evaporated under reduced pressure and the residue was triturated with DCM and pentane followed by lyophilization to give the title compound (120 mg, 70%). LCMS (Method H): R T = 1.93 min, m / z = 363 [M+H] + . 1 H NMR at 100 ℃(400 MHz, DMSO-d6): δ 9.35 (br s, 1H), 7.63 (d, 2H), 7.47 - 7.44 (m, 3H), 4.50 (d, 1H), 4.28 - 4.24 (m, 1H), 4.14 (m, 1H), 3.46 - 3.24 (m, 4H), 2.85 - 2.83 (m, 2H), 2.73 - 2.60 (m, 2H), 2.03 (d, 1H), 1.92 (d, 1H)

[0434] Intermediate 44: 2,2,2-trifluoro-N-((2S,4R)-2-phenylpiperidin-4-yl)-N-(pyridin-2-ylmethyl)acetamide hydrochloride [ka] Step 1: tert-Butyl (2S)-2-phenyl-4-((pyridin-2-ylmethyl)amino)piperidine-1-carboxylate: To a stirring solution of tert-butyl (S)-4-oxo-2-phenylpiperidine-1-carboxylate (1.0 g, 3.63 mmol) in MeOH (10 mL) was added pyridin-2-ylmethanamine (436 mg, 4.03 mmol) at rt. After 2 h, NaBHCN (914 mg, 14.5 mmol) was added. After an additional 16 h, the reaction mixture was diluted with water (100 mL) and extracted with 9:1 DCM / MeOH (2 x 250 mL). The organic layer was dried (NaSO) and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (50% EtOAc in hexanes) to give the title compound (1.2 g, 90%). LCMS (Method C): R T = 3.27 minutes, m / z = 368 [M+H] +

[0435] Step 2: tert-butyl (2S)-2-phenyl-4-(2,2,2-trifluoro-N-(pyridin-2-ylmethyl)acetamido)piperidine-1-carboxylate: To a stirring solution of tert-butyl (2S)-2-phenyl-4-((pyridin-2-ylmethyl)amino)piperidine-1-carboxylate (1.2 g, 3.26 mmol) in DCM (25 mL) was added triethylamine (1.36 mL, 9.76 mmol) at 0 °C. After 10 min, trifluoroacetic anhydride (0.68 mL, 4.89 mmol) was added. The temperature was raised to rt. After 16 h, the reaction mixture was diluted with water (50 mL) and extracted using DCM (2 x 50 mL). The organic layer was washed with saturated NaHCO 3(水性) The resulting mixture was washed with hexane (100 mL) and dried (Na2SO4). The solvent was removed under reduced pressure to give the crude product, which was purified by flash chromatography (30% EtOAc in hexane) to give the title compound (350 mg, 45%). LCMS (Method C): T = 3.81 min, m / z = 464 [M+H] +

[0436] Step 3: tert-Butyl (2S,4R)-2-phenyl-4-(2,2,2-trifluoro-N-(pyridin-2-ylmethyl)acetamido)piperidine-1-carboxylate: tert-Butyl (2S)-2-phenyl-4-(2,2,2-trifluoro-N-(pyridin-2-ylmethyl)acetamido)piperidine-1-carboxylate was separated into single stereoisomers by chiral HPLC using a Chiralpak OD-H (4.6 mm x 250 mm, 5 μm) column in isocratic conditions: 90 / 10 hexane / EtOH + 0.1% isopropylamine (flow rate: 21 mL / min) to give tert-butyl (2S,4S)-2-phenyl-4-(2,2,2-trifluoro-N-(pyridin-2-ylmethyl)acetamido)piperidine-1-carboxylate (first eluting isomer: 120 mg). LCMS (Method C): R T = 3.81 min, m / z = 464 [M+H] + . 1 H NMR at 100 °C (400 MHz, DMSO-d6): δ 8.53 (d, 1H), 7.77 (t. 1H), 7.38 - 7.23 (m, 5H), 7.17 (d, 2H), 5.47 (br s, 1H), 4.81 - 4.71 (m, 2H), 4.05 - 3.99 (m, 2H), 2.78 (br s, 1H), 2.43 (d, 1H), 2.32 - 2.16 (m, 1H), 1.86 - 1.76 (m, 1H), 1.67 (d, 1H), 1.42 (m, 9H); and the title compound (second-eluting isomer: 250 mg LCMS (Method C): R T = 3.81 min, m / z = 464 [M+H] + [Note: cis and trans stereochemistry was assigned by comparison of NMR data with analogs]

[0437] Step 4: 2,2,2-Trifluoro-N-(1-methylcyclopropyl)-N-((2S,4R)-2-phenylpiperidin-4-yl)acetamide hydrochloride: To a stirring suspension of tert-butyl (2S,4R)-2-phenyl-4-(2,2,2-trifluoro-N-(pyridin-2-ylmethyl)acetamido)piperidine-1-carboxylate (230 mg, 0.496 mmol) in DCM (5 mL) was added 4M HCl in 1,4-dioxane (2.5 mL) at rt. After 3 h, the solvent was evaporated under reduced pressure and the residue was triturated with DCM and pentane followed by lyophilization to give the title compound (220 mg, quantitative). LCMS (Method H): R T = 1.71 min, m / z = 364 [M+H] + . 1 H NMR at 100 ℃(400 MHz, DMSO-d6): δ 9.69 (br s, 1H), 9.29 (br s, 1H), 8.52 (s, 1H), 7.80 (t, 1H), 7.64 - 7.57 (m, 3H), 7.42 - 7.28 (m, 5H), 4.83 (s, 2H), 4.49 - 4.46 (m, 2H), 3.42 - 3.20 (m, 3H), 2.33 (br s, 2H), 2.06 (d, 1H), 1.95 (d, 1H)

