RU2776482C2 - Pharmaceutical compounds - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a heterocyclic compound of the formula (I), where values of radicals R₁, R₂, R₃, R₄, R₅, R₆, R₇, W, X, Y, Z are specified in the claims; or a compound

. The invention also relates to a method for the treatment of Parkinson’s disease.

EFFECT: new heterocyclic compounds are obtained, useful as USP19 inhibitor.

14 cl, 1 dwg, 2 tbl, 253 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to inhibitors of ubiquitin-specific protease 19 (USP19) and methods of their use.

BACKGROUND OF THE INVENTION

Over the past decade, protein ubiquitination has come to be regarded as an important post-translational modification with an important role in a variety of cellular processes, including but not limited to proteolysis, gene expression, DNA repair, immune response, metabolism, or cell cycle regulation. Dysregulation of the ubiquitin proteasome system (UPS) is also implicated in the pathogenesis of many human diseases, including, but not limited to, 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), as well as immune and inflammatory conditions (Wang J. et al., J. Cell. Immunol. (2006)3, 255-261; Corn J et al., Nat Struct. & Mol. Biol. (2014)21, 297-300; Nicholson, B. et al., Cell Biochem. Biophys. (2013), 60, 61-68).

The approval and clinical success of the proteasome inhibitors Velcade® (bortezomib) or Kyprolis® (carfilzomib) for the treatment of mantle cell lymphoma (AML) and multiple myeloma (MM) confirmed that UPS in cancer is a target amenable to pharmacological intervention. Despite their effectiveness, their clinical use has been severely limited due to poor selectivity and acute toxicity concerns. By inhibiting the 26S proteasome, current proteasome inhibitors indiscriminately impair proteolysis in both cancerous and normal cells and have a low therapeutic index. To circumvent this problem, a promising alternative approach would be to target UPSs to cellular signaling objects and mechanisms ahead of the proteasome. Interference with the ubiquitin (Ub) conjugation/deconjugation mechanism, for example at the level of ubiquitin-specific proteases (USPs), would allow the development of improved therapeutics with increased specificity and reduced toxicity profiles.

USPs are the largest subfamily of the deubiquitinating enzyme (DUB) family, and more than 60 family members are known to date (Komander D. et al., Nat. Rev. Mol. (2009), 10, 550-563; Claque M. et al. ., Physiol Rev. (2013), 93, 1289-1315). USPs are typically cysteine proteases that catalyze the removal of Ub from specific target substrates, thus preventing their proteasome-induced degradation or regulating their 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 activation of numerous proteins involved in the pathogenesis of human diseases, including both oncogenes and tumor suppressors. Thus, USPs represent a new and attractive class of targeted agents for pharmacological intervention.

USP19, among all USPs, is an important family member due to its effect on pathological conditions including, but not limited to, cancer, muscle wasting disorders, neurodegeneration and degenerative diseases, and antiviral immune response. USP19 is expressed as several isoforms ranging in length from 71.09 kDa (isoform 2) to 156.03 kDa (isoform 5) with a canonical sequence (isoform 1) of 145.65 kDa (uniprot.org). Cellular localization of USP19 can be either cytosolic 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 last steps of the protein quality control mechanism by rescuing ERAD substrates that have been retro-translocated into the cytosol. USP19 has also been shown to regulate the stability of MARCH6 and HRD1 E3 ligases (Nakamura N. et al., Exp. Cell Res. (2014)328, 207-216; Harada K. et al., Int. J. Mol. Sci (2016)17, E1829). In addition, USP19 has recently been shown to be involved in the stabilization of a variety of potentially important protein substrates. For example, USP19 interacts with SIAH proteins to rescue HIF1α from degradation under hypoxic conditions (Altun M. et al., J. Biol. Chem. (2012) 287, 1962-1969; Velasco K. et al., Biochem. Biophys. Res. Commun. (2013), 433, 390-395). USP19 also stabilizes the KPC1 ubiquitin ligase, which is involved in the regulation of the p27 cyclin-dependent kinase inhibitor ^Kip1 (Lu Y. et al., Mol. Cell Biol. (2009), 29, 547-558). Knockout of USP19 by RNAi leads to accumulation of p27 ^Kip1 and inhibition of cell proliferation (Lu L. et al., PLoS ONE (201 1), 6, e15936). USP19 has also been found to interact with inhibitors of apoptosis (IAP), including c-IAP1 and c-IAP2 (Mei Y. et al., J. Biol. Chem. (2011), 286, 35380-35387). Knockdown of USP19 reduces the overall levels of these c-IAPs, while overexpression increases the levels of both BIRC2/cIAP1 and BIRC3/cIAP2. Knockdown of USP19 also enhances TNFα-induced caspase activation and apoptosis associated with BIRC2/c-IAP1 and BIRC3/c-IAP2. In addition to some direct involvement in the regulation of the response to hypoxia and ER stress, USP19 has also recently been found to be involved as a positive regulator of autophagy and a negative regulator of type I interferon (IFN, antiviral immune response) signaling by deubiquitinating beclin-1. USP19 was found to stabilize beclin-1 at the post-translational level by removing K11-linked beclin-1 ubiquitin chains at lysine 437 (Jin S. et al., EMBO J. (2016), 35, 866-880). USP19 negatively regulates the type I IFN signaling pathway by blocking RIG-I-MAVS interaction in a Beclin-1 dependent manner. Depletion of either USP19 or Beclin-1 inhibits autophagic flux and stimulates type I IFN signaling as well as cellular antiviral immunity (Jin S. et al., EMBO J. (2016), 35, 866-880; Cui J. et al ., Autophagy (2016), 12, 1210-1211). Recent evidence also indicates that USP19 may negatively affect IFN type I antiviral signaling in cells by regulating the TRAF3 substrate (Gu Z. et al., Future Microbiol. (2017), 12, 767-779). It has also recently been found that USP19 is involved in the Wnt signaling pathway by stabilizing the LRP6 co-receptor (Perrody E. et al., ELife (2016), 5, e19083), and in DNA repair processes, especially chromosomal DNA, maintaining their stability and integrity by regulating proteins. HDAC1 and HDAC2 (Wu M. et al., Oncotarget (2017), 8, 2197-2208).

In addition to cancer and related conditions, USP19 is often implicated in muscle wasting syndromes and other skeletal muscle wasting 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). This is confirmed, for example, by studies where USP19 silencing has been shown to induce the expression of myofibrillar proteins and promote 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 More recently, in vivo studies further demonstrated that mice lacking the USP19 gene (USP19 KO mice) were resistant to muscle wasting in response to glucocorticoid, a common systemic cause of muscle atrophy, as well as in response to denervation in an atrophy model (Bedard N. et al., FASEB J. (2015), 29, 3889-3898). USP19 KO mice tended to retain greater muscle strength and had less myofibrillar atrophy while protecting type I and type IIb fibers. The rate of muscle protein synthesis was similar in both WT and KO mice, suggesting that suppression of atrophy is associated with suppression of protein degradation. Consistently, the expression of MuRF1 ubiquitin ligase and MAFbx/atrogin-1, as well as several autophagy genes, were reduced in the muscles of catabolic KO mice (Bedard N. et al., FASEB J. (2015), 29, 3889-3898) . Therefore, inhibition of USP19 may be a useful approach in the treatment of many atrophic conditions, including but not limited to cachexia and sarcopenia. For example, cachexia is well known to impair quality of life and response to therapy, which increases disease severity and mortality in cancer patients. However, the above findings have potentially much broader clinical implications beyond cancer, as 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 characteristic feature of aging. In addition to the above pathological conditions, USP19 may also play a role in the pathogenesis of degenerative diseases, including, but not limited to, Parkinson's disease and other prion-like signaling disorders, by regulating important substrates such as α-synuclein or polyglutamine-containing proteins, ataxin3, Huntington (He W. et al., PLoS ONE (2016), 11, e0147515 Bieri G. et al., Neurobiol Dis. (2017), doi: 10.1016/j.nbd.2017.03.007). The regulation of coronin 2A (COR02A) through USP19 activity has been shown to influence the transcriptional repressive activity of the retinoic acid receptor (RAR), suggesting that USP19 may also be involved in the regulation of RAR-mediated adipogenesis (Lim K. et al., Oncotarget ( 2016), 7, 34759-34772).

Established and continually discovered links between USP19 and numerous proteins involved in human pathologies indicate that small molecule inhibitors of USP19 may have a wide range of therapeutic applications beneficial to human health. However, to the best of our knowledge, nothing has been reported on any inhibitors targeting USP19, and therefore the identification of such inhibitors with drug-like potential remains of paramount importance and a high priority in research and development.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides a compound of formula (I):

including a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof, where:

R ₁ is an optionally substituted alkyl, alkenyl, alkynyl, ether, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group;

R ₂ is H or an optionally substituted alkyl group,

R ₃ is H or an optionally substituted alkyl group,

R ₄ is H or an optionally substituted alkyl group,

R ₅ is H or an optionally substituted alkyl group,

R ₂ and R ₄ can be connected to each other to form an optionally substituted cycloalkyl or heterocycloalkyl ring containing the carbon atoms to which they are attached,

R ₄ and R ₅ may be connected to each other to form an optionally substituted cycloalkyl or heterocycloalkyl ring containing the carbon atoms to which they are attached;

R ₆ is H or an optionally substituted alkyl group;

W is C or N;

X is N or CR ₈ where R ₈ is H or optionally substituted C1-C6 alkyl,

Y is N or CR ₉

Z is CH or NH,

where R ₉ represents H or optionally substituted alkyl, amido, amino, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, halogen, carbonyl, ester, aminoalkyl or cyano;

R ₇ is hydrogen, halogen, or an optionally substituted alkyl, alkenyl, alkynyl, amino, aryl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryl, or heterocycloalkyl group;

or connection

or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof.

In a second aspect, the invention relates to a pharmaceutical composition comprising a compound according to the first aspect and a pharmaceutically acceptable carrier or diluent.

USP19 is associated with a number of diseases and conditions, including (but not limited to) cancer and neoplastic conditions, as well as muscle wasting, including (but not limited to) cachexia and sarcopenia.

The compounds described herein are capable of selectively inhibiting the activity of USP19. Therefore, the compounds provided herein may be suitable for the treatment and prevention of cancers and tumors, immunological and inflammatory pathologies, for example, by stimulating an antiviral immune response, as well as for the treatment and prevention of muscle atrophy, such as cachexia and sarcopenia, neurodegenerative diseases, including Parkinson's and other prion disorders. The compounds may be used as monotherapy or in combination therapy with radiation and/or additional therapeutic agents.

Therefore, in a further aspect, the invention provides a compound according to the first aspect, or a pharmaceutical composition according to the second aspect, for use in therapy. In a further aspect, the invention provides a compound according to a first aspect, or a pharmaceutical composition according to a second aspect, for use in a method for treating or preventing cancer. In a further aspect, the invention provides a compound according to a first aspect, or a pharmaceutical composition according to a second aspect, for use in a method for treating or preventing muscle atrophy, optionally cachexia or sarcopenia. In a further aspect, the invention provides a compound according to the first aspect, or a pharmaceutical composition according to the second aspect, for use in a method for the treatment or prevention of Parkinson's disease.

In a further aspect, the invention relates to a method for treating cancer or muscle wasting, comprising administering to a subject an effective amount of a compound according to the first aspect or a pharmaceutical composition according to the second aspect.

In a further aspect, the invention relates to a method for treating Parkinson's disease comprising administering to a subject an effective amount of a compound according to the first aspect or a pharmaceutical composition according to the second aspect.

Other preferred variants of the compounds according to the invention are presented in the description and, in particular, in the examples. Particularly preferred are those listed as having greater potency as tested. Compounds having higher activity are preferred over compounds having lower activity.

Each aspect or embodiment of the invention as defined herein may be combined with any other aspect(s) or embodiment(s) unless otherwise indicated. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

figures

Fig.1. The overall selectivity profile of the compound of Example 124 with respect to the DUB panel. Included in this panel are 24 USPs and 19 other DUBs (as listed). The compound of example 124 was screened at a fixed concentration of 100 μmol using the substrate Ub-Rh110 (Ubiquigent). Y-axis shows residual activity, normalized to control, without compound (DMSO).

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise defined, the scientific and technical terms used herein in connection with the present invention have the meanings that are commonly understood by those skilled in the art. The meaning and scope of the terms is clear, however, in case of any possible ambiguity, the definitions provided in this document take precedence over any dictionary or third party definitions.

Unless otherwise indicated, the following terms used in the description of the invention and the appended claims have the meanings indicated.

The term "alkyl group" (by itself or in combination with other term(s)) means a linear or branched saturated hydrocarbon substituent typically containing 1 to 15 carbon atoms, e.g., 1 to 10, 1 to 8, 1 up to 6, or from 1 to 4 carbon atoms. "C _n alkyl" group refers to an aliphatic group containing n carbon atoms. For example, a C ₁ -C ₁₀ alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Attachment to the alkyl group occurs through a carbon atom. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (branched or straight), hexyl (branched or straight), heptyl (branched or straight), octyl (branched or straight). ), nonyl (branched or unbranched), and decyl (branched or unbranched).

The term "alkenyl group" (by itself or in combination with other term(s)) means a linear or branched hydrocarbyl 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.

The term "alkynyl group" (by itself or in combination with other term(s)) means a linear or branched hydrocarbyl 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.

The term "heteroalkyl group" (by itself or in combination with other term(s)) means a straight or branched saturated hydrocarbon substituent, typically containing from 1 to 15 atoms, for example 1 to 10, 1 to 8, from 1 to 6, or 1 to 4 atoms, where at least one of the atoms is a heteroatom (ie oxygen, nitrogen or sulfur) and the remaining atoms are carbon atoms. The term "C _n heteroalkyl" refers to an aliphatic group containing n carbon atoms and one or more heteroatoms, such as one heteroatom. For example, a C ₁ -C ₁₀ heteroalkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in addition to one or more heteroatoms, for example one heteroatom. Attachment to a heteroalkyl group occurs through a carbon atom or through a heteroatom.

The term "heteroalkenyl group" (by itself or in combination with other term(s)) means a straight or branched hydrocarbon substituent containing one or more carbon-carbon double bonds and typically 2 to 15 atoms; for example, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 atoms, where at least one of the atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur) and the remaining atoms are carbon atoms . The term "C _n heteroalkenyl" refers to an aliphatic group containing n carbon atoms and one or more heteroatoms, such as one heteroatom. For example, a C ₂ -C ₁₀ heteroalkenyl group contains 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms in addition to one or more heteroatoms, such as one heteroatom. Attachment to a heteroalkenyl group occurs through a carbon atom or through a heteroatom.

The term "heteroalkynyl group" (by itself or in combination with other term(s)) means a straight or branched hydrocarbon substituent containing one or more carbon-carbon triple bonds and typically 2 to 15 carbon atoms; for example, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms, where at least one of the atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur) and the remaining atoms are atoms carbon. The term "C _n heteroalkynyl" refers to an aliphatic group containing n carbon atoms and one or more heteroatoms, such as one heteroatom. For example, a C ₂ -C ₁₀ heteroalkynyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in addition to one or more heteroatoms, eg one heteroatom. Attachment to the heteroalkynyl group occurs through a carbon atom or through a heteroatom.

The term "carbocyclyl group" (by itself or in combination with other term(s)) means saturated cyclic (i.e. "cycloalkyl"), partially saturated cyclic (i.e. "cycloalkenyl") or fully unsaturated (i.e. "aryl") a hydrocarbon substituent containing from 3 to 14 carbon ring atoms ("ring atoms" are atoms bonded together to form a ring or rings of a cyclic substituent). Carbocyclyl can be only one ring (monocyclic carbocyclyl) or a polycyclic ring structure.

Carbocyclyl may be a structure with only one ring, which typically contains 3 to 8 ring atoms, more typically 3 to 7 ring atoms, and even more typically 5 to 6 ring atoms. Examples of such carbocyclyls with only one ring include cyclopropyl (cyclopropanyl), cyclobutyl-(cyclobutanyl), cyclopentyl (cyclopentanyl), cyclopentenyl, cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl, cyclohexadienyl and phenyl. Alternatively, carbocyclyl may be polycyclic (ie may contain more than one ring). Examples of polycyclic carbocyclyls include bridged, fused and spirocyclic carbocyclyls. In spirocyclic carbocyclyl, one atom is shared by two different rings. An example of a spirocyclic carbocyclyl is spiropentanyl. In a bridged carbocyclyl, the rings share at least two non-adjacent atoms in common. Examples of bridged carbocyclyls include bicyclo[2.2.1]heptanyl, bicyclo-[2.2.1]hept-2-enyl and adamantyl. In a carbocyclyl with a fused ring system, two or more rings may be fused, whereby the two rings share one common bond. Examples of carbocyclyls with two or three fused rings include naphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.

The term "cycloalkyl group" (by itself or in combination with other term(s)) means a saturated cyclic hydrocarbon substituent containing from 3 to 14 carbon ring atoms. Cycloalkyl may be only one carbon ring, which typically contains 3 to 8 carbon ring atoms, and more typically 3 to 6 ring atoms. It should be borne in mind that the attachment to the cycloalkyl group occurs through the ring atom of the cycloalkyl group. Examples of single ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Alternatively, cycloalkyl may be polycyclic or contain more than one ring. Polycyclic cycloalkyls include bridged, fused and spirocyclic cycloalkyls.

The term "alkylcycloalkyl" refers to a cycloalkyl substituent attached through an alkyl chain. Examples of the alkylcycloalkyl substituent include cyclohexylethane, where the cyclohexane is attached via an ethane linker. Other examples include cyclopropylethane, cyclobutylethane, cyclopentylethane, cycloheptylethane, cyclohexylmethane. In "C _n " alkylcycloalkyl, C _n includes carbon atoms in the alkyl chain and in the cycloalkyl ring. For example, cyclohexylethane is C ₈ alkylcycloalkyl.

The term "aryl group" (by itself or in combination with other term(s)) means an aromatic carbocyclyl containing 5 to 14 carbon atoms, optionally 5 to 8, 5 to 7, optionally 5 to 6 carbon atoms . "C _n aryl" refers to an aromatic group containing n carbon atoms. For example, a C ₆ -C ₁₀ aryl group contains 6, 7, 8, 9, or 10 carbon atoms. Attachment to the aryl group occurs through a carbon atom. The aryl group may be monocyclic or polycyclic (ie may contain more than one ring). In the case of polycyclic aromatic rings, only one ring in the polycyclic system is required to be unsaturated, while the remaining rings may be saturated, partially saturated, or unsaturated. Attachment to the aryl group occurs through the carbon atom of the ring. Examples of aryl groups include phenyl, naphthyl, acridinyl, indenyl, indanyl and tetrahydronaphthyl.

The term "arylalkyl" refers to an aryl substituent attached through an alkyl chain. Examples of the arylalkyl substituent include phenylethane/ethylbenzene where the ethane chain bonds to the phenyl group up to the point of attachment. In "C _n " arylalkyl, C _n includes carbon atoms in the alkyl chain and in the aryl group. For example, ethylbenzene is C ₈ arylalkyl.

The term "heterocyclyl group" (by itself or in combination with other term(s)) 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, where at least one of the ring atoms is a heteroatom (ie oxygen, nitrogen or sulfur), while the remaining ring atoms are carbon atoms. The heterocyclyl group may, for example, contain one, two, three, four or five heteroatoms. Attachment to a heterocyclyl group can occur either through a carbon atom and/or through one or more heteroatoms that are in the ring. The heterocyclyl may be a single ring (monocyclic) or polycyclic ring structure.

The heterocyclyl group may be a single ring which typically contains 3 to 7 ring atoms, more typically 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples of single ring heterocyclyls include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolidinyl , isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (furazanil) or 1 ,3,4-oxadiazolyl), oxatriazolyl, imidazolinyl, imidazolidinyl, dioxazolyl oxathiolyl, pyranyl, dihydropyranyl, thiopyranyl, tetrahydrothiopyranyl, pyridinyl (azinyl), piperidinyl, diazinyl (including pyridazinyl (1,2-diazinyl), pyrimidinyl (1,2-diazinyl), 3-diazinyl) or pyrazinyl (1,4-diazinyl), piperazinyl, triazinyl (including 1,3,5-triazinyl, 1,2,4-triazinyl and 1,2,3-triazinyl)), oxazinyl (in including 1,2-oxazinyl, 1,3-oxazinyl or 1,4-oxazinyl), oxadiazinil (including 1,2,3-oxadiazinyl, 1,2,4-oxadiazinyl, 1,4,2-oxadiazinyl or 1,3,5-oxadiazinyl), morpholinyl, azepinil, oxepinil, thiepinyl and diazepinil.

Alternatively, the heterocyclyl group may be polycyclic (ie may contain more than one ring). Examples of polycyclic heterocyclyl groups include bridged, fused, and spirocyclic heterocyclyl groups. In a spirocyclic heterocyclyl group, one atom is shared by two different rings. In a bridged heterocyclyl group, the rings share at least two common non-adjacent atoms. In a fused ring heterocyclyl group, two or more rings may be fused, whereby the two rings share one common bond. Examples of fused ring heterocyclyl groups containing two or three rings include indolizinyl, pyranopyrrolyl, 4H-quinolisinyl, 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 benzofused heterocyclyl groups such as indolyl, isoindolyl (isobenzazolyl, pseudoisoindolyl), indoleninyl (pseudoindolyl), isoindazolyl (benzpyrazolyl), benzazinyl (including quinolinyl (1-benzazinyl) or isoquinolinyl (2-benzazinyl) ), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (1,2-benzodiazinyl) or quinazolinyl (1,3-benzodiazinyl)), benzopyranyl (including chromanil or isochromanil), and benzisoxazinyl (including 1,2 -benzisoxazinyl or 1,4-benzisoxazinyl).

The term "heterocycloalkyl group" (by itself or in combination with other term(s)) means a saturated heterocyclyl. The term "C _n heterocycloalkyl" refers to a cyclic aliphatic group containing n carbon atoms in addition to at least one heteroatom, such as nitrogen. For example, a C ₁ -C ₁₀ heterocycloalkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ring carbon atoms in addition to at least one heteroatom. Attachment to the heterocycloalkyl group occurs via a carbon atom or at least one heteroatom.

The term "alkylheterocycloalkyl" refers to a heterocycloalkyl substituent attached through an alkyl chain. In "C _n " alkylheterocycloalkyl, C _n includes carbon atoms in the alkyl chain and in the heterocycloalkyl ring. For example, ethylpiperidine is C ₇ alkylheterocycloalkyl.

The term "heteroaryl group" (by itself or in combination with other term(s)) means an aromatic heterocyclyl containing from 5 to 14 ring atoms. The term "C _n heteroaryl" refers to an aromatic group containing n carbon atoms and at least one heteroatom. For example, a C ₂ -C ₁₀ aryl group contains 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms in addition to at least one heteroatom. Attachment to a heteroaryl group occurs through a carbon atom or through a heteroatom. The heteroaryl group may be monocyclic or polycyclic. The heteroaryl may be one ring or 2 or 3 fused rings. Examples of monocyclic heteroaryl groups include 6-membered rings such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and 1,3,5-, 1,2,4- or 1,2,3-triazinyl; 5-membered rings such as imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-oxadiazolyl and isothiazolyl. Polycyclic heteroaryl groups may be 2 or 3 fused rings. Examples of polycyclic heteroaryl groups include 6/5-membered fused ring groups such as benzothiofuranyl, benzisoxazolyl, benzoxazolyl and purinyl; and 6/6-membered fused ring groups such as benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and benzoxazinyl. In the case of polycyclic heteroaryl groups, only one ring in the polycyclic system needs to be unsaturated, while the remaining ring(s) may be saturated, partially saturated or unsaturated.

A nitrogen-containing heteroaryl group is a heteroaryl group in which at least one of one or more heteroatoms in the ring is nitrogen.

The term "heteroarylalkyl" refers to a heteroaryl substituent attached through an alkyl chain. Examples of the heteroarylalkyl substituent include ethylpyridine, where the ethane chain links the pyridine group to the point of attachment.

The term "amino" refers to the group -NR'R''. The amino group may be optionally substituted. In an unsubstituted amino group, R' and R'' are hydrogen. In a substituted amino group, each R' and R'' can independently be, but not limited to, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, sulfonyl, alkenyl, alkanoyl, aryl, arylalkyl, or heteroaryl, provided that R' and R'' are not both hydrogen. In a substituted amino group, R' and R'' may be cyclized to form a cyclic amino group, such as a pyrrolidine group or a piperidine group. Such a cyclic amino group may include other heteroatoms, for example to form a piperazine or morpholine group. Such a cyclic amino group may be optionally substituted with, for example, an amino group, a hydroxyl group, or an oxo group.

The term "aminoalkyl" group refers to the group -R ^a NR'R'', where R ^a represents an alkyl chain, as defined above, and NR'R'' represents an optionally substituted amino group, as defined above. "C _n aminoalkyl" refers to a group containing n carbon atoms. For example, a C ₁ -C ₁₀ aminoalkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. When the amino group in an aminoalkyl group is a substituted amino group, the number of carbon atoms includes any carbon atoms in the substituent groups. Attachment to the aminoalkyl group occurs through the carbon atom R ^a of the alkyl group. Examples of aminoalkyl substituents include methylamine, ethylamine, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, methylpyrrolidine, and ethylpyrrolidine.

The term "amido" refers to the group -C(=O)-NR-. Attachment may be via a carbon atom and/or a nitrogen atom. For example, the amido group can only be attached as a substituent through the carbon atom, in which case the nitrogen atom has two attached R groups (-C(=O)-NR ₂ ). The amido group can only be attached through the nitrogen atom, in which case the carbon atom has two attached R groups (-NR-C(=O)R).

The term "ether" refers to an -O-alkyl group or -alkyl-O-alkyl group, such as a methoxy group, a methoxymethyl group, or an ethoxyethyl group. The ether alkyl chain(s) may be straight, branched or cyclic. The ether group may be optionally substituted ("substituted ester") with one or more substituents. The term "C _n ether" refers to an ester group having n carbon atoms in all alkyl chains of the ether group. For example, CH(CH ₃ )-OC ₆ H ₁₁ ether is a C ₈ ether group.

The term "alkoxy group" refers to an -O-alkyl group. The alkoxy group may refer to linear, branched or cyclic saturated or unsaturated oxo hydrocarbon chains including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, tert-butoxyl and pentoxyl. The alkoxy group may be optionally substituted ("substituted alkoxy group") with one or more alkoxy substituent groups.

The term "alkyl ether" refers to the group -C(O)OR, where R is an alkyl group as defined herein. An example of an alkyl ether is ethyl methanoate, i.e. where R is an ethyl group.

The term "hydroxyl" refers to the -OH group.

The term "oxo group" refers to a (=O) group, that is, an r substituent from an oxygen atom linked to another atom by a double bond. For example, a carbonyl group (-C(=O)-) is a carbon atom linked by a double bond to an oxygen atom, that is, an oxo group attached to a carbon atom. Examples of carbonyl substituents include aldehyde (-C(=O)H), acetyl (-C(=O)CH ₃ ) and carboxylic/carboxylic acid (-C(=O)OH) groups.

The term "halogen" refers to a group selected from chlorine, fluorine, bromine and iodine. Preferably, the halogen is selected from chlorine and fluorine.

Alkyl, alkenyl, alkynyl, carbocyclyl (including cycloalkyl, cycloalkenyl, and aryl), heterocyclyl (including heterocycloalkyl, heterocycloalkenyl, heteroaryl, and nitrogen containing heterocyclyl), amino, amido, ether, ester, alkoxy, or sulfonamide may be optionally substituted with one or more substituents, which may be the same or different. The substituent may be attached via a carbon atom and/or a heteroatom in alkyl, alkenyl, alkynyl, carbocyclyl (including cycloalkyl, cycloalkenyl and aryl), heterocyclyl (including heterocycloalkyl, heterocycloalkenyl and heteroaryl, nitrogen-containing heterocyclyl amino, amido, simple ether, ester, alkoxy, or sulfonamide 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, halogen, 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, aryloxy , alkoxy, alkylthio, arylthio, aralkyloxy, aralkylthio, carboxyl, alkoxycarbonyl, oxo, alkylsulfonyl, arylsulfonyl, and sulfoximine ill.

In some aspects of the invention, the substituent is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, 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, aryloxy, alkoxy, alkylthio, arylthio, aralkyloxy, aralkylthio, carboxyl, alkoxycarbonyl, oxo, alkylsulfonyl and arylsulfonyl.

When a group, such as an alkyl group, is "optionally substituted", it is understood that the group has one or more linked (substituted) substituents, or no linked (substituted) substituents.

When a group is further substituted with an optionally substituted group, it is understood that the first substituent may itself be either unsubstituted or substituted.

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

In any aspect, the compounds of the present invention may have some signs of stereochemistry. For example, the compounds may have chiral centers and/or planes and/or axes of symmetry. Therefore, the compounds may be obtained as individual stereoisomers, individual diastereomers, mixtures of stereoisomers, or as racemic mixtures, unless otherwise indicated. Stereoisomers are molecules that have the same molecular formula and sequence of linked atoms, but which differ in the spatial orientations of their atoms and/or groups.

In addition, the compounds of the present invention may exhibit tautomerism. Each tautomeric form is intended to be within the scope of the invention.

In addition, the compounds of the present invention can be obtained in the form of prodrugs. Prodrugs are converted, usually in vivo, from one form to active forms of the drugs described in the invention.

In addition, it should be borne in mind that the chemical elements described in the invention may be a conventional isotope or an isotope that is not a conventional isotope. For example, the hydrogen atom may be ¹ H, ² H (deuterium), or ³ H (tritium).

In addition, the compounds of the present invention can be obtained in the form of their pharmaceutically acceptable salts or co-crystals.

The term "pharmaceutically acceptable salt" refers to ionic compounds formed by adding an acid to a base. The term refers to such salts that are considered suitable for use in patient contact, eg in vivo, and pharmaceutically acceptable salts are generally selected based on their lack of toxicity and irritant action.

The term "co-crystal" refers to a multicomponent molecular crystal, which may include non-ionic interactions.

Pharmaceutically acceptable salts and co-crystals can be obtained by ion exchange chromatography or by reacting the free base or acid form of the compound with stoichiometric amounts or excess of the desired salt-forming inorganic or organic acid or base in one or more suitable solvents, or by mixing the compound with another pharmaceutically acceptable compound. capable of forming a cocrystal.

Known salts commonly used in patient contact 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 alkali and alkaline earth metal cations such as sodium, potassium, calcium and magnesium, as well as ammonium, tetramethylammonium, tetraethylammonium. References may be made to a number of literature references that discuss suitable pharmaceutically acceptable salts, such as the Handbook of pharmaceutical salts published by the International Union of Pure and Applied Chemistry (IUPAC).

In addition, the compounds of the present invention may sometimes exist in the form of zwitterions, which are considered part of the invention.

Accordingly, in a first aspect, the present invention relates to a compound of formula (I):

including a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof, where:

R ₁ is an optionally substituted alkyl, alkenyl, alkynyl, ether, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group;

R ₂ is H or an optionally substituted alkyl group,

R ₃ is H or an optionally substituted alkyl group,

R ₄ is H or an optionally substituted alkyl group,

R ₅ is H or an optionally substituted alkyl group,

R ₂ and R ₄ can be connected to each other to form an optionally substituted cycloalkyl or heterocycloalkyl, including the carbon atoms to which they are attached,

R ₄ and R ₅ can be connected to each other with the formation of optionally substituted cycloalkyl or heterocycloalkyl, including the carbon to which they are attached;

R ₆ is H or an optionally substituted alkyl group;

W is C or N;

X is N or CR ₈ where R ₈ is H or optionally substituted C ₁ -C ₆ alkyl,

Y is N or CR ₉

Z is CH or NH,

where R ₉ represents H or optionally substituted alkyl, amido, amino, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, halogen, carbonyl, ester, aminoalkyl or cyano;

R ₇ is hydrogen, halogen, or an optionally substituted alkyl, alkenyl, alkynyl, amino, aryl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryl, or heterocycloalkyl group;

or to the connection

or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof.

In some embodiments, R ₁ is an optionally substituted C1-C6 alkyl, an optionally substituted C4-C10 alkylcycloalkyl, an optionally substituted C7-C10 arylalkyl, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted C3-C6 heteroaryl, wherein the optional substituent is selected from C1 -C6-alkyl, C2-C6-alkenyl, methoxymethyl, benzyloxymethyl, phenyl, C3-C6-cycloalkyl, CF3, CHF2, OH or halogen. In some such embodiments, R ₁ is an optionally substituted cyclohexylalkane, preferably an optionally substituted cyclohexylethane; optionally substituted alkylbenzene, preferably ethylbenzene; or an optionally substituted 3,3,3-trifluoropropane and the optional substituent is selected from C1-C6 alkyl, C2-C6 alkenyl, hydroxymethyl, methoxymethyl, OH, or halogen. In some embodiments, R ₁ is substituted and the substituent is C1-C6 alkyl, optionally methyl.

In some embodiments, R ₇ is optionally substituted with C6-C10 aryl, C1-C12 heteroaryl, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, amino, C1-C3 alkoxy, or halogen, and the optional substituent is selected from C1- C6 alkyl, hydroxy-substituted C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 heterocycloalkyl, C1-C6 alkoxy, halo-substituted C1-C6 alkoxy, amido, cyano or halogen. In some embodiments, R ₇ is optionally substituted phenyl, naphthalenyl, indazole, pyrimidine, thiophene, or pyrazole, wherein the optional substituent is selected from C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 heterocycloalkyl, C1 -C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamine, amido, cyano or halogen.

In some embodiments, R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are independently selected from H and C1-C6 alkyl.

In some such embodiments, R ₂ , R ₃ and R ₆ are H, and R ₄ and R ₅ are methyl. Thus, the connection includes the following kernel structure:

In some alternative embodiments, R ₄ and R ₅ are bonded to each other to form an optionally substituted C3-C6 cycloalkyl or C3-C6 heterocycloalkyl that includes the carbon to which they are attached, and R ₂ , R ₃ and R ₆ are independently selected from H and C1-C6 alkyl. In some such embodiments, R ₂ , R ₃ and R ₆ are H, and R ₄ and R ₅ are attached to each other to form a C3-C6 cycloalkyl which includes the carbon to which they are attached, optionally a C4 or C5 cycloalkyl , which includes the carbon they are attached to. Thus, the connection includes the following kernel structure:

These nuclear structures are particularly preferred because they have an unexpected high potency for USP19 inhibition. In some embodiments of the invention, compounds having one of these nuclear structures have increased activity compared to equivalent unsubstituted compounds (ie, where R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are H).

When R ₂ and/or R ₃ are not hydrogen and R ₄ and R ₅ are hydrogen (or alternatively when R ₂ and R ₃ are hydrogen and R ₄ and/or R ₅ are not hydrogen), the tertiary alcohol of piperidinol is chiral. Embodiments relating to compounds with this structure cover all stereosomers unless otherwise noted. That is, embodiments of the invention relating to chiral compounds encompass both R- and S-stereoisomers unless the R- or S-stereoisomer is explicitly stated. In certain preferred embodiments of the invention, the chiral stereoisomer of the compounds is the S-isomer.

In some embodiments, R ₂ and R ₄ are connected to each other to form a C5 cycloalkyl that includes the carbon atoms to which they are attached, and where R ₃ , R ₅ and R ₆ are independently H or C 1 -C 6 alkyl.

In certain embodiments, W is N and X is CR ₈ where R ₈ is H or methyl.

In some embodiments, Y is N or CR ₉ where R ₉ is H, C1-C6 alkyl, NR'R'', C(O)NR'R'', cyano, carboxyl, halogen, C1-C6 alkylamine, C3-C6 alkyl ether, optionally substituted C6-C10 aryl, or optionally substituted C2-C6 heteroaryl, wherein one or more heteroatoms are selected from N and O and one or more optional aryl or heteroaryl substituents are selected from C1-C6 alkyl, C1 -C6 alkylamine, amido and cyano, and wherein R' and R'' are independently selected from H, C1-C6 alkyl optionally substituted with OH, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, C4-C7 alkylcycloalkyl, C3-C7 alkylheterocycloalkyl, benzyl, phenyl and methoxy. Alternatively, R' and R'' may be linked together to form a C2-C7 heterocycle that includes the N to which they are attached, where the heterocycle is optionally hydroxyl-substituted, oxo-substituted, methyl-substituted, CH2OH-substituted, or acetyl-substituted.

In certain embodiments, R ₉ is selected from: phenyl, optionally substituted amido, cyano, or methylamine; pyridine; oxazole, pyrazole; carboxyl; C(O)NR'R''; or NR'R''; where R' and R'' are independently selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, where the heteroatom is N or O, or alternatively R' and R'' may be connected to each other to form a C2-C7 heterocycloalkyl which includes the N to which they are attached, wherein the heterocycloalkyl is optionally hydroxyl-substituted, oxo-substituted, methyl-substituted, CH2OH-substituted or acetyl-substituted.

In some embodiments, the heterocycloalkyl formed by R' and R'' includes one or more heteroatoms selected from N, O, or S in addition to the N to which they are attached. For example, in some embodiments, the heterocycloalkyl formed by R' and R'' is a pyrrolidine, piperidine, piperazine, or morpholine group, where the heterocycloalkyl is optionally hydroxyl-substituted, oxo-substituted, methyl-substituted, CH2OH-substituted, or acetyl-substituted.

In certain embodiments of the invention:

R ₁ is selected from optionally substituted ethylcyclohexane, optionally substituted ethylbenzene and optionally substituted 3,3,3-trifluoropropane, where the optional substituent is one or more of methyl, ethyl, propyl, propenyl, hydroxymethyl and methoxymethyl,

R ₂ and R ₃ are independently selected from H, methyl,

R ₄ and R ₅ are independently selected from H, methyl, or connected to each other to form a C3-C6 cycloalkyl or heterocycloalkyl which includes the carbon to which they are attached, optionally a C4 or C5 cycloalkyl which includes the carbon to which they are attached ,

R ₆ is H or methyl,

R ₇ is selected from optionally substituted phenyl, indazole, thiophene, or pyrazole, where the optional substituent is selected from C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 heterocycloalkyl, C1-C6 alkoxy, halo-substituted C1-C6 alkoxy , C1-C6 alkylamine, amido, cyano or halogen,

W is N or C,

X is CH or N,

Z is C or NH,

Y is N or CR ₉ where R ₉ is phenyl optionally substituted with amido, cyano or methylamine; pyridine; oxazole; pyrazole; C(O)NR'R''; or NR'R'';

where R' and R'' are independently selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, where the heteroatom is N or O, or where R' and R'' are connected to each other to form C2 -C7 heterocycloalkyl which includes the N to which they are attached, where heterocycloalkyl is optionally hydroxyl-substituted, oxo-substituted, methyl-substituted, CH2OH-substituted or acetyl-substituted.

In some embodiments, Y is CR ₉ , where R ₉ is C(O)NR'R'', and where R' and R'' are joined to each other to form an optionally substituted pyrrolidine, piperidine, piperazine, or morpholine, which includes the N to which they are attached, where pyrrollidine, piperidine, piperazine or morpholine is optionally hydroxyl-substituted, oxo-substituted, methyl-substituted, CH2OH-substituted or acetyl-substituted.

In certain embodiments of the invention, the compound of formula (I) is selected from the following compounds, and is:

( R )-5-bromo-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2( 1H )-one,

6-(2-fluorophenyl)-3-((4-hydroxy-1-(3-phenylpropanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one,

3-((1-(3-cyclobutylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one,

3-((1-(3-cyclopentylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one,

( R , S )-6-(2-fluorophenyl)-3-((4-hydroxy-1-(2-methyl-3-phenylpropanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one ,

( R ) -N- (3-(1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3- yl)phenyl)acetamide,

( R )-3-(1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)6-oxo-4-phenyl-1,6-dihydropyridin-3-yl)benzamide,

( R )-5-(furan-2-yl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2( 1H )-one,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(1-methyl- 1H -pyrazol-5-yl)-4-phenylpyridin-2 (1 H )-he,

( R )-4-chloro-1-((4-hydroxy-1(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-phenylpyridin-2( 1H )-one,

( R )-4-(dimethylamino)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-phenylpyridin-2( 1H )-one,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-phenyl-4-(prop-1-en-2-yl)pyridine-2(1 H )-he,

( R )-ethyl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate,

( R,S )-4-(2-fluorophenyl)-1-((4-hydroxy-1-(2-methyl-1,2,3,4-tetrahydronaphthalene-2-carbonyl)piperidin-4-yl)methyl ) -N -isopropyl- N -methyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

( R , S )-1-((1-(3-cyclobutyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-phenyl-5-(piperidine-1-carbonyl)pyridine-2( 1 H )-he,

( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(1-methyl- 1H -indazol-7-yl)pyrimidin-4( 3H )-he,

( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4( 3H )-one,

( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-2-methyl-6-phenylpyrimidin-4( 3H )-one,

( R )-2-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5,6-diphenylpyridazin-3( 2H )-one,

( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(naphthalen-1-yl)pyrimidin-4( 3H )-one,

( R )-6-(3-(1,3-dioxolan-2-yl)phenyl)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3 H )-he,

( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(thiophen-3-yl)pyrimidin-4( 3H )-one,

4-(2-fluorophenyl)-1-((4-hydroxy-1-(1-methylcyclopentan-1-carbonyl)piperidin-4-yl)methyl) -N -isopropyl- N -methyl-6-oxo-1, 6-dihydropyridine-3-carboxamide,

3-((1-(1-ethylcyclohexane-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one,

3-((1-(2-(cyclohexylmethyl)-3-methylbutanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidine-4(3 H )- he,

( R )-6-(furan-2-yl)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2( 1H )-one,

( R )-6-(cyclohex-1-en-1-yl)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one ,

( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(prop-1-en-2-yl)pyrimidin-4( 3H )-one ,

( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(2-(trifluoromethoxy)phenyl)pyrimidin-4( 3H )-one,

3-(((1 R ,5 S )-3-(( R )-3-cyclohexyl-2-methylpropanoyl)-8-hydroxy-3-azabicyclo[3.2.1]octan-8-yl)methyl)-6 -(2-fluorophenyl)pyrimidin-4(3 H )-one,

( R )-6-(2-fluorophenyl)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one,

( R )-5-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-2-phenylpyrimidin-4( 3H )-one,

3-((4-hydroxy-1-(3-phenylpropanoyl)piperidin-4-yl)methyl)-2-methyl-6-phenylpyrimidin-4( 3H )-one,

( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(isobutylamino)pyrimidin-4( 3H )-one,

( R )-1-((1-(3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-phenyl-5-(piperidine-1-carbonyl)pyridine-2( 1H )-he,

( R )-2-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-phenylpyridazin-3( 2H )-one,

( R )-4-(2-cyanophenyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl) -N -isopropyl- N -methyl-6-oxo-1, 6-dihydropyridine-3-carboxamide,

( R )-3-((1-(3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one,

3-((1-(2-(cyclohexylmethyl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one,

rac- 6-(2-fluorophenyl)-3-((4-hydroxy-1-( cis -2-phenylcyclopropanecarbonyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one,

6-(2-fluorophenyl)-3-((4-hydroxy-1-(1-methylcyclohexanecarbonyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one,

3-(( S )-1-(1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)propyl)-6-phenylpyrimidin-4( 3H )-one,

3-(( R )-1-(1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)propyl)-6-phenylpyrimidin-4( 3H )-one,

( R , S )-3 - ((1-(3-cyclohexyl-2-hydroxypropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbaldehyde,

( R )-5-((dimethylamino)methyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2( 1H )-one,

3-(( R )-1-(4-hydroxy-1-(( R )-3-phenylbutanoyl)piperidin-4-yl)ethyl)-6-phenylpyrimidin-4( 3H )-one,

3-(( S )-1-(4-hydroxy-1-(( R )-3-phenylbutanoyl)piperidin-4-yl)ethyl)-6-phenylpyrimidin-4( 3H )-one,

( R )-6-(2-fluorophenyl)-3-((4-hydroxy-1-(4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H ) -he,

( R , S )-3-((1-(3-cyclohexyl-2-fluoropropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one,

3-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-phenylpyrimidine-4(3 H ) -he,

3-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-phenylpyrimidine-4(3 H ) -he,

3-((( R )-6-(( R )-3-cyclohexyl-2-methylpropanoyl)-9-hydroxy-6-azaspiro[3.5]nonan-9-yl)methyl)-6-(2-fluorophenyl) pyrimidin-4(3 H )-one,

3-((( S )-6-(( R )-3-cyclohexyl-2-methylpropanoyl)-9-hydroxy-6-azaspiro[3.5]nonan-9-yl)methyl)-6-(2-fluorophenyl) pyrimidin-4(3 H )-one,

( R )-5-(3-(aminomethyl)phenyl)-1-((1-(3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-(2-fluorophenyl)pyridine -2(1 H )-he,

3-((( S )-4-hydroxy-3,3-dimethyl-1-(( R )-3-phenylbutanoyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4( 3H )-one,

3-((( R )-4-hydroxy-3,3-dimethyl-1-(( R )-3-phenylbutanoyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4( 3H )-one,

( R )-6-(4-fluorophenoxy)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(2-oxopyrrolidin-1-yl)-4-phenylpyridin-2( 1H )- he,

6-(2-fluorophenyl)-3-((4-hydroxy-1-(1-methyl-4-methylenecyclohexanecarbonyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one,

( R , S )-3-((1-(3-cyclobutyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one,

( R,S )-3-((1-(3-cycloheptyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one,

3-((1-(3-cyclobutyl-2,2-dimethylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one,

6-(2-fluorophenyl)-3-(((1 R ,5 S )-8-hydroxy-3-(( R )-3-phenylbutanoyl)-3-azabicyclo[3.2.1]octan-8-yl) methyl)pyrimidin-4(3 H )-one,

3-((( R )-4-hydroxy-2,2-dimethyl-1-(( R )-3-phenylbutanoyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4( 3H )-one,

3-((( S )-4-hydroxy-2,2-dimethyl-1-(( R )-3-phenylbutanoyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4( 3H )-one,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(4-hydroxypiperidine-1-carbonyl)-4-phenylpyridine-2( 1H )- he,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-5-(pyrrolidin-1-carbonyl)pyridin-2( 1H )-one ,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-5-(1,4-dioxa-8-azaspiro[4.5]decan-8 -carbonyl)pyridine-2(1 H )-one,

( R ) -N -cyclohexyl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-( cis -2-phenylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)pyrimidin-4(3 H ) -he,

( R,S ) - 3-((1-(3-cyclohexyl- 1H -pyrazole-4-carbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl )pyrimidin-4(3 H )-one,

( R,S ) - 6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(3-phenylpropanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H ) -he,

( R , S ) -6- (2-fluorophenyl)-3-((4-hydroxy-1-(1-isobutylcyclopropane-1-carbonyl)-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4 (3 H )-he,

( R , S ) -6- (2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(3-methyl-3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4 (3 H )-he,

( S )-1-((1-(4,4-difluoro-3-phenylbutanoyl)-4-hydroxypiperidin-4-yl)methyl)- N -isopropyl- N -methyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide,

1-((4-hydroxy-1-(1-(thiophen-2-yl)cyclopropan-1-carbonyl)piperidin-4-yl)methyl) -N -isopropyl- N -methyl-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxamide,

1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N -isopropyl- N -methyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl) -N -isopropyl- N -methyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(2-(hydroxymethyl)phenyl)pyrimidin-4( 3H )-one,

( R ) -N , N -diethyl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3- carboxamide,

3-((1-(3-cyclohexylbutanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(morpholine-4-carbonyl)-4-phenylpyridin-2( 1H )-one,

( R , S )-3 - ((1-(3-cyclohexylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidine-4( 3H )- he,

( R,S )-1-((1-(3-cyclobutylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N -isopropyl- N -methyl-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxamide,

( R,S ) - 1-((1-(2-ethylhexanoyl)-4-hydroxypiperidin-4-yl)methyl)- N -isopropyl- N -methyl-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxamide,

( R,S )-6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(1-methylcyclohexane-1-carbonyl)piperidin-4-yl)methyl)pyrimidin-4 (3 H )-he,

6-(2-fluorophenyl)-3-((1-(3-(4-fluorophenyl)propanoyl)-4-hydroxypiperidin-4-yl)methyl)pyrimidin-4( 3H )-one,

( R , S )-3 - ((1-(3-cyclopropylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidine-4( 3H )- he,

1-((1-(2,2-dimethylbutanoyl)-4-hydroxypiperidin-4-yl)methyl)- N -isopropyl- N -methyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide ,

( R ) -N- (2-(1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-1,6-dihydropyrimidin-4-yl)phenyl) acetamide,

( R )-5-(4-(aminomethyl)phenyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2( 1H )-one ,

( R )-1-((1-(3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)- N -isopropyl- N -methyl-6-oxo-4-phenyl-1,6 -dihydropyridine-3-carboxamide,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-5-(piperidine-1-carbonyl)pyridin-2( 1H )-one ,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl) -N -isopropyl-4-(2-methoxyphenyl) -N -methyl-6-oxo-1, 6-dihydropyridine-3-carboxamide,

( R )-4-(2-fluorophenyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl) -N -isopropyl- N -methyl-6-oxo-1, 6-dihydropyridine-3-carboxamide,

( R )-1'-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4'-phenyl-[2,3'-bipyridine]-6'( 1'H ) -he,

1-((1-(3-cyclohexylpropanoyl)-4-hydroxypiperidin-4-yl)methyl) -N -isopropyl- N -methyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

( R )-tert-Butyl- 4- (1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3 -carbonyl)piperazine-1-carboxylate,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-5-(piperazin-1-carbonyl)pyridine-2( 1H )-one ,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3- carboxamide,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl) -N -isopropyl- N -methyl-6-oxo-4-(p-tolyl)-1, 6-dihydropyridine-3-carboxamide,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)- N -methoxy- N -methyl-6-oxo-4-phenyl-1,6-dihydropyridine- 3-carboxamide,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4,5-diphenylpyridin-2( 1H )-one,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-[3,3'-bipyridin]-6( 1H )-one,

( R )-5-(3-(aminomethyl)phenyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2( 1H )-one ,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)- N -isopropyl- N -methyl-6-oxo-4-phenyl-1,6-dihydropyridine- 3-carboxamide,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl) -N -isopropyl- N -methyl-6-oxo-4-( m -tolyl)-1, 6-dihydropyridine-3-carboxamide,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-5-(pyrimidin-5-yl)pyridin-2( 1H )-one ,

( R ) -N- (cyclopropylmethyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3- carboxamide,

( R ) -N -benzyl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-N-methyl-6-oxo-4-phenyl-1,6-dihydropyridine- 3-carboxamide,

( R )-2-(1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridin-3-yl)benzonitrile ,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)- N -methyl-6-oxo- N ,4-diphenyl-1,6-dihydropyridine-3- carboxamide,

3-(1-(1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)ethyl)-6-phenylpyrimidin-4( 3H )-one,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(1-methyl- 1H -pyrazol-4-yl)-4-phenylpyridin-2 (1 H )-he,

( R )-3-((1-(2-(cyclohexylmethyl)pent-4-enoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one ,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-methyl-4-phenylpyridin-2( 1H )-one,

( R )-6-(1,5-dimethyl- 1H -pyrazol-4-yl)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3 H )-he,

3-(((1 R ,5 S )-3-(3-cyclohexylpropanoyl)-8-hydroxy-3-azabicyclo[3.2.1]octan-8-yl)methyl)-6-(2-fluorophenyl)pyrimidine- 4(3 H )-he,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonitrile,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)- N- (2-hydroxyethyl)-6-oxo-4-phenyl-1,6-dihydropyridine- 3-carboxamide,

1-((4-hydroxy-1-(( R )-3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(( S )-2-methylpyrrolidin-1-carbonyl)-4-phenylpyridine-2( 1 H )-he,

( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(4-(hydroxymethyl)piperidine-1-carbonyl)-4-phenylpyridine-2(1 H )-he,

3-((1-(2-(cyclohexylmethyl)butanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one,

3-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3 H )-he,

1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl) -N -isopropyl- N -methyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo -4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo -4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-phenyl-5-(pyrrolidin- 1-carbonyl)pyridine-2(1 H )-one,

1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-phenyl-5-(piperazin- 1-carbonyl)pyridine-2(1 H )-one,

1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-phenyl-5-(piperazin- 1-carbonyl)pyridine-2(1 H )-one,

3-((1-(2-(cyclohexyloxy)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one,

1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-1 ,6-dihydropyridine-3-carboxamide,

1-((1-(( R )-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxamide,

1-((1-(( R )-3-cyclopropyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxamide,

1-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-[4,5'-bipyrimidine]-6(1 H )-he,

3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(1-methyl- 1H -pyrazol-5 -yl)pyrimidin-4(3 H )-one,

3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(1 H -pyrazol-4-yl)pyrimidine -4(3 H )-he,

3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(1 H -pyrazol-5-yl)pyrimidine -4(3 H )-he,

3-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4( 3H )-one,

3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(thiophen-3-yl)pyrimidin-4( 3 H )-he,

1-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(oxazol-2-yl)-4-phenylpyridine -2(1 H )-he,

3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-(hydroxymethyl)phenyl)pyrimidin-4 (3 H )-he,

3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(3-(hydroxymethyl)phenyl)pyrimidin-4 (3 H )-he,

3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(4-(hydroxymethyl)phenyl)pyrimidin-4 (3 H )-he,

6-(4-(aminomethyl)phenyl)-3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4 (3 H )-he,

6-(2-(Aminomethyl)phenyl)-3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4 (3 H )-he,

6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(2,4,4-trimethylpentanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one ,

6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(4,4,4-trifluoro-2-methylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4(3 H )-he,

4-chloro-1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6 -oxo-1,6-dihydropyridine-3-carboxamide,

1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(dimethylamino)- N , N -dimethyl -6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((1-(( S )-3-(benzyloxy)-2-(cyclohexylmethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6- oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((10-hydroxy-7-isobutyryl-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide ,

1-((10-hydroxy-7-(( R )-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide,

1-((7-(( R )-3-cyclopropyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxamide,

6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(2-methyl-3-(1 H -pyrazol-1-yl)propanoyl)piperidin-4-yl)methyl )pyrimidin-4(3 H )-one,

1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-(hydroxymethyl)phenyl)- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((( S )-1-(( S )-3-cyclohexyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( R )-1-(( S )-3-cyclohexyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1'-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4'-(2-fluorophenyl)-[2, 3'-bipyridine]-6'(1' H )-he,

1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4 -(thiophen-3-yl)-1,6-dihydropyridine-3-carboxamide,

1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(3-(hydroxymethyl)phenyl)- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((7-(3-cyclohexyl-2-hydroxypropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide,

1-((10-hydroxy-7-(2-methyl-3-(piperidin-1-yl)propanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6- oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

6-(3-(Aminomethyl)phenyl)-3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4 (3 H )-he,

1-((( S )-1-(( S )-3-cyclohexyl-2-(methoxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

4-(2-(aminomethyl)phenyl)-1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(4-(hydroxymethyl)phenyl)- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((10-hydroxy-7-(2-methyl-3-morpholinepropanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide,

1-((( S )-1-(( S )-2-(cyclohexylmethyl)-4-hydroxybutanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( R )-1-(( S )-2-(cyclohexylmethyl)-4-hydroxybutanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( S )-1-(( S )-3-cyclobutyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( R )-1-(( S )-3-cyclobutyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(morpholine-4-carbonyl)-4-phenylpyridine -2(1 H )-he,

5-(4-acetylpiperazin-1-carbonyl)-1-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4 -phenylpyridin-2(1 H )-one,

1-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(4-methylpiperazin-1-carbonyl)-4 -phenylpyridin-2(1 H )-one,

1-((10-hydroxy-7-(4,4,4-trifluoro-3-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxamide,

1-((10-hydroxy-7-(4,4,4-trifluorobutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide,

1-((10-hydroxy-7-(3-(tetrahydrofuran-3-yl)propanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxamide,

1-((10-hydroxy-7-((1 R ,2 S )-2-phenylcyclopropane-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((7-(cyclopropanecarbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3 -carboxamide,

1-((10-hydroxy-7-(1-methylcyclohexane-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide,

1-((7-(3-fluorocyclopentan-1-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide,

1-((7-(1-(2,2-difluoroethyl)cyclopropane-1-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6- oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((7-(bicyclo[2.2.1]heptane-1-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxamide,

1-((7-(( S )-4,4-difluoro-3-phenylbutanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo -4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((7-(( R )-4,4-difluoro-3-phenylbutanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo -4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((7-(3-ethoxypropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxamide,

1-((10-hydroxy-7-(( S )-3-phenylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide,

1-((7-(3-(4-fluorophenyl)propanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxamide,

1-((10-hydroxy-7-(( R )-3-phenylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide,

1-((10-hydroxy-7-(1-methylcyclopentan-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide,

1-((10-hydroxy-7-(1 H -pyrazole-3-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxamide,

1-((10-hydroxy-7-(1 H -indazole-3-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxamide,

1-((7-(3-cyclohexyl- 1H -pyrazole-4-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo- 4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((10-hydroxy-7-(1 H -indole-3-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxamide,

1-((7-(bicyclo[1.1.1]pentan-1-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxamide,

1-((10-hydroxy-7-(5-phenyloxazole-4-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide,

1-((7-(5-cyclopropyloxazole-4-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide,

1-((7-(2-(cyclohexyloxy)acetyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1, 6-dihydropyridine-3-carboxamide,

1-((10-hydroxy-7-(spiro[2.2]pentan-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxamide,

1-((10-hydroxy-7-(3-(trifluoromethyl)cyclopentane-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxamide,

1-((7-(2,4-dimethylpentanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6 -dihydropyridine-3-carboxamide,

1-((7-(1-benzyl-1 H --pyrrole-2-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo -4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((7-(2-(cyclohexyloxy)propanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1, 6-dihydropyridine-3-carboxamide,

3-((1-(( S )-3-cyclobutyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4 (3 H )-he,

1-((7-(2-cyclobutoxyacetyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxamide,

1-((7-(3,3-difluorocyclopentan-1-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxamide,

1-((10-hydroxy-7-(2-hydroxy-3-phenylpropanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide,

1-((( S )-4-hydroxy-3,3-dimethyl-1-(( R )-4,4,4-trifluoro-2-methylbutanoyl)piperidin-4-yl)methyl)- N , N - dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl) -N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)-5 -(piperazine-1-carbonyl)pyridine-2(1 H )-one,

( S )-1-((4-hydroxy-3,3-dimethyl-1-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)piperidin-4-yl)methyl) - N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(( S )-2- (hydroxymethyl)piperazin-1-carbonyl)-4-phenylpyridin-2(1 H )-one,

1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl-5-( piperazine-1-carbonyl)pyridine-2(1 H )-one,

1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl-5-( piperazine-1-carbonyl)pyridine-2(1 H )-one,

1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(( R )-3- methylpiperazin-1-carbonyl)-4-phenylpyridin-2(1 H )-one,

1-((( S )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( S )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl-5-( piperazine-1-carbonyl)pyridine-2(1 H )-one,

1-((( S )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( S )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl -5-(piperazin-1-carbonyl)pyridine-2(1 H )-one,

( S )-1-((10-hydroxy-7-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl ) -N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

( S )-1-((10-hydroxy-7-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl )-4-phenyl-5-(piperazin-1-carbonyl)pyridin-2(1 H )-one,

1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-cyclopropyl- N , N -dimethyl -6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-cyclopropyl-5-(piperazin- 1-carbonyl)pyridine-2(1 H )-one,

1-((( S )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl) - N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

4-(2-fluorophenyl)-1-((( S )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decane-10- yl) methyl) - N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((( S )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl) -5-(piperazin-1-carbonyl)pyridine-2(1 H )-one,

4-(2-fluorophenyl)-1-((( S )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decane-10- yl)methyl)-5-(piperazin-1-carbonyl)pyridin-2(1 H )-one,

1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl) - N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl) -5-(piperazin-1-carbonyl)pyridine-2(1 H )-one,

1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(4-hydroxypiperidin-1- carbonyl)-4-phenylpyridin-2(1 H )-one,

1-((10-hydroxy-7-(3-(trifluoromethyl)cyclobutane-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( S )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((( S )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl-5-( piperazine-1-carbonyl)pyridine-2(1 H )-one,

1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl-5-( piperazine-1-carbonyl)pyridine-2(1 H )-one,

1-((2-(( R )-3-cyclohexyl-2-methylpropanoyl)-5-hydroxy-9-oxa-2-azaspiro[5.5]undecan-5-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( S )-1-(( R )-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl) -N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((( S )-1-(( R )-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)-5 -(piperazine-1-carbonyl)pyridine-2(1 H )-one,

1-((2-(( R) -3-cyclohexyl-2-methylpropanoyl)-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)methyl)- N , N -dimethyl-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxamide,

1-((2-(( R )-3-cyclohexyl-2-methylpropanoyl)-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)methyl)-4-phenyl-5-(piperazin-1- carbonyl)pyridine-2(1 H )-one,

1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-5-(morpholin-4- carbonyl)-4-phenylpyridin-2(1 H )-one,

1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-5-(4-methylpiperazin- 1-carbonyl)-4-phenylpyridin-2(1 H )-one,

1-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxylic acid,

1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-methoxy- N , N -dimethyl-6 -oxo-1,6-dihydropyridine-3-carboxamide,

1-((7-(4,4-difluoro-2-methylbutanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxamide,

1-((7-(4,4-difluoro-2,2-dimethylbutanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxamide,

1-((10-hydroxy-7-(4-(trifluoromethyl)thiazole-2-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxamide,

1-((10-hydroxy-7-(2-(trifluoromethyl)thiazole-4-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( S )-10-hydroxy-7-(( S )-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( S )-10-hydroxy-7-(( S )-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- 5-(morpholine-4-carbonyl)-4-phenylpyridin-2(1 H )-one,

1-((( S )-10-hydroxy-7-(( S )-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- 4-phenyl-5-(piperazin-1-carbonyl)pyridin-2(1 H )-one,

1-((( S )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-5-( morpholine-4-carbonyl)-4-phenylpyridin-2(1 H )-one,

1-((( S )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-5-( 4-methylpiperazin-1-carbonyl)-4-phenylpyridin-2(1 H )-one,

ethyl-1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxylate,

1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxylic acid,

1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N -isopropyl- N -methyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-phenyl-5-(pyrrolidin- 1-carbonyl)pyridine-2(1 H )-one,

1-((( R )-1-(( S )-3-cyclohexyl-2-(methoxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( R )-4-hydroxy-3,3-dimethyl-1-(( R )-4,4,4-trifluoro-2-methylbutanoyl) piperidin-4-yl) methyl) - N , N - dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)-5 -(piperazine-1-carbonyl)pyridine-2(1 H )-one,

( R )-1-((4-hydroxy-3,3-dimethyl-1-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)piperidin-4-yl)methyl) - N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(( S )-2- (hydroxymethyl)piperazin-1-carbonyl)-4-phenylpyridin-2(1 H )-one,

1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(( R )-3- methylpiperazin-1-carbonyl)-4-phenylpyridin-2(1 H )-one,

1-((( R )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( R )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl-5-( piperazine-1-carbonyl)pyridine-2(1 H )-one,

1-((( R )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( R )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl -5-(piperazin-1-carbonyl)pyridine-2(1 H )-one,

( R )-1-((10-hydroxy-7-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl ) -N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

( R )-1-((10-hydroxy-7-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl )-4-phenyl-5-(piperazin-1-carbonyl)pyridin-2(1 H )-one,

1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-cyclopropyl- N , N -dimethyl -6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-cyclopropyl-5-(piperazin- 1-carbonyl)pyridine-2(1 H )-one,

1-((( R )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl) - N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

4-(2-fluorophenyl)-1-((( R )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decane-10- yl) methyl) - N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((( R )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl) -5-(piperazin-1-carbonyl)pyridine-2(1 H )-one,

4-(2-fluorophenyl)-1-((( R )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decane-10- yl)methyl)-5-(piperazin-1-carbonyl)pyridin-2(1 H )-one,

1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl) - N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl) -5-(piperazin-1-carbonyl)pyridine-2(1 H )-one,

1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(4-hydroxypiperidin-1- carbonyl)-4-phenylpyridin-2(1 H )-one,

1-((( R )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((( R )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl-5-( piperazine-1-carbonyl)pyridine-2(1 H )-one,

1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl-5-( piperazine-1-carbonyl)pyridine-2(1 H )-one,

1-((( R )-1-(( R )-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,

1-((( R )-1-(( R )-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)-5 -(piperazine-1-carbonyl)pyridine-2(1 H )-one,

1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-5-(morpholine-4- carbonyl)-4-phenylpyridin-2(1 H )-one,

1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-5-(4-methylpiperazin- 1-carbonyl)-4-phenylpyridin-2(1 H )-one,

1-((( R )-10-hydroxy-7-(( S )-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide,

1-((( R )-10-hydroxy-7-(( S )-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- 5-(morpholine-4-carbonyl)-4-phenylpyridin-2(1 H )-one,

1-((( R )-10-hydroxy-7-(( S )-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- 4-phenyl-5-(piperazin-1-carbonyl)pyridin-2(1 H )-one,

1-((( R )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-5-( morpholine-4-carbonyl)-4-phenylpyridin-2(1 H )-one,

1-((( R )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-5-( 4-methylpiperazin-1-carbonyl)-4-phenylpyridin-2(1 H )-one,

ethyl-1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxylate,

1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxylic acid,

or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof.

In a second aspect, the present invention relates to a pharmaceutical composition comprising a compound according to any embodiment of the first aspect and at least one pharmaceutically acceptable excipient.

Pharmaceutical compositions may be prepared according to their particular use and purpose by mixing, for example, an excipient, a binder, a lubricant, a disintegrant, a coating material, an emulsifier, a suspending agent, a solvent, a stabilizer, an absorption enhancer, and/or an ointment base. The composition may be formulated for oral, injection, rectal or topical administration.

Suitable pharmaceutically acceptable excipients are known to the person skilled in the art and are, for example: fats, water, saline, alcohol (e.g. ethanol), glycerol, polyols, aqueous glucose, thinner, disintegrant, binder, lubricant , wetting agent, stabilizer, emulsifier, dispersant, preservative, sweetener, coloring agent, flavoring or flavoring agent, concentrating agent, diluent, buffering agent, solvent or solubilizing agent, storage chemical, osmotic pressure changing salt, coating agent or an antioxidant, saccharides such as lactose or glucose; starch from corn, wheat or rice; fatty acids such as stearic acid; inorganic salts such as magnesium metasilicate aluminate or anhydrous calcium phosphate; synthetic polymers such as polyvinylpyrrolidone or polyalkylene glycol; alcohols such as stearyl alcohol or benzyl alcohol; synthetic cellulose derivatives such as methylcellulose, carboxymethylcellulose, ethylcellulose or hydroxypropylmethylcellulose; as well as other commonly used additives such as gelatin, talc, vegetable oil and gum arabic.

For example, the pharmaceutical composition can be administered orally, in particular in the form of tablets, coated tablets, hard or soft gelatin capsules, solutions, emulsions or suspensions. The introduction can also be carried out rectally, for example, using suppositories; locally or transdermally, for example, using ointments, creams, gels or solution; or parenterally, for example, using injectable solutions.

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

Excipients for preparing solutions and syrups include, for example, water, polyols, sucrose, invert sugar and glucose.

Excipients for injections include, for example, water, alcohols, polyols, glycerol and vegetable oil. For suppositories and for topical or transdermal use, excipients useful include, for example, natural or hardened oils, waxes, fats, and semi-solid or liquid polyols.

The pharmaceutical compositions may also contain preservatives, solubilizing agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colors, odorants, buffers, coating agents and/or antioxidants.

For combination therapy, the second drug may be present in a pharmaceutical composition according to the invention or may be presented separately. Thus, a pharmaceutical composition for oral administration may be, for example, a granule, tablet, sugar-coated tablet, capsule, pill, suspension or emulsion. For parenteral injection, eg, intravenous, intramuscular, or subcutaneous administration, a sterile aqueous solution may be used, which may contain other substances, including, for example, salts and/or glucose, to render the solution isotonic. The anticancer agent may also be administered in the form of a suppository or pessary, or may be applied topically in the form of a lotion, solution, cream, ointment or powder.

In a third aspect, the invention relates to a compound or composition, in accordance with any embodiment of the first aspect or the second aspect, for use in therapy. In certain embodiments, the invention relates to a compound or composition, according to any embodiment of the first aspect or the second aspect, for use in the treatment and/or prevention of cancer. Cancer or neoplastic conditions suitable for treatment with the compounds or compositions of the invention include, for example, prostate cancer, colon cancer, breast cancer, lung cancer, kidney cancer, CNS cancer (e.g., neuroblastomas, glioblastomas), osteosarcoma, hematologic malignancies (eg, leukemia, multiple myeloma, and mantle cell lymphoma). In some preferred embodiments, the cancer is associated with dysregulation of p53. In some preferred embodiments, the cancer is selected from hematologic malignancy (eg, mantle cell lymphoma, multiple myeloma), prostate cancer, neuroblastoma, or glioblastoma.

In certain embodiments, the present invention relates to a compound or composition according to any embodiment of the first aspect or the second aspect, for use in the treatment and/or prevention of muscle wasting. In certain embodiments, the invention relates to a compound or composition according to any embodiment of the first aspect or the second aspect, for use in the treatment and/or prevention of cachexia or sarcopenia. Muscle wasting, cachexia, or sarcopenia may be associated with or caused by HIV/AIDS, heart failure, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, multiple sclerosis, motor neurone disease (MND), Parkinson's disease, dementia, or cancer .

The compound or composition of the invention can be used as a monotherapy and/or as a combination. Suitable agents to be used in such combinations with the compounds or compositions of the invention include one or more anti-cancer agents, anti-inflammatory agents, immunomodulatory agents, e.g., immunosuppressive agents, neurological agents, antidiabetic agents, antiviral agents, antibacterial agents, and/or radiation therapy. .

Agents used in combination with the compounds of the invention may target the same or similar biological pathway that the compounds of the invention target, or may act on a different or different pathway.

Depending on the disease being treated, various combination partners may be used in conjunction with the compounds of the invention. The second active ingredient may include, without limitation: alkylating agents including cyclophosphamide, ifosfamide, thiotepa, melphalan, chloroethylnitrosourea, and bendamustine; platinum derivatives including cisplatin, oxaliplatin, carboplatin and satraplatin; antimitotic agents, including vinca alkaloids (vincristine, vinorelbine, and vinblastine), taxanes (paclitaxel, docetaxel), epothilones, and mitotic kinase inhibitors, including Aurora kinase and polo kinase inhibitors; topoisomerase inhibitors, including anthracyclines, epipodophyllotoxins, camptothecin, and camptothecin analogs; antimetabolites, including 5-fluorouracil, capecitabine, cytarabine, gemcitabine, 6-mercaptopurine, 6-thioguanine, fludarabine, methotrexate, and premetrexed; protein kinase inhibitors including imatinib, gefitinib, sorafenib, sunitinib, erlotinib, dasatinib, and lapatinib; proteasome inhibitors, including bortezomib; histone deacetylase inhibitors, including valproate and SAHA; anti-angiogenic drugs, including bevacizumab; monoclonal antibodies, including trastuzumab, rituximab, alemtuzumab, tositumomab, cetuximab, panitumumab; myoclonal antibody conjugates including gemtuzumab ozogamicin, ibritumomab tiuxetan; hormone therapy agents, including antiestrogen (tamoxifen, raloxifene, anastrozole, letrozole, examestan), antiandrogens (flutamide, biclotamide), and luteinizing hormone analogues or antagonists.

In a fourth aspect, the present invention relates to a method for treating or preventing cancer, comprising administering to a subject a compound according to any embodiment of the first aspect of the invention, or a composition according to any embodiment of the second aspect of the invention. Cancer or neoplastic conditions suitable for treatment with the compounds or compositions of the invention include, for example, prostate cancer, colon cancer, breast cancer, lung cancer, kidney cancer, CNS cancer (e.g., neuroblastomas, glioblastomas), osteosarcoma, hematologic malignancies (eg, leukemia, multiple myeloma, and mantle cell lymphoma). In some preferred embodiments, the cancer is associated with dysregulation of p53. In some preferred embodiments, the cancer is selected from hematologic malignancy (eg, mantle cell lymphoma, multiple myeloma), prostate cancer, neuroblastoma, or glioblastoma.

As part of the method within the fourth aspect, the compound or composition may be used as monotherapy and/or in combination. Suitable agents to be used in such combinations with the compounds or compositions of the invention include one or more anti-cancer agents, anti-inflammatory agents, immunomodulatory agents, immunosuppressive agents, neurological agents, anti-diabetic agents, anti-viral agents, anti-bacterial agents, and/or radiation therapy.

Agents used in combination with the compounds of the invention may target the same or similar biological pathway that the compounds of the invention target, or may act on a different or different pathway.

In a fifth aspect, the invention relates to the use of a compound according to any embodiment of the first aspect in the manufacture of a medicament for the treatment or prevention of cancer.

Cancer or neoplastic conditions suitable for treatment with the compounds or compositions of the invention include, for example, prostate cancer, colon cancer, breast cancer, lung cancer, kidney cancer, CNS cancer (e.g., neuroblastomas, glioblastomas), osteosarcoma, hematologic malignancies (eg, leukemia, multiple myeloma, and mantle cell lymphoma). In some preferred embodiments, the cancer is associated with dysregulation of p53. In some preferred embodiments, the cancer is selected from hematologic malignancy (eg, mantle cell lymphoma, multiple myeloma), prostate cancer, neuroblastoma, or glioblastoma.

In a sixth aspect, the invention relates to a method for treating or preventing muscle atrophy, optionally cachexia or sarcopenia, comprising administering to a subject a compound according to any embodiment of the first aspect of the invention or a composition according to any embodiment of the second aspect of the invention. Muscle wasting, cachexia, or sarcopenia may be associated with or caused by HIV/AIDS, heart failure, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, multiple sclerosis, motor neurone disease (MND), Parkinson's disease, dementia, or cancer.

In a seventh aspect, the invention provides the use of a compound according to any embodiment of the first aspect in the manufacture of a medicament for the treatment or prevention of muscle atrophy, optionally cachexia or sarcopenia. Muscle wasting, cachexia, or sarcopenia may be associated with or caused by HIV/AIDS, heart failure, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, multiple sclerosis, motor neurone disease (MND), Parkinson's disease, dementia, or cancer.

In a further aspect, the present invention relates to a compound or composition according to any embodiment of the first aspect or the second aspect for use in the treatment and/or prevention of Parkinson's disease. In a further aspect, the invention relates to a method for treating or preventing Parkinson's disease comprising administering to a subject an effective amount of a compound or pharmaceutical composition of the invention. In a further aspect, the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of Parkinson's disease.

With respect to aspects of the invention relating to the therapeutic use of the compounds of the invention, the compounds may be administered with a combination partner. Depending on the disease being treated, a wide variety of drugs can be co-administered with the compounds of the present invention. The second active ingredient may include, but is not limited to, alkylating agents including cyclophosphamide, ifosfamide, thiotepa, melphalan, chloroethylnitrosourea, and bendamustine; platinum derivatives including cisplatin, oxaliplatin, carboplatin and satraplatin; antimitotics, including vinca alkaloids (vincristine, vinorelbine, and vinblastine), taxanes (paclitaxel, docetaxel), epothilones, and mitotic kinase inhibitors, including inhibitors of Aurora kinases and polo kinases; topoisomerase inhibitors, including anthracyclines, epidophyllotoxins, camptothecin and analogs of camptothecin; antimetabolites, including 5-fluorouracil, capecitabine, cytarabine, gemcitabine, 6-mercaptopurine, 6-thioguanine, fludarabine, methotrexate, and premetrexed; protein kinase inhibitors including imatinib, gefitinib, sorafenib, sunitinib, erlotinib, dasatinib, and lapatinib; proteasome inhibitors, including bortezomib; histone deacetylase inhibitors, including valproate and SAHA; anti-angiogenic drugs, including bevacizumab; monoclonal antibodies, including trastuzumab, rituximab, alemtuzumab, tositumomab, cetuximab, panitumumab; monoclonal antibody conjugates including gemtuzumab ozogamicin, ibritutomab tiuxetan; hormonal drugs, including antiestrogen (tamoxifen, raloxifene, anastrozole, letrozole, exemestane), antiandrogens (flutamide, bicalutamide) and luteinizing hormone analogs or antagonists.

With respect to aspects of the invention relating to the therapeutic use of the compounds of the invention, the compounds may be administered to a subject in need of treatment in an "effective amount". The term "effective amount" refers to the amount or dose of a compound which, when administered to a subject in a single or multiple dose, provides therapeutic efficacy in the treatment of a disease. Therapeutically effective amounts of a compound of the invention may comprise an amount of the compound in the range of about 0.1 mg/kg to about 20 mg/kg per dose. The therapeutically effective amount for each individual patient may be determined by the healthcare professional by methods known to one of skill in the art. The amount of the compound administered at any given point in time may vary so that optimal amounts of the compound are administered during the course of treatment, whether used alone or in combination with any other therapeutic agent. It is also contemplated to administer the compounds of the invention, or pharmaceutical compositions containing such compounds, in combination with any other cancer treatment as a combination therapy.

With respect to aspects of the invention relating to the therapeutic use of the compounds of the invention, in preferred embodiments of the present invention, the subject to be treated is a human.

When presenting an element of the present invention or preferred embodiment(s) of the invention, it is intended that the forms presented in the singular suggest the possibility of having one or more elements. The terms "comprising", "comprising" and "having" are intended to be non-limiting and are meant to imply that there may be additional elements in addition to the listed elements.

The following is a detailed description of the invention with the help of examples and illustrations, but this does not mean that they limit the scope of the claims of the attached claims. One of ordinary skill in the art will appreciate that there may be many different variations of the illustrated and presently preferred embodiments of the invention, all of which are within the scope of the appended claims, as well as their equivalents.

EXAMPLES

Next, the present invention is described using various examples.

Compounds according to the respective examples were synthesized by the appropriate methods, which are described here. IC ₅₀ values were determined as described below and are presented in the following table.

Table 1. Inhibition of USP19 with Exemplary Compounds Example Activity against USP19,
IC _fifty Example Activity against USP19,
IC _fifty Example Activity against USP19,
IC _fifty Example Activity against USP19,
IC _fifty one * 65 ** 129 ** 193 ** 2 * 66 N.D. 130 *** 194 ** 3 * 67 ** 131 *** 195 ** four * 68 ** 132 ** 196 *** 5 ** 69 ** 133 *** 197 **** 6 ** 70 ** 134 ** 198 ** 7 *** 71 ** 135 **** 199 ** eight ** 72 * 136 *** 200 *** 9 ** 73 **** 137 *** 201 ** ten * 74 * 138 **** 202 * eleven * 75 *** 139 **** 203 *** 12 ** 76 *** 140 *** 204 *** 13 * 77 *** 141 **** 205 **** fourteen *** 78 *** 142 * 206 **** fifteen ** 79 *** 143 ** 207 ** 16 ** 80 ** 144 **** 208 **** 17 ** 81 * 145 **** 209 ** eighteen ** 82 * 146 *** 210 ** 19 ** 83 * 147 * 211 **** twenty ** 84 * 148 ** 212 **** 21 ** 85 * 149 **** 213 **** 22 ** 86 ** 150 * 214 **** 23 ** 87 *** 151 ** 215 **** 24 ** 88 *** 152 **** 216 **** 25 *** 89 *** 153 ** 217 **** 26 * 90 *** 154 ** 218 *** 27 * 91 *** 155 **** 219 *** 28 * 92 *** 156 **** 220 *** 29 * 93 ** 157 **** 221 *** thirty * 94 *** 158 * 222 **** 31 *** 95 ** 159 *** 223 *** 32 ** 96 ** 160 **** 224 **** 33 ** 97 ** 161 ** 225 *** 34 * 98 ** 162 **** 226 **** 35 * 99 ** 163 ** 227 **** 36 *** 100 ** 164 **** 228 **** 37 * 101 ** 165 ** 229 ** 38 * 102 *** 166 **** 230 *** 39 ** 103 ** 167 ** 231 *** 40 ** 104 ** 168 **** 232 **** 41 ** 105 ** 169 **** 233 **** 42 ** 106 ** 170 **** 234 *** 43 ** 107 ** 171 * 235 *** 44 ** 108 *** 172 ** 236 **** 45 * 109 * 173 * 237 **** 46 * 110 *** 174 **** 238 **** 47 * 111 * 175 * 239 **** 48 * 112 * 176 ** 240 **** 49 * 113 * 177 * 241 *** fifty **** 114 ** 178 * 242 *** 51 *** 115 ** 179 * 243 ** 52 *** 116 *** 180 ** 244 ** 53 *** 117 *** 181 *** 245 ** 54 * 118 *** 182 ** 246 ** 55 ** 119 **** 183 ** 247 **** 56 ** 120 **** 184 *** 248 **** 57 ** 121 **** 185 *** 249 **** 58 ** 122 * 186 * 250 **** 59 ** 123 **** 187 * 251 **** 60 ** 124 **** 188 * 252 **** 61 * 125 ** 189 *** 253 **** 62 *** 126 * 190 * 63 *** 127 *** 191 * 64 ** 128 *** 192 **

For representative examples of compounds shown in Table 1, inhibitory activity against USP19 is classified as follows:

**** *** ** * N.D. Activity against USP19,
IC ₅₀ [µmol] _IC50 <0.5 0.5≤IC ₅₀ <5 5≤IC ₅₀ <50 50≤IC ₅₀ <250 undefined

A typical overall selectivity profile for the compound of Example 124 is shown in FIG. 1 showing selectivity for a panel of 24 USPs and 19 other DUBs.

EXPERIMENTAL PART

Abbreviations and abbreviations

aq: water; dba: dibenzylideneacetone; Bn: benzyl; Boc: tert-butyloxycarbonyl; width: wide (in spectrum); DCM: dichloromethane; e: doublet (in the spectrum); DIPEA: diisopropylethylamine; DME: dimethoxyethane; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; dppf: 1,1'-bis(diphenylphosphino)ferrocene; EDC: N-(3-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride; equiv.: equivalent; EtOAc: ethyl acetate; PE: petroleum ether 40/60; ESI: electrospray ionization; h: hour(s); HATU: N-oxide hexafluorophosphate N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanamine HBTU: N,N,N',N'-tetramethyl-hexafluorophosphate O-(1H-benzotriazol-1-yl)uronium hept: heptet (in spectrum) HPLS (HPLC): high performance liquid chromatography LC (LC): liquid chromatography LCMS: liquid chromatography with mass spectrometry M: mol ;m/z: ratio of mass to charge; m-CPBA: 3-chloroperbenzoic acid; MeCN: acetonitrile; MeOH: methanol; min: minutes; MS: mass spectrometry; m: multiplet (in spectrum); NaHMDS: sodium bis(trimethylsilyl)amide; NMR: nuclear magnetic resonance; n: pentet (in spectrum); kv: quartet (in spectrum); quint: quintet (in spectrum); R_T: retention time; RT (RT): room temperature; c: singlet (in spectrum); SM: starting material; TBS: t-butyldimethylsilyl; TFA: trifluoroacetic acid; THF: tetrahydrofuran; t: triplet (in spectrum); v/v: volume per unit volume; Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

General experimental conditions

Solvents and reagents

Common organic solvents that were used in the reactions (eg, THF, DMF, DCM, and methanol) were purchased as anhydrous reagents from Sigma-Aldrich® in Sure/Seal™ containers and handled appropriately under nitrogen. The water was deionized on an Elga PURELAB Option-Q unit. All other solvents used (in processing and cleaning procedures) were typically HPLC grade and were used as supplied from various commercial sources.

Unless otherwise noted, all raw materials used were purchased from commercial suppliers and used as supplied.

Microwave (MW) synthesis

Microwave experiments were performed using the Biotage Initiator™ Eight system, unless otherwise noted for cases where the CEM Discover™/Explorer24™ system controlled by Synergy 1.5 software was used.

Both units provided good reproducibility and control over temperature ranges from 60 to 250°C and at maximum pressures up to 20 bar.

Flash chromatography

Compound purification by flash chromatography was performed using a Biotage Isolera Four system. Unless otherwise noted, Biotage KP-Sil SNAP cartridge columns (10-340 g) or Grace GraceResolv cartridge columns (Grace, 4-330 g) were used along with the indicated solvent system and an appropriate solvent gradient, depending on compound polarity. For more polar and basic compounds, Biotage KP-NH SNAP cartridge columns (11 g) were used.

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. Residual solvent signals were used as an internal standard and representative solvent peaks were corrected to reference data given in J. Org. Chem., 1997, 62, pp. 7512-7515; in other cases, the NMR solvents contained tetramethylsilane, which was used as an internal standard.

Liquid chromatography with mass spectrometry (LCMS)

Liquid chromatography with mass spectrometry (LCMS) experiments to determine retention time ( _RT ) and bound mass ions were performed using the following methods:

Method A : A system of an Agilent Technologies 6130 quadrupole mass spectrometer coupled to an Agilent Technologies 1290 Infinity LC chromatography system with UV diode array detector and automatic sampler. The spectrometer includes an electrospray ionization source operating in positive and negative ion modes. LCMS experiments were performed on each sample presented under the following conditions: LC column: Agilent Eclipse Plus C18 RRHD, 1.8 µm, 50×2.1 mm, maintained at 40°C. Mobile phases: A) 0.1% (v/v) formic acid in water; C) 0.1% (v/v) formic acid in acetonitrile.

Time
gradient
elution
(min) Consumption
(ml/min) %A %B 0.00 0.5 80 twenty 1.80 0.5 0 100 2.20 0.5 0 100 2.50 0.5 80 twenty 3.00 0.5 80 twenty

Method B : The system consists of an Agilent Technologies 6140 single quadrupole mass spectrometer coupled to an Agilent Technologies 1290 Infinity Liquid Chromatography System with a diode array UV detector and an autosampler. The spectrometer consists of a multi-mode ionization source (electrospray ionization and atmospheric pressure chemical ionization) operating in positive and negative ion modes. Liquid chromatography-mass spectrometry (LCMS) experiments were performed for each sample presented using the following conditions: liquid chromatography column: Zorbax Eclipse Plus C18 RRHD 1.8 micron 50×2.1 mm at 40°C. Mobile phases: A) 0.1% (v/v) formic acid in water; B) 0.1% (v/v) formic acid in acetonitrile.

Gradient elution time
(min) Consumption
(ml/min) %A %B 0.00 1.0 95 5 1.80 1.0 0 100 2.20 1.0 0 100 2.21 1.0 95 5 2.50 1.0 95 5

Preparative High Performance Liquid Chromatography

The system consisted of an Agilent Technologies 6120 single quadrupole mass spectrometer connected to an Agilent Technologies 1200 preparative liquid chromatography system with a multiwavelength detector and an automatic sampler. The mass spectrometer uses a multi-mode ionization source (electrospray ionization and atmospheric pressure chemical ionization) operating in positive and negative ion modes. The collection of fractions was controlled by weight (multimode source of positive and negative ions). Purification experiments, unless otherwise indicated, were carried out under basic conditions with an appropriate solvent gradient, which was usually determined from the retention time found using the LCMS method. In cases where basic (alkaline) conditions did not give a positive result, acidic conditions were used.

Basic conditions : Liquid chromatography column: Waters XBridge™ Prep C18 5 µm OBD ^TM 19×50 mm column at room temperature. Mobile phase: A) 0.1% (v/v) ammonium hydroxide in water; B) 0.1% (v/v) ammonium hydroxide in 95:5 acetonitrile/water. The total run time was approximately 10 minutes and a typical implementation of the method is given below:

Time
gradient
elution
(min) Consumption
(ml/min) %A %B 0.00 20.0 fifty fifty 3.00 20.0 12 88 5.00 20.0 12 88 7.00 20.0 0 100 8.0 20.0 0 100 8.20 20.0 fifty fifty

Acidic conditions: LC column: Waters XBridge™ Prep C18 5 µm OBD™ 19x50 mm column at room temperature. Mobile phase: A) 0.1% (v/v) formic acid in water; B) 0.1% (v/v) formic acid in 95:5 acetonitrile/water. The total time of the experiment was approximately 10 or 20 minutes and an example of the implementation of the method is given below:

Time
gradient
elution
(min) Consumption
(ml/min) %A %B 0.00 20.0 95 5 7.00 20.0 0 100 9.00 20.0 0 100 9.20 20.0 95 5

Pure fractions were pooled and concentrated using a Genevac EZ-2 Elite evaporator unless otherwise noted.

Chiral separation of stereoimers by supercritical liquid chromatography (SFC)

Separation of mixtures of stereoisomers was performed using the following general procedure.

The mixture of stereoisomers was dissolved to 50 mg/ml in methanol and purified with SFC under the indicated conditions. The combined fractions of each of the stereoisomers were evaporated to near dryness using a rotary evaporator, transferred to final vessels using DCM, which was then removed in a compressed air stream at 40° C. before being placed in a vacuum oven at 40° C. and 5 mbar pressure for 16 hours.

Chiral purity analysis

After chiral separation of a mixture of stereoisomers, analysis was performed to determine chiral purity using the following SFC analytical methods under the indicated conditions.

Method A:

Column Lux A1 (4.6 mm × 250 mm, 5 µm) Column temperature 40°C Flow rate 4 ml/min BPR (differential pressure) 125 bar Detector wavelength 210-400 nm Injectable sample volume 1 µl isocratic conditions 20:80 IPA:CO ₂ (0.1% v/v NH ₃ )

Method B:

Column Lux C4 (4.6 mm × 250 mm, 5 µm) Column temperature 40°C Flow rate 4 ml/min BPR (differential pressure) 125 bar Detector wavelength 210-400 nm Injectable sample volume 1 µl isocratic conditions _35:65 MeOH:CO2

Method C:

Column AMS (4.6 mm × 250 mm, 5 µm) Column temperature 40°C Flow rate 4 ml/min Detector wavelength 210-400 nm Injectable sample volume 1.0 µl BPR (differential pressure) 125 bar isocratic conditions 25:75 MeOH:CO ₂ (0.1% v/v NH ₃ )

X-ray crystallography

A suitable crystal was chosen and installed in a Rigaku AFC1 1 007-HF diffractometer on a MITIGEN holder in silicone oil. The crystal was kept at T=100(2) K during data collection. Structure was determined using Olex2 (Dolomanov et al., J. Appl. Cryst, 2009, 42, p339-341) using the SheIXT structure resolver (Sheldrick, Acta Cryst, 2015, A71, p3-8) using the Intrinsic solver phasing. The model has been enhanced with ShelXL version 2016/6 (Sheldrick, Acta Cryst, 2015, C71, p3-8) using least squares minimization.

Nomenclature

Unless otherwise indicated, structure nomenclature was determined using the structure-to-name conversion function in ChemBioDraw Ultra 12.0 or ChemDraw Professional 15.1 (CambridgeSoft/Perkin Elmer). In the case of amines 7 and 9, acids 4 and 13 and Examples 120, 121, 122, 123, 204, 205, 206, 207, 208, 213, 220, 221, 228, 235 and 236, the chiral tertiary alcohol configuration was set to based on X-ray crystallography data of the enantiopure intermediate ethyl-(S)-1-((1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-chloro-6-oxo- 1,6-dihydropyridine-3-carboxylate (amine 7, step 2: 2nd eluted compound from chiral supercritical liquid chromatography, with 99.4% ee, which was then used to obtain the desired compounds, and was known to lead to to more active stereoisomers). The absolute configuration of the molecules was determined by analyzing the anomalous X-ray scattering on a single crystal that was grown by the ethyl acetate/cyclohexane diffusion method. Differences in anomalous scatter intensities were compared to calculated scatter intensities for each enantiomer, and the measured and calculated intensities were adjusted to the Flack parameter (Chirality, 2008, 20, p681-690; and references cited). The Flack parameter should be close to 0 if the configuration of the structure being solved is correct, or close to 1 if the inverse model is correct, or close to 0.5 for a racemic mixture. Measured Flack parameter for ethyl-(S)-1-((1-tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-chloro-6-oxo-1,6- dihydropyridine-3-carboxylate shown in Table 2, along with other data and crystal characteristics, along with data collection parameters, is determined to -0.005 with a standard uncertainty of 0.004.

Table 2 : Crystal characteristics and data collection parameters for ethyl-(S)-1-((tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-chloro-6-oxo- 1,6-dihydropyridine-3-carboxylate Formula C ₂₁ H ₃₁ ClN ₂ O ₆ Z 2 D _{calc .} /gcm- ³ 1.335 Z' one μ /mm ^-1 1.873 Wavelength /Å 1.54184 Mol. mass according to the formula 442.93 Radiation type _CuKα Color transparent, colorless Θmin _/ ^° 4.458 The form prism Θmax ^/ _° 70.578 Size/mm ³ 0.12×0.10×0.06 Measured Reflections 21281 T /K 100(2) Independent Reflections 4195 Crystal system monoclinic Used reflections 4166 Flack parameter -0.005(4) R _int 0.0242 Parameter Hooft -0.010(3) Options 281 space group P2 ₁ Restrictions one a /Å 10.22890(10) highest peak 0.268 b /Å 9.20890(10) largest depression -0.211 c /Å 12.06510(10) goof 1.048 α / ^° 90 wR ₂ (all data) 0.0666 β / ^° 104.1540(10) wR ₂ 0.0665 γ / ^° 90 R ₁ (all data) 0.0254 V/Å ³ 1101.994(19) R _one 0.0253

The measured Flack parameter of -0.005(4) is classified as significant/enantiopure and confirms the S-configuration with a high degree of confidence. Therefore, the following absolute model configuration is correct. The chiral center located on the tertiary alcohol has been confirmed to have the S-configuration.

In Examples 124, 125, 152, 153, 160, 164, 165, 166 and 167, in which compounds were not synthesized directly from this intermediate but contained the same gem-dimethylpiperidinol, the tertiary alcohol configuration was derived from X-ray crystallography data for intermediate product. The most active diastereoisomers had the S-configuration, while the less active diastereoisomers (usually 50-500 times less active) had the R-configuration of the chiral tertiary alcohol. For amines 10, 1 1 and 12 and Examples 209, 210, 211, 212, 214, 215, 216, 217, 218, 219, 222, 223, 224, 225, 226, 227, 230, 231, 232, 233, 239, 240, 247, 248, 249, 250, 251, 252 and 253 in which the compounds were not synthesized from this intermediate but contained the analogous spirocyclopentylpiperidinol, the tertiary alcohol configuration was also deduced from X-ray crystallography data of the gem-dimethylpiperidinol intermediate . The most active stereoisomers were in the S configuration, while the less active stereoisomers (usually 5000-8000 times less active) were in the R configuration in the chiral tertiary alcohol. However, it should be noted that for each of the examples listed above, there may be a case where they had an incorrect configuration in the position of the tertiary alcohol due to an unforeseen error in the X-ray crystallography data or stereochemistry inference strategy based on other compounds in the Examples for which it was wrong conclusion is made. Therefore, for each of these Examples, compounds are also claimed which have the opposite configuration at the indicated position.

General procedures

General Procedure 1: Opening an Epoxide by a Nucleophile

The appropriate nucleophile (1 equiv.), epoxide (1-3 equiv.) and base, Cs ₂ CO ₃ (1-3 equiv.) or DIPEA (1.5 equiv.), suspended in DMF and the mixture was heated at 80°C within 10-24 hours or as directed. The reaction mixture was cooled to room temperature. Saturated aqueous ammonium chloride or water was added and the mixture was extracted with DCM or EtOAc (x 3). The combined organic extracts were dried (using a Biotage or MgSO ₄ phase separator), concentrated, and the residue was purified by flash chromatography (Biotage KP-Sil and/or KP-NH, 0-100% EtOAc in cyclohexane; then 0-30% MeOH in EtOAc ), with the receipt of the product.

General procedure 2: combination with acid chloride

The appropriate amine (1 eq) was dissolved in DCM and DIPEA (2 eq) was added followed by the desired acid chloride (1.1 eq). The mixture was stirred for 30 minutes, then quenched by adding water. The resulting mixture was extracted with DCM and the phases were separated using a Biotage phase separator. The organic layer was concentrated and the residue was purified by flash chromatography (GraceResolv, 0-90% EtOAc in cyclohexane) to give the product.

General Procedure 3: Combine with HATU

The appropriate amine (1 eq.), carboxylic acid (1.5 eq.) and HATU (1.5 eq.) were dissolved in DCM or DMF and DIPEA (4 eq.) was added. The reaction mixture was stirred for 1-24 hours then quenched by adding saturated aqueous sodium bicarbonate. The resulting mixture was extracted with DCM (x 3) using a Biotage phase separator. The combined organic extracts were concentrated and the residue was purified by flash chromatography (GraceResolv, 0-100% EtOAc in cyclohexane; then 0-30% MeOH in EtOAc) to give the product.

General procedure 4: Suzuki combination

The reaction vessel was charged with a mixture of the appropriate halide (1 eq.), organoboron reagent (1-3 eq.), Pd catalyst (0.05-0.1 eq.) and inorganic base (2-5 eq.) in a mixture of water and 1 ,4-dioxane or DME. The mixture was degassed three times by evacuation and refilling with N ₂ or by bubbling N ₂ for 5 minutes, and then the reaction tube was sealed. The reaction mixture was heated under the indicated conditions for the indicated time, then cooled to room temperature. Water or saturated aqueous ammonium chloride was added and the mixture was extracted with DCM (x 3). The combined organic extracts were dried (Biotage phase separator), concentrated, and the residue was purified by flash chromatography (Biotage KP-Sil and/or KP-NH, 0-100% EtOAc in cyclohexane, then 0-30% MeOH in EtOAc) to give product.

General Procedure 5: Combination with HBTU

The intermediate amine (1 eq) was dissolved in DCM and the appropriate carboxylic acid (1.1 eq) was added followed by DIPEA (1-5 eq) at room temperature. HBTU (1.1 eq.) was added and, in cases where poor solubility was observed, DMF (0.2 ml) was added. The mixture was stirred at this temperature for 2-67 hours until completion of the reaction, controlled by LCMS. Water or 2M aqueous sodium hydroxide (1-2.5 ml) was added and the resulting mixture was stirred at room temperature for 5-15 minutes. The biphasic mixture was then filtered through a Biotage phase separator and the organic layer concentrated. The residue was purified by flash chromatography (Biotage KP-NH, 0-100% EtOAc in cyclohexane; then 0-30% MeOH in EtOAc unless otherwise noted) to give the product.

General procedure 6: Wittig olefination

The corresponding triphenylphosphonium salt (1.4 eq.) was dissolved in anhydrous THF (10 ml) and the solution was cooled to -78°C. Then n-butyllithium (2.5M in hexane, 1.5 eq.) was added dropwise. The resulting solution was stirred at the same temperature for 5 minutes, then warmed to room temperature and stirred for another 20-30 minutes. The mixture was cooled to -78° C. and a solution of the ketone (1.0 eq.) in THF (5 ml) was added over 10 minutes. The resulting suspension was allowed to warm to room temperature and stirred for 19-22 hours. Water (5 ml) was added and the mixture was extracted with Et2O (x3). The combined organic extracts were washed with saturated aqueous sodium bicarbonate, dried over anhydrous MgSO ₄ and concentrated. The residue was purified by flash chromatography to give the product.

General Procedure 7: Removal of the Boc Protecting Group to Recover the Free Base

The appropriate Boc protected amine (1 eq) was dissolved in DCM (1-4 ml) and 2,2,2-trifluoroacetic acid (0.2-1.0 ml) was added. The mixture was stirred at room temperature for 1-3.5 hours, then concentrated. The residue was dissolved in a mixture of MeOH and DCM and loaded onto an SCX-2 cartridge. The column was eluted with a mixture of DCM and MeOH, then with a mixture of 3:2 DCM: 2M NH ₃ in MeOH. The ammonia fractions were concentrated to give the desired product.

General Procedure 8: Epoxidation

A solution of m-CPBA (1.2 eq.) in DCM (2.5-5 ml) was added dropwise to a solution of alkene (1 eq.) in DCM (5-10 ml) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 2-2.5 hours. The reaction mixture was diluted with DCM (10 ml). The mixture was washed with aqueous sodium hydroxide (1M), water and saturated aqueous sodium thiosulfate, then filtered through a Biotage phase separator and concentrated under reduced pressure to give the desired epoxide, which was used without further purification.

General Procedure 9: Removing the Boc Protecting Group to Give the Hydrochloride Salt

The Boc-protected amine was dissolved in DCM (5 ml) and HCl (4M in 1,4-dioxane, 1-15 eq.) was added. The reaction mixture was stirred at room temperature for 1-24 hours. The mixture was concentrated or the insoluble product was collected by filtration. In any case, the crude product was washed with excess Et ₂ O and dried in vacuo.

General Procedure 10: Hydrolysis of Heteroaryl Chloride

The corresponding chlorinated heterocycle was suspended in water (1-3.5 ml) and acetic acid (4-10 ml) was added. The reaction mixture was heated under reflux for 2-5 days. The mixture was concentrated and the residue was dissolved in saturated aqueous sodium bicarbonate (10 ml). The mixture was extracted with DCM (3×10 ml) and the combined organic extracts were concentrated to give the product, which was used without further purification.

General Procedure 11: Cori-Tchaikovsky Epoxidation

Trimethylsulfonium iodide (2.5 eq.) was suspended in DMSO (1-5 ml) under N ₂ atmosphere. Sodium hydride (60% dispersion in mineral oil, 2.5 eq.) was added portionwise. The mixture was allowed to warm to room temperature and stirred for 2 hours, then a solution of the ketone (1 eq.) in DMSO (0.5-2.5 ml) was slowly added. The mixture was heated to 50°C and stirred for 16 hours, then cooled to room temperature and the reaction was quenched by the addition of H ₂ O. The mixture was extracted with Et ₂ O. The organic layer was dried over MgSO ₄ and concentrated to give crude epoxide.

General Procedure 12: BioShake Combination with HATU

The appropriate carboxylic acid (1 eq) was dissolved in DMF (0.3 ml) and DIPEA (2 eq) and HATU (1-1.5 eq) was added as a solution in DMF (0.3 ml). The appropriate amine (1 eq.) was added as a solution in DMF (0.3 ml) and the reaction mixture was stirred using BioShake IQ at room temperature for 2 hours. The crude reaction mixture was purified by preparative HPLC using the general method.

General Procedure 13: EDC Amide Coupling Library

The appropriate carboxylic acids (0.035 mmol, 1.2 eq.) were added to each 4 ml vial of EDC solution (1.23 mg, 0.059 mmol, 2 eq.), DIPEA (0.01 ml, 0.059 mmol, 2 eq. ), DMAP. (0.35 mg, 0.003 mmol) in DCM (0.5 ml). The resulting suspensions were stirred for 10 minutes at room temperature (shaking while heating). A solution of amine 8 (12 mg, 0.029 mmol, 1 eq.) in DCM (0.2 ml) was added to each vial and the resulting solutions were stirred at room temperature overnight. Parallel processing was carried out using a 96-well phase separator in a 3-step process: washing with saturated sodium bicarbonate, washing with 2N HCl, and then a second wash with saturated sodium bicarbonate. The resulting DCM filtrates were diluted with DCM (0.5 ml), transferred to tared vials and concentrated. The residues were dissolved in methanol (1 ml), analyzed by LCMS and concentrated in vacuo (Genevac).

Amine 1: 6-(2-fluorophenyl)-3-((4-hydroxypiperidin-4-yl)methyl)pyrimidin-4(3H)-one hydrochloride

Step 1: tert-butyl 4-((4-chloro-6-oxopyrimidin-1(6H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate: Prepared according to general procedure 1 using 6-chloropyrimidine- 4(3H)-one (3.18 g, 24.4 mmol), tert-butyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (5.2 g, 24.4 mmol) and N-ethyl-N-isopropylpropan-2-amine (6.39 ml, 36.6 mmol) in DMF (32 ml). The crude product was triturated with a mixture of cyclohexane and EtOAc to give the title compound (3.70 g, 44%). LCMS (method B): R _T= 1.01 min, m/z =244 [M+H-Boc] ⁺ . ¹ H-NMR (400 MHz CDCl ₃ ): δ 8.08 (s, 1H), 6.57 (s, 1H), 4.0 (br d, 4H), 3.15 (br t, 2H ), 2.78 (s, 1H), 1.69-1.59 (m, 1H), 1.54-1.49 (m, 1H), 1.46 (m, 11H).

Step 2: tert-Butyl 4-((4-(2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate: Prepared according to General Procedure 4 using tert-Butyl 4-((4-chloro-6-oxopyrimidin-1(6H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate (1 g, 2.91 mmol), (2-fluorophenyl)boronic acid (0.61 g, 4.36 mmol), sodium carbonate (0.617 g, 5.82 mmol), 1,4-dioxane (12 ml), water (4.8 ml) and Pd(Ph ₃ P) ₄ ( 0.168 g, 0.145 mmol). The reaction mixture was heated in a microwave oven at 150° C. for 15 minutes. The crude product was triturated with diethyl ether to give the title compound (1.71 g, 73%). LCMS (Method B): R _T =1.22 min, m/z =304 [M-Boc+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.19 (s, 1H), 8.05 (td, 1H), 7.44 (cd, 1H), 7.29 (d, 1H), 7 .17 (dd, 1H), 7.11 (s, 1H), 4.0 (brd, 4H), 3.56 (s, 1H), 3.22-3.07 (m, 2H), 1.56-1.67 (m, 4H), 1.46 (s, 9H).

Step 3: 6-(2-fluorophenyl)-3-((4-hydroxypiperidin-4-yl)methyl)pyrimidin-4(3H)-one hydrochloride : Prepared according to general procedure 9 using tert-butyl-4- ((4-(2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate (3.37 g, 8.35 mmol) and hydrogen chloride (4M in 1, 4-dioxane, 30.6 ml, 122 mmol) in DCM (33.4 ml) to give the title compound (3.29 g, quant.). LCMS (method B): R _T =0.58 min, m/z =304 [M+H] ⁺ . ¹ H-NMR (400 MHz, methanol- d ₄ ): δ 8.62 (s, 1H), 8.05 (td, 1H), 7.57 (br cd, 1H), 7.39 (d, 1H), 7.31 (dd, 1H), 7.00 (s, 1H), 4.19 (s, 2H), 3.34-3.27 (m, 4H), 2.03-1.90 (m, 2H), 1.80 (d, 2H).

Amin 2 :( R,S )-3-(1-(4-hydroxypiperidin-4-yl)ethyl)-6-phenylpyrimidine-4(3 H )-one hydrochloride

Stage 1: tert-butyl-4-ethylidene-piperidine-1-carboxylate: Prepared according to general procedure 6 using ethyltriphenylphosphonium iodide (1.47 g, 3.51 mmol), n-butyllithium (2.5M in hexane, 1, 51 ml, 3.76 mmol) and tert-butyl-4-oxo-piperidine-1-carboxylate (0.5 g, 2.51 mmol) in anhydrous THF (15 ml) at a reaction time of 19 hours. The crude product was purified by flash chromatography (GraceResolv 24 g, 100% cyclohexane; then isocratic 50% EtOAc in cyclohexane) to give the title compound (0.51 g, 83%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 5.28 (q, 1H), 3.38 (t, 4H), 2.20 (t, br, 2H), 2.12 (t, br ., 2H), 1.60 (d, 3H), 1.47 (s, 9H).

Step 2: (R,S)-tert-Butyl-2-methyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate : Prepared according to General Procedure 8 using m-CPBA (0. 56 g, 2.50 mmol), tert-butyl-4-ethylidene-piperidine-1-carboxylate (0.44 g, 2.09 mmol) in DCM (15 ml) and a reaction time of 2 hours, to give the title compound ( 0.46 g, 82%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.80-3.62 (br. m, 2H), 3.45-3.33 (m, 2H), 2.93 (q. 1H), 1.82-1.70 (bm, 2H), 1.56-1.36 (m, 11H), 1.31 (d, 3H).

Step 3: (R,S)-tert-butyl-4-hydroxy-4-(1-(6-oxo-4-phenylpyrimidin-1(6H)-yl)ethyl)piperidine-1-carboxylate: Prepared according to general procedure 1, using tert-butyl-2-methyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.39 g, 1.73 mmol), 6-phenylpyrimidine-4(3H )-one (0.248 g, 1.44 mmol) and cesium carbonate (1.41 g, 4.33 mmol) in DMF (20 ml) at 120°C for 96 hours, and purified by flash chromatography (GraceResolv 24 g, 10-50% EtOAc in cyclohexane) to give the title compound (0.28 g, 49%). ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.50 (s, 1H), 8.12-8.05 (m, 2H), 7.54-7.47 (m, 3H), 6.98 (s, 1H), 5.16 (s, 1H), 4.99-4.86 (m, 1H), 3.85-3.7 (bm, 1H), 3.65 ( d, 1H), 3.17-2.81 (m, 2H), 1.66 (d, 1H), 1.56-1.21 (m, 14H), 1.13-1, 04 (m, lat., 1H).

Step 4 (R,S)-3-(1-(4-hydroxypiperidin-4-yl)ethyl)-6-phenylpyrimidin-4(3H)-one hydrochloride: Prepared according to general procedure 9 using t-butyl -4-hydroxy-4-(1-(6-oxo-4-phenylpyrimidin-1(6H)-yl)ethyl)piperidine-1-carboxylate (250 mg, 0.63 mmol) in DCM (5 ml) and chloride hydrogen in 1,4-dioxane (4M, 2.29 mL, 9.16 mmol) to give the title compound (0.20 g, 97%) which was used without further purification. LCMS (Method B): R_T=0.61 min,m/z=300 [M+H]⁺.^oneH-NMR (400 MHz, methanol-d _four ): δ 8.75 (br s, 1H), 8.04-7.98 (m, 2H), 7.59-7.52 (m, 3H), 6.99 (s, 1H), 5 .18 (s, 1H), 3.44-3.13 (m, 4H), 2.08 (m, 1H),2.00-1.88(m, 1H), 1.87-1.76(m, 1H), 1.58(d, 3H), 1.55-1.47(m, 1H).

Amin 3 :( R,S )-1-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N -isopropyl- N -methyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Step 1: (R,S)-tert-butyl-4-((4-chloro-5-(isopropyl(methyl)carbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-4-hydroxy-3 ,3-dimethylpiperidine-1-carboxylate: Prepared according to general procedure 1 using epoxide 3 (197 mg, 0.818 mmol), 4-chloro-N-isopropyl-N-methyl-6-oxo-1,6-dihydropyridine -3-carboxamide (170 mg, 0.743 mmol), Cs ₂ CO ₃ (363 mg, 1.12 mmol) and DMF (3 ml). The crude product was purified by flash chromatography (GraceResolv 24 g, 0-100% EtOAc in cyclohexane) to give the title compound (0.217 g, 62%). LCMS (method B): R _T= 1.25 min, m/z =414 [M+H- ^t Bu] ⁺ .

Step 2: (R,S)-tert-butyl-4-hydroxy-4-((5-(isopropyl(methyl)carbamoyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-3 ,3-dimethylpiperidine-1-carboxylate : Prepared according to general procedure 4 using tert-butyl-4-((4-chloro-5-(isopropyl(methyl)carbamoyl)-2-oxopyridine-1(2H)- yl)methyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (217 mg, 0.46 mmol), phenylboronic acid (84 mg, 0.693 mmol), sodium carbonate (122 mg, 1.15 mmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (39.1 mg, 0.046 mmol), 1,4-dioxane (2 ml) and water (0.67 ml). The reaction mixture was heated in a microwave oven at 150° C. for 15 minutes to give the title compound (205 mg, 87%). LCMS (Method B): R _T =1.37 min, m/z= 456 [M+H- ^t Bu] ⁺ .

Step 3: (R,S)-1-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-4-phenyl-1,6- dihydropyridine-3-carboxamide: Prepared according to general procedure 7 using tert-butyl-4-hydroxy-4-((5-(isopropyl(methyl)carbamoyl)-2-oxo-4-phenylpyridine-1(2H- )-yl)methyl)-3,3-dimethylpiperidine-1-carboxylate (204 mg, 0.40 mmol), DCM (3 mL) and TFA (1 mL, 13.0 mmol) to give the title compound ( 151 mg, 92%). LCMS (method B): R _T= 0.76 min, m/z =412 [M+H] ⁺ .

Amine 4: 4-(2-fluorophenyl)-1-((4-hydroxypiperidin-4-yl)methyl)- N -isopropyl- N -methyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Step 1: 4,6-dichloro-N-isopropyl-N-methylnicotinamide : Prepared according to general procedure 5 using 4,6-dichloronicotinic acid (5.04 g, 26.3 mmol), HBTU (1.0 g , 28.9 mmol), DCM (100 ml) and DIPEA (9.17 ml, 52.5 mmol). The crude product was purified by flash chromatography (GraceResolv 120 g, 10-33% EtOAc in cyclohexane) to give the title compound (5.77 g, 89%). LCMS (method B): R _T= 1.02 min, m/z= 247, 249 [M+H] ⁺ .

Stage 2. 4-chloro-N-isopropyl-N-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide: 4,6-dichloro-N-isopropyl-N-methylnicotinamide (2.5 g, 10, 1 mmol) and sodium acetate (4.15 g, 50.6 mmol) were dissolved in acetic acid (40 ml, 700 mmol) and the mixture was heated under reflux for 7 days. The mixture was concentrated, the residue was diluted with water and basified with solid potassium carbonate. The mixture was extracted with DCM. The organic layer was dried (phase separator), concentrated, and the residue was purified by flash chromatography (GraceResolv, 50-100% EtOAc in cyclohexane) to give the title compound (600 mg, 26%). LCMS (method B): R _T= 0.64 min, m/z =229/231 [M+H] ⁺ .

Step 3: tert-Butyl 4-((4-chloro-5-(isopropyl(methyl)carbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate : Prepared according to with general procedure 1, using epoxide 1 (233 mg, 1.09 mmol), 4-chloro-N-isopropyl-N-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (250 mg, 1.09 mmol). 09 mmol), cesium carbonate (534 mg, 1.64 mmol) and DMF (5 ml). The mixture was heated at 90°C for 16 hours. The crude product was purified by flash chromatography (GraceResolv (12 g), 20-80% EtOAc in cyclohexane) to give the title compound (389 mg, 81%). LCMS (method B): R _T= 1.06 min, m/z =342 [M+H-Boc] ⁺ .

Stage 4: tert-butyl-4-((4-(2-fluorophenyl)-5-(isopropyl(methyl)carbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate : Prepared according to general procedure 4 using tert-butyl-4-((4-chloro-5-(isopropyl(methyl)carbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-4-hydroxypiperidine- 1-carboxylate (100 mg, 0.23 mmol), 1,4-dioxane (1.5 ml), (2-fluorophenyl)boronic acid (47.5 mg, 0.34 mmol), sodium carbonate (2M in water , 0.226 ml, 0.45 mmol), Pd(dppf)Cl ₂ .CHCl ₂ (9.31 mg, 0.01 1 mmol) and water (0.3 ml). The mixture was heated in a microwave oven at 120° C. for 30 minutes. The crude product was purified by chromatography (GraceResolv, 0-100% EtOAc in cyclohexane; then 0-25% MeOH in EtOAc) to give the title compound (91 mg, 80%). LCMS (method B): R _T= 1.19 min, m/z =402 [M+H-Boc] ⁺ .

Stage 5: 4-(2-fluorophenyl)-1-((4-hydroxypiperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide : Prepared in according to general procedure 7 using tert-butyl-4-((4-(2-fluorophenyl)-5-(isopropyl(methyl)carbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-4-hydroxypiperidine -1-carboxylate (190 mg, 0.379 mmol), TFA (2 ml) and DCM (2 ml) to give the title compound (152 mg, quant.). LCMS (method B): R _T= 0.68 min, m/z =402 [M+H] ⁺ .

Amin 5 :( R,S )-6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4(3 H )-he

Stage 1: (R,S)-tert-butyl-4-((4-(2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)methyl)-4-hydroxydimethylpiperidine-1-carboxylate : Prepared according to with general procedure 1 using 6-(2-fluorophenyl)pyrimidin-4(3H)-one (1.5 g, 7.89 mmol), epoxide 3 (2.72 g, 7.89 mmol) and cesium carbonate ( 3.08 g, 9.47 mmol) in DMF (20 ml). The crude material was suspended in diethyl ether and the resulting solid was collected by filtration to give the title compound (1.8 g, 53%). LCMS (method B): R _T= 1.39 min, m/z =432 [M+H] ⁺ .

Step 2: (R,S)-6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4(3H)-one : Prepared according to general procedure 7 using tert-butyl 4-((4-(2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (1 4 g, 3.24 mmol), DCM (10 ml) and TFA (3 ml, 39 mmol) to give the title compound (920 mg, 86%). LCMS (method B): R _T =0.65 min, m/z =332 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ (ppm) 8.44 (s, 1H), 8.07-8.00 (m, 1H), 7.58-7.52 (m, 1H), 7.40-7.34 (m, 2H), 6.80 (s, 1H), 4.64 (s, 1H), 4.45 (d, 1H), 3.67 ( d, 1H), 2.76-2.63 (m, 3H), 2.26 (d, 1H), 1.61-1.50 (br. m, 1H), 1.13-1.04 ( m, 4H), 0.93 (s, 3H).

Amine 6: 1-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide hydrochloride

Stage 1: ethyl-1-((1-(tert-butoxycarbonyl)- 4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3- carboxylate : Prepared according to general procedure 1 using ethyl 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (intermediate 1, step 2) (1.77 g, 7.28 mmol) , epoxide 3 (1.93 g, 8.00 mmol) and cesium carbonate (3.56 g, 10.9 mmol) in DMF (30 mL), heated to 80° C. for 24 hours to give the title compounds (2.15 g, 61%). LCMS (method A): R _T= 1.75 min, m/z =485 [M+H] ⁺ .

Stage 2: 1-((1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid : To a stirred solution of ethyl 1-((1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3 -carboxylate (1.0 g, 2.06 mmol) in THF (10 ml) and water (2 ml) was added 4M sodium hydroxide (aqueous solution) (2.58 ml, 10.3 mmol). The reaction mixture was heated to 60° C. and stirred overnight at this temperature. The solution was allowed to cool to room temperature and the solvent volume was reduced in vacuo. The mixture was acidified with 2M HCl (aq) and extracted with EtOAc (x3). The combined organic phases were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound (937 mg, 99%). LCMS (method B): R _T= 1.25 min, m/z =401 [M+H] ⁺ .

Step 3: tert-Butyl 4-((5-(dimethylcarbamoyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate : Obtained according to general procedure 5 using 1-((1-( tert -butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3 -carboxylic acid (480 mg, 1.05 mmol), DIPEA (0.220 ml, 1.26 mmol), HBTU (439 mg, 1.16 mmol) and dimethylamine (2M in THF, 0.790 ml, 1.58 mmol) in DCM (6 ml) at room temperature for 16 hours to give the title compound (500 mg, 98%). LCMS (method A): R _T =1.20 min, m/z =484 [M+H] ⁺ .

Step 4: 1-((4-Hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide hydrochloride: Prepared according to general procedure 9 using tert-butyl-4-((5-(dimethylcarbamoyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin- 1-carboxylate (500 mg, 1.03 mmol) and 4M HCl in dioxane (3.1 ml, 12.4 mmol) in DCM (8 ml) to give the title compound (434 mg, quant.). LCMS (method A): R _T =0.60 min, m/z =384 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.82 (s, 1H), 7.47-7.42 (m, 3H), 7.41-7.36 (m, 2H), 6.47 (s, 1H), 4.48 (d, 1H), 3.81 (d, 1H), 3.10 (bd, 1H), 3.00-2.88 (m, 2H) , 2.83-2.72(m, 4H), 2.63(s, 3H), 1.96-1.83(m, 1H), 1.43-1.34(m, 1H), 1 .33-1.23 (m, 1H), 1.19 (s, 3H), 1.03 (s, 3H).

Amin 7 :( S )-1-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Stage 1. ethyl 4-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate : a mixture of ethyl 4,6-dichloronicotinate (25 g, 114 mmol) and sodium acetate (46.6 g, 568 mmol ) in acetic acid (325 ml, 5.68 mol) was heated at reflux for 3 days. The reaction mixture was allowed to cool to room temperature, diluted with water (650 ml) and the resulting precipitate was isolated by filtration. The precipitate was washed with water (6×100 ml) and dried in a vacuum oven at 50° C. to give the title compound (18.7 g, 81%) as a light beige solid. LCMS (Method A): R _T = 0.73 min, m/z = 202, 204 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 12.40 (br, s, 1H), 8.11 (s, 1H), 6.55 (s, 1H), 4.22 (q , J= 7.1 Hz, 2H), 1.27 (t, J =7.1 Hz, 3H).

Stage 2. ethyl-1-((1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-chloro-6-oxo-1,6-dihydropyridine-3- carboxylate . A suspension of ethyl 4-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (4.00 g, 19.8 mmol), epoxide 3 (6.22 g, 25.8 mmol) and cesium carbonate (8 .40 g, 25.8 mmol) (dried at 120° C. under high vacuum for 5 hours) in DMF (66 ml) and heated at 90° C. for 19 hours. The reaction mixture was allowed to cool to room temperature, diluted with saturated NH ₄ Cl (aq.) (200 ml) and the mixture was extracted with EtOAc (3×100 ml). The combined organic phases were passed through a Biotage phase separator, concentrated in vacuo and the residue purified by flash chromatography (100 g Biotage KP-Sil cartridge, 0-60% EtOAc in cyclohexane) to give the title compound (3.31 g, 37 % as pale yellow foam LCMS (Method A): R _T = 1.54 min, m/z = 443.445 [M+H] ^{+ 1} H-NMR (500 MHz, DMSO- d ₆ ): δ 8.44 (s, 1H), 6.64 (s, 1H), 4.84 (s, 1H), 4.49 (d, J =13.4 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.74-3.60 (m, 2H), 3.30-2.85 (m, 3H), 1.62-1.48 (m, 1H), 1 .38 (s, 9H), 1.29 (t, J = 7.1 Hz, 3H), 1.08-0.99 (m, 1H), 0.97 (s, 3H), 0.92 ( s, 3H).

Ethyl 1-((1-( tert -butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (9 89 g) was separated into individual stereoisomers by chiral supercritical liquid chromatography using an AmyC column (20 mm x 250 mm, 5 µm) under isocratic solvent conditions: 20:80 IPA/CO ₂ (0.1% v/v ) NH ₃ ). The first material eluted was ( R )-1-((1-( tert -butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-chloro-6-oxo-1,6- dihydropyridine-3-carboxylate (4.55 g, 46% yield), orange solid. Chiral purity (method A): R _{T =} 1.85 min, 100% ee. The second eluted material was ( S )-1-((1-( tert -butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-chloro-6-oxo-1,6- dihydropyridine-3-carboxylate (4.36 g, 44% yield), orange solid. Chiral purity (method A): R _{T =} 2.18 min, 99.4% ee.

Stage 3: ethyl-(S)-1-((1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6- dihydropyridine-3-carboxylate: Prepared according to general procedure 4 using ethyl-(S)-1-((1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl) -4-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (200 mg, 0.452 mmol), phenylboronic acid (82.5 mg, 0.677 mmol), Pd(dppf)Cl ₂ •DCM (19 mg, 22.6 mmol), sodium carbonate (96 mg, 0.903 mmol), 1,4-dioxane (1.5 ml) and water (0.5 ml). The reaction mixture was heated in a microwave oven at 120° C. for 30 minutes to give the title compound (220 mg, quantitative yield) as a pale yellow foam. LCMS (method A): R _T= 1.68 min, m/z =485 [M+H] ⁺ .

Step 4: (S)-1-((1-(tert-Butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine- 3-carboxylic acid: Ethyl-(S)-1-((1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1 solution ,6-dihydropyridine-3-carboxylate (220 mg, 0.454 mmol) in 1M NaOH (aq) (0.910 ml, 0.910 mmol) and 1,4-dioxane (2.2 ml) was stirred at 50°C for 5 hours , then allowed to cool to room temperature. The pH was adjusted to 3 with 1M HCl (aq) and the mixture was extracted with DCM (3×20 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo to give the title compound (193 mg, 93%) as a colorless foam. LCMS (method A): R _T= 1.31 min, m/z =457 [M+H] ⁺ .

Step 5: tert-Butyl-(S)-4-((5-(dimethylcarbamoyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-1 - carboxylate : Prepared according to general procedure 3 using (S)-1-((1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxylic acid (193 mg, 0.423 mmol), dimethylamine (2M in THF, 0.254 ml, 0.507 mmol), DIPEA (0.295 ml, 1.69 mmol), HATU (193 mg, 0.507 mmol) and DCM (8.5 ml) to give the title compound (241 mg, >100%) as a pale yellow foam. This material was used without further purification. LCMS (method A): R _T= 1.29 min, m/z =484 [M+H] ⁺ .

Stage 6: (S)-1-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3- carboxamide: Prepared according to general procedure 7 using tert-butyl-(S)-4-((5-(dimethylcarbamoyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-4- hydroxy-3,3-dimethylpiperidine-1-carboxylate (204 mg, 0.422 mmol), TFA (1 ml) and DCM (2 ml) to give the title compound (157 mg, 97%) as a colorless solid. LCMS (method A): R _T =0.46 min, m/z =384 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.79 (s, 1H), 7.50-7.40 (m, 3H), 7.40-7.32 (m, 2H), 6.43 (s, 1H), 4.59 (s, 1H), 4.46 (d, J = 13.3 Hz, 1H), 3.72 (d, J = 13.3 Hz, 1H), 3.17 (s, 1H), 2.74 (s, 3H), 2.71-2.64 (m, 3H), 2.62 (s, 3H), 2.20 (d, J =12, 5 Hz, 1H), 1.59-1.46 (m, 1H), 1.13-0.97 (m, 1H), 1.05 (s, 3H), 0.89 (s, 3H).

Amine 8: 1-((10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Stage 1: tert-Butyl-10-((4-chloro-5-(ethoxycarbonyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7-carboxylate : Prepared according to general procedure 1 using ethyl 4-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (1.06 g, 5.24 mmol), epoxide 6 (1.75 g, 5.24 mmol) and cesium carbonate (2.56 g, 7.85 mmol) in DMF (20 ml). The reaction mixture was stirred at 80° C. for 16 hours to give the title compound (1.02 g, 41%). LCMS (Method A): R _T= 1.66 min, m/z =413, 415 [M-butene+H] ⁺ .

Step 2: tert-Butyl 10-((5-(ethoxycarbonyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7-carboxylate : Prepared according to general procedure 4 using tert-butyl-10-((4-chloro-5-(ethoxycarbonyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro [4.5]decane-7-carboxylate (1.02 g, 2.18 mmol), phenylboronic acid (0.40 g, 3.26 mmol), Pd(dppf)Cl ₂ •DCM (186 mg, 0.218 mmol), sodium carbonate (0.58 g, 5.44 mmol), 1,4-dioxane (9 ml) and water (3 ml). The reaction mixture was heated under microwave irradiation at 150° C. for 15 minutes to give the title compound (1.02 g, 91%). LCMS (Method A): R _T= 1.77 min, m/z =511 [M+H] ⁺ .

Step 3: 1-((7-(tert-butoxycarbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3- carboxylic acid: To a solution of tert-butyl-10-((5-(ethoxycarbonyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7 -carboxylate (1.24 g, 2.43 mmol) in ethanol (9 ml) was added 2M NaOH (aq.) (9 ml). The resulting mixture was stirred at 55°C for 3 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in water. The aqueous layer was washed with diethyl ether and 2M HCl (aq) was added to the aqueous phase until pH <4. The resulting precipitate was collected by filtration to give the title compound (900 mg, 76%). LCMS (method A): R _T= 1.42 min, m/z =483 [M+H] ⁺ .

Step 4: tert-Butyl 10-((5-(dimethylcarbamoyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7-carboxylate : Prepared according to General Procedure 3 using 1-((7-(tert-butoxycarbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxylic acid (1.00 g, 2.07 mmol), dimethylamine (2M in THF, 1.55 ml, 3.11 mmol), HATU (0.87 g, 2.28 mmol) and DIPEA (1.09 ml, 6.22 mmol) in DCM (20 ml) to give the title compound (1.00 g, 94%). LCMS (method A): R _T= 1.39 min, m/z =510 [M+H] ⁺ .

Stage 5: 1-((10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide: Prepared according to general procedure 7 using tert-butyl-10-((5-(dimethylcarbamoyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[ 4.5]decane-7-carboxylate (1.00 g, 1.95 mmol), DCM (20 ml) and TFA (10 ml) to give the title compound (0.56 g, 70%). LCMS (method A): R _T= 0.49 min, m/z =410 [M+H] ⁺ .

Amine 9: ethyl-(S)-4-(2-fluorophenyl)-1-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-1,6-dihydropyridine-3- carboxylate

Stage 1: ethyl-(S)-1-((1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)-6-oxo- 1,6-dihydropyridine-3-carboxylate: Prepared according to general procedure 4 using ethyl-(S)-1-((1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidine-4- yl)methyl)-4-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (amine 7, step 2) (100 mg, 0.226 mmol), (2-fluorophenyl)boronic acid (47 mg, 0.339 mmol ), Pd(dppf)Cl ₂ •DCM (9.6 mg, 1.3 µmol), sodium carbonate (48 mg, 0.452 mmol), 1,4-dioxane (0.75 ml) and water (0.25 ml). The reaction mixture was heated under microwave irradiation at 120° C. for 30 min to give the title compound (96 mg, 84%) as a glassy solid. LCMS (Method A): R _T= 1.67 min, m/z =503 [M+H] ⁺ .

Stage 2: ethyl-(S)-4-(2-fluorophenyl)-1-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-1,6-dihydropyridine-3- carboxylate: Prepared according to general procedure 7 using ethyl-( S )-1-((1-( tert -butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2 -fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (96 mg, 0.191 mmol), TFA (0.5 ml) and DCM (1 ml) to give the title compound (67 mg, 87 %) as a colorless solid. LCMS (Method A): R _T= 0.81 min, m/z =403 [M+H] ⁺ .

Amine 10: ethyl-( S )-1-((10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate

Stage 1: tert-Butyl-10-((4-chloro-5-(ethoxycarbonyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7-carboxylate : Solution of ethyl 4-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (377 mg, 1.87 mmol), epoxide 6 (500 mg, 1.87 mmol) and DIPEA (1.63 ml, 9.35 mmol) in 1-methyl-2-pyrrolidinone (4 ml) was heated at 110°C for 48 hours. The reaction mixture was allowed to cool to room temperature, diluted with saturated NaHCO ₃ (aq.) (30 ml) and the mixture was extracted with DCM (3×20 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv silica gel cartridge (40 g), 0-50% EtOAc in cyclohexane) to give the title compound (338 mg, 38%) as a colorless foam. LCMS (Method A): R _T =1.67 min, m/z =469, 471 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 8.48 (s, 1H), 6.64 (s, 1H), 4.86 (s, 1H), 4.64 (d, J = 13.4 Hz, 1H), 4.27 (cd, J =7.1, 2.1 Hz, 2H), 3.61 (d, J =13.4 Hz, 1H), 3.57-3, 47 (m, 1H), 3.27-3.11 (m, 3H), 1.93-1.83 (m, 1H), 1.68-1.49 (m, 5H), 1.68- 1.49(m, 1H), 1.38(s, 9H), 1.32-1.23(m, 4H), 1.13(dq, J =12.6, 6.8, 6 .4 Hz, 2H).

tert-Butyl-10-((4-chloro-5-(ethoxycarbonyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7-carboxylate (9, 9 g) was separated into individual stereoisomers by chiral supercritical liquid chromatography using a Lux C4 column (21.2 mm x 250 mm, 5 μm) under isocratic solvent conditions: 35:65 MeOH/CO ₂ . The first material eluted was tert-butyl-(S)-10-((4-chloro-5-(ethoxycarbonyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5] decane-7-carboxylate (4.61 g, 46% yield) as a white solid. Chiral purity (method B): R _T= 1.59 min, 100% ee. The second eluted material was t-butyl-(R)-10-((4-chloro-5-(ethoxycarbonyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5] decane-7-carboxylate (4.65 g, 47% yield) as a white solid. Chiral purity (method B): R _{T =} 2.29 min, 99.6% ee.

Step 2: tert-Butyl-(S)-10-((5-(ethoxycarbonyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decane -7-carboxylate: Prepared according to general procedure 4 using tert-butyl-(S)-10-((4-chloro-5-(ethoxycarbonyl)-2-oxopyridin-1(2H)-yl)methyl)- 10-hydroxy-7-azaspiro[4.5]decane-7-carboxylate (250 mg, 0.533 mmol), phenylboronic acid (97.5 mg, 0.800 mmol), Pd(dppf)Cl ₂ •DCM (22.5 mg, 26 .7 µmol), sodium carbonate (113 mg, 1.07 mmol), 1,4-dioxane (2 ml) and water (0.66 ml). The reaction mixture was heated under microwave irradiation at 120° C. for 30 minutes to give the title compound (274 mg, quantitative yield) as a pale yellow foam. LCMS (Method A): R _{T =} 1.79 min, m/z = 511 [M+H] ⁺ .

Stage 3: ethyl-(S)-1-((10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate : Prepared according to general procedure 7 using tert-butyl-(S)-10-((5-(ethoxycarbonyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-10-hydroxy-7 -azaspiro[4.5]decane-7-carboxylate (272 mg, 0.533 mmol), TFA (1.5 ml) and DCM (3 ml) to give the title compound (206 mg, 94%) as a colorless solid . LCMS (method B): R _T= 0.82 min, m/z =411 [M+H] ⁺ .

Amine 11: ethyl-(S)-4-(2-fluorophenyl)-1-((10-hydroxy-7-azaspiro [4,5-idecan-10-yl)methyl)-6-oxo-1,6- dihydropyridine-3 carboxylate

Step 1: tert-Butyl-(S)-10-((5-(ethoxycarbonyl)-4-(2-fluorophenyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro [4.5]decane-7-carboxylate : Prepared according to general procedure 4 using tert-butyl-(S)-10-((4-chloro-5-(ethoxycarbonyl)-2-oxopyridin-1(2H)-yl )methyl)-10-hydroxy-7-azaspiro[4.5]decane-7-carboxylate (amine 10, step 1) (250 mg, 0.533 mmol), (2-fluorophenyl)boronic acid (112 mg, 0.800 mmol), Pd(dppf)Cl ₂ •DCM (43.5 mg, 53.3 µmol), sodium carbonate (141 mg, 1.33 mmol), 1,4-dioxane (2.1 ml) and water (0.7 ml ). The reaction mixture was heated under microwave irradiation at 150° C. for 15 min to give the title compound (280 mg, quantitative yield) as a pale yellow foam. LCMS (method A): R _T= 1.78 min, m/z =529 [M+H] ⁺ ; 473 [M-butene+H] ⁺ .

Stage 2: ethyl-(S)-4-(2-fluorophenyl)-1-((10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-1,6-dihydropyridine- 3-carboxylate: Prepared according to general procedure 7 using a solution of tert-butyl-(S)-10-((5-(ethoxycarbonyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)- 10-hydroxy-7-azaspiro[4.5]decane-7-carboxylate (280 mg, 0.530 mmol), HCl (4M in 1,4-dioxane, 5 mL) and DCM (5 mL) to give the title compound ( 200 mg, 88%) as a colorless solid. LCMS (method A): R _T= 0.85 min, m/z =429 [M+H] ⁺ .

Amine 12: ethyl-( S )-4-cyclopropyl-1-((10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

Stage 1: tert-butyl-(S)-10-((4-cyclopropyl-5-(ethoxycarbonyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decane -7-carboxylate: Prepared according to general procedure 4 using tert-butyl-(S)-10-((4-chloro-5-(ethoxycarbonyl)-2-oxopyridin-1(2H)-yl)methyl)- 10-hydroxy-7-azaspiro[4.5]decane-7-carboxylate (250 mg, 0.533 mmol), cyclopropylboronic acid (183 mg, 2.13 mmol), Pd(dppf)Cl ₂ •DCM (21.8 mg, 26 .7 µmol), sodium carbonate (339 mg, 3.20 mmol), 1,4-dioxane (1.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 120° C. for 1 hour to give the title compound (182 mg, 71%) as a beige foam. LCMS (method A): R _T= 1.72 min, m/z =475 [M+H] ⁺ .

Stage 2. ethyl-(S)-4-cyclopropyl-1-((10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylate : Prepared according to general procedure 7 using a solution of tert-butyl-(S)-10-((4-cyclopropyl-5-(ethoxycarbonyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy- 7-azaspiro[4.5]decane-7-carboxylate (180 mg, 0.379 mmol), TFA (2 ml) and DCM (5 ml) to give the title compound (140 mg, quantitative yield) as a beige foam. LCMS (method A): R _T= 0.78 min, m/z =375 [M+H] ⁺ .

Intermediate 1: ( R ) - 2,5-dioxopyrrolidin-1-yl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3- carboxylate

Stage 1: ethyl 6-chloro-4-phenylnicotinate : 5-bromo-2-chloro-4-phenylpyridine (0.5 g, 1.86 mmol) was dissolved in anhydrous THF (15 ml) and the mixture was cooled to -78° C in a nitrogen atmosphere. n-Butyl lithium (2.5M in hexane, 0.894 ml, 2.23 mmol) was added slowly and the mixture was stirred for 15 minutes. Ethyl chloroformate (0.197 ml, 2.05 mmol) was added and the mixture was stirred for 1 hour at -60° C., then allowed to warm to room temperature. The reaction was quenched by adding water and extracted with EtOAc (x 3). The combined organic extracts were washed with brine, dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (GraceResolv, 0-5% EtOAc in cyclohexane) to give the title compound (279 mg, 57%). LCMS (method B): R _T= 1.44 min, m/z =262 [M+H] ⁺ .

Step 2: Ethyl 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate : Prepared according to general procedure 10 using ethyl 6-chloro-4-phenylnicotinate (100 mg, 0.382 mmol) in acetic acid (4 ml, 69.9 mmol) and water (1 ml) to give the title compound (90 mg, 97%). LCMS (method B): R _T= 0.91 min, m/z =244 [M+H] ⁺ .

Stage 3: (R)-ethyl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate : Ethyl 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (1.45 g, 5.96 mmol) and epoxide 2 (1.55 g, 5.96 mmol) were dissolved in DMF (30 ml) and pyridine (0.723 ml, 8.94 mmol). The reaction mixture was heated to 80°C and stirred for 18 hours. The solution was cooled to room temperature and diluted with water, then the mixture was extracted with EtOAc. The organic layer was washed with water (x 3), then brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (GraceResolv, 0-70% EtOAc in cyclohexane) to give the title compound (883 mg, 30%). LCMS (method B): R _T= 1.29 min, m/z =503 [M+H] ⁺ .

Stage 4: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid : (R)-ethyl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (884 mg , 1.76 mmol) was dissolved in THF (2 ml) and sodium hydroxide (2M in water, 4.4 ml, 8.8 mmol) was added. The reaction mixture was stirred for 18 hours at room temperature. More aqueous sodium hydroxide (2 ml) was added and the reaction mixture was stirred for 48 hours at room temperature. The solution was concentrated by removing THF. The residue was diluted with water and extracted with diethyl ether (x 3) and the organic layer was discarded. The aqueous layer was acidified to ~pH 4 and extracted with EtOAc (x 3). The combined organic extracts were dried (MgSO ₄ ) and concentrated to give the title compound (738 mg, 88%). LCMS (method B): R _T= 1.04 min, m/z 47 [M+H] ⁺ .

Step 5: (R)-2,5-dioxopyrrolidin-1-yl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxylate : (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxylic acid (450 mg, 0.95 mmol) and 1-hydroxypyrrolidine-2,5-dione (142 mg, 1.23 mmol) were dissolved in DMF (6 ml) and EDC (273 mg, 1.42 mmol). The reaction mixture was stirred for 19 hours at room temperature. The solution was diluted with EtOAc and washed with water (x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (GraceResolv, 0-100% EtOAc in cyclohexane) to give the title compound (532 mg, 98%). LCMS (method B): R _T= 1.19 min, m/z =572 [M+H] ⁺ .

Intermediate 2: (R)-5-bromo-4-chloro-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyridin-2(1H)-one

Stage 1: 5-bromo-4-chloropyridin-2(1H)-one: A mixture of water (2.2 ml) and concentrated sulfuric acid (0.31 ml, 5.78 mmol) was cooled to 0°C and added in one portion 5-bromo-4-chloropyridine-2-amine (500 mg, 2.41 mmol). A solution of sodium nitrite (183 mg, 2.65 mmol) in water (0.2 ml) was added dropwise so that the internal temperature did not rise above 5°C. The reaction mixture was stirred at 0°C for 3 hours. The suspension was adjusted to pH 7 by adding concentrated aqueous ammonia and the precipitate was collected by filtration to give the title compound (440 mg, 88%) as a pale yellow solid. LCMS (method B): R _T= 0.70 min, m/z =209 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d 6): δ 7.94 (s, 1H), 6.75 (s, 1H).

Step 2: (R)-5-Bromo-4-chloro-1-((4-hydroxy-1-(3-genylbutanoyl)piperidin-4-yl)methyl)pyridin-2(1H)-one : Mixture 5- bromo-4-chloropyridin-2(1H)-one (200 mg, 0.960 mmol), epoxide 2 (299 mg, 1.15 mmol) and pyridine (0.2 ml, 2.88 mmol) in DMF (5 ml) stirred at 80°C for 16 hours. The mixture was cooled and partitioned between EtOAc and 50% brine. The organic layer was washed with 4×50% brine and the aqueous layer was extracted with 3×EtOAc. The combined organic extracts were dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (GraceResolv 12 g, 5-80% EtOAc in cyclohexane) to give the title compound (248 mg, 55%). LCMS (Method B): R _T = 1.17 min, m / z = 469 [M+H] ⁺ . ¹ H-NMR (400 MHz, methanol- d ₄ ): δ 7.98-7.93 (m, 1H), 7.34-7.15 (m, 5H), 6.79 (s, 1H), 4.24-4.10(m, 2H), 4.06-3.77(m, 2H), 3.70-3.60(m, 1H), 3.28-3.12(m, 2H ), 3.05-2.86 (m, 1H), 2.82-2.69 (m, 1H), 2.62-2.45 (m, 1H), 1.62-1.49 (m , 1H), 1.47-1.26 (m, 5H), 0.90-0.81 (m, 1H).

Intermediate 3: 6-chloro-3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4(3 H )-he

Stage 1: tert-butyl-4-((4-chloro-6-oxopyrimidin-1(6H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate: Prepared according to general procedure 1 using 6-chloropyrimidin-4(3H)-one (600 mg, 4.60 mmol), epoxide 3 (1.22 g, 5.06 mmol) and potassium tert-butoxide (0.57 g). 5.06 mmol) in DMSO (6 ml). The mixture was heated to 70° C. for 64 hours to give the title compound (0.55 g, 32%). LCMS (method A): R _T= 1.36 min, m/z =316, 318 [M-butene+H] ⁺ .

Step 2: 6-chloro-3-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4(3H)-one hydrochloride: Prepared according to general procedure 9 using t-butyl- 4-(((4-chloro-6-oxopyrimidin-1(6H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (550 mg, 1.48 mmol) and HCl (4M in 1,4-dioxane, 8 ml, 32.0 mmol), stirred at 45° C. for 1 hour to give the title compound (0.42 g, 92%) LCMS (Method A): R _{T =} 0 .32 min, m/z =272 [M+H] ⁺ .

Stage 3: 6-chloro-3-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4(3H)- he hydrochloride : Prepared according to General Procedure 3 using 6-chloro-3-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4(3H)-one (420 mg, 1 .36 mmol), (R)-3-cyclohexyl-2-methylpropanoic acid (acid 1) (255 mg, 1.50 mmol), HATU (622 mg, 1.64 mmol) and DIPEA (0.952 ml, 5.45 mmol) in DCM (15 ml) to give the title compound (450 mg, 77%). LCMS (method A): R _T= 1.62 min, m/z =424 [M+H] ⁺ .

Acid 1:( R )-3-cyclohexyl-2-methylpropanoic acid

Stage 1: 3-cyclohexylpropanoyl chloride : 3-cyclohexylpropanoic acid (2.19 ml, 12.8 mmol) was dissolved in anhydrous DCM (40 ml) and the mixture was cooled to 0°C. Thionyl chloride (1.88 ml, 25.6 mmol) was added. The colorless solution was refluxed for 1.75 hours, then the reaction mixture was cooled to room temperature and stirred for another 67.5 hours. The mixture was concentrated and the yellow oil was azeotropically dried with toluene (2 x 10 mL) to give the title crude compound (2.3 g, quantitative) which was used without further purification. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.90 (t, 2H), 1.76-1.47 (m, 7H), 1.33-1.07 (m, 4H), 0. 96-0.84 (m, 2H).

Step 2. (R)-4-benzyl-3-(3-cyclohexylpropanoyl)oxazolidin-2-one: (R)-4-benzyloxazolidin-2-one (2.33 g, 13.2 mmol) was dissolved in anhydrous THF (40 ml) and the mixture was cooled to -78°C. n-Butyl lithium (2.5M in hexane, 5.27 ml, 13.2 mmol) was added dropwise to form a colorless solution which was stirred at -78° C. for 1.5 hours. 3-Cyclohexylpropanoyl chloride (2.3 g, 13.2 mmol) was added dropwise as a solution in anhydrous THF (20 ml). The mixture was stirred at -78°C for 1 hour, then allowed to warm to room temperature and stirred for another 18 hours. A saturated aqueous ammonium chloride solution (14 ml) was added and the mixture was concentrated. The residue was partitioned between EtOAc (20 ml) and water (20 ml). The aqueous layer was extracted with EtOAc (3×20 ml) and the combined organic extracts were washed with brine (1×20 ml), dried over anhydrous magnesium sulfate and concentrated. The crude product was washed with ice-cold cyclohexane to give the title compound (3.84 g, 93%).^oneH-NMR (400 MHz, CDCl₃): δ 7.38-7.18(m, 5H), 4.72-4.63(m, 1H), 4.24-4.13(m, 2H), 3.30(dd, 1H), 3, 04-2.87 (m, 2H), 2.77 (dd, 1H), 1.80-1.52 (m, 7H), 1.37-1.08 (m, 4H), 1.00- 0.87 (m, 2H).