[0438] Intermediate 45: 2,2,2-trifluoro-N-(1-methyl-1H-pyrazol-3-yl)-N-((2S,4R)-2-phenylpiperidin-4-yl)acetamide hydrochloride [ka] Step 1: tert-Butyl (2S)-4-((1-methyl-1H-pyrazol-3-yl)amino)-2-phenylpiperidine-1-carboxylate: To a stirring solution of tert-butyl (S)-4-oxo-2-phenylpiperidine-1-carboxylate (500 mg, 1.82 mmol) in MeOH (5 mL) was added 1-methyl-1H-pyrazol-3-amine (530 mg, 5.46 mmol) and catalytic AcOH (1-2 drops) at rt. After 1 h, NaBHCN (571 mg, 9.10 mmol) was added portionwise. After an additional 16 h, the reaction mixture was quenched with water (10 mL) and concentrated under reduced pressure to remove volatiles. The reaction mixture was diluted with water (25 mL) and extracted using ethyl acetate (2 x 50 mL). The combined organic phases were dried (Na2SO4) and concentrated to give the crude product, which was purified by flash chromatography (70-80% EtOAc in hexanes) to give the title compound (450 mg, 69%). LCMS (Method C): T = 3.43 minutes, m / z = 357 [M+H] +

[0439] Step 2: tert-Butyl (2S,4R)-4-((1-methyl-1H-pyrazol-3-yl)amino)-2-phenylpiperidine-1-carboxylate: tert-Butyl (2S)-4-((1-methyl-1H-pyrazol-3-yl)amino)-2-phenylpiperidine-1-carboxylate (900 mg) was resolved into single stereoisomers by reverse-phase preparative HPLC (C18 column) to give the title compound (first eluting isomer: 480 mg). LCMS (Method C): R T = 3.41 min, m / z = 357 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 7.32 - 7.26 (m, 3H), 7.21 - 7.17 (m, 3H), 5.33 (d, 1H), 4.82 - 4.78 (m, 1H), 4.65 (d, 1H), 3.87 - 3.82 (m, 1H), 3.57 (s, 3H), 3.51 - 3.49 (m, 1H), 3.37 - 3.34 (m, 1H), 2.17 - 2.13 (m, 1H), 2.05 - 2.02 (m, 1H), 1.84 - 1.81 (m, 1H), 1.51 - 1.47 (m, 1H), 1.22 (s, 9H); and tert-butyl (2S,4S)-4-((1-methyl-1H-pyrazol-3-yl)amino)-2-phenylpiperidine-1-carboxylate (second eluting isomer: 120 mg). LCMS (Method C): R T = 3.46 min, m / z = 357 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.39 (t, 2H), 7.28 - 7.26 (m, 4H), 5.40 (bs, 1H), 5.30 (s, 1H), 4.97 (d, 1H), 3.98 (d, 1H), 3.57 (s, 3H), 2.74 - 2.63 (m, 2H), 1.88 (d, 1H), 1.62 - 1.54 (m, 1H), 1.41 (s, 9H). [Note: Stereochemistry confirmed by nOe data]

[0440] Step 3: tert-Butyl (2S,4R)-2-phenyl-4-(2,2,2-trifluoro-N-(1-methyl-1H-pyrazol-3-yl)acetamido)piperidine-1-carboxylate: To a stirring solution of tert-butyl (2S,4R)-4-((1-methyl-1H-pyrazol-3-yl)amino)-2-phenylpiperidine-1-carboxylate (432 mg, 1.21 mmol) in DCM (5 mL) was added triethylamine (1.02 mL, 7.28 mmol) followed by trifluoroacetic anhydride (0.36 mL, 2.55 mmol) at 0 °C. The temperature was allowed to rise to rt. After 16 h, the reaction mixture was diluted with water (30 mL) and extracted with DCM (2 x 75 mL). The combined organic phases were dried (Na2SO4) and concentrated to give the crude product, which was purified by flash chromatography (0-30% EtOAc in hexanes) to give the title compound (350 mg, 64%). LCMS (Method C): T = 3.67 min, m / z = 453 [M+H] +

[0441] Step 4: 2,2,2-Trifluoro-N-(1-methyl-1H-pyrazol-3-yl)-N-((2S,4R)-2-phenylpiperidin-4-yl)acetamide hydrochloride: To a stirring solution of tert-butyl (2S,4R)-2-phenyl-4-(2,2,2-trifluoro-N-(1-methyl-1H-pyrazol-3-yl)acetamido)piperidine-1-carboxylate (325 mg, 1.07 mmol) in DCM (5 mL) was added 4M HCl in 1,4-dioxane (0.2 mL) at 0° C. at rt. After 3 h, the reaction mixture was concentrated under reduced pressure to give the crude product, which was triturated with diethyl ether and pentane to give the title compound (280 mg, 71%). LCMS (Method H): R T = 1.65 min, m / z = 353 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 9.47 (br s, 2H), 7.81 (d, 1H), 7.51 (d, 2H), 7.44 - 7.37 (m, 3H), 6.33 (d, 1H), 4.82 (t, 1H), 4.51 (t, 1H), 3.84 (s, 3H), 3.35 (br s, 1H), 3.26 - 3.20 (m, 1H), 2.10 - 1.96 (m, 2H), 1.90 - 1.79 (m, 2H)