Stage 3: (R)-4-benzyl-3-((R)-3-cyclohexyl-2-methylpropanoyl)oxazolidin-2-one : (R)-4-benzyl-3-(3-cyclohexylpropanoyl)oxazolidin-2 -one (2.50 g, 7.93 mmol) was dissolved in anhydrous THF (40 ml) and cooled to -78°C. NaHMDS (1M in THF, 8.72 ml, 8.72 mmol) was added dropwise and the yellow solution was stirred at -78 °C for 40 minutes. Methyl iodide (2.48 mL, 39.6 mmol) was added dropwise and the reaction mixture was allowed to stir for 21 hours. Saturated brine (10 ml) was added dropwise and the mixture was allowed to return to room temperature. The volatiles were removed, then the residue was partitioned between DCM and water. DCM was separated and the aqueous layer was extracted with DCM (x 3). The combined organic extracts were washed with brine, then filtered through a Biotage phase separator and concentrated. The residue was purified by flash chromatography (GraceResolv (40 g), 0 to 10% EtOAc in PE) to give the title compound (1.66 g, 64%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.39-7.17 (m, 5H), 4.71-4.64 (m, 1H), 4.24-4.14 (m, 2H ), 3.84 (m, 1H), 3.27 (dd, 1H), 2.76 (dd, 1H), 1.78-1.58 (bm, 6H), 1.32-1, 08 (b.m., 8H), 0.96-0.82 (b.m., 2H).

Stage 4: (R)-3-cyclohexyl-2-methylpropanoic acid:A solution of lithium hydroxide (0.143 g, 5.99 mmol) in water (3 ml) was added to 30% w/w. hydrogen peroxide (3.06 ml, 29.9 mmol) at 0°C and the solution was stirred for 10 min at this temperature. The resulting mixture was added dropwise to a solution of (R)-4-benzyl-3-((R)-3-cyclohexyl-2-methylpropanoyl)oxazolidin-2-one (0.99 g, 2.99 mmol) in a mixture of water ( 10 ml) and THF (40.0 ml) at 0° C. and the solution was allowed to warm to room temperature over 2 hours, then stirred at room temperature for 14 hours. A saturated aqueous sodium thiosulfate solution (35 ml) was added dropwise at 0° C. and the reaction mixture was stirred for 30 minutes. The solution was partitioned between DCM (50 ml) and water (50 ml) and the layers were separated. The aqueous layer was extracted with DCM (3×20 ml) and the organic layers were discarded. The aqueous layer was acidified with HCl (aq.) (2M) to pH 2. The resulting solution was extracted with EtOAc (3×20 ml). The combined organic extracts were washed with water (3 x 20 ml), brine (2 x 20 ml), dried over anhydrous magnesium sulfate and concentrated to give the title compound (0.51 g, 95%) which was used without further purification. .^oneH-NMR (400 MHz, DMSO-d ₆ ): δ 11.99 (s, 1H), 2.44-2.35 (m, 1H), 1.75-1.55 (br. m, 5H), 1.53-1.43 (m, 1H), 1.30-1.07 (m, 5H), 1.04 (d, 3H), 0.91-0.77 (m, 2H).

Acid 2: (R)-2-(cyclohexylmethyl)pent-4-enoic acid

Received similarly to acid 1, with the following changes:

Step 3: (R)-4-benzyl-3-((R)-2-(cyclohexylmethyl)pent-4-enoyl)oxazolidin-2-one: Prepared using (R)-4-benzyl-3-(3-cyclohexylpropanoyl)oxazolidin-2-one (0.20 g, 0.63 mmol), NaHMDS (1M in THF, 0.70 mL, 0.70 mmol) and 3-bromoprop-1-ene (0.27 ml, 3.17 mmol) in THF (3.5 ml) with stirring for 1 hour. The reaction mixture was then allowed to warm to room temperature over 21.5 hours and the crude product was purified by flash chromatography (GraceResolv (12 g), 0-10% EtOAc in PE) to give the title compound (0.18 g, 80%).^oneH-NMR (400 MHz, CDCl₃): δ 7.36-7.20 (m, 5H), 5.89-5.77 (m, 1H), 5.13-5.01 (m, 2H), 4.69 (m, 1H), 4. 21-4.09 (m, 2H), 4.08-4.00 (m, 1H), 3.31 (dd, 1H), 2.65 (dd, 1H), 2.47-2.27 ( m, 2H), 1.75-1.78 (m, 6H), 1.38-1.29 (m, 1H), 1.28-1.05 (m, 4H), 0.97-0, 79 (m, 2H).

Step 4: (R)-2-(cyclohexylmethyl)pent-4-enoic acid: Mixture of (R)-4-benzyl-3-((R)-2-(cyclohexylmethyl)pent-4-enoyl)oxazolidin-2- she (173 mg, 0.487 mmol) and lithium hydroxide (23.3 mg, 0.973 mmol) were dissolved in water (0.5 ml). Hydrogen peroxide solution 30 wt./wt. % (0.50 ml, 4.87 mmol) in a mixture of water (1 ml) and THF (4.00 ml) was added at 0°C and the mixture was stirred at the same temperature for 1.5 hours. The mixture was allowed to warm to room temperature and stirred for 20 hours to give the title compound (79.8 mg, 84%) which was used without further purification. ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 12.08 (s, 1H), 5.77-5.65 (m, 1H), 5.06-4.94 (m, 2H), 2.43-2.33 (m, 1H), 2.25-2.06 (m, 2H), 1.73 (br. l, 1H), 1.68-1.52 (b. m, 4H ), 1.48-1.36 (b.m., 1H), 1.29-1.02 (b.m., 5H), 0.91-0.73 (b.m., 2H).

Acid 3: 1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1, 6-dihydropyridine-3-carboxylic acid

Step 1: 4-((5-(ethoxycarbonyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-1-ium chloride : Ethyl-(( 1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dirnetylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (amine 6, step 1) ( 485 mg, 1.00 mmol) was added to 4M HCl in 1,4-dioxane (5.0 ml) and the resulting mixture was stirred at room temperature. After 30 minutes the solvents were removed in vacuo to give the title crude compound (535 mg, >100%) as an off-white solid which was carried to the next step without purification. LCMS (Method A): R _T= 0.86 min , m/z= 385 [M- ^t Bu+H] ⁺ .

Stage 2: ethyl-1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxylate: DIPEA (0.35 ml, 2.00 mmol) was added to a stirred solution of 4-((5-(ethoxycarbonyl)-2-oxo-4-phenylpyridin-1(2H)-yl )methyl)-4-hydroxy-3,3-dimethylpiperidin-1-ium chloride (421 mg, 1.00 mmol), (R)-3-cyclohexyl-2-methylpropanoic acid (acid 1) (170 mg, 1, 00 mmol) and HATU (456 mg, 1.2 mmol) in DCM (10 ml) at room temperature. After 1 hour, the reaction mixture was partitioned between DCM and saturated sodium bicarbonate solution (aq.). The resulting biphasic mixture was separated, dried (on a phase separator), solvents were removed in vacuo, and the remaining residue was purified by flash chromatography (cyclohexane; then 0-10%, MeOH in EtOAc) to give the crude title compound (crude 841 mg, >100%) as a pale yellow oil, which was carried to the next step without further purification. LCMS (Method A): R _T= 1.86 min , m/z= 537 [M+H] ⁺ .

Stage 3: 1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1, 6-dihydropyridine-3-carboxylic acid: 1M NaOH (aq) (2.0 ml, 2.00 mmol) was added to a stirred solution of ethyl 1-((1-((R)-3-cyclohexyl-2- methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (estimated amount 537 mg, 1.00 mmol) in 1 ,4-dioxane (2.0 ml) at room temperature. After 16 hours the temperature was raised to 50°C. After an additional 2 hours, the reaction mixture was cooled and the pH was adjusted to pH 2-3 with 2M HCl (aq) and extracted with EtOAc (x 3). The combined organic phase was washed using saturated sodium bicarbonate solution (aq.). After separation, due to incomplete extraction, the pH of the main aqueous phase was adjusted to approximately pH 6, and extraction was performed using additional EtOAc (x 3). The combined organic phases, which contained product, were concentrated in vacuo to give the title crude compound (539 mg, >100%) as a pale yellow solid, which was carried to subsequent steps without further purification. LCMS (Method A): R _T = 1.52 min, m / z = 509 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 8.01 (s, 1H), 7.61-7.03 (m, 5H), 6.17-6.12 (m, 1H), 5.25 (br s, 1H), 4.46-4.28 (m, 1H), 4.13-3.58 (m, 3H), 3.29-2.78 (m, 3H, overlap with solvent peak), 1.85-1.37 (m, 7H), 1.33-0.62 (m, 18H).

Acid 4: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxylic acid

Stage 1: ethyl-(S)-1-((1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6- dihydropyridine-3-carboxylate : PdCl ₂ (dppf). DCM (18.4 mg, 0.0226 mmol) was added to a pre-degassed solution of ethyl-(S)-1-((1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl )-4-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (amine 7, step 2) (200 mg, 0.452 mmol), phenylboronic acid (82.6 mg, 0.677 mmol) and sodium carbonate (95 .7 mg 0.903 mmol) in a mixture of 1,4-dioxane (0.75 ml) and water (0.25 ml) in a 10 ml vial. The vial was sealed and heated under microwave irradiation (CEM) at 120°C with stirring for 30 minutes. Due to the incompleteness of the reaction, it was repeated again under the same conditions. The reaction mixture was partitioned between EtOAc and brine, separated, extracted (EtOAc x 2), the combined organic phase was dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-5%, MeOH in DCM) , to give the title compound (227 mg, >100%) as a pale yellow oil. LCMS (method A): R _T= 1.67 min, m/z =485 [M+H] ⁺ .

Step 2: (S)-4-((5-(ethoxycarbonyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-1-ium chloride : To ethyl-(S)-1-((1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine- 3-carboxylate was added 4M HCl in 1,4-dioxane (2.2 ml, 63.4 mmol) and the resulting mixture was stirred at room temperature. After 1 hour, the solvents were removed in vacuo to give the title crude compound (229 mg, >100%) as a pale yellow solid, which was taken to the next step without further purification. LCMS (method A): R _T= 0.82 min , m/z= 419 [M-H] ^- .

Stage 3: ethyl-1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidyl)methyl)-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxylate : To a stirred solution of (S)-4-((5-(ethoxycarbonyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-4-hydroxy-3 ,3-dimethylpiperidin-1-ium chloride (190 mg, 0.452 mmol), (R)-3-cyclohexyl-2-methylpropanoic acid (acid 1) (76.9 mg, 0.452 mmol) and HATU (206 mg, 0.542 mmol ) in DCM (5.0 ml) at room temperature was added DIPEA (0.24 ml, 1.35 mmol). After 2 hours, the reaction mixture was partitioned between additional DCM and saturated sodium bicarbonate solution (aq.). The resulting biphasic mixture was separated, dried (phase separator), solvents removed in vacuo and the remaining residue purified by flash chromatography (0-50%, EtOAc in cyclohexane) to give the title compound (153 mg, 63%) as a colorless resins. LCMS (Method A): R _T= 1.86 min, m/z =537 [M+H] ⁺ .

Step 4: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxylic acid : To a stirred solution of ethyl 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3- dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (153 mg, 0.285 mmol) in 1,4-dioxane (1.4 ml) was added at room temperature 1M sodium hydroxide solution (aq.) (0.57 ml, 0.571 mmol). The temperature was raised to 50°C. After 2 hours, the reaction mixture was cooled and the pH was adjusted to 4-5 by adding 1M HCl (aq.) (ca. 0.75 ml) and extracted using EtOAc (x 3). The combined organic phase was dried, the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-100%, EtOAc in cyclohexane) to give the title compound (101 mg, 70%) as a white solid. LCMS (Method A): R _T= 1.53 min, m/z=509 [M+H] ⁺ .

Acid 5 :( R )-3-cyclobutyl-2-methylpropanoic acid

Step 1: (R)-4-benzyl-3-(3-cyclobutylpropanoyl)oxazolidin-2-one : To a suspension of 3-cyclobutylpropionic acid (500 mg, 3.90 mmol), (R)-4-benzyl-2- oxazolidinone (760 mg, 4.29 mmol) and lithium chloride (331 mg, 7.80 mmol) in THF (10 mL) pivaloyl chloride (1.2 mL, 9.75 mmol) was added at -20°C followed by triethylamine (1.41 ml, 10.1 mmol). After 30 minutes the reaction mixture was allowed to slowly warm to room temperature and then quenched by adding saturated NaHCO ₃ (aq.) (60 ml). The resulting mixture was extracted with DCM (3×30 ml) using a Biotage phase separator, the combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv cartridge with silica gel (80 g), 0-30% EtOAc in cyclohexane), to give the title compound (966 mg, 86%) as a colorless viscous oil. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.37-7.31 (m, 2H), 7.30-7.27 (m, 1H), 7.24-7.16 (m, 2H ), 4.67 (ddt, J =10.5, 6.9, 3.2 Hz, 1H), 4.22-4.14 (m, 2H), 3.30 (dd, J =13.4 , 3.4 Hz, 1H), 2.91-2.73 (m, 3H), 2.34 (hept., J = 7.8 Hz, 1H), 2.12-2.03 (m, 2H ), 1.92-1.72 (m, 4H), 1.69-1.60 (m, 2H).

Step 2: (R)-4-benzyl-3-((R)-3-cyclobutyl-2-methylpropanoyl)oxazolidin-2-one : To a solution of (R)-4-benzyl-3-(3-cyclobutylpropanoyl)oxazolidine -2-one (500 mg, 1.74 mmol) in THF (8.7 ml) at -78°C was added dropwise NaHMDS (1M in THF, 1.91 ml, 1.91 mmol), and after 90 minutes iodomethane (0.542 ml, 8.70 mmol) was added dropwise. The reaction mixture was allowed to stir at -78° C. overnight and then slowly warmed to room temperature. The reaction was quenched by adding saturated NH ₄ Cl (aq.) (60 ml), and the resulting mixture was extracted with DCM (3×30 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv silica gel cartridge (80 g), 0-30% EtOAc in cyclohexane) to give the title compound (360 mg, 68%) as a viscous colorless oil . LCMS (method A): R _T =1.91 min, m/z =302 [M+H] ⁺ . ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.36-7.24 (m, 3H), 7.23-7.17 (m, 2H), 4.65 (ddt, J =10.3 , 7.0, 3.1 Hz, 1H), 4.23-4.13 (m, 2H), 3.69 (hept., J = 6.9 Hz, 1H), 3.27 (dd, J = 13.4, 3.3 Hz, 1H), 2.76 (dd, J = 13.4, 9.6 Hz, 1H), 2.33 (hept., J = 7.9 Hz, 1H), 2.01 (ddt, J =19.0, 11.7, 7.7, 3.9 Hz, 2H), 1.89-1.73 (m, 3H), 1.63 (tt, J =18 .3, 9.0 Hz, 2H), 1.56-1.49 (m, 1H), 1.19 (d, J =6.8 Hz, 3H).

Step 3: (R)-3-cyclobutyl-2-methylpropanoic acid : To a solution of (R)-4-benzyl-3-((R)-3-cyclobutyl-2-methylpropanoyl)oxazolidin-2-one (334 mg, 1.1 1 mmol) in THF (5.5 ml) and water (5.5 ml) at 0°C was added 30% aqueous hydrogen peroxide solution (0.453 ml, 4.43 mmol). After 5 minutes, lithium hydroxide (53 mg, 2.22 mmol) was added and the mixture was stirred for 2 hours, after which the reaction was quenched by the addition of saturated sodium thiosulfate (aq.) (2 ml). The reaction mixture was allowed to warm to room temperature, concentrated in vacuo to remove THF, and the resulting biphasic mixture was extracted with DCM (3×10 ml). The pH of the aqueous phase was adjusted to 2 with 2M HCl (aq) and the mixture was extracted with Et2O (3×10 mL). The combined ether extractions were passed through a Biotage phase separator, carefully concentrated at 45° C. (no vacuum) and the residue dried at 300 mbar (no heat) for 5 minutes to give the title compound (172 mg, 92%) as very pale yellow oil containing 15% wt./wt. Et ₂ O. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 2.45-2.30 (m, 2H), 2.05 (dtt, J =19.1, 7.9, 3.9 Hz , 2H), 1.91-1.74 (m, 3H), 1.67-1.48 (m, 3H), 1.18-1.10 (m, 3H).

Acid 6:( R )-3-cyclopropyl-2-methylpropanoic acid

Step 1: (R)-4-benzyl-3-(3-cyclopropylpropanoyl)oxazolidin-2-one : To a suspension of 3-cyclopropylpropionic acid (504 mg, 4.42 mmol), (R)-4-benzyl-2- oxazolidinone (861 mg, 4.86 mmol) and lithium chloride (374 mg, 8.83 mmol) in THF (11 mL) pivaloyl chloride (1.36 mL, 11.0 mmol) was added at -20°C followed by triethylamine (1.60 ml, 1.5 mmol). After 30 minutes the reaction mixture was allowed to slowly warm to room temperature and then quenched by adding saturated NaHCO ₃ (aq.) (60 ml). The resulting mixture was extracted with DCM (3×30 ml) using a Biotage phase separator, the combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv cartridge with silica gel (80 g), 0-30% EtOAc in cyclohexane), to give the title compound (1.16 g, 96%) as a colorless viscous oil. LCMS (method A): R _T =1.65 min, m/z =274 [M+H] ⁺ . ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.38-7.30 (m, 2H), 7.30-7.26 (m, 1H), 7.24-7.17 (m, 2H ), 4.68 (ddt, J = 10.4, 6.9, 3.1 Hz, 1H), 4.23-4.14 (m, 2H), 3.31 (dd, J = 13.4 , 3.3 Hz, 1H), 3.05 (q.t., J =16.8, 7.4 Hz, 2H), 2.77 (dd, J =13.4, 9.6 Hz, 1H) , 1.60 (kv, J= 7.3 Hz, 2H), 0.79 (d, td, d, J = 15.0, 7.3, 6.2, 4.9, 2.4 Hz, 1H), 0.51-0.41 (m, 2H), 0.14-0.04 (m, 2H).

Step 2. (R)-4-benzyl-3-((R)-3-cyclopropyl-2-methylpropanoyl)oxazolidin-2-one : To a solution of (R)-4-benzyl-3-(3-cyclopropylpropanoyl)oxazolidine -2-one (500 mg, 1.83 mmol) in THF (9 ml) at -78°C was added dropwise NaHMDS (1M in THF, 2.29 ml, 2.29 mmol) and added dropwise after 90 minutes iodomethane (0.569 ml (9.15 mmol). The reaction mixture was allowed to stir at -78°C for 18.5 hours, and quenched by the addition of saturated NH ₄ Cl (aq.) (60 ml). After warming to room temperature, the mixture was extracted DCM (3 x 30 ml) using a Biotage phase separator, the combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (80 g GraceResolv silica gel cartridge, 0-20% EtOAc in cyclohexane) to give the indicated title compound (441 mg, 83%) as a viscous colorless oil LCMS (method A): R _T = 1.78 min, m/z = 288 [M+H] ^{+ .1} H-NMR (500 MHz, CDCl ₃ ): δ 7.36-7.30 (m, 2H), 7.30-7.25 (m, 1H), 7.24-7.19 (m, 2H), 4.67 (ddt, J =10.1, 6.8, 3.3 Hz, 1H), 4.22-4.14 (m, 2H), 3.88 (hept., J =6.9 Hz, 1H), 3.28 (dd, J= 13.4, 3.3 Hz, 1H), 2.78 (dd, J =13.4, 9.6 Hz, 1H), 1.58 (dt, J =14.2, 7 .2 Hz, 1H), 1.43 (dt, J = 13.6, 6.7 Hz, 1H), 1.26 (d, J= 6.9 Hz, 3H), 0.73 (ddt, J =10.2, 7.4, 3.7Hz, 1H), 0.41(dtt, J =21.1, 8.3, 4.2Hz, 2H), 0.07(dtt, J= 14 .8, 8.6, 4.2 Hz, 2H).

Step 4: (R)-3-cyclopropyl-2-methylpropanoic acid : To a solution of (R)-4-benzyl-3-((R)-3-cyclopropyl-2-methylpropanoyl)oxazolidin-2-one (426 mg, 1.48 mmol) in THF (7.4 ml) and water (7.4 ml) at 0°C was added 30% aqueous hydrogen peroxide solution (0.606 ml, 5.93 mmol). After 5 minutes, lithium hydroxide (71 mg, 2.97 mmol) was added and the mixture was stirred for 30 minutes, after which the reaction was quenched by the addition of saturated sodium thiosulfate (aq.) (2 ml). The reaction mixture was allowed to warm to room temperature, concentrated in vacuo to remove THF, and the resulting biphasic mixture was extracted with DCM (3×10 ml). The pH of the aqueous phase was adjusted to 2 with 2M HCl (aq) and the mixture was extracted with Et ₂ O (3×10 ml). The combined ether extractions were passed through a Biotage phase separator, carefully concentrated at 45° C. (no vacuum) and the residue dried at 300 mbar (no heat) for 5 minutes to give the title compound (21.1 mg, 96%) in as a very pale yellow oil containing 13 wt.% Et ₂ O. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 2.60 (hpt., J = 7.0 Hz, 1H), 1.59 ( dt, J =14.1, 7.2 Hz, 1H), 1.39 (dt, J =13.8, 6.8 Hz, 1H), 1.23 (d, J =7.0 Hz, 3H ), 0.74 (d sq.d, J = 12.4, 7.5, 4.9 Hz, 1H), 0.54-0.37 (m, 2H), 0.14-0.00 ( m, 2H).

Acid 7: (S)-3-(benzyloxy)-2-(cyclohexylmethyl)propanoic acid

Step 1: (R)-4-benzyl-3-((S)-3-(benzyloxy)-2-(cyclohexylmethyl)propanoyl)oxazolidin-2-one : To an ice-cold solution of (R)-4-benzyl-3 -(3-cyclohexylpropanoyl)oxazolidin-2-one (acid 1, step 2) (200 mg, 0.634 mmol) in DCM (4 ml) TiCl ₄ (76 μl, 0.698 mmol) was added under nitrogen atmosphere. The mixture was stirred at 0° C. for 10 minutes, then triethylamine (97 μl, 0.698 mmol) was added. The reaction mixture was stirred at this temperature for 45 minutes, after which benzylchloromethyl ether (0.106 ml, 0.761 mmol) was added. The reaction mixture was stirred at 0° C. for 2.5 hours and then quenched with saturated NH ₄ Cl (aq.) (50 ml). The mixture was extracted with DCM (3×50 ml), and the combined organic phases were washed with saturated NH ₄ Cl (aq.) (50 ml). The organic phase was washed with brine (50 ml), passed through a Biotage phase separator, concentrated in vacuo, and the residue was purified by flash chromatography (GraceResolv cartridge with silica gel (12 g), 0-50% EtOAc in cyclohexane) to give the title compound (223 mg, 80%) as a very pale yellow oil. LCMS (method A): R _T= 2.21 min, m/z =436 [M+H] ⁺ .

Step 2: (S)-3-(benzyloxy)-2-(cyclohexylmethyl)propanoic acid : 30% aqueous hydrogen peroxide solution (0.209 ml, 2.05 mmol) was added to a solution of (R)-4-benzyl-3-( (S)-3-(benzyloxy)-2-(cyclohexylmethyl)propanoyl)oxazolidin-2-one (223 mg, 0.512 mmol) in THF (2.5 ml) and water (2.5 ml) at 0°C, and then lithium hydroxide (24.5 mg, 1.02 mmol) was added after 5 minutes. After 2 hours, the reaction mixture was allowed to warm to room temperature and stirred for an additional 16 hours, after which the reaction was quenched by the addition of saturated sodium thiosulfate (aq.) (2 ml). The reaction mixture was concentrated in vacuo without heating to remove THF. The resulting biphasic mixture was diluted with water (2 ml) and extracted with DCM (3×5 ml). The aqueous phase was acidified to pH ~2 with 2M HCl (aq) and extracted with DCM (3×5 ml) using a Biotage phase separator. The DCM extracts under basic and acidic conditions were combined, concentrated in vacuo, and the residue was purified by flash chromatography (GraceResolv cartridge with silica gel (12 g), 0-60% EtOAc in cyclohexane) to give the title compound (73 mg, 51%) as a pale yellow resin. LCMS (method A): R _T =1.71 min, m/z =275 [MH] ^- . ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.46-7.07 (m, 5H), 4.55 (s, 1H), 3.63 (t, J =8.7 Hz, 1H) , 3.56 (dd, J =9.3, 4.9 Hz, 1H), 2.83 (tt, J =8.7, 5.3 Hz, 1H), 1.77 (d, J =12 .8 Hz, 1H), 1.73-1.50 (m, 5H), 1.39-1.03 (m, 6H), 0.97-0.78 (m, 2H).

Acid 8: (S)-3-cyclohexyl-2-(hydroxymethyl)propanoic acid

Stage 1: (R)-4-benzyl-3-((S)-3-cyclohexyl-2-((2-(trimethylsilyl)ethoxy)methyl)propanoyl)oxazolidin-2-one: DIPEA (0.210 ml, 1, 20 mmol) was added to a solution of (R)-4-benzyl-3-(3-cyclohexylpropanoyl)oxazolidin-2-one (acid 1, step 2) (315 mg, 1.00 mmol) in DCM (5 ml) at 0 °C, and after stirring for 5 minutes, titanium tetrachloride (0.121 ml, 1.10 mmol) was added dropwise, and the resulting purple mixture was stirred at 0°C for 1 hour before adding 2-(chloromethoxyethyl)trimethylsilane (0.263 ml, 1.50 mmol). After 70 minutes, the reaction was quenched by adding saturated NH ₄ Cl (aq.) (20 ml) and water (20 ml). After warming to room temperature, the resulting mixture was extracted with DCM (3×30 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv cartridge with silica gel (80 g), 0-15% EtOAc in cyclohexane; then GraceResolv cartridge with silica gel (40 g), 0-15% EtOAc in cyclohexane), to give the title compound (184 mg, 41%) as a colorless oil. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.40-7.16 (m, 5H), 4.72 (ddt, J=12.8, 6.9, 3.1 Hz, 1H), 4.32-4.24 (m, 1H), 4.22-4.12 (m, 2H), 3.65 (t, J=8.5 Hz, 1H), 3.60-3.46 ( m, 3H), 3.28 (dd, J=13.5, 3.2 Hz, 1H), 2.75 (dd, J=13.4, 9.5 Hz, 1H), 1.78-1 .58 (m, 6H), 1.35 (dt, J=13.5, 6.6 Hz, 1H), 1.29-1.07 (m, 4H), 0.97-0.82 (m , 4H), 0.00 (s, 9H). ¹³ C-NMR (126 MHz, CDCl ₃ ): δ 175.80, 153.26, 135.66, 129.67, 129.05, 127.40, 71.93, 68.58, 65.94, 55 .53, 41.12, 37.97, 36.79, 35.75, 33.68, 33.52, 26.62, 26.42, 26.37, 18.26, -1.21.

Step 2: (R)-4-benzyl-3-((S)-3-cyclohexyl-2-(hydroxymethyl)propanoyl)oxazolidin-2-one : To a solution of (R)-4-benzyl-3-((S )-3-cyclohexyl-2-((2-(trimethylsilyl)ethoxy)methyl)propanoyl)oxazolidin-2-one (176 mg, 0.390 mmol) in DCM (4 ml) was added boron trifluoride diethyl etherate (0.150 ml, 1.18 mmol), and after 90 minutes the reaction was quenched by the addition of saturated NaHCO ₃ (aq.) (30 ml). The resulting mixture was extracted with DCM (3×15 ml), the combined organic phases were passed through a Biotage phase separator, concentrated in vacuo, and the residue was purified by flash chromatography (GraceResolv cartridge with silica gel (12 g), 0-40% EtOAc in cyclohexane), with obtaining the title compound (126 mg, 92%) as a colorless solid. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.38-7.14 (m, 5H), 4.70 (ddt, J =10.0, 6.6, 3.1 Hz, 1H), 4.26-4.15 (m, 2H), 4.09 (cd, J = 7.3, 4.2 Hz, 1H), 3.88 (dt, J = 10.9, 4.3 Hz, 1H), 3.78 (dt, J = 10.8, 8.1 Hz, 1H), 3.31 (dd, J = 13.6, 3.4 Hz, 1H), 2.81 (dd, J = 13.5, 9.4 Hz, 1H), 2.21 (dd, J = 8.5, 4.4 Hz, 1H), 1.79-1.58 (m, 6H), 1.40 ( dt, J =13.5, 6.7 Hz, 1H), 1.33-1.07 (m, 4H), 0.90 (pd, J =14.1, 13.4, 3.7 Hz, 2H).

Step 3: (S)-3-cyclohexyl-2-(hydroxymethyl)propanoic acid : 30% aqueous hydrogen peroxide solution (0.137 ml, 1.34 mmol) was added to a solution of (R)-4-benzyl-3-((S )-3-cyclohexyl-2-(hydroxymethyl)propanoyl)oxazolidin-2-one (116 mg, 0.340 mmol) in THF (1.5 ml) and water (1.5 ml) at 0°C. After 5 minutes, lithium hydroxide (16 mg, 0.670 mmol) was added and the mixture was stirred for 45 minutes, after which the reaction was quenched by the addition of saturated sodium thiosulfate (aq.) (0.5 ml). The reaction mixture was allowed to warm to room temperature, then concentrated in vacuo without heating to remove THF. The resulting biphasic mixture was diluted with water (5 ml) and extracted with DCM (3×5 ml) to remove the oxazolidinone. The aqueous phase was acidified to pH ~2 with 2M HCl (aq) and extracted with DCM (3×5 ml). The combined organic layers from the acidic extracts were passed through a Biotage phase separator and concentrated in vacuo to give the title compound (81 mg, >100%) as a colorless oil. This material was used without further purification.

Acid 9: (S)-4-((tert-butyldimethylsilyl)oxy)-2-(cyclohexylmethyl)butanoic acid

Step 1: tert-Butyl-(S)-4-((R)-4-benzyl-2-oxooxazolidin-3-yl)-3-(cyclohexylmethyl)-4-oxobutanoate : NaHMDS (1M in THF, 3.75 ml, 3.75 mmol) was slowly added to a solution of (R)-4-benzyl-3-(3-cyclohexylpropanoyl)oxazolidin-2-one (946 mg, 3.00 mmol) in THF (15 ml) at -78° C. After stirring at -78° C. for 90 minutes, tert-butyl bromoacetate (1.33 ml, 9.00 mmol) was added dropwise. The reaction mixture was left to stir at -78°C for 18 hours, and then extinguished by adding saturated NH ₄ Cl (aq.) (30 ml). The resulting mixture was allowed to warm to room temperature, then diluted with water (30 ml) and extracted with EtOAc (3×30 ml). The combined organic phases were passed through a Biotage phase separator, concentrated in vacuo and the residue was purified by flash chromatography (Biotage KP-Sil cartridge, (100 g), 0-20% EtOAc in cyclohexane) to give the title compound (1.11 g, 86%) as a colorless solid. LCMS (method A): R _T= 2.10 min, m/z =374 [M-butene+H] ⁺ .

Step 2: (S)-4-((R)-4-benzyl-2-oxooxazolidin-3-yl)-3-(cyclohexylmethyl)-4-oxobutanoic acid : tert-butyl-(S)-4-( (R)-4-benzyl-2-oxooxazolidin-3-yl)-3-(cyclohexylmethyl)-4-oxobutanoate (1.10 g, 2.56 mmol) in TFA (3 ml) and DCM (12 ml) stirred for 40 minutes after which the reaction mixture was concentrated in vacuo, the residue was azeotropically distilled with toluene (2×5 ml) and dried in a vacuum oven at 50° C. to give the title compound (990 mg, >100%) as a colorless glassy solid. This material was used without further purification. LCMS (method A): R _T= 1.58 min, m/z =374 [M+H] ⁺ .

Step 3: (R)-4-benzyl-3-((S)-2-(cyclohexylmethyl)-4-hydroxybutanoyl)oxazolidin-2-one : To a solution of (S)-4-((R)-4-benzyl -2-oxooxazolidin-3-yl)-3-(cyclohexylmethyl)-4-oxobutanoic acid (956 mg, 2.56 mmol) in THF (6.4 ml) was added dropwise borane-dimethyl sulfide complex (2M in THF, 1 .70 ml, 17.9 mmol) and after 90 min the reaction mixture was cooled to 0° C. and MeOH (10 ml) was added slowly. The resulting solution was stirred at room temperature overnight, concentrated in vacuo and saturated NaHCO ₃ (aq.) (60 ml) was added to the residue. The resulting mixture was extracted with DCM (3×30 ml) using a Biotage phase separator, the combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv cartridge with silica gel (80 g), 0-30% EtOAc in cyclohexane), to give the title compound (331 mg, 36%) as a colorless oil. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.36-7.30 (m, 2H), 7.30-7.27 (m, 1H), 7.25-7.21 (m, 2H ), 4.68 (ddt, J = 9.8, 5.8, 3.8 Hz, 1H), 4.23-4.15 (m, 2H), 4.01 (tt, J = 8.6 , 5.3 Hz, 1H), 3.69 (t, J = 5.9 Hz, 2H), 3.36 (dd, J = 13.4, 3.3 Hz, 1H), 2.72 (dd , J = 13.3, 10.1 Hz, 1H), 2.11 (t, J = 5.5 Hz, 1H), 2.00-1.92 (m, 1H), 1.82 (ddt, J = 14.1, 6.8, 5.2 Hz, 1H), 1.72 (ddt, J = 23.5, 10.4, 4.7 Hz, 5H), 1.65-1.59 ( m, 1H), 1.35 (ddd, J = 13.5, 7.6, 5.7 Hz, 1H), 1.17 (d qd, J = 24.8, 12.6, 11, 8, 4.9 Hz, 4H), 0.90 (d, td, J =20.7, 11.7, 11.3, 5.6 Hz, 2H), ¹³ C-NMR (126 MHz, CDCl ₃ ): δ 177.36, 153.86, 135.51, 129.56, 129.14, 127.52, 66.39, 60.80, 56.11, 40.27, 37.99, 37.44 , 36.46, 35.87, 33.60, 33.44, 26.60, 26.43, 26.36.

Step 4: (R)-4-benzyl-3-((S)-4-((tert-butyldimethylsilyl)oxy)-2-(cyclohexylmethyl)butanoyl)oxazolidin-2-one : Tert-butyldimethylsilyl chloride solution (195 mg, 1.29 mmol) in DCM (4.5 ml) at room temperature was added dropwise to a suspension of (R)-4-benzyl-3-((S)-2-(cyclohexylmethyl)-4-hydroxybutanoyl)oxazolidin-2- she (310 mg, 0.860 mmol) and imidazole (117 mg, 1.72 mmol) in DCM (4.5 ml). After 50 minutes, the resulting suspension was diluted with saturated NaHCO ₃ (aq.) (60 ml) and extracted with DCM (3×30 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv silica gel cartridge (40 g), 0-15% EtOAc in cyclohexane) to give the title compound (408 mg, 99%) as a colorless oil. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.37-7.30 (m, 2H), 7.30-7.26 (m, 1H), 7.25-7.20 (m, 2H ), 4.70-4.63 (m, 1H), 4.20-4.10 (m, 2H), 4.02-3.94 (m, 1H), 3.73-3.61 (m , 2H), 3.35 (dd, J = 13.3, 3.3 Hz, 1H), 2.68 (dd, J = 13.3, 10.1 Hz, 1H), 1.96 (d, td, J = 13.2, 7.5, 5.7 Hz, 1H), 1.78-1.58 (m, 7H), 1.36 (dt, J = 13.5, 6.7 Hz, 1H), 1.30-1.07 (m, 4H), 1.03-0.75 (m, 2H), 0.90 (s, 9H), 0.05 (s, 3H), 0.05 (s, 3H), ¹³ C-NMR (126 MHz, CDCl ₃ ): δ 177.03, 153.05, 135.65, 129.54, 129.11, 127.46, 66.06, 61.28 , 55.77, 39.74, 38.23, 37.49, 35.70, 35.24, 33.73, 33.26, 26.65, 26.49, 26.38, 26.10, 18 .47, -5.12, -5.16.

Step 5: (S)-4-((tert-butyldimethylsilyl)oxy)-2-(cyclohexylmethyl)butanoic acid : 30% aqueous hydrogen peroxide solution (0.345 ml, 3.38 mmol) was added to a solution of (R)-4- benzyl-3-((S)-4-((tert-butyldimethylsilyl)oxy)-2-(cyclohexylmethyl)butanoyl)oxazolidin-2-one (400 mg, 0.840 mmol) in THF (2 ml) and water (2 ml ) at 0°C. After 5 minutes, lithium hydroxide (40 mg, 1.69 mmol) was added and the mixture was stirred for 1 hour 40 minutes before adding THF (2 ml). The mixture was stirred for 4 hours and then quenched by adding saturated sodium thiosulfate (aq.) (2 ml). The resulting mixture was diluted with water (10 ml) and extracted with DCM (3×15 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv silica gel cartridge (24 g), 0-20% EtOAc in cyclohexane) to give the title compound (262 mg, 98%) as a colorless oil. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 10.65 (br, s, 1H), 3.67 (t, J =6.2 Hz, 2H), 2.65 (td, d, J = 8.8, 5.8, 4.4 Hz, 1H), 1.91-1.82 (m, 1H), 1.79 (d, J = 13.2 Hz, 1H), 1.72- 1.56 (m, 6H), 1.35-1.09 (m, 5H), 0.89 (s, 2H), 0.89 (s, 9H), 0.05 (s, 3H), 0 .05 (s, 3H), ¹³ C-NMR (126 MHz, CDCl ₃ ): δ 181.07, 61.29, 39.97, 39.52, 35.51, 35.11, 33.58, 33 .17, 26.69, 26.35, 26.10, 26.04, 18.43, -5.29, -5.32.

Acid 10: (S)-3-cyclobutyl-2-(hydroxymethyl)propanoic acid

Stage 1: (R)-4-benzyl-3-((S)-3-cyclobutyl-2-((2-(trimethylsilyl)ethoxy)methyl)propanoyl)oxazolidin-2-one: DIPEA (0.328 ml, 1, 88 mmol) was added to a stirred solution of (R)-4-benzyl-3-(3-cyclobutylpropanoyl)oxazolidin-2-one (acid 5, step 1) (449 mg, 1.56 mmol) in DCM (8 ml) at 0°C. After 5 minutes, titanium tetrachloride (0.189 ml, 1.72 mmol) was added dropwise and the resulting purple mixture was stirred at 0°C for 1 hour before adding 2-(chloromethoxyethyl)trimethylsilane (0.411 ml, 2.34 mmol ). After 1 hour, the reaction was quenched by adding saturated NH ₄ Cl (aq.) (20 ml) and water (20 ml). After warming to room temperature, the mixture was extracted with DCM (3×30 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (40 g GraceResolv silica gel cartridge, 0-30% EtOAc in cyclohexane) to give the title compound (275 mg, 42%) as a colorless oil. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.39-7.18 (m, 5H), 4.70 (ddt, J =9.3, 7.6, 3.2 Hz, 1H), 4.22-4.08 (m, 3H), 3.68 (t, J = 8.7 Hz, 1H), 3.51 (td, d, J = 9.9, 6.2, 2.2 Hz, 3H), 3.25 (dd, J =13.5, 3.3 Hz, 1H), 2.78 (dd, J =13.5, 9.3 Hz, 1H), 2.32 (hept ., J= 7.8 Hz, 1H), 2.02 (d sq.d, J = 19.0, 7.9, 4.0 Hz, 2H), 1.88-1.72 (m, 3H ), 1.62 (ddd, J =17.7, 13.4, 6.7 Hz, 3H), 0.97-0.85 (m, 2H), -0.01 (s, 9H), ¹³ C-NMR (126 MHz, CDCl ₃ ): δ 175.55, 153.23, 135.59, 129.70, 129.04, 127.42, 71.48, 68.56, 65.88, 55, 49, 42.17, 37.97, 36.48, 34.26, 29.03, 28.57, 18.52, 18.27, -1.21.

Step 2: (R)-4-benzyl-3-((S)-3-cyclobutyl-2-(hydroxymethyl)propanoyl)oxazolidin-2-one : To a solution of (R)-4-benzyl-3-((S )-3-Cyclobutyl-2-((2-(trimethylsilyl)ethoxy)methyl)propanoyl)oxazolidin-2-one (275 mg, 0.660 mmol) in DCM (6.5 ml) was added boron trifluoride diethyl etherate (0.250 ml, 1 .98 mmol) and after 90 minutes the reaction was quenched by the addition of saturated NaHCO ₃ (aq.) (30 ml). The resulting mixture was extracted with DCM (3×15 ml), the combined organic phases were passed through a Biotage phase separator, concentrated in vacuo, and the residue was purified by flash chromatography (GraceResolv cartridge with silica gel (12 g), 0-40% EtOAc in cyclohexane), with obtaining the title compound (208 mg, 99%) as a colorless solid. LCMS (method A): R _T =1.41 min, m/z= 318 [M+H] ⁺ . ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.36-7.30 (m, 2H), 7.30-7.26 (m, 1H), 7.25-7.20 (m, 2H ), 4.68 (ddt, J = 9.6, 7.2, 3.1 Hz, 1H), 4.24-4.15 (m, 2H), 3.93 (cd, J = 7.1 , 4.1 Hz, 1H), 3.88-3.75 (m, 2H), 3.29 (dd, J = 13.5, 3.5 Hz, 1H), 2.81 (dd, J = 13.5, 9.4 Hz, 1H), 2.34 (hept., J = 7.9 Hz, 1H), 2.21 (br., s, 1H), 2.08-1.96 (m , 2H), 1.89-1.73 (m, 3H), 1.72-1.59 (m, 3H), ¹³ C-NMR (126 MHz, CDCl ₃ ): δ 176.24, 153.61 , 135.33, 129.62, 129.10, 127.52, 66.28, 63.96, 55.77, 44.13, 38.01, 35.72, 34.13, 28.97, 28 .28, 18.49.

Step 3: (S)-3-cyclobutyl-2-(hydroxymethyl)propanoic acid : 30% aqueous hydrogen peroxide solution (0.348 ml, 3.40 mmol) was added to a solution of (R)-4-benzyl-3-((S )-3-cyclobutyl-2-(hydroxymethyl)propanoyl)oxazolidin-2-one (270 mg, 0.850 mmol) in THF (2 ml) and water (2 ml) at 0°C. After 5 minutes, lithium hydroxide (41 mg, 1.70 mmol) was added and the mixture was stirred for 50 minutes, after which the reaction was quenched by the addition of saturated sodium thiosulfate (aq.) (0.5 ml). The reaction mixture was allowed to warm to room temperature, then concentrated in vacuo to remove THF. The resulting biphasic mixture was diluted with water (2 ml) and extracted with DCM (3×2 ml) to remove the oxazolidinone. The aqueous phase was diluted with water (2×2 ml), acidified to pH ~2 with 2M HCl (aq) and extracted with DCM (3×5 ml) using a Biotage phase separator. The product was contained in the basic and acidic DCM extracts, so they were combined, concentrated in vacuo and purified by flash chromatography (GraceResolv silica gel cartridge, 12 g, 0-100% EtOAc in cyclohexane; mixed fractions were repurified on a GraceResolv silica gel cartridge ( 12 g), 0-100% EtOAc in cyclohexane) to give the title compound (121 mg, 89%) as a colorless oil. This material still contained oxazolidinone and was used without further purification. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 3.73 (d, J =6.0 Hz, 2H), 2.58-2.50 (m, 1H), 2.35 (dp, J = 14.6, 7.5, 7.1 Hz, 1H), 2.12-2.00 (m, 2H), 1.91-1.71 (m, 3H), 1.67-1.51 ( m, 3H), ¹³ C-NMR (126 MHz, CDCl ₃ ): δ 180.46, 63.08, 45.95, 35.49, 34.03, 28.64, 28.45, 18.44.

Acid 11: (R)-4,4,4-trifluoro-2-methylbutanoic acid

Step 1: (R)-4-benzyl-3-(4,4,4-trifluorobutanoyl)oxazolidin-2-one: To a suspension of 4,4,4-trifluorobutanoic acid (3.00 g, 21.11 mmol), (R)-4-benzyl-2-oxazolidinone (3.74 g, 21.11 mmol) and lithium chloride (1.79 g) (42.2 mmol) in THF (50 ml) at -20°C was added pivaloyl chloride (6.50 ml, 52.8 mmol) followed by triethylamine (7.65 ml, 54.9 mmol). After 30 minutes the reaction mixture was allowed to slowly warm to room temperature and then quenched by adding saturated NaHCO ₃ (aq.) (60 ml). The resulting mixture was extracted with DCM (3×30 ml) using a Biotage phase separator, the combined organic phases were concentrated in vacuo, the residue was dissolved in DCM (75 ml) and washed with ~15% NH ₃ (aq.). The organic phase was passed through a Biotage phase separator, concentrated in vacuo and the residue was purified by flash chromatography (Biotage KP-Sil cartridge (100 g), 0-15% EtOAc in cyclohexane) to give the title compound (2.04 g, 32%) as a pale yellow viscous oil. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.37-7.32 (m, 2H), 7.32-7.27 (m, 1H), 7.23-7.18 (m, 2H ), 4.69 (ddt, J =9.5, 7.3, 3.2 Hz, 1H), 4.28-4.18 (m, 2H), 3.34-3.15 (m, 3H ), 2.78 (dd, J= 13.4, 9.6 Hz, 1H), 2.64-2.47 (m, 2H).

Step 2: (R)-4-benzyl-3-((R)-4,4,4-trifluoro-2-methylbutanoyl oxazolidin-2-one : NaHMDS (1M in THF, 3.07 ml, 3.07 mmol ) was added dropwise to a solution of (R)-4-benzyl-3-(4,4,4-trifluorobutanoyl)oxazolidin-2-one (0.740 g, 2.46 mmol) in THF (12 ml) at -78°C and after 90 minutes iodomethane (0.765 ml, 12.3 mmol) was added dropwise. The reaction mixture was allowed to warm slowly to -20° C. and stirred at -20° C. overnight. NH ₄ Cl (aq.) (50 ml) and water (50 ml) After warming to room temperature, the mixture was extracted with DCM (3×50 ml), the combined organic phases were passed through a Biotage phase separator, concentrated in vacuo, and the residue was purified with flash chromatography (GraceResolv cartridge with silica gel (80 g), 0-20% EtOAc in cyclohexane) to give the title compound (473 mg, 61%) as a pale yellow viscous oil.LCMS (Method A): R _T = 1.59 min, m/z = 316 [M+H] ^{+ .1} H-NMR (500 MHz, CDCl ₃ ): δ 7.38-7.31 (m, 2H ), 7.31-7.26 (m, 1H), 7.23-7.18 (m, 2H), 4.73-4.67 (m, 1H), 4.28-4.18 (m , 2H), 4.16-4.07 (m, 1H), 3.25 (dd, J =13.4, 3.4 Hz, 1H), 2.89-2.76 (m, 2H), 2.19 (d qd, J =15.5, 10.8, 4.8 Hz, 1H), 1.34 (d, J =7.0 Hz, 3H), ¹³ C-NMR (126 MHz , CDCl ₃ ): δ 174.82, 152.97, 135.08, 129.57, 129.13, 127.62, 126.45 (kv, J =276.9 Hz), 66.47, 55, 44, 37.99, 36.62 (kv, J =28.7 Hz), 32.52 (kv, J =2.6 Hz), 18.56.

Step 3: (R)-4,4,4-trifluoro-2-methylbutanoic acid : 30% aqueous hydrogen peroxide solution (0.613 ml, 6.00 mmol) was added to a solution of (R)-4-benzyl-3-(( R)-4,4,4-trifluoro-2-methylbutanoyl)oxazolidin-2-one (473 mg, 1.50 mmol) in THF (4 ml) and water (4 ml) at 0°C. After 5 minutes, lithium hydroxide (72 mg, 3.00 mmol) was added and the mixture was stirred for 70 minutes, after which the reaction was quenched by the addition of saturated sodium thiosulfate (aq.) (2 ml). The reaction mixture was allowed to warm to room temperature, concentrated in vacuo to remove THF, and the resulting biphasic mixture was extracted with DCM (3×10 ml). The pH of the aqueous phase was adjusted to 2 with 2M HCl (aq.) and the mixture was extracted with DCM (3×10 ml). The combined acidic DCM extracts were passed through a Biotage phase separator, carefully concentrated at 50° C. (no vacuum) and the residue dried at 50 mbar (no heat) for 5 minutes to give the title compound (250 mg, quantitative yield) as very pale yellow oil containing 8% wt./wt. DCM. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 10.96 (s, 1H), 2.84 (hept., J =7.0 Hz, 1H), 2.69 (d qd, J = 15.1, 10.9, 7.0 Hz, 1H), 2.18 (d qd, J = 15.1, 10.6, 6.3 Hz, 1H), 1.35 (d, J =7.2 Hz, 3H).

Acid 12: Lithium 4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoate

Step 1: Methyl 4,4,4-trifluoro-2-(triphenyl- λ5- ^{phosphanylidene} )butanoate : Lithium bis(trimethylsilyl)amide (1M in THF, 167 mL, 167 mmol) was added dropwise to the triphenyl(3 ,3,3-trifluoropropyl)phosphonium iodide (40.7 g, 83.6 mmol) in THF (167 ml) at -5°C for 1 hour 40 minutes. The reaction mixture was cooled to -78°C and methyl chloroformate (13.0 ml, 167 mmol) was added dropwise over 15 minutes. The reaction mixture was stirred for 1 hour at -78°C, then allowed to warm slowly to room temperature overnight, brine (300 ml) was added, and after stirring for 30 minutes, the layers were separated. The organic layer was washed with brine (40 ml) and the combined aqueous phases were extracted with DCM (2×40 ml). The combined organic phases were passed through a Biotage phase separator, concentrated in vacuo and purified by flash chromatography (Biotage KP-Sil cartridge (340 g), 50% EtOAc in cyclohexane). After concentration in vacuo, the resulting dark brown/orange material was suspended using Et ₂ O (50 ml). The precipitate was collected by filtration, washed with Et ₂ O (50 mL) and dried under high vacuum to give the title compound (16.5 g, 47%) as a beige solid. LCMS (Method A): R _T =0.86 min, m/z =417 [M+H] ⁺ . ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.68-7.43 (m, 15H), 3.60 (s, 1.3H (rotomer)), 3.11 (s, 1.7H ( rotomer)), 2.83-2.63 (m, 2H).

Stage 2: methyl 4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)but-2-enoate : 2,2,2-trifluoroethane-1,1-diol (2.00 ml, 25 .7 mmol) was added to sodium bicarbonate (300 mg, 3.57 mmol) in a conical flask; slight foaming was observed. To this was added a mixture of magnesium sulfate (1.2 g, 9.97 mmol) and tert-butyl methyl ether (6 ml) and placed in a water bath at 10°C. After 10 minutes, the suspension was passed through corrugated filter paper into a reaction tube, which was charged with methyl 4,4,4-trifluoro-2-(triphenyl-λ ⁵ -phosphanylidene)butanoate (4.00 g, 9.61 mmol) and sulfate magnesium (1.2 g, 9.97 mmol). The solids were washed on filter paper with tert-butyl methyl ether (2×5 ml). The reaction tube was sealed and heated at 70°C for 19 hours. The reaction mixture was allowed to cool to room temperature, filtered through Celite®, and the solids washed with Et ₂ O (2×10 ml). The filtrate was concentrated at 60° C. (no vacuum) and the residue was purified by Kugelrohr distillation (high vacuum, to 120° C.) to give the title compound (689 mg, 30%) as a colorless liquid. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 6.96 (q, J =8.1 Hz, 1H), 3.88 (s, 3H), 3.50 (q, J =10.3, 9.8 Hz, 2H).

Step 3: Methyl 4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoate : Suspension of methyl 4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)but- 2-enoate (689 mg, 2.92 mmol), ammonium formate (1.84 g, 29.2 mmol) and 10% palladium on carbon (31.1 mg, 0.290 mmol) were refluxed for 70 minutes. The reaction mixture was allowed to cool to room temperature, diluted with DCM (5 ml) and the resulting suspension was filtered through Celite®. The solids were washed with DCM (3×5 ml) and the filtrate was concentrated at 50° C. (no vacuum, then 700 mbar) to give a colorless liquid. This material was diluted with water (70 ml) and the resulting mixture was extracted with Et ₂ O (4×80 ml). The combined organic phases were washed with brine (30 mL), passed through a Biotage phase separator, and concentrated at 50° C. (no vacuum) to give the title compound (947 mg, 54%) as a colorless liquid. This material was 40% wt./wt. solution in Et ₂ O. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 3.77 (s, 3H), 3.03 (tt, J =8.2, 5.3 Hz, 1H), 2, 65 (d qd, J =15.2, 10.4, 8.2 Hz, 2H), 2.38 (d qd, J =15.4, 10.3, 5.3 Hz, 2H ).

Step 4: Lithium 4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoate : Methyl 4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoate solution (40 % w/w in Et ₂ O, 947 mg, 1.59 mmol) and lithium hydroxide (46 mg, 1.91 mmol) in THF (7.5 ml) and water (1.5 ml) were heated at 50 °C for 17 hours. The reaction mixture was concentrated in vacuo and the residue was dried in a vacuum oven at 50° C. to give the title compound (275 mg, 75%) as a colorless solid. ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 2.77 (d qd, J =14.0, 11.8, 6.0 Hz, 2H), 2.38-2.20 ( m, 3H).

Acid 13: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-cyclopropyl-6- oxo-1,6-dihydropyridine-3-carboxylic acid

Stage 1: ethyl-(S)-1-((1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl-4-cyclopropyl-6-oxo-1,6-dihydropyridine -3-carboxylate : PdCl ₂ (dppf) DCM (18.4 mg, 0.0226 mmol) was added to a pre-degassed solution of ethyl-(S)-1-((1-(tert-butoxycarbonyl)-4-hydroxy- 3,3-dimethylpiperidin-4-yl)methyl)-4-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (amine 7, step 2) (200 mg, 0.452 mmol), cyclopropylboronic acid (58, 2 mg, 0.677 mmol) and sodium carbonate (95.7 mg, 0.903 mmol) in a 10 ml vial. The vial was sealed and heated by microwave irradiation (CEM) at 120°C with stirring for 30 minutes. Then cyclopropylboronic acid (58, 2 mg, 0.677 mmol) and PdCl ₂ (dppf) DCM (18.4 mg, 0.0226 mmol) and the reaction was repeated under the same conditions Due to incomplete conversion, the reaction was repeated under the same conditions Next, cyclopropylboronic acid was added (77.6 mg, 0.903 mmol) and PdCl ₂ (dppf) DCM (18.4 mg, 0.0226 mmol) and repeat the reaction or at 120°C for 1 hour. The reaction mixture was partitioned between EtOAc and brine, layers were separated, extracted (EtOAc x 2), the combined organic phase was dried (phase separator), solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-40%, EtOAc in cyclohexane ) to give the title compound (143 mg, 71%) as a pale yellow oil. LCMS (Method A): R _T= 1.59 min, m/z =449 [M+H] ⁺ .

Step 2: (S)-4-((4-cyclopropyl-5-(ethoxycarbonyl)-2-oxopyridin-1(2H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-1-ium chloride : 4M HCl in 1,4-dioxane (1.5 mL, 43.2 mmol) was added to ethyl-(S)-1-((1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidine-4 -yl)methyl)-4-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate (143 mg, 0.320 mmol) and the resulting mixture was stirred at room temperature. After 30 minutes, the solvents were removed in vacuo to give the title crude compound (153 mg, >100%) as a pale yellow solid, which was taken to the next step without further purification. LCMS (Method A): R _T= 0.71 min, mlz=385 [M+H] ⁺ .

Stage 3: ethyl-1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-cyclopropyl- 6-oxo-1,6-dihydropyridine-3-carboxylate : DIPEA (0.17 ml, 0.959 mmol) was added to a stirred solution of (S)-4-((4-cyclopropyl-5-(ethoxycarbonyl)-2-oxopyridine- 1(2H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-1-ium chloride (123 mg, 0.320 mmol), (R)-3-cyclohexyl-2-methylpropanoic acid (acid 1) (54 .4 mg, 0.320 mmol) and HATU (146 mg, 0.383 mmol) in DCM (5.0 ml) at room temperature. After 2 hours, the reaction mixture was partitioned between additional DCM and saturated sodium bicarbonate solution (aq.). The resulting biphasic mixture was separated, dried (phase separator), solvents were removed in vacuo and the remaining residue was purified by flash chromatography using a KP-NH column (0-100%, EtOAc in cyclohexane) to give the title compound (125 mg, 78%) as a pale yellow solid. LCMS (Method A): R _T = 1.81 min, m/z = 501 [M+H] ⁺ .

Stage 4: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-cyclopropyl-6- oxo-1,6-dihydropyridine-3-carboxylic acid : 1M sodium hydroxide solution (aqueous solution) (0.5 ml, 0.499 mmol) was added to a stirred solution of ethyl 1-(((S)-1-((R) -3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate (125 mg, 0.249 mmol ) in 1,4-dioxane (1.5 ml) at room temperature. The temperature was raised to 50°C. After 2 hours, the reaction mixture was cooled, the pH was adjusted to 4-5 with 1M HCl solution (aq.), and was extracted using EtOAc (x 3). Due to the fact that the product remained in the aqueous phase, the pH was adjusted to approximately 2-3 using an additional 1M HCl solution (aq.), followed by extraction using EtOAc (x 3). The combined organic phases were dried (phase separator) and concentrated in vacuo. The remaining residue was purified by flash chromatography (0-5%, MeOH in DCM) to give the title compound (67.6 mg, 57%) as a white solid. LCMS (method A): R _T= 1.44 min, m/z =473 [M+H] ⁺ .

Acid 14: (S)-4,4,4-trifluoro-2-(hydroxymethyl)butanoic acid

Step 1: (R)-4-benzyl-3-((S)-4,4,4,4-trifluoro-2-((2-(trimethylsilyl)ethoxy)methyl)butanoyl)oxazolidin-2-one : K a solution of (R)-4-benzyl-3-(4,4,4-trifluorobutanoyl)oxazolidin-2-one (1 g, 3.32 mmol) and titanium tetrachloride (0.400 ml, 3.65 mmol) in DCM (16 .5 ml) DIPEA (0.696 ml, 3.98 mmol) was added dropwise at 0°C. The resulting purple mixture was stirred at 0°C for 1 hour, after which 2-(chloromethoxyethyl)trimethylsilane (0.699 ml, 3.98 mmol) was added. After 1 hour, the reaction was quenched by adding saturated NH ₄ Cl (aq.) (20 ml) and water (20 ml). After warming to room temperature, the mixture was extracted with DCM (3×30 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv cartridge with silica gel (80 g), 0-60% EtOAc in cyclohexane; then GraceResolv cartridge with silica gel (40 g), 0-40% EtOAc in cyclohexane), to give the title compound (373 mg, 26%) as a colorless oil. LCMS (method A): R _T =2.04 min, m/z =404 [M-2Me+3H] ⁺ . ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.37-7.30 (m, 2H), 7.30-7.26 (m, 1H), 7.25-7.18 (m, 2H ), 4.73 (ddt, J = 9.4, 7.9, 3.2 Hz, 1H), 4.44-4.36 (m, 1H), 4.24 (ddd, J = 8.6 , 7.9, 0.7 Hz, 1H), 4.19 (dd, J = 9.1, 3.1 Hz, 1H), 3.72-3.61 (m, 2H), 3.61- 3.49 (m, 2H), 3.25 (dd, J =13.5, 3.4 Hz, 1H), 2.90-2.73 (m, 2H), 2.44 (d qd , J =15.2, 11.1, 4.1 Hz, 1H), 0.96-0.88 (m, 2H), 0.01 (s, 9H).

Step 2: (R)-4-benzyl-3-((S)-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)oxazolidin-2-one : To a solution of (R)-4-benzyl-3 -((S)-4,4,4-trifluoro-2-((2-(trimethylsilyl)ethoxy)methyl)butanoyl)oxazolidin-2-one (363 mg, 0.841 mmol) in DCM (8.4 ml) was added boron trifluoride diethyl etherate (0.320 ml, 2.52 mmol). After 2 hours 15 minutes the reaction was quenched by adding saturated NaHCO ₃ (aq.) (40 ml), and the mixture was extracted with DCM (3×20 ml). The combined organic phases were passed through a Biotage phase separator, concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv cartridge with silica gel (12 g), 0-50% EtOAc in cyclohexane) to give the title compound (276 mg, 99% ) as a colorless gum that solidified on stirring. LCMS (method A): R _T =1.30 min, m/z =332 [M+H] ⁺ . ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.38-7.31 (m, 2H), 7.31-7.27 (m, 1H), 7.25-7.20 (m, 2H ), 4.73 (dddd, J =9.3, 7.6, 3.6, 2.7 Hz, 1H), 4.37-4.31 (m, 1H), 4.30-4.25 (m, 1H), 4.22 (dd, J =9.1, 2.7 Hz, 1H), 3.93-3.83 (m, 2H), 3.28 (dd, J =13.6 , 3.6 Hz, 1H), 2.88-2.75 (m, 2H), 2.38 (d q.d, J = 15.0, 10.9, 4.1 Hz, 1H), 2 .04 (dd, J =7.5, 5.3 Hz, 1H).

Step 3: (S)-4,4,4-trifluoro-2-(hydroxymethyl)butanoic acid: 30% hydrogen peroxide aqueous solution (91 µl, 0.894 mmol) was added to the (R)-4-benzyl-3-( (S)-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)oxazolidin-2-one (74 mg, 0.223 mmol) in THF (1.1 ml) and water (1.1 ml) ml) at 0°C. After 5 minutes, LiOH (10.7 mg, 0.447 mmol) was added and the reaction mixture was stirred for 2 hours and then quenched by adding saturated sodium thiosulfate (aq.) (0.5 ml). The reaction mixture was extracted with DCM (3×5 ml) and the pH of the aqueous phase was adjusted to pH 2 by adding 1M HCl (aq.). The mixture was extracted with EtOAc (5 x 5 ml), the combined EtOAc extracts were passed through a Biotage phase separator and concentrated in vacuo to give the title compound (40 mg, quantitative yield) as a pale yellow oil. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 3.98 (dd, J =11.1, 4.3 Hz, 1H), 3.88 (dd, J =11.1, 5.9 Hz, 1H), 2.94 (cd, J = 6.3, 4.3 Hz, 1H), 2.70 (d qd, J = 15.3, 11.0, 6.6 Hz, 1H), 2.48 (d qd, J =15.3, 10.7, 6.4 Hz, 1H).

Acid 15 :( R )-4,4-difluoro-3-phenylbutanoic acid

Stage 1: ethyl 4,4-difluoro-3-phenylbut-2-enoate: A suspension of sodium hydride (60% dispersion in mineral oil, 1.54 g, 38.4 mmol) in anhydrous THF (100 ml) was cooled to 0 °C before adding dropwise triethylphosphonoacetate (7.05 ml, 35.2 mmol). After stirring at 0° C. for 30 minutes, 2,2-difluoro-1-phenylethanone (5.0 g, 32.0 mmol) was added dropwise and the mixture was stirred at 0° C. for another 60 minutes. The reaction mixture was quenched by adding water (100 ml) and was extracted with EtOAc (3×50 ml). The combined organic phases were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered, concentrated to dryness under reduced pressure and purified by flash chromatography (GraceResolv™ cartridge with silica gel (120 g), cyclohexane:ethyl acetate, gradient elution from 95 :5 to 60:40) to give the title compound (3.38 g, 47%) as a colorless oil.

Stage 2: ethyl 4,4-difluoro-3-phenylbutanoate: A solution of ethyl 4,4-difluoro-3-phenylbut-2-enoate (1.00 g, 4.42 mmol) in methanol (88 ml) was hydrogenated with using H-Cube® (cartridge with 10% Pd/C, H ₂ 60 bar, 60°C, 1 ml/min). The reaction mixture was concentrated to dryness under reduced pressure and purified by flash chromatography (GraceResolv™ silica gel cartridge (80 g), cyclohexane:ethyl acetate, gradient elution from 100:0 to 80:20) to give the title compound (975 mg, 97% ) as a colorless oil. LCMS (method A): R _T =1.55 min, m/z =229 [M+H] ⁺ , ¹H-NMR (300 MHz, CDCl ₃ ): δ 7.23-7.39 (m, 5H) , 5.94 (td, 1H), 3.98-4.15 (m, 2H), 3.51-3.74 (m, 1H), 2.96 (dd, 1H), 2.78 (dd , 1H), 1.15 (t, 3H).

Stage 3: 4,4-difluoro-3-phenylbutanoic acid: To a solution of ethyl 4,4-difluoro-3-phenylbutanoate (975 mg, 4.27 mmol) in 1,4-dioxane (8.5 ml) was added 1M sodium hydroxide solution (8.5 ml, 8.54 mmol) and the reaction mixture was stirred at room temperature for 60 minutes. The reaction mixture was acidified to pH 4 with 2M HCl (aq.) followed by extraction with EtOAc (3×30 ml). The combined organic phases were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered, concentrated to dryness under reduced pressure and suspended in cyclohexane (20 ml) to give the title compound (682 mg, 80%) as a colorless solid. LCMS (method A): R _T =1.10 min, m/z =199 [MH] ^- , ¹H-NMR (300 MHz, CDCl ₃ ): 7.20-7.40 (m, 5H), 5, 92 (td, 1H), 3.48-3.72 (m, 1H), 3.02 (dd, 1H), 2.83 (dd, 1H).

Step 4: (S)-4-benzyl-3-((R)-4,4-difluoro-3-phenylbutanoyl)oxazolidin-2-one: 4,4-difluoro-3-phenylbutanoic acid solution (2.00 g , 10.0 mmol), (S)-4-benzyloxazolidin-2-one (1.95 g, 11.0 mmol) and lithium chloride (850 mg, 20.0 mmol) in anhydrous THF (25 ml) were cooled to -20°C followed by dropwise addition of pivaloyl chloride (3.07 ml, 25.0 mmol) and then triethylamine (3.62 ml, 26.0 mmol). The resulting mixture was stirred at -20°C for 30 minutes, then allowed to warm to room temperature, diluted with saturated ammonium chloride solution (30 ml) and was extracted with EtOAc (3×20 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered, concentrated to dryness under reduced pressure and purified by flash chromatography (GraceResolv™ cartridge with silica gel (330 g), cyclohexane:ethyl acetate, gradient elution from 95:5 to 60:40). The 2nd diastereoisomer eluted was the title compound (1.42 g, 40%) as a colorless solid. LCMS (method A): R _T =1.67 min, m/z =360 [M+H] ⁺ , ¹H-NMR (300 MHz, CDCl ₃ ): δ 7.19-7.43 (m, 8H) , 6.96-7.06(m, 2H), 5.99(td, 1H), 4.59-4.69(m, 1H), 4.20(ddd, 1H), 4.14(dd , 1H), 3.76-3.90 (m, 1H), 3.69 (dd, 1H), 3.44 (dd, 1H), 3.02 (dd, 1H), 2.62 (dd, 1H).

Step 5: (R)-4,4-difluoro-3-phenylbutanoic acid: Solution of (S)-4-benzyl-3-((R)-4,4-difluoro-3-phenylbutanoyl)oxazolidin-2-one ( 1.42 g, 3.95 mmol) in a mixture of THF (28 ml) and water (5.6 ml) was cooled to 0°C before adding 30% aqueous hydrogen peroxide solution (1.01 ml, 9.88 mmol), and then a solution of lithium hydroxide (237 mg, 9.88 mmol) in water (5.6 ml) was added dropwise. The reaction mixture was stirred at 0°C for 90 minutes, then quenched by adding 2M sodium thiosulfate (aq.) (19.8 ml, 39.5 mmol), diluted with water (20 ml) and washed with EtOAc (3×20 ml). The organic phase was extracted with saturated sodium bicarbonate solution (3×20 ml) and the aqueous phases were combined with those previously obtained. The combined aqueous phases were adjusted to pH ~4 by adding 2M HCl followed by extraction with EtOAc (3 x 20 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered, concentrated to dryness under reduced pressure and suspended in cyclohexane (15 ml) to give the title compound (683 mg, 86%) as a colorless solid. LCMS (method A): R _T =1.11 min, m/z =199 [MH] ^- , ¹H-NMR (300 MHz, CDCl ₃ ): δ 7.23-7.40 (m, 5H), 5 .92 (td, 1H), 3.49-3.70 (m, 1H), 3.02 (dd, 1H), 2.82 (dd, 1H).

Acid 16 :( R )-4,4,4-trifluoro-3-phenylbutanoic acid

Step 1: (E)-4,4,4-trifluoro-3-phenylbut-2-enoic acid: LiOH (132 mg, 5.5 mmol) was added to a solution of (E)-ethyl-4,4,4-trifluoro -3-phenylbut-2-enoate (J. Fluorine Chem., 2013, 152, p.56) (1.22 g, 5 mmol) in THF (10 ml) and water (5 ml) at room temperature. After 1 hour, the pH of the reaction mixture was adjusted to 4 with 1M HCl (aq.) and the mixture was extracted with DCM (3×10 ml) using a Biotage phase separator. The combined organic phases were concentrated and the product dried in vacuo to give the title compound (1.06 g, 98%) as a colorless solid. LCMS (method A): R _T =1.27 min, m/z =215 [MH] ^- , ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 13.22 (br s, 1H), 7.54-7.38 (m, 3H), 7.36-7.22 (m, 2H), 6.84 (s, 1H).

Step 2: (R)-4,4,4-trifluoro-3-phenylbutanoic acid : Suspension of bis(norbornadiene)rhodium(I) tetrafluoroborate (3.46 mg, 9.25 µmol) and Walphos SL-W008-2 (8 .7 mg, 9.25 µmol) in MeOH (6 ml) was degassed with nitrogen. After 30 minutes a solution was obtained and (E)-4,4,4-trifluoro-3-phenylbut-2-enoic acid (200 mg, 0.925 mmol) was added. The reaction mixture was then shaken in a Parr® Shaker under H ₂ at 3.5-4 bar for 22 hours. Since no conversion occurred, more rhodium(I) bis(norbornadiene) tetrafluoroborate (3.5 mg, 9.25 µmol) and Walphos SL-W008-2 (8.7 mg, 9.25 µmol) were added and the reaction mixture was shaken in Parr® Shaker under H ₂ at 5 bar for 24 hours. The mixture was concentrated and the residue was purified by flash chromatography (Biotage KP-Sil, 10 g, 0-20% MeOH in DCM) to give the title compound (100 mg, 49%) as a colorless solid. LCMS (method A): R _T =1.24 min, m/z =217 [MH] ^- , ¹H-NMR (300 MHz, CDCl ₃ ): δ 10.67 (br s, 1H), 7.49 -7.21(m, 5H), 3.89(m, 1H), 3.20-2.82(m, 2H).

Epoxide 1: tert-butyl-1-oxa-6-azaspiro[2,5]-octane-6-carboxylate

Received in accordance with a modified literature procedure (J. Med. Chem., 2008, 51, p. 2170): Trimethylsulfoxonium iodide (22.5 g, 102 mmol) was suspended in DME (100 ml) under N ₂ atmosphere, and tert was added -potassium butoxide (12.5 g, 11.1 mmol). After 30 minutes, the mixture was cooled to 0°C and a solution of tert-butyl-4-oxo-piperidine-1-carboxylate (20 g, 100 mmol) in DME (20 ml) was added dropwise over 45 minutes. The reaction mixture was allowed to warm to room temperature over 16 hours, then quenched by adding water (150 ml). The mixture was extracted with Et ₂ O (3×100 ml). The combined organic extracts were washed with brine (100 ml), dried over MgSO ₄ and concentrated. The residue was azeotropically dried with toluene to give the title compound (16.5 g, 83%). ¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.81-3.58 (m, 2H), 3.40 (ddd, 2H), 2.67 (s, 2H), 1.78 (ddd, 2H), 1.56-1.30 (m, 2H), 1.45 (s, 9H).

Epoxy 2: (R) -3-phenyl-1-(1-oxa-6-azaspiro[2.5]octan-6-yl)butan-1-one

Step 1: (R)-1-(3-Phenylbutanoyl)piperidin-4-one : Piperidin-4-one hydrochloride (1.70 g, 12.6 mmol) was suspended in DCM (15 ml). EDC (2.89 g, 15.1 mmol) and DMAP (153 mg, 1.26 mmol) were added followed by DIPEA (11 ml, 62.7 mmol). The mixture was stirred for 10 minutes, then a solution of (R)-3-phenylbutanoic acid (2.47 g, 15.1 mmol) in DCM (10 ml) was added. The mixture was stirred for 20 hours, then an additional portion of EDC (2.89 g, 15.1 mmol) was added. The reaction mixture was stirred for another 4 hours and then quenched by adding saturated ammonium bicarbonate (150 ml). The mixture was extracted with EtOAc (3×50 ml). The combined organic extracts were washed with water (50 ml) and brine (50 ml), dried over MgSO ₄ and concentrated. The residue was purified by flash chromatography (Biotage KP-Sil (50 g), 0-60% EtOAc in petroleum ether) to give the title compound (2.93 g, 95%). LCMS (method B): R _T =1.07 min, m/z =246 [M+H] ⁺ , ¹H-NMR (300 MHz, CDCl ₃ ): δ 7.44-7.13 (m, 5H) , 4.30-4.03 (m, 1H), 3.77-3.58 (m, 1H), 3.46 (td, d, 2H), 3.11-2.93 (m, 2H) , 2.82-2.61(m, 4H), 1.86(m, 1H), 1.77-1.62(m, 1H), 1.54-1.33(m, 2H).

Step 2: (R)-3-Phenyl-1-(1-oxa-6-azaspiro[2.5]octan-6-yl)butan-1-one : Prepared according to general procedure 11 using trimethylsulfonium iodide (6 09 g, 29.9 mmol), sodium hydride (60% dispersion in mineral oil, 1.19 g, 29.9 mmol) and (R)-1-(3-phenylbutanoyl)piperidin-4-one (2, 93 g, 11.9 mmol) in DMSO (15 mL) to give the title compound (2.68 g, 87%). LCMS (method B): R _T =1.02 min, m/z =260 [M+H] ⁺ , ¹H-NMR (300 MHz, CDCl ₃ ): δ 7.43-7.14 (m, 5H) , 4.30-3.95 (m, 1H), 3.69-3.18 (m, 4H), 2.84-2.47 (m, 4H), 1.87-1.66 (m, 2H), 1.51-1.31 (m, 2H), 1.37 (d, 3H).

Epoxide 3: (R,S)-tert-butyl-4,4-dimethyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate

Prepared according to General Procedure 11 using trimethylsulfonium iodide (0.561 g, 2.75 mmol), sodium hydride (60% dispersion in mineral oil, 0.110 g, 2.75 mmol) and tert-butyl-3,3-dimethyl -4-oxo-piperidine-1-carboxylate (0.25 g, 1.100 mmol) in DMSO (2.6 mL) to give the title compound (0.290 g, >100%) which was used without further purification. LCMS (method B): R _T =1.47 min, m/z= 142 [M+H-Boc] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.84-3.74 (m, 1H), 3.41-3.33 (m, 2H), 3.13 (d, 1H), 2, 84 (d, 1H), 2.47 (d, 1H), 1.98-1.87 (m, 1H), 1.47 (s, 9H), 1.38 (d, 1H), 0.97 (s, 3H), 0.83 (s, 3H).

Epoxide 4: (R,S)-tert-butyl-1-oxa-9-azadispiro[2.0.3 ^four .four ³ ]undecane-9-carboxylate

Step 1: 6-benzyl-6-azaspiro[3,5]nonan-9-one : 1-cyclobutyl ethanone (1.08 ml, 9.9 mmol) was dissolved in ethanol (5 ml) and then concentrated aqueous HCl ( 0.81 ml, 9.8 mmol). The mixture was heated to reflux temperature. A mixture of benzylamine (1.02 ml, 9.33 mmol) and 37% aqueous formaldehyde (1.56 ml, 21 mmol) in ethanol (5 ml) was added and the mixture was refluxed for 16 hours. Triethylamine (1.43 ml, 10.3 mmol) was added followed by aqueous formaldehyde (0.21 ml, 2.80 mmol) and the reaction mixture was heated at reflux for another 24 hours. The mixture was cooled to 5° C. and a solution of potassium hydroxide (0.55 g, 9.8 mmol) in water (1 ml) was added. The mixture was concentrated and the residue was dissolved in water and extracted with Et ₂ O (x 2). The combined organic extracts were washed with brine, dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (GraceResolv (40 g), 0-1% MeOH in DCM) to give the title compound (600 mg, 28%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.27-7.40 (m, 5H), 3.60 (s, 2H), 2.67-2.71 (m, 4H), 2, 44 (t, 2H), 2.32-2.40 (m, 2H), 1.75-1.89 (m, 4H).

Step 2: 6-azaspiro[3,5]nonan-9-one hydrochloride : 6-benzyl-6-azaspiro[3,5]nonan-9-one (150 mg, 0.65 mmol) was dissolved in DCM (2 ml ) and cooled to 0°C. α-Chloroethyl chloroformate (0.071 ml, 0.65 mmol) was added and the reaction mixture was stirred at 0° C. for 20 minutes. The mixture was concentrated and the residue was dissolved in MeOH. The resulting solution was heated under reflux for 40 minutes. The mixture was concentrated and the residue was dissolved in chloroform. Diethyl ether was added and the precipitate was collected by filtration to give the title compound (70 mg, 61%). ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 3.52-3.40 (m, 4H), 3.35 (m, 2H), 2.59 (t, 2H), 2.28 ( m, 2H), 2.04-1.88 (m, 3H), 1.77-1.56 (m, 1H).

Step 3: tert-butyl 9-oxo-6-azaspiro[3,5]nonane-6-carboxylate : 6-azaspiro[3,5]nonan-9-one hydrochloride (70 mg, 0.40 mmol) was suspended in mixtures of 1,4-dioxane (1 ml) and water (0.25 ml). DIPEA (0.17 ml, 1.00 mmol) was added followed by di-tert-butyl dicarbonate (0.14 ml, 0.60 mmol). The reaction mixture was stirred at room temperature for 64 hours. The mixture was concentrated and the residue was dissolved in water and DCM. The organic layer was dried (Biotage phase separator) and concentrated to give the title compound (86 mg, 90%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.61-3.76 (m, 4H), 2.41 (t, 2H), 2.30-2.41 (m, 2H), 1, 92-2.08 (m, 1H), 1.75-1.92 (m, 3H), 1.50 (s, 9H).

Step 4: (R,S)-tert-butyl-1-oxa-9-azadispiro[2.0.3. ^4.4 . ³ ]undecane-9-carboxylate : Prepared according to general procedure 11 using tert-butyl 9-oxo-6-azaspiro[3,5]nonane-6-carboxylate (0.30 g, 1.25 mmol), trimethylsulfonium iodide (0.640 g, 3.13 mmol) and sodium hydride (60% dispersion in mineral oil, 0.125 g, 3.13 mmol) in DMSO (6.3 ml). The crude product was purified by flash chromatography (GraceResolv, 11 g, 0-40% EtOAc in cyclohexane) to give the title compound (200 mg, 63%). LCMS (Method B): R _T =1.48 min, m/z =154 [M+H-Boc] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 4.02-3.72 (m, 2H), 3.23-3.06 (m, 2H), 2.74 (br dd, 1H), 2.60 (d, 1H), 1.98-1.68 (m, 6H), 1.49 (s, 9H), 1.45-1.35 (m, 2H).

Epoxy 5: tert-butyl (one R, 5 S, eight r )-3-azaspiro[bicyclo[3.2.1]octane-8,2'-oxirane]-3-carboxylate

Prepared according to general procedure 11 using (1 R, 5 S ) -tert -butyl-8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (0.150 g, 0.67 mmol) in DMSO (2.2 ml), trimethylsulfonium iodide (0.34 g, 1.66 mmol) and sodium hydride (60% dispersion in mineral oil, 0.067 g, 1.67 mmol) to give the title compound (160 mg, quantitative yield), which was used without further purification. LCMS (Method B): R _T =1.26 min, m/z =140 [M+H-Boc] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 4.00 (d, 1H), 3.84 (d, 1H), 3.30 (d, 1H), 3.20 (d, 1H), 2 .86 (s, 2H), 1.90-1.80 (m, 2H), 1.75-1.55 (m, 4H), 1.47 (s, 9H).

Epoxide 6: tert-butyl-1-oxa-10-azadispiro[2.0.4 ^four .four ³ ]dodecane-10-carboxylate

Step 1: tert-Butyl 10-oxo-7-azaspiro[4.5]decane-7-carboxylate: Potassium tert-butoxide (24.8 g, 221 mmol) was added portionwise to a solution of tert-butyl-4-oxo-piperidine-1- carboxylate (20 g, 100 mmol) in toluene (200 ml) in a 1 L 3-neck RBF flask equipped with a reflux condenser under nitrogen at room temperature. After 1 hour, 1,4-dibromobutane (12.0 mL, 100 mmol) was added dropwise over 15 minutes and the reaction mixture was heated at reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted 1:1 with saturated NH ₄ Cl (aq.)/water (200 ml) and was extracted with EtOAc (3×75 ml). The combined organic phases were washed with brine (100 ml), dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage KP-Sil cartridge (340 g), 0-10% EtOAc in cyclohexane; mixed fractions were repurified, Biotage KP-Sil cartridge (100 g), 0-15% EtOAc in cyclohexane), with obtaining the title compound (8.26 g, 32%) as a colorless solid. LCMS (method A): R _T =1.52 min, m/z =198 [M-butene+H] ⁺ . ¹ H-NMR (500 MHz, CDCl ₃ ): δ 3.70 (t, J =6.6 Hz, 2H), 3.45 (s, 2H), 2.48 (t, J =6.4 Hz , 2H), 1.97-1.88 (m, 2H), 1.72-1.62 (m, 4H), 1.52-1.43 (m, 2H), 1.49 (s, 9H ).

Step 2: tert-butyl-1-oxa-10-azadispiro[2.0.44.43 ] ^dodecan - ¹⁰ -carboxylate: To a suspension of trimethylsulfonium iodide (18.8 g, 92.1 mmol) in DMF (200 ml) at 0° C. under nitrogen atmosphere, sodium hydride (60% dispersion in mineral oil, 3.68 g, 92.1 mmol) was added portionwise over 15 minutes. After stirring for 30 minutes, the mixture was allowed to warm to room temperature and stirred for another 1 hour, and then a solution of tert-butyl 10-oxo-7-azaspiro[4.5]decan-7-carboxylate (15, 6 g, 61.4 mmol) in DMF (100 mL) using a pressure equalizing addition funnel. The reaction mixture was stirred at room temperature for 2 days and slowly quenched by adding water (20 ml). The resulting mixture was concentrated in vacuo, water (600 ml) was added and the mixture was extracted with EtOAc (3×200 ml). The combined organic phases were dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage KP-Sil (100 g), 0-20% EtOAc in cyclohexane) to give the title compound (14.0 g, 85%) as a colorless liquid. ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 3.57 (s, 2H), 3.35-3.16 (m, 2H), 2.75 (d, J =4.5 Hz, 1H ), 2.53 (d, J =4.5 Hz, 1H), 1.47 (s, 9H), 1.78-1.21 (m, 10H (with signal overlap from HDO)).

Epoxide 7: tert-butyl-1-oxa-11-azadispiro[2.0.5 ^four .four ³ ]tridecane-11-carboxylate

Step 1: tert-Butyl 5-oxo-2-azaspiro[5.5]undecane-2-carboxylate: Potassium tert-butoxide (0.62 g, 5.52 mmol) was added portionwise to a solution of tert-butyl-4-oxo-piperidine- 1-carboxylate (0.5 g, 2.51 mmol) in toluene (5 ml) in a 50 ml 3-neck reflux reactor equipped with a reflux condenser under nitrogen at room temperature. After 1 hour, 1,5-dibromopentane (0.342 mL, 2.51 mmol) was added dropwise over 10 minutes and the reaction mixture was heated at reflux for 3 hours. The reaction mixture was allowed to cool to room temperature, diluted 1:1 with saturated NH ₄ Cl (aq.)/water, and was extracted with EtOAc (x 3). The combined organic phases were washed with brine, passed through a Biotage phase separator and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage KP-Sil cartridge (50 g), 0-5% EtOAc in cyclohexane) to give the title compound (0.18 g, 26%). ¹ H-NMR (500 MHz, CDCl ₃ ): δ 3.77-3.61 (b.s., 2H), 3.60-3.46 (br.s., 2H), 2.48 (t , J = 6.5 Hz, 2H), 1.77-1.29 (m, 10H (with signal overlap from HDO)), 1.50 (s, 9H).

Step 2: tert-butyl-1-oxa-11-azadispiro[2.0.54.43 ^] tridecane - ¹¹ -carboxylate: To a suspension of trimethylsulfonium iodide (206 mg, 1.01 mmol) in DMF (2 ml) at 0 °C under nitrogen atmosphere, sodium hydride (60% dispersion in mineral oil) (40.4 mg, 1.01 mmol) was added portionwise over 15 minutes. After stirring for 30 minutes, the mixture was allowed to warm to room temperature and stirred for another 30 minutes, then a solution of tert-butyl 5-oxo-2-azaspiro[5.5]undecane-2-carboxylate (180 mg, 0.673 mmol) in DMF (1.5 ml). The reaction mixture was stirred at room temperature for 18 hours and then slowly quenched by adding water. The resulting mixture was concentrated in vacuo, water was added and the mixture was extracted with EtOAc (x3). The combined organic phases were dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage KP-Sil, 50 g, 0-20% EtOAc in cyclohexane) to give the title compound (120 mg, 63%) as a colorless liquid. ¹H-NMR (500 MHz, CDCl ₃ ): δ 3.73-3.51 (m, 2H), 3.51-3.29 (m, 2H), 2.92 (d, J =4.4 Hz , 1H), 2.42 (d, J =4.4 Hz, 1H), 1.48 (s, 9H), 1.72-1.33 (m, 9H (with signal overlap from HDO)), 1 .23-1.02 (m, 3H).

Example 1: (R)-5-bromo-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one

Step 1: 5-bromo-4-phenylpyridin-2(1H)-one : 5-bromo-2-chloro-4-phenylpyridine (1.13 g, 4.21 mmol) (prepared as described in Eur. J. Org. Chem, 2013, p.2316-2324) was dissolved in DMSO (14 ml) and a solution of sodium hydroxide (1.18 g, 29.5 mmol) in water (14.0 ml) was added. The mixture was heated in a microwave oven at 130° C. for 30 minutes. The mixture was acidified using 2M HCl and extracted with EtOAc (x 3). The combined organic extracts were washed with water/brine 1:1, dried over MgSO ₄ , filtered and concentrated. The residue was dissolved in a small volume of DCM and the solid was collected by filtration through a sintered funnel. The crude product was washed with diethyl ether and dried to give the title compound (0.60 g, 57%). LCMS (method B): R _T= 0.91 min, m/z =250, 252 [M+H] ⁺ .

Stage 2: (R)-5-bromo-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one: 5-bromo mixture -4-phenylpyridin-2(1H)-one (640 mg, 2.56 mmol), epoxide 2 (796 mg, 3.07 mmol) and pyridine (0.62 ml, 7.68 mmol) in DMF (10 ml ) was heated in a sealed tube at 80°C for 64 hours. The mixture was concentrated and the residue was purified by flash chromatography (Biotage KP-Sil, 0-100% EtOAc in cyclohexane, then 0-10% MeOH in EtOAc) to give the title compound (368 mg, 28%). LCMS (method B): R _T =1.27 min, m/z =509.511 [M+H] ⁺ , ¹H-NMR (400 MHz, methanol- d ₄ , compound presented as two conformational isomers): δ 7.96 (m, 1H), 7.48 (m, 5H), 7.30 (m, 5H), 6.55 (s, 1H), 4.26-3.87 (m, 3H), 3 .70 (m, 1H), 3.22 (m, 2H), 3.01 (m, 1H), 2.77 (m, 1H), 2.54 (m, 1H), 1.61 (m, 1H), 1.51-1.29 (m, 6.4H), 0.93 (m, 0.6H, only one conformational isomer).

Example 2: 6-(2-fluorophenyl)-3-((4-hydroxy-1-(3-phenylpropanoyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one

Prepared according to general procedure 2 using amine 1 (45 mg, 0.132 mmol), 3-phenylpropanoyl chloride (27.5 mg, 0.163 mmol), DIPEA (52 μl, 0.297 mmol) and DCM (3 ml) to give the indicated in the title compound (48.4 mg, 84%). LCMS (method B): R _T =1.10 min, m/z =436 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.12 (s, 1H), 8.08-8.03 (m, 1H), 7.46-7.44 (m, 1H), 7, 32-7.15(m, 7H), 7.10(s, 1H), 4.47-4.40(m, 1H), 4.05-3.92(m, 2H), 3.87( s, 1H), 3.65-3.58 (m, 1H), 3.40-3.31 (m, 1H), 3.04-2.96 (m, 3H), 2.66-2, 61 (m, 2H), 1.51-1.23 (m, 4H).

Example 3: 3-((1-(3-cyclobutylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one

Amine 1 (30 mg, 0.088 mmol), 3-cyclobutylpropanoic acid (12.7 mg, 0.099 mmol) and triethylamine (17 μl, 0.119 mmol) were dissolved in DMF and EDC (20.9 mg, 0.109 mmol) was added. The mixture was stirred overnight, then partitioned between DCM and a mixture of brine and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with DCM and the combined organic extracts were dried over MgSO ₄ and concentrated. The residue was purified by flash chromatography (GraceResolv (4 g), 10-90% EtOAc in cyclohexane) to give the title compound (24.1 mg, 66%). LCMS (method B): R _T =1.13 min, m/z =414 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.17 (m, 1H), 8.08-8.03 (m, 1H), 7.48-7.42 (m, 1H), 7, 30-7.24 (m, 1H), 7.20-7.14 (m, 1H), 7.12 (s, 1H), 4.45-4.38 (m, 1H), 4.18- 4.12(m, 1H), 3.99-3.93(m, 1H), 3.81(s, 1H), 3.73-3.65(m, 1H), 3.48-3, 39 (m, 1H), 3.10-3.01 (m, 1H), 2.31-2.19 (m, 3H), 2.09-2.00 (m, 2H), 1.90- 1.76 (m, 2H), 1.74-1.60 (m, 6H), 1.58-1.53 (m, 2H).

Example 4 3-((1-(3-cyclopentylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one

Prepared according to general procedure 2 using amine 1 (40 mg, 0.118 mmol), 3-cyclopentylpropanoyl chloride (23.3 mg, 0.145 mmol), DIPEA (46 μl, 0.264 mmol) and DCM (2 ml) to give the title compound (49.4) mg, 98%). LCMS (method B): R _T =1.21 min, m/z =428 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.17 (s, 1H), 8.08-8.04 (m, 1H), 7.48-7.43 (m, 1H), 7, 30-7.25(m, 1H), 7.20-7.15(m, 1H), 7.12(s, 1H), 4.47-4.38(m, 1H), 4.19- 3.92 (m, 2H), 3.81-3.78 (m, 1H), 3.75-3.67 (m, 1H), 3.49-3.40 (m, 1H), 3. 11-3.01 (m, 1H), 2.38-2.30 (m, 2H), 1.83-1.72 (m, 3H), 1.69-1.45 (m, 10H), 1.16-1.05 (m, 2H).

Example 5: (S)-6-(2-fluorophenyl)-3-((4-hydroxy-1-(2-methyl-3-phenylpropanoyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one

Prepared according to general procedure 3 using amine 1 (40 mg, 0.118 mmol), (R,S)-2-methyl-3-phenylpropanoic acid (21.7 mg, 0.132 mmol), DIPEA (46 µl, 0.264 mmol), HATU (105 mg, 0.277 mmol) and DMF (2 ml) to give the title compound (14.2 mg, 27%). LCMS (method B): R _T =1.15 min, m/z =450 [M+H] ⁺ . ¹ H-NMR (400 MHz, methanol- d ₄ ): δ 8.39-8.31 (m, 1H), 8.05-8.00 (m, 1H), 7.53-7.46 (m , 1H), 7.34-7.17 (m, 6H), 7.17-7.11 (m, 1H), 6.94-6.91 (m, 1H), 4.62-4.57 (s, 1H), 4.29-4.23 (m, 1H), 4.09-3.96 (m, 1H), 3.90-3.67 (m, 2H), 3.67-3 .60 (m, 1H), 3.26-3.14 (m, 2H), 3.07-2.98 (m, 1H), 2.89-2.80 (m, 2H), 2.73 -2.61(m, 1H), 1.62-1.53(m, 1H), 1.48-1.22(m, 3H), 0.51-0.41(m, 1H).

Example 6: (R)-N-(3-(1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine -3-yl)phenyl)acetamide

Prepared according to general procedure 4 using (R)-5-bromo-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridine-2(1H) -one (50 mg, 0.098 mmol), (3-acetamidophenyl) boronic acid (26.3 mg, 0.147 mmol), sodium carbonate (20.8 mg, 0.196 mmol), Pd (PPh ₃ ) ₄ (5.7 mg , 0.005 mmol), 1,4-dioxane (1 ml) and water (0.4 ml). The mixture was heated in a microwave oven at 150° C. for 15 minutes to give the title compound (38 mg, 69%). LCMS (Method B): R _T =1.37 min, m/z =564 [M+H] ⁺ . ¹ H-NMR (400 MHz, methanol- d ₄ ): δ 7.72-7.61 (m, 1H), 7.42-7.36 (m, 2H), 7.33-7.22 (m , 7H), 7.20-7.10 (m, 4H), 6.77-6.72 (m, 1H), 7.59 (s, 1H), 4.62 (s, 2H), 4, 30-4.06(m, 2.5H), 3.95-3.88(m, 0.5H), 3.75-3.63(m, 1H), 3.37-3.13(m , 2H), 3.08-2.91 (m, 1H), 2.85-2.71 (m, 1H), 2.64-2.46 (m, 1H), 2.07 (s, 2H ), 1.71-1.39 (m, 4H), 1.35-1.32 (m, 3H), 0.96-0.85 (m, 1H).

Example 7: (R)-3-(1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3- yl)benzamide

Prepared according to general procedure 4 using (R)-5-bromo-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridine-2(1H) -one (50 mg, 0.098 mmol), (3-carbamoylphenyl) boronic acid (24.3 mg, 0.147 mmol), sodium carbonate (20.8 mg, 0.196 mmol), Pd (PPh ₃ ) ₄ (5.7 mg , 0.005 mmol), 1,4-dioxane (1 ml) and water (0.4 ml). The mixture was heated in a microwave oven at 150° C. for 15 minutes to give the title compound (37.5 mg, 69%). LCMS (method B): R _T= 1.27 min, m/z =550 [M+H] ⁺ . ¹ H-NMR (400 MHz, methanol-d ₄ ): δ 7.76-7.67 (m, 3H), 7.33-7.23 (m, 8H), 7.21-7.10 (m , 4H), 6.61 (s, 1H), 4.30-3.90 (m, 4H), 3.76-3.64 (m, 1H), 3.27-3.12 (m, 2H ), 3.08-2.92 (m, 1H), 2.84-2.71 (m, 1H), 2.65-2.47 (m, 1H), 1.72-1.37 (m , 4H), 1.35-1.32 (m, 3H), 1.00-0.83 (m, 2H).

Example 8: (R)-5-(furan-2-yl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)- he

Prepared according to general procedure 4 using (R)-5-bromo-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridine-2(1H)- he (20 mg, 0.039 mmol), furan-2-ylboronic acid (4.4 mg, 0.039 mmol), sodium carbonate (8.3 mg, 0.079 mmol), Pd(PPh ₃ ) ₄ (2.3 mg, 0.002 mmol), 1,4-dioxane (0.7 ml) and water (0.3 ml). The mixture was heated in a microwave oven at 150° C. for 15 minutes to give the title compound (4.9 mg, 25%). LCMS (Method B): R _T =1.33 min, m/z =497 [M+H] ⁺ . ¹ H-NMR (400 MHz, methanol- d ₄ ): δ 8.00-7.93 (m, 1H), 7.45-7.15 (m, 11H), 6.49 (s, 1H), 6.30-6.27 (m, 1H), 5.66-5.64 (m, 1H), 4.61 (br s, 1H), 4.30-4.12 (m, 2H), 4.10-3.90(m, 2H), 3.74-3.63(m, 1H), 3.07-2.91(m, 1H), 2.84-2.71(m, 1H ), 2.64-2.47 (m, 1H), 1.69-1.41 (m, 4H), 1.36-1.32 (m, 3H), 0.97-0.87 (m , 1H).

Example 9: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(1-methyl-1-pyrazol-5-yl)-4-phenylpyridine -2(1H)-he

Prepared according to general procedure 4 using (R)-5-bromo-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridine-2(1H)- he (20 mg, 0.039 mmol), (1-methyl-1H-pyrazol-5-yl)boric acid (4.9 mg, 0.039 mmol), sodium carbonate (8.3 mg, 0.079 mmol), Pd (PPh ₃ ) ₄ (2.3 mg, 0.002 mmol), 1,4-dioxane (0.7 ml) and water (0.3 ml). The mixture was heated in a microwave oven at 150° C. for 15 minutes to give the title compound (3.7 mg, 18%). LCMS (method B): R _T =1.13 min, m/z =511 [M+H] ⁺ . ¹ H-NMR (400 MHz, methanol- d ₄ ): δ 7.77-7.69 (m, 1H), 7.40-7.16 (m, 11H), 6.66 (s, 1H), 6.30 (t, 1H), 4.51 (s, 1H), 4.19-3.77 (m, 3H), 3.66-3.50 (m, 1H), 3.27-3, 06 (m, 5H), 3.01-2.81 (m, 1H), 2.77-2.59 (m, 1H), 2.56-2.36 (m, 1H), 1.63- 0.97 (m, 6H), 0.89-0.71 (s, 1H).

Example 10: (R)-4-chloro-1-((4-hydroxy-1(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-phenylpyridin-2(1H)-one

Prepared according to general procedure 4 using intermediate 2 (41 mg, 0.083 mmol), phenylboronic acid (9 mg, 0.075 mmol), sodium carbonate (11 mg, 0.183 mmol), Pd(PPh ₃ ) ₄ (1, 1 mg, 0.004 mmol), 1,4-dioxane (0.7 ml) and water (0.3 ml). The mixture was heated in a microwave oven at 80° C. for 1 hour. The crude product was purified by preparative HPLC to give the title compound (4.7 mg, 12%). LCMS (Method B): R _T =1.30 min, m/z =465 [M+H] ⁺ . ¹ H-NMR (300 MHz, methanol- d ₄ ): δ 7.71-7.58 (m, 1H), 7.50-7.12 (m, 10H), 6.79-6.72 (s , 1H), 4.29-3.80 (m, 4H), 3.74-3.60 (m, 1H), 3.25-3.13 (m, 1H), 3.09-2.68 (m, 2H), 2.67-2.43 (m, 1H), 1.70-1.36 (m, 4H), 1.35-1.29 (m, 3H), 0.94-0 .81 (m, 1H).

Example 11: (R)-4-(dimethylamino)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-phenylpyridin-2(1H)-one

A mixture of the compound of Example 10 (46 mg, 0.10 mmol) and dimethylamine (2M in THF, 1.1 ml, 2.2 mmol) in DMF (1.5 ml) was heated under reflux for 72 hours. The mixture was cooled and partitioned between EtOAc and 50% brine. The organics were washed with 50% brine (x 4) and the aqueous layer was extracted with EtOAc (x 3). The combined organic extracts were dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (GraceResolv, 5-100% EtOAc in cyclohexane; then 0-20% MeOH in EtOAc) to give the title compound (6.4 mg, 13%). LCMS (Method B): R _T =1.25 min, m/z =474 [M+H] ⁺ . ¹ H-NMR (400 MHz, methanol- d ₄ ): δ 7.46-7.38 (m, 4H), 7.37-7.21 (m, 6H), 7.19-7.09 (m , 1H), 5.84 (s, 1H), 4.62 (br s, 1H), 4.28-4.11 (m, 2H), 3.98-3.71 (m, 2H), 3.69-3.61 (m, 1H), 3.05-2.89 (m, 1H), 2.83-2.69 (m, 1H), 2.66-2.62 (m, 6H ), 2.62-2.46 (m, 1H), 1.63-1.36 (m, 4H), 1.34-1.30 (m, 3H), 0.92-0.79 (m , 1H).

Example 12: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-phenyl-4-(prop-1-en-2-yl)pyridin- 2(1H)-on

Prepared according to general procedure 4 using the compound of Example 10 (46.5 mg, 0.100 mmol), prop-1-en-2-ylboronic acid (10.6 μl, 0.110 mmol), sodium carbonate (13.2 mg, 0.220 mmol), Pd(PPh ₃ ) ₄ (2.6 mg, 0.010 mmol), 1,4-dioxane (0.7 ml) and water (0.3 ml). The mixture was heated in a microwave oven at 150° C. for 15 minutes. The crude product was purified by preparative HPLC to give the title compound (14.7 mg, 31%). LCMS (method B): R _T =1.36 min, m/z =471 [M+H] ⁺ . ¹ H-NMR (400 MHz, methanol- d ₄ ): δ 7.57-7.47 (m, 1H), 7.44-7.22 (m, 9H), 7.19-7.13 (m , 1H), 6.47 (s, 1H), 5.17-5.14 (m, 1H), 5.12-5.10 (m, 1H), 4.28-4.13 (m, 2H ), 4.06-3.85 (m, 2H), 3.74-3.62 (m, 1H), 3.28-3.21 (m, 1H), 3.06-2.89 (m , 1H), 2.89-2.70 (m, 1H), 2.63-2.46 (m, 1H), 1.68-1.55 (m, 4H), 1.53-1.27 (m, 6H), 0.94-0.85 (m, 1H).

Example 13: (R)-ethyl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate

Prepared according to general procedure 1 using epoxide 2 (273 mg, 1.05 mmol), ethyl 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (256 mg, 1.05 mmol) and DIPEA (0.28 ml, 1.58 mmol) in DMF (2 ml). The reaction mixture was stirred at 80°C for 64 hours. The crude product was purified by flash chromatography (GraceResolv, 5-100% EtOAc in cyclohexane) to give the title compound (230 mg, 44%). LCMS (method B): R _T =1.29 min, m/z =503 [M+H] ⁺ . ¹ H-NMR (400 MHz, methanol- d ₄ , the compound is presented as two conformational isomers A:B in a ratio of 2:3): δ 8.41 (s, 0.4H, conformational isomer A), 8.36 ( s, 0.6H, conformational isomer B), 7.46-7.16 (m, 10H), 6.42 (s, 1H), 4.30-3.89 (m, 5H), 3.76- 3.62 (m, 1H), 3.30-3.17 (m, 2H), 3.10-2.46 (m, 3H), 1.71-1.28 (m, 6H), 1, 03 (t, 3H), 0.97-0.83 (m, 1H).

Example 14: (S)-4-(2-fluorophenyl)-1-((4-hydroxy-1-(2-methyl-1,2,3,4-tetrahydronaphthalene-2-carbonyl)piperidin-4-yl) methyl)-N-isopropyl-N-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate

Prepared according to general procedure 3 using 4-(2-fluorophenyl)-1-((4-hydroxypiperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-1,6-dihydropyridine- 3-carboxamide (20 mg, 0.05 mmol), DCM (2 ml), DIPEA (0.026 ml, 0.149 mmol), (S)-2-methyl-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1 1.4 mg, 0.060 mmol) and HATU (24.6 mg, 0.065 mmol). The crude product was chromatographed (GraceResolv, 4 g, 10-100% EtOAc in cyclohexane; then 0-10% MeOH in EtOAc) to give the title compound (27 mg, 94%). LCMS (method B): R _T =1.30 min, m/z =574 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 7.77 (s, 1H), 7.46 (m, 1H), 7.35 (m, 1H), 7.28 (m, 2H) , 7.05 (m, 4H), 6.45 (s, 1H), 5.00 (s, 1H), 4.43 (br s, 1H), 4.01 (m, 4H), 3, 20 (m, 3H), 2.75 (m, 1H), 2.67 (m, 3H), 2.58 (m, 1H), 2.11 (m, 1H), 1.82 (m, 1H ), 1.49 (m, 4H), 1.26 (m, 4H), 0.94 (br s, 6H).

Example 15: (S)-1-((1-(3-cyclobutyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-phenyl-5-(piperidine-1-carbonyl)pyridine-2 (1H)-he

Step 1: Ethyl 1-((1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate : Prepared according to general procedure 1, using ethyl 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (1 g, 4.1 1 mmol), epoxide 1 (1.05 g, 4.93 mmol), DMF (20 ml) and pyridine (0.83 ml, 10.3 mmol). The mixture was stirred at 90°C for 16 hours. The crude product was purified by flash chromatography (GraceResolv (40 g), 10-100% EtOAc in cyclohexane) to give the title compound (640 mg, 34%). LCMS (method B): R _T= 1.38 min, m/z =357 [M+H-Boc] ⁺ .

Stage 2: 1-((1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid : Ethyl-1-( (1-(tert-Butoxycarbonyl)-4-hydroxypiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (120 mg, 0.26 mmol) was dissolved in ethanol ( 1 ml) and sodium hydroxide solution (2M in water, 1 ml, 2.00 mmol). The mixture was stirred at 50°C for 16 hours. The solution was concentrated and 2M HCl (aq) was added until the pH reached approximately 4. The mixture was extracted with EtOAc (x 3). The combined organic extracts were washed with brine, then dried over MgSO ₄ and concentrated to give the title compound (91 mg, 81%) which was used without further purification. LCMS (method B): R _T= 1.12 min, m/z =329 [M+H-Boc] ⁺ .

Steps 3 and 4: 1-((4-hydroxypiperidin-4-yl)methyl)-4-genyl-5-(piperidine-1-carbonyl)pyridin-2(1H)-one : Prepared according to general procedure 3, using 1-((1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (70 mg, 0.16 mmol), piperidine (0.021 ml, 0.21 mmol), DIPEA (0.086 ml, 0.49 mmol), HATU (68 mg, 0.18 mmol) and DMF (1.5 ml), to give t-butyl -4-hydroxy-4-((2-oxo-4-phenyl-5-(piperidine-1-carbonyl)pyridin-1(2H)-yl)methyl)piperidine-1-carboxylate. The crude product was dissolved in DCM (1 ml) and TFA (1 ml) and stirred at room temperature for 1 hour. The solution was concentrated and the residue was dissolved in MeOH and transferred to an SCX-2 cartridge (2 g). The column was washed with MeOH, then eluted with 2M NH ₃ in MeOH and the ammonia fractions were concentrated to give the title compound (61 mg, 94%). LCMS (method B): R _T= 0.74 min, m/z =396 [M+H] ⁺ .

Step 5: (R,S)-1-((1-(3-cyclobutyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-phenyl-5-(piperidine-1-carbonyl)pyridine -2(1H)-one : Prepared according to general procedure 3 using 1-((4-hydroxypiperidin-4-yl)methyl)-4-phenyl-5-(piperidine-1-carbonyl)pyridine-2( 1H)-one (17 mg, 0.043 mmol), DCM (0.5 ml), DIPEA (0.019 ml, 0.107 mmol), (S)-3-cyclobutyl-2-methylpropanoic acid (commercial) (7.3 mg, 0.052 mmol) and HATU (21.2 mg, 0.056 mmol). The crude product was purified by flash chromatography (GraceResolv, 4 g, 10-100% EtOAc in cyclohexane; then 0-10% MeOH in EtOAc) to give the title compound (9 mg, 40%). LCMS (method B): R _T =1.32 min, m/z =520 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 7.73 (m, 1H), 7.40 (m, 5H), 6.45 (s, 1H), 4.99 (s, 1H) , 4.02 (m, 3H), 3.71 (m, 1H), 3.45 (m, 1H), 3.28 (m, 1H), 3.10 (m, 1H), 2.96 ( m, 2H), 2.70 (m, 1H), 2.46 (m, 1H), 2.18 (m, 1H), 1.95 (m, 2H), 1.76 (m, 3H), 1.24-1.64 (m, 12H), 0.94 (m, 3H), 0.63 (m, 1H).

Example 16: (R)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(1-methyl-1H-indazol-7-yl)pyrimidin-4( 3 H )-he

Stage 1: (R)-6-chloro-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one:

Prepared according to general procedure 1 using 6-chloropyrimidin-4(3H)-one (0.34 g, 2.60 mmol), epoxide 2 (0.676 g, 2.60 mmol), DMF (7 ml) and DIPEA (0.682 ml, 3.91 mmol). The reaction mixture was heated at 80°C for 21 hours. The crude product was purified by flash chromatography (GraceResolv, 0-100% EtOAc in cyclohexane) to give the title compound (0.372 g, 37%). LCMS (method B): R _T= 0.99 min, m/z =390 [M+H] ⁺ .

Step 2: (R)-3-((4-hydroxy-1-(3-genylbutanoyl)piperidin-4-yl)methyl)-6-(1-methyl-1H-indazol-7-yl)pyrimidin-4( 3H)-one : Prepared according to general procedure 4 using (R)-6-chloro-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H)-one (40 mg, 0.10 mmol), (1-methyl-1H-indazol-7-yl)boronic acid (18 mg, 0.10 mmol), 1,4-dioxane (1.5 ml) , water (0.3 ml), sodium carbonate (21.8 mg, 0.21 mmol) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (8.4 mg, 10.3 µmol). The mixture was heated in a microwave oven at 140° C. for 15 minutes. The crude product was purified by flash chromatography (Biotage, 1 g, KP-NH, 10-100% EtOAc in cyclohexane; then 0-15% MeOH in EtOAc) to give the title compound (21 mg, 42%). LCMS (Method B): R _T 1.05 min, m/z =486 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.43 (d, 1H), 8.17 (s, 1H), 7.88 (d, 1H), 7.43 (d, 1H) , 7.22 (m, 6H), 6.70 (m, 1H), 5.04 (m, 1H), 4.00 (m, 2H), 3.90 (m, 4H), 3.69 ( m, 1H), 3.19 (m, 2H), 2.90 (m, 1H), 2.60 (m, 2H), 1.40 (m, 3H), 1.21 (m, 4H).

Example 17: (R)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4(3H)-one

Prepared according to general procedure 4 using (R)-6-chloro-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one (50 mg, 0.13 mmol), (2-methoxyphenyl)boronic acid (29 mg, 0.19 mmol), 1,4-dioxane (1.5 ml), water (0.5 ml), sodium carbonate (27 mg , 0.26 mmol) and Pd(PPh ₃ ) ₄ (7.4 mg, 6.4 µmol). The mixture was heated in a microwave oven at 140° C. for 15 minutes. The crude product was purified by flash chromatography (Biotage KP-NH, 0-100% EtOAc in cyclohexane; then 0-15% MeOH in EtOAc) to give the title compound (14 mg, 0.030 mmol). LCMS (method B): R _T =1.15 min, m/z =462 [M+H] ⁺ . ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 8.35 (d, 1H), 7.96 (d, 1H), 7.45 (t, 1H), 7.25 (m, 4H) , 7.17 (d, 2H), 7.06 (t, 1H), 7.01 (s, 1H), 4.99 (m, 1H), 3.80-4.05 (m, 6H), 3.72 (m, 1H), 3.23 (m, 2H), 2.92 (m, 1H), 2.59 (m, 2H), 1.25-1.55 (m, 4H), 1 .20 (d, 3H).

Example 18: (R)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-2-methyl-6-phenylpyrimidin-4(3H)-one

Prepared according to general procedure 1 using epoxide 2 (75 mg, 0.29 mmol), DMF (2 mL), cesium carbonate (188 mg, 0.58 mmol) and 2-methyl-6-phenylpyrimidine-4(3H )-one (53.9 mg, 0.29 mmol). The mixture was heated at 80° C. for 16 hours to give the title compound (65 mg, 50%). LCMS (method B): R _T =1.41, m/z= 446 [M+H] ⁺ . ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 8.08 (m, 2H), 7.49 (m, 3H), 7.25 (m, 4H), 7.14 (m, 1H) , 6.85(m, 1H), 5.05(m, 1H), 4.05(m, 3H), 3.66(m, 1H), 3.17(m, 2H), 2.82( m, 1H), 2.73 (m, 3H), 2.57 (m, 2H), 1.44 (m, 4H), 1.20 (d, 3H).

Example 19: (R)-2-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5,6-diphenylpyridazin-3(2H)-one

Prepared according to general procedure 1 using epoxide 2 (50 mg, 0.19 mmol), DMF (1 ml), 5,6-diphenylpyridazin-3(2H)-one (47.9 mg, 0.19 mmol) and DIPEA (0.051 ml, 0.29 mmol). The mixture was heated at 80° C. for 16 hours to give the title compound (22 mg, 22%). LCMS (method B): R _T =1.39, m/z =508 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 7.29 (m, 10H), 7.17 (m, 5H), 6.99 (m, 1H), 4.87 (d, 1H) , 4.16 (m, 3H), 3.71 (m, 1H), 3.18 (m, 2H), 2.83 (m, 1H), 2.57 (m, 2H), 1.53 ( m, 1H), 1.48 (m, 2H), 1.19 (m, 4H).

Example 20: (R)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(naphthalen-1-yl)pyrimidin-4(3H)-one

Prepared according to general procedure 4 using (R)-6-chloro-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one (35 mg, 0.09 mmol), naphthalene-1-ylboronic acid (23 mg, 0.13 mmol), 1,4-dioxane (1.5 ml), water (0.3 ml), sodium carbonate (19 mg, 0.18 mmol) and a complex of 1,1'-bis(diphenylphosphino)ferrocenepalladium (II) dichloride and toluene (7.4 mg, 9.0 μmol). The mixture was heated in a microwave oven at 140° C. for 30 minutes to give the title compound (13 mg, 30%). LCMS (method B): R _T 1.24 min, m/z= 482 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.44 (d, 1H), 8.17 (d, 1H), 8.04 (m, 2H), 7.58 (m, 4H) , 7.28 (m, 4H), 7.17 (m, 1H), 6.64 (s, 1H), 5.05 (d, 1H), 4.00 (m, 3H), 3.70 ( m, 1H), 3.20 (m, 2H), 2.94 (m, 1H), 2.62 (m, 2H), 1.45 (m, 3H), 1.23 (m, 4H).

Example 21: (R)-6-(3-(1,3-dioxolan-2-yl)phenyl)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidine -4(3H)-he

Prepared according to general procedure 4 using sodium carbonate (21.8 mg, 0.21 mmol), (R)-6-chloro-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidine-4- yl)methyl)pyrimidin-4(3H)-one (40 mg, 0.10 mmol), 1,4-dioxane (1.5 ml), water (0.5 ml), 2-(3-(1, 3-dioxolan-2-yl)phenyl)-1,3,2-dioxaborolane (33.9 mg, 0.15 mmol) and Pd(PPh ₃ ) ₄ (5.9 mg, 5.1 μmol). The mixture was heated in a microwave oven at 140° C. for 15 minutes to give the title compound (17 mg, 33%). LCMS (method B): R _T =1.26 min, m/z =504 [M+H] ⁺ . ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 8.40 (d, 1H), 8.15 (s, 1H), 8.08 (d, 1H), 7.54 (m, 2H) , 7.26 (m, 4H), 7.17 (m, 1H), 7.00 (m, 1H), 5.81 (s, 1H), 4.99 (d, 1H), 4.07 ( m, 6H), 3.64 (m, 1H), 3.18 (m, 2H), 2.87 (m, 1H), 2.59 (m, 1H), 2.52 (m, 2H), 1.38 (m, 3H), 1.21 (m, 4H).

Example 22: (R)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(thiophen-3-yl)pyrimidin-4(3H)-one

Prepared according to general procedure 4 using sodium carbonate (21.8 mg, 0.21 mmol), (R)-6-chloro-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidine-4- yl)methyl)pyrimidin-4(3H)-one (40 mg, 0.10 mmol), 1,4-dioxane (1.5 ml), water (0.5 ml), thiophen-3-ylboronic acid (19 .7 mg, 0.15 mmol) and a complex of 1,1'-bis (diphenylphosphino) ferrocene palladium (II) dichloride with toluene (8.4 mg, 10.3 μmol). The mixture was heated in a microwave oven at 140° C. for 15 minutes to give the title compound (24 mg, 54%). LCMS (Method B): R _T =1.08 min, m/z =438 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.32 (d, 1H), 8.28 (d, 1H), 7.71 (d, 1H), 7.68 (d, 1H) , 7.25(m, 4H), 7.17(m, 1H), 6.88(m, 1H), 4.99(m, 1H), 3.85-4.04(m, 3H), 3.86 (m, 1H), 3.16 (m, 2H), 2.88 (m, 1H), 2.59 (m, 2H), 1.40 (m, 3H), 1.20 (m , 4H).

Example 23 4-(2-fluorophenyl)-1-((4-hydroxy-1-(1-methylcyclopentan-1-carbonyl)piperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo -1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using amine 4 (20 mg, 0.050 mmol), DCM (2 ml), DIPEA (0.026 ml, 0.15 mmol), HATU (24.6 mg, 0.065 mmol) and 1- methylcyclopentanecarboxylic acid (7.7 mg, 0.060 mmol) to give the title compound (25 mg, 98%). LCMS (method B): R _T= 1.16 min, m/z =512 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.76 (s, 1H), 7.47 (m, 1H), 7.36 (m, 1H), 7.26 (m, 2H) , 6.44 (s, 1H), 4.98 (s, 1H), 4.43-3.62 (m, 3H), 3.91 (br s, 2H), 3.16 (m, 2H ), 2.60 (m, 2H), 2.06 (m, 2H), 1.50 (m, 9H) 1.20 (m, 2H), 1.16 (s, 3H), 0.94 ( m, 6H).

Example 24 3-((1-(1-ethylcyclohexane-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one

Prepared according to general procedure 3 using 6-(2-fluorophenyl)-3-((4-hydroxypiperidin-4-yl)methyl)pyrimidin-4(3H)-one hydrochloride (40 mg, 0.12 mmol), DCM (2 ml), DIPEA (0.062 ml, 0.35 mmol), 1-ethylcyclohexanecarboxylic acid (22.0 mg, 0.14 mmol) and HATU (58.2 mg, 0.15 mmol) to give title compound (11 mg, 21%). LCMS (method B): R _T =1.30 min, m/z =442 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.44 (s, 1H), 8.02 (t, 1H), 7.55 (m, 1H), 7.36 (m, 2H) , 6.81 (s, 1H), 5.05 (s, 1H), 3.99 (m, 4H), 3.19 (m, 2H), 2.05 (m, 2H), 1.19- 1.56 (m, 14H), 0.73 (m, 3H).

Example 25: 3-((1-(2-(cyclohexylmethyl)-3-methylbutanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3 H )-he

Prepared according to general procedure 12 using (R,S)-2-(cyclohexylmethyl)-3-methylbutanoic acid (8.9 mg, 0.045 mmol), HATU (19 mg, 0.050 mmol), DIPEA (16 µl, 0.091 mmol) and amine 5 (15 mg, 0.045 mmol) in DMF (0.6 ml) to give the title compound (4.2 mg, 18%). LCMS (Method B): R _T= 2.14 min, m/z =512 [M+H] ⁺ .

Example 26: ( R )-6-(furan-2-yl)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4(3 H )-he

Prepared according to general procedure 4 using sodium carbonate (22.8 mg, 0.21 mmol), (R)-6-chloro-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidine-4 -yl)methyl)pyrimidin-4(3H)-one (40 mg, 0.10 mmol), 1,4-dioxane (1.5 ml), water (0.3 ml), furan-2-ylboronic acid ( 17.2 mg, 0.15 mmol) and a complex of 1,1'-bis(diphenylphosphino)ferrocenepalladium (II) dichloride with toluene (8.44 mg, 10, µmol). The mixture was heated in a microwave oven at 140° C. for 15 minutes to give the title compound (23 mg, 53%). LCMS (method B): R _T =1.01 min, m/z =422 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.31 (d, 1H), 7.93 (d, 1H), 7.26 (m, 4H), 7.19 (m, 2H) , 6.70 (d, 1H), 6.57 (d, 1H), 4.98 (m, 1H), 3.85-4.04 (m, 3H), 3.64 (m, 1H), 3.17 (m, 2H), 2.88 (m, 1H), 2.59 (m, 2H), 1.30 (m, 3H), 1.20 (m, 4H).

Example 27: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one

Prepared according to general procedure 1 using epoxide 2 (60 mg, 0.23 mmol), DMF (2 mL), cesium carbonate (151 mg, 0.46 mmol) and 4-phenylpyridin-2(1H)-one ( 39.6 mg, 0.23 mmol). The reaction mixture was heated at 80° C. for 24 hours to give the title compound (18 mg, 18%). LCMS (method B): R _T =1.32, m/z =431 [M+H] ⁺ . ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 7.72 (m, 3H), 7.50 (m, 3H), 7.25 (m, 4H), 7.17 (m, 1H) , 6.70 (m, 1H), 6.62 (m, 1H), 5.03 (m, 1H), 3.92 (m, 3H), 3.65 (m, 1H), 3.15 ( m, 2H), 2.90 (m, 1H), 2.60 (m, 2H), 1.40 (m, 4H), 1.20 (d, 3H).

Example 28: (R)-6-(cyclohex-1-en-1-yl)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4(3H) -he

Prepared according to general procedure 4 using sodium carbonate (28 mg, 0.27 mmol), (R)-6-chloro-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl) methyl)pyrimidin-4(3H)-one (35 mg, 0.090 mmol), 1,4-dioxane (1.5 ml), water (0.3 ml), cyclohex-1-en-1-ylboronic acid (28 .0 mg, 0.24 mmol) and a complex of 1,1'-bis(diphenylphosphino)ferrocenepalladium (II) dichloride and toluene (12 mg, 13.5 µmol). The mixture was heated in a microwave oven at 140° C. for 30 minutes to give the title compound (13 mg, 33%). LCMS (method B): R _T =1.22 min, m/z =436 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.20 (d, 1H), 7.25 (m, 4H), 7.17 (m, 1H), 7.07 (m, 1H) , 6.24 (s, 1H), 4.93 (m, 1H), 4.02 (m, 1H), 3.86 (m, 1H), 3.81 (m, 1H), 3.64 ( m, 1H), 3.17 (m, 3H), 2.98 (m, 1H), 2.58 (m, 1H), 2.24 (m, 4H), 1.69 (m, 2H), 1.59 (m, 2H), 1.27 (m, 3H), 1.19 (m, 4H).

Example 29: (R)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(prop-1-en-2-yl)pyrimidin-4(3H) -he

Step 1 : 3-((4-hydroxypiperidin-4-yl)methyl)-6-(prop-1-en-2-yl)pyrimidin-4(3H)-one: tert-butyl-4-((4- chloro-6-oxopyrimidin-1(6H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate (see preparation of amine 1) (100 mg, 0.29 mmol) and 4,4,5,5-tetramethyl- 2-(prop-1)-en-2-yl)-1,3,2-dioxaborolane (73 mg, 0.44 mmol) was dissolved in 1,4-dioxane (2 ml) and sodium carbonate solution (62 mg, 0.58 mmol) in water (1 ml). The mixture was purged with nitrogen and Pd(PPh ₃ ) ₄ (16.8 mg, 0.015 mmol) was added. The mixture was heated in a microwave oven at 150°C for 15 minutes, then cooled and diluted with water. The mixture was extracted with ethyl acetate (x 2) and the combined organic extracts were dried over MgSO ₄ and concentrated. The residue was triturated with diethyl ether to give an off-white solid. This was dissolved in DCM (1 ml) and TFA (1 ml) and stirred for 15 minutes, then concentrated. The residue was dissolved in MeOH and loaded onto a Biotage SCX-2 cartridge (2 g). The column was washed with MeOH, then eluted with 2M NH ₃ in MeOH to give the title compound (61 mg, 84%). LCMS (method B): R _T= 1.21 min, m/z =250 [M+H] ⁺ .

Stage 2: (R)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(prop-1-en-2-yl)pyrimidin-4(3H) -one : 3-((4-hydroxypiperidin-4-yl)methyl)-6-(prop-1-en-2-yl)pyrimidin-4(3H)-one (60 mg, 0.24 mmol) and ( R)-3-phenylbutanoic acid (39.5 mg, 0.24 mmol) was dissolved in DCM (2 ml) and DIPEA (0.05 ml, 0.29 mmol) was added followed by HATU (101 mg, 0.27 mmol). The mixture was stirred at room temperature for 90 minutes, then purified by flash chromatography (GraceResolv, 12 g, 25-100% EtOAc in cyclohexane; then 0-15% MeOH in EtOAc) to give the title compound (69 mg, 73 %). LCMS (method B): R _T =1.19 min, m/z= 396 [M+H] ⁺ , NMR (300 MHz, DMSO- d ₆ ): δ 8.24 (d, 1H), 7.25 (m, 4H), 7.17 (m, 1H), 6.41 (s, 1H), 6.17 (s, 1H), 5.42 (s, 1H), 4.95 (s, 1H) , 4.00 (m, 1H), 3.89 (d, 1H), 3.82 (m, 1H), 3.63 (m, 1H), 3.15 (m, 2H), 2.87 ( m, 1H), 2.60 (m, 2H), 2.02 (s, 3H), 1.25-1.55 (m, 4H), 1.20 (d, 3H).

Example 30: (R)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(2-(trifluoromethoxy)phenyl)pyrimidin-4(3H)-one

Prepared according to general procedure 4 using sodium carbonate (22 mg, 0.21 mmol), (R)-6-chloro-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl) methyl)pyrimidin-4(3H)-one (40mg, 0.10mmol), 1,4-dioxane (1.5mL), water (0.3mL), (2-(trifluoromethoxy)phenyl)boronic acid (32 mg, 0.15 mmol) and a complex of 1,1'-bis(diphenylphosphino)ferrocenepalladium (II) dichloride and toluene (8.4 mg, 10.3 µmol). The mixture was heated in a microwave oven at 140° C. for 30 minutes to give the title compound (25 mg, 47%). LCMS (method B): R _T =1.24 min, m/z =516 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.41 (d, 1H), 7.88 (d, 1H), 7.62 (m, 1H), 7.52 (m, 2H) , 7.27 (m, 4H), 7.18 (m, 1H), 6.70 (m, 1H), 5.01 (m, 1H), 3.96 (m, 3H), 3.67 ( m, 1H), 3.20 (m, 2H), 2.88 (m, 1H), 2.56 (m, 2H), 1.32 (m, 3H), 1.19 (m, 4H) .

Example 31: 3-(((1R,5S)-3-((R)-3-cyclohexyl-2-methylpropanoyl)-8-hydroxy-3-azabicyclo[3.2.1]octan-8-yl)methyl)- 6-(2-fluorophenyl)pyrimidin-4(3H)-one

Step 1: (1R,5S)-tert-butyl-8-((4-(2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)methyl)-8-hydroxy-3-azabicyclo[3.2.1 ]octane-3-carboxylate : Prepared according to general procedure 1, using 6-(2-fluorophenyl)pyrimidin-4(3H)-one (0.1-16 g, 0.608 mmol), epoxide 5 (0.16 g , 0.67 mmol) and DIPEA (0.159 ml, 0.912 mmol) in DMF (0.9 ml) to give the title compound (0.15 g, 58%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.15 (br s, 1H), 8.06 (td, 1H), 7.49-7.41 (m, 1H), 7.30- 7.24 (m, 1H), 7.18 (ddd, 1H), 7.13 (s, 1H), 4.51 (s, 1H), 4.18-4.03 (m, 2H), 3 .75 (br dd, 1H), 3.60 (br dd, 1H), 3.41 (dd, 2H), 1.89-1.67 (m, 5H), 1.62 (s, 1H ), 1.46 (s, 9H).

Step 2: 6-(2-fluorophenyl)-3-(((1R,5S)-8-hydroxy-3-azabicyclo[3.2.1]octan-8-yl)methyl)pyrimidin-4(3H)-one hydrochloride : Prepared according to general procedure 9 using (1R,5S)-tert-butyl-8-((4-(2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)methyl)-8-hydroxy -3-azabicyclo[3.2.1]octane-3-carboxylate (0.150 g, 0.349 mmol) and hydrogen chloride (4M in 1,4-dioxane, 1.2 ml, 4.8 mmol) in DCM (1.7 ml ) to give the title compound (0.12 g, 94%) which was used without further purification. LCMS (method B): R _T =0.70 min, m/z =330 [M+H] ⁺ . ¹ H-NMR (400 MHz, methanol- d ₄ ): δ 8.66 (br s, 1H), 8.04 (td, 1H), 7.62-7.54 (m, 1H), 7, 38 (dd, 1H), 7.36-7.27 (m, 1H), 7.00 (s, 1H), 4.25 (s, 2H), 3.63 (d, 2H), 3.04 (dd, 2H), 2.46-2.35 (m, 2H), 2.12 (br s, 2H), 1.92-1.83 (m, 2H).

Step 3: 3-(((1R,5S)-3-((R)-3-cyclohexyl-2-methylpropanoyl)-8-hydroxy-3-azabicyclo[3.2.1]octan-8-yl)methyl)- 6-(2-fluorophenyl)pyrimidin-4(3H)-one : Prepared according to general procedure 5 using 6-(2-fluorophenyl)-3-(((1R,5S)-8-hydroxy-3- azabicyclo[3.2.1]octan-8-yl)methyl)pyrimidin-4(3H)-one hydrochloride (0.030g, 0.082mmol), (R)-3-cyclohexyl-2-methylpropanoic acid (acid 1) (0.021g , 0.12 mmol), HBTU (0.047 g, 0.12 mmol) and DIPEA (0.057 ml, 0.328 mmol) in DCM (0.8 ml) to give the title compound (34 mg, 61%). LCMS (Method B): R _T =1.57 min, m/z =482 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ , the compound is presented as two conformational isomers in a ratio of 1:1): δ 8.16-8.12 (m, 1H), 8.07 (br. td, 1H), 7.50-7.43 (m, 1H), 7.29 (br dd, 1H), 7.22-7.17 (m, 1H), 7.16 (s, 1H), 4.77 ( s, 0.5H), 4.70 (s, 0.5H), 4.29-4.18 (m, 1H), 4.15 (cd, 2H), 3.75 (dd, 1H), 3 .54 (br. td, 1H), 3.27 (br. dd, 1H), 2.84 (sq., 1H), 1.94-1.77 (m, 4H), 1.77-1.60 (m, 7H), 1.29-1.15 (m, 6H), 1.14 (d, 1.5H), 1.04 (d, 1.5H), 0.93-0.79 (m , 2H).

Example 32: (R)-6-(2-fluorophenyl)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one

Step 1: 4-(2-fluorophenyl)-6-methoxypyrimidine : 4,6-dichloropyrimidine (5 g, 33.6 mmol) and (2-fluorophenyl)boronic acid (4.70 g, 33.6 mmol) were suspended in mixtures of toluene (100 ml) and MeOH (50 ml). Potassium carbonate (4.64, 33.6 mmol) was added and the mixture was degassed by bubbling N ₂ through it. Pd(PPh ₃ ) ₄ (0.97 g, 0.84 mmol) was added and the mixture was heated at 90° C. for 3 hours. The mixture was cooled to room temperature and concentrated. The residue was diluted with water and extracted (EtOAc x 2). The combined organic extracts were washed with brine, dried over MgSO ₄ and concentrated. The residue was chromatographed (GraceResolv (80 g), 0-20% EtOAc in cyclohexane) to give the title compound (ca. 5.5 g) contaminated with 4-chloro-6-(2-fluorophenyl)pyrimidine (ca. 0, 5 g) and 4,6-bis(2-fluorophenyl)pyrimidine (approx. 1.5 g). The product was used without further purification. LCMS (method B): R _T= 1.26 min, m/z =209 [M+H] ⁺ .

Step 2: 6-(2-fluorophenyl)pyrimidin-4(3H)-one : A crude sample of 4-(2-fluorophenyl)-6-methoxypyrimidine prepared as above (7.5 g total weight) hydrochloric acid (2M in water, 30 ml, 60 mmol) and 1,4-dioxane (10 ml). The reaction mixture was heated at 110°C for 5 hours. The mixture was cooled and made basic with aqueous sodium hydroxide. The mixture was extracted with Et2O (x 2) and the organic extracts were discarded. The aqueous layer was acidified with HCl (aq) and the resulting white precipitate was collected by filtration to give the title compound (3.99 g, 62% over two steps). LCMS (method B): R _T= 0.70 min, m/z =191 [M+H] ⁺ .

Step 3: (R)-6-(2-fluorophenyl)-3-((4-hydroxy-1-(3-genylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one : 6-( 2)-fluorophenyl)pyrimidin-4(3H)-one (50 mg, 0.26 mmol) was dissolved in DMF (0.5 ml) and epoxide 2 (68 mg, 0.26 mmol) was added. Added cesium carbonate (128 mg, 0.39 mmol) and the mixture was heated at 80°C for 16 hours. The mixture was cooled to room temperature and diluted with saturated aqueous ammonium chloride, then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (GraceResolv (12 g), 0-100% EtOAc in cyclohexane; then 0-15% MeOH in EtOAc) to give the title compound (58 mg, 49%). LCMS (method B): R _T =1.31 min, m/z =450 [M+H] ⁺ . ¹ H-NMR (300 MHz, CDCl ₃ , compound presented as two conformational isomers A and B in a ratio of 2:3, respectively): δ 8.26 (s, 0.4H, conformational isomer A), 8.18 ( s, 0.6H, conformational isomer B), 8.04 (m, 1H), 7.44 (m, 1H), 7.15-7.40 (m, 7H), 7.06 (s, 1H) , 3.80-4.35(m, 3H), 3.60(m, 1H), 3.26(m, 2H), 2.95-3.15(m, 1H), 2.65(m , 1H), 2.50 (m, 1H), 1.25-1.70 (m, 7.4H), 0.81 (m, 0.6H, conformational isomer B only).

Example 33: (R)-5-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-2-phenylpyrimidin-4(3H)-one

Step 1: tert-Butyl 4-((2-chloro-4-methoxypyrimidin-5-yl)methylene)piperidine-1-carboxylate : Prepared according to general procedure 4 using 5-bromo-2-chloro-4- methoxypyrimidine (259 mg, 1.16 mmol), tert-butyl-4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate (application PCT 2013/027001, dated February 28, 2013) (450 mg, 1.39 mmol), Pd(PPh ₃ ) ₄ (67 mg, 0.058 mmol), sodium carbonate (2M in water, 1.16 ml, 2, 32 mmol) and DME (5.8 ml). The mixture was heated at 80° C. for 24 hours to give the title compound (334 mg, 85%). LCMS (Method B): R _T =1.80 min, m/z =340, 342 [M+H] ⁺ . ¹ H-NMR (300 MHz, CDCl ₃ ): δ 8.10 (s, 1H), 6.07 (s, 1H), 4.04 (s, 3H), 3.52 (t, 2H), 3 .42 (t, 2H), 2.37 (t, 2H), 2.32 (t, 2H), 1.48 (s, 9H).

Steps 2 and 3: (R)-1-(4-((2-chloro-4-methoxypyrimidin-5-yl)methylene)piperidin-1-yl)-3-phenylbutan-1-one : To a stirred solution of tert- butyl 4-((2-chloro-4-methoxypyrimidin-5-yl)methylene)piperidine-1-carboxylate (334 mg, 0.983 mmol) in DCM (5 mL) TFA (4.5 mL, 59.0 mmol) was added ). The resulting mixture was stirred at room temperature for 2 hours, then the reaction mixture was concentrated and the crude product was dried under high vacuum. The TFA salt was purged with nitrogen before adding DCM (9.8 ml) and DIPEA (1.72 ml, 9.84 mmol). After 20 minutes, (R)-3-phenylbutanoic acid (194 mg, 1.18 mmol) in DCM (0.3 ml), EDC (245 mg, 1.28 mmol) and DMAP (12 mg, 0.098 mmol) was added. The resulting solution was stirred at room temperature for 24 hours, then diluted with DCM (25 ml) and washed with saturated aqueous sodium bicarbonate (20 ml). The phases were separated using a Biotage phase separator and the organic layer was concentrated. The residue was purified by flash chromatography (Biotage KP-Sil (25 g), 0-100% EtOAc in PE; then 0-20% MeOH in EtOAc) to give the title compound (195 mg, 51%). LCMS (method B): R _T= 1.67 min, m/z =386.387 [M+H] ⁺ .

Step 4: (R)-1-(4-((4-methoxy-2-genylpyrimidin-5-yl)methylene)piperidin-1-yl)-3-phenylbutan-1-one : Prepared according to general procedure 4 , using (R)-1-(4-((2-chloro-4-methoxypyrimidin-5-yl)methylene)piperidin-1-yl)-3-phenylbutan-1-one (195 mg, 0.505 mmol), phenylboronic acid (74 mg, 0.606 mmol), Pd(PPh ₃ ) ₄ (29 mg, 0.025 mmol), sodium carbonate (2M in water, 0.505 ml, 1.011 mmol) and DME (2.5 ml). The mixture was heated at 75° C. for 24 hours to give the title compound (143 mg, 66%). LCMS (method B): R _T= 1.98 min, m/z =428 [M+H] ⁺ .

Step 5: (3R)-1-(2-(4-methoxy-2-phenylpyrimidin-5-yl)-1-oxa-6-azaspiro[2.5]octan-6-yl)-3-phenylbutan-1-one : (R)-1-(4-((4-Methoxy-2-phenylpyrimidin-5-yl)methylene)piperidin-1-yl)-3-phenylbutan-1-one (136 mg, 0.318 mmol) was dissolved in DCM (3 ml) and m-CPBA (purity 50-55%, 165 mg, 0.477 mmol). The reaction mixture was stirred for 1.5 hours then quenched by adding saturated sodium thiosulfate (10 ml). The mixture was extracted with DCM (2×10 ml) using a Biotage phase separator and the combined organic extracts washed with saturated aqueous sodium bicarbonate (10 ml). The organic layer was concentrated and the crude material was purified by flash chromatography (Biotage KP-Sil (25 g), 0-100% EtOAc in PE) to give the title compound (69 mg, 49%). LCMS (method B): R _T= 1.86 min, m/z =444 [M+H] ⁺ .

Step 6: (R)-1-(4-hydroxy-4-((4-methoxy-2-phenylpyrimidin-5-yl)methyl)piperidin-1-yl)-3-phenylbutan-1-one : Solution (3R )-1-(2-(4-methoxy-2-phenylpyrimidin-5-yl)-1-oxa-6-azaspiro[2.5]octan-6-yl)-3-phenylbutan-1-one ( 130 mg , 0.293 mmol) in MeOH (20 ml) was hydrogenated in H-Cube® (Pd/C CatCart®, 1 ml/min, 20°C, H ₂ , 50 bar then at 40°C, filled with H ₂ , then at 40°C, H ₂ , 50 bar). The resulting solution was concentrated and the residue was purified by flash chromatography (Biotage KP-Sil (10 g), 0-100% EtOAc in PE; then 0-30% MeOH in EtOAc) to give the title compound (69 mg, 52% ), LCMS (method B): R _T= 1.62 min, m/z =446 [M+H] ⁺ .

Step 7: (R)-5-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-2-phenylpyrimidin-4(3H)-one : To a solution of (R)-1- (4-hydroxy-4-((4-methoxy-2-phenylpyrimidin-5-yl)methyl)piperidin-1-yl)-3-phenylbutan-1-one (69 mg, 0.155 mmol) and sodium iodide (139 mg , 0.929 mmol) in MeCN (3 ml) was added chlorotrimethylsilane (119 μl, 0.929 mmol). The mixture was heated at 80°C for 15 hours, then cooled to room temperature and concentrated. The residue was dissolved in saturated aqueous sodium bicarbonate (25 ml) and was extracted with EtOAc (3×25 ml). The combined organic extracts were washed with saturated aqueous sodium thiosulfate (25 ml), saturated sodium bicarbonate (25 ml) and brine (50 ml). The organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography (Biotage KP-Sil, 0-10% MeOH in DCM) to give the title compound (60 mg, 90%) as a colorless solid. LCMS (method B): R _T= 1.15 min, m/z =432 [M+H] ⁺ . ¹ H-NMR (300 MHz, CDCl ₃ , this compound is presented as two conformational isomers A and B, in a 2:3 ratio): δ 13.03 (br s, 1H), 8.1 1-7.99 (m, 2H), 7.91 (d, 1H), 7.54-7.39 (m, 3H), 7.28-7.04 (m, 5H), 4.54 (br s, 1H ), 4.29 (t, 1H), 3.53-3.36 (m, 1H), 3.35-3.09 (m, 2H), 2.99-2.81 (m, 1H), 2.70-2.35 (m, 4H), 1.58-1.20 (m, 6.4H), 0.67 (td, 0.6H, conformational isomer B).

Example 34 3-((4-hydroxy-1-(3-phenylpropanoyl)piperidin-4-yl)methyl)-2-methyl-6-phenylpyrimidin-4(3H)-one

Steps 1 and 2: 1-(3-Phenylpropanoyl)piperidin-4-one : tert-Butyl-4-oxo-piperidine-1-carboxylate (5 g, 25.1 mmol) was dissolved in DCM (25 ml) and TFA (9, 67 ml, 125 mmol). The reaction mixture was stirred at room temperature for 24 hours, then concentrated. The residue was dried under high vacuum to give the amine trifluoroacetate salt. The salt was suspended in dry DCM (125 ml) under nitrogen and DIPEA (13.2 ml, 75.0 mmol) was added dropwise over 5 minutes. 3-Phenylpropanoic acid (4.52 g, 30.1 mmol) was added followed by EDC (6.26 g, 32.6 mmol) and DMAP (0.307 g, 2.510 mmol). The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with DCM (150 ml) and washed with saturated aqueous sodium bicarbonate (250 ml). The phases were separated and the aqueous layer was extracted with DCM (75 ml). The combined organic extracts were washed with 3% HCl (aq.) (150 ml) then brine (150 ml) and concentrated. The residue was purified by flash chromatography (Biotage KP-Sil, 100 g, 0-100% EtOAc in PE) to give the title compound (2.38 g, 41%). ¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.51-6.98 (m, 5H), 3.89 (t, 2H), 3.66 (t, 2H), 3.04 (t, 2H), 2.73 (t, 2H), 2.44 (t, 2H), 2.26 (t, 2H).

Step 3: 3-Phenyl-1-(1-oxa-6-azaspiro[2.5]octan-6-yl)propan-1-one : Prepared according to General Procedure 11 using trimethylsulfonium iodide (4.59 g, 22.5 mmol), dry DMSO (20 ml), sodium hydride (60% dispersion in mineral oil, 0.899 g, 22.5 mmol) and a solution of 1-(3-phenylpropanoyl)piperidin-4-one (2, 08 g, 8.99 mmol) in dry DMSO (10 ml). The crude product was purified by flash chromatography (Biotage KP-Sil, 50 g, 0-60% EtOAc in PE) to give the title compound (1.41 g, 64%). LCMS (Method B): R _T =1.07 min, m/z= 246 [M+H] ⁺ , ¹H-NMR (300 MHz, CDCl ₃ ): δ 7.44-7.13 (m, 5H) , 4.30-4.03 (m, 1H), 3.77-3.58 (m, 1H), 3.46 (td, d, 2H), 3.11-2.93 (m, 2H) , 2.82-2.61(m, 4H), 1.86(m, 1H), 1.77-1.62(m, 1H), 1.54-1.33(m, 2H).

Stage 4: 3-((4-hydroxy-1-(3-phenylpropanoyl)piperidin-4-yl)methyl)-2-methyl-6-phenylpyrimidin-4(3H)-one : 2-methyl-6-phenylpyrimidin- 4(3H)-one (40 mg, 0.22 mmol) was dissolved in DMF (0.43 ml) and 3-phenyl-1-(1-oxa-6-azaspiro[2.5]octan-6-yl)propane was added -1-one (53 mg, 0.22 mmol) followed by cesium carbonate (210 mg, 0.64 mmol). The reaction mixture was heated at 80° C. overnight, then cooled to room temperature and quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate and the organic extract was dried over MgSO ₄ then filtered and concentrated. The residue was purified by flash chromatography (Biotage KP-Sil (10 g), 0-100% EtOAc in cyclohexane; then 0-15% MeOH in EtOAc) to give the title compound (58 mg, 63%). LCMS (method B): R _T =1.36, m/z =432 [M+H] ⁺ . ¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.96 (m, 2H), 7.47 (m, 3H), 7.16-7.30 (m, 5H), 6.81 (s, 1H), 4.82 (s, 1H), 4.49 (d, 1H), 4.01-4.22 (m, 2H), 3.60 (d, 1H), 3.34 (d, 1H ), 2.95 (m, 3H), 2.63 (m, 5H), 1.05-1.60 (m, 4H).

Example 35: (R)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(isobutylamino)pyrimidin-4(3H)-one

(R)-6-chloro-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one (25 mg, 0.064 mmol) was suspended in 1, 4-dioxane (0.5 ml). 2-methylpropan-1-amine (0.064 ml, 0.64 mmol) was added and the mixture was heated in a microwave oven at 150° C. for 15 minutes. The mixture was cooled and diluted with brine, then extracted with DCM. The organic layer was dried (Biotage phase separator), concentrated and the residue was purified by flash chromatography (Biotage KP-Sil (10 g), 0-100% EtOAc in cyclohexane; then 0-15% MeOH in EtOAc) to give the title compound (20 mg, 73%). LCMS (method B): R _T =1.17 min, m/z =427 [M+H] ⁺ . ¹ H-NMR (300 MHz, CDCl ₃ , the compound is presented as two conformational isomers A and B in a ratio of 2:3, respectively): δ 7.72 (s, 0.4H, conformational isomer A), 7.61 ( s, 0.6H, conformational isomer B), 7.22-7.32 (m, 5H), 5.40-5.11 (m, 2H), 5.10-4.20 (m, 1H), 4.35-4.46(m, 1H), 3.47-4.03(m, 3H), 2.80-3.45(m, 4H), 2.67(m, 1H), 2, 52 (m, 1H), 2.08 (s, 1H), 1.88 (m, 1H), 1.18-1.55 (m, 7H), 0.97 (m, 6.4H), 0 .55 (m, 0.6H, conformational isomer B).

Example 36: (R)-1-((1-(3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-phenyl-5-(piperidine-1-carbonyl)pyridine-2 (1H)-he

Prepared according to general procedure 5 using 1-((4-hydroxypiperidin-4-yl)methyl)-4-phenyl-5-(piperidine-1-carbonyl)pyridin-2(1H)-one (40 mg, 0.101 mmol), (R)-3-cyclohexyl-2-methylpropanoic acid (acid 1) (25.8 mg, 0.15 mmol), DIPEA (0.071 ml, 0.405 mmol) and HBTU (57.5 mg, 0.152 mmol) in DCM (2.0 ml) to give the title compound (33.9 mg, 61%). LCMS (Method B): R_T=1.45 min,m/z=548[M+H]⁺.^oneH-NMR (400 MHz, DMSO-d ₆ ): δ 7.73 (s, 1H), 7.49-7.38 (m, 5H), 6.45 (s, 1H), 5.00 (brd, 1H), 4.15-3.91 ( m, 3H), 3.81-3.69 (b.m., 1H), 3.52-3.20 (b.m., 1H), 3.17 (s, 1H), 3.16-2, 81 (m, 4H), 1.69-1.02 (m, 21H), 0.95 (dd, 3H), 0.89-0.74 (m, 2H), 0 .73-0.51 (width m, 1H).