[0442] Intermediate 46: 2,2,2-trifluoro-N-((5-fluoropyridin-2-yl)methyl)-N-((2S,4R)-2-phenylpiperidin-4-yl)acetamide hydrochloride [ka] The title compound was prepared according to the method for 2,2,2-trifluoro-N-((2S,4R)-2-phenylpiperidin-4-yl)-N-(pyridin-2-ylmethyl)acetamide hydrochloride (Intermediate 44), except that (5-fluoropyridin-2-yl)methanamine (330 mg, 2.61 mmol) was reacted with tert-butyl-4-oxo-2-phenylpiperidine-1-carboxylate (700 mg, 2.55 mmol) instead of pyridin-2-ylmethanamine, and a Chiralpak IG (4.6 mm x 250 mm, 5 μm) column was used for separation of diastereoisomers under the following conditions: isocratic solvent conditions: 80:20 hexane / EtOH + 0.1% isopropylamine (flow rate: 21 mL / min). LCMS (Method H): T = 1.74 min, m / z = 382 [M+H] + . 1 H NMR at 100 ℃(400 MHz, DMSO-d6): δ 8.45 (s, 1H), 7.64 (br s, 1H), 7.39 - 7.19 (m, 5H), 4.75 (s, 2H), 4.14 (br s, 1H), 3.63 (d, 1H), 3.13 (d, 1H), 2.71 (t, 1H), 2.19 (br s, 1H), 1.8 - 1.68 (m, 4H)

[0443] Intermediate 47: 2,2,2-trifluoro-N-phenyl-N-((2S,4R)-2-phenylpiperidin-4-yl)acetamide hydrochloride [ka] The title compound was prepared according to the method for 2,2,2-trifluoro-N-(1-methyl-1H-pyrazol-3-yl)-N-((2S,4R)-2-phenylpiperidin-4-yl)acetamide hydrochloride (Intermediate 45), except that aniline (0.246 mL, 2.72 mmol) and tert-butyl-4-oxo-2-phenylpiperidine-1-carboxylate (500 mg, 1.81 mmol) were used instead of 1-methyl-1H-pyrazol-3-amine, and a Chiralpak IG (21 mm x 250 mm, 5 μm) column was used under the following conditions for separation of diastereoisomers: isocratic solvent conditions: 90:10 hexane / EtOH + 0.1% isopropylamine (flow rate: 21 mL / min). LCMS (Method I): T = 1.57 min, m / z = 349 [M+H] + . 1 H NMR at 100 ℃(400 MHz, DMSO-d6): δ 9.20 (br s, 1H), 7.51 - 7.39 (m, 10H), 4.85 (t, 1H), 4.49 (d, 1H) 3.42 - 3.39 (m, 1H), 3.29 - 3.22 (m, 1H), 2.32 - 2.26 (m, 1H), 2.11 (d, 1H) 1.94 - 1.83 (m, 2H)

[0444] Intermediate 48: 2,2,2-trifluoro-N-(1-methylcyclopropyl)-N-((2S,4R)-2-phenylpiperidin-4-yl)acetamide hydrochloride [ka] Step 1: tert-Butyl (2S)-4-((1-methylcyclopropyl)amino)-2-phenylpiperidine-1-carboxylate: To a stirring solution of tert-butyl (S)-4-oxo-2-phenylpiperidine-1-carboxylate (1.0 g, 3.63 mmol) in MeOH (50 mL) was added 1-methylcyclopropan-1-amine hydrochloride (584 mg, 5.44 mmol) at rt. After 2 h, NaBHCN (684 mg, 10.9 mmol) was added. After an additional 16 h, the reaction mixture was diluted with water (100 mL) and extracted with 5% (v / v) MeOH in DCM (2 x 200 mL). The combined organic phases were dried (NaSO) and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (50% EtOAc in hexanes) to give the title compound (600 mg, 50%). LCMS (Method C): R T = 3.62 min, m / z = 331 [M+H] +

[0445] Step 2: tert-Butyl (2S)-2-phenyl-4-(2,2,2-trifluoro-N-(1-methylcyclopropyl)acetamido)piperidine-1-carboxylate: To a stirring solution of tert-butyl (2S)-4-((1-methylcyclopropyl)amino)-2-phenylpiperidine-1-carbox...