Example 37: (R)-2-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-phenylpyridazin-3(2H)-one

Stage 1: (R)-5-chloro-2-((4-hydroxy-1-(3-genylbutanoyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one : 5-chloropyridazin-3(2H )-one (100 mg, 0.766 mmol) (commercially available) and epoxide 1 (199 mg, 0.766 mmol) were dissolved in DMF (1 ml) and DIPEA (0.201 ml, 1.15 mmol) was added. The solution was heated to 80°C for 16 hours. The mixture was diluted with water and extracted with EtOAc (x 2). The combined organic extracts were washed with water, dried over MgSO ₄ and concentrated. The residue was purified by flash chromatography (GraceResolv, 0-100% EtOAc in cyclohexane; then 0-10% MeOH in EtOAc) to give the title compound (50 mg, 17%). LCMS (method B): R _T= 1.03 min, m/z =390 [M+H] ⁺ .

Step 2: (R)-2-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-phenylpyridazin-3(2H)-one : Prepared according to general procedure 4, using (R)-5-chloro-2-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one (50mg, 0.128mmol), phenylboronic acid (23.5 mg, 0.192 mmol), sodium carbonate (27.2 mg, 0.256 mmol) and tetrakis(triphenylphosphine)palladium (0) (7.41 mg, 6.41 µmol) in 1,4-dioxane (0 .5 ml) and water (0.2 ml). The reaction mixture was heated in a microwave oven at 150° C. for 10 minutes to give the title compound (44.8 mg, 81%). LCMS (method B): R _T =1.19 min, m/z= 432 [M+H] ⁺ . ¹ H-NMR (400 MHz, methanol- d ₄ , the compound is presented as two conformational isomers A and B in a ratio of 3:2, respectively): δ 8.36 (1H, d), 7.78 (2H, ddt) , 7.60-7.53(3H, m), 7.30-7.23(4H, m), 7.21-7.13(2H, m), 4.34-4.05(3H, m), 3.76-3.62(1H, m, br), 3.31-3.14(2H, m), 3.04-2.88(1H, m), 2.82(0 .6H, dd, conformational isomer A), 2.74 (0.4H, dd, conformational isomer B), 2.61 (0.4H, dd, conformational isomer B), 2.50 (0.6H, dd, conformational isomer A), 1.72-1.49 (2H, m), 1.47-1.23 (5H, m), 0.91 (ddd, 1H).

Example 38: (R)-4-(2-cyanophenyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo -1,6-dihydropyridine-3-carboxamide

(2-cyanophenyl)boronic acid (22.6 mg, 0.154 mmol) and (R)-4-chloro-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-N -isopropyl-N-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (50 mg, 0.102 mmol) was dissolved in 1,4-dioxane (1.0 ml) and tribasic potassium phosphate (54.4 mg, 0.256 mmol). The mixture was degassed by bubbling nitrogen through it for 5 minutes. A complex of dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) with dichloromethane (1:1) (4.3 mg, 5.1 µmol) was added and the mixture was heated in a microwave oven for 30 minutes at 130° FROM. The mixture was concentrated and the residue was diluted with water and extracted with DCM. The organic extract was dried (Biotage phase separator), concentrated, and the residue was purified by preparative HPLC to give the title compound (11.4 mg, 20%). LCMS (Method B): R _T =1.14 min, m/z =555 [M+H] ⁺ . ¹ H-NMR (400 MHz, methanol- d ₄ , compound presented as two A:B conformational isomers in a 2:3 ratio): δ 7.83-7.59 (m, 3H), 7.58-7, 46 (m, 1H), 7.37 (d, 1H), 7.27-7.02 (m, 5H), 6.54 (s, 1H), 4.47-4.31 (m, 0, 6H), 4.17-3.78 (m, 3H), 3.67-3.48 (m, 1.4H), 3.15-2.35 (m, 9H), 1.62-0, 68 (m, 13H).

Example 39: (R)-3-((1-(3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one

Prepared according to general procedure 5 using amine 1 (40 mg, 0.1-18 mmol), acid 1 (34 mg, 0.20 mmol), DIPEA (0.092 ml, 0.53 mmol) and HBTU (75 mg, 0.20 mmol) in DCM (2.5 ml) to give the title compound (34.6 mg, 65%). LCMS (Method B): R _T =1.40 min, m/z =456 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO - d ₆ ): δ 8.45 (d, 1H), 8.03 (t, 1H), 7.60-7.52 (m, 1H), 7.41- 7.32 (m, 2H), 6.81 (s, 1H), 5.07 (d, 1H), 4.14-3.89 (m, 3H), 3.82-3.69 (m, 1H), 3.06-2.92(m, 1H), 2.85(q, 1H), 1.70-1.01(bm, 16H), 1.00-0.90(m, 3H), 0.89-0.75 (broad m, 2H).

Example 40 3-((1-(2-(cyclohexylmethyl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one

Prepared according to general procedure 5 using amine 1 (40 mg, 0.1-18 mmol), 2-(cyclohexylmethyl)butanoic acid (36.4 mg, 0.20 mmol), DIPEA (0.092 ml, 0.53 mmol) and HBTU (75 mg, 0.20 mmol) in DCM (2.5 ml) to give the title compound (36 mg, 66%). LCMS (Method B): R_T=1.44 min,m/z=470 [M+H]⁺.^oneH-NMR (400 MHz, DMSO-d ₆ ): δ 8.45 (d, 1H), 8.03 (tt, 1H), 7.59-7.52 (m, 1H), 7.41-7.33 (m, 2H), 6.81 (s, 1H), 5.09 (d, 1H), 4.16-3.99 (m, 2H), 3.93 (d, 1H), 3.88-3.76 (m, 1H), 3.08-2.95 (m, 1H), 2.84-2.74 (m, 1H), 1.72-1.22 (bm, 13H), 1.21-0.99 (b . m, 5H), 0.91-0.73 (br. m, 5H).

Example 41 rac-6-(2-fluorophenyl)-3-((4-hydroxy-1-(cis-2-phenylcyclopropanecarbonyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one

Prepared according to general procedure 5 using amine 1 (30 mg, 0.088 mmol), cis-2-phenylcyclopropanecarboxylic acid (24 mg, 0.15 mmol), DIPEA (0.069 ml, 0.39 mmol) and HBTU (56 mg, 0.15 mmol) in DCM (1.5 ml) to give the title compound (26.3 mg, 67%). LCMS (method B): R _T =1.10 min, m/z =448 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ , compound presented as a 2:3 mixture of conformational isomers A:B): δ 8.39 (s, 0.4H, conformational isomer A), 8.32 (s, 0.6H, conformational isomer B), 8.07-7.97 (m, 1H), 7.59-7.52 (m, 1H), 7.41-7.33 (m, 2H) , 7.26-7.16(m, 2H), 7.15-7.06(m, 3H), 6.79(s, 1H), 4.91(s, 1H), 4.03-3 .74 (m, 3H), 3.62 (s, 1H), 3.25 (t, 0.6H, conformational isomer B), 3.07 (t, 0.4H, conformational isomer A), 2.81 -2.70 (td, br, 1H), 2.48 (m, 1H), 2.38-2.26 (m, 1H), 1.63-1.33 (m, 2H), 1, 31-1.11 (m, 3H), 0.71 (dq, 1H),

Example 42 6-(2-fluorophenyl)-3-((4-hydroxy-1-(1-methylcyclohexanecarbonyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one

Prepared according to general procedure 5 using amine 1 (40 mg, 0.12 mmol), DCM (2.5 mL), 1-methyl-1-cyclohexanecarboxylic acid (28.1 mg, 0.198 mmol), DIPEA ( 0.092 ml, 0.53 mmol) and HBTU (75 mg, 0.20 mmol) to give the title compound (22 mg, 45%). LCMS (Method B): R _T =1.23 min, m/z =428 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO - d ₆ ): δ 8.44 (s, 1H), 8.02 (td, 1H), 7.59-7.52 (m, 1H), 7.40- 7.33(m, 2H), 6.81(s, 1H), 5.04(s, 1H), 4.03-3.92(m, 4H), 3.23-3.11(m , 2H), 1.98-1.89 (m, 2H), 1.57-1.34 (b.m., 9H), 1.33-1.20 (b.m., 3H), 1.16 (s, 3H).

Example 43 3-((S)-1-(1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)propyl)-6-phenylpyrimidin-4(3H)-one and 3-((R)-1-(1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)propyl)-6-phenylpyrimidin-4(3H)-one

Stage 1: tert-butyl-4-propylidene-piperidine-1-carboxylate: Prepared according to General Procedure 6 using triphenyl(propyl)phosphonium bromide (0.53 g, 1.37 mmol) in THF (10.0 ml), n-butyllithium (2.5M in hexane, 0.59 ml , 1.47 mmol), tert-butyl 4-oxo-piperidine-1-carboxylate (0.195 g, 0.98 mmol) in THF (5.0 mL). The crude product was purified by flash chromatography (GraceResolv, 12 g, 0-100% EtOAc in cyclohexane) to give the title compound (181 mg, 82%).^oneH-NMR (400 MHz, CDCl₃): δ 5.21 (brt, 1H), 3.38 (q, 4H), 2.19 (t, br, 2H), 2.12 (br t, 2H), 2.01 (quint, 2H), 1.47 (s, 9H) , 0.95 (t, 3H).

Step 2: (R,S)-tert-butyl-2-ethyl-1-oxa-6-azaspiro[2,5]octane-6-carboxylate : Prepared according to general procedure 8 using tert-butyl-4- propylidene-piperidine-1-carboxylate (0.180 g, 0.799 mmol), DCM (5 mL) and m-CPBA (0.22 g, 0.96 mmol) in DCM (2.5 mL) to give the title compound (0.179 g, 93%). The crude product was used further without further purification. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.80-3.64 (br. m, 2H), 3.45-3.33 (m, 2H), 2.76 (t, 1H), 1.83-1.72 (bm, 2H), 1.66-1.37 (m, 13H), 1.04 (t, 3H).

Step 3: (R,S)-tert-butyl-4-hydroxy-4-(1-(6-oxo-4-phenylpyrimidin-1(6H)-yl)propyl)piperidine-1-carboxylate : Prepared according to general procedure 1, using 6-phenylpyrimidin-4(3H)-one (0.106 g, 0.62 mmol), (R,S)-tert-butyl-2-ethyl-1-oxa-6-azaspiro[2, 5]octane-6-carboxylate (0.179 mg, 0.741 mmol), cesium carbonate (0.604 g, 1.85 mmol) and DMF (10 ml) with stirring at 80°C for 72 hours, 120°C for an additional 24 hours and then at 130°C for another 48 hours. The crude material was azeotropically dried with toluene (1×10 mL) and purified by flash chromatography (GraceResolv (12 g), 0-100% EtOAc in cyclohexane; then 0-10% MeOH in EtOAc), to give the title compound ( 96.5 mg, 38%). LCMS (method B): R _T= 1.34 min, m/z =414 [M+H] ⁺ .

Step 4: (R,S)-3-(1-(4-hydroxypiperidin-4-yl)propyl)-6-phenylpyrimidin-4(3H)-one hydrochloride : Prepared according to general procedure 9 using (R, S)-tert-butyl-4-hydroxy-4-(1-(6-oxo-4-phenylpyrimidin-1(6H)-yl)propyl)piperidine-1-carboxylate (96 mg, 0.23 mmol) and HCl in 1,4-dioxane (4M, 0.85 ml, 3.40 mmol) in DCM (2 ml) to give the title compound (0.132 g, 81%) which was used without further purification. LCMS (method B): R _T= 0.61 min, m/z =314 [M+H] ⁺ .

Stage 5: 3-((S)-1-(1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)propyl)-6-phenylpyrimidin-4(3H)-one and 3-((R)-1-(1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)propyl)-6-phenylpyrimidin-4(3H)-one : Obtained according to general procedure 5 using (R,S)-3-(1-(4-hydroxypiperidin-4-yl)propyl)-6-phenylpyrimidin-4(3H)-one hydrochloride (43 mg, 0.123 mmol) , DIPEA (0.086 ml, 0.49 mmol), (R)-3-cyclohexyl-2-methylpropanoic acid (acid 1) (31.4 mg, 0.184 mmol), HBTU (70 mg, 0.184 mmol) in DCM (2 0 ml) and DMF (0.2 ml) to give a mixture of the title compounds (21.4 mg, 37%). LCMS (Method B): R _T =1.52 min, m/z =466 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.52 (s, 1H), 8.14-8.07 (m, 2H), 7.55-7.47 (m, 3H), 7.04-6.99(m, 1H), 5.22(s, 1H), 4.80-4.71(m, 1H), 4.29-4.03(m, 1H), 3, 89-3.67(m, 1H), 3.20(bt, 1H), 2.94-2.75(m, 2H), 2.05-1.70(bm, 4H), 1.69-1.41(m, 7H), 1.29-1.01(m, 6H), 1.00-0.89(m, 3H), 0.88-0.75 (m, 2H), 0.71 (t, 3H).

Example 44: (S)-3-((1-(3-cyclohexyl-2-hydroxypropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one

Prepared according to general procedure 5 using amine 1 (40 mg, 0.12 mmol), (R,S)-3-cyclohexyl-2-hydroxypropanoic acid (34 mg, 0.20 mmol), DIPEA (0.092 ml , 0.53 mmol) and HBTU (75 mg, 0.20 mmol) in anhydrous DCM (2.5 ml) to give the title compound (14.3 mg, 27%). LCMS (Method B): R _T =1.20 min, m/z =458 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.44 (s, 1H), 8.03 (td, 1H), 7.59-7.53 (m, 1H), 7.39- 7.34 (m, 2H), 6.82 (s, 1H), 5.08 (d, 1H), 4.69-4.66 (m, 1H), 4.35 (m, 1H), 4 .08-3.92 (m, 3H), 3.68 (br. l, 1H), 3.22-3.34 (b. m, 1H), 3.08-2.93 (m, 1H) , 1.81 (b.l, 1H), 1.70-1.52 (b.m., 5H), 1.51-1.38 (b.m., 4H), 1.36-1.30 ( m, 2H), 1.27-1.04 (m, 3H), 0.99-0.77 (m, 2H).

Example 45: (R)-1-((4-Hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbaldehyde

Stage 1: 6-chloro-4-phenylnicotinaldehyde : 5-bromo-2-chloro-4-phenylpyridine (obtained according to Eur. J. Org. Chem., 2013, 12, p.2316-2324) (1 g, 3.72 mmol) was dissolved in THF (15 ml) and the solution was cooled to -78° C. under nitrogen. n-Butyl lithium (2.5M in hexane, 1.79 ml, 4.48 mmol) was added and the mixture was stirred for 15 minutes. DMF (0.32 ml, 4.10 mmol) was added, the mixture was heated to -60°C and stirred for 1 hour, then allowed to warm to room temperature. The reaction was quenched by adding water. The mixture was extracted with EtOAc (x 3). The combined organic extracts were dried over MgSO ₄ and concentrated. The residue was chromatographed (GraceResolv (24g), 0-20% EtOAc in cyclohexane) to give the title compound (0.33g, 41%). LCMS (method B): R _T= 1.28 min, m/z =218 [M+H] ⁺ .

Step 2: 6-oxo-4-phenyl-1,6-dihydropyridine-3-carbaldehyde : Prepared according to general procedure 10 using 6-chloro-4-phenylnicotinaldehyde (255 mg, 1.17 mmol) to give the indicated the title compound (210 mg, 90%) was used further without further purification. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 13.37 (br s, 1H), 9.70 (s, 1H), 8.27 (s, 1H), 7.54-7.45 ( m, 3H), 7.42-7.38 (m, 2H), 6.55 (s, 1H).

Stage 3: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbaldehyde: Prepared according to general procedure 1 using epoxide 2 (0.091 g, 0.351 mmol), 6-oxo-4-phenyl-1,6-dihydropyridine-3-carbaldehyde (0.058 g, 0.29 mmol) and pyridine (0.071 ml, 0.876 mmol) in DMF (2.2 ml). The crude product was purified by flash chromatography (GraceResolv (12 g), 0-100% EtOAc in cyclohexane; then 0-5% MeOH in EtOAc; then GraceResolv, 4 g, 50-100% EtOAc in cyclohexane; then 0-15% MeOH in EtOAc) to give the title compound (7 mg, 5%). LCMS (Method B): R_T=1.28 min,m/z=459[M+H]⁺.^oneH-NMR (400 MHz, DMSO-d ₆): δ 9.60 (s, 1H), 8.49 (d, 1H), 7.59-7.48 (m, 5H), 7.38-7.29 (m, 3H), 7.27 -7.20 (m, 1H), 6.41 (d, 1H), 5.09 (d, 1H), 4.22-3.98 (m, 3H), 3.79-3.67 (br .m, 1H), 3.36-3.18 (m, 3H), 3.00-2.91 (bm, 1H), 2.75-2.61 (m, 1H), 1.65-1.29 (m, 5H), 1.27 (dd, 3H).

Example 46: (R)-5-((dimethylamino)methyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-yl)methyl)-4-phenylpyridin-2(1H)-one

(R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbaldehyde (see Example 45 ) (46 mg, 0.10 mmol) was dissolved in anhydrous DCM (1.0 ml) and methanol (0.25 ml) under N ₂ positive pressure. Dimethylamine (2M in THF, 0.055 ml, 0.11 mmol) was added and the mixture was stirred for 1.5 hours, then sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added and the mixture was stirred for another 16.5 hours. Glacial acetic acid (2 drops) was added and the mixture was stirred for another 26 hours. The mixture was diluted with 1M sodium hydroxide (4.8 ml) and extracted with DCM (3×5 ml). The combined organic extracts were washed with brine (1×5 ml), dried (Biotage phase separator), then concentrated. The residue was purified by flash chromatography (GraceResolv (4 g), isocratic 100% EtOAc; then 0-50% MeOH in EtOAc) to give the title compound (7.0 mg, 14%). LCMS (method B): R _T =0.79 min, m/z =488 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 7.61 (d, 1H), 7.54-7.40 (m, 5H), 7.32-7.24 (m, 4H), 7.21-7.14(m, 1H), 6.27(d, 1H), 5.04(d, 1H), 4.09-3.87(m, 3H), 3.72-3, 61 (m, 1H), 3.37-3.12 (m, 2H), 3.00 (s, 2H), 2.97-2.86 (m, 1H), 2.66-2.54 ( m, 1H), 2.07 (s, 6H), 1.61-1.17 (m, 8H).

Example 47: 3-((R)-1-(4-hydroxy-1-((R)-3-phenylbutanoyl)piperidin-4-yl)ethyl)-6-phenylpyrimidin-4(3H)-one and 3- ((S)-1-(4-hydroxy-1-((R)-3-phenylbutanoyl)piperidin-4-yl)ethyl)-6-phenylpyrimidin-4(3H)-one

Prepared according to general procedure 5 using amine 2 (40 mg, 0.1-19 mmol), (R)-3-phenylbutanoic acid (0.027 ml, 0.179 mmol), DIPEA (0.083 ml, 0.476 mmol) and HBTU ( 67.8 mg, 0.18 mmol) in DCM (2.25 ml) to give a mixture of the title compounds (24.5 mg, 46%). LCMS (method B): R _T =1.21 min, m/z =446 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO - d ₆ ): δ 8.53-8.46 (m, 1H), 8.12-8.05 (m, 2H), 7.54-7.46 (m , 3H), 7.34-7.13 (m, 5H), 6.98 (s, 1H), 5.18 (m, 1H), 4.96-4.74 (m, 1H), 4, 23-4.01 (m, br, 1H), 3.80-3.61 (m, br, 1H), 3.26-2.75 (m, 2H), 2.74-2.37 (m, 2H), 1.74-1.47 (m, 1H), 1.46-1.29 (b.m., 4H), 1.28-1.16 (b.m., 4H), 1 .15-0.94 (width m, 2H).

Example 48: (R)-6-(2-fluorophenyl)-3-((4-hydroxy-1-(4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H)-he

Prepared according to general procedure 5 using amine 1 (40 mg, 0.118 mmol), (R)-4,4,4-trifluoro-3-phenylbutanoic acid (acid 16) (43 mg, 0.20 mmol), DIPEA (0.092 ml, 0.525 mmol) and HBTU (75 mg, 0.198 mmol) in DCM (2.5 ml) to give the title compound (29 mg, 50%). LCMS (method B): R _T =1.25 min, m/z =504 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.17-8.02 (m, 2H), 7.49-7.42 (m, 1H), 7.41-7.24 (m, 6H ), 7.18 (ddd, 1H), 7.11 (d, 1H), 4.38-4.29 (m, 1H), 4.21-4.03 (m, 1H), 4.00- 3.80 (m, 3H), 3.76-3.60 (m, 1H), 3.47-3.33 (m, 1H), 3.05-2.85 (m, 3H), 1, 70-0.81 (m, 4H).

Example 49: (S)-3-((1-(3-cyclohexyl-2-fluoropropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one

Prepared according to general procedure 5 using amine 1 (40 mg, 0.12 mmol), (R,S)-3-cyclohexyl-2-fluoropropanoic acid (34.5 mg, 0.20 mmol), DIPEA ( 0.092 ml, 0.525 mmol) and HBTU (75 mg, 0.20 mmol) in DCM (2.5 ml) to give the title compound (30 mg, 56%). LCMS (method B): R _T =1.44 min, m/z =460 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.16 (bd, 1H), 8.07 (td, 1H), 7.49-7.42 (m, 1H), 7.32- 7.23 (m, 1H), 7.18 (ddd, 1H), 7.13 (s, 1H), 5.21 (d, td, 1H), 4.40 (brt, 1H), 4 .17-3.74 (m, 4H), 3.53-3.40 (m, 2H), 3.13 (br. q, 1H), 1.95-1.79 (b. m, 2H) , 1.78-1.47 (m, 7H), 1.35-1.10 (m, 4H), 1.07-0.87 (m, 3H).

Example 50: 3-(((R)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-phenylpyrimidin-4( 3H)-one and 3-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-phenylpyrimidine- 4(3H)-he

Step 1: (R,S)-tert-butyl-4-hydroxy-3,3-dimethyl-4-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)piperidine-1-carboxylate : Prepared according to general procedure 1 using 6-phenylpyrimidin-4(3H)-one (0.172 g, 1.00 mmol), epoxide 3 (0.242 g, 1.00 mmol) and DIPEA (0.262 ml, 1.50 mmol ) in DMF (1.43 mmol) ml). After 16 hours at 80°C, cesium carbonate (0.163 g, 0.499 mmol) was added and the mixture was heated at 120°C for another 4 hours. The crude product was triturated with EtOAc to give the title compound (0.215 g, 52%). LCMS (method B): R _T= 1.34 min, m/z =414 [M+H] ⁺ .

Step 2: (R,S)-3-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-phenylpyrimidin-4(3H)-one hydrochloride : Prepared according to general procedure 9, using (R,S)-tert-butyl-4-hydroxy-3,3-dimethyl-4-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl)piperidine-1-carboxylate (0.215g , 0.520 mmol), DCM (2.60 ml) and hydrogen chloride (4M in 1,4-dioxane, 1.820 ml, 7.28 mmol) to give the title compound (0.200 g, quant.). LCMS (method B): R _T =0.59 min, m/z =314 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 9.17 (brd, 1H), 8.47 (s, 1H), 8.47-8.39 (m, 1H), 8. 13-8.05 (m, 2H), 7.54-7.46 (m, 3H), 7.02 (s, 1H), 5.3 (br s, 1H), 4.45 (d, 1H), 3.77 (d, 1H), 3.05 (br. d, 1H), 3.00-2.75 (m, 3H), 1.85 (br. td, 1H), 1.35 (brd, 1H), 1.21 (s, 3H), 1.04 (s, 3H).

Step 3: 3-(((R)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-phenylpyrimidine-4( 3H)-one and 3-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-phenylpyrimidine- 4(3H)-one : Prepared according to general procedure 5 using (R,S)-3-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-phenylpyrimidin-4( 3H)-one hydrochloride (0.05 g, 0.143 mmol), (R)-3-cyclohexyl-2-methylpropanoic acid (acid 1) (0.036 g, 0.214 mmol), HBTU (0.081 g, 0.214 mmol), DCM ( 1.5 ml) and DIPEA (0.103 ml, 0.572 mmol) to give a mixture of the title compounds (36 mg, 54%). LCMS (method B): R _T =1.53 min, m/z =466 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ , mixture of diastereomers and conformational isomers): δ 8.44 (s, 1H), 8.13-8.05 (m, 2H), 7.54-7.46 (m, 3H), 7.01 (d, 1H), 4.91 (br s, 1H), 4.50-4.36 (m, 1H), 4.13-3.97 (m, 0 .5H), 3.80-3.62 (m, 2H), 3.32-3.16 (m, 1.5H), 3.03-2.83 (m, 2H), 1.73-1 .55 (m, 6H), 1.55-1.43 (m, 1H), 1.26-1.06 (m, 6H), 1.03 (brd, 1H), 1.02-0 .95 (m, 6H), 0.91 (d, 2H), 0.87-0.76 (m, 2H).

Example 51: 3-(((R)-6-((R)-3-cyclohexyl-2-methylpropanoyl)-9-hydroxy-6-azaspiro[3.5]nonan-9-yl)methyl)-6-(2 -fluorophenyl)pyrimidin-4(3H)-one and 3-(((S)-6-((R)-3-cyclohexyl-2-methylpropanoyl)-9-hydroxy-6-azaspiro[3.5]nonan-9- yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one

Step 1: (R,S)-tert-butyl-9-((4-(2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)methyl)-9-hydroxy-6-azaspiro[3.5]nonane -6-carboxylate : Prepared according to general procedure 1 using 6-(2-fluorophenyl)pyrimidin-4(3H)-one (0.136 g, 0.72 mmol), epoxide 4 (0.2 g, 0.789 mmol ) and DIPEA (0.193 ml, 1.077 mmol) in DMF (1.4 ml) at 80°C for 16 hours, then at 120°C for 2 days. The crude product was purified by precipitation from water and triturated with DCM and cyclohexane to give the title compound (110 mg, 35%). LCMS (method B): R _T= 1.50 min, m/z =388 [M+2H- ^t Bu] ⁺ .

Step 2: (R,S)-6-(2-fluorophenyl)-3-((9-hydroxy-6-azaspiro[3,5]nonan-9-yl)methyl)pyrimidin-4(3H)-one hydrochloride : Prepared according to General Procedure 9 using (R,S)-tert-butyl-9-((4-(2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)methyl)-9-hydroxy -6-azaspiro[3,5]nonane-6-carboxylate (0.110 g, 0.25 mmol) and hydrogen chloride (4M in 1,4-dioxane, 0.87 ml, 3.47 mmol) in DCM (1, 2 ml) to give the crude title compound (100 mg, >100%) which was used without further purification. LCMS (method B): R _T =0.70 min, m/z =344 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.94-8.83 (m, 1H), 8.71-8.59 (m, 1H), 8.54 (s, 1H), 8.04 (td, 1H), 7.60-7.52 (m, 1H), 7.42-7.34 (m, 2H), 6.83 (s, 1H), 4.64 (d, 1H), 4.45 (br s, 1H), 3.72 (d, 1H), 3.42-3.33 (m, 1H), 3.29-3.16 (m, 2H), 3 .03-2.92 (m, 1H), 2.47-2.24 (m, 2H), 2.04-1.87 (m, 1H), 1.83-1.66 (m, 3H) , 1.50-1.33 (m, 2H).

Step 3: 3-(((R)-6-((R)-3-cyclohexyl-2-methylpropanoyl)-9-hydroxy-6-azaspiro[3.5]nonan-9-yl)methyl)-6-(2 -fluorophenyl)pyrimidin-4(3H)-one and 3-(((S)-6-((R)-3-cyclohexyl-2-methylpropanoyl)-9-hydroxy-6-azaspiro[3.5]nonan-9- yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one : Prepared according to general procedure 5 using (R,S)-6-(2-fluorophenyl)-3-((9 -hydroxy-6-azaspiro[3,5]nonan-9-yl)methyl)pyrimidin-4(3H)-one hydrochloride (0.025 g, 0.066 mmol), (R)-3-cyclohexyl-2-methylpropanoic acid (acid 1) (0.017 g, 0.099 mmol), HBTU (0.037 g, 0.099 mmol) and DIPEA (0.047 ml, 0.26 mmol) in DCM (0.7 ml). The crude product was purified by flash chromatography (Biotage KP-NH, 11 g, 0-50% EtOAc in cyclohexane; then GraceResolv, 4 g, 10-70% EtOAc in cyclohexane) to give a mixture of the title compounds (4.5 mg, 13 ,eight%). LCMS (Method B): R _T =1.58 min, m/z =496 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ , compound presented as two conformational isomers A:B in a ratio of 2:3): δ 8.27 (brd, 0.6H, conformational isomer B ), 8.22 ( s, 0.4H, conformational isomer A), 8.07 (td, 1H), 7.49-7.41 (m, 1H), 7.31-7.27 (d, 1H), 7.18 ( dd, 1H), 7.12-7.07 (m, 1H), 4.50-4.35 (m, 1H), 4.26-3.96 (m, 2H), 3.86- 3.57 (m, 3H), 3.54-3.40 (m, 1H), 3.00-2.82 (m, 1H), 2.44-2.33 (m, 0.4H, conformational isomer A), 2.29-2.08 (m, 2.6H), 2.04-1.82 (m, 1H), 1.75-1.59 (m, 7H), 1.50-1 .33 (m, 2H), 1.31-1.16 (m, 5H), 1.16-1.11 (m, 2H), 1.11-1.05 (m, 2H), 0.96 -0.80 (m, 2H).

Example 52: (R)-5-(3-(aminomethyl)phenyl)-1-((1-(3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-(2- fluorophenyl)pyridin-2(1H)-one

Step 1: 5-bromo-4-(2-fluorophenyl)pyridin-2(1H)-one : Prepared as for 5-bromo-4-phenylpyridin-2(1H)-one (see Example 1) using (5-bromo-2-chloro-4-(2-fluorophenyl)pyridine (3.1 g, 10.8 mmol) (prepared according to Eur J. Org. Chem., 2013, p. 2316-2324) and sodium hydroxide (3.03 g, 76 mmol) in 1,4-dioxane (36 ml) and water (36 ml) to give the title compound (2.50 g, 86%) which was used without further purification. LCMS (method B): R _T= 1.18 min, m/z =268, 270 [M+H] ⁺ .

Stage 2: tert-butyl-4-((5-bromo-4-(2-fluorophenyl)-2-oxopyridin-1(2H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate : Prepared according to general procedure 1 using 5-bromo-4-(2-fluorophenyl)pyridin-2(1H)-one (1 g, 3.73 mmol), epoxide 1 (0.796 g, 3.73 mmol) and DIPEA (0.98 ml, 5.60 mmol) in DMF (5.0 ml) to give the title compound (0.28 g, 16%) which was used without further purification. LCMS (method B): R _T= 0.98 min, m/z =423, 425 [M+H] ⁺ .

Step 3: 5-bromo-4-(2-fluorophenyl)-1-((4-hydroxypiperidin-4-yl)methyl)pyridin-2(1H)-one hydrochloride : Prepared according to general procedure 9 using tert- butyl 4-((5-bromo-4-(2-fluorophenyl)-2- oxopyridine- (2H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate (0.1 g, 0.208 mmol) and chloride hydrogen (4M in 1,4-dioxane, 0.76 ml, 3.03 mmol) in DCM (0.83 ml) to give the title compound (0.080 g, 92%). ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.91-8.83 (m, 1H), 8.60-8.49 (m, 1H), 8.05 (s, 1H), 7.58-7.50(m, 1H), 7.39-7.30(m, 3H), 6.50(s, 1H), 4.04(s, 2H), 3.20-3, 11 (m, 2H), 3.09-2.95 (m, 2H), 1.79 (br td, 2H), 1.60 (br d, 2H).

Stage 4: (R)-5-bromo-1-((1-(3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-(2-fluorophenyl)pyridine-2(1H )-one: Prepared according to general procedure 5 using 5-bromo-4-(2-fluorophenyl)-1-((4-hydroxypiperidin-4-yl)methyl)pyridin-2(1H)-one hydrochloride ( 0.08 g, 0.192 mmol), acids 1 (0.049 g, 0.287 mmol), HBTU (0.109 g, 0.287 mmol) and DIPEA (0.13 ml, 0.77 mmol) in DMF (0.5 ml), c obtaining the title compound (97 mg, 95%). LCMS (method B): R _T =1.58 min, m/z =533/535 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.56 (s, 1H), 7.49-7.42 (m, 1H), 7.26-7.22 (m, 2H), 7, 18 (bt, 1H), 6.66 (s, 1H), 4.53-4.42 (m, 2H), 4.20-4.09 (m, 2H), 3.97 (d, 1H), 3.82 (brd, 1H), 3.49 (brd, 1H), 3.07 (brd, 1H), 2.84 (q, 1H), 1.78-1 .62 (m, 8H), 1.61-1.49 (m, 1H), 1.30-1.15 (m, 6H), 1.09 (t, 3H), 0.96-0.81 (m, 2H).

Step 5: (R)-tert-butyl-3-(1-((1-(3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-(2-fluorophenyl)-6 -oxo-1,6-dihydropyridin-3-yl)benzylcarbamate: Prepared according to general procedure 4 using (R)-5-bromo-1-((1-(3-cyclohexyl-2-methylpropanoyl)-4 -hydroxypiperidin-4-yl)methyl)-4-(2-fluorophenyl)pyridin-2(1H)-one (0.097 g, 0.182 mmol), (3-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (0.068 g, 0.273 mmol), sodium carbonate (0.039 g, 0.364 mmol), 1,4-dioxane (1.5 ml), water (0.6 ml) and Pd (Ph ₃ P) ₄ (10.51 mg, 9.09 µmol). The reaction mixture was heated in a microwave oven for 20 minutes at 150°C. The crude product was loaded into an SCX-2 cartridge (2 g) and eluted with 0-30% MeOH in DCM. Volatiles were removed and the residue was purified by flash chromatography (Biotage KP-NH, 11 g, 0-100% EtOAc in cyclohexane) to give the title compound (29 mg, 24%) which was used without further purification. LCMS (method B): R _T= 1.71 min, m/z =604 [M+H] ⁺ .

Step 6: (R)-5-(3-(aminomethyl)phenyl)-1-((1-(3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-(2- fluorophenyl)pyridin-2(1H)-one: Prepared according to general procedure 7 using (R)-tert-butyl-3-(1-((1-(3-cyclohexyl-2-methylpropanoyl)-4- hydroxypiperidin-4)-yl)methyl)-4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridin-3-yl)benzylcarbamate (0.029 g, 0.044 mmol), 2,2,2-trifluoroacetic acid ( 0.230 ml, 2.99 mmol) and DCM (0.15 ml) to give the title compound (19 mg, 77%). LCMS (method B): R _T =1.02 min, m/z =560 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.26-7.36 (m, 2H), 7.21-7.09 (m, 4H), 6.98-6.83 (m, 3H ), 6.73 (s, 1H), 5.40-4.80 (br s, 2H), 4.50 (br d, 1H), 4.28 (br dd, 1H), 4, 01 (br. dd, 1H), 3.81 (b. d, 1H), 3.74 (s, 2H), 3.56-3.45 (m, 2H), 3.05 (b. d, 1H), 2.85(q, 1H), 1.80-1.50(m, 8H), 1.29-1.09(m, 6H), 1.08(d, 3H), 0.95 -0.78 (m, 2H).

Example 53: 3-(((S)-4-hydroxy-3,3-dimethyl-1-((R)-3-phenylbutanoyl)piperidin-4-yl)methyl)-6-phenylpyrimidine-4(3H)- he and 3-(((R)-4-hydroxy-3,3-dimethyl-1-((R)-3-phenylbutanoyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4(3H)-one

Prepared according to general procedure 5 using (R,S)-3-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-phenylpyrimidin-4(3H)-one hydrochloride (see Example 50) (50 mg, 0.14 mmol), (R)-3-phenylbutanoic acid (35 mg, 0.21 mmol), HBTU (81 mg, 0.21 mmol) and DIPEA (0.10 ml, 0.57 mmol) in DCM (1.4 mL) to give a mixture of the title compounds (32 mg, 49%). LCMS (method B): R _T =1.31 min, m/z= 460 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ , mixture of diastereomers and conformational isomers): δ 8.41 (d, 1H), 8.08 (m, 2H), 7.50 (m, 3H), 7, 27 (m, 4H), 7.17 (m, 1H), 7.00 (s, 1H), 4.86 (br s, 1H), 4.42 (m, 0.4H), 4.36 (m, 0.6H), 4.03 (m, 0.6H), 3.70 (m, 2.4H), 3.33-3.09 (m, 2H), 2.86 (t, 1H ), 2.77-2.56 (m, 2H), 1.68-1.45 (m, 1H), 1.22-0.81 (m, 10H).

Example 54: ( R )-6-(4-fluorophenoxy)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4(3 H )-he

(R)-6-chloro-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one (40 mg, 0.10 mmol) and 4 -fluorophenol (17 mg, 0.15 mmol) was dissolved in a mixture of THF (0.5 ml) and toluene (1.5 ml). 2-(Dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (4.9 mg, 10.3 µmol) was added and the mixture was purged with nitrogen. Added Pd ₂ (dba) ₃ (4.7 mg, 5.1 μmol), the tube was closed and the mixture was heated at 110°C for 16 hours. The mixture was cooled to room temperature and diluted with water, then extracted with DCM. The organic layer was dried (Biotage phase separator), concentrated, and the residue was purified by flash chromatography (Biotage KP-NH, 11 g, 10-100% EtOAc in cyclohexane; then 0-15% MeOH in EtOAc) to give the title compound ( 14 mg, 29%). LCMS (method B): R _T 1.14, m/z= 466 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.22 (d, 1H), 7.26 (m, 9H), 5.56 (m, 1H), 4.94 (m, 1H) , 4.01(m, 1H), 3.95(m, 1H), 3.81(m, 1H), 3.62(m, 1H), 3.16(m, 2H), 2.88( m, 1H), 2.56 (m, 2H), 1.21 (m, 3H), 1.10 (m, 4H).

Example 55: ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(2-oxopyrrolidin-1-yl)-4-phenylpyridin-2(1 H )-he

Stage 1: 1-(6-chloro-4-phenylpyridin-3-yl)pyrrolidin-2-one : 5-bromo-2-chloro-4-phenylpyridine (0.50 g, 1.86 mmol) (obtained as described in Eur., J. Org. Chem., 2013, p.2316-2324), pyrrolidin-2-one (0.170 ml, 2.23 mmol), cesium carbonate (0.849 g, 2.61 mmol) and XantPhos ( 0.108 g, 0.186 mmol) were suspended in anhydrous 1,4-dioxane (15 ml). The suspension was purged and filled with nitrogen (x 3), then Pd ₂ (dba) ₃ (0.085 g, 0.093 mmol) was added. The mixture was heated at 100°C for 16 hours, then cooled to room temperature and diluted with water (20 ml). The mixture was filtered through a pad of Celite® and extracted with EtOAc. The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography (GraceResolv, 11 g, 0-100% EtOAc in cyclohexane; then 0-10% MeOH in EtOAc) to give the title compound (74 mg, 14%) . LCMS (Method B): R _T =1.42 min, m/z =273 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.37 (s, 1H), 7.44-7.49 (m, 3H), 7.34-7.38 (m, 3H), 3, 24 (t, 2H), 2.46 (t, 2H), 1.96 (m, 2H).

Step 2: 5-(2-oxopyrrolidin-1-yl)-4-phenylpyridin-2(1H)-one : 1-(6-chloro-4-phenylpyridin-3-yl)pyrrolidin-2-one solution (0.075 g , 0.28 mmol) in water (1.0 ml) and acetic acid (3.1 ml, 53.6 mmol) was heated in a microwave oven at 180°C for 9 hours. The mixture was concentrated and the residue was diluted with saturated aqueous sodium bicarbonate and extracted with DCM. The organic layer was dried (Biotage phase separator) and concentrated to give the title compound (61 mg, 87%) which was used without any further purification. LCMS (method B): R _T =0.75 min, m/z =255 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.46-7.42 (m, 3H), 7.39 (s, 1H), 7.38-7.33 (m, 2H), 6.59 (s, 1H), 3.09 (t, 2H), 2.39 (t, 2H), 1.84 (m, 2H).

Step 3: (R)-1-((4-hydroxy-1-(3-genylbutanoyl)piperidin-4-yl)methyl)-5-(2-oxopyrrole-phenylpyridin-2(1H)-one : Prepared according to with general procedure 1 using 5-(2-oxopyrrolidin-1-yl)-4-phenylpyridin-2(1H)-one (0.061 g, 0.240 mmol), epoxide 2 (0.068 g, 0.264 mmol) and DIPEA (0.063 ml , 0.360 mmol) in DMF (0.7 ml) The reaction mixture was heated to 80°C for 64 hours The crude product was purified by flash chromatography (Biotage KP-NH, 0-100% EtOAc in cyclohexane; then 0-5% MeOH in EtOAc), followed by preparative HPLC under basic conditions to give the title compound (15 mg, 12%) LCMS (Method B): R _T = 1.08 min, m/z = 514 [M+H ] ^{+ 1} H-NMR (400 MHz, CDCl ₃ , the compound is presented as two conformational isomers): δ 7.46-7.42 (m, 3H), 7.34-7.17 (m, 8H), 6.64 (d, 1H), 4.80 (s, 0.6H), 4.68 (s, 0.4H), 4.51-4.38 (m, 1H), 4.14 (d, 1H, 0.4H), 3.94 (br dd, 1H), 3.82 (d, 0.6H), 3.65-3.55 (m, 1H), 3.45-3.20 ( m, 2H), 3.15-3.01 (m, 2H), 2.95 (br ddd, 1H), 2.70-2.62 (m, 1H), 2.55-2.47 (m, 1H), 2.42 (m, 2H), 1.93-1.78 (m, 2H), 1.59-1.44 (m , 2H), 1.43 (br. dd, 1H), 1.35 (dd, 2.4H), 1.28 (br td, 1H), 0.73 (td, 0.6H).

Example 56 6-(2-fluorophenyl)-3-((4-hydroxy-1-(1-methyl-4-methylenecyclohexanecarbonyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one

Step 1: Ethyl 1-methyl-4-methylenecyclohexanecarboxylate : Potassium tert-butoxide (0.183 g, 1.63 mmol) was added to an ice-cold solution of methyltriphenylphosphonium bromide (0.620 g, 1.74 mmol) in THF (1.6 ml), and the solution was stirred at 0° C. for 40 minutes. A solution of ethyl 1-methyl-4-oxocyclohexanecarboxylate (0.2 g, 1.086 mmol) in THF (2.0 ml) was added dropwise at 0°C and the mixture was stirred at 0°C for 24 hours. The mixture was warmed to room temperature, quenched with H ₂ O and extracted with Et ₂ O. The organic layer was dried over MgSO ₄ , filtered and concentrated. The residue was purified by flash chromatography (GraceResolv (11 g), 0-10% EtOAc in cyclohexane) to give the title compound (140 mg, 71%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 4.62 (s, 2H), 2.24-2.06 (m, 9H), 1.51 (d, 1H), 1.37-1, 29 (m, 3H), 1.18 (s, 3H).

Stage 2: 1-methyl-4-methylenecyclohexanecarboxylic acid : A solution of potassium hydroxide (0.215 g, 3.84 mmol) in H ₂ O (0.55 ml) was added to a solution of ethyl 1-methyl-4-methylenecyclohexanecarboxylate (0.14 g, 0.77 mmol) in EtOH (0.55 ml), and the mixture was heated in a microwave oven at 120°C for 20 minutes. The mixture was cooled to room temperature and extracted with EtOAc and the organic layer was discarded. The aqueous layer was acidified to pH 2 with 1M HCl and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated to give the title compound (100 mg, 84%) which was used without further purification. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 4.64 (s, 2H), 2.26-2.12 (m, 6H), 2.11 (s, 1H), 1.75-1, 50 (m, 1H), 1.41-1.32 (m, 2H), 1.28-1.24 (m, 3H).

Step 3: 6-(2-fluorophenyl)-3-((4-hydroxy-1-(1-methyl-4-methylenecyclohexanecarbonyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one: Prepared according to with general procedure 5, using 6-(2-fluorophenyl)-3-((4-hydroxypiperidin-4-yl)methyl)pyrimidin-4(3H)-one hydrochloride (0.073 g, 0.216 mmol), 1-methyl- 4-methylenecyclohexanecarboxylic acid (0.050 g, 0.324 mmol), HBTU (0.123 g, 0.324 mmol) and DIPEA (0.151 ml, 0.865 mmol) in DCM (3.6 ml) to give the title compound (4.8 mg, 5%). LCMS (Method B): R _T =1.26 min, m/z =440 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.18 (br s, 1H), 8.07 (td, 1H), 7.49-7.42 (m, 1H), 7.29 ( br dd, 1H), 7.17 (m, 1H), 7.12 (s, 1H), 4.60 (s, 2H), 4.23 (br d, 2H), 4.07 (s , 2H), 3.75 (s, 1H), 3.31 (br td, 2H), 2.30-2.13 (m, 6H), 1.68-1.57 (m, 4H), 1.49-1.40 (m, 2H), 1.28 (s, 3H).

Example 57: ( R,S ) - 3-((1-(3-cyclobutyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidine-4(3 H )-he

Step 1: (R,S)-3-cyclobutyl-2-methylpropanoic acid : n-butyllithium (2.5M in hexane, 0.687 ml, 1.72 mmol) was added dropwise at 0°C to a solution of diisopropylamine (0.234 ml, 1.64 mmol) in THF (1.3 ml). The solution was stirred at 0°C for 30 minutes, then 3-cyclobutylpropanoic acid (0.1 g, 0.78 mmol) was added and the mixture was heated at 45°C for 1 hour. The mixture was cooled to 0° C. and iodomethane (0.097 ml, 1.56 mmol) was added. The mixture was heated at 45°C for 3 hours. The reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was removed and the aqueous layer was acidified to pH 2 with 1M HCl and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated to give the title compound (0.10 g, 90%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 11.0 (br s, 1H), 2.45-2.29 (m, 2H), 2.11-1.98 (m, 2H), 1.91-1.76 (m, 3H), 1.68-1.47 (m, 3H), 1.15 (d, 3H).

Step 2: (R,S)-3-((1-(3-cyclobutyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidine-4(3H)- it: Prepared according to general procedure 5 using amine 1 (0.080 g, 0.235 mmol), (R,S)-3-cyclobutyl-2-methylpropanoic acid (commercially available) (0.063 g) 0.353 mmol), HBTU (0.134 g, 0.353 mmol) and DIPEA (0.16 ml, 0.942 mmol) in DCM (4.1 ml). The crude product was purified by preparative HPLC under basic conditions to give the title compound (6.2 mg, 6%). LCMS (Method B): R _T =1.22 min, m/z =428 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.18 (d, 1H), 8.06 (brt, 1H), 7.49-7.42 (m, 1H), 7.29 ( br dd, 1H), 7.18 (br dd, 1H), 7.12 (s, 1H), 4.49-4.39 (m, 1H), 4.17 (dd, 1H), 3 .98 (t, 1H), 3.83-3.72 (m, 2H), 3.45 (br. t, 1H), 3.13-3.03 (m, 1H), 2.65 (p , 1H), 2.32-2.19 (m, 1H), 2.07-1.95 (m, 2H), 1.88-1.73 (m, 3H), 1.70-1.53 (m, 5H), 1.51-1.41 (m, 1H), 1.33-1.23 (m, 1H), 1.08 (t, 3H).

Example 58: ( R,S )-3-((1-(3-cycloheptyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidine-4(3 H )-he

Prepared according to general procedure 5 using amine 1 (0.061 g, 0.181 mmol), (R,S)-3-cycloheptyl-2-methylpropanoic acid (0.05 g, 0.271 mmol) (commercially available), HBTU (0.103 g, 0.271 mmol) and DIPEA (0.13 ml, 0.724 mmol) in DCM (3.0 ml) to give the title compound (39.5 mg, 46%). LCMS (Method B): R _T =1.49 min, m/z =470 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.18 (br s, 1H), 8.06 (td, 1H), 7.49-7.42 (m, 1H), 7.29 ( br dd, 1H), 7.18 (br dd, 1H), 7.02 (s, 1H), 4.44 (br d, 1H), 4.17 (dd, 1H), 3.98 (dd, 1H), 3.85-3.76 (m, 2H), 3.47 (br. d, 1H), 3.09 (br. t, 1H), 2.83-2.75 (m , 1H), 1.71-1.52 (m, 9H), 1.51-1.34 (m, 6H), 1.32-1.11 (m, 4H), 1.08 (t, 3H ).

Example 59 3-((1-(3-cyclobutyl-2,2-dimethylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one

Prepared according to general procedure 5 using amine 1 (0.080 g, 0.235 mmol), 3-cyclobutyl-2,2-dimethylpropanoic acid (0.074 g, 0.353 mmol), HBTU (0.134 g, 0.353 mmol) and DIPEA (0.353 mmol) 16 ml, 0.94 mmol) in DCM (4.0 ml) to give the title compound (33 mg, 32%). LCMS (method B): R _T =1.35 min, m/z =442 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.11 (br s, 1H), 7.99 (td, 1H), 7.42-7.35 (m, 1H), 7.22 ( br dd, 1H), 7.11 (br dd, 1H), 7.05 (s, 1H), 4.14 (br d, 2H), 4.05 (q, 1H), 4.00 (s, 1H), 3.66 (s, 1H), 3.21 (brt, 2H), 3.28 (m, 1H), 1.98 (s, 1H), 1.97-1, 90 (m, 2H), 1.80-1.71 (m, 1H), 1.64 (d, 3H), 1.21-1.16 (m, 4H), 1.15 (s, 6H) .

Example 60: 6-(2-fluorophenyl)-3-(((1 R, 5 S )-8-hydroxy-3-(( R )-3-phenylbutanoyl)-3-azabicyclo[3.2.1]octan-8-yl)methyl)pyrimidin-4(3 H )-he

Prepared according to general procedure 5 using 6-(2-fluorophenyl)-3-(((1 R, 5 S )-8-hydroxy-3-azabicyclo[3.2.1]octan-8-yl)methyl) pyrimidin-4( 3H )-one hydrochloride (0.030 g, 0.082 mmol), (R)-3-phenylbutanoic acid (0.020 g, 0.12 mmol), HBTU (0.047 g, 0.12 mmol) and DIPEA (0.057 ml, 0.328 mmol) in DCM (0.8 ml) to give the title compound (22 mg, 56%). LCMS (method B): R _T =1.37 min, m/z =476 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ , compound presented as two conformational isomers in a 1:1 ratio): δ 8.10 (dd, 1H), 8.06 (m, 1H), 7.49-7, 42 (m, 1H), 7.32-7.23 (m, 5H), 7.22-7.16 (m, 2H), 7.14 (s, 1H), 4.71 (s, 0, 5H), 4.62 (s, 0.5H), 4.23-4.01 (m, 3H), 3.69 (d, 0.5H), 3.53 (d, 0.5H), 3 .45-3.29 (m, 2H), 3.23 (dd, 1H), 2.69 (dd, 0.5H), 2.65-2.53 (m, 1H), 2.46 (dd , 0.5H), 1.91-1.46 (m, 5H), 1.34-1.10 (m, 4H).

Example 61: 3-((( R )-4-hydroxy-2,2-dimethyl-1-(( R )-3-phenylbutanoyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4(3 H )-he and 3-((( S )-4-hydroxy-2,2-dimethyl-1-(( R )-3-phenylbutanoyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4(3 H )-he

Step 1: (R,S)-tert-butyl-5,5-dimethyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate: Prepared according to general procedure 11 using tert-butyl-2 ,2-dimethyl-4-oxopiperidine-1-carboxylate (0.5 g, 2.20 mmol), trimethylsulfonium iodide (1.12 g, 5.50 mmol) and sodium hydride (60% oil dispersion, 0.220 g, 5 .50 mmol) in DMSO (4.89 ml + 2.44 ml). The crude product was purified by flash chromatography (24 g, GraceResolv, 0-40% EtOAc in cyclohexane) to give the title compound (390 mg, 74%). LCMS (method B): R _T =1.39 min, m/z =142 [M+H-Boc] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.72-3.59 (m, 2H), 2.68 (q. 2H), 2.00-1.92 (m, 1H), 1, 80-1.75 (m, 1H), 1.76 (d, 2H), 1.49 (s, 3H), 1.48 (s, 9H), 1.45 (s, 3H).

Step 2: (R,S)-tert-butyl-4-hydroxy-2,2-dimethyl-4-((6-oxo-4-genylpyrimidin-1(6H)-yl)methyl)piperidine-1-carboxylate : Prepared according to general procedure 1 using 6-phenylpyrimidin-4(3H)-one (0.162 g, 0.94 mmol), (R,S)-tert-butyl-5,5-dimethyl-1-oxa-6 -azaspiro[2.5]octane-6-carboxylate (0.25 g, 1.04 mmol) and cesium carbonate (0.368 g, 1.13 mmol) in DMF (1.4 ml). The mixture was heated at 120° C. for 3 hours to give the title compound (0.32 g, 81%) which was used without further purification. LCMS (method B): R _T =1.35 min, m/z =314 [M+H-Boc] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.20 (s, 1H), 8.00-7.95 (m, 2H), 7.52-7.46 (m, 3H), 6, 93 (s, 1H), 4.03 (q, 2H), 3.81-3.74 (m, 1H), 3.53 (s, 1H), 3.47-3.39 (m, 1H) , 2.01 (s, 1H), 1.78-1.66 (m, 3H), 1.51 (s, 3H), 1.47 (s, 9H), 1.45 (s, 3H),

Stage 3: (R,S)-3-((4-hydroxy-2,2-dimethylpiperidin-4-yl)methyl)-6-phenylpyrimidin-4(3H)-one hydrochloride: Prepared according to general procedure 9 using (R,S)-tert-butyl-4-hydroxy-2,2-dimethyl-4-((6-oxo-4-phenylpyrimidin-1(6H)-yl)methyl )piperidine-1-carboxylate (0.315 g, 0.762 mmol) and hydrogen chloride (4M in 1,4-dioxane, 2.7 mL, 10.8 mmol) in DCM (3.7 mL) to give the title compound (0.285 g, quantitative yield), which was used without further purification. LCMS (Method B): R_T=0.63 min,m/z=314[M+H]⁺.^oneH-NMR (400 MHz, DMSO-d ₆): δ 9.00 (brd 1H), 8.60 (br s, 1H), 8.45 (s, 1H), 8.12-8.06 (m, 2H), 7.53-7 .47 (m, 3H), 7.01 (s, 1H), 3.96 (d, 1H), 3.95 (d, 1H), 3.16-3.06 (m, 2H), 1, 88-1.78 (m, 1H), 1.70-1.54 (m, 3H), 1.43 (s, 3H), 1.30 (s, 3H).

Step 4: 3-(((R)-4-hydroxy-2,2-dimethyl-1-((R)-3-phenylbutanoyl)piperidin-4-yl)methyl)-6-phenylpyrimidine-4(3H)- he and 3-(((S)-4-hydroxy-2,2-dimethyl-1-((R)-3-phenylbutanoyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4(3H)-one : Prepared according to general procedure 5 using 3-((4-hydroxy-2,2-dimethylpiperidin-4-yl)methyl)-6-phenylpyrimidin-4(3H)-one hydrochloride (0.050) g, 0.143 mmol ), (R)-3-phenylbutanoic acid (0.035 g, 0.214 mmol), HBTU (0.081 g, 0.214 mmol) and DIPEA (0.103 ml, 0.572 mmol) in DCM (1.4 ml), to give a mixture of these compounds ( 22 mg, 33%). LCMS (Method B): R _T =1.32 min, m/z =460 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.41 (s, 1H), 8.12-8.06 (m, 2H), 7.53-7.47 (m, 3H), 7.29-7.23(m, 4H), 7.19-7.12(m, 1H), 7.00(s, 1H), 4.93(d, 1H), 4.06(dd, 1H), 3.82 (d, 1H), 3.48-3.39 (m, 1H), 3.18-3.10 (m, 1H), 2.65-2.55 (m, 1H) , 2.49-2.42 (m, 1H), 1.75-1.63 (m, 2H), 1.51-1.41 (m, 2H), 1.40 (d, 3H), 1 .35 (d, 3H), 1.22-1.17 (m, 3H), 0.90-0.85 (m, 1H).

Example 62: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(4-hydroxypiperidine-1-carbonyl)-4-phenylpyridine-2(1H )-he

Intermediate 1 (15 mg, 0.026 mmol) and 4-hydroxypiperidine (3.1 mg, 0.031 mmol) were shaken at room temperature in DMF (0.3 ml) using BioShake IQ for 18 hours. The mixture was concentrated and the residue was purified by preparative HPLC to give the title compound (10.1 mg, 70%). LCMS (method B): R _T= 1.02 min, m/z =558 [M+H] ⁺ .

Example 63: (R)-1-((4-Hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-5-(pyrrolidin-1-carbonyl)pyridine-2(1H) -he

Intermediate 1 (15 mg, 0.026 mmol) and pyrrolidine (2.2 mg, 0.031 mmol) were shaken at room temperature in DMF (0.3 ml) using BioShake IQ for 18 hours. The mixture was concentrated and the residue was purified by preparative HPLC to give the title compound (1.5 mg, 84%). LCMS (method B): R _T= 1.23 min, m/z =528 [M+H] ⁺ .

Example 64: (R)-1-((4-Hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-5-(1,4-dioxa-8-azaspiro[4.5] decane-8-carbonyl)pyridine-2(1H)-one

A solution of Intermediate 1 (15 mg, 0.026 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (4.4 mg, 0.031 mmol) in DMF (0.6 mL) was stirred using a BioShake IQ at room temperature within 2 hours. The reaction mixture was concentrated. The residue was diluted with DCM (0.3 ml) and water (0.5 ml). The organic layer was dried (Biotage phase separator) and concentrated to give the title compound (13 mg, 83%). LCMS (method B): R _T= 1.23 min, m/z =600 [M+H] ⁺ .

Example 65: (R)-N-cyclohexyl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3 -carboxamide

A solution of intermediate 1 (15 mg, 0.026 mmol) and cyclohexylamine (3.1 mg, 0.031 mmol) in DMF (0.6 ml) was stirred using a BioShake IQ at room temperature for 2 hours. The mixture was concentrated and the residue was diluted with DCM (0.3 ml) and water (0.5 ml). The organic layer was dried (Biotage phase separator) and concentrated to give the title compound (12 mg, 83%). LCMS (method B): R _T= 1.46 min, m/z =556 [M+H] ⁺ .

Example 66 6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(cis-2-phenylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)pyrimidin-4( 3H)-he

Prepared according to general procedure 12 using rac-cis- 2-phenylcyclopropane-1-carboxylic acid (7.0 mg, 0.043 mmol), HATU (20.6 mg, 0.054 mmol), DIPEA (15.2 μg, 0.087 mmol) and (R,S)-6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4(3H)-one (12 mg, 0.036) mmol) to give the title compound (10 mg, 59%). LCMS (method B): R _T= 1.37, 1.46 min, m/z =476 [M+H] ⁺ .

Example 67: (R,S)-3-((1-(3-cyclohexyl-1H-pyrazole-4-carbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2 -fluorophenyl)pyrimidin-4(3H)-one

Prepared according to general procedure 12 using 3-cyclohexyl-1H-pyrazole-4-carboxylic acid (8.3 mg, 0.043 mmol), HATU (20.6 mg, 0.054 mmol), DIPEA (15 μg, 0.087 mmol ) and (R,S)-6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4(3H)-one (12 mg, 0.036 mmol ) in DMF (0.6 ml) to give the title compound (4.4 mg, 24%). LCMS (method B): R _T= 1.28 min, m/z =508 [M+H] ⁺ .

Example 68: (S)-6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(3-phenylpropanoyl)piperidin-4-yl)methyl)pyrimidin-4(3H) -he

Prepared according to general procedure 12 using 3-phenylpropanoic acid (8.1 mg, 0.054 mmol), HATU (20.6 mg, 0.054 mmol), DIPEA (15.8 μl, 0.091 mmol) and (S)- 6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4(3H)-one (15 mg, 0.045 mmol) in DMF (0.6 ml ), to give the title compound (4.4 mg, 21%). LCMS (method B): R _T= 1.57 min, m/z =464 [M+H] ⁺ .

Example 69: (R,S)-6-(2-fluorophenyl)-3-((4-hydroxy-1-(1-isobutyl cyclopropan-1-carbonyl)-3,3-dimethylpiperidin-4-yl)methyl) pyrimidin-4(3H)-one

Prepared according to general procedure 12 using 1-isobutylcyclopropane-1-carboxylic acid (7.6 mg, 0.054 mmol), HATU (20.6 mg, 0.054 mmol), DIPEA (15.8 μl, 0.091 mmol) and (R,S)-6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4(3H)-one (15 mg, 0.045 mmol) in DMF (0.6 ml) to give the title compound (6.2 mg, 30%). LCMS (method B): R _T= 1.57 min, m/z =456 [M+H] ⁺ .

Example 70: (S)-6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(3-methyl-3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin- 4(3H)-he

Prepared according to general procedure 12 using 3-methyl-3-phenylbutanoic acid (9.6 mg, 0.054 mmol), HATU (20.6 mg, 0.054 mmol), DIPEA (15.8 μl, 0.091 mmol) and (S)-6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4(3H)-one (15 mg, 0.045 mmol) to give the title compound (7.2 mg, 33%). LCMS (method B): R _T= 1.71 min, m/z =492 [M+H] ⁺ .

Example 71: (S)-1-((1-(4,4-difluoro-3-phenylbutanoyl)-4-hydroxypiperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 12 using (S)-4,4-difluoro-3-phenylbutanoic acid (Angew. Chem. Int. Ed., 2013, 52, p. 14191-14195) (6.2 mg, 0.031 mmol), HATU (12.9 mg, 0.034 mmol), DIPEA (9.1 μg, 0.052 mmol) and 1-((4-hydroxypiperidin-4-yl)methyl)-N-isopropyl-N-methyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide (10 mg, 0.026 mmol) to give the title compound (6.0 mg, 41%). LCMS (method B): R _T= 1.80 min, m/z =566 [M+H] ⁺ .

Example 72: 1-((4-hydroxy-1-(1-(thiophen-2-yl)cyclopropan-1-carbonyl)piperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo- 4-phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 12 using 1-(thiophen-2-yl)cyclopropan-1-carboxylic acid (5.2 mg, 0.031 mmol), HATU (12.9 mg, 0.034 mmol), DIPEA (9, 11 µl, 0.052 mmol) and 1-(((4-hydroxypiperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide (10 mg, 0.026 mmol) to give the title compound (7.0 mg, 51%) LCMS (Method B): R _{T =} 1.17 min, m/z = 534 [M+H] ⁺ .

Example 73: 1-((( R )-one-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N -isopropyl- N -methyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide and 1-((( S )-one-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N -isopropyl- N -methyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 5 using amine 3 (30 mg, 0.073 mmol), acid 1 (18.6 mg, 0.1 1 mmol), DIPEA (0.051 ml, 0.29 mmol), HBTU (41.5 mg, 0.109 mmol) and DCM (1 ml) at room temperature for 48 hours to obtain a mixture of these compounds (26.2 mg, 64%). LCMS (method B): R _T =1.53 min, m/z 564 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ , mixture of diastereomers and conformational isomers): δ 7.50-7.33 (m, 6H), 6.68 (d, 1H), 5.17-4.45 (m , 3H), 4.09-3.18 (m, 4H), 3.03-2.78 (m, 2H), 2.69 (d, 1.5H), 2.27 (d, 1.5H ), 1.84-1.58 (b.m., 8H), 1.58-0.60 (b.m., 20H), 0.30-0.19 (m, 2H).

Example 74: (R)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(2-(hydroxymethyl)phenyl)pyrimidin-4(3H)-one

Sodium carbonate (27.2 mg, 0.26 mmol) and (R)-6-chloro-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4(3H )-one (50 mg, 0.13 mmol) was suspended in a mixture of 1,4-dioxane (1.5 ml) and water (0.5 ml). (2-(Hydroxymethyl)phenyl)boronic acid (29.2 mg, 0.19 mmol) was added and the mixture was purged with nitrogen. Pd(PPh ₃ ) ₄ (7.4 mg, 6.41 µmol) was added and the mixture was heated in a microwave oven at 140° C. for 15 minutes. The mixture was cooled and diluted with water, then extracted with DCM. The organic layer was dried (Biotage phase separator) and concentrated, and the residue was purified by flash chromatography (Biotage KP-NH (11 g), 0-100% EtOAc in cyclohexane; then 0-15% MeOH in EtOAc), giving the indicated in header compound (10 mg, 17%). LCMS (method B): R _T =1.00 min, m/z =462 [M+H] ⁺ . ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 8.36 (d, 1H), 7.58 (d, 1H), 7.48 (m, 2H), 7.38 (d, 1H) , 7.27 (m, 4H), 7.17 (m, 1H), 6.61 (m, 1H), 5.25 (t, 1H), 5.00 (d, 1H), 4.59 ( d, 2H), 4.00 (m, 3H), 3.70 (m, 1H), 3.20 (m, 2H), 2.90 (m, 1H), 2.60 (m, 2H), 1.25-1.60 (m, 4H), 1.21 (m, 3H).

Example 75: (R)-N,N-diethyl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxamide

Stage 1: (R)-ethyl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate : Ethyl 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (1.45 g, 5.96 mmol) and epoxide 2 (1.55 g, 5.96 mmol) were dissolved in DMF (30 ml) and pyridine (0.723 ml, 8.94 mmol). The reaction mixture was stirred at 80°C for 21 hours. The mixture was allowed to cool to room temperature, diluted with water and extracted with EtOAc (x 2). The combined organic extracts were washed with water (x 3) and brine (x 1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography (GraceResolv, 0-100% EtOAc in cyclohexane) to give the title compound (883 mg, 29%). LCMS (method B): R _T= 1.29 min, m/z =503 [M+H] ⁺ .

Step 2: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid : (R)-ethyl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (884 mg , 1.76 mmol) was dissolved in THF (2 ml) and sodium hydroxide (2M in water, 4.40 ml, 8.80 mmol) was added. The mixture was stirred at room temperature for 21 hours, then an additional portion of 2M sodium hydroxide (2 ml) was added and the mixture was stirred for another 48 hours. The solution was concentrated and the residue was diluted with water. The resulting solution was extracted with Et ₂ O (x 3) and the organic extracts were discarded. The aqueous layer was acidified to pH ~4 with 2M HCl (aq) and extracted with EtOAc (x 3). The combined organic extracts were dried (MgSO ₄ ) and concentrated to give the title compound (738 mg, 88%). LCMS (method B): R _T= 1.11 min, m/z =475 [M+H] ⁺ .

Step 3: (R)-N,N-diethyl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxamide : (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (40 mg, 0.084 mmol) and DIPEA (0.044 ml, 0.253 mmol) were dissolved in DMF (1 ml) and HATU (35.3 mg, 0.093 mmol) was added. The mixture was stirred at room temperature for 10 minutes, then diethylamine (9.59 μl, 0.093 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated and the residue partitioned between DCM and H ₂ O. The organic layer was separated using a Biotage phase separator and concentrated, and the residue was purified by flash chromatography (Biotage KP-NH, 0-100% EtOAc in cyclohexane) to give the title compounds (17.8 mg, 40%). LCMS (method B): R _T =1.17 min, m/z= 530 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 7.70 (d, 1H), 7.47-7.38 (m, 5H), 7.32-7.24 (m, 4H), 7.21-7.13(m, 1H), 6.44(d, 1H), 4.93(d, 1H), 4.08-3.87(bm, 3H), 3.72- 3.60 (bm, 1H), 3.31-3.13 (m, 3H), 3.08-2.91 (m, 3H), 2.65-2.54 (m, 2H), 1.57-1.19 (bm, 8H), 0.89-0.80 (m, 6H).

Example 76 3-((1-(3-cyclohexylbutanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one

Prepared according to general procedure 12 using (R,S)-3-cyclohexylbutanoic acid (7.7 mg, 0.045 mmol), HATU (19 mg, 0.050 mmol), DIPEA (16 μl, 0.091 mmol), amine 5 (15 mg, 0.045 mmol) and DMF (0.6 ml) to give the title compound (4.6 mg, 21%) as a mixture of diastereomers. LCMS (method B): R _T= 1.96 min, m/z =484 [M+H] ⁺ .

Example 77: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(morpholine-4-carbonyl)-4-phenylpyridine-2(1H)- he

(R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (15 mg 0.026 mmol) was dissolved in DMF (0.3 ml) and morpholine (2.7 mg, 0.031 mmol) was added as a solution in DMF (0.3 ml) followed by HATU (1.1 eq.). The reaction mixture was stirred using BioShake IQ for 18 hours at room temperature. The crude product was purified by preparative HPLC to give the title compound (7.1 mg, 48%). LCMS (method B): R _T= 1.16 min, m/z =544 [M+H] ⁺ .

Example 78: (S)-3-((1-(3-cyclohexylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidine-4(3H)- he

Prepared according to general procedure 12 using 3-cyclohexylpropanoic acid (7.0 mg, 0.045 mmol), HATU (19 mg, 0.050 mmol), DIPEA (16 µl, 0.091 mmol) and amine 5 (15 mg, 0.045 mmol ) in DMF (0.6 ml) to give the title compound (5.7 mg, 27%). LCMS (method B): R _T= 1.87 min, m/z =470 [M+H] ⁺ .

Example 79: (R,S)-1-((1-(3-cyclobutylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo- 4-phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 5 using amine 3 (30 mg, 0.073 mmol), 3-cyclobutylpropanoic acid (14.0 mg, 0.109 mmol), DIPEA (0.051 ml, 0.292 mmol), HBTU (41.5 mg, 0.109 mmol) and DCM (1 ml) to give the title compound (34.7 mg, 91%). LCMS (method B): R _T =1.32 min, m/z= 522 [M+H] ⁺ . ¹ H-NMR (400 MHz, methanol- d ₄ , compound presented as a 1:1 mixture of conformational isomers): δ 7.73-7.66 (broad m, 1H), 7.40-7.32 (m, 5H), 6.52 (s, 0.5H), 6.49 (s, 0.5H), 4.58-4.07 (br.m, 2H), 3.98-3 .77 (b.m, 1H), 3.77-3.50 (b.m., 2H), 3.38-3.22 (m, 1H), 3.18-2.93 (b.m., 1H), 2.61 (s, 1.5H), 2.37 (s, 1.5H), 2.31-2.10 (m, 3H), 2.04-1.91 (m, 2H) , 1.88-1.67 (m, 3H), 1.64-1.47 (m, 4H), 1.31-1.11 (bm, 2H) 1.06-0.68 (b .m, 11H), 0.32 (dd, 1H).

Example 80: (R,S)-1-((1-(2-ethylhexanoyl)-4-hydroxypiperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-4-phenyl-1, 6-dihydropyridine-3-carboxamide

Prepared according to general procedure 12 using (R,S)-2-ethylhexanoic acid (4.3 mg, 0.026 mmol), HATU (13 mg, 0.034 mmol), DIPEA (10 μl, 0.052 mmol) and 1- ((4-hydroxypiperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide (10 mg, 0.026 mmol) in DMF (0. 6 ml) to give the title compound (7.3 mg, 55%). LCMS (method B): R _T= 1.30 min, m/z =510 [M+H] ⁺ .

Example 81: (R,S)-6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(1-methylcyclohexane-1-carbonyl)piperidin-4-yl)methyl) pyrimidin-4(3H)-one

Prepared according to general procedure 12 using 1-methylcyclohexane-1-carboxylic acid (7.7 mg, 0.045 mmol), HATU (22.5 mg, 0.059 mmol), DIPEA (17 μl, 0.099 mmol) and amine 5 (15 mg, 0.049 mmol) in DMF (0.6 mL) to give the title compound (2.0 mg, 24%). LCMS (method B): R _T= 1.79 min, m/z =456 [M+H] ⁺ .

Example 82 6-(2-fluorophenyl)-3-((1-(3-(4-fluorophenyl)propanoyl)-4-hydroxypiperidin-4-yl)methyl)pyrimidin-4(3H)-one

Prepared according to general procedure 12 using 3-(4-fluorophenyl)propanoic acid (8.2 mg, 0.049 mmol), HATU (22.5 mg, 0.059 mmol), DIPEA (17 μl, 0.099 mmol) and amine 1 (15 mg, 0.049 mmol) in DMF (0.6 mL) to give the title compound (9.2 mg, 42%). LCMS (method B): R _T= 1.39 min, m/z =454 [M+H] ⁺ .

Example 83: (R,S)-3-((1-(3-cyclopropylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H )-he

Prepared according to general procedure 12 using 3-cyclopropylpropanoic acid (5.1 mg, 0.045 mmol), HATU (19 mg, 0.050 mmol), DIPEA (16 μl, 0.091 mmol) and amine 5 (15 mg, 0.045 mmol ) in DMF (0.6 ml) to give the title compound (5.0 mg, 26%). LCMS (method B): R _T= 1.51 min, m/z =428 [M+H] ⁺ .

Example 84 3-carboxamide

Prepared according to general procedure 12 using 2,2-dimethylbutanoic acid (3.5 mg, 0.026 mmol), HATU (13 mg, 0.034 mmol), DIPEA (10 μl, 0.02 mmol) and 1-(( 4-hydroxypiperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide (10 mg, 0.026 mmol) in DMF (0.6 ml ) to give the title compound (8.4 mg, 67%). LCMS (method B): R _T= 1.15 min, m/z =482 [M+H] ⁺ .