Claims

1. Formula (I) 【Chemistry 1】 [During the ceremony, R ０ H, NH ２ , F or OCH ３ and R １ is NR a R b or NR a CH 2 R b , where R a and R b are independently selected from the group consisting of H, methyl, ethyl, propyl, CF 3 , optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted pyridinyl, pyrazole, imidazole, furan, benzodioxole, optionally substituted oxadiazole, thiazole and thiophene, where the optional substituents are independently selected from halo, methyl, cyclopropyl and CN; Optionally, R 1 is NR a CH 2 R b , in which the methylene group is replaced with CF 3 . or; R 1 is NR a R b , where R a and R b together form, together with the N to which they are attached, an optionally substituted C 3 -C 9 heterocycle; wherein each of the one or more optional substituents is selected from OH, oxo, C 1 -C 3 alkyl optionally substituted with OH and / or halo, optionally substituted phenyl, optionally substituted benzyl, C 1 -C 3 alkoxy, NR m R n , NHC(O)R m and NHCH 2 R n ; wherein R m and R n are independently selected from H; C 1 -C 3 alkyl optionally substituted with OH, methoxy or halo; C 3 -C 4 cycloalkyl optionally substituted with methyl and / or halo; C 3 -C 4 heterocycloalkyl optionally substituted with oxo, methyl or fluoro-methyl; C 3 -C 5 heteroaryl optionally substituted with methyl; and Boc; and / or wherein R n is further selected from CH 2 OCH 3 , COOH and COOCH 3 ; or R m and R n together with the N to which they are attached form a C 3 -C 5 heterocyclyl group, optionally R m and R n together with the N to which they are attached form a morpholinyl group; R ２ and R ３ are independently H and C １ -C ６ alkyl or together with the carbon to which they are attached, C ３ -C ６ Cycloalkyl or C ３ -C ６ Forming a heterocycloalkyl; X is absent, C, CR ４ａ , C.R. ４ａ R ４ｂ , N.R. ４ａ or C=O, Here, R ４ａ and R ４ｂ are independently H, optionally substituted C １ -C ６ selected from alkyl and halo; wherein for each optionally substituted group, each one or more optional substituents are independently selected from C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, halo, CHF 2 , CF 3 , hydroxyl, NH 2 , NHCH 3 , NHCH 2 CH 3 , NO 2 , CH 2 OH, CH 2 OCH 3 , methoxy, OCHF 2 , OCF 3 , cyclopropyloxy, phenyl, fluoro-substituted phenyl (e.g., difluoro-substituted phenyl), benzyl, and oxo; Or R ４ａ and R ４ｂ includes the carbon to which they are attached, C ３ -C ６ Cycloalkyl or C ３ -C ６ Forming a heterocycloalkyl; Y is C, CR ５ , C.R. ５ R ６ , N.R. ５ or O, Here, R ５ and R ６ are independently H, halo, optionally substituted C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, optionally substituted C ３ -C ６ Cycloalkyl, optionally substituted C ３ -C ６ Heterocycloalkyl, optionally substituted C ５ -C ８ Aryl, optionally substituted C ６ -C ９ Arylalkyl, optionally substituted C ３ -C ８ Heteroaryl, CH ２ OH, NR'R", NS(O)R'R", SO ２ R', C(O)R', COR', C(O)OR', C(O)NR'R", OR', where R' and R" are independently selected from the group consisting of H, C １ -C ６ Alkyl, C ５ -C ８ Aryl, C ６ -C ９ Arylalkyl and C ３ -C ８ Heteroaryl or R ５ is NR'R'', where R' and R'' are optionally substituted C ３ - ６ forming a heterocycloalkyl, where for each optionally substituted group, each one or more optional substituents are independently selected from C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, halo, CHF 2 , CF 3 , hydroxyl, NH 2 , NHCH 3 , NHCH 2 CH 3 , NO 2 , CH 2 OH, CH 2 OCH 3 , methoxy, OCHF 2 , OCF 3 , cyclopropyloxy, phenyl, fluoro-substituted phenyl (e.g., difluoro-substituted phenyl), benzyl, and oxo; Or R ５ and R ６ includes the carbon to which they are attached, C ３ - ６ Cycloalkyl or C ３ -C ６ Forming a heterocycloalkyl; Z is N, NR ７ , C.R. ７ , C.R. ７ R ８ or C=O, Here, R ７ and R ８ are independently H, halo, cyano, oxo, optionally substituted C １ -C ６ Alkyl, C ２ -C ６ Alkenes, C ２ -C ６ Alkyne, C ３ -C ６ Cycloalkyl, optionally substituted C ３ -C ６ Heterocycloalkyl, C ５ -C ８ Aryl, C ６ -C ９ Aryl alkyl, C ３ -C ８ Heteroaryl, CN, C(O)OR ｃ , C.O.R. ｃ R ｄ , N.R. ｃ R ｄ , N.S.(O)R. ｃ R ｄ , S(O)(R ｃ ) N.R. ｄ , S.O.R. ｃ , S.O. ２ R ｃ and S.R. ｃ wherein R ｃ and R ｄ are independently H, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C ５ -C ６ Aryl, C ６ -C ９ Aryl alkyl, C ３ -C ６ Heteroaryl, CN, COOH or COCH ３ or R ｃ and R ｄ are taken together with the heteroatom to which they are attached and optionally substituted C ３ -C ７ forming a heterocycle, wherein for each optionally substituted group, each one or more optional substituents are independently selected from C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, halo, CHF 2 , CF 3 , hydroxyl, NH 2 , NHCH 3 , NHCH 2 CH 3 , NO 2 , CH 2 OH, CH 2 OCH 3 , methoxy, OCHF 2 , OCF 3 , cyclopropyloxy, phenyl, fluoro-substituted phenyl (e.g., difluoro-substituted phenyl), benzyl, and oxo; Or R ７ and R ８ includes the carbon to which they are attached, C ３ - ６ Cycloalkyl or C ３ -C ６ Forming a heterocycloalkyl; M is non-existent, C, CR １３ or CR １３ R １４ where R １３ and R １４ are independently H and C １ -C ６ alkyl or R １３ and R １４ are united with the carbon to which they are attached. ３ -C ６ Cycloalkyl or C ３ -C ６ Forming a heterocycloalkyl; and A is CR ９ , CHR ９ , N.R. ９ , S or O; D is CR ９ , CHR ９ , N or NR ９ and G is non-existent, CR ９ , CHR ９ or N, Here, R ９ are independently H, halo, and C １ -C ６ Alkyl, CF ３ and OR * where R * is optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ Cycloalkyl and optionally substituted C ３ -C ６ heterocycloalkyl, where for each optionally substituted group, each one or more optional substituents are independently selected from C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, halo, CHF 2 , CF 3 , hydroxyl, NH 2 , NHCH 3 , NHCH 2 CH 3 , NO 2 , CH 2 OH, CH 2 OCH 3 , methoxy, OCHF 2 , OCF 3 , cyclopropyloxy, phenyl, fluoro-substituted phenyl (e.g., difluoro-substituted phenyl), benzyl, and oxo; E is CR １０ , CHR １０ , N.R. １０ , S or O; Here, R １０ H, halo, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C ５ -C ８ Aryl, C ６ -C ９ Aryl alkyl, C ４ -C ８ Heteroaryl, SR ｘ , OR ｘ , N.R. ｘ R ｙ and N.S.(O)R. ｘ R ｙ , S(O)(R ｘ ) N.R. ｙ is selected from Here, R ｘ and R ｙ are independently H, C １ -C ６ Alkyl, CF ３ , C ３ -C ６ Cycloalkyl, C ５ -C ８ Aryl, C ６ -C ９ Aryl alkyl, C ４ -C ８ Heteroaryl, COOH, Amido, Cyano, C ２ -C ６ Alkenes, C ２ -C ６ alkynes or R ｘ and R ｙ are taken together with the nitrogen to which they are attached and optionally substituted C ４ -C ６ forming a heterocycloalkyl, where for each optionally substituted group, each one or more optional substituents are independently selected from C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, halo, CHF 2 , CF 3 , hydroxyl, NH 2 , NHCH 3 , NHCH 2 CH 3 , NO 2 , CH 2 OH, CH 2 OCH 3 , methoxy, OCHF 2 , OCF 3 , cyclopropyloxy, phenyl, fluoro-substituted phenyl (e.g., difluoro-substituted phenyl), benzyl, and oxo; or A, D, E and G are all absent, optionally wherein X and M are absent or optionally wherein Y and Z together are optionally substituted C ５ -C ６ Aryl or C ３ -C ６ Z and M together form a heteroaryl fused ring or are optionally substituted C ５ -C ６ Aryl or C ５ -C ６ and forming a heteroaryl fused ring, where for each optionally substituted group, each one or more optional substituents are independently selected from C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, halo, CHF 2 , CF 3 , hydroxyl, NH 2 , NHCH 3 , NHCH 2 CH 3 , NO 2 , CH 2 OH, CH 2 OCH 3 , methoxy, OCHF 2 , OCF 3 , cyclopropyloxy, phenyl, fluoro-substituted phenyl (e.g., difluoro-substituted phenyl), benzyl, and oxo. or a stereoisomer, tautomer, hydrate, N-oxide derivative or a pharma- ceutically acceptable salt thereof, 【Chemistry 2】 A compound having a structure selected from:

2. R １ is NR ａ R ｂ where R ａ and R ｂ together with the N to which they are attached, optionally substituted C ３ -C ９ Forming a heterocycle, optionally OH, CH ２ O.H., C.H. ２ OCH ３ , oxo, NH ２ , C １ -C ３ Aminoalkyl, amino-thietane dioxide, methyl, ethyl, propyl, CF ３ , substituted with phenyl, substituted phenyl and benzyl; wherein optionally R 1 is NR a R b , and R a and R b together with the N to which they are attached form an optionally substituted heterocycle, wherein the heterocycle is selected from pyrrolidinyl, piperidinyl, morpholino, piperazinyl, and thiomorpholino; The compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharma- ceutically acceptable salt of claim 1, wherein the heterocycle is optionally substituted with one or more substituents independently selected from methyl, NH2, C1-C2 aminoalkyl, CH2CF3, oxo, thiophene and phenyl optionally substituted with one or more substituents independently selected from F and CF3 and OH, provided that the same ring carbon is not also substituted with methyl.

3. R ａ and R ｂ together with the N to which they are attached form a heterocycle, wherein the heterocycle is selected from a piperidinyl or piperazinyl ring, wherein the heterocycle is optionally methyl, NH ２ , N.H.H. ３ , N.H.H. ２ CH ３ , C.H. ２ CF ３ , oxo, thiophene, optionally F or CF ３ and OH, provided that the same ring carbon is not also substituted with methyl; wherein optionally R 1 is NR a R b , and R a and R b together with the N to which they are attached form a piperazinyl group substituted with phenyl, fluoro-phenyl, or difluoro-phenyl, wherein the piperazinyl group is optionally further substituted with methyl; Further, optionally, R 1 is 【Chemistry 3】 Selected from:

3. A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharma- ceutically acceptable salt of claim 1 or 2.

4. R １ is NR ａ R ｂ and R ａ and R ｂ together with the N to which they are attached form a piperidinyl group optionally substituted with phenyl, fluoro-phenyl or difluoro-phenyl, where the piperidinyl group is optionally NR ｍ R ｎ , NHC(O)R ｍ or NHCH ２ R ｎ is further substituted with Here, R ｍ and R ｎ is H; C optionally substituted with OH, methoxy or halo １ -C ３ alkyl; C optionally substituted with methyl and / or halo ３ -C ４ Cycloalkyl; C optionally substituted with oxo, methyl or fluoro-methyl ３ -C ４ Heterocycloalkyl; C optionally substituted with methyl ３ -C ５ heteroaryl; and Boc; and / or where R ｎ More CH ２ OCH ３ , COOH and COOCH ３ is selected from Or R ｍ and R ｎ are combined with the N to which they are attached to form C ３ -C ５ Forms a heterocyclyl group, optionally R ｍ and R ｎ together with the N to which they are attached form a morpholinyl group; 3. A compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharma- ceutically acceptable salt of claim 1 or 2.

5. R １ is NR ａ R ｂ and R ａ and R ｂ together with the N to which they are attached form a piperidinyl group, where the piperidinyl group occupies the 4-position with NR ｍ R ｎ , NHC(O)R ｍ and N.H.H. ２ R ｎ and further substituted at the 2-position with phenyl, fluoro-phenyl or difluoro-phenyl; optionally R a and R b together with the N to which they are attached form a piperidinyl group optionally substituted with phenyl, fluoro-phenyl or difluoro-phenyl, where the piperidinyl group is optionally further substituted with NH 2 , NHCH 3 or NHCH 2 CH 3 ; Further, optionally, R 1 is 【Chemistry 4】 5. The compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharma- ceutically acceptable salt of any one of claims 1 to 4, selected from:

6. R １ is NR ａ CH ２ R ｂ where R ａ is H or methyl, R ｂ is selected from cyclobutyl optionally substituted with F, cyclohexyl, phenyl optionally substituted with F, furan and thiophene; Optionally, the methylene group is CF ３ has been replaced by 2. The compound of claim 1, a stereoisomer, a tautomer, a hydrate, an N-oxide derivative, or a pharma- ceutically acceptable salt thereof.