Example 85: (R)-N-(2-(1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-1,6-dihydropyrimidin-4-yl )phenyl)acetamide

Step 1: (R)-6-(2-aminophenyl)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one : Prepared according to with general procedure 4, using (R)-6-chloro-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one (30mg, 0.077 mmol), (2-aminophenyl)boronic acid hydrochloride (20.01 mg, 0.115 mmol), sodium carbonate (20.4 mg, 0.192 mmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (6.6 mg , 7.69 µmol), 1,4-dioxane (0.75 ml) and water (0.25 ml) when heated in a microwave oven at 150°C for 15 minutes to give the title compound (30 mg, 87 %). LCMS (method B): R _T= 1.17 min, m/z =447 [M+H] ⁺ .

Step 2: (R)-N-(2-(1-((4-Hydroxy-1-(3-genylbutanoyl)piperidin-4-yl)methyl-6-dihydropyrimidin-4-yl)phenyl)acetamide : Prepared in according to general procedure 5, using (R)-6-(2-aminophenyl)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4(3H)- she (30 mg, 0.067 mmol), acetic acid (4.62 μl, 0.081 mmol), DIPEA (0.023 ml, 0.134 mmol), HBTU (38.2 mg, 0.101 mmol) and DCM (1 ml), to obtain the indicated in title compound (12.6 mg, 38%) LCMS (method B): R _T = 1.17 min, m/z = 489 [M+H] ^{+ 1} H-NMR (400 MHz, DMSO - d ₆ ): δ 10.68 (s, 1H), 8.52 (d, 1H), 8.07 (brd, 1H), 7.73 (dd, 1H), 7.50 (td, 1H) , 7.38-7.19 (m, 6H), 6.77 (d, 1H), 5.05 (d, 1H), 4.14-3.94 (br. m, 3H), 3.79 -3.68 (b.m., 1H), 3.37-3.18 (b.m., 2H), 3.03-2.92 (b.t.d., 1H), 2.71-2.59 ( m, 2H), 2.10 (s, 3H), 1.65-1.23 (br. m, 7H).

Example 86: (R)-5-(4-(aminomethyl)phenyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridine-2(1H) -he

Step 1: (R)-tert-butyl-4-(1-((4-hydroxy-1-(3-genylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6- dihydropyridin-3-yl)benzylcarbamate : Prepared according to general procedure 4 using (R)-5-bromo-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)- 4-phenylpyridin-2(1H)-one (30mg, 0.059mmol), 4-(N-Boc-aminomethyl)phenylboronic acid (22.2mg, 0.088mmol), sodium carbonate (8.3mg, 0.079mmol) , 1,4-dioxane (0.5 ml), water (0.2 ml) and Pd(Ph ₃ P) ₄ (3.4 mg, 2.9 μmol). The mixture was heated in a microwave oven at 150° C. for 20 minutes. The crude product was purified by flash chromatography (Biotage KP-Sil, 20-100% EtOAc in cyclohexane; then 5% MeOH in EtOAc) to give the title compound (11 mg, 29%). LCMS (method B): R _T= 1.42 min, m/z =636 [M+H] ⁺ .

Step 2: (R)-5-(4-(aminomethyl)phenyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridine-2(1H) -one : Prepared according to general procedure 7, using ( R ) -tert -butyl 4-(1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo -4-phenyl-1,6-dihydropyridin-3-yl)benzylcarbamate (11 mg, 0.017 mmol) in DCM (2 ml) and TFA (1 ml) to give the title compound (6 mg, 65%). LCMS (method B): R _T =0.93 min, m/z =536 [M+H] ⁺ . ¹ H-NMR (400 MHz, methanol- d ₄ , the compound is presented as two conformational isomers A:B in a ratio of 2:3): δ 7.59 (s, 0.4H, conformational isomer A), 7.52 ( s, 0.6H, conformational isomer B), 7.25-6.90 (m, 14H), 6.48 (s, 1H), 4.20-3.78 (m, 3H), 3.80 ( s, 2H), 3.66-3.54 (m, 1H), 3.18-3.05 (m, 2H), 2.99-2.80 (m, 1H), 2.76-2, 60 (m, 1H), 2.55-2.35 (m, 1H), 1.62-1.10 (m, 6H), 0.90-0.75 (m, 1H).

Example 87: (R)-1-((1-(3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxamide

Stage 1: tert-Butyl-4-hydroxy-4-((5-(isopropyl(methyl)carbamoyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)piperidine-1-carboxylate : Obtained in according to general procedure 4, using tert-butyl-4-((4-chloro-5-(isopropyl(methyl)carbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-4-hydroxypiperidin-1- carboxylate (820 mg, 1.86 mmol), 1,4-dioxane (12 ml), phenylboronic acid (339 mg, 2.78 mmol), sodium carbonate (2M in water, 1.86 ml, 3.71 mmol) , water (2.4 ml) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (76 mg, 0.093 mmol). The reaction mixture was heated in a microwave oven at 120° C. for 45 minutes to give the title compound (730 mg, 81%). LCMS (method B): R _T= 1.18 min, m/z =428 [M+H- ^t Bu] ⁺ .

Stage 2: 1-((4-hydroxypiperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide : Prepared according to the general procedure 7 using tert-butyl 4-hydroxy-4-((5-(isopropyl(methyl)carbamoyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)piperidine-1-carboxylate (730 mg) 1.51 mmol), DCM (6 ml) and TFA (2 ml, 26.0 mmol) to give the title compound (448 mg, 77%). LCMS (method B): R _T= 0.67 min, m/z =384 [M+H] ⁺ .

Step 3: (R)-1-((1-(3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxamide: Prepared according to general procedure 5 using (R)-3-cyclohexyl-2-methylpropanoic acid (acid 1) (26.6 mg, 0.156 mmol), 1-(( 4-hydroxypiperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide (40 mg, 0.104 mmol), HBTU (59.3 mg , 0.156 mmol) and DIPEA (0.055 ml, 0.313 mmol) in DCM (2 ml). The residue was purified by preparative HPLC to give the title compound (38 mg, 68%). LCMS (method B): R _T =1.38 min, m/z =536 [M+H] ⁺ . ¹ H-NMR (400 MHz, methanol- d ₄ , compound presented as two conformational isomers in a 1:1 ratio): δ 7.80 (d, 1H), 7.48 (m, 5H), 6.61 ( d, 1H), 4.65 (m, 0.5H), 4.33-4.05 (m, 3H), 3.92 (m, 1H), 3.71 (m, 0.5H), 3 .51 (m, 1H), 3.19 (m, 1H), 3.01 (m, 1H), 2.73 (s, 1.5H), 2.49 (s, 1.5H), 1, 81-1.53 (m, 10H), 1.37-0.80 (m, 15H), 0.44 (m, 1H).

Example 88: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-5-(piperidine-1-carbonyl)pyridine-2(1H) -he

Prepared according to general procedure 3 using (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxylic acid (40 mg, 0.084 mmol), HATU (35.3 mg, 0.093 mmol), DIPEA (0.044 ml, 0.253 mmol) and piperidine (9.2 µmol, 0.093 mmol) in DMF (1 ml), to give the title compound (32) mg, 70%). LCMS (Method B): R _T =1.20 min, m/z =542 [M+H] ⁺ , ¹H-NMR (400 MHz, methanol- d ₄ , the compound is presented as two conformational isomers A and B, in ratio 2:3): δ 7.77 (s, 0.4 H, conformational isomer A), 7.72 (s, 0.6H, conformational isomer B), 7.54-7.41 (m, 5H) , 7.39-7.14(m, 5H), 6.60(s, 1H), 4.32-3.84(m, 3H), 3.77-3.63(m, 1H), 3 .61-3.48 (m, 1H), 3.46-3.39 (m, 1H), 3.28-2.86 (m, 5H), 2.86-2.71 (m, 1H) , 2.67-2.48 (m, 1H), 1.73-1.19 (m, 11H), 1.03-0.86 (m, 1H), 0.68 (s, 1H).

Example 89: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-N-isopropyl-4-(2-methoxyphenyl)-N-methyl-6-oxo -1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 4 using (2-methoxyphenyl)boronic acid (23.4 mg, 0.154 mmol), (R)-4-chloro-1-((4-hydroxy-1-(3-phenylbutanoyl) piperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (50 mg, 0.102 mmol), 1,4-dioxane (0.5 ml), 2M sodium carbonate (0.1-13 ml, 0.225 mmol) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (4.3 mg, 5.1 µmol). The mixture was heated at 90° C. overnight. The crude product was purified by preparative HPLC to give the title compound (4 mg, 7%). LCMS (method B): R _T =1.16 min, m/z =560 [M+H] ⁺ , ¹H-NMR (400 MHz, DMSO- d ₆ ): δ 7.65 (m, 1H), 7 .39-6.95 (m, 9H), 6.30 (m, 1H), 4.98 (br s, 1H), 4.38 (m, 1H), 4.12-3.83 (m , 3H), 3.74-3.60 (m, 4H), 3.29-3.13 (m, 3H), 2.96 (m, 1H), 2.71-2.54 (m, 4H ), 1.59-1.10 (m, 7H), 1.05-0.76 (m, 5H), 0.61-0.48 (m, 1H).

Example 90: (R)-4-(2-fluorophenyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidine-isopropyl-N-methyl-6-oxo-1,6-dihydropyridine-3- carboxamide

Prepared according to the procedure for Example 89, except that (2-fluorophenyl)boronic acid (21.5 mg, 0.154 mmol) and (R)-4-chloro-1-((4-hydroxy-1-( 3-phenylbutanoyl)piperidine)-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (50 mg, 0.102 mmol) to give the title compound ( 7.5 mg, 13%). LCMS (method B): R _T =1.18 min, m/z =548 [M+H] ⁺ , ¹H-NMR (400 MHz, DMSO- d ₆ , compound presented as two conformational isomers in a 1:1 ratio ): δ 7.74 (m, 1H), 7.45 (m, 1H), 7.38-7.16 (m, 8H), 6.44 (d, 1H), 4.96 (br s , 1H), 4.42 (br s, 0.5 H), 4.12-3.81 (m, 3.5H), 3.68 (m, 1H), 3.34-3.15 ( m, 2H), 2.91 (m, 1H), 2.70-2.55 (m, 5H), 1.55-1.17 (m, 7H), 1.11-0.72 (m, 6H).

Example 91: (R)-1'-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4'-phenyl-[2,3'-bipyridine]-6'(1 'H)-he

Step 1: (6-chloro-4-phenylpyridin-3-yl)boronic acid : 5-bromo-2-chloro-4-phenylpyridine (0.5 g, 1.86 mmol) was dissolved in anhydrous THF (15 ml) and cooled to -78°C. n-Butyl lithium (0.89 ml, 2.23 mmol) was added and the reaction mixture was stirred for 20 minutes at -78°C. Triisopropyl borate (0.87 mL, 3.72 mmol) was then added quickly. The mixture was stirred for 1 hour at -78°C. The reaction was quenched with water and allowed to warm to room temperature, then concentrated. The residue was diluted with water, the pH was adjusted to 10 using 5% aqueous sodium hydroxide solution, and the solution was washed with diethyl ether. The pH was then adjusted to 4 using 48% HBr. The precipitated solid was collected on a sintered funnel, washed with water and dried to give the title compound (0.23 g, 52%). LCMS (method B): R _T= 0.92 min, m/z =234 [M+H] ⁺ .

Step 2: 6'-chloro-4'-phenyl-2,3'-bipyridine : 2-bromopyridine (0.041 ml, 0.43 mmol), (6-chloro-4-phenylpyridin-3-yl)boronic acid (50 mg, 0.214 mmol) and sodium carbonate (45.4 mg, 0.43 mmol) were dissolved in 1,4-dioxane (0.5 ml) and water (0.2 ml). The mixture was degassed by bubbling nitrogen through it for 5 minutes, then Pd(Ph ₃ P) ₄ (12.4 mg, 10.7 µmol) was added. The reaction mixture was heated in a microwave oven at 100° C. for 20 minutes. The mixture was diluted with water and extracted with DCM. The organic layer was dried (Biotage phase separator), concentrated, and the residue was purified by flash chromatography (GraceResolv, 0-50% EtOAc in cyclohexane) to give the title compound (48 mg, 84%). LCMS (method B): R _T= 1.24 min, m/z =267 [M+H] ⁺ .

Step 3: 4'-phenyl-[2,3'-bipyridine]-6'(1'H)-one : 6'-chloro-4'-phenyl-2,3'-bipyridine (50 mg, 0.187 mmol) and DMSO (0.5 ml) was added to a solution of sodium hydroxide (52.5 mg, 1.31 mmol) in water (0.5 ml). The mixture was heated in a microwave oven at 130° C. for 30 minutes. The mixture was diluted with water and extracted with DCM and the organic layer was dried (Biotage phase separator) and concentrated to give the title compound (45 mg, 97%). LCMS (method B): R _T= 0.66 min, m/z =249 [M+H] ⁺ .

Stage 4: (R)-1'-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4'-phenyl-[2,3'-bipyridine]-6'(1 'H)-one: Prepared according to general procedure 1 using 4'-phenyl-[2,3'-bipyridine]-6'(1'H)-one (45 mg, 0.181 mmol), epoxide 2 ( 51.7 mg, 0.199 mmol) and cesium carbonate (118 mg, 0.362 mmol) in DMF (1 mL) to give the title compound (11.5 mg, 13%). LCMS (Method B): R _T =1.10 min, m/z =508 [M+H] ⁺ , ¹H-NMR (400 MHz, methanol -d ₄ , the compound is presented as two A:B conformational isomers in the ratio 2:3): δ 8.51 (td, d, 1H), 7.95 (s, 0.4H, conformational isomer A), 7.89 (s, 0.6H, conformational isomer B), 7.62 (td, 1H), 7.39-7.11 (m, 11H), 7.02-6.97 (m, 1H), 6.62 (s, 1H), 4.33-3.92 (m , 3H), 3.78-3.63 (m, 1H), 3.30-3.16 (m, 2H), 3.11-2.90 (m, 1H), 2.88-2.71 (m, 1H), 2.69-2.47 (m, 1H), 1.77-1.19 (m, 6H), 1.02-0.87 (m, 1H).

Example 92: 1-((1-(3-cyclohexylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-4-phenyl-1,6-dihydropyridine-3- carboxamide

Prepared according to General Procedure 3 using 3-cyclohexylpropanoic acid (24.4 mg, 0.156 mmol), 1-((4-hydroxypiperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo- 4-phenyl-1,6-dihydropyridine-3-carboxamide (40 mg, 0.104 mmol), HATU (35.2 mg, 0.093 mmol) and DIPEA (0.059 ml, 0.337 mmol) in DCM (2 ml). The crude product was purified by preparative HPLC to give the title compound (29 mg, 53%). LCMS (Method B): R_T=1.33 min,m/z=522[M+H]⁺, ¹H-NMR (400 MHz, methanol-d _four, the compound is presented as two conformational isomers in a ratio of 1:1): δ 7.80 (m, 1H), 7.48 (m, 5H), 6.61 (d, 1H), 4.62 (m, 0 .5H), 4.30-4.04 (m, 3H), 3.76-3.58 (m, 1.5H), 3.49 (m, 1H), 3.14 (m, 1H), 2.72 (s, 1.5H), 2.50 (s, 1.5H), 2.47 (m, 2H), 1.83-1.48 (m, 11H), 1.39-1, 17 (m, 5H), 1.15-0.79 (m, 6H), 0.44 (m, 1H).

Example 93: (R)-tert-Butyl-4-(1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6- dihydropyridine-3-carbonyl)piperazine-1-carboxylate

Prepared according to general procedure 3 using (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxylic acid (40 mg, 0.084 mmol), tert-butylpiperazine-1-carboxylate (17.3 mg, 0.093 mmol), DIPEA (0.04 ml, 0.253 mmol) and HBTU (35 mg, 0.093 mmol) in DMF (1 ml). The crude product was purified by flash chromatography (GraceResolv, 40-100% EtOAc in cyclohexane; then 0-10% MeOH in EtOAc) to give the title compound (35 mg, 65%). LCMS (Method B): R _T = 1.28 min, m/z = 643 [M+H] ⁺ , ¹H-NMR (400 MHz, methanol- d ₄ , compound presented as two A:B conformational isomers in the ratio 2:3): δ 7.70 (s, 0.4H, conformational isomer A), 7.65 (s, 0.6H, conformational isomer B), 7.45-7.33 (m, 5H), 7 .27-7.03 (m, 5H), 6.49 (s, 1H), 4.18-3.72 (m, 3H), 3.65-3.30 (m, 4H), 3.12 -2.74 (m, 6H), 2.75-2.59 (m, 1H), 2.55-2.36 (m, 1H), 2.17 (s, 1H), 1.60-1 .12 (m, 16H), 0.94-0.74 (m, 1H).

Example 94: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-5-(piperazine-1-carbonyl)pyridine-2(1H) -he

Prepared according to general procedure 7 using (R)-tert-butyl-4-(1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate (30 mg, 0.047 mmol) and TFA (0.5 ml) in DCM (2 ml). The crude product was purified by flash chromatography (Biotage KP-NH, 20-100% EtOAc in cyclohexane; then 5% MeOH in EtOAc) to give the title compound (10 mg, 40%). LCMS (method B): R _T =0.71 min, m/z =543 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ , compound presented as two conformational isomers A:B in a 1:1 ratio): δ 7.73 (s, 0.5H, conformational isomer A), 7.70 ( s, 0.5H, conformational isomer B), 7.52-7.34 (m, 5H), 7.33-7.23 (m, 4H), 7.21-7.12 (m, 1H), 6.44 (d, 1H), 4.94 (d, 1H), 4.17-3.82 (m, 3H), 3.73-3.60 (m, 1H), 3.29-2, 71 (m, 8H), 2.66-2.53 (m, 3H), 2.44-2.20 (m, 2H), 1.87-1.69 (m, 1H), 1.58- 1.10 (m, 7H).

Example 95: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxamide

(R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (40 mg 0.084 mmol) was dissolved in DMF (1 ml) and HATU (35.3 mg, 0.093 mmol) was added followed by DIPEA (0.044 ml, 0.253 mmol). The reaction mixture was stirred at room temperature for 10 minutes, then dimethylamine (2M in THF, 0.046 mL, 0.093 mmol) was added. The reaction mixture was then stirred at room temperature for 16 hours. Added another 1 ml of dimethylamine solution, and the mixture was stirred for another 2 hours. The mixture was concentrated and the residue was dissolved in water. The mixture was extracted with DCM and the organic layer was dried (Biotage phase separator) and concentrated. The crude residue was purified by flash chromatography (GraceResolv, eluted with 50-100% EtOAc in cyclohexane; then 5% MeOH in EtOAc) to give the title compound (10 mg, 24%). LCMS (Method B): R _T = 1.04 min, m/z = 502 [M+H] ⁺ , ¹H-NMR (400 MHz, methanol- d ₄ , compound presented as two A:B conformational isomers in the ratio 2:3): δ 7.69 (s, 0.4H, conformational isomer A), 7.63 (s, 0.6H, conformational isomer B), 7.42-7.29 (m, 5H), 7 .27-7.03(m, 5H), 6.49(s, 1H), 4.18-3.76(m, 3H), 3.66-3.52(m, 1H), 3.12 -2.80 (m, 3H), 2.77-2.58 (m, 4H), 2.55-2.32 (m, 4H), 1.61-1.11 (m, 6H), 0 .90-0.72 (m, 1H).

Example 96: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-4-(p-tolyl) -1,6-diguropyridine-3-carboxamide

Prepared according to General Procedure 4 using p-tolylboronic acid (16.7 mg, 0.123 mmol), (R)-4-chloro-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidine-4- yl)methyl)-N-isopropyl-N-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (40 mg, 0.082 mmol), 1,4-dioxane (0.5 ml), sodium carbonate (2M in water, 0.082 ml, 0.164 mmol) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (3.5 mg, 4.10 µmol). The reaction mixture was heated in a microwave oven at 130° C. for 30 minutes. The crude product was purified by preparative HPLC to give the title compound (5 mg, 11%). LCMS (method B): R _T =1.27 min, m/z =544 [M+H] ⁺ , ¹H-NMR (400 MHz, methanol- d ₄ , compound presented as a mixture of conformational isomers): δ 7, 72 (m, 1H), 7.41-7.16 (m, 9H), 6.59 (m, 1H), 3.82-4.29 (m, 3H), 3.68 (m, 2H) , 3.30-3.19 (m, 2H), 3.11-2.90 (m, 1H), 2.86-2.48 (m, 5H), 2.40 (s, 3H), 1 .71-0.74 (m, 12H), 0.44 (m, 1H).

Example 97: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-N-methoxy-N-methyl-6-oxo-4-phenyl-1,6 -dihydropyridine-3-carboxamide

Prepared according to general procedure 5 using (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxylic acid (40 mg, 0.084 mmol), N,O-dimethylhydroxylamine hydrochloride (10.7 mg, 0.1-10 mmol), DIPEA (0.06 ml, 0.337 mmol) and HBTU (35 mg, 0.093 mmol ) in DMF (1 ml) to give the title compound (22 mg, 50%). LCMS (method B): R _T =1.23 min, m/z =518 [M+H] ⁺ , ¹H-NMR (400 MHz, DMSO- d ₆ , compound presented as a mixture of conformational isomers): δ 7, 85 (d, 1H), 7.49-7.32 (m, 5H), 7.32-7.20 (m, 4H), 7.20-7.11 (m, 1H), 6.43 ( d, 1H), 4.96 (d, 1H), 4.09-3.87 (m, 3H), 3.73-3.58 (m, 1H), 3.43 (d, 3H), 3 .31-3.11 (m, 2H), 3.00 (s, 3H), 2.96-2.85 (m, 1H), 2.66-2.53 (m, 2H), 1.59 -1.12 (m, 7H).

Example 98: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4,5-diphenylpyridin-2(1H)-one

Prepared according to general procedure 4 using (R)-5-bromo-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridine-2(1H) -one (25 mg, 0.049 mmol), phenylboronic acid (8.98 mg, 0.074 mmol), sodium carbonate (10.4 mg, 0.098 mmol), 1,4-dioxane (0.5 ml), water (0.200 ml ) and Pd(Ph ₃ P) ₄ (2.8 mg, 2.45 µmol). The mixture was heated in a microwave oven at 150° C. for 10 minutes to give the title compound (14.5 mg, 58%). LCMS (Method B): R _T = 1.39 min, m/z = 507 [M+H] ⁺ , ¹ H-NMR (400 MHz, methanol- d ₄ , compound presented as two conformational isomers in a ratio of approximately 1: 1): δ 7.71 (s, 0.5H), 7.64 (s, 0.5H), 7.09-7.36 (m, 15H), 6.61 (s, 1H), 4, 29-3.72 (m, 4H), 3.27-2.73 (m, 4H), 2.65-2.50 (m, 1H), 1.74-1.23 (m, 6H), 0.95 (s, 1H).

Example 99: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-[3,3'-bipyridin-6(1H)-one

Prepared according to general procedure 4 using (R)-5-bromo-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridine-2(1H) -one (20 mg, 0.039 mmol), pyridin-3-ylboronic acid (7.2 mg, 0.059 mmol), sodium carbonate (8.3 mg, 0.078 mmol), 1,4-dioxane (0.5 ml), water (0.200 ml) and Pd(Ph ₃ P) ₄ (2.3 mg, 1.95 µmol). The mixture was heated in a microwave oven at 150° C. for 10 minutes to give the title compound (4 mg, 20%). LCMS (Method B): R _T =0.98 min, m/z =508 [M+H], ¹H-NMR (400 MHz, methanol- d ₄ , compound presented as two A:B conformational isomers in a ratio of 2 :3): δ 8.40 (d, 1H), 8.28 (s, 1H), 7.80 (s, 0.4H, conformational isomer A), 7.74 (s, 0.6H, conformational isomer B), 7.57-7.47 (m, 1H), 7.41-7.10 (m, 11H), 6.64 (s, 1H), 4.33-3.92 (m, 3H ), 3.80-3.63 (m, 1H), 3.29-3.17 (m, 2H), 3.12-2.93 (m, 1H), 2.89-2.71 (m , 1H), 2.68-2.48 (m, 1H), 1.75-1.20 (m, 6H), 1.06-0.84 (m, 1H).

Example 100: (R)-5-(3-(aminomethyl)phenyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridine-2(1H) -he

Prepared according to general procedure 4 using (R)-5-bromo-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridine-2(1H) -one (30 mg, 0.059 mmol), 3-(aminomethyl) benzeneboronic acid hydrochloride (16.6 mg, 0.088 mmol), sodium carbonate (19.2 mg, 0.18 mmol), water (0.2 ml), 1,4-dioxane (0.5 ml) and Pd(Ph ₃ P) ₄ (1.5 mg, 2.9 µmol). The mixture was heated in a microwave oven at 150° C. for 20 minutes to give the title compound (12 mg, 38%). LCMS (Method B): R _T = 1.01 min, m/z = 536 [M+H] ⁺ , ¹ H-NMR (400 MHz, methanol- d ₄ , compound presented as two A:B conformational isomers in the ratio 2:3): δ 7.73 (s, 0.4H, conformational isomer A), 7.67 (s, 0.6H, conformational isomer B), 7.36-7.07 (m, 13H), 7 .00-6.92 (m, 1H), 6.62 (s, 1H), 4.33-3.89 (m, 3H), 3.81-3.60 (m, 3H), 3.30 -3.17(m, 2H), 3.13-2.90(m, 1H), 2.87-2.69(m, 1H), 2.67-2.46(m, 1H), 1 .74-1.26 (m, 6H), 1.05-0.86 (m, 1H).

Example 101: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-4-phenyl-1,6 -dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxylic acid (40 mg, 0.084 mmol), N-methylpropan-2-amine (0.012 ml, 0.1-18 mmol), DIPEA (0.06 ml, 0.337 mmol) and HBTU (38 mg, 0.093 mmol) in DMF (1 ml) to give the title compound (22 mg, 46%). LCMS (Method B): R _T =1.19 min, m/z =530 [M+H] ⁺ , ¹H-NMR (400 MHz, methanol- d ₄ , compound presented as a 1:1 mixture of conformational isomers ): δ 7.62 (dd, 1H), 7.44-7.29 (m, 5H), 7.27-7.02 (m, 5H), 6.49 (d, 1H), 4.51 (hept., 0.5H) 4.19-3.71 (m, 3H), 3.64-3.49 (m, 1.5H), 3.19-3.02 (m, 2H), 3 .00-2.79 (m, 1H), 2.74-2.55 (m, 2.5H), 2.54-2.29 (m, 2.5H), 1.60-1.13 ( m, 7H), 1.04-0.46 (m, 4.5H), 0.39-0.23 (m, 1.5H).

Example 102: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-4-(m-tolyl) -1,6-dihydropyridine-3-carboxamide

Stage 1: (R)-4-chloro-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-1,6 -dihydropyridine-3-carboxamide : epoxide solution 2 (410 mg, 1.58 mmol), 4-chloro-N-isopropyl-N-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (329 mg, 1 .44 mmol) and DIPEA (0.377 ml, 2.16 mmol) in DMF (6 ml) were heated at 70°C for 2 days. Added cesium carbonate (703 mg, 2.16 mmol) and the reaction mixture was heated at 70°C for another 2 days. The mixture was diluted with water and extracted with ethyl acetate (x 3). The combined organic extracts were washed with water and brine, dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (GraceResolv, 15-100% EtOAc in cyclohexane) to give the title compound (314 mg, 45%). LCMS (method B): R _T= 1.06 min, m/z =488 [M+H] ⁺ .

Step 2: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-4-(m-tolyl) -1,6-dihydropyridine-3-carboxamide : Prepared according to general procedure 4 using m-tolylboronic acid (16.7 mg, 0.123 mmol), (R)-4-chloro-1-((4-hydroxy -1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-N-isopropyl-N-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (40 mg, 0.082 mmol), sodium carbonate (2M in water, 0.082 ml, 0.164 mmol) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (3.5 mg, 4.10 μmol) in 1,4-dioxane (0.5 ml). The mixture was heated in a microwave oven at 130° C. for 30 minutes to give the title compound (9 mg, 20%). LCMS (method B): R _T =1.28 min, m/z =544 [M+H] ⁺ , ¹H-NMR (400 MHz, methanol- d ₄ , compound presented as a mixture of conformational isomers): δ 7, 76 (d, 0.4H), 7.70 (d, 0.6H), 7.40-7.15 (m, 9H), 6.60 (d, 1H), 4.71-4.57 ( m, 0.6H), 4.31-3.83 (m, 3H), 3.77-3.61 (m, 1.4H), 3.29-3.14 (m, 2H solvent overlap) , 3.13-2.92 (m, 1H), 2.87-2.43 (m, 5H), 2.40 (s, 3H), 1.73-1.25 (m, 7H), 1 .15-0.70 (m, 4.6H), 0.45 (s, 1.4H).

Example 103: (R)-1-((4-Hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-5-(pyrimidin-5-yl)pyridin-2 (1H) -he

Prepared according to general procedure 4 using (R)-5-bromo-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridine-2(1H) -oa (25 mg, 0.049 mmol), pyrimidin-5-ylboronic acid (9.1 mg, 0.074 mmol), sodium carbonate (10.4 mg, 0.098 mmol), 1,4-dioxane (0.5 ml), water (0.2 ml) and Pd(Ph ₃ P) ₄ (2.9 mg, 2.5 μmol). The mixture was heated in a microwave oven at 150° C. for 10 minutes. The crude product was purified by preparative HPLC to give the title compound (4 mg, 16%). LCMS (method B): R _T =1.06 min, m/z =509 [M+H] ⁺ , ¹H-NMR (400 MHz, methanol- d ₄ , the compound is presented as two A:B conformational isomers in the ratio 2:3): δ 9.00 (s, 1H), 8.48 (s, 2H), 7.87 (s, 0.4H, conformational isomer A), 7.82 (s, 0.6H, conformational isomer B), 7.45-7.14 (m, 10H), 6.65 (s, 1H), 4.32-3.94 (m, 3H), 3.79-3.67 (m, 1H ), 3.30-3.17 (m, 2H), 3.14-2.94 (m, 1H), 2.88-2.73 (m, 1H), 2.70-2.48 (m , 1H), 1.76-1.28 (m, 6H), 1.09-0.95 (m, 1H).

Example 104: (R)-N-(cyclopropylmethyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxamide

Prepared according to general procedure 5 using (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxylic acid (40 mg, 0.084 mmol), (aminomethyl)cyclopropane hydrochloride (11.8 mg, 0.11 mmol), DIPEA (0.06 ml, 0.337 mmol) and HBTU (35 mg, 0.093 mmol) in DMF (1 ml) to give the title compound (25 mg, 56%). LCMS (method B): R _T =1.34 min, m/z =528 [M+H] ⁺ , ¹H-NMR (400 MHz, DMSO- d ₆ , compound presented as a mixture of conformational isomers): δ 8, 03 (t, 1H), 7.75 (d, 1H), 7.37-7.25 (m, 5H), 7.24-7.13 (m, 4H), 7.12-7.03 ( m, 1H), 6.27 (d, 1H), 4.91 (d, 1H), 4.00-3.75 (m, 3H), 3.64-3.48 (m, 1H), 3 .19-3.00 (m, 2H), 2.90-2.73 (m, 3H), 2.53-2.46 (m, 2H), 1.50-1.04 (m, 7H) , 0.80-0.67 (m, 1H), 0.32-0.22 (m, 2H), 0.04--0.06 (m, 2H).

Example 105: (R)-N-benzyl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-N-methyl-6-oxo-4-phenyl-1,6 -dihydropyridine-3-carboxamide

Prepared according to general procedure 5 using (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxylic acid (40 mg, 0.084 mmol), N-methylbenzylamine (0.014 ml, 0.11 mmol), DIPEA (0.06 ml, 0.337 mmol) and HBTU (35 mg, 0.093 mmol) in DMF (1 ml ) to give the title compound (41 mg, 84%). LCMS (Method B): R _T =1.46 min, m/z =578 [M+H] ⁺ , ¹H-NMR (400 MHz, DMSO- d ₆ ): δ 7.80 (m, 1H), 7 .55-7.12(m, 13H), 7.10-6.97(m, 2H), 6.44(m, 1H), 4.97(m, 1H), 4.45(m, 1H ), 4.10-3.85 (m, 3H), 3.60 (m, 1H), 3.20 (m, 3H), 2.91 (m, 1H), 2.56 (m, 5H) , 1.59-1.16 (m, 7H).

Example 106: (R)-2-(1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3- yl)benzonitrile

Step 1: 2-(6-chloro-4-phenylpyridin-3-yl)benzonitrile : Prepared according to general procedure 4 using 2-bromobenzonitrile (78 mg, 0.428 mmol), 6-chloro-4-phenylpyridine-3 -yl)boronic acid (50 mg, 0.214 mmol), sodium carbonate (45.4 mg, 0.428 mmol), 1,4-dioxane (0.5 ml), water (0.2 ml) and Pd(Ph ₃ P ) ₄ (12.4 mg, 10.7 µmol). The mixture was heated in a microwave oven at 100° C. for 20 minutes to give the title compound (50 mg, 80%). LCMS (method B): R _T= 1.42 min, m/z =291 [M+H] ⁺ .

Step 2: 2-(6-oxo-4-phenyl-1,6-dihydropyridin-3-yl)benzonitrile : Solution of 2-(6-chloro-4-phenylpyridin-3-yl-benzonitrile (50 mg, 0.172 mmol) in acetic acid (2 ml, 34.9 mmol) and water (0.5 ml) were heated under reflux for 64 hours The mixture was concentrated and the residue was dissolved in saturated aqueous sodium bicarbonate and extracted with DCM The organic layer was concentrated to give the indicated in title compound (46 mg, 98%) which was used without further purification LCMS (method B): RT ₌ 0.95 min, m/z =273 [M+H] ⁺ .

Stage 3: (R)-2-(1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3- yl)benzonitrile : Epoxide solution 2 (46 mg, 0.177 mmol), 2-(6-oxo-4-phenyl-1,6-dihydropyridin-3-yl)benzonitrile (48.3 mg, 0.177 mmol) and DIPEA (0.046 ml, 0.27 mmol) in DMF (2 ml) was heated at 80°C for 16 hours. Then cesium carbonate (116 mg, 0.355 mmol) was added and the mixture was heated at 80° C. for 4 hours. The mixture was diluted with water and extracted with DCM (x 2). The combined organic extracts were dried (Biotage phase separator), concentrated, and the residue was purified by flash chromatography (GraceResolv, 20-100% EtOAc in cyclohexane; then 0-10% MeOH in EtOAc) followed by preparative HPLC to give the title compound (5 mg, 5%). LCMS (Method B): R _T = 1.30 min, m/z = 532 [M+H] ⁺ , ¹ H-NMR (400 MHz, methanol- d ₄ , compound presented as two A:B conformational isomers in the ratio 2:3): δ 7.82 (s, 0.4H, conformational isomer A), 7.74 (s, 0.6H, conformational isomer B), 7.70-7.56 (m, 2H), 7 .52-7.36 (m, 2H), 7.36-7.07 (m, 10H), 6.67 (s, 1H), 4.33-3.87 (m, 3H), 3.79 -3.65(m, 1H), 3.29-3.16(m, 2H), 3.12-2.93(m, 1H), 2.88-2.71(m, 1H), 2 .68-2.46 (m, 1H), 1.77-1.23 (m, 6H), 1.06-0.89 (m, 1H).

Example 107: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-N-methyl-6-oxo-N,4-diphenyl-1,6-dihydropyridine -3-carboxamide

Prepared according to general procedure 5 using (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxylic acid (40 mg, 0.084 mmol), HBTU (35.2 mg, 0.093 mmol), DIPEA (0.059 ml, 0.337 mmol) and N-methylaniline (0.012 ml, 0.110 mmol) in DMF (1 ml). The crude product was purified by flash chromatography (GraceResolv, 40-100% EtOAc in cyclohexane; then 0-10% MeOH in EtOAc) to give the title compound (10 mg, 21%). LCMS (method B): R _T =1.36 min, m/z =564 [M+H] ⁺ _, ¹H-NMR (400 MHz, DMSO- d ₆ , compound presented as a mixture of conformational isomers): δ 7, 92 (d, 1H), 7.60-7.94 (m, 13H), 6.55-6.33 (m, 2H), 6.26 (s, 1H), 5.02 (d, 1H) , 4.12-3.85 (m, 3H), 3.75-3.59 (m, 1H), 3.30-3.14 (m, 2H), 3.10 (s, 3H), 3 .00-2.85 (m, 1H), 2.66-2.54 (m, 2H), 1.53-1.11 (m, 7H).

Example 108 3-(1-(1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)ethyl)-6-phenylpyrimidin-4(3H)-one

Prepared according to general procedure 5 using amine 2 (40 mg, 0.12 mmol), acid 1 (30.4 mg, 0.18 mmol), DIPEA (0.083 ml, 0.48 mmol) and HBTU (68 mg, 0.18 mmol) in DCM (2.3 ml). The reaction mixture was stirred for 3.5 hours before adding water (2.2 ml). The crude product was purified by flash chromatography (Biotage KP-NH column (11 g), 20-100% EtOAc in cyclohexane) to give the title compound (22.0 mg, 41%). LCMS (Method B): R _T =1.43 min, m/z =452 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.52 (s, 1H), 8.06-8.12 (m, 2H), 7.55-7.47 (m, 3H), 7.02-6.96(m, 1H), 5.22(s, 1H), 4.98-4.87(m, 1H), 4.29-4.04(m, 1H), 3, 87-3.69 (m, 1H), 3.37-3.12 (m, 1H), 2.97-2.71 (m, 2H), 1.79-1.29 (m, 11H), 1.28-1.01 (bm, 7H), 1.00-0.89 (m, 3H), 0.88-0.72 (m, 2H).

Example 109: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(1-methyl-1-pyrazol-4-yl)-4-phenylpyridine -2(1H)-he

Prepared according to general procedure 4 using (R)-5-bromo-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridine-2(1H)- he (20 mg, 0.039 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12.3 mg, 0.059 mmol ), sodium carbonate (8.3 mg, 0.078 mmol), 1,4-dioxane (0.5 ml), water (0.200 ml) and Pd(Ph ₃ P) ₄ (2.3 mg, 1.95 µmol) . The mixture was heated in a microwave oven at 150° C. for 10 minutes to give the title compound (4 mg, 20%). LCMS (Method B): R _T = 1.09 min, m/z = 511 [M+H] ⁺ , ¹ H-NMR (400 MHz, methanol- d ₄ , compound presented as two A:B conformational isomers in the ratio 2:3): δ 7.63 (s, 0.4H, conformational isomer A), 7.57 (s, 0.6H, conformational isomer B), 7.34-7.04 (m, 11H), 6 .93 (d, 1H), 6.42 (s, 1H), 4.19-3.75 (m, 3H), 3.70-3.52 (m, 4H), 3.18-3.05 (m, 2H), 2.99-2.81 (m, 1H), 2.74-2.59 (m, 1H), 2.54-2.36 (m, 1H), 1.62-0 .80 (m, 7H).

Example 110: (R)-3-((1-(2-(cyclohexylmethyl)pent-4-enoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidine-4(3H) -he

Prepared according to general procedure 5 using amine 1 (40 mg, 0.12 mmol), acid 2 (39 mg, 0.20 mmol), DIPEA (0.092 ml, 0.525 mmol) and HBTU (75 mg, 0. 20 mmol) in DCM (2.5 ml) to give the title compound (15.1 mg, 27%). LCMS (Method B): R _T =1.46 min, m/z =482 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.17 (s, 1H), 8.07 (td, 1H), 7.49-7.42 (m, 1H), 7.32-7, 23 (m, 1H), 7.18 (ddd, 1H), 7.13 (s, 1H), 5.81-5.66 (m, 1H), 5.10-4.94 (m, 2H) , 4.47 (t, br, 1H), 4.15 (d, 1H), 3.98 (dd, 1H), 3.88-3.75 (m, br, 2H), 3.52 -3.42(m, 1H), 3.16-3.04(m, 1H), 2.91-2.80(m, br, 1H), 2.42-2.29(m, 1H ), 2.20-2.10 (m, 1H), 1.77-1.47 (m, br, 8H), 1.35-1.05 (m, 6H), 0.96- 0.78 (broad m, 3H).

Example 111: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-methyl-4-phenylpyridin-2(1H)-one

(R)-5-bromo-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one (25 mg, 0.049 mmol), trimethylboroxine (0.014 ml, 0.098 mmol) and potassium carbonate (20.4 mg, 0.147 mmol) were suspended in 1,4-dioxane (0.5 ml) and the mixture was degassed. Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (2.0 mg, 2.45 µmol) was added and the mixture was sealed and stirred at 85° C. for 16 hours. The mixture was cooled and diluted with saturated aqueous sodium bicarbonate. The solution was extracted with DCM (x 3) and the combined organic extracts were dried (Biotage phase separator) and concentrated. The residue was purified by flash chromatography (GraceResolv, 0-100% EtOAc in cyclohexane; then 0-10% MeOH in EtOAc) to give the title compound (13.8 mg, 63%). LCMS (method B): R _T= 1.23 min, m/z =445 [M+H] ⁺ .

Example 112: (R)-6-(1,5-dimethyl-1H-pyrazol-4-yl)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin- 4(3H)-he

Prepared according to general procedure 4 using (R)-6-chloro-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4(3H)-one ( 20 mg, 0.051 mmol), 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,3-dioxaborolan-2-yl)-1H-pyrazole (17.1 mg, 0.077 mmol) sodium carbonate (10.9 mg, 0.103 mmol) and Pd(PPh ₃ ) ₄ (3.0 mg, 2.56 μmol) in 1,4-dioxane (500 μl) and water (200 μl). The reaction mixture was heated in a microwave oven at 150° C. for 10 minutes to give the title compound (11.4 mg, 49%). LCMS (Method B): R _T = 0.93 min, m/z= 450 [M+H] ⁺ , ¹H-NMR (400 MHz, methanol- d ₄ , the compound is presented as two A:B conformational isomers in the ratio 2:3): δ 8.34 (s, 0.4H, conformational isomer A), 8.30 (s, 0.6H, conformational isomer B), 7.40-7.16 (m, 5H), 6 .59 (s, 1H), 4.30-3.82 (m, 5H), 3.94 (s, 3H), 3.75-3.62 (m, 1H), 3.30-3.17 (m, 2H), 3.10-2.92 (m, 1H), 2.85-2.72 (m, 1H), 2.63 (s, 3H), 2.55-2.47 (m , 1H), 1.71-1.28 (m, 6H), 0.97-0.83 (m, 1H).

Example 113: 3-(((1 R ,5 S )-3-(3-cyclohexylpropanoyl)-8-hydroxy-3-azabicyclo[3.2.1]octan-8-yl)methyl)-6-(2-fluorophenyl)pyrimidine-4(3 H )-he

Prepared according to general procedure 5 using 6-(2-fluorophenyl)-3-(((1 R, 5 S )-8-hydroxy-3-azabicyclo[3.2.1]octan-8-yl)methyl) pyrimidin-4( 3H )-one hydrochloride (0.030 g, 0.082 mmol), 3-cyclohexylpropanoic acid (0.019 g, 0.123 mmol), DIPEA (0.057 ml, 0.328 mmol) and HBTU (0.047 g, 0.123 mmol) in DCM ( 0.8 ml) to give the title compound (21 mg, 55%). LCMS (method B): R _T =1.53 min, m/z= 468 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.14 (d, 1H), 8.07 (td, 1H), 7.49-7.43 (m, 1H), 7.29 (dd, 1H), 7.21-7.17(m, 1H), 7.15(s, 1H), 4.71(s, 1H), 4.20(dd, 1H), 4.13(q, 2H ), 3.74 (d, 1H), 3.40 (br dd, 1H), 3.27 (d, 1H), 2.41-2.25 (m, 2H), 1.94-1, 87 (m, 2H), 1.87-1.75 (m, 2H), 1.75-1.60 (m, 6H), 1.56-1.49 (m, 2H), 1.29- 1.10 (m, 5H), 0.95-0.84 (m, 2H).

Example 114: (R)-1-((4-Hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonitrile

(R)-5-bromo-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2(1H)-one (25 mg, 49.1 µmol), zinc cyanide (11.5 mg, 98.1 µmol) and DMF (0.5 ml), and degassed by bubbling nitrogen through the mixture for 5 minutes. Pd(PPh ₃ ) ₄ (6.8 mg, 5.89 µmol) was added and the reaction mixture was heated at 95° C. for 20 hours. Zinc cyanide (11.5 mg, 98.1 µmol) and Pd(PPh ₃ ) ₄ (6.8 mg, 5.89 µmol) were then added and the reaction mixture was heated at 95° C. for another 3 days. Additional Pd(PPh ₃ ) ₄ (6.8 mg, 5.89 µmol) was added to the mixture and the reaction mixture was heated at 95° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and quenched by adding NH ₄ OH (aq.) (20 ml). The resulting mixture was extracted with EtOAc (20 ml), the organic layer was dried over Na2SO ₄ , concentrated in vacuo, and the residue was purified by flash chromatography (GraceResolv silica gel cartridge, 4 g, 0-100% EtOAc in cyclohexane; then GraceResolv silica gel cartridge, 4 g, 0-50% EtOAc in cyclohexane) to give the title compound (6.3 mg, 28%) as an off-white solid. LCMS (Method B): R _T =1.19 min, m/z =456 [M+H] ⁺ . ¹ H-NMR (400 MHz, methanol- d ₄ ): δ 8.39-8.25 (m, 1H), 7.73-7.39 (m, 5H), 7.39-7.14 (m , 5H), 6.59 (s, 1H), 4.28-4.03 (m, 2H), 4.03-3.86 (m, 1H), 3.73-3.60 (m, 1H ), 3.28-3.15 (m, 2H), 3.08-2.89 (m, 1H), 2.86-2.70 (m, 1H), 2.65-2.46 (m , 1H), 1.68-1.24 (m, 6H), 0.98-0.82 (m, 1H).

Example 115: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-N-(2-hydroxyethyl)-6-oxo-4-phenyl-1,6 -dihydropyridine-3-carboxamide

Prepared according to general procedure 5 using (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxylic acid (40 mg, 0.084 mmol), 2-hydroxyethylamine (6.7 mg, 0.110 mmol), DIPEA (0.06 ml, 0.337 mmol) and HBTU (35 mg, 0.093 mmol) in DCM (1 ml ) to give the title compound (14 mg, 32%). LCMS (method B): R _T= 0.96 min, m/z= 518 [M+H] ⁺ , ¹H-NMR (400 MHz, DMSO- d 6): δ 8.06 (dt, 1H), 7 .85 (d, 1H), 7.44-7.34 (m, 5H), 7.32-7.24 (m, 4H), 7.21-7.14 (m, 1H), 6.35 (d, 1H), 5.01 (d, 1H), 4.66 (t, 1H), 4.10-3.84 (m, 3H), 3.73-3.62 (m, 1H), 3.40-3.24 (m, 2H), 3.24-3.07 (m, 4H), 2.96-2.83 (m, 1H), 2.66-2.53 (m, 2H ), 1.59-1.11 (m, 7H).

Example 116: 1-((4-hydroxy-1-((R)-3-phenylbutanoyl)piperidin-4-yl)methyl)-5-((S)-2-methylpyrrolidin-1-carbonyl)-4-phenylpyridine -2(1H)-he

A solution of intermediate 1 (15 mg, 0.026 mmol) and (S)-2-methylpyrrolidine (2.64 mg, 0.031 mmol) in DMF (0.6 ml) was stirred using a BioShake IQ at room temperature for 2 hours. The reaction mixture was concentrated. The residue was diluted with DCM (0.3 ml) and water (0.5 ml). The organic layer was dried (Biotage phase separator) and concentrated to give the title compound (11 mg, 78%). LCMS (Method A): R _T= 1.33 min, m/z =542 [M+H] ⁺ .

Example 117: (R)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(4-(hydroxymethyl)piperidine-1-carbonyl)-4-phenylpyridine- 2(1H)-on

A solution of intermediate 1 (15 mg, 0.026 mmol) and piperidin-4-ylmethanol (3.6 mg, 0.031 mmol) in DMF (0.6 mL) was stirred using a BioShake IQ at room temperature for 2 hours. The reaction mixture was concentrated. The residue was diluted with DCM (0.3 ml) and water (0.5 ml). The organic layer was dried (Biotage phase separator) and concentrated to give the title compound (10 mg, 68%). LCMS (method A): R _T= 1.05 min, m/z =572 [M+H] ⁺ .

Example 118: 3-((1-(2-(cyclohexylmethyl)butanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3 H )-he

Prepared according to general procedure 12 using 2-(cyclohexylmethyl)butanoic acid (8.3 mg, 0.043 mmol), HATU (20.6 mg, 0.054 mmol), DIPEA (15 μl, 0.087 mmol) and 6-( 2-fluorophenyl)-3-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4(3H)-one (12 mg, 0.036 mmol) in DMF (0.6 ml), with obtaining the title compound (6 mg, 33%). LCMS (Method A): R _T= 2.01 min, m / z= 498 [M+H] ⁺ .

Example 119 3-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-fluorophenyl)pyrimidine -4(3H)-he

Step 1: tert-Butyl 10-((4-(2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7-carboxylate : Obtained according to general procedure 1, using 6-(2-fluorophenyl)pyrimidin-4(3H)-one (65.2 mg, 0.343 mmol), tert-butyl-1-oxa-10-azadispiro[2.0.4 ⁴ .4 ³ ]dodecan-10-carboxylate (epoxide 6) (110 mg, 0.411 mmol) and cesium carbonate (145 mg, 0.446 mmol) in DMF (2 ml) at 90°C for 16 hours. The residue was purified with a 1:1 EtOAc/cyclohexane suspension to give the title compound (90 mg, 57%). LCMS (method B): R _T= 1.47 min, m/z =402 [M-butene+H] ⁺ .

Step 2: 6-(2-fluorophenyl)-3-((10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one hydrochloride : Prepared according to general procedure 9 using tert-butyl 10-((4-(2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7-carboxylate (90 mg , 0.20 mmol) and hydrogen chloride (4M in 1,4-dioxane, 0.69 mL, 2.75 mmol) in DCM (1 mL) to give the title compound (75 mg, 97%) which used without further purification.

Step 3: 3-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-fluorophenyl)pyrimidine -4(3H)-one : Prepared according to general procedure 5 using 6-(2-fluorophenyl)-3-((10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin- 4-(3H)-one hydrochloride (25 mg, 0.063 mmol), acid 1 (17 mg, 0.095 mmol), HBTU (0.036 g, 0.095 mmol) and DIPEA (0.033 ml, 0.19 mmol) in DCM (1 ml ). The crude product was purified by flash chromatography (GraceResolv, 4 g, 20-100% EtOAc in cyclohexane) to give the title compound (22 mg, 68%). LCMS (method B): R _T =1.62 min, m/z =510 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.49 (s, 1H), 8.04 (t, 1H), 7.56 (q, 1H), 7.40-7.32 ( m, 2H), 6.82 (s, 1H), 4.96-4.86 (m, 1H), 4.68-4.53 (m, 1H), 4.10 (q, 1H), 3 .75-3.58 (m, 2H), 3.57-3.21 (m, 2H), 2.97-2.79 (m, 1H), 2.05-1.83 (m, 1H) , 1.78-1.02 (m, 20H), 1.00-0.91 (m, 3H), 0.90-0.76 (m, 2H).

Example 120: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-N-isopropyl-N- methyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 5 using acid 4 (20 mg, 39.3 µmol), N-methylpropan-2-amine (8 µmol, 78.6 µmol), HBTU (22.4 mg, 59.0 µmol) and DIPEA (10 μl, 59.0 μmol) in DCM (0.7 ml) for 3 days at room temperature to give the title compound (9.0 mg, 40%) as a white solid. LCMS (method B): R _T= 1.54 min, m/z =564 [M+H] ⁺ , ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.51-7.32 (m, 6H ), 6.71-6.64 (m, 1H), 5.10-5.06 (m, 0.25H), 4.84-4.44 (m, 2.75H), 4.08-3 .17 (m, 4H), 3.04-2.77 (m, 2H), 2.71-2.67 (m, 1.5H), 2.27 (bd. 1.5H), 1 .86-1.60 (m, 6H), 1.54-1.30 (m, 1H), 1.30-0.60 (m, 21.5H), 0.29-0.20 (m, 1.5H).

Example 121: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-N,N-dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

DIPEA (0.052 ml, 0.295 mmol) was added to a stirred solution of acid 4 (50.0 mg, 0.0983 mmol), dimethylamine (2M in THF) (0.098 ml, 0.197 mmol) and HATU (44.9 mg, 0.1 18 mmol) in DCM (2.0 ml) at room temperature. After 2 hours, the reaction mixture was partitioned between additional DCM and saturated sodium bicarbonate solution (aq.). The resulting biphasic mixture was separated, dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography using a KP-NH column (11 g) (0-100%, EtOAc in cyclohexane) and frozen. Drying gave the title compound (42.5 mg, 80%) as a white solid. LCMS (Method A): R _T = 1.52 min, m / z = 536 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.81 (d, 1H), 7.47-7.34 (m, 5H), 6.45 (d, 1H), 4.93 ( d, 1H), 4.42 (dd, 1H), 4.15-3.35 (m, 2H), 3.26 (apparent t, 1H, overlap with solvent peak), 3.05-2.80 ( m, 2H), 2.75 (s, 3H), 2.62 (s, 3H, solvent peak overlap), 1.79-1.40 (m, 7H), 1.30-0.71 (m , 18H).

Example 122: 1-(((R)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-N,N-dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

The title compound was prepared in the same manner as in Example 121, except that the first eluted compound from the chiral resolution of ethyl 1-((1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidine-4 -yl)methyl)-4-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (amine 7, step 2) and following the instructions for acid 4 to obtain the analogous diastereoisomer 1-(((R)-1 -((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid , followed by a coupling reaction similar to that described for the diastereomeric compound in Example 121, the title compound was obtained as a white solid. LCMS (Method A): R _T = 1.51 min, m / z = 536 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.81 (s, 1H), 7.47-7.20 (m, 5H), 6.45 (d, 1H), 4.92 ( d, 1H), 4.44 (dd, 1H), 4.06-3.66 (m, 2H), 3.31-3.16 (m, 1H, solvent peak overlap), 3.04-2 .83 (m, 2H), 2.75 (s, 3H), 2.62 (s, 3H, solvent peak overlap), 1.80-1.37 (m, 7H), 1.30-0, 75 (m, 18H).

Example 123: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-phenyl-5- (pyrrolidine-1-carbonyl)pyridine-2(1H)-one

Prepared according to general procedure 5 using acid 4 (20 mg, 39.3 µmol), pyrrolidine (6.5 µl, 78.6 µmol), HBTU (22.4 mg, 59.0 µmol) and DIPEA (10 µl, 59.0 µmol) in DCM (0.7 ml) for three days at room temperature to give the title compound (5.2 mg, 23%) as a white solid. LCMS (method B): R _T= 1.46 min, m / z =562 [M+H] ⁺ . ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.51-7.39 (m, 6H), 6.70-6.68 (m, 1H), 4.99-4.90 (m, 0 .5H), 4.73(brd, 0.5H), 4.66-4.56(m, 1H), 4.51(brd, 0.5H), 4.02(brd , 0.5H), 3.78 (brd, 1H), 3.62 (brd, 0.5H), 3.50-3.26 (m, 3H), 3.23 (brd , 0.5H), 3.03-2.65 (m, 3H), 1.85-1.60 (m, taken as 8H, solvent overlap), 1.51-1.34 (m, 3H) , 1.30-1.00 (m, 16H), 0.93-0.78 (m, 2H).

Example 124: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-phenyl-5- (piperazine-1-carbonyl)pyridine-2(1H)-one

Stage 1: tert-butyl-4-(1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo -4-phenyl-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate : DIPEA (0.26 ml, 1.47 mmol) was added to a stirred solution of acid 3 (250 mg, 0.492 mmol), tert-butylpiperazine -1-carboxylate (91.5 mg, 0.492 mmol) and HATU (224 mg, 0.589 mmol) in DCM (5.0 ml) at room temperature. After 2 hours, saturated sodium bicarbonate solution (aqueous solution) and additional DCM were added. The resulting biphasic mixture was separated, extracted using DCM (x 2), the combined organic phase was dried (phase separator), the solvents were removed in vacuo, and the remaining residue was purified by flash chromatography (cyclohexane; 0-10%, MeOH in DCM) to give the indicated title crude compound (451 mg, >100%) as a pale yellow oil, which was carried to the next step without further purification. LCMS (method A): R _T= 1.78 min , m/z= 677 [M+H] ⁺ .

Step 2: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-phenyl-5- (piperazine-1-carbonyl)pyridine-2(1H)-one : To a stirred solution of tert-butyl 4-(1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3 ,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate (estimated mass 333 mg, 0.492 mmol) in DCM (2.0 ml) TFA (2.0 ml, 26.0 mmol) was added at room temperature. After 1 hour, the solvents were removed in vacuo and the remaining residue was loaded into an SCX-2 cartridge previously equilibrated with MeOH, washed with MeOH and eluted with 7N ammonia in MeOH. Solvents were removed in vacuo and the remaining residue was purified by flash chromatography (cyclohexane, then 0-10% MeOH in DCM) and lyophilized to give 1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy -3,3-dimethylpiperidin-4-yl)methyl)-4-phenyl-5-(piperazin-1-carbonyl)pyridin-2(1H)-one (180 mg, white solid), The mixture of diastereoisomers was separated by chiral supercritical liquid chromatography using a Chiralpak AS-H column (20 mm x 250 mm, 5 μm) and isocratic conditions with solvent: 25:75 MeOH/CO ₂ (0.1% v/v NH ₃ ). The first eluted sample was freeze dried to give the title compound (54.8 mg, 19%) as a white solid. LCMS (method A): R _T =1.03 min, m / z =577 [M+H] ⁺ , Chiral purity (method C): R _T =2.29 min, 99.8%ee, ¹ H- NMR (500 MHz, DMSO- d ₆ ): δ 7.80 (br s, 1H), 7.51-7.34 (m, 5H), 6.49-6.40 (m, 1H), 5 .06-4.74 (m, 1H), 4.54-4.28 (m, 1H), 4.17-3.35 (m, 3H), 3.31-2.23 (m, 10H, overlap with solvent peak), 1.95-1.39 (m, 8H), 1.31-0.71 (m, 18H).

Example 125: 1-((( R )-one-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-phenyl-5-(piperazine-1-carbonyl)pyridine-2(1 H )-he

The title compound was isolated as the second eluted compound by chiral chromatography 1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- 4-phenyl-5-(piperazin-1-carbonyl)pyridin-2(1H)-one as described in Example 124, step 2. The material was freeze-dried to give the title compound (54.1 mg, 19%) in form of a white solid. LCMS (method A): R _T =1.00 min, m / z =577 [M+H] ⁺ , Chiral purity (method C): R _T =2.87 min, 99.6%ee, ¹ H- NMR (500 MHz, DMSO- d ₆ ): δ 7.80 (br s, 1H), 7.51-7.34 (m, 5H), 6.49-6.39 (m, 1H), 5 .07-4.73 (m, 1H), 4.50-4.35 (m, 1H), 4.08-3.35 (m, 3H), 3.31-2.20 (m, 10H, overlap with solvent peak), 2.04-1.37 (m, 8H), 1.33-0.61 (m, 18H).

Example 126 3-((1-(2-(cyclohexyloxy)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4(3H)-one

Prepared according to general procedure 3 using amine 5 (25 mg, 75.4 µmol), 2-(cyclohexyloxy)propanoic acid (14.3 mg, 83.0 µmol), HATU (34.4 mg, 90.5 µmol) and DIPEA (40 µl, 0.226 mmol) in DCM (1 ml) to give the title compound (23 mg, 62%). LCMS (Method A): R _T =1.53 min, m / z =486 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 8.45 (s, 1H), 8 .06-8.00 (m, 1H), 7.59-7.51 (m, 1H), 7.39-7.32 (m, 2H), 6.81 (s, 1H), 4.90 (s, 1H), 4.59-4.34 (m, 2H), 4.14-3.86 (m, 1H), 3.78-3.57 (m, 2H), 3.41-2 .74 (m, 3H (with HDO overlap)), 1.90-1.41 (m, 6H), 1.36-0.90 (m, 15H).

Example 127: 1-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6- oxo-1,6-dihydropyridine-3-carboxamide

Step 1: 1-((7-(tert-Butoxycarbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid : K a stirred solution of methyl 6-oxo-1,6-dihydropyridine-3-carboxylate (68.7 mg, 0.45 mmol) (commercially available) and tert-butyl-1-oxo-10-azadispiro[2.0.4 ⁴ . 4 ³ ]dodecan-10-carboxylate (epoxide 6) (100 mg, 0.37 mmol) in DMF (1.0 ml) at room temperature under nitrogen atmosphere was added cesium carbonate (183 mg, 0.56 mmol). The temperature was raised to 80°C. After 50 hours the temperature was increased to 100° C. due to an incomplete reaction. After an additional 24 hours, the reaction mixture was diluted 1:1 with brine/water and diethyl ether, the resulting biphasic mixture was separated. The aqueous layer was acidified using 2M HCl (aq) which caused a white precipitate to break out of the solution. EtOAc was added, the mixture was shaken and settled. The resulting biphasic mixture was separated by extraction with additional EtOAc. The combined organic phase was washed with saturated sodium bicarbonate solution (aq.). The aqueous phase was carefully acidified to pH 1-2 and extracted using EtOAc (3 times), dried (phase separator) and solvents removed in vacuo to give the title compound (90.8 mg, 60%). LCMS (method A): R _T= 1.26 min, m/z =407 [M+H] ⁺ .

Step 2: tert-Butyl 10-((5-(dimethylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7-carboxylate : To a stirred solution 1-((7-( tert -butoxycarbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (90.8 mg , 0.22 mmol), 2M dimethylamine in THF (0.17 ml, 0.34 mmol) and HATU (84.9 mg, 0.22 mmol) in DCM (5.0 ml) DIPEA (0 .12 ml, 0.67 mmol). After 18 hours, the reaction mixture was partitioned between additional DCM and saturated sodium bicarbonate solution (aq.). The resulting biphasic mixture was separated, dried (phase separator), solvents were removed in vacuo and the remaining residue was purified by flash chromatography using a Grace column (24 g) (0-100%, EtOAc in cyclohexane; then 0-5%, MeOH in DCM ) to give the title compound (76.9 mg, 79%) as a white solid. LCMS (Method A): R _{T =} 1.22 min, m / z = 434 [M+H] ⁺ .

Step 3: 1-((10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide : To a stirred solution of tert -butyl-10-((5-(dimethylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7-carboxylate (76.9 mg, 0, 18 mmol) in DCM (2.0 ml) TFA (0.5 ml, 6.49 mmol) was added at room temperature. After 30 minutes, the reaction mixture was loaded onto a pre-equilibrated SCX-2 cartridge, washed with MeOH and eluted with 7N ammonia in MeOH. The eluted solution was concentrated in vacuo to give the title crude compound (62.5 mg, >100%) which was carried to the next step without further purification. LCMS (method A): R _T= 0.40 min, m / z =334 [M+H] ⁺ .

Step 4: 1-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6- oxo-1,6-dihydropyridine-3-carboxamide : To a stirred solution of 1-((10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6-oxo-1, 6-dihydropyridine-3-carboxamide (20.0 mg, 0.060 mmol), acids 1 (10.2 mg, 0.060 mmol) and HATU (27.4 mg, 0.072 mmol) in DCM (1.0 ml) at room temperature TFA (0.5 ml, 6.49 mmol) was added. After 2 hours the reaction mixture was diluted with saturated sodium bicarbonate solution (aq.) and was extracted into DCM (x 3). The combined organic phases were dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-5%, MeOH in DCM) and lyophilized to give the title compound (25.7 mg, 88%) as white solid. LCMS (Method A): R _T = 1.46 min, m / z = 486 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.98-7.93 (m, 1H), 7.56-7.51 (m, 1H), 6.45-6.39 (m , 1H), 4.91-4.80 (m, 1H), 4.74-4.52 (m 1H), 3.90-2.78 (m, 11H, solvent peak overlap), 2.00 -1.80 (m, 1H), 1.77-0.75 (m, 26H).

Example 128: 1-((1-((R)-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-N,N-dimethyl-6-oxo- 4-phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using amine 6 (20 mg, 47.6 µmol), acid 5 (9.6 mg, 57.2 µmol), HATU (22 mg, 57.2 µmol), DIPEA (33 µl, 0.191 mmol) and DCM (1 ml). Lyophilization gave the title compound (15.2 mg, 62%) as a colorless solid. LCMS (Method A): R _T = 1.41 min, m / z = 508 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.85-7.78 (m, 1H), 7.57-7.27 (m, 5H), 6.48-6.42 (m , 1H), 4.97-4.87 (m, 1H), 4.48-4.37 (m, 1H), 4.10-4.01 (m, 0.6H), 3.86-3 .63 (m, 2.4H), 3.28-3.19 (m, 1H), 2.98-2.86 (m, 1H), 2.85-2.66 (m, 1H), 2 .75 (s, 3H), 2.62 (s, 3H), 2.26-2.13 (m, 1H), 2.02-1.87 (m, 2H), 1.84-1.47 (m, 6H), 1.39-1.10 (m, 3H), 1.06-0.87 (m, 8H).

Example 129: 1-((1-((R)-3-cyclopropyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-N,N-dimethyl-6-oxo- 4-phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using amine 6 (20 mg, 47.6 µmol), acid 6 (8.4 mg, 57.2 µmol), HATU (22 mg, 57.2 µmol), DIPEA (33 μl, 0.191 mmol) and DCM (1 ml) and lyophilization gave the title compound (15.1 mg, 63%) as a colorless solid. LCMS (Method A): R _T = 1.38 min, m / z = 494 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84-7.79 (m, 1H), 7.54-7.29 (m, 5H), 6.48-6.43 (m , 1H), 4.96-4.88 (m, 1H), 4.49-4.37 (m, 1H), 4.12-4.05 (m, 0.6H), 3.85-3 .65 (m, 2.4H), 3.39-3.22 (m, 1H (with HDO overlap)), 3.03-2.87 (m, 2H), 2.75 (s, 3H ), 2.62 (s, 3H), 1.77-1.54 (m, 2H), 1.54-1.38 (m, 1H), 1.24-0.93 (m, 10H), 0.68-0.57 (m, 1H), 0.42-0.29 (m, 2H), 0.08-0.06 (m, 2H).

Example 130: 1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-[4,5'-bipyrimidine]-6 (1H)-he

Prepared according to general procedure 4 using intermediate 3 (30 mg, 70.8 µmol), pyrimidin-5-ylboronic acid (13.2 mg, 0.106 mmol), tetrakis(triphenylphosphine)palladium (0) (4.09 mg, 3.50 µmol), sodium carbonate (15.0 mg, 0.142 mmol), 1,4-dioxane (0.5 ml) and water (0.2 ml). The reaction mixture was heated under microwave irradiation at 150° C. for 10 minutes to give the title compound (21 mg, 62%). LCMS (method A): R _T =1.40 min, m / z =468 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 9.42 (s, 2H), 9 .30 (s, 1H), 8.50 (s, 1H), 7.29-7.23 (m, 1H), 4.90-4.85 (m, 1H), 4.51-4.38 (m, 2H), 3.81-3.62 (m, 2H), 3.35-3.13 (m, 1H (with HDO overlap)), 3.03-2.76 (m, 2H ), 1.76-1.36 (m, 7H), 1.27-0.73 (m, 17H).

Example 131: 3-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(1-methyl-1H-pyrazole -5-yl)pyrimidin-4(3H)-one

Prepared according to general procedure 4 using intermediate 3 (30 mg, 70.8 µmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole (22.1 mg, 0.106 mmol), tetrakis(triphenylphosphine)palladium (0) (4.09 mg, 3.50 µmol), sodium carbonate (15.0 mg, 0.142 mmol), 1, 4-dioxane (0.5 ml) and water (0.2 ml). The reaction mixture was heated under microwave irradiation at 150° C. for 10 minutes to give the title compound (10 mg, 33%). LCMS (method A): R _T =1.52 min, m/z =470 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 8.43 (s, 1H), 7 .49 (s, 1H), 6.87 (s, 1H), 6.82-6.78 (m, 1H), 4.89-4.84 (br s, 1H), 4.48-4, 34 (m, 1H), 4.13 (s, 3H), 3.80-3.62 (m, 2H), 3.29-3.15 (m, 1H (with HDO overlap)), 3 .02-2.76 (m, 2H), 1.75-1.39 (m, 7H), 1.28-0.75 (m, 18H).

Example 132: 3-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(1H-pyrazol-4-yl )pyrimidin-4(3H)-one

Prepared according to general procedure 4 using intermediate 3 (30 mg, 70.8 µmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H -pyrazole (20.6 mg, 0.106 mmol), tetrakis(triphenylphosphine)palladium (0) (4.09 mg, 3.50 µmol), sodium carbonate (15.0 mg, 0.142 mmol), 1,4-dioxane ( 0.5 ml) and water (0.2 ml). The reaction mixture was heated under microwave irradiation at 150° C. for 15 minutes to give the title compound (19 mg, 58%). LCMS (method A): R _T =1.32 min, m / z =456 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 13.20 (s, 1H), 8 .45-7.94 (br s, 2H), 8.31 (s, 1H), 6.73-6.68 (m, 1H), 4.91-4.84 (br s, 1H), 4 .46-4.31 (m, 1H), 3.79-3.58 (m, 2H), 3.30-3.14 (m, 2H (with HDO overlap)), 3.02-2 .76 (m, 2H), 1.76-1.38 (m, 7H), 1.25-0.74 (m, 17H).

Example 133: 3-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(1H-pyrazol-5-yl )pyrimidin-4(3H)-one

Prepared according to general procedure 4 using intermediate 3 (30 mg, 70.8 µmol), (1H-pyrazol-5-yl)boronic acid (11.9 mg, 0.106 mmol), tetrakis(triphenylphosphine)palladium ( 0) (4.09 mg, 3.50 µmol), sodium carbonate (15.0 mg, 0.142 mmol), 1,4-dioxane (0.5 ml) and water (0.2 ml). The reaction mixture was heated under microwave irradiation at 150° C. for 15 minutes to give the title compound (8 mg, 24%). LCMS (method A): R _T =1.36 min, m/z =456 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 13.70-13.13 (br s , 1H), 8.38 (s, 1H), 7.93-7.53 (br s, 1H), 6.98-6.74 (br s, 2H), 4.91-4.85 (br s, 1H), 4.53-4.33 (m, 1H), 3.80-3.58 (m, 2H), 3.34-3.13 (m, 2H (with HDO overlap)) , 3.03-2.75(m, 2H), 1.75-1.38(m, 7H), 1.28-0.73(m, 17H).

Example 134 3-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one

Step 1: tert-Butyl 10-hydroxy-10-((6-oxopyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decan-7-carboxylate : Prepared according to general procedure 1, with using pyrimidin-4(3H)-one (30 mg, 0.312 mmol), epoxide 6 (100 mg, 0.375 mmol) and cesium carbonate (52.6 mg, 0.468 mmol) in DMF (1.8 ml), when heated to 80° C. for 24 hours to give the title compound (37 mg, 32%). LCMS (method A): R _T= 1.22 min, m/z =308 [M-butene+H] ⁺ .

Step 2: 3-((10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one : Prepared according to general procedure 7 using t-butyl-10- hydroxy-10-((6-oxopyrimidin-1(6H)-yl)methyl)-7-azaspiro[4.5]decan-7-carboxylate (35 mg, 96.3 µmol) DCM (2 ml) and TFA (1 ml ), the mixture was stirred at room temperature for 10 minutes to give the title compound (25 mg, 98%). LCMS (method A): R _T= 0.32 min, m/z =264 [M+H] ⁺ .

Stage 3: 3-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one : Prepared according to general procedure 3 using 3-((10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4(3H)-one (25 mg, 94.9 µmol), acid 1 (17.8 mg, 0.105 mmol), HATU (43.3 mg, 0.1-14 mmol) and DIPEA (50 µl, 0.285 mmol) in DCM (1.5 ml) to give the title compound (24 mg, 60%). LCMS (method A): R _T =1.47 min, m / z =416 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 8.36 (s, 1H), 7 .90 (d, J = 7 Hz, 1H), 6.43-6.37 (m, 1H), 4.89-4.80 (m, 1H), 4.65-4.49 (m, 1H ), 3.72-3.07 (m, 5H (with HDO overlap)), 2.95-2.78 (m, 1H), 2.01-1.80 (m, 1H), 1, 79-0.75 (m, 25H).

Example 135: 3-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(thiophen-3-yl)pyrimidine -4(3H)-he

Prepared according to general procedure 4 using intermediate 3 (30 mg, 70.8 μg), thiophen-3-ylboronic acid (13.6 mg, 0.106 mmol), tetrakis(triphenylphosphine)palladium (0) (4, 09 mg, 3.50 µmol), sodium carbonate (15.0 mg, 0.142 mmol), 1,4-dioxane (0.5 ml) and water (0.2 ml). The reaction mixture was heated under microwave irradiation at 150° C. for 10 minutes to give the title compound (19 mg, 56%). LCMS (Method A): R _T =1.74 min, m/z =472 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 8.36 (s, 1H), 8 .28 (s, 1H), 7.74-7.69 (m, 1H), 7.68-7.64 m, 1H), 6.90-6.85 (m, 1H), 4.90- 4.85 (br s, 1H), 4.47-4.33 (m, 1H), 3.84-3.58 (m, 2H), 3.33-3.14 (m, 2H (overlapped) signal from HDO)), 3.03-2.74 (m, 2H), 1.75-1.37 (m, 7H), 1.27-0.68 (m, 17H).