7. R ２ and R ３ together with the carbon to which they are attached form optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted pyrrolidine, optionally substituted tetrahydropyran or optionally substituted tetrahydrofuran, where for each optionally substituted group, each one or more optional substituents are independently selected from C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, halo, CHF 2 , CF 3 , hydroxyl, NH 2 , NHCH 3 , NHCH 2 CH 3 , NO 2 , CH 2 OH, CH 2 OCH 3 , methoxy, OCHF 2 , OCF 3 , cyclopropyloxy, phenyl, fluoro-substituted phenyl (e.g., difluoro-substituted phenyl), benzyl and oxo; optionally, R 2 and R 3 are independently selected from H and methyl, preferably where R 2 and R 3 are both H; or R 2 and R 3 together with the carbon to which they are attached form cyclohexyl, cyclopentyl or cyclobutyl, preferably cyclopentyl; A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 6.

8. 8. The compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharma- ceutically acceptable salt of any of claims 1 to 7, wherein when ring XYADE (optionally G) is present, Y is not N.

9. X is C or N; Y is C or N; Z is N, NR ７ or CR ７ , where R ７ is as defined in claim 1, M is absent, CH or C-CH ３ and A is CR ９ , CHR ９ , N.R. ９ , S or O; D is CR ９ , CHR ９ , N or NR ９ and G is absent, CR ９ , CHR ９ or N, Here, R ９ are independent of H, halo, and C １ -C ６ Alkyl, CF ３ and OR * where R * is optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ Cycloalkyl and optionally substituted C ３ -C ６ heterocycloalkyl; E is CR １０ , CHR １０ , N.R. １０ , S or O; Here, R １０ H, halo, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C ５ -C ８ Aryl, C ６ -C ９ Aryl alkyl, C ４ -C ８ Heteroaryl, SR ｘ , OR ｘ , N.R. ｘ R ｙ and NS(O)(R ｘ )R ｙ , S(O)(R ｘ ) N.R. ｙ is selected from optionally, when E is CR 10 , R 10 is H or SR x , where R x is C 1 -C 6 alkyl, preferably R x is methyl; Here, R ｘ and R ｙ are independent and H, C １ -C ６ Alkyl, CF ３ , C ３ -C ６ Cycloalkyl, C ５ -C ８ Aryl, C ６ -C ９ Aryl alkyl, C ４ -C ８ Heteroaryl, COOH, Amido, Cyano, C ２ -C ６ Alkenes, C ２ -C ６ alkynes or R ｘ and R ｙ together with the nitrogen to which they are attached, optionally substituted C ４ -C ６ forming a heterocycloalkyl, Optionally, Z is N or CR 7 , where R 7 is selected from H, C 1 -C 6 alkyl, CN, or C(O)NR c R d , where R c and R d are independently H, methyl, or taken together with the nitrogen to which they are attached form an optionally substituted piperidine, piperazine, or morpholine ring, where for each optionally substituted group, each one or more optional substituents are C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, halo, CHF 2 , CF 3 , hydroxyl, NH 2 , NHCH 3 , NHCH 2 CH 3 , NO 2 , CH 2 OH, CH 2 OCH 3 , methoxy, OCHF 2 , OCF 3 . , cyclopropyloxy, phenyl, fluoro-substituted phenyl (e.g., difluoro-substituted phenyl), benzyl, and oxo; Alternatively, X, Y, M, A and G are C, Z is N, D is CR9 and E is CR10, such that the ring comprising A, D, E, G, X, Y, Z and M forms a fused aromatic ring system, where R9 is halo, preferably F or Cl, and R10 is H or halo, optionally F or Cl; Alternatively, G is absent, A is C, D and Z are N, and E is NR 10 , such that the ring comprising A, D, E, X, Y, Z and M forms a fused aromatic ring system, where R 10 is selected from H, ethyl, phenyl and benzyl; A compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 8.

10. E is CR １０ , CHR １０ , N.R. １０ , S or O; Here, R １０ is H, F, Cl, Br, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, SR ｘ , OR ｘ , N.R. ｘ R ｙ and NS(O)(CH ３ ) ２ is selected from Here, R ｘ and R ｙ are independently H, methyl, ethyl, CF ３ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, COOH, amido, cyano, or where R ｘ and R ｙ 10. The compound, stereoisomer, tautomer, hydrate, N-oxide derivative, or pharma- ceutically acceptable salt of claim 9, wherein together with the nitrogen to which they are attached form a piperidine, piperazine, or morpholine, optionally substituted with methyl.

11. A compound selected from the following: (R)-6-phenyl-3-((1-(2-phenylpiperazine-1-carbonyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one (R)-6-phenyl-3-((7-(2-phenylpiperazine-1-carbonyl)-7-azaspiro[4.5]dec-9-en-10-yl)methyl)pyrimidin-4(3H)-one (R,Z)-6-phenyl-3-((7-(2-phenylpiperazine-1-carbonyl)-7-azaspiro[4.5]decan-10-ylidene)methyl)pyrimidin-4(3H)-one 6-phenyl-3-((7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one 4-phenyl-1-((7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one (R)-4-Phenyl-1-((1-(2-phenylpiperazine-1-carbonyl)piperidin-4-yl)methyl)pyridin-2(1H)-one 6-phenyl-3-((7-((S)-4,4,4-trifluoro-2-(methoxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one 6-phenyl-3-((7-((S)-2-phenylpyrrolidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one 3-((1-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4(3H)-one N-benzyl-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carboxamide 3-((7-((R)-2-(3,5-difluorophenyl)piperazine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-((7-((3R,4R)-1-imino-1-oxide-4-phenyltetrahydro-1H-1λ ６ -Thiophene-3-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-((7-((3S,4S)-1-imino-1-oxide-4-phenyltetrahydro-1H-1λ ６ -Thiophene-3-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 6-phenyl-3-(((S)-7-((R)-2-phenylpiperazine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one 6-phenyl-3-(((R)-7-((R)-2-phenylpiperazine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one 4-Phenyl-1-(((S)-7-((R)-2-phenylpiperazine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one 4-Phenyl-1-(((R)-7-((R)-2-phenylpiperazine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one 1-((1-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one 3-((3,3-dimethyl-1-((R)-2-phenylpiperazine-1-carbonyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-((1-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-3,3-dimethylpiperidin-4-yl)methyl)-6-phenylpyrimidin-4(3H)-one 1-((3,3-dimethyl-1-((R)-2-phenylpiperazine-1-carbonyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one 1-((1-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-3,3-dimethylpiperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one (R)-1-((1-(2-(2,5-difluorophenyl)piperazine-1-carbonyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one 1-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 1-(((S)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 3-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((S)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(difluoromethyl)pyrimidin-4(3H)-one 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-cyclopropylpyrimidin-4(3H)-one 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one 1-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrazin-2(1H)-one 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-methylpyrimidin-4(3H)-one 2-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-2,7-naphthyridin-1(2H)-one 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one 5-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-1-cyclopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(1-methylcyclopropyl)pyrimidin-4(3H)-one 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6,7-difluoroquinazolin-4(3H)-one 1-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(difluoromethyl)pyridin-2(1H)-one 1-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-methylpyridin-2(1H)-one 6-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one 4-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)morpholin-3-one 7-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-7,8-dihydroimidazo[1,2-a]pyrazin-6(5H)-one 1-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(trifluoromethyl)pyridin-2(1H)-one 1-(((R)-7-((2S,4R)-4-hydroxy-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 1-(((R)-7-((2S,4R)-4-(ethylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 1-(((R)-7-((2S,4R)-4-(dimethylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 1-((1-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one 1-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 3-((10-amino-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 1-(((R)-7-((2S,4R)-4-((1,1-dioxidothietan-3-yl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 1-(((R)-7-((2S,4S)-4-((1,1-dioxidothietan-3-yl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 1-(((R)-7-((2S,4R)-4-hydroxy-4-methyl-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 4-(2-Methoxyphenyl)-1-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one 1-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(o-tolyl)pyridin-2(1H)-one 4-(2-fluorophenyl)-1-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one 3-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-((7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-10-fluoro-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 1-(((S)-10-Methoxy-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 1-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)pyridin-2(1H)-one 1-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(o-tolyl)pyridin-2(1H)-one 1-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl)pyridin-2(1H)-one 3-(((R)-7-((2S,4R)-4-(ethylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(3-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 1-(((R)-7-((2S,4R)-2-(3-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 1-(((R)-7-((2S,4R)-4-amino-2-(3-fluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 3-(((R)-7-((2S,4R)-4-amino-2-(3-fluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 1-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-chloropyridin-2(1H)-one 1-(((R)-7-((2R,4R)-4-amino-2-ethylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 1-(((R)-1-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-3,3-dimethylpiperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one 3-(((R)-7-((2S,4S)-4-amino-2-phenylpyrrolidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-((2,2-difluoroethyl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 1-(((R)-3,3-dimethyl-1-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one 1-(((S)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-10-methoxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 3-((1-((2S,4R)-2-(3-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-((1-((2S,4R)-4-(ethylamino)-2-phenylpiperidine-1-carbonyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4(3H)-one Methyl (2S,4R)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)-2-phenylpiperidine-4-carboxylate 3-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-(cyclopropylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-amino-2-(2,4-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-amino-2-(3-fluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one 4-Chloro-1-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one 3-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one 1-(((R)-7-((2S,4S,5R)-4-amino-5-fluoro-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 1-(((R)-7-((2S,4S,5S)-4-amino-5-fluoro-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 3-(((R)-7-((2S,4R)-4-amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 1-(((R)-7-((2S,4R)-4-amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 1-(((R)-7-((2S,4R)-4-amino-2-(3-fluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)pyridin-2(1H)-one 1-(((R)-7-((2S,4R)-4-amino-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)pyridin-2(1H)-one 3-(((R)-7-((2S,4S)-4-(methylamino)-2-phenylpyrrolidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 1-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 3-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one N-((2S,4R)-1-((R)-10-((2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)-2-phenylpiperidin-4-yl)acetamide 3-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 1-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one N-((2S,4R)-1-((R)-10-((2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)-2-phenylpiperidin-4-yl)cyclopropanecarboxamide 6-(2-Methoxyphenyl)-3-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one 1-((1-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one 6-Fluoro-3-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)quinazolin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(3-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(2-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(4-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one Methyl ((2S,4R)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)-2-phenylpiperidin-4-yl)glycinate Sodium ((2S,4R)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)-2-phenylpiperidin-4-yl)glycinate 3-(((R)-7-((2S,4R)-4-amino-2-(3,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 