Example 136: 1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(oxazol-2-yl)- 4-phenylpyridin-2(1H)-one

Stage 1: tert-butyl-4-((5-carbamoyl-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate : Suspension 1- ((1-(tert-butoxycarbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (amine 6, step 2) (50 mg, 0.1-10 mmol) and 1,1'-carbonyldiimidazole (27 mg, 0.164 mmol) were stirred at room temperature for 15 minutes, then the temperature was raised to 60°C. After 45 minutes, no imidazolide was observed, so 1,1'-carbonyldiimidazole (151 mg, 0.931 mmol) was added and the reaction mixture was stirred at 60° C. for 15 hours. The reaction mixture was allowed to cool to room temperature and ammonium hydroxide (0.213 mL, 5.48 mmol) was added. After 70 min, the reaction mixture was diluted with saturated NaHCO ₃ (aq.) (15 ml) and the resulting mixture was extracted with DCM (3×10 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue purified by flash chromatography (12 g GraceResolv silica gel cartridge, 0-100% EtOAc in cyclohexane; then 0-15% MeOH in EtOAc) to give the title compound (27.5 mg, 55 g%) as a colorless solid. LCMS (method A): R _T= 1.21 min, m / z =456 [M+H] ⁺ .

Step 2: tert-Butyl-4-hydroxy-3,3-dimethyl-4-((5-(oxazol-2-yl)-2-oxo-4-chenylpyridin-1(2H)-yl)methyl)piperidine- 1-carboxylate : Suspension of tert-butyl-4-((5-carbamoyl-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (27 .5 mg, 60.4 µmol) in bromoacetaldehyde diethyl acetal (0.5 ml, 3.32 mmol) was heated under microwave irradiation at 100°C for 15 minutes, then at 120°C for 1 hour, after which the reaction mixture purified by flash chromatography (GraceResolv cartridge, 12 g silica gel, 0-100% EtOAc in cyclohexane) to give the title compound (12 mg, 41%) as a colorless solid. LCMS (Method A): R _T= 1.48 min, m/z =480 [M+H] ⁺ .

Step 3: 1-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(oxazol-2-yl)-4-phenylpyridin-2(1H)-one : tert-butyl- 4-hydroxy-3,3-dimethyl-4-((5-(oxazol-2-yl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)piperidine-1-carboxylate (12 mg, 25.0 µmol) was stirred in TFA (0.5 ml) and DCM (1 ml) for 5 minutes before the reaction mixture was purified using a pre-equilibrated Biotage SCX-2 cartridge (2 g) and then washed using 1:1 DCM/MeOH before eluting with 1:1 DCM/7M NH ₃ in MeOH). The main eluents were concentrated in vacuo to give the title compound (7.5 mg, 78%) as a colorless solid. LCMS (method A): R _T= 0.62 min, m/z =380 [M+H] ⁺ .

Step 4: 1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(oxazol-2-yl)- 4-phenylpyridin-2(1H)-one : Prepared according to general procedure 3 using 1-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(oxazol-2-yl )-4-phenylpyridin-2(1H)-one (7.5 mg, 19.8 µmol), acids 1 (4 mg, 23.7 µmol), HATU (9 mg, 23.7 µmol), DIPEA (14 µl, 79.1 µmol) and DCM (0.4 ml) to give the title compound (9.5 mg, 86%) as a colorless solid after lyophilization. LCMS (Method A): LCMS (Method A): R _T =1.68, 1.69 min (2 diastereomers), m/z =532 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 8.29 (d, J =3.6 Hz, 1H), 7.95 (s, 1H), 7.46-7.27 (m, 3H), 7.28-7.02 (m, 3H), 6.43 (d, J =4.7 Hz, 1H), 4.96 (d, J =3.5 Hz, 1H), 4, 65-4.51 (m, 1H), 4.06 (dd, J =38.6, 11.7 Hz, 0.6H), 3.83-3.59 (m, 2.4H), 3, 27-3.16 (m, 1H), 3.03-2.79 (m, 2H), 1.83-1.38 (m, 7H), 1.36-0.61 (m, 17H).

Example 137: 3-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-(hydroxymethyl)phenyl) pyrimidin-4(3H)-one

Prepared according to general procedure 4 using intermediate 3 (45 mg, 0.106 mmol), (2-(hydroxymethyl)phenyl)boronic acid (24.2 mg, 0.160 mmol), tetrakis(triphenylphosphine)palladium (0) ( 6.13 mg, 5.30 µmol), sodium carbonate (22.5 mg, 0.212 mmol), 1,4-dioxan (0.75 ml) and water (0.3 ml). The reaction mixture was heated under microwave irradiation at 150° C. for 10 minutes to give the title compound (28 mg, 53%). LCMS (method A): R _T =1.46 min, m/z =496 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 8.40 (s, 1H), 7 .66-7.41(m, 3H), 7.40-7.31(m, 1H), 6.61(s, 1H), 5.26-5.17(m, 1H), 4.93 -4.84 (br s, 1H), 4.63-4.54 (m, 2H), 4.50-4.35 (m, 1H), 3.83-3.60 (m, 2H), 3.35-3.16 (m, 2H (with HDO overlap)), 3.05-2.79 (m, 2H), 1.76-1.40 (m, 7H), 1.30- 0.74 (m, 17H).

Example 138: 3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(3-(hydroxymethyl)phenyl)pyrimidin-4(3 H )-he

Prepared according to general procedure 4 using intermediate 3 (45 mg, 0.106 mmol), (3-(hydroxymethyl)phenyl)boronic acid (24.2 mg, 0.160 mmol), tetrakis(triphenylphosphine)palladium (0) ( 6.13 mg, 5.30 µmol), sodium carbonate (22.5 mg, 0.212 mmol), 1,4-dioxan (0.75 ml) and water (0.3 ml). The reaction mixture was heated under microwave irradiation at 150° C. for 10 minutes to give the title compound (30 mg, 56%). LCMS (method A): R _T =1.41 min, m/z =496 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 8.44 (s, 1H), 8 .04 (s, 1H), 7.96-7.88 (m, 1H), 7.48-7.38 (m, 2H), 6.98-6.89 (m, 1H), 5.30 -5.22(m, 1H), 4.89(s, 1H), 4.61-4.51(m, 2H), 4.49-4.35(m, 1H), 3.80-3 .60 (m, 2H), 3.29-3.13 (m, 2H (with HDO overlap)), 3.04-2.76 (m, 2H), 1.76-1.40 (m , 7H), 1.26-0.73 (m, 17H).

Example 139: 3-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(4-(hydroxymethyl)phenyl) pyrimidin-4(3H)-one

Prepared according to general procedure 4 using intermediate 3 (40 mg, 94.3 µmol), (4-(hydroxymethyl)phenyl)boronic acid (21.5 mg, 0.142 mmol), tetrakis(triphenylphosphine)palladium (0 ) (5.45 mg, 4.70 µmol), sodium carbonate (20.0 mg, 0.189 mmol), 1,4-dioxane (0.75 ml) and water (0.3 ml). The reaction mixture was heated under microwave irradiation at 150° C. for 10 minutes to give the title compound (31 mg, 66%). LCMS (method A): R _T =1.39 min, m/z =496 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 8.42 (s, 1H), 8 .05 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 6.98-6.91 (m, 1H), 5.31-5, 23 (m, 1H), 4.91-4.83 (br s, 1H), 4.60-4.50 (m, 2H), 4.49-4.34 (m, 1H), 3.80 -3.59 (m, 2H), 3.29-3.13 (m, 2H (with HDO overlap)), 3.03-2.76 (m, 2H), 1.76-1.39 (m, 7H), 1.28-0.73 (m, 17H).

Example 140: 6-(4-(Aminomethyl)phenyl)-3-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl) pyrimidin-4(3H)-one

Step 1: tert-butyl-(4-(1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6- oxo-1,6-dihydropyrimidin-4-yl)benzyl)carbamate : Prepared according to general procedure 4 using intermediate 3 (50 mg, 0.1-18 mmol), (4-(((tert-butoxycarbonyl) amino)methyl)phenyl))boronic acid (44.4mg, 0.177mmol), tetrakis(triphenylphosphine)palladium (0) (6.81mg, 5.9µmol), sodium carbonate (25.0mg, 0.236mmol) , 1,4-dioxan (0.75 ml) and water (0.3 ml). The reaction mixture was heated under microwave irradiation at 150° C. for 10 minutes to give the title compound (52 mg, 74%). LCMS (method A): R _T= 1.75 min, m/z =595 [M+H] ⁺ .

Step 2: 6-(4-(aminomethyl)phenyl)-3-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl) pyrimidin-4(3H)-one : tert-Butyl-(4-(1-((1-((R)-3-cyclohexyl-2-methylpropanoyl))-4-hydroxy-3,3-dimethylpiperidine-4 solution -yl)methyl)-6-oxo-1,6-dihydropyrimidin-4-yl)benzyl)carbamate (50 mg, 84.1 µmol) in DCM (1 ml) and HCl (4M in 1,4-dioxane, 0 .5 ml, 2.00 mmol) was stirred for 30 minutes at room temperature. The reaction mixture was quenched with NaHCO ₃ (aq.) and the aqueous phase was extracted with DCM (x 3) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography to give the title compound (17 mg, 40%). LCMS (Method A): R _T =0.91 min, m / z =495 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 8.42 (s, 1H), 8 .02 (d, J = 8.1 Hz, 2H), 7.48-7.32 (m, 2H), 6.98-6.90 (m, 1H), 4.92-4.82 (br s, 1H), 4.49-4.34 (m, 1H), 3.83-3.57 (m, 4H), 3.33-3.14 (m, 2H (with HDO overlap)) , 3.03-2.76 (m, 2H), 2.46-2.16 (br s, 2H (with DMSO signal overlap)), 1.76-1.40 (m, 7H), 1, 26-0.72 (m, 17H).

Example 141 6-(2-(aminomethyl)phenyl)-3-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl) pyrimidin-4(3H)-one

Step 1: tert-Butyl-(2-(1-((1-((R)-3-cyclohexyl-2-methylpropanoyl))-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6 -oxo-1,6-dihydropyrimidin-4-yl)benzyl)carbamate : Prepared according to general procedure 4 using intermediate 3 (50 mg, 0.1-18 mmol), (2-(((tert-butoxycarbonyl) amino)methyl)phenyl)boronic acid (44.4mg, 0.177mmol), tetrakis(triphenylphosphine)palladium (0) (6.81mg, 5.9µmol), sodium carbonate (25.0mg, 0.236mmol), 1,4-dioxane (0.75 ml) and water (0.3 ml). The reaction mixture was heated under microwave irradiation at 150° C. for 10 minutes to give the title compound (53 mg, 75%). LCMS (method A): R _T= 1.79 min, m/z =595 [M+H] ⁺ .

Step 2: 6-(2-(aminomethyl)phenyl)-3-((1-((R)-3-cyclohexyl-2-methylpropan-3-dimethylpiperidin-4-yl)methyl)pyrimidin-4(3H)- it : Solution of tert-butyl-(2-(1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6- oxo-1,6-dihydropyrimidin-4-yl)benzyl)carbamate (50 mg, 84.1 µmol) in DCM (1 ml) and HCl (4M in 1,4-dioxane, 0.5 ml, 2.00 mmol ) was stirred for 16 hours at room temperature. The reaction mixture was quenched with saturated NaHCO ₃ (aq.) and the aqueous phase was extracted with DCM (x 3) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography to obtain title compound (26 mg, 62%) LCMS (method A): R _T =0.93 min, m / z =495 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ) : δ 8.40 (s, 1H), 7.58-7.51 (m, 1H), 7.46-7.37 (m, 2H), 7.35-7.27 (m, 1H), 6.63-6.56 (br s, 1H), 4.94-4.86 (br s, 1H), 4.50-4.28 (m, 1H), 3.83-3.60 (m , 4H), 3.35-3.17 (m, 2H (with signal overlap from HDO)), 3, 05-2.79 (m, 2H), 2.02-1.76 (br s, 2H), 1.75-1.40 (m, 7H), 1.29-0.74 (m, 17H) .

Example 142 6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(2,4,4-trimethylpentanoyl)piperidin-4-yl)methyl)pyrimidin-4(3H) -he

Prepared according to general procedure 3 using amine 5 (25 mg, 75.4 µmol), 2,4,4-trimethylpentanoic acid (12.0 mg, 83.0 µmol), HATU (34.4 mg, 90. 8 µmol) and DIPEA (40 µl, 0.226 mmol) in DCM (1 ml) to give the title compound (13 mg, 37%). LCMS (method A): R _T =1.55 min, m/z =458 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 8.46 (s, 1H), 8 .07-7.97(m, 1H), 7.59-7.48(m, 1H), 7.40-7.28(m, 2H), 6.81(s, 1H), 4.88 (s, 1H), 4.48-4.34 (m, 1H), 3.91-3.64 (m, 2H), 3.41-3.18 (m, 2H (with HDO overlap) ), 2.98-2.76 (m, 2H), 2.06-1.80 (m, 1H), 1.76-1.49 (m, 1H), 1.30-0.68 (m , 20H).

Example 143: 6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(4,4,4-trifluoro-2-methylbutanoyl)piperidin-4-yl)methyl)pyrimidin- 4(3H)-he

Prepared according to general procedure 3 using amine 5 (25 mg, 75.4 µmol), 4,4,4-trifluoro-2-methylbutanoic acid (13.0 mg, 83.0 µmol), HATU (34, 4 mg, 90.8 µmol) and DIPEA (40 µl, 0.226 mmol) in DCM (1 ml) to give the title compound (17 mg, 47%). LCMS (method A): R _T =1.33 min, m/z =470 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 8.45 (s, 1H), 8 .06-7.98(m, 1H), 7.59-7.50(m, 1H), 7.40-7.28(m, 2H), 6.81(s, 1H), 4.95 -4.84 (m, 1H), 4.50-4.31 (m, 1H), 3.83-3.63 (m, 2H), 3.37-3.06 (m, 2H (overlapped) signal from HDO)), 3.00-2.56 (m, 2H (with signal overlap from traces of DMSO)), 2.32-2.14 (m, 1H), 1.76-1.41 (m, 1H), 1.30-0.79 (m, 11H).

Example 144 4-chloro-1-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N- dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Step 1: 1-((7-(tert-butoxycarbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-chloro-6-oxo-1,6-dihydropyridine-3- carboxylic acid : A stirred suspension of tert-butyl-1-oxa-10-azadispiro[2.0.4 ⁴ .4 ³ ]dodecan-10-carboxylate (1.68 g, 5.03 mmol), ethyl-4-chloro-6- oxo-1H-pyridine-3-carboxylate (1.01 g, 5.03 mmol) and cesium carbonate (2.46 g, 7.54 mmol) in DMF (20 ml) was heated at 100°C. After 16 hours the reaction mixture was partitioned between 1:1 brine and water and EtOAc. The resulting biphasic mixture was separated. The aqueous layer was acidified to pH approximately 2-3 using 2M HCl (aq) and extracted using EtOAc (x 3), dried (phase separator) removing solvents in vacuo to give the title compound (664 mg, 30%) as a pale yellow oil. This compound was carried to the next step without further purification. LCMS (method A): R _T= 1.28 min, m/z =441 [M+H] ⁺ .

Step 2: tert-Butyl 10-((4-chloro-5-(dimethylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7-carboxylate : DIPEA (0.79 ml, 4.51 mmol) was added to a stirred solution of 1-((7-(tert-butoxycarbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4- chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (664 mg, 1.50 mmol), 2M dimethylamine in THF (1.13 ml, 2.26 mmol) and HATU (572 mg, 1.50 mmol) in DCM (15 ml) at room temperature. After 2 hours, saturated sodium bicarbonate solution (aq.) was added. The resulting biphasic mixture was separated, extracted (DCM x 2), the combined organic phase was dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-5% MeOH in DCM) to give the title compound (423 mg, 60%) as a pale yellow solid. LCMS (method A): R _T= 1.25 min , m/z= 468 [M+H] ⁺ . In addition, a byproduct of tert-butyl-10-((4-(dimethylamino)-5-(dimethylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decane -7-carboxylate (43.2 mg, 6%) was isolated as a yellow oil. LCMS (method A): R _T= 1.12 min, m/z =477 [M+H] ⁺ .

Stage 3: 4-chloro-1-((10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide hydrochloride : 4M HCl in 1,4-dioxane (0.5 ml, 14.4 mmol) was added to tert-butyl-10-((4-chloro-5-(dimethylcarbamoyl)-2-oxopyridin-1(2H)-yl )methyl)-10-hydroxy-7-azaspiro[4.5]decane-7-carboxylate (30.0 mg, 0.0641 mmol) and the resulting mixture was stirred at room temperature. After 2 hours, the solvents were removed in vacuo to give the title crude compound (28.0 mg, >100%) as a pale yellow oil, which was taken to the next step without further purification. LCMS (method A): R _T= 0.29 min, m/z =402 [M-H] ^- .

Stage 4: 4-chloro-1-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N- dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide : DIPEA (0.022 ml, 0.128 mmol) was added to a stirred solution of 4-chloro-1-((10-hydroxy-7-azaspiro[4.5]decane)-10 -yl)methyl)-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide hydrochloride (25.9 mg, 0.0641 mmol), acid 1 (10.9 mg, 0.064 mmol) and HATU (29.2 mg, 0.0769 mmol) in DCM (1.0 ml) at room temperature. After 1 hour, the reaction mixture was loaded directly onto the column and purified by flash chromatography (0-5%, MeOH in DCM) and lyophilized to give material which was shown to contain impurities by ¹ H-NMR analysis. The material was dissolved in DCM and saturated sodium bicarbonate solution (aq) was added. The resulting biphasic mixture was separated, dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography using a KP-NH (1 g) column (0-100%, EtOAc in cyclohexane) and frozen. Drying gave the title compound (12.7 mg, 36%) as a white solid. LCMS (Method A): R _T = 1.48 min, m / z = 520 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.82 (s, 1H), 6.68-6.55 (m, 1H), 4.83-4.69 (m, 1H), 4.68-4.47 (m, 1H), 3.89-3.33 (m, 3H), 3.28-3.05 (m, 1H, solvent overlay), 3.02-2.75 (m, 7H), 1.98-1.79 (m, 1H), 1.74-0.70 (m, 26H).

Example 145: 1-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(dimethylamino)-N, N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Step 1: 4-(dimethylamino)-1-((10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-oxo-1,6-dihydropyridine-3-carboxamide : TFA (1.0 ml) was added to a stirred solution of tert-butyl-10-((4-(dimethylamino)-5-(dimethylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7 -azaspiro[4.5]decane-7-carboxylate (Example 144, by-product of step 2) (38.3 mg, 0.0804 mmol) in DCM (1.0 ml) at room temperature. After 30 minutes, the reaction mixture was loaded into a pre-equilibrated SCX-2 cartridge (2 g), washed with MeOH and eluted with 7N ammonia in MeOH. Solvents were removed in vacuo to give the title compound (20.5 mg, 68%) as a pale yellow solid which was carried to the next step without further purification. LCMS (Method A): R _T= 0.23 min, m/z =377 [M+H] ⁺ .

Step 2: 1-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(dimethylamino)-N, N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide : DIPEA (0.019 ml, 0.109 mmol) was added to a stirred solution of 4-(dimethylamino)-1-((10-hydroxy-7-azaspiro)[4.5 ]decan-10-yl)methyl)-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (20.5 mg, 0.0545 mmol), acids 1 (9.3 mg, 0 .0545 mmol) and HATU (24.8 mg, 0.0653 mmol) in DCM (1.0 mL) at room temperature under nitrogen. After 2 hours, the reaction mixture was diluted with saturated sodium bicarbonate solution (aq.) and was extracted into DCM (x 3). The combined organic phases were dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography using a KP-NH column (1 g) (0-100%, EtOAc in cyclohexane; then 0-10% MeOH in EtOAc) and lyophilized to give the title compound (10.6 mg, 36%). LCMS (Method A): R _T = 1.34 min, m / z = 529 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.54 (s, 1H), 5.63-5.09 (m, 2H), 4.47-4.06 (m, 1H), 3.98-3.55 (m, 2H), 3.53-3.33 (m, 1H), 3.27-3.04 (m, 1H, solvent overlay), 3.02-2.70 (m, 13H), 1.96-1.77 (m, 1H), 1.75-0.66 (m, 26H).

Example 146: 1-((1-(( S )-3-(benzyloxy)-2-(cyclohexylmethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using amine 6 (65 mg, 0.155 mmol), acid 7 (43 mg, 0.155 mmol), HATU (65 mg, 0.170 mmol), DIPEA (0.108 ml, 0.619 mmol) and DCM ( 3 ml). Lyophilization gave the title compound (57 mg, 56%) as a colorless solid. LCMS (Method A): LCMS (Method A): R _T =1.73, 1.76 min (2 diastereomers), m/z =642 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.87-7.69 (m, 1H), 7.61-7.08 (m, 10H), 6.51-6.39 (m , 1H), 4.95-4.84 (m, 1H), 4.53-4.30 (m, 3H), 4.20-3.99 (m, 1H), 3.93-3.63 (m, 3H), 3.59-3.38 (m, 2H), 3.25-3.12 (m, 1H), 3.06-2.81 (m, 1H), 2.75 (s , 3H), 2.62 (s, 3H), 1.77-1.48 (m, 6H), 1.49-1.33 (m, 1H), 1.23-1.06 (m, 7H ), 1.00-0.74 (m, 7H).

Example 147 3-carboxamide

Prepared according to general procedure 3 using amine 8 (25 mg, 61.0 µmol), isobutyric acid (6.45 mg, 73.3 µmol), HATU (30.2 mg, 79.4 µmol) and DIPEA (32 μl, 0.183 mmol) in DCM (1 ml) to give the title compound (20 mg, 68%). LCMS (method A): R _T =1.06 min, m/z =480 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84 (s, 1H), 7 .48-7.30(m, 5H), 6.48-6.40(m, 1H), 4.97(s, 0.3H), 4.91(s, 0.7H), 4.67 -4.55 (m, 1H), 3.82-3.61 (m, 2H), 3.51-3.18 (m, 3H (with HDO overlap)), 2.93-2.81 (m, 1H), 2.75 (s, 3H), 2.63 (s, 3H (with DMSO trace overlap)), 1.99-1.83 (m, 1H), 1.76-0 .88 (m, 15H).

Example 148: 1-((10-hydroxy-7-((R)-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using amine 8 (25 mg, 61.0 µmol), (R)-2-methylbutanoic acid (7.48 mg, 73.3 µmol), HATU (30.2 mg, 79. 4 µmol) and DIPEA (32 µl, 0.183 mmol) in DCM (1 ml) to give the title compound (24 mg, 79%). LCMS (method A): R _T =1.16 min, m/z =494 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84 (s, 1H), 7 .50-7.32(m, 5H), 6.49-6.42(m, 1H), 4.97(s, 0.3H), 4.91(s, 0.7H), 4.69 -4.55(m, 1H), 3.87-3.61(m, 2H), 3.58-3.35(m, 2H), 2.80-2.67(m, 1H), 2 .75 (s, 3H), 2.63 (s, 3H (with DMSO trace overlap)), 1.99-1.84 (m, 1H), 1.78-1.06 (m, 12H) , 1.02-0.89 (m, 3H), 0.87-0.70 (m, 3H).

Example 149: 1-((7-((R)-3-cyclopropyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6- oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using amine 8 (25 mg, 61.0 µmol), acid 6 (9.39 mg, 73.3 µmol), HATU (30.2 mg, 79.4 µmol) and DIPEA (32 μl, 0.183 mmol) in DCM (1 ml) to give the title compound (25 mg, 78%). LCMS (Method A): R _T =1.28 min, m/z =520 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.87-7.81 (m, 1H), 7.48-7.32(m, 5H), 6.49-6.42(m, 1H), 4.97(s, 0.35H), 4.91(s, 0.65H) , 4.70-4.55 (m, 1H), 3.90-3.62 (m, 2H), 3.53-3.19 (m, 3H (with HDO overlap)), 2.95 -2.82 (m, 1H), 2.75 (s, 3H), 2.63 (s, 3H (with signal overlap from DMSO traces)), 1.96-1.84 (m, 1H), 1 .79-0.89 (m, 14H), 0.68-0.56 (m, 1H), 0.43-0.28 (m, 2H), 0.08 - -0.70 (m, 2H ).

Example 150 6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(2-methyl-3-(1-pyrazol-1-yl)propanoyl)piperidin-4-yl )methyl)pyrimidin-4(3H)-one

DIPEA (0.032 ml, 0.181 mmol) was added to a stirred suspension of amine 5 (30.0 mg, 0.091 mmol), 2-methyl-3-(1-pyrazol-1-yl)propanoic acid (14.0 mg, 0.091 mmol) and HATU (41.3 mg, 0.109 mmol) in DCM (1.0 ml) at room temperature. After 2 hours the reaction mixture was diluted with DCM and saturated sodium bicarbonate solution (aq) was added. The resulting biphasic mixture was separated, extracted (DCM x 2), dried (phase separator), solvents removed in vacuo and the remaining residue purified by flash chromatography using a KP-NH column (0-100%, EtOAc in cyclohexane, 0-10% MeOH in EtOAc) to give the title compound (16.7 mg, 39%) as a white solid. LCMS (Method A): R _T = 1.08 min, m / z = 468 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 8.47-8.33 (m, 1H), 8.07-7.92 (m, 1H), 7.67-7.48 (m , 2H), 7.46-7.22 (m, 3H), 6.84-6.70 (m, 1H), 6.24-6.06 (m, 1H), 4.92-4.75 (m, 1H), 4.46-4.18 (m, 2H), 4.12-3.93 (m, 1H), 3.75-3.55 (m, 2H), 3.53-3 .36 (m, 1H), 3.26-3.00 (m, 1H, solvent overlay), 2.92-2.75 (m, 1H), 1.72-1.39 (m, 1H) , 1.30-0.60 (m, 11H).

Example 151: 1-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-(hydroxymethyl) phenyl)-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Step 1: tert-Butyl-10-((5-(dimethylcarbamoyl)-4-(2-(hydroxymethyl)phenyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[ 4.5]decane-7-carboxylate : PdCl ₂ (dppf). DCM (2.6 mg, 0.0032 mmol) was added to a previously degassed solution of tert-butyl-10-((4-chloro-5-(dimethylcarbamoyl)-2 -oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7-carboxylate (Example 144, step 2) (30.0 mg, 0.0641 mmol), (2- (hydroxymethyl)phenyl)boronic acid (14.6 mg, 0.0962 mmol) and sodium carbonate (13.6 mg, 0.128 mmol) in 1,4-dioxane (0.75 ml) and water (0.25 ml) in a 10 ml container. The vessel was sealed and heated under microwave irradiation (CEM) at 120°C with stirring for 30 minutes. The solvents were removed in vacuo, the remaining residue was partitioned between EtOAc and water, separated, extracted (EtOAc x 2), and the combined organic phase was dried (phase separator. Solvents were removed in vacuo and the remaining residue was purified using flash chromatography (0-100%, EtOAc in cyclohexane) to give the title compound (16.2 mg, 47%) as a colorless gum LCMS (Method A): R _T= 1.23 min, m / z =540 [M+H] ⁺ .

Step 2: 10-((5-(dimethylcarbamoyl)-4-(2-(hydroxymethyl)phenyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan- 7-ium chloride : 4M HCl in 1,4-dioxane (0.5 ml, 14.4 mmol) was added to tert-butyl-10-((5-(dimethylcarbamoyl)-4-(2-(hydroxymethyl)phenyl) -2)-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7-carboxylate (16.2 mg, 0.030 mmol) and the resulting mixture was stirred at room temperature. After 2 hours, the solvents were removed in vacuo to give the title crude compound (17.3 mg, >100%) as a pale yellow oil, which was taken to the next step without further purification. LCMS (Method A): R _T= 0.36 min , m/z= 440 [M+H] ⁺ .

Step 3: 1-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-(hydroxymethyl) phenyl)-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide : DIPEA (0.012 mL, 0.0668 mmol) was added to a stirred solution of 10-((5-(dimethylcarbamoyl)-4-( 2-(hydroxymethyl)phenyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7-um chloride (estimated weight 15.9 mg, 0.0334 mmol ), acid 1 (5.7 mg, 0.0334 mmol) and HATU (15.2 mg, 0.0401 mmol) in DCM (1.0 ml) at room temperature. After 2 hours the reaction mixture was diluted with DCM and saturated sodium bicarbonate solution (aqueous solution) was added. The resulting biphasic mixture was separated, dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography using a KP-NH (1 g) column (0-100%, EtOAc in cyclohexane) and frozen. Dried to give the title compound (8.7 mg, 43%) as a white solid. LCMS (Method A): R _T = 1.45 min, m / z = 592 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.83 (s, 1H), 7.53 (d, 1H), 7.38 (t, 1H), 7.26 (t, 1H) , 7.07 (d, 1H), 6.36-6.25 (m, 1H), 5.14 (t, 1H), 5.03-4.85 (m, 1H), 4.73-4 .52 (m, 1H), 4.42 (d, 2H), 3.94-3.37 (m, 3H), 3.24-3.12 (m, 1H, solvent peak overlap), 2, 96-2.58 (m, 7H), 2.02-1.82 (m, 1H), 1.79-0.70 (m, 26H).

Example 152 and Example 153: 1-((( S )-one-(( S )-3-cyclohexyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide and 1-((( R )-one-(( S )-3-cyclohexyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using amine 6 (128 mg, 0.333 mmol), acid 8 (62 mg, 0.333 mmol), HATU (129 mg, 0.366 mmol), DIPEA (0.233 ml, 1.33 mmol) and DCM (6.7 ml) to give a mixture of diastereomers which was purified by preparative HPLC under basic conditions to give a second eluted compound 1-((( S )-1-(( S )-3-cyclohexyl-2-(hydroxymethyl) propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide (26 mg, 14%) , and the first eluted compound 1-((( R )-1-(( S )-3-cyclohexyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl) -N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide (39 mg, 21%), both as colorless solids after lyophilization. 1-((( S )-1-(( S )-3-cyclohexyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide: LCMS (method A): R _T = 1.22 min, m/z = 552 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84-7.78 (m, 1H), 7.49-7.30 (m, 5H), 6.49-6.40 (m , 1H), 4.97-4.84 (m, 1H), 4.64-4.45 (m, 2H), 4.39-4.32 (m, 0.5H), 4.20-4 .13 (m, 0.5H), 3.90-3.79 (m, 1H), 3.76-3.62 (m, 1H), 3.48-3.39 (m, 1H), 3 .35-3.19 (m, 2H (with HDO overlap)), 3.06-2.96 (m, 1.5H), 2.85-2.78 (m, 0.5H), 2 .75 (s, 3H), 2.63 (s, 3H), 1.78-1.46 (m, 6H), 1.45-1.32 (m, 1H), 1.27-1.06 (m, 6H), 1.05-0.91 (m, 6H), 0.88-0.75 (m, 2H). 1-((( R )-1-(( S )-3-cyclohexyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide: LCMS (Method A: R _T = 1.20 min, m/z = 552 [M+H] ^{+ .1} H-NMR (500 MHz , DMSO- d ₆ ): δ 7.83-7.77 (m, 1H), 7.47-7.33 (m, 5H), 6.48-6.41 (m, 1H), 4.97 -4.83(m, 1H), 4.58-4.43(m, 2H), 4.03-3.94(m, 0.4H), 3.88-3.67(m, 2, 6H), 3.54-3.39 (m, 1H), 3.34-3.20 (m, 2H (with HDO overlap)), 3.11-2.88 (m, 2H), 2 .75 (s, 3H), 2.62 (s, 3H), 1.76-1.49 (m, 6H), 1.45-1.32 (m, 1H), 1.27-1.06 (m, 6H), 1.05-0.91 (m, 6H), 0.90-0.76 (m, 2H).

Example 154: 1'-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4'-(2-fluorophenyl)- [2,3'-bipyridine-6'(1'H)-one

Stage 1: tert-butyl-4-((5-bromo-4-(2-fluorophenyl)-2-oxopyridin-1(2H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate : Solution of 5-bromo-4-(2-fluorophenyl)pyridin-2(1H)-one (200 mg, 0.746 mmol), epoxide 3 (360 mg, 1.49 mmol) and cesium carbonate (267 mg, 0.821) mmol ) in DMF (2.5 ml) was heated at 90°C for 16 hours. The reaction mixture was allowed to cool to room temperature, diluted with saturated NH ₄ Cl (aq.) (15 ml) and the mixture was extracted with DCM (3×10 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv silica gel cartridge (40 g), 0-70% EtOAc in cyclohexane) to give the title compound (174 mg, 45%) as a pale yellow foam. LCMS (Method A): R _T =1.66 min, m/z =509.511 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 8.06 (s, 1H), 7.56-7.46 (m, 1H), 7.41-7.23 (m, 3H), 6.47 (s, 1H), 4.89 (s, 1H), 4.45 (d, J =13.4 Hz, 1H), 3.80-3.62 (m, 2H), 3.25 -3.25(m, 1H), 3.12-2.91(m, 2H), 1.68-1.57(m, 1H), 1.39(s, 9H), 1.15-1 .04 (m, 1H), 0.99 (s, 3H), 0.94 (s, 3H).

Step 2: tert-butyl-4-((4-(2-fluorophenyl)-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine- 1(2H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (2H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (169 mg, 0.332 mmol), bis(pinacolato)diborone (126 mg, 0.498 mmol), Pd(dppf)Cl ₂ . CH ₂ Cl ₂ (28 mg, 33.2 µmol), dppf (18 mg, 33.2 µmol) and potassium acetate (98 mg, 0.995 mmol) in 1,4-dioxane (3.3 ml) were degassed by bubbling nitrogen through the mixture for 20 minutes before heating the reaction mixture at 90° C. for 15 hours. The reaction mixture was allowed to cool to room temperature, diluted with NaHCO ₃ (aq.) (30 ml) and the mixture was extracted with DCM (3×20 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv silica gel cartridge (12 g), 0-70% EtOAc in cyclohexane) to give the title compound (65 mg, 35%) as off-white foam. LCMS (method A): R _T= 1.87 min, m/z =557 [M+H] ⁺ .

Stage 3: tert-butyl-4-((4'-(2-fluorophenyl)-6'-oxo-[2,3'-bipyridin]-1'(6'H)-yl)methyl)-4-hydroxy -3,3-dimethylpiperidine-1-carboxylate : Prepared according to general procedure 4 using tert-butyl-4-((4-(2-fluorophenyl)-2-oxo-5-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (65 mg, 0.117 mmol), 2 -bromopyridine (23 μl, 0.234 mmol), Pd(PPh ₃ ) ₄ (14 mg, 11.7 μmol), Na ₂ CO ₃ (37 mg, 0.350 mmol), 1,4-dioxane (1 ml) and water ( 0.2 ml) at 140° C. for 2 hours under microwave irradiation to give the title compound (8 mg, 13%) as a yellow gum. LCMS (method A): R _T= 1.36 min, m/z =508 [M+H] ⁺ .

Step 4: 4'-(2-fluorophenyl)-1'-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-[2,3'-bipyridine]-6'(1'H) -one : A solution of tert-butyl-4-((4'-(2-fluorophenyl)-6'-oxo-[2,3'-bipyridin]-1'(6'H)-yl)methyl)-4- hydroxy-3,3-dimethylpiperidine-1-carboxylate (8 mg, 15.8 µmol) in TFA (0.5 ml) and DCM (1 ml) was stirred for 5 minutes, then the reaction mixture was purified using an SCX-2 cartridge (2 g) (pre-equilibrated and then washed with 1:1 DCM/MeOH before eluting with 1:1 DCM/7M NH ₃ in MeOH). The main eluents were concentrated in vacuo to give the title compound (6 mg, 93%) as a colorless solid. LCMS (method A): R _T= 0.39 min, m/z =408 [M+H] ⁺ .

Stage 5: 1'-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4'-(2-fluorophenyl)- [2,3'-bipyridine]-6'(1'H)-one : Prepared according to general procedure 3 using 4'-(2-fluorophenyl)-1'-((4-hydroxy-3,3 -dimethylpiperidin-4-yl)methyl)-[2,3'-bipyridine]-6'(1'H)-one (6 mg, 14.7 µmol), acid 1 (2.8 mg, 16.2 µmol ), HATU (6 mg, 16.2 µmol), DIPEA (10 µl, 58.9 µmol) and DCM (0.5 ml) to give the title compound (5.5 mg, 66 %) as a colorless solid after lyophilization. LCMS (Method A): R _T =1.59, 1.60 min (2 diastereomers), m/z =560 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 8.56-8.46 (m, 1H), 7.75-7.66 (m, 1H), 7.65-7.52 (m , 2H), 7.52-7.45(m, 1H), 7.45-7.37(m, 1H), 7.35-7.19(m, 2H), 6.13(s, 1H ), 6.04-5.93 (m, 1H), 5.06-4.90 (m, 1H), 4.42-4.19 (m, 1H), 4.11-3.95 (m , 1H), 3.90-3.64 (m, 2H), 3.61-3.48 (m, 1H), 3.28-3.18 (m, 2H), 3.05-2.80 (m, 2H), 1.72-0.75 (m, 22H).

Example 155: 1-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6- oxo-4-(thiophen-3-yl)-1,6-dihydropyridine-3-carboxamide

Step 1: tert-Butyl-10-((5-(dimethylcarbamoyl)-2-oxo-4-(thiophen-3-yl)pyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[ 4.5] decane-7-carboxylate : To a pre-degassed solution of tert-butyl-10-((4-chloro-5-(dimethylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7- azaspiro[4.5]decane-7-carboxylate (30.0 mg, 0.0641 mmol), thiophen-3-ylboronic acid (12.3 mg, 0.0962 mmol) and sodium carbonate (13.6 mg, 0.128 mmol) in a mixture of 1,4-dioxane (0.75 ml)/water (0.25 ml) in a 10 ml vial was added PdCl ₂ (dppf).DCM (2.6 mg, 0.0032 mmol). The vial was sealed and heated under microwave irradiation (CEM) at 120°C with stirring for 30 minutes. The solvents were removed in vacuo and the remaining residue was partitioned between EtOAc and water, separated and extracted (EtOAc x 2). The combined organic phase was dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-100%, EtOAc in cyclohexane) to give the title compound (19.0 mg, 57%) as colorless resin. LCMS (Method A): R _T= 1.35 min, m/z =516 [M+H] ⁺ .

Step 2: 10-((5-(dimethylcarbamoyl)-2-oxo-4-(thiophen-3-yl)pyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan- 7-ium chloride : 4M HCl in 1,4-dioxane (0.61 ml, 17.7 mmol) was added to tert-butyl-10-((5-(dimethylcarbamoyl)-2-oxo-4-(thiophene-3 -)yl)pyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7-carboxylate (19.0 mg, 0.0368 mmol) and the resulting mixture was stirred at room temperature. After 1 hour, the solvents were removed in vacuo to give the title crude compound (20.2 mg, >100%) as a pale yellow oil, which was carried to the next step without further purification. LCMS (method A): R _T= 0.48 min , m/z= 416 [M+H] ⁺ .

Step 3: 1-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6- oxo-4-(thiophen-3-yl)-1,6-dihydropyridine-3-carboxamide : DIPEA (0.0129 mL, 0.0736 mmol) was added to a stirred solution of 10-((5-(dimethylcarbamoyl)-2- oxo-4-(thiophen-3-yl)pyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7-ium chloride (estimated weight 16.6 mg, 0.0368 mmol), acid 1 (6.3 mg, 0.0368 mmol) and HATU (16.8 mg, 0.0368 mmol) in DCM (1.0 ml) at room temperature. After 2 hours, the reaction mixture was partitioned between saturated sodium bicarbonate (aq) and additional DCM, separated, extracted (2 x DCM), the organic phase was dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0- 5%, MeOH in DCM) and lyophilized to give the title compound (16.2 mg, 77%) as a white solid. LCMS (Method A): R _T = 1.56 min, m / z = 568 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 7.80-7.75 (m, 1H), 7.73-7.70 (m, 1H), 7.66-7.62 (m , 1H), 7.24-7.20 (m, 1H), 6.62-6.57 (m, 1H), 5.01-4.88 (m, 1H), 4.70-4.49 (m, 1H), 3.92-3.37 (m, 3H), 3.28-3.16 (m, 1H, solvent peak overlap), 2.95-2.78 (m, 4H), 2.66 (s, 3H), 2.00-1.80 (m, 1H), 1.79-0.70 (m, 26H).

Example 156: 1-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(3-(hydroxymethyl) phenyl)-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Step 1: tert-Butyl-10-((5-(dimethylcarbamoyl)-4-(3-(hydroxymethyl)phenyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[ 4.5]decane-7-carboxylate : PdCl ₂ (dppf). DCM (2.6 mg, 0.0032 mmol) was added to a pre-degassed solution of tert-butyl-10-((4-chloro-5-(dimethylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-10 -hydroxy-7-azaspiro[4.5]decane-7-carboxylate (30.0 mg, 0.0641 mmol), (3-(hydroxymethyl)phenyl)boronic acid (14.6 mg, 0.962 mmol) and sodium carbonate (13 .6 mg, 0.128 mmol) in 1,4-dioxane (0.75 ml)/water (0.25 ml) in a 10 ml vial. The vial was sealed and heated under microwave irradiation (CEM) at 120°C with stirring for 30 minutes. The solvents were removed in vacuo and the remaining residue was partitioned between EtOAc and water. Separated, extracted (EtOAc x 2), the combined organic phase was dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified using flash chromatography (0-100%, EtOAc in cyclohexane). Pure fractions were concentrated to give the title compound (16.1 mg, 47%) as a colorless gum. LCMS (Method A): R _T= 1.17 min, m/z =540 [M+H] ⁺ .

Step 2: 10-((5-(dimethylcarbamoyl)-4-(3-(hydroxymethyl)phenyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan- 7-ium chloride : 4M HCl in 1,4-dioxane (0.5 ml, 14.3 mmol) was added to tert-butyl-10-((5-(dimethylcarbamoyl)-4-(3-(hydroxymethyl)phenyl) -2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7-carboxylate (16.1 mg, 0.0298 mmol) and the resulting mixture was stirred at room temperature. After 1 hour, the solvents were removed in vacuo to give the crude title compound (18.1 mg, >100%) as a pale yellow oil, which was carried to the next step without further purification. LCMS (method A): R _T= 0.34 min , m/z= 440 [M+H] ⁺ .

Step 3: 1-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(3-(hydroxymethyl) phenyl)-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxami : DIPEA (0.010 mL, 0.0596 mmol) was added to a stirred solution of 10-((5-(dimethylcarbamoyl)-4-( 3-(hydroxymethyl)phenyl)-2-oxopyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decan-7-ium chloride (estimated mass 14.2 mg, 0.0298 mmol ), acid 1 (5.1 mg, 0.0298 mmol) and HATU (13.6 mg, 0.0358 mmol) in DCM (1.0 ml) at room temperature. After 2 hours, the reaction mixture was partitioned between saturated sodium bicarbonate (aq.) and additional DCM. The mixture was separated, extracted (2 x DCM), the organic phase was dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-5%, MeOH in DCM) and lyophilized to give the title compound (11 .7 mg, 65%) as a white solid. LCMS (Method A): R _T = 1.38 min, m / z = 592 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 7.86-7.81 (m, 1H), 7.41-7.32 (m, 3H), 7.27-7.20 (m , 1H), 6.47-6.41(m, 1H), 5.25(t, 1H), 5.00-4.88(m, 1H), 4.72-4.59(m, 1H ), 4.52 (d, 2H), 3.93-3.37 (m, 3H), 3.26-3.10 (m, 1H, solvent peak overlap), 2.94-2.80 ( m, 1H), 2.76 (s, 3H), 2.64 (s, 3H), 2.02-1.81 (m, 1H), 1.79-0.73 (m, 26H).

Example 157: 1-((7-(3-cyclohexyl-2-hydroxypropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using amine 8 (25 mg, 61.0 µmol), 3-cyclohexyl-2-hydroxypropanoic acid (1.6 mg, 67.2 µmol), HATU (27.8 mg, 73 .3 µmol) and DIPEA (32 µl, 0.13 mmol) in DCM (1 ml) to give 1-((7-(3-cyclohexyl-2-hydroxypropanoyl)-10-hydroxy-7-azaspiro[4.5]decane -10-yl)methyl)-N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide (8 mg, 22%). LCMS (Method A): R _T =1.39 min, m/z =564 [M+H] ⁺ , ¹H-NMR (400 MHz, DMSO- d ₆ ): δ 7.86-7.81 (m, 1H), 7.47-7.35(m, 5H), 6.47-6.43(m, 1H), 5.02-4.90(m, 1H), 4.79-4.53( m, 1H), 4.43-4.26 (m, 1H), 3.78-3.56 (m, 2H), 3.47-3.26 (m, 3H (with signal overlap from HDO)) , 2.75 (s, 3H), 2.63 (s, 3H (with DMSO trace overlap)), 2.01-0.76 (m, 24H).

Example 158: 1-((10-hydroxy-7-(2-methyl-3-(piperidin-1-yl)propanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl -6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

DIPEA (0.038 mL, 0.220 mmol) was added to a stirred solution of amine 8 (30.0 mg, 0.0733 mmol), 2-methyl-3-(piperidin-1-yl)propanoic acid hydrochloride (15.2 mg, 0.0733 mmol). 0733 mmol) and HATU (33.4 mg, 0.0879 mmol) in DCM (1.0 ml) at room temperature. After 2 hours the reaction mixture was diluted with DCM and saturated sodium bicarbonate solution (aqueous solution) was added. The resulting biphasic mixture was separated, dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography using a KP-NH column (1 g) (0-100%, EtOAc in cyclohexane; then 0-10% MeOH in EtOAc ) and lyophilized to give the title compound (37.6 mg, 91%) as a white solid. LCMS (Method A): R _T = 0.66 min, m / z = 563 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 7.86-7.80 (m, 1H), 7.47-7.33 (m, 5H), 6.48-6.42 (m , 1H), 5.00-4.85 (m, 1H), 4.75-4.52 (m, 1H), 3.95-3.38 (m, 4H), 3.28-2.93 (m, 2H, solvent peak overlap), 2.75 (s, 3H), 2.63 (s, 3H), 2.46-2.38 (m, 1H, solvent peak overlap), 2.29 (br s, 4H), 2.13-2.04 (m, 1H), 1.95-1.80 (m, 1H), 1.75-1.07 (m, 15H), 0.98 -0.87 (m, 3H).

Example 159: 6-(3-(aminomethyl)phenyl)-3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4(3 H )-he

Step 1: tert-butyl-(3-(1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6- oxo-1,6-dihydropyrimidin-4-yl)benzyl)carbamate : Prepared according to general procedure 4 using intermediate 3 (50 mg, 0.118 mmol), (3-(((tert-butoxycarbonyl)amino)methyl) phenyl) boronic acid (44.4 mg, 0.177 mmol), tetrakis(triphenylphosphine) palladium (0) (6.81 mg, 5.90 µmol), sodium carbonate (25.0 mg, 0.236 mmol), 1,4- dioxane (0.75 ml) and water (0.3 ml). The reaction mixture was heated under microwave irradiation at 150° C. for 10 minutes to give the title compound (52 mg, 74%). LCMS (method A): R _T= 1.77 min, m/z =595 [M+H] ⁺ .

Step 2: 6-(3-(aminomethyl)phenyl)-3-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl) pyrimidin-4(3H)-one : tert-Butyl-(3-(1-((1-((R)-3-cyclohexyl-2-methylpropanoyl))-4-hydroxy-3,3-dimethylpiperidine-4 solution -yl)methyl)-6-oxo-1,6-dihydropyrimidin-4-yl)benzyl)carbamate (52 mg, 87.4 µmol) in DCM (1 ml) and HCl (4M in 1,4-dioxane, 0 .5 ml, 2.00 mmol) was stirred for 30 minutes at room temperature. The reaction mixture was quenched with saturated NaHCO ₃ (aq.) and the aqueous phase was extracted with DCM (x 3) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography to give the title compound (34 mg, 77%). LCMS (method A): R _T =1.53 min, m/z =495 [M+H] ⁺ , ¹H-NMR (400 MHz, DMSO- d ₆ ): δ 8.43 (s, 1H), 8 .05 (s, 1H), 7.90 (d, J= 7.2 Hz, 1H), 7.47-7.38 (m, 2H), 6.98 (d, J= 5.6 Hz 1H ), 4.90 (s, 1H), 4.50-4.34 (m, 1H), 3.81-3.58 (m, 4H), 3.40-3.14 (m, 2H (s signal overlap from HDO)), 3.04-2.76 (m, 2H), 2.19-1.86 (br s, 2H), 1.76-1.37 (m, 7H), 1.27 -0.72 (m, 17H).

Example 160: 1-((( S )-one-(( S )-3-cyclohexyl-2-(methoxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Sodium hydride (60% dispersion in mineral oil, 2.4 mg, 58.9 µmol) was added to a solution of 1-(((S)-1-((S)-3-cyclohexyl-2-(hydroxymethyl)propanoyl)- 4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide (13 mg, 23.6 µmol) in THF (0.24 ml) and iodomethane (0.2M in THF, 0.177 ml, 35.3 µmol) was added after 1 hour. The reaction mixture was stirred overnight, then diluted with water (5 ml) and extracted with DCM (3×5 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv cartridge with silica gel (12 g), 0-5% MeOH in DCM) and preparative HPLC under basic conditions to give the title compound (4.2 mg , 31%) as a colorless solid after lyophilization. LCMS (method A): R _T =1.45 min, m/z =566 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.83-7.79 (m, 1H), 7.48-7.33 (m, 5H), 6.48-6.41 (m , 1H), 4.92 (s, 1H), 4.55-4.44 (m, 1H), 4.55-4.44 (m, 0.5H), 4.17-4.11 (m , 0.5H), 3.88-3.63 (m, 3H), 3.40-3.12 (m, 6H (with HDO overlap)), 3.02-2.98 (m, 0 .5H), 2.87-2.79 (m, 0.5H), 2.75 (s, 3H), 2.62 (s, 3H), 1.76-1.50 (m, 6H), 1.44-1.33 (m, 1H), 1.22-1.05 (m, 6H), 1.04-0.91 (m, 6H), 0.87-0.76 (m, 2H ).

Example 161 4-(2-(aminomethyl)phenyl)-1-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl) methyl)-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Step 1: tert-butyl-(2-(1-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- 5-(dimethylcarbamoyl)-2-oxo-1,2-dihydropyridin-4-yl)benzyl)carbamate : PdCl ₂ (dppf). DCM (2.6 mg, 0.0032 mmol) was added to a pre-degassed solution of 4-chloro-1-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5 ]decan-10-yl)methyl)--N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (example 144) (30.0 mg, 0.0641 mmol), tert-butyl- (2-(4,4,5,5-tetramethyl-1,3,3-dioxaborolan-2-yl)benzyl)carbamate (32.0 mg, 0.0962 mmol) and sodium carbonate (13.6 mg, 0.128 mmol) in a 10 ml vial. The vial was sealed and heated under microwave irradiation (CEM) at 120° C. with stirring for 30 minutes. The reaction mixture was partitioned between EtOAc and water, separated, extracted (EtOAc x 2), the combined organic phase was dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-100%, EtOAc in cyclohexane), obtaining the title compound (17.2 mg, 39%) as a colorless gum. LCMS (Method A): R _T= 1.77 min, m/z =691 [M+H] ⁺ .

Step 2: 4-(2-(aminomethyl)phenyl)-1-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl) methyl)-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide : TFA (1.0 ml, 13.0 mmol) was added to a stirred solution of tert-butyl-(2-(1-( (7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-5-(dimethylcarbamoyl)-2-oxo-1,2- dihydropyridin-4-yl)benzyl)carbamate (17.2 mg, 0.0249 mmol) in DCM (1.0 ml) at room temperature. After 1 hour the solvents were removed in vacuo and the remaining residue in MeOH solution was loaded onto a pre-equilibrated SCX-2 cartridge, washed with MeOH and eluted with 7M ammonia in MeOH. Solvents were removed in vacuo and the remaining residue was purified by flash chromatography using a KP-NH (1 g) column (0-100%, EtOAc in cyclohexane; 0-10%, MeOH in EtOAc) to give the title compound (11, 3 mg, 74%) as an off-white solid. LCMS (Method A): R _T = 1.05 min, m / z = 591 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.88-7.75 (m, 1H), 7.54 (d, 1H), 7.35 (t, 1H), 7.21 ( t, 1H), 7.09-6.95 (m, 1H), 6.40-6.22 (m, 1H), 5.13-4.47 (m, 2H), 4.15-3, 38 (m, 6H), 3.24-3.08 (m, 1H, solvent peak overlap), 2.97-2.59 (m, 7H), 2.03-1.82 (m, 1H) , 1.80-0.67 (m, 25H), [note: the 2H signal is invisible].

Example 162: 1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(4-(hydroxymethyl)phenyl)- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Pd(dppf)Cl ₂ .DCM (2.4 mg, 0.0029 mmol) was added to a previously degassed solution of 4-chloro-1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10- hydroxy-7-azaspiro[4.5]decan-10-yl)methyl) -N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (Example 144) (30.0 mg, 0.0577 mmol ), (4-(hydroxymethyl)phenyl)boronic acid (13.2 mg, 0.0865 mmol) and sodium carbonate (12.2 mg, 0.1-15 mmol) in a 10 ml vial. The vessel was sealed and heated under microwave irradiation (CEM) at 120°C with stirring for 30 minutes. The reaction mixture was partitioned between EtOAc and water, separated, extracted (EtOAc x 2), the combined organic phase was dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (cyclohexane; 0-10%, MeOH in DCM), to give material that required further purification by flash chromatography (0-100% EtOAc in cyclohexane; then 0-10% MeOH in EtOAc) to give the title compound (11.5 mg, 32%) as a white solid substances. LCMS (Method A): R _T = 1.37 min, m / z = 592 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.86-7.77 (m, 1H), 7.41-7.29 (m, 4H), 6.47-6.40 (m , 1H), 5.27 (t, 1H), 5.02-4.87 (m, 1H), 4.72-4.47 (m, 3H), 3.93-3.10 (m, 4H , overlap with solvent peak), 2.95-2.80 (m, 1H), 2.76 (s, 3H), 2.65 (s, 3H), 2.03-1.82 (m, 1H) , 1.79-0.74 (m, 26H).

Example 163: 1-((10-hydroxy-7-(2-methyl-3-morpholinepropanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

DIPEA (0.026 ml, 0.147 mmol) was added to a stirred solution of amine 8 (30.0 mg, 0.0733 mmol), 2-methyl-3-morpholinopropanoic acid (14.0 mg, 0.0806 mmol) and HATU (33, 4 mg, 0.0879 mmol) in DCM (1.0 ml) at room temperature. After 2 hours, the reaction mixture was diluted with more DCM and saturated sodium bicarbonate solution (aqueous) was added. The resulting biphasic mixture was separated, dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography using a KP-NH column (0-100%, EtOAc in cyclohexane; 0-10%, MeOH in EtOAc) and lyophilized to give the title compound (23.6 mg, 57%) as a white solid. LCMS (Method A): R _T = 0.71 min, m / z = 565 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.88-7.78 (m, 1H), 7.47-7.30 (m, 5H), 6.49-6.39 (m , 1H), 5.02-4.82 (m, 1H), 4.77-4.50 (m, 1H), 3.97-3.35 (m, 7H, solvent peak overlap), 3, 31-2.97 (m, 2H, solvent peak overlap), 2.75 (s, 3H), 2.63 (s, 3H), 2.55-2.07 (m, 6H, solvent peak overlap) ), 2.03-0.77 (m, 14H).

Example 164 and Example 165: 1-(((S)-1-((S)-2-(cyclohexylmethyl)-4-hydroxybutanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-N ,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide and 1-(((R)-1-((S)-2-(cyclohexylmethyl)-4-hydroxybutanoyl)-4 -hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Step 1: 1-((1-((S)-4-((tert-Butyldimethylsilyl)oxy)-2-(cyclohexylmethyl)butanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide: Prepared according to general procedure 3 using amine 6 (55 mg, 0.143 mmol), acid 9 (50 mg, 0.158 mmol), HATU (60 mg, 0.158 mmol), DIPEA (100 μl, 0.574 mmol) and DCM (3 ml) to give the title compound (92 mg, 94%) as a colorless foam. LCMS (method A): R _T= 2.19 and 2.21 min (2 diastereomers), m/z =680 [M+H] ⁺ .

Step 2: 1-(((S)-1-((S)-2-(cyclohexylmethyl)-4-hydroxybutanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-N,N- dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide and 1-(((R)-1-((S)-2-(cyclohexylmethyl)-4-hydroxybutanoyl)-4-hydroxy- 3,3-dimethylpiperidin-4-yl)methyl)-N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide: : TBAF (1M in THF, 0.271 ml, 0.271 mmol) was added to a solution of 1-((1-((S)-4-((tert-butyldimethylsilyl)oxy)-2-(cyclohexylmethyl)butanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide (92 mg, 0.135 mmol) in THF (0.54 ml) at 0°C. After 1 hour the reaction mixture was allowed to warm to room temperature and after 21 hours the reaction mixture was purified directly by flash chromatography (GraceResolv silica gel cartridge (12 g), 0-20% MeOH in DCM) to give the crude product as a mixture of diastereomers. The diastereomers were separated by preparative HPLC under basic conditions to give the second eluted compound 1-((( S )-1-(( S )-2-(cyclohexylmethyl)-4-hydroxybutanoyl)-4-hydroxy-3,3-dimethylpiperidine-4- yl)methyl) -N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide (15.6 mg, 20%) and the first eluted compound 1-((( R )-1 -(( S )-2-(cyclohexylmethyl)-4-hydroxybutanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1, 6-dihydropyridine-3-carboxamide (15.8 mg, 20%) as colorless solids after lyophilization. (15.8 mg, 20%). 1-((( S )-1-(( S )-2-(cyclohexylmethyl)-4-hydroxybutanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide: LCMS (method A): R _T = 1.24 min, m/z = 566 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.83-7.78 (m, 1H), 7.51-7.28 (m, 5H), 6.48-6.42 (m , 1H), 4.99-4.83 (m, 1H), 4.52-4.34 (m, 2H), 4.18-4.11 (m, 0.4H), 3.90-3 .70 (m, 2H), 3.68-3.62 (m, 0.6H), 3.42-3.18 (m, 3H (with HDO overlap)), 3.05-2.95 (m, 1.6H), 2.87-2.79 (m, 0.4H), 2.75 (s, 3H), 2.63 (s, 3H), 1.76-1.49 (m , 7H), 1.47-1.36 (m, 2H), 1.27-1.04 (m, 6H), 1.04-0.91 (m, 6H), 0.89-0.73 (m, 2H). 1-((( R )-1-(( S )-2-(cyclohexylmethyl)-4-hydroxybutanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide: LCMS (method A): R _T = 1.20 min, m/z = 566 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.83-7.78 (m, 1H), 7.48-7.34 (m, 5H), 6.48-6.42 (m , 1H), 4.97-4.85 (m, 1H), 4.52-4.35 (m, 2H), 4.05-3.98 (m, 0.4H), 3.86-3 .68 (m, 2.6H), 3.40-3.18 (m, 3H (with HDO overlap)), 3.05-2.87 (m, 2H), 2.75 (s, 3H ), 2.62 (s, 3H), 1.74-1.34 (m, 9H), 1.27-1.07 (m, 6H), 1.07-0.91 (m, 6H), 0.90-0.77 (m, 2H).

Example 166 and Example 167: 1-((( S )-one-(( S )-3-cyclobutyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide and 1-((( R )-one-(( S )-3-cyclobutyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using amine 6 (50 mg, 0.130 mmol), acid 10 (31 mg, 0.196 mmol), HATU (74 mg, 0.196 mmol), DIPEA (91 μl, 0.522 mmol) and DCM ( 2.6 ml) to give a mixture of diastereomers which were separated by preparative HPLC under basic conditions to give a second eluted compound 1-((( S )-1-(( S )-3-cyclobutyl-2-(hydroxymethyl)propanoyl) -4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide (9 mg, 13%) and the first eluted compound 1-((( R )-1-(( S )-3-cyclobutyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N - dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide (8.3 mg, 12%) as colorless solids after lyophilization. 1-((( S )-1-(( S )-3-cyclobutyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide: LCMS (method A): R _T = 1.06 min, m/z = 524 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84-7.78 (m, 1H), 7.56-7.24 (m, 5H), 6.48-6.42 (m , 1H), 4.97-4.85(m, 1H), 4.59(s, 1H), 4.52-4.37(m, 1.4H), 4.11-4.04(m , 0.6H), 3.87-3.67(m, 2.6H), 3.49-3.13(m, 2H), 2.99-2.80(m, 2.4H), 2 .75 (s, 3H), 2.62 (s, 3H), 2.20-2.06 (m, 1H), 2.03-1.87 (m, 2H), 1.81-1.64 (m, 3H), 1.61-1.36 (m, 4H), 1.21-1.15 (m, 1H), 1.09-0.87 (m, 6H). 1-((( R )-1-(( S )-3-cyclobutyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide: LCMS (method A): R _T = 1.05 min, m/z = 524 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84-7.79 (m, 1H), 7.50-7.30 (m, 5H), 6.48-6.42 (m , 1H), 4.99-4.85 (m, 1H), 4.62-4.37 (m, 2.4H), 4.13-4.03 (m, 0.6H), 3.83 -3.74(m, 1.4H), 3.71-3.65(m, 0.6H), 3.54-3.49(m, 0.4H), 3.46-3.40( m, 0.6H), 3.36-3.21 (m, 2H (with HDO overlap)), 3.00-2.88 (m, 1H), 2.87-2.80 (m, 1H), 2.75 (s, 3H), 2.62 (s, 3H), 2.23-2.11 (m, 1H), 2.02-1.87 (m, 2H), 1.82 -1.38(m, 7H), 1.28-1.15(m, 1H), 1.06-0.88(m, 6H).

Example 168: 1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(morpholine-4-carbonyl)- 4-phenylpyridin-2(1H)-one

DIPEA (0.031 ml, 0.177 mmol) was added to a stirred solution of 1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (30.0 mg, 0.0590 mmol), morpholine (0.0052 ml, 0.0590 mmol) and HATU (26.9 mg, 0 .0708 mmol) in DCM (5.0 ml) at room temperature. After 16 hours, saturated sodium bicarbonate solution (aqueous) was added and the resulting biphasic mixture was separated, extracted (DCM x 2), the combined organic phase was dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (cyclohexane, then 0-10%, MeOH in DCM) and lyophilized to give the title compound (29.8 mg, 85%) as a white solid. LCMS (Method A): R _T = 1.49 min, m / z = 578 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.83 (s, 1H), 7.51-7.36 (m, 5H), 6.48-6.43 (m, 1H), 5.07-4.70 (m, 1H), 4.53-4.33 (m, 1H), 4.15-2.74 (m, 9H, solvent peak overlap), 2.69 (s, 4H), 1.80-1.39 (m, 7H), 1.32-0.68 (m, 18H

Example 169 5-(4-acetylpiperazin-1-carbonyl)-1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl )-4-phenylpyridin-2(1H)-one

DIPEA (0.031 ml, 0.177 mmol) was added to a stirred solution of 1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (30.0 mg, 0.0590 mmol), N-acetylpiperazine (7.6 mg, 0.0590 mmol) and HATU (26.9 mg , 0.0708 mmol) in DCM (5.0 ml) at room temperature. After 18 hours, saturated sodium bicarbonate solution (aqueous) was added and the resulting biphasic mixture was separated, extracted (DCM x 2), the combined organic phase was dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (cyclohexane, then 0 -10%, MeOH in DCM) and lyophilized to give the title compound (24.9 mg, 67%) as a white solid. LCMS (Method A): R _T = 1.32 min, m / z = 619 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84 (s, 1H), 7.52-7.22 (m, 5H), 6.53-6.40 (m, 1H), 5.10-4.67 (m, 1H), 4.56-4.32 (m, 1H), 4.16-2.13 (m, 13H, solvent peak overlap), 2.03-1, 82 (m, 3H), 1.80-1.39 (m, 7H), 1.33-0.73 (m, 18H).

Example 170: 1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(4-methylpiperazine-1-carbonyl )-4-phenylpyridin-2(1H)-one

DIPEA (0.031 ml, 0.177 mmol) was added to a stirred solution of 1-((1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (30.0 mg, 0.0590 mmol), 1-methylpiperazine (0.0065 ml, 0.0590 mmol) and HATU (26.9 mg , 0.0708 mmol) in DCM (1.0 ml) at room temperature. After 18 hours, saturated sodium bicarbonate solution (aqueous) was added and the resulting biphasic mixture was separated, extracted (DCM x 2), the combined organic phase was dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (cyclohexane, then 0 -10%, MeOH in DCM), further purified by flash chromatography (0-100%, EtOAc in cyclohexane; then 0-25%, MeOH in EtOAc) and lyophilized to give the title compound (21.2 mg, 61% ) as a white solid. LCMS (Method A): R _T = 1.05 min, m / z = 591 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.81 (br s, 1H), 7.52-7.33 (m, 5H), 6.49-6.41 (m, 1H ), 5.07-4.73 (m, 1H), 4.53-4.31 (m, 1H), 4.15-2.74 (m, 9H, overlap with solvent peak), 2.33- 0.74 (m, 32H).

The following Table of Examples was prepared using parallel synthesis according to the general procedure 13. In Example 181, acid 15 was used. The carboxylic acid used in Example 180 can be prepared using the same procedure as for acid 15, for except that the 1st eluted diastereoisomer from Step 4 was used and according to the method described in Step 5 to obtain (S)-4,4-difluoro-3-phenylbutanoic acid.

Example Structure Name LCMS
(method A):
R _T , m / z 171

1-((10-hydroxy-7-(4,4,4-trifluoro-3-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxamide 1.38 min, 548 [M+H] ⁺ 172

1-((10-hydroxy-7-(4,4,4-trifluorobutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide 1.28 min, 534 [M+H] ⁺ 173

1-((10-hydroxy-7-(3-(tetrahydrofuran-3-yl)propanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxamide 1.05 min, 536 [M+H] ⁺ 174

1-((10-hydroxy-7-((1 R ,2 S )-2-phenylcyclopropane-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide 1.32 min, 554 [M+H] ⁺ 175

1-((7-(cyclopropanecarbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3 -carboxamide 1.09 min
478 [M+H] ⁺ 176

1-((10-hydroxy-7-(1-methylcyclohexane-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide 1.50 min, 534 [M+H] ⁺ 177

1-((7-(3-fluorocyclopentan-1-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide 1.18 min, 524 [M+H] ⁺ 178

1-((7-(1-(2,2-difluoroethyl)cyclopropane-1-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6- oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide 1.18 min, 542 [M+H] ⁺ 179

1-((7-(bicyclo[2.2.1]heptane-1-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxamide 1.38 min, 532 [M+H] ⁺ 180

1-((7-(( S )-4,4-difluoro-3-phenylbutanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo -4-phenyl-1,6-dihydropyridine-3-carboxamide 1.41 min, 592 [M+H] ⁺ 181

1-((7-(( R )-4,4-difluoro-3-phenylbutanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo -4-phenyl-1,6-dihydropyridine-3-carboxamide 1.41 min, 592 [M+H] ⁺ 182

1-((7-(3-ethoxypropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxamide 1.08 min, 510 [M+H] ⁺ 183

1-((10-hydroxy-7-(( S )-3-phenylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide 1.41 min, 556 [M+H] ⁺ 184

1-((7-(3-(4-fluorophenyl)propanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxamide 1.38 min, 560 [M+H] ⁺ 185

1-((10-hydroxy-7-(( R )-3-phenylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide 1.41 min, 556 [M+H] ⁺ 186

1-((10-hydroxy-7-(1-methylcyclopentan-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide 1.37 min, 520 [M+H] ⁺ 187

1-((10-hydroxy-7-(1 H -pyrazole-3-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxamide 0.864 min, 504 [M+H] ⁺ 188

1-((10-hydroxy-7-(1 H -indazole-3-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxamide 1.09 min, 554 [M+H] ⁺ 189

1-((7-(3-cyclohexyl- 1H -pyrazole-4-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo- 4-phenyl-1,6-dihydropyridine-3-carboxamide 1.10 min, 586 [M+H] ⁺ 190

1-((10-hydroxy-7-(1 H -indole-3-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxamide 1.10 min, 553 [M+H] ⁺ 191

1-((7-(bicyclo[1.1.1]pentan-1-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxamide 1.14 min, 504 [M+H] ⁺ 192

1-((10-hydroxy-7-(5-phenyloxazole-4-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide 1.23 min, 581 [M+H] ⁺ 193

1-((7-(5-cyclopropyloxazole-4-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide 1.11 min, 545 [M+H] ⁺ 194

1-((7-(2-(cyclohexyloxy)acetyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1, 6-dihydropyridine-3-carboxamide 1.30 min, 550 [M+H] ⁺ 195

1-((10-hydroxy-7-(spiro[2.2]pentan-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxamide 1.14 min, 504 [M+H] ⁺ 196

1-((10-hydroxy-7-(3-(trifluoromethyl)cyclopentane-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxamide 1.33 min, 574 [M+H] ⁺ 197

1-((7-(2,4-dimethylpentanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6 -dihydropyridine-3-carboxamide 1.37 min, 522 [M+H] ⁺ 198

1-((7-(1-benzyl-1 H -pyrrole-2-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo- 4-phenyl-1,6-dihydropyridine-3-carboxamide 1.41 min, 593 [M+H] ⁺ 199

1-((7-(2-(cyclohexyloxy)propanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1, 6-dihydropyridine-3-carboxamide 1.32 min, 564 [M+H] ⁺

Example 200: 3-((1-((S)-3-cyclobutyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl-6-(2-fluorophenyl)pyrimidine -4(3H)-he

Prepared according to general procedure 3 using amine 5 (50 mg, 0.151 mmol), acid 10 (35.8 mg, 0.226 mmol), HATU (86.1 mg, 0.226 mmol) and DIPEA (105 µmol, 0.604 mmol ) in DCM (2 ml) to give the title compound (32 mg, 44%). LCMS (Method A): R _T =1.22 min, m / z =472 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 8.48-8.42 (m, 1H), 8.07-7.99(m, 1H), 7.59-7.50(m, 1H), 7.39-7.32(m, 2H), 6.83-6.78( m, 1H), 4.93-4.80 (m, 1H), 4.62-4.48 (m, 1H), 4.48-4.37 (m, 1H), 3.83-3, 64 (m, 2H), 3.56-3.14 (m, 3H (with HDO overlap)), 3.00-2.79 (m, 2H), 2.23-2.06 (m, 1H), 2.04-1.12 (m, 11H), 1.08-0.92 (m, 6H).

Example 201: 1-((7-(2-cyclobutoxyacetyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6-oxo-4-phenyl-1, 6-dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using amine 8 (30 mg, 73.3 µmol), 2-cyclobutoxyacetic acid (14.3 mg, 0.1-10 mmol), HATU (41.8 mg, 0.1-10 mmol) and DIPEA (51 μl, 0.293 mmol) in DCM (1 ml) to give the title compound (11 mg, 28%). LCMS (method A): R _T =1.12 min, m/z =522 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.85-7.81 (m, 1H), 7.47-7.42 (m, 3H), 7.41-7.36 (m, 2H), 6.47-6.44 (m, 1H), 4.97 (s, 0, 35H), 4.92 (s, 0.65H), 4.69-4.57 (m, 1H), 4.05-3.90 (m, 3H), 3.79-3.54 (m, 2H), 3.43-3.13 (m, 3H (with signal overlap from HDO)), 2.75 (s, 3H), 2.63 (s, 3H (with signal overlap from DMSO traces)), 2 .17-2.08 (m, 1H), 1.99-1.77 (m, 3H), 1.72-0.89 (m, 12H).

Example 202: 1-((7-(3,3-difluorocyclopentan-1-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6-oxo- 4-phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using amine 8 (30 mg, 73.3 µmol), 3,3-difluorocyclopentane-1-carboxylic acid (16.5 mg, 0.1-10 mmol), HATU (41.8 mg, 0.1-10 mmol) and DIPEA (51 μl, 0.293 mmol) in DMF (1 ml) to give the title compound (16 mg, 40%). LCMS (method A): R _T =1.22 min, m/z =542 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.86-7.80 (m, 1H), 7.48-7.42 (m, 3H), 7.41-7.35 (m, 2H), 6.48-6.44 (s, 1H), 5.00 (s, 0, 25H), 4.92 (s, 0.75H), 4.76-4.50 (m, 1H), 3.80-3.12 (m, 6H (with HDO overlap)), 2.75 (s, 3H), 2.63 (s, 3H), 2.25-1.08 (m, 16H).

Example 203: 1-((10-hydroxy-7-(2-hydroxy-3-phenylpropanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using amine 8 (23 mg, 56.2 µmol), 2-hydroxy-3-phenylpropanoic acid (14.0 mg, 84.2 µmol), HATU (32.0 mg, 84. 2 µmol) and DIPEA (39 µl, 0.225 mmol) in DMF (1 ml) to give the title compound (11 mg, 34%). LCMS (Method A): R _T =1.18 min, m/z =558 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.85-7.80 (m, 1H), 7.48-7.41(m, 3H), 7.41-7.35(m, 2H), 7.31-7.13(m, 5H), 6.48-6.43( m, 1H), 5.20-4.86 (m, 2H), 4.66-4.40 (m, 2H), 3.91-3.59 (m, 2H), 3.55-3, 11 (m, 3H (with signal overlap from HDO)), 2.98-2.67 (m, 5H), 2.62 (s, 3H (with signal overlap from DMSO traces)), 1.94-1, 82 (m, 1H), 1.68-0.96 (m, 9H).