1-(((R)-7-((2S,4R)-4-amino-2-(3,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 6-(2-fluorophenyl)-3-(((R)-7-((2S,4R)-4-(methylamino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one 6-(2-Methoxyphenyl)-3-(((R)-7-((2S,4R)-4-morpholino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one 1-(((R)-7-((2S,4R)-4-((3-methyloxetan-3-yl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 1-(((R)-7-((2S,4R)-4-((3-(fluoromethyl)oxetan-3-yl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 1-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)pyridin-2(1H)-one 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one 3-(((R)-7-((R)-2-(3-fluorophenyl)piperazine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one 3-(((R)-7-((R)-2-(2,5-difluorophenyl)piperazine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one 1-(((R)-7-((2S,4R)-2-(2-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)pyridin-2(1H)-one 3-(((R)-7-((2S,4R)-2-(3-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one 1-(((R)-7-((2S,4R)-2-(4-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)pyridin-2(1H)-one 1-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 3-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 4-Chloro-1-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one 3-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one 1-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)pyridin-2(1H)-one 1-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)-5,6-dihydropyridin-2(1H)-one 1-(((S)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)-5,6-dihydropyridin-2(1H)-one 1-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-2(1H)-one 2-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridazin-3(2H)-one 6-(difluoromethyl)-3-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one 1-(((R)-7-((2S,4R)-2-(2,3-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-methoxyphenyl)pyridin-2(1H)-one 3-(((R)-7-((2S,4R)-2-(2,3-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(3,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-((3,3-difluorocyclobutyl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(2,3-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(3,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(3,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(2,3-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(3,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one 6-phenyl-3-(((R)-7-((2S,4R)-2-phenyl-4-((pyridin-2-ylmethyl)amino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(o-tolyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-((1-methyl-1H-pyrazol-3-yl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-(((5-fluoropyridin-2-yl)methyl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(2,3-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one 6-phenyl-3-(((R)-7-((2S,4R)-2-phenyl-4-(phenylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-((1-methylcyclopropyl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(difluoromethyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one tert-Butyl ((2S,4R)-2-(2,5-difluorophenyl)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)piperidin-4-yl)glycinate N-((2S,4R)-2-(2,5-difluorophenyl)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)piperidin-4-yl)acetamide 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one ((2S,4R)-2-(2,5-difluorophenyl)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)piperidin-4-yl)glycine 4-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)morpholin-3-one 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-((2-hydroxyethyl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one 6-Cyclopropyl-3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one N-((2S,4R)-2-(2,5-difluorophenyl)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)piperidin-4-yl)cyclopropanecarboxamide N-((2S,4R)-2-(2,5-difluorophenyl)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)piperidin-4-yl)picolinamide 3-(((R)-7-((2S,4R)-2-(2,3-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one 6-Fluoro-3-(((R)-7-((2S,4R)-2-(3-fluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)quinazolin-4(3H)-one 1-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl-5,6-dihydropyridin-2(1H)-one 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-((pyrimidin-2-ylmethyl)amino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-((pyrimidin-4-ylmethyl)amino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 6-Fluoro-3-(((R)-7-((2S,4R)-4-morpholino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)quinazolin-4(3H)-one hydrochloride N-((2S,4R)-2-(2,5-difluorophenyl)-1-((R)-10-((6-fluoro-4-oxoquinazolin-3(4H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)piperidin-4-yl)acetamide N-((2S,4R)-2-(2,5-difluorophenyl)-1-((R)-10-((6-fluoro-4-oxoquinazolin-3(4H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)piperidin-4-yl)cyclopropanecarboxamide 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one (2S,4R)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)-2-phenylpiperidine-4-carboxylic acid (2S,4R)-N-Methyl-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)-2-phenylpiperidine-4-carboxamide (2S,4R)-N,N-Dimethyl-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)-2-phenylpiperidine-4-carboxamide 1-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl-1,5-dihydro-2H-pyrrol-2-one 4-Chloro-1-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one 1-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(ethylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyridin-2(1H)-one 3-(((R)-7-((2S,4R)-4-amino-2-(3,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one hydrochloride 6-Cyclopropyl-3-(((R)-7-((2S,4R)-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-((3,3-difluorocyclobutyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-(difluoromethyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(dimethylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one hydrochloride 4-Chloro-1-(((R)-7-((2S,4R)-4-((2,2-difluoroethyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one 4-Chloro-1-(((R)-7-((2S,4R)-4-((3,3-difluorocyclobutyl)amino)-2-(2,5-difluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)pyridin-2(1H)-one 3-(((S)-7-((R)-2-(2,5-difluorophenyl)piperazine-1-carbonyl)-10-methoxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,5R)-5-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2R,5S)-5-amino-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one 3-(((S)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-10-methoxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(2,4-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(3,5-difluorophenyl)-4-(isopropylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-(((3-methylpyridin-2-yl)methyl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-(((4,6-dimethylpyrimidin-2-yl)methyl)amino)-2-phenylpiperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(3-fluorophenyl)-4-((2-methoxyethyl)amino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-(((R)-7-((2S,4R)-4-((2-fluoroethyl)amino)-2-(3-fluorophenyl)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one 3-((2S,4R)-2-(3-fluorophenyl)-1-((R)-10-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decane-7-carbonyl)piperidin-4-yl)oxazolidin-2-one 6-chloro-3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)quinazolin-4(3H)-one 3-(((R)-7-((2S,4R)-2-(2,5-difluorophenyl)-4-(methylamino)piperidine-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)quinazolin-4(3H)-one 3-(((R)-7-((2S,5R)-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-fluoroquinazolin-4(3H)-one 3-(((R)-7-((2S,5R)-5-(2,5-difluorophenyl)-2-methylmorpholine-4-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-phenylpyrimidin-4(3H)-one or a stereoisomer, tautomer, hydrate, N-oxide derivative, or a pharma- ceutically acceptable salt thereof.

12. 12. A pharmaceutical composition comprising a compound of any one of claims 1 to 11, or a stereoisomer, tautomer, hydrate, N-oxide derivative, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or diluent.

13. A medicament comprising as an active ingredient a compound, stereoisomer, tautomer, hydrate, N-oxide derivative or a pharma- ceutically acceptable salt of any one of claims 1 to 11 for use in therapy.

14. 14. The medicament of claim 13 for use in the treatment of muscle wasting, obesity, insulin resistance or type II diabetes.

15. Use of a compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharma- ceutically acceptable salt of any of claims 1 to 11 for the manufacture of a medicament for treating muscle wasting, obesity, insulin resistance or type II diabetes.

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