Example 204: 1-(((S)-4-hydroxy-3,3-dimethyl-1-((R)-4,4,4-trifluoro-2-methylbutanoyl)piperidin-4-yl)methyl)-N ,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using amine 7 (20 mg, 52.2 µmol), acid 11 (10 mg, 62.6 µmol), HATU (24 mg, 62.6 µmol), DIPEA (36 µl, 0.209 mmol) and DCM (1 ml) to give the title compound (21.7 mg, 79%) as a colorless solid after lyophilization. LCMS (method A): R _T =1.16 min, m/z =522 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.81 (s, 0.5H), 7.81 (s, 0.5H), 7.54-7.20 (m, 5H), 6.46 (s, 0.5H), 6.45 (s, 0.5H), 4.97 (s, 0.5H), 4.94 (s, 0.5H), 4.45 (d, J =13.4Hz, 0.5H), 4.35(d, J =13.4Hz, 0.5H), 4.16(d, J =13.0Hz, 0.5H), 3, 85 (d, J =13.4Hz, 0.5H), 3.79 (d, J =13.5Hz, 1H), 3.68 (d, J =12.7Hz, 0.5H), 3.36-3.12 (m, 2H), 2.96 (d, J =12.8 Hz, 0.5H), 2.86-2.77 (m, 1H), 2.75 (s, 3H), 2.62 (s, 3H), 2.29-2.20 (m, 1H), 1.79-1.72 (m, 0.5H), 1.66-1.60 (m, 0.5H), 1.30-1.14 (m, 2H), 1.12 (d, J =6.9 Hz, 1.5H), 1.04 (d, J =7.0 Hz, 1 .5H), 1.00 (s, 3H), 0.95 (s, 1.5H), 0.95 (s, 1.5H).

Example 205: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl )-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Stage 1: ethyl-1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2 -fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate : Prepared according to general procedure 3 using amine 9 (67 mg, 0.167 mmol), acid 1 (28 mg, 0.167 mmol), HATU ( 63 mg, 0.167 mmol), DIPEA (0.116 ml, 0.666 mmol) and DCM (3.3 ml) to give the title compound (108 mg, >100%) as a colorless foam. LCMS (method A): R _T= 1.86 min, m/z =555 [M+H] ⁺ .

Stage 2: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl ))-6-oxo-1,6-dihydropyridine-3-carboxylic acid : Ethyl-1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3 solution ,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (108 mg, 0.195 mmol) in 1 M NaOH (aq) (0.389 ml , 0.389 mmol) and 1,4-dioxane (1 ml) were stirred at 50° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and the pH was adjusted to ~2 with 1M HCl (aq.). The resulting mixture was extracted with DCM (3×20 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue purified by flash chromatography (GraceResolv silica gel cartridge (12 g), 0-100% EtOAc in cyclohexane) to give the title compound (61 mg, 59%) as a colorless solid . LCMS (method A): R _T= 1.54 min, m/z =527 [M+H] ⁺ .

Stage 3: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl ))-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide : Prepared according to general procedure 3 using 1-(((S)-1-((R)-3- cyclohexyl-2)-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (28 mg , 53.2 µmol), dimethylamine (2M in THF, 32 µl, 63.8 µmol), HATU (24 mg, 63.8 µmol), DIPEA (37 ml, 0.213 mmol) and DCM (1 ml), to give the title compound (28.6 mg, 96%) as a colorless solid after lyophilization. LCMS (method A): R _T =1.53 min, m/z =554 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84 (s, 0.5H), 7.83 (s, 0.5H), 7.46 (td, d, J =7.5 , 5.2, 1.8 Hz, 1H), 7.36 (tt, J = 7.7, 2.1 Hz, 1H), 7.29-7.20 (m, 2H), 6.45 ( s, 0.5), 6.43 (s, 0.5H), 4.90 (s, 0.5H), 4.88 (s, 0.5H), 4.52 (d, J =13, 4 Hz, 0.5H), 4.39 (d, J =13.4 Hz, 0.5H), 4.11 (d, J =12.5 Hz, 0.5H), 3.84 (d, J =13.5Hz, 0.5H), 3.78-3.69(m, 1H), 3.60(d, J =12.6Hz, 0.5H), 3.31-3.22 (m, 1.5H), 3.02 (d, J =12.8 Hz, 0.5H), 2.96-2.66 (m, 7.5H), 1.77-1.42 (m , 7H), 1.29-0.89 (m, 15H), 0.88-0.74 (m, 2H).

Example 206: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl )-5-(piperazine-1-carbonyl)pyridine-2(1H)-one

Stage 1: tert-butyl-4-(1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl) -4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate : Prepared according to General Procedure 3 using 1-(((S)-1-( (R))-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3 -carboxylic acid (Example 205, step 2) (33 mg, 62.7 µmol), tert-butylpiperazine-1-carboxylate (14 mg, 75.2 µmol), HATU (29 mg, 75.2 µmol), DIPEA ( 44 μl, 0.251 mmol) and DCM (1.2 ml) to give the title compound (43 mg, 98%) as a colorless foam. LCMS (method A): R _T= 1.80 min, m/z =695 [M+H] ⁺ .

Stage 2: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl ))-5-(piperazine-1-carbonyl)pyridine-2(1H)-one : Solution of tert-butyl-4-(1-(((S)-1-((R)-3-cyclohexyl)-2 -methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate (43 mg, 61.9 µmol) in TFA (0.25 ml) and DCM (0.5 ml) was stirred for 20 minutes, after which the reaction mixture was purified using a Biotage SCX-2 cartridge (2 g) (pre-equilibrated and then washed with 1:1 DCM/MeOH before eluting with 1:1 DCM/7M NH ₃ in MeOH). The main eluents were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv silica gel cartridge (12 g), 0-20% MeOH in DCM) to give the title compound (34.5 mg, 92%) as a colorless solid after lyophilization. LCMS (Method A): R _T =1.09 min, m/z =595 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.81 (s, 1H), 7.47 (d, td, J =7.6, 6.2, 5.2, 1.8 Hz , 1H), 7.37 (ddd, J =9.4, 6.9, 1.8 Hz, 1H), 7.32-7.24 (m, 2H), 6.45 (s, 0.5H ), 6.43 (s, 0.5H), 4.87 (s, 1H), 4.51 (d, J =13.4 Hz, 0.5H), 4.39 (d, J =12, 9 Hz, 0.5H), 4.11 (d, J =12.8 Hz, 0.5H), 3.84 (d, J =8.5 Hz, 0.5H), 3.78-3, 70 (m, 1H), 3.60 (d, J =12.9 Hz, 0.5H), 3.45-3.09 (m, 9H (with HDO overlap)), 3.03 (d , J =12.8Hz, 0.5H), 2.96-2.80(m, 2H), 2.41(br, s, 1H), 1.75-1.43(m, 7H) , 1.29-0.89 (m, 15H), 0.88-0.74 (m, 2H).

Example 207: (S)-1-((4-Hydroxy-3,3-dimethyl-1-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)piperidin-4-yl )methyl)-N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

DIPEA (36 µl, 0.209 mmol) was added to a suspension of amine 7 (20 mg, 52.2 µmol), acid 12 (18 mg, 78.2 µmol) and HATU (30 mg, 78.2 µmol) in DMF (1 ml ). After 30 minutes, the reaction was quenched by adding saturated NaHCO ₃ (aq.) (15 ml), and the mixture was extracted with DCM (3×10 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (Biotage KP-NH cartridge (11 g), 0-100% EtOAc in cyclohexane; then GraceResolv cartridge with silica gel (12 g), 0-10% MeOH in DCM) and lyophilization gave the title compound (18.2 mg, 57%) as a colorless solid. LCMS (method A): R _T =1.31 min, m/z =590 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.81 (s, 0.4H), 7.81 (s, 0.6H), 7.51-7.41 (m, 3H), 7.41-7.33(m, 2H), 6.46(s, 0.4H), 6.45(s, 0.6H), 4.99(s, 0.4H), 4.95( s, 0.6H), 4.47 (d, J =13.4 Hz, 0.6H), 4.40 (d, J =13.4 Hz, 0.4H), 4.14-4.08 (m, 0.4H), 3.92-3.62 (m, 2.6H), 3.47-3.36 (m, 1H), 3.31-3.20 (m, 2H), 2 .97-2.88 (m, 1H), 2.87-2.70 (m, 1H), 2.75 (s, 3H), 2.63 (s, 3H), 2.62-2.53 (m, 2H), 1.77-1.70 (m, 0.6H), 1.63 (ddd, J =14.0, 11.6, 4.9 Hz, 0.4H), 1.29 -1.20 (m, 1H), 1.02 (s, 1H), 0.99 (s, 1H), 0.96 (s, 2H), 0.95 (s, 2H).

Example 208: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-((S) -2-(hydroxymethyl)piperazine-1-carbonyl)-4-phenylpyridin-2(1H)-one

Stage 1: tert-butyl-(S)-4-(1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidine-4- yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonyl)-3-(hydroxymethyl)piperazine-1-carboxylate : Tert-butyl-(S)-3-(hydroxymethyl)piperazine- 1-carboxylate (6.4 mg, 0.0295 mmol) was added to a stirred solution of acid 4 (15.0 mg, 0.0295 mmol), HATU (13.5 mg, 0.0354 mmol) and DIPEA (0.016 ml, 0.0885 mmol) in DCM (5.0 ml) at room temperature. After 22 hours, additional tert-butyl-(S)-3-(hydroxymethyl)piperazine-1-carboxylate (2.1 mg, 0.00983 mmol) was added. After another 4 hours, saturated sodium bicarbonate solution (aqueous solution) and additional DCM were added. The resulting biphasic mixture was separated, extracted (x 2), the combined organic phase was dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography using a column of KP-NH (1 g) (0-100%, EtOAc in cyclohexane) to give the title compound (12.8 mg, 61%) as a white solid. LCMS (method A): R _T= 1.64 min, m/z =707 [M+H] ⁺ .

Step 2: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-((S) -2-(hydroxymethyl)piperazine-1-carbonyl)-4-phenylpyridin-2(1H)-one : TFA (0.5 ml, 6.49 mmol) was added to a stirred solution of tert-butyl-(S)-4- (1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carbonyl)-3-(hydroxymethyl)piperazine-1-carboxylate (12.8 mg, 0.0181 mmol) in DCM (0.5 ml) at room temperature. After 30 minutes, the solvents were removed in vacuo and the remaining residue was loaded into an SCX-2 cartridge pre-equilibrated in MeOH, washed with MeOH and eluted with 7N ammonia in MeOH. Solvents were removed in vacuo, the remaining residue was purified by flash chromatography (cyclohexane, then 0-10% MeOH in DCM) and lyophilized to give the title compound (3.4 mg, 31%) as a white solid. LCMS (Method A): R _T = 1.06 min, m / z = 607 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.87-7.70 (m, 1H), 7.57-7.27 (m, 5H), 6.49-6.38 (m , 1H), 5.08-3.37 (m, 8H), 3.31-3.19 (1H, solvent peak overlap), 3.13-2.57 (m, 5H, solvent peak overlap) , 2.04-1.79 (m, 1H), 1.76-1.42 (m, 8H), 1.30-0.74 (m, 20H).

Example 209: 1-(((R)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N- dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Step 1: tert-Butyl-(R)-10-((5-(ethoxycarbonyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-10-hydroxy-7-azaspiro[4.5]decane -7-carboxylate : Prepared according to general procedure 4 using tert-butyl-(R)-10-((4-chloro-5-(ethoxycarbonyl)-2-oxopyridin-1(2H)-yl)methyl) -10-hydroxy-7-azaspiro[4.5]decane-7-carboxylate (amine 10, step 1) (200 mg, 0.427 mmol), phenylboronic acid (78 mg, 0.640 mmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (18 mg, 21.33 µmol), Na ₂ CO ₃ (90 mg, 0.853 mmol), 1,4-dioxane (1.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 120° C. for 30 minutes to give the title compound (230 mg, >100%) as a pale yellow foam. LCMS (method A): R _T= 1.78 min, m/z =511 [M+H] ⁺ .

Step 2: Ethyl (R)-1-((10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate : Obtained according to general procedure 7 using tert-butyl-(R)-10-((5-(ethoxycarbonyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-10-hydroxy-7- azaspiro[4.5]decane-7-carboxylate (230 mg, 0.450 mmol), TFA (1 ml) and DCM (2 ml) to give the title compound (154 mg, 83%) as a colorless solid. LCMS (method B): R _T= 0.82 min, m/z =41 1 [M+H] ⁺ .

Stage 3: ethyl-1-(((R)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6- oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate : Prepared according to general procedure 3 using ethyl-(R)-1-((10-hydroxy-7-azaspiro[4.5]decane-10- yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (154 mg, 0.375 mmol), acids 1 (70 mg, 0.413 mmol), HATU (157 mg, 0.413 mmol), DIPEA (0.262 ml, 1.50 mmol) and DCM (7.5 ml) to give the title compound (233 mg, >100%) as a colorless foam. LCMS (method A): R _T= 1.95 min, m/z =563 [M+H] ⁺ .

Step 4: 1-((((R)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo -4-phenyl-1,6-dihydropyridine-3-carboxylic acid : Ethyl-1-(((R)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro solution [4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (233 mg, 0.414 mmol) in 1M NaOH (aq) (0.828 ml, 0.828 mmol) and 1,4-dioxane (2 ml) was stirred at 50°C for 16 hours.The reaction mixture was allowed to cool to room temperature, and the pH was adjusted to ~2 by adding 1M HCl (aq.).The resulting mixture was extracted with DCM (3×10 ml) using a Biotage phase separator, the combined organic phases were concentrated in vacuo and the crude product was purified by flash chromatography GraceResolv silica gel cartridge (24 g, 0-100% EtOAc in cyclohexane), to give the title compound (136 mg , 61%) as a colorless solid. LCMS (method A): R _T= 1.61 min, m/z =535 [M+H] ⁺ .

Step 5: 1-((((R)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide : Prepared according to General Procedure 3 using 1-(((R)-7-((R)-3-cyclohexyl- 2-)methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (67 mg, 0.125 mmol) , dimethylamine (2M in THF, 75 µl, 0.150 mmol), HATU (57 mg, 0.150 mmol), DIPEA (88 µl, 0.501 mmol) and DCM (2.5 ml) to give the title compound (61 mg, 85%) as a colorless solid after lyophilization. LCMS (method B): R _T =1.45 min, m/z =562 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84 (s, 1H), 7.56-7.25 (m, 5H), 6.46 (s, 0.3H), 6, 45 (s, 0.7H), 4.98 (s, 0.3H), 4.91 (s, 0.7H), 4.70-4.57 (m, 1H), 3.77-3, 61 (m, 2H), 3.57-3.35 (m, 2H), 3.29-3.16 (m, 1H), 2.95-2.81 (m, 1H), 2.75 ( s, 3H), 2.63 (s, 3H), 1.97-1.84 (m, 1H), 1.79-1.43 (m, 11.5H), 1.37-1.03 ( m, 8.5H), 0.97 (d, J =6.6 Hz, 1H), 0.93 (d, J =6.6 Hz, 2H), 0.89-0.77 (m, 2H ).

Example 210: 1-(((R)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4,5]-decan-10-yl)methyl)-4 -phenyl-5-(piperazin-1-carbonyl)pyridine-2(1H)-one

Step 1: tert-Butyl-4-(1-(((R)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl) methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate : Prepared according to General Procedure 3 using 1-(((R)-7-((R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (Example 209, Step 4) (69 mg, 0.129 mmol), tert-butylpiperazine-1-carboxylate (29 mg, 0.155 mmol), HATU (59 mg, 0.155 mmol), DIPEA (90 μL, 0.516 mmol) and DCM (2, 5 ml) to give the title compound (88 mg, 97%) as a colorless foam. LCMS (Method A): R _T= 1.87 min, m/z =703 [M+H] ⁺ .

Step 2: 1-(((R)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl- 5-(piperazine-1-carbonyl)pyridine-2(1H)-one : Solution of tert-butyl-4-(1-(((R)-7-((R)-3-cyclohexyl-2-methylpropanoyl)- 10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate (88 mg, 0.125 mmol) in TFA (0.3 ml) and DCM (0.6 ml) were stirred for 20 minutes and then the reaction mixture was purified using a Biotage SCX-2 cartridge (2 g) (pre-equilibrated and then washed with 1:1 DCM/ MeOH before eluting with 1:1 DCM/7M NH ₃ in MeOH). The main eluents were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv silica gel cartridge (12 g), 0-20% MeOH in DCM) to give the title compound (68.5 mg, 89%) as a colorless solid after lyophilization. LCMS (Method B): R _T =0.97 min, m/z =603 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.83 (s, 1H), 7.65-7.18 (m, 5H), 6.46 (s, 0.3H), 6, 45 (s, 0.7H), 5.06-4.79 (m, 1H), 4.69-4.52 (m, 1H), 3.78-3.61 (m, 2H), 3. 57-2.21 (m, 13H (with HDO and DMSO overlap)), 1.98-1.42 (m, 13H), 1.37-1.03 (m, 8H), 0.97 ( d, J =6.6 Hz, 1H), 0.93 (d, J =6.7 Hz, 2H), 0.89-0.77 (m, 2H).

Example 211: 1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Stage 1: ethyl-1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6- oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate : Prepared according to general procedure 3 using amine 10 (140 mg, 0.342 mmol), acid 1 (69.8 mg, 0.410 mmol), HATU ( 195 mg, 0.513 mmol) and DIPEA (240 μl, 1.37 mmol) in DCM (5 ml) to give the title compound (170 mg, 88%). LCMS (Method A): R _T= 1.96 min, m/z =563 [M+H] ⁺ .

Step 2: 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo- 4-phenyl-1,6-dihydropyridine-3-carboxylic acid : Ethyl-1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[ 4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (170 mg, 0.302 mmol) in ethanol (1.5 ml) and 2M NaOH (aq.) (1.5 ml, 3.00 mmol) was stirred at 60°C for 1 hour. The reaction mixture was concentrated in vacuo. The residue was dissolved in water and washed with diethyl ether. The aqueous phase was acidified by adding 2M HCl (aq.) to pH <4. The resulting suspension was extracted with EtOAc (x 3), the combined organic phases were washed with brine, passed through a Biotage phase separator and concentrated in vacuo to give the title compound (150 mg, 92%). LCMS (Method A): R _T= 1.63 min, m/z =535 [M+H] ⁺ .

Step 3: 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-cyl)methyl)-N,N- dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide : Prepared according to general procedure 3 using 1-(((S)-7-((R)-3-cyclohexyl-2 -methylpropanoyl))-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (60 mg, 0.112 mmol), dimethylamine (2M in THF, 84 µl, 0.168 mmol), HATU (51.2 mg, 0.135 mmol) and DIPEA (59 µl, 0.337 mmol) in DCM (2 ml) to give the title compound (49 mg, 76 %). LCMS (Method B): R _T =1.46 min, m/z =562 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.86-7.82 (m, 1H), 7.47-7.41(m, 3H), 7.41-7.35(m, 2H), 6.47(s, 0.35H), 6.45(s, 0.65H) , 4.99 (s, 0.35H), 4.92 (s, 0.65H), 4.69 (d, J =13.5 Hz, 0.65H), 4.56 (d, J =13 .5 Hz, 0.35H), 3.93-3.59 (m, 2H), 3.53-3.10 (m, 3H (with HDO overlap)), 2.96-2.81 ( m, 1H), 2.75 (s, 3H), 2.63 (s, 3H (with signal overlap from DMSO traces)), 2.01-1.82 (m, 1H), 1.75-0, 99 (m, 20H), 0.99-0.91 (m, 3H), 0.89-0.74 (m, 2H).

Example 212: 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl- 5-(piperazine-1-carbonyl)pyridine-2(1H)-one

Step 1: tert-Butyl-4-(1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl) methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate : Prepared according to general procedure 3 using 1-(((S)-7-((R )-3)-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid ( Example 211, Step 2) (85 mg, 0.159 mmol), tert-butylpiperazine-1-carboxylate (44.4 mg, 0.239 mmol), HATU (72.5 mg, 0.191 mmol) and DIPEA (83 µl, 0.477 mmol) in DCM (2 ml) to give the title compound (111 mg, quant.). LCMS (Method A): R _T = 1.88 min, m/z = 703 [M+H] ⁺ .

Step 2: 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl- 5-(piperazine-1-carbonyl)pyridine-2(1H)-one : Prepared according to general procedure 7 using t-butyl-4-(1-(((S)-7-((R)- 3)-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonyl)piperazine-1 -carboxylate (125 mg, 0.178 mmol), DCM (3 ml) and TFA (1 ml). The crude product was further purified by flash chromatography to give the title compound (86 mg, 78%). LCMS (method B): R _T =0.99 min, m/z =603 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.83 (s, 1H), 7 .51-7.35(m, 5H), 6.46(s, 0.35H), 6.44(s, 0.65H), 5.09-4.79(m, 1H), 4.68 (d, J =13.5 Hz, 0.65H), 4.55 (d, J =13.5 Hz, 0.35H), 3.94-3.57 (m, 2H), 3.55- 2.80 (m, 7H (with HDO overlap)), 2.79-2.24 (m, 5H (with DMSO overlap)), 2.02-1.01 (m, 22H), 1 .00-0.91 (m, 3H), 0.91-0.74 (m, 2H).

Example 213: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethyl)methyl)-5-((R)-3-methylpiperazine -1-carbonyl)-4-phenylpyridin-2(1H)-one

Stage 1: tert-butyl-(R)-4-(1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidine-4- yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonyl)-2-methylpiperazine-1-carboxylate : Tert-butyl-(R)-2-methylpiperazine-1-carboxylate (5, 9 0.0295 mmol) was added to a stirred solution of acid 4 (15.0 mg, 0.0295 mmol), HATU (13.5 mg, 0.0354 mmol) and DIPEA (0.015 ml, 0.0885 mmol) in DCM ( 1.0 ml) at room temperature. After 2 hours, saturated sodium bicarbonate solution (aqueous solution) and additional DCM were added. The resulting biphasic mixture was separated, extracted (x 2), the combined organic phase was dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-100%, EtOAc in cyclohexane) to give the title compound (16.1 mg, 79%) as a white solid. LCMS (Method A): R _T= 1.86 min, m/z =691 [M+H] ⁺ .

Step 2: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-((R) -3-methylpiperazin-1-carbonyl)-4-phenylpyridin-2(1H)-one : TFA (0.5 ml, 6.49 mmol) was added to a stirred solution of tert-butyl-(R)-4-(1- (((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6 -dihydropyridine-3-carbonyl)-2-methylpiperazine-1-carboxylate (16.1 mg, 0.0233 mmol) in DCM (0.5 ml) at room temperature. After 30 minutes, the solvents were removed in vacuo and the remaining residue was loaded into an SCX-2 cartridge pre-equilibrated in MeOH, washed with MeOH and eluted with 7N ammonia in MeOH. Solvents were removed in vacuo and the remaining residue was purified by flash chromatography (cyclohexane, then 0-5% MeOH in DCM) and lyophilized to give the title compound (6.8 mg, 49%) as a white solid. LCMS (method B): R _T =0.97 min, m / z= 591 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.89-7.72 (m, 1H), 7.51-7.25 (m, 5H), 6.44 (d, 1H), 5.04-4.75 (m, 1H), 4.55-4.28 (m, 1H), 4.23-3.44 (m, 3H), 3.31-2.66 (m, 4H , solvent peak overlap), 2.61-1.80 (m, 3H, solvent peak overlap), 1.77-1.42 (m, 8H), 1.42-0.57 (m, 23H) .

Example 214: 1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N- dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Stage 1: ethyl-1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6- oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate : Prepared according to general procedure 3 using amine 10 (72 mg, 0.175 mmol), acid 5 (30 mg, 0.21 1 mmol), DIPEA ( 0.123 ml, 0.702 mmol), HATU (80 mg, 0.211 mmol) and DCM (3.5 ml) to give the title compound (81 mg, 86%) as a colorless foam. LCMS (method B): R _T= 1.59 min, m/z =535 [M+H] ⁺ .

Step 2: 1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo- 4-phenyl-1,6-dihydropyridine-3-carboxylic acid : Ethyl 1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[ 4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (81 mg, 0.152 mmol) in 1 M NaOH (aq.) (0.606 ml, 0.606 mmol) and 1,4-dioxane (1.5 ml) was stirred at 50°C for 4 hours. The reaction mixture was allowed to cool to room temperature and the pH was adjusted to ~2 with 1M HCl (aq.). The resulting mixture was extracted with DCM (3×5 ml) using a Biotage phase separator and the combined organic phases concentrated in vacuo to give the title compound (78 mg, quant) as a light beige foam. LCMS (method B): R _T= 1.32 min, m/z =507 [M+H] ⁺ .

Step 3: 1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N- dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide : Prepared according to general procedure 3 using 1-(((S)-7-((R)-3-cyclobutyl-2 -methylpropanoyl))-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (38 mg, 75.0 µmol ), dimethylamine (2M in THF, 45 µl, 90.0 µmol), HATU (34 mg, 90.0 µmol), DIPEA (52 µl, 0.300 mmol) and DCM (1.5 ml), to give the title compounds (33.6 mg, 82%) as a colorless solid. after lyophilization. LCMS (Method B): R _T =1.32 min, m/z =534 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84 (s, 0.4H) 7.84 (s, 0.6H), 7.50-7.28 (m, 5H), 6 .46 (s, 0.4H), 6.45 (s, 0.6H), 4.98 (s, 0.4H), 4.91 (s, 0.6H), 4.65 (d, J =13.5Hz, 0.6H), 4.60(d, J =13.5Hz, 0.4H), 3.84-3.62(m, 2H), 3.46-3.17( m, 3H (with signal overlap from HDO)), 2.81-2.57 (m, 1H), 2.75 (s, 3H), 2.63 (s, 3H), 2.24-2.13 (m, 1H), 2.02-1.85 (m, 3H), 1.83-1.42 (m, 10H), 1.39-1.07 (m, 5H), 0.99-0 .89 (m, 3H).

Example 215: 1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4- phenyl-5-(piperazine-1-carbonyl)pyridine-2(1H)-one

Step 1: tert-Butyl-4-(1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl) methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate : Prepared according to general procedure 3 using 1-(((S)-7-((R )-3)-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid ( Example 214 Step 2) (40 mg, 79.0 µmol), tert-butylpiperazine-1-carboxylate (17.6 mg, 94.7 µmol), HATU (36 mg, 94.7 µmol), DIPEA (55 µl , 0.316 mmol) and DCM (1.5 mL) to give the title compound (50 mg, 93%) as a colorless foam. LCMS (method B): R _{T =} 1.54 min, m/z = 619 [M-butene+H] ⁺ .

Step 2: 1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl- 5-(piperazine-1-carbonyl)pyridine-2(1H)-one : tert-Butyl-4-(1-(((S)-7-((R)-3-cyclobutyl-2)-methylpropanoyl) solution -10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate (50 mg, 74.1 µl) in TFA (0.3 ml) and DCM (0.6 ml) were stirred for 20 minutes and then the reaction mixture was purified using a Biotage SCX-2 cartridge (2 g) (pre-equilibrated and then washed with 1: 1 DCM/MeOH before eluting with 1:1 DCM/7M NH ₃ in MeOH). The main eluents were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv silica gel cartridge (12 g), 0-20% MeOH in DCM) to give the title compound (40 mg, 91%) as a colorless solid after lyophilization. LCMS (Method B): R _T =0.90 min, m/z =575 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.82 (s, 1H), 7.61-7.28 (m, 5H), 6.46 (s, 0.4H), 6, 44 (s, 0.6H), 5.04-4.83 (m, 1H), 4.68-4.55 (m, 1H), 3.84-3.60 (m, 2H), 3. 48-2.24 (m, 13H (with HDO and DMSO overlap)), 2.24-2.13 (m, 1H), 2.02-1.09 (m, 18H), 1.02- 0.86 (m, 3H).

Example 216: 1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Stage 1: ethyl 1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl )-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate : Prepared according to general procedure 3 using amine 10 (69 mg, 0.169 mmol), acid 11 (31 mg, 0.202 mmol), HATU (77 mg, 0.202 mmol), DIPEA (0.117 ml, 0.672 mmol) and DCM (3.3 ml) to give the title compound (82 mg, 88%) as a colorless foam. LCMS (method B): R _T= 1.44 min, m/z =549 [M+H] ⁺ .

Step 2: 1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid : Ethyl-1-((( S )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2 solution -methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (82 mg, 0.149 mmol) in 1 M NaOH (aq.) (0.598 ml, 0.598 mmol) and 1,4-dioxane (1.5 ml) were stirred at 50° C. for 3 hours and 20 minutes. The reaction mixture was allowed to cool to room temperature and the pH was adjusted to ~2 with 1M HCl (aq.). The resulting mixture was extracted with DCM (3 x 5 ml) using a Biotage phase separator and the combined organic phases concentrated in vacuo to give the title compound (80 mg, quantitative) as a light beige foam. LCMS (method B): R _T= 1.18 min, m/z =521 [M+H] ⁺ .

Step 3: 1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide : Prepared according to General Procedure 3 using 1-((( S )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid ( 38 mg, 73.0 µmol), dimethylamine (2M in THF, 44 µl, 87.6 µmol), HATU (33 mg, 87.6 µmol), DIPEA (51 µl, 0.292 mmol), and DCM (1.5 ml ) to give the title compound (33 mg, 80%) as a colorless solid after lyophilization. LCMS (Method B): R _T =1.18 min, m/z =548 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84 (s, 0.4H), 7.84 (s, 0.6H), 7.61-7.22 (m, 5H), 6.46 (s, 0.4H), 6.45 (s, 0.6H), 5.00 (s, 0.4H), 4.94 (s, 0.6H), 4.63 (d, J =13.4Hz, 0.6H), 4.51(d, J =13.5Hz, 0.4H), 4.03-3.95(m, 0.4H), 3.80-3 .64 (m, 1.6H), 3.53-3.39 (m, 1.4H), 3.37-3.25 (m, 0.6H (with HDO signal overlap)), 3.21 -2.98 (m, 1.4H), 2.87-2.64 (m, 0.6H), 2.75 (s, 3H), 2.63 (s, 3H), 2.32-2 .19 (m, 1H), 2.03-1.96 (m, 0.4H), 1.92-1.85 (m, 0.6H), 1.83-0.91 (m, 13H) .

Example 217: 1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- 4-phenyl-5-(piperazin-1-carbonyl)pyridin-2(1H)-one

Step 1: tert-butyl-4-(1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan- 10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate : Prepared according to General Procedure 3 using 1-((( S )-10 -hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6- dihydropyridine-3-carboxylic acid (Example 216, step 2) (42 mg, 80.7 µmol), tert-butylpiperazine-1-carboxylate (18 mg, 96.8 µmol), HATU (37 mg, 96.8 µmol) , DIPEA (56 μl, 0.323 mmol) and DCM (1.5 ml) to give the title compound (50 mg, 89%) as a colorless foam. LCMS (method B): R _T= 1.40 min, m/z =633 [M-butene+H] ⁺ .

Step 2: 1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- 4-phenyl-5-(piperazine-1-carbonyl)pyridin-2(1H)-one : Solution of tert -butyl-4-(1-((( S )-10-hydroxy-7-(( R )-4 ,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate (50 mg, 72.6 µmol) in TFA (0.3 ml) and DCM (0.6 ml) were stirred for 20 minutes before the reaction mixture was purified using a Biotage SCX-2 cartridge (2 g) (preliminary equilibrated and then washed with 1:1 DCM/MeOH before eluting with 1:1 DCM/7M NH ₃ in MeOH). The main eluents were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv silica gel cartridge (12 g), 0-20% MeOH in DCM) to give the title compound (41.8 mg, 94%) as a colorless solid after lyophilization. LCMS (Method B): R _T = 0.81 min, m/z = 589 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.83 (s, 1H), 7.70-7.05 (m, 5H), 6.46 (s, 0.4H), 6, 45 (s, 0.6H), 5.12-4.83 (m, 1H), 4.62 (d, J =13.4 Hz, 0.6H), 4.50 (d, J =13, 6Hz, 0.4H), 4.04-3.93(m, 0.4H), 3.86-3.60(m, 1.6H), 3.53-2.19(m, 15H( with overlapping signals from HDO and DMSO)), 2.07-0.98 (m, 13H).

Example 218: (S)-1-((10-hydroxy-7-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decane-10- yl)methyl)-N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Stage 1: ethyl-(S)-1-((10-hydroxy-7-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decan- 10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate : DIPEA (0.111 ml, 0.633 mmol) was added to a suspension of amine 10 (65 mg, 0.158 mmol), acid 12 (73 mg, 0.317 mmol) and HATU (120 mg, 0.317 mmol) in DMF (3.2 ml). After 1 hour, the reaction was quenched by adding saturated NaHCO ₃ (aq.) (15 ml) and the mixture was extracted with DCM (3×10 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (Biotage KP-NH cartridge (11 g), 0-100% EtOAc in cyclohexane) to give the title compound (87 mg, 89%) as a colorless foam . LCMS (method B): R _T= 1.53 min, m/z =617 [M+H] ⁺ .

Step 2: (S)-1-((10-hydroxy-7-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decane-10- yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid : Ethyl-( S )-1-((10-hydroxy-7-(4,4,4-trifluoro- 2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (87 mg, 0.141 mmol) in 1M NaOH (aq.) (0.564 ml, 0.564 mmol) and 1,4-dioxane (1.4 ml) was stirred at 50°C for 3 hours. The reaction mixture was allowed to cool to room temperature and the pH was adjusted to ~2 with 1M HCl (aq.). The resulting mixture was extracted with DCM (3×5 ml) using a Biotage phase separator and the combined organic phases were concentrated in vacuo to give the title compound (84 mg, quant) as a beige foam. LCMS (method B): R _T= 1.28 min, m/z =589 [M+H] ⁺ .

Step 3: (S)-1-((10-hydroxy-7-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decane-10- yl)methyl)-N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxes : Prepared according to General Procedure 3 using (S)-1-((10-hydroxy -7-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxylic acid (40 mg, 68.0 µmol), dimethylamine (2M in THF, 41 µg, 81.6 µmol), HATU (31 mg, 0.0816 mmol), DIPEA (48 µl, 0.272 mmol) and DCM (1.4 ml) to give the title compound (31.8 mg, 73%) as a colorless solid after lyophilization. LCMS (Method B): R _T =1.29 min, m/z =616 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84 (s, 1H), 7.48-7.33 (m, 5H), 6.46 (s, 0.3H), 6, 45 (s, 0.7H), 5.02 (s, 0.3H), 4.94 (s, 0.7H), 4.67-4.56 (m, 1H), 3.89-3, 82 (m, 0.3H), 3.79-3.62 (m, 2H), 3.58-3.51 (m, 0.7H), 3.46-3.19 (m, 2H (s signal overlap from HDO)), 2.89-2.53 (m, 4H), 2.75 (s, 3H), 2.63 (s, 3H), 2.00-1.87 (m, 1H) , 1.73-1.10 (m, 10H).

Example 219: (S)-1-((10-hydroxy-7-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decane-10- yl)methyl)-4-phenyl-5-(piperazin-1-carbonyl)pyridin-2(1H)-one

Stage 1: tert-butyl-(S)-4-(1-((10-hydroxy-7-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro [4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate: Prepared according to general procedure 3 using (S)- 1-((10-hydroxy-7-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6- oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (Example 218, step 2) (44 mg, 74.8 µmol), tert-butylpiperazine-1-carboxylate (16.7 mg, 89.7 µmol ), HATU (34 mg, 89.7 µmol), DIPEA (52 µl, 0.299 mmol) and DCM (1.5 ml) to give the title compound (52 mg, 91%) as a colorless foam. LCMS (method B): R _T= 1.49 min, m/z =657 [M-Boc+2H] ⁺ .

Step 2: (S)-1-((10-hydroxy-7-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decane-10- yl)methyl)-4-phenyl-5-(piperazine-1-carbonyl)pyridine-2(1H)-one : Solution of tert-butyl-(S)-4-(1-((10-hydroxy-)7- (4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6- dihydropyridine-3-carbonyl)piperazine-1-carboxylate (52 mg, 68.7 µmol) in TFA (0.3 ml) and DCM (0.6 ml) was stirred for 20 minutes before the reaction mixture was purified using Biotage SCX-2 cartridge (2 g) (pre-equilibrated and then washed with 1:1 DCM/MeOH before eluting with 1:1 DCM/7M NH ₃ in MeOH). The main eluents were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv silica gel cartridge (12 g), 0-20% MeOH in DCM) to give the title compound (40.2 mg, 88%) as a colorless solid substances after lyophilization. LCMS (Method B): R _T = 0.88 min, m/z = 657 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.83 (s, 1H), 7.68-7.18 (m, 5H), 6.46 (s, 0.4H), 6, 45 (s, 0.6H), 5.10-4.83 (m, 1H), 4.68-4.52 (m, 1H), 3.88-3.47 (m, 3H), 3. 47-2.25 (m, 15H (with DMSO and HDO overlap)), 2.03-1.07 (m, 11H).

Example 220: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-cyclopropyl-N, N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

DIPEA (0.022 mL, 0.127 mmol) was added to a stirred solution of acid 13 (20.0 mg, 0.0423 mmol), 2M dimethylamine in THF (0.042 mL, 0.0846 mmol) and HATU (19.3 mg, 0.0423 mmol). 0508 mmol) in DCM (1.0 ml) at room temperature. After 2 hours, the reaction mixture was partitioned between additional DCM and saturated sodium bicarbonate solution (aq.). The resulting biphasic mixture was separated, dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography using a KP-NH column (11 g) (0-100%, EtOAc in cyclohexane). Pure fractions were concentrated and lyophilized to give the title compound (1.9 mg, 55%) as a white solid. LCMS (method A): R _T =1.37 min, m/z=500 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.62 (d, 1H), 5.90 (d, 1H), 4.95 (d, 1H), 4.27 (dd, 1H) , 4.12-3.52 (m, 2H), 3.31-3.17 (m, 1H, solvent peak overlap), 3.05-2.76 (m, 8H), 1.74-1 .42 (m, 8H), 1.30-0.71 (m, 22H).

Example 221: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-cyclopropyl-5- (piperazine-1-carbonyl)pyridine-2(1H)-one

Stage 1: tert-butyl-4-(1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl) -4-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate : tert-Butylpiperazine-1-carboxylate (7.9 mg, 0.0423 mmol) was added to a stirred solution of acid 13 ( 20.0 mg, 0.0423 mmol), HATU (19.3 mg, 0.0508 mmol) and DIPEA (0.022 ml, 0.127 mmol) in DCM (1.0 ml) at room temperature. After 2 hours, saturated sodium bicarbonate solution (aqueous solution) and additional DCM were added. The resulting biphasic mixture was separated, extracted (x 2), the combined organic phase was dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography using a KP-NH column (1 g) (0-100%, EtOAc in cyclohexane ) to give the title compound (20.6 mg, 76%) as a white solid. LCMS (Method A): R _{T =} 1.68 min, m/z = 641 [M+H] ⁺ .

Stage 2: 1-(((S)-1-((R)-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-cyclopropyl-5- (piperazine-1-carbonyl)pyridin-2(1H)-one: TFA (0.5 ml, 6.49 mmol) was added to a stirred solution of tert -butyl 4-(1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carbonyl)piperazine-1 -carboxylate (20.6 mg, 0.0321 mmol) in DCM (0.5 ml) at room temperature. After 30 minutes, the solvents were removed in vacuo and the remaining residue was loaded into an SCX-2 cartridge pre-equilibrated in MeOH, washed with MeOH and eluted with 7M ammonia in MeOH. Solvents were removed in vacuo and the remaining residue was purified by flash chromatography (cyclohexane, then 0-10% MeOH in DCM) and lyophilized to give the title compound (1.7 mg, 66%) as a white solid. LCMS (Method A): R _T = 0.95 min, m / z = 541 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.67-7.51 (m, 1H), 5.90 (d, 1H), 5.10-4.75 (m, 1H), 4.39-3.41 (m, 5H), 3.31-3.10 (m, 3H, solvent peak overlap), 3.05-2.55 (m, 7H, solvent peak overlap), 1 .78-1.40 (m, 8H), 1.30-0.55 (m, 22H).

Example 222: 1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2 -fluorophenyl)-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Stage 1: ethyl-1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4- (2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate: Prepared according to general procedure 3 using amine 11 (60 mg, 0.140 mmol), acid 5 (23.9 mg, 0.168 mmol ), HATU (79.9 mg, 0.210 mmol) and DIPEA (98 μl, 0.560 mmol) in DCM (2 ml) to give the title compound (70 mg, 90%). LCMS (method A): R _T= 1.79 min, m/z =553 [M+H] ⁺ .

Step 2: 1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2 -fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid : Ethyl 1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy- 7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (70 mg, 0.127 mmol) in ethanol (1.5 ml ) and 2M NaOH (aq.) (1.5 ml, 3.00 mmol) was stirred at 40°C for 16 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in water and washed with diethyl ether. The aqueous phase was acidified by adding 2M HCl (aq.) to pH <4. The resulting suspension was extracted with EtOAc (x 3), the combined organic phases were washed with brine, passed through a Biotage phase separator and concentrated in vacuo to give the title compound (66 mg, quant.). LCMS (method A): R _T= 1.61 min, m/z =525 [M+H] ⁺ .

Stage 3: 1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2 -fluorophenyl)-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide: Prepared according to General Procedure 3 using 1-((( S )-7-(( R )-3 -cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid ( 33 mg, 62.9 µmol), dimethylamine (2M in THF, 47 µl, 94.4 µmol), HATU (28.7 mg, 75.5 µmol) and DIPEA (33 µmol, 0.189 mmol) in DCM (2 ml ) to give the title compound (25 mg, 70%). LCMS (method B): R _T =1.33 min, m / z =552 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.86 (s, 1H), 7 .49-7.43(m, 1H), 7.39-7.33(m, 1H), 7.29-7.22(m, 2H), 6.45(s, 0.4H), 6 .43 (s, 0.6H), 4.93 (s, 0.4H), 4.88 (s, 0.6H), 4.68 (d, J = 13.5 Hz, 0.6H), 4.63(d, J =13.5Hz, 0.4H), 3.85-3.60(m, 2H), 3.46-3.19(m, 3H (with HDO overlap)) , 2.88 (s, 3H), 2.83-2.62 (m, 4H (overlap with traces of DMSO)), 2.25-2.13 (m, 1H), 2.03-1.84 ( m, 3H), 1.84-1.48 (m, 10H), 1.48-1.08 (m, 5H), 0.99-0.91 (m, 3H).

Example 223 4-(2-fluorophenyl)-1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decane -10-yl)methyl)-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Stage 1: ethyl-4-(2-fluorophenyl)-1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5 ]decan-10-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylate: Prepared according to General Procedure 3 using amine 11 (70 mg, 0.163 mmol), acid 11 (30.6 mg, 0.196 mmol), HATU (93.2 mg, 0.245 mmol) and DIPEA (114 μl, 0.653 mmol) in DCM (2 ml) to give the title compound (80 mg, 86%). LCMS (method A): R _T= 1.61 min, m/z =567 [M+H] ⁺ .

Step 2: 4-(2-fluorophenyl)-1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decane -10-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid : Solution of ethyl-4-(2-fluorophenyl)-1-((((S)-10-)hydroxy-7- ((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (80 mg, 0.141 mmol) in ethanol (1.5 ml) and 2M NaOH (aqueous solution) (1.5 ml, 3.00 mmol) were stirred at 45°C for 16 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in water and washed with diethyl ether. The aqueous phase was acidified by adding 2M HCl (aq.) to pH <4. The resulting suspension was extracted with EtOAc (x 3), the combined organic phases were washed with brine, passed through a Biotage phase separator and concentrated in vacuo to give the title compound (70 mg, 92%). LCMS (method A): R _T= 1.30 min, m/z =539 [M+H] ⁺ .

Step 3: 4-(2-fluorophenyl)-1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decane -10-yl)methyl)-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide: Prepared according to General Procedure 3 using 4-(2-fluorophenyl)-1-(( (S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-1,6 -dihydropyridine-3-carboxylic acid (35 mg, 65.0 µmol), dimethylamine (2M in THF, 49 µmol, 97.5 µmol), HATU (29.7 mg, 78.0 µmol) and DIPEA (34 µl, 0.195 mmol) in DCM (2 ml) to give the title compound (30 mg, 78%). LCMS (Method B): R _T =1.18 min, m/z =566 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.87-7.85 (m, 1H), 7.49-7.43(m, 1H), 7.38-7.33(m, 1H), 7.29-7.22(m, 2H), 6.45(s, 0, 35H), 6.44 (s, 0.65H), 4.95 (s, 0.35H), 4.91 (s, 0.65H), 4.67 (d, J =13.5 Hz, 0 .65H), 4.54(d, J =13.5Hz, 0.35H), 4.04-3.62(m, 2H), 3.53-2.99(m, 4H (with signal overlap) from HDO)), 2.88 (s, 3H), 2.83-2.65 (m, 4H), 2.32-2.19 (m, 1H), 2.05-1.84 (m, 1H), 1.74-1.20 (m, 8H), 1.20-1.11 (m, 1H), 1.11-1.04 (m, 3H).

Example 224: 1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2 -fluorophenyl)-5-(piperazin-1-carbonyl)pyridin-2(1H)-one

Step 1: tert-Butyl-4-(1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl) methyl)-4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate: Prepared according to general procedure 3 using 1-((( S )-7 -(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl)-6-oxo-1,6- dihydropyridine-3-carboxylic acid (Example 222, Step 2) (33 mg, 62.9 µmol), tert-butylpiperazine-1-carboxylate (17.6 mg, 94.4 µmol), HATU (28.7 mg, 75 .5 µmol) and DIPEA (33 µl, 0.189 mmol) in DCM (2 ml) to give the title compound (37 mg, 84%). LCMS (method A): R _T= 1.73 min, m/z =693 [M+H] ⁺ .

Stage 2: 1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2 -fluorophenyl)-5-(piperazin-1-carbonyl)pyridin-2(1H)-one: Prepared according to general procedure 7 using tert -butyl 4-(1-((( S )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3 -carbonyl)piperazine-1-carboxylate (35 mg, 50.5 μmol), DCM (1 ml) and TFA (0.5 ml). The crude product was further purified by flash chromatography to give the title compound (20 mg, 65%). LCMS (Method B): R _T =0.91 min, m/z =593 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84 (s, 1H), 7 .50-7.44 (m, 1H), 7.40-7.34 (m, 1H), 7.31-7.25 (m, 2H), 6.45 (s, 0.4H), 6 .43 (s, 0.6H), 5.01-4.77 (m, 1H), 4.73-4.58 (m, 1H), 3.85-3.58 (m, 2H), 3 .47-3.08 (m, 7H (with HDO overlap)), 2.79-2.46 (m, 6H (with DMSO overlap)), 2.25-2.13 (m, 1H ), 2.03-1.85 (m, 3H), 1.85-1.08 (m, 15H), 0.99-0.91 (m, 3H).

Example 225 4-(2-fluorophenyl)-1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decane -10-yl)methyl)-5-(piperazin-1-carbonyl)pyridin-2(1H)-one

Step 1: tert-butyl-4-(4-(2-fluorophenyl)-1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)- 7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate: Prepared according to general procedure 3 using 4-(2-fluorophenyl )-1-((( S )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6 -oxo-1,6-dihydropyridine-3-carboxylic acid (Example 223, Step 2) (35 mg, 65.0 µmol), tert-butylpiperazine-1-carboxylate (18.2 mg, 97.5 µmol), HATU (29.7 mg, 78.0 µmol) and DIPEA (34 µl, 0.195 mmol) in DCM (2 ml) to give the title compound (46 mg, quant.). LCMS (method A): R _T= 1.55 min, m/z =707 [M+H] ⁺ .

Step 2: 4-(2-fluorophenyl)-1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decane -10-yl)methyl)-5-(piperazin-1-carbonyl)pyridin-2(1H)-one: Prepared according to general procedure 7 using tert -butyl 4-(4-(2-fluorophenyl)-1 -((( S )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo- 1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate (60 mg, 84.9 µmol), DCM (1.5 ml) and TFA (0.8 ml). The crude product was further purified by flash chromatography to give the title compound (31 mg, 59%). LCMS (Method B): R _T =0.82 min, m/z =607 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84 (s, 1H), 7 .50-7.43(m, 1H), 7.40-7.34(m, 1H), 7.31-7.25(m, 2H), 6.45(s, 0.4H), 6 .44 (s, 0.6H), 5.00-4.82 (m, 1H), 4.66 (d, J =13.5 Hz, 0.6H), 4.53 (d, J =13 .5 Hz, 0.4H), 4.04-3.61 (m, 2H), 3.52-3.00 (m, 8H (with HDO overlap)), 2.84-2.19 ( m, 7H (with signal overlap from DMSO)), 2.05-1.84 (m, 1H), 1.85-1.20 (m, 8H), 1.19-1.11 (m, 1H) , 1.11-1.04 (m, 3H).

Example 226: 1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl)- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Stage 1: ethyl-1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4- (2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate: Prepared according to general procedure 3 using amine 11 (70 mg, 0.163 mmol), acid 1 (33.4 mg, 0.196 mmol) , HATU (93.2) mg (0.245 mmol) and DIPEA (114 μl, 0.653 mmol) in DCM (2 ml) to give the title compound (90 mg, 94%). LCMS (method A): R _T= 1.96 min, m/z =581 [M+H] ⁺ .

Step 2: 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2 -fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid : Ethyl-1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy- 7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (90 mg, 0.155 mmol) in ethanol (2 ml) and 2M NaOH (aq.) (2 ml, 4.00 mmol) was stirred at 40° C. for 45 minutes. The reaction mixture was concentrated in vacuo. The residue was dissolved in water and washed with diethyl ether. The aqueous phase was acidified by adding 2M HCl (aq.) to pH <4. The resulting suspension was extracted with EtOAc (x 3), the combined organic phases were washed with brine, passed through a Biotage phase separator and concentrated in vacuo to give the title compound (70 mg, 81%). LCMS (method A): R _T= 1.66 min, m/z =553 [M+H] ⁺ .

Step 3: 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2 -fluorophenyl)-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide: Prepared according to General Procedure 3 using 1-((( S )-7-(( R )-3- cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (35 mg, 63.3 µmol), dimethylamine (2M in THF, 48 µl, 95.0 µmol), HATU (28.9 mg, 76.0 µmol) and DIPEA (33 ml, 0.190 mmol) in DCM (2 ml) , to get the connection specified in the header. (29 mg, 76%). LCMS (method B): R _T =1.47 min, m/z =580 [M+H] ⁺ . ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.86 (s, 1H), 7.49-7.42 (m, 1H), 7.39-7.32 (m, 1H), 7 .29-7.22(m, 2H), 6.45(s, 0.35H), 6.43(s, 0.65H), 4.94(s, 0.35H), 4.89(s , 0.65H), 4.72 (d, J =13.5 Hz, 0.65H), 4.58 (d, J =13.5 Hz, 0.35H), 3.93-3.58 ( m, 2H), 3.53-3.11 (m, 2H (with HDO overlap)), 2.96-2.72 (m, 7H), 2.02-1.81 (m, 1H) .1.72-1.02 (m, 21H), 0.99-0.91 (m, 3H), 0.90-0.75 (m, 2H).

Example 227: 1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl)-5-(piperazin-1-carbonyl)pyridine-2 (one H )-he

Step 1: tert-Butyl-4-(1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl) methyl)-4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate: Prepared according to general procedure 3 using 1-((( S )-7 -(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl)-6-oxo-1,6- dihydropyridine-3-carboxylic acid (Example 226, step 2) (35 mg, 63.3 µmol), tert-butylpiperazine-1-carboxylate (17.7 mg, 95.0 µmol), HATU (28.9 mg, 76 .0 µmol) and DIPEA (33 µl, 0.190 mmol) in DCM (2 ml) to give the title compound (35 mg, 76%). LCMS (Method A): R _{T =} 1.89 min, m/z = 721 [M+H] ⁺ .

Step 2: 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2 -fluorophenyl)-5-(piperazin-1-carbonyl)pyridin-2(1H)-one: Prepared according to General Procedure 7 using t -butyl 4-(1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3- carbonyl)piperazine-1-carboxylate (35 mg, 48.5 µmol), DCM (1.5 ml) and TFA (0.5 ml). The crude product was further purified by flash chromatography to give the title compound (23 mg, 74%). LCMS (Method B): R _T =0.99 min, m/z =621 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84 (s, 1H), 7 .51-7.44(m, 1H), 7.40-7.34(m, 1H), 7.31-7.25(m, 2H), 6.45(s, 0.35H), 6 .43 (s, 0.65H), 5.01-4.79 (m, 1H), 4.71 (d, J =13.5 Hz, 0.65H), 4.58 (d, J =13 .5Hz, 0.35H), 3.95-3.57(m, 2H), 3.55-3.03(m, 6H (with HDO overlap)), 2.96-2.80( m, 1H), 2.73-2.21 (m, 5H (with DMSO signal overlap)), 2.03-1.82 (m, 1H), 1.77-1.01 (m, 21H) , 1.00-0.90 (m, 3H), 0.90-0.75 (m, 2H).

Example 228: 1-((( S )-one-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(4-hydroxypiperidine-1-carbonyl)-4-phenylpyridine-2(1 H )-he

DIPEA (0.012 ml, 0.0672 mmol) was added to a stirred solution of acid 4 (11.4 mg, 0.0224 mmol), 4-hydroxypiperidine (2.3 mg, 0.0224 mmol) and HATU (10.2 mg, 0.0269 mmol) in DCM (1.0 ml) at room temperature. After 2 hours, the reaction mixture was partitioned between additional DCM and saturated sodium bicarbonate solution (aq.). The resulting biphasic mixture was separated, dried (phase separator), solvents were removed in vacuo, the remaining residue was purified by flash chromatography (0-5%, MeOH in DCM) and lyophilized to give the title compound (8.5 mg, 64%) as a white solid. LCMS (Method A): R _T = 1.33 min, m / z = 592 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.79 (s, 1H), 7.50-7.34 (m, 5H), 6.48-6.42 (m, 1H), 5.06-2.69 (m, 13H, overlap with solvent peak), 1.77-0.28 (m, 29H).

Example 229: 1-((10-hydroxy-7-(3-(trifluoromethyl)cyclobutan-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to the general procedure, 3 using amine 8 (20 mg, 48.8 µmol), 3-(trifluoromethyl) cyclobutanecarboxylic acid (9.9 mg, 58.6 µmol), HATU (22.3 mg, 58. 6 µmol), DIPEA (34 µl, 0.195 mmol) and DCM (1 ml) to give the title compound (25.3 mg, 90%) as a colorless solid after lyophilization. LCMS (method B): R _T =1.20, 1.23 (2 diastereomers) min, m/z= 560 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.86-7.77 (m, 1H), 7.65-7.19 (m, 5H), 6.50-6.41 (m , 1H), 5.01-4.88 (m, 1H), 4.67-4.53 (m, 1H), 3.86-3.74 (m, 0.5H), 3.74-3 .64 (m, 1H), 3.53-3.17 (m, 4H (with HDO overlap)), 3.15-2.97 (m, 1.5H), 2.75 (s, 3H ), 2.63 (s, 3H), 2.46-2.16 (m, 4H), 1.99-1.85 (m, 1H), 1.74-1.49 (m, 5H), 1.48-1.28 (m, 2H), 1.28-1.19 (m, 1H), 1.19-1.08 (m, 1H).

Example 230: 1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Stage 1: ethyl-1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4- cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate: Prepared according to general procedure 3 using amine 12 (50 mg, 0.134 mmol), acid 5 (22.8 mg, 0.160 mmol), HATU ( 76.2 mg, 0.200 mmol) and DIPEA (93 μl, 0.534 mmol) in DCM (2 ml) to give the title compound (48 mg, 72%). LCMS (method A): R _T= 1.74 min, m/z =499 [M+H] ⁺ .

Step 2: 1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- 6-oxo-1,6-dihydropyridine-3-carboxylic acid : Solution 1-((( S )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5] decan-10-yl)methyl)-4-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate (48 mg, 96.3 µmol) in ethanol (1.2 ml) and 2M NaOH (aq.) (1.2 ml, 2.40 mmol) was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in water and washed with diethyl ether. The aqueous phase was acidified by adding 2M HCl (aq.) to pH <4. The resulting suspension was extracted with EtOAc (x 3), the combined organic phases were washed with brine, passed through a Biotage phase separator and concentrated in vacuo to give the title compound (30 mg, 66%). LCMS (Method A): R _T= 1.36 min, m/z =471 [M+H] ⁺ .

Step 3: 1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide: Prepared according to general procedure 3 using 1-((( S )-7-(( R )-3-cyclobutyl-2 -methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (30 mg, 63.7 µmol) , dimethylamine (2M in THF, 48 µl, 95.6 µl), HATU (29.1 mg, 76.5 µl) and DIPEA (33 µl, 0.191 mmol) in DMF (2 ml), to give the title compound (28 mg, 84%). LCMS (method B): R _T =1.22 min, m/z =498 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.67-7.60 (m, 1H), 5.93-5.86(m, 1H), 5.01(s, 0.4H), 4.92(s, 0.6H), 4.55-4.39(m, 1H) , 3.81-3.58 (m, 2H), 3.44-3.13 (m, 3H (with HDO overlap)), 3.05-2.87 (br s, 6H), 2, 76-2.61 (m, 1H (overlap with traces of DMSO)), 2.55-2.12 (m, 1H), 2.02-1.44 (m, 14H), 1.44-1.06 (m, 5H), 1.03-0.90 (m, 5H), 0.83-0.71 (m, 2H).

Example 231: 1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- 5-(piperazine-1-carbonyl)pyridine-2(1H)-one

Step 1: tert-Butyl-4-(1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl) methyl)-4-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate: Prepared according to General Procedure 3 using 1-((( S )-7-(( R ) -3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (Example 230 , step 2) (20 mg, 42.5 µmol), tert-butylpiperazine-1-carboxylate (11.9 mg, 63.7 µmol), HATU (19.4 mg, 51.0 µmol) and DIPEA (22 µl , 0.128 mmol) in DCM (1 mL) to give the title compound (17 mg, 60%). LCMS (method A): R _T= 1.61 min, m/z =639 [M+H] ⁺ .

Step 2: 1-(((S)-7-((R)-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- 5-(piperazine-1-carbonyl)pyridine-2(1H)-one: Prepared according to general procedure 7 using tert-butyl 4-(1-(((S)-7-((R)-3 -cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate (17 mg, 26.6 µmol), DCM (1 ml) and TFA (0.4 ml). The crude product was further purified by flash chromatography to give the title compound (12 mg, 81%). LCMS (Method B): R _T =0.84 min, m/z =539 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.67-7.57 (br s , 1H), 5.95-5.88 (m, 1H), 5.13-4.79 (br s, 1H), 4.54-4.35 (m, 1H), 3.82-3, 14 (m, 8H (with signal overlap from HDO)), 2.80-2.45 (m, 7H (with signal overlap from DMSO and trace solvent)), 2.23-2.12 (m, 1H), 2.02-1.45 (m, 14H), 1.42-0.50 (m, 12H).

Example 232: 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Stage 1: ethyl-1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4- cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate: Prepared according to general procedure 3 using amine 12 (50 mg, 0.134 mmol), acid 1 (27.3 mg, 0.160 mmol), HATU ( 76.2 mg, 0.200 mmol) and DIPEA (93 μl, 0.534 mmol) in DCM (2 ml) to give the title compound (34 mg, 48%). LCMS (method A): R _T= 1.92 min, m/z =527 [M+H] ⁺ .

Step 2: 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- 6-oxo-1,6-dihydropyridine-3-carboxylic acid : Ethyl-1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[ 4.5]decan-10-yl)methyl)-4-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate (34 mg, 64.6 µmol) in ethanol (1 ml) and 2M NaOH (aq.) (1 ml, 2.00 mmol) was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in water and washed with diethyl ether. The aqueous phase was acidified by adding 2M HCl (aq.) to pH <4. The resulting suspension was extracted with EtOAc (x 3), the combined organic phases were washed with brine, passed through a Biotage phase separator and concentrated in vacuo to give the title compound (30 mg, 93%). LCMS (method A): R _T= 1.55 min, m/z =499 [M+H] ⁺ .

Step 3: 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide: Prepared according to general procedure 3 using 1-(((S)-7-((R)-3-cyclohexyl-2 -methylpropanoyl))-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (20 mg, 40.1 µmol ), dimethylamine (2M in THF, 30 µl, 60.2 µl), HATU (18.3 mg, 48.1 µl) and DIPEA (21 µl, 0.120 mmol) in DMF (1 ml), to give the title compounds (11 mg, 52%). LCMS (method B): R _T =1.38 min, m/z =526 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.67-7.61 (m, 1H), 5.93-5.87(m, 1H), 5.03(s, 0.35H), 4.92(s, 0.65H), 4.54(d, J =14Hz, 0 .65H), 4.39(d, J =14Hz, 0.35H), 3.92-3.56(m, 2H), 3.49-3.20(m, 2H (with signal overlap from HDO )), 3.19-2.77 (m, 7H), 1.97-1.78 (m, 1H), 1.72-0.70 (m, 31H).

Example 233: 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- 5-(piperazine-1-carbonyl)pyridine-2(1H)-one

Step 1: tert-Butyl-4-(1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl) methyl)-4-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate: Prepared according to General Procedure 3 using 1-((( S )-7-(( R ) -3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (Example 232 , stage 2) (30 mg, 60.2 µmol), tert-butylpiperazine-1-carboxylate (16.8 mg, 90.2 µmol), HATU (27.5 mg, 72.2 µmol) and DIPEA (32 µl , 0.181 mmol) in DMF (1 ml) to give the title compound (40 mg, quantitation). LCMS (method A): R _T= 1.79 min, m/z =667 [M+H] ⁺ .

Step 2: 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- 5-(piperazine-1-carbonyl)pyridine-2(1H)-one: Prepared according to general procedure 7 using t -butyl 4-(1-((( S )-7-(( R )-3- cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate ( 40 mg, 60.0 µmol), DCM (3 ml) and TFA (1 ml). The crude product was further purified by flash chromatography to give the title compound (26 mg, 74%). LCMS (Method B): R _T =0.97 min, m/z =567 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.67-7.57 (m, 1H), 5.94-5.88 (m, 1H), 5.12-4.79 (br s, 1H), 4.58-4.32 (m, 1H), 3.90-3.06 (m, 9H (with signal overlap from HDO)), 2.94-2.55 (m, 6H (overlap with traces of DMSO)), 1.98-1.79 (m, 1H), 1.74-1 .42 (m, 12H), 1.41-0.58 (m, 18H).

Example 234: 1-((2-((R)-3-cyclohexyl-2-methylpropanoyl)-5-hydroxy-9-oxa-2-azaspiro[5.5]undecan-5-yl)methyl)-N,N- dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Step 1: tert-butyl 5-oxo-9-oxa-2-azaspiro[5.5]undecane-2-carboxylate : To a solution of tert-butyl 4-oxo-piperidine-1-carboxylate (3.98 g, 20.0 mmol ) in toluene (40 mL) in a 250 mL 3-neck RBF flask equipped with a reflux condenser, potassium tert-butoxide (4.94 g, 44.0 mmol) was added portionwise under nitrogen at room temperature. After stirring for 1 hour, bis(2-bromoethyl)ether (2.51 ml, 20.0 mmol) was added dropwise over 5 minutes and the reaction mixture was heated under reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted 1:1 with saturated NH ₄ Cl (aq.) with water (40 ml) and was extracted with EtOAc (3×40 ml). The combined organic phases were washed with brine (100 ml), passed through a Biotage phase separator, concentrated in vacuo, and the residue was purified by flash chromatography (GraceResolv cartridge with silica gel (120 g), 0-15% EtOAc in cyclohexane) to give the indicated in the title compound (458 mg, 8.5%) as a pale yellow solid. LCMS (method A): R _T =1.13 min, m/z =214 [M-butene+H] ⁺ . ¹ H-NMR (500 MHz, CDCl ₃ ): δ 3.82-3.65 (m, 6H), 3.57 (s, 2H), 2.49 (t, J =6.4 Hz, 2H) , 1.94 (dt, J =13.9, 5.1 Hz, 2H), 1.49 (s, 9H), 1.47-1.43 (m, 2H), ¹³ C-NMR (126 MHz , CDCl ₃ ): δ 211.13, 154.71, 80.70, 63.96, 52.48 (br. ), 48.00, 43.92 (b. ), 38.13, 30, 85, 28.52.

Step 2: tert-Butyl-1,7-dioxa-11-azadispiro[2.0.54.43 ^] tridecane - ¹¹ -carboxylate : Sodium hydride (60% dispersion in mineral oil, 98 mg, 2.45 mmol) was added to a suspension of trimethylsulfonium iodide (500 mg, 2.45 mmol) in DMF (4 ml) at room temperature. After stirring for 1 hour at room temperature, a solution of tert-butyl 5-oxo-9-oxa-2-azaspiro[5.5]undecane-2-carboxylate (440 mg, 1.63 mmol) in DMF ( 4 ml). After 16 hours, the reaction mixture was diluted 1:1 with water/saturated NH ₄ Cl (aq.) (40 ml) and the mixture was extracted with EtOAc (3×20 ml). The combined organic phases were washed with water (20 ml) and brine (20 ml) and then passed through a Biotage phase separator. The resulting solution was concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv silica gel cartridge (40 g), 0-30% EtOAc in cyclohexane) to give the title compound (355 mg, 76%) as a colorless oil. LCMS (method A): R _T =1.18 min, m/z =228 [M-butene+H] ⁺ . ¹ H-NMR (500 MHz, CDCl ₃ ): δ 3.86-3.74 (m, 2H), 3.73-3.42 (m, 6H), 2.92 (d, J =4.1 Hz, 1H), 2.46 (d, J =4.2 Hz, 1H), 1.72-1.55 (m, 4H), 1.48 (s, 9H), 1.42-1.36 (m, 1H), 1.32-1.24 (m, 1H).

Step 3: tert-Butyl-5-((4-chloro-5-(ethoxycarbonyl)-2-oxopyridin-1(2H)-yl)methyl)-5-hydroxy-9-oxa-2-azaspiro[5.5]undecane -2-carboxylate : Ethyl 4-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate solution (245 mg, 1.22 mmol), tert-butyl-1,7-dioxa-11-azadispiro[2.0 .5 ⁴ .4 ³ ]tridecane-11-carboxylate (345 mg, 1.22 mmol) and DIPEA (1.06 ml, 6.09 mmol) in 1-methyl-2-pyrrolidinone (2.4 ml) were heated at 120°C for 88 hours. The reaction mixture was allowed to cool to room temperature, diluted with saturated NaHCO ₃ (aq.) (50 ml) and the mixture was extracted with DCM (3×50 ml). The combined organic phases were passed through a Biotage phase separator, concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv cartridge with silica gel (40 g), 0-60% EtOAc in cyclohexane) to give the title compound (223 mg, 37% ) as a colorless solid. LCMS (method A): R _T =1.38 min, m/z =485 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 8.45 (s, 1H), 6.63 (s, 1H), 4.95 (s, 1H), 4.65 (d, J = 13.4Hz, 1H), 4.27(kv, J =7.0Hz, 2H), 3.82-3.58(m, 4H), 3.58-3.33(m, 4H), 3.20 (ddd, J =13.2, 8.9, 4.0 Hz, 1H), 1.91-1.70 (m, 2H), 1.39 (s, 9H), 1.32- 1.20 (m, 3H), 1.29 (t, J =7.1 Hz, 3H), 1.18-1.08 (m, 1H).

Step 4: tert-Butyl-5-((5-(ethoxycarbonyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-5-hydroxy-9-oxa-2-azaspiro[5.5]undecane -2-carboxylate: Prepared according to general procedure 4 using tert - butyl-5-((4-chloro-5-(ethoxycarbonyl)-2- oxopyridin -1(2H)-yl)methyl)-5- hydroxy-9-oxa-2-azaspiro[5.5]undecane-2-carboxylate (197 mg, 0.406 mmol), phenylboronic acid (74 mg, 0.609 mmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (17 mg, 20.3 µmol), Na ₂ CO ₃ (86 mg, 0.812 mmol), 1,4-dioxane (1.5 ml) and water (0.5 ml) at 140°C for 2 hours under microwave irradiation. Then additional phenylboronic acid (74 mg, 0.609 mmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (17 mg, 20.3 µmol) and Na ₂ CO ₃ (86 mg, 0.812 mmol) were added and the reaction mixture was heated at 140° C. for 30 minutes under microwave irradiation to give the title compound (108 mg, 50%) as a pale yellow foam. LCMS (Method A): R _T= 1.52 min, m/z =527 [M+H] ⁺ .

Step 5: 1-((2-(tert-Butoxycarbonyl)-5-hydroxy-9-oxa-2-azaspiro[5.5]undecan-5-yl)methyl)-6-oxo-4-phenyl-1,6- dihydropyridine-3-carboxylic acid : Solution of tert-butyl-5-((5-(ethoxycarbonyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-5-hydroxy-9-oxa-2- azaspiro[5.5]undecane-2-carboxylate (108 mg, 0.205 mmol) in 1 M NaOH (aq.) (0.410 ml, 0.410 mmol) and 1,4-dioxane (1 ml) was stirred at 50°C for 18 hours. The reaction mixture was allowed to cool to room temperature and the pH was adjusted to ~2 with 1M HCl (aq.). The resulting mixture was extracted with DCM (3×20 ml) using a Biotage phase separator and the combined organic phases concentrated in vacuo to give the title compound (100 mg, 97%) as a colorless foam. LCMS (method A): R _T= 1.18 min, m/z =499 [M+H] ⁺ .

Step 6: tert-Butyl-5-((5-(dimethylcarbamoyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-5-hydroxy-9-oxa-2-azaspiro[5.5]undecane -2-carboxylate: Prepared according to general procedure 3 using 1-((2-(tert-butoxycarbonyl)-5-hydroxy-9-oxa-2-azaspiro[5.5]undecan-5-yl)methyl)-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (100 mg, 0.201 mmol), dimethylamine (2M in THF, 0.120 ml, 0.241 mmol), HATU (91.5 mg, 0.241 mmol), DIPEA (0.140 ml, 0.802 mmol) and DCM (4 ml) to give the title compound (99 mg, 93%) as a pale yellow foam. LCMS (Method A): R _T= 1.15 min, m/z =526 [M+H] ⁺ .

Stage 7: 1-((5-hydroxy-9-oxa-2-azaspiro[5.5]undecan-5-yl)methyl)-N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine- 3-carboxamide : Solution of tert-butyl-5-((5-(dimethylcarbamoyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-5-hydroxy-9-oxa-2-azaspiro[5 ,5] undecane-2-carboxylate (99 mg, 0.188 mmol) in TFA (0.5 ml) and DCM (1 ml) was stirred for 15 minutes before the reaction mixture was purified using a Biotage SCX-2 cartridge (5 d) (pre-equilibrated and then washed with 1:1 DCM/MeOH before eluting with 1:1 DCM/7M NH ₃ in MeOH). The main eluents were concentrated in vacuo to give the title compound (79 mg, 98%) as a colorless solid. LCMS (Method A): R _T= 0.38 min, m/z =426 [M+H] ⁺ .

Step 8: 1-((2-((R)-3-cyclohexyl-2-methylpropanoyl)-5-hydroxy-9-oxa-2-azaspiro[5.5]undecan-5-yl)methyl)-N,N- dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide: Prepared according to General Procedure 3 using 1-((5-hydroxy-9-oxa-2-azaspiro[5.5]undecan-5 -yl)methyl)-N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide (20 mg, 47.0 µl), acid 1 (8.8 mg, 51.7 µg), HATU (20 mg, 51.7 µmol), DIPEA (33 µl, 0.188 mmol) and DCM (1 ml) to give the title compound (24 mg, 87%) as a colorless solid after lyophilization. LCMS (method B): R _T =1.31, 1.33 (2 diastereomers) min, m/z =578 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.83-7.77 (m, 1H), 7.55-7.26 (m, 5H), 6.48-6.42 (m , 1H), 5.13-4.99 (m, 1H), 4.70-4.58 (m, 1H), 4.02-3.37 (m, 9H), 2.96-2.86 (m, 1H), 2.75 (s, 3H), 2.63 (s, 3H), 1.98-1.41 (m, 9H), 1.36-1.03 (m, 8H), 1.00-0.89 (m, 3H), 0.89-0.76 (m, 2H).

Example 235: 1-(((S)-1-((R)-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl )-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Stage 1: ethyl-1-(((S)-1-((R)-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2 -fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate : Prepared according to general procedure 3 using amine 9 (50 mg, 0.124 mmol), acid 5 (21.2 mg, 0.149 mmol), HATU (70.9 mg, 0.186 mmol) and DIPEA (87 μl, 0.497 mmol) in DCM (2 ml) to give the title compound (54 mg, 82%). LCMS (method B): R _T= 1.55 min, m/z =527 [M+H] ⁺ .

Stage 2: 1-(((S)-1-((R)-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl ))-6-oxo-1,6-dihydropyridine-3-carboxylic acid : Ethyl-1-(((S)-1-((R)-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3 solution ,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (54 mg, 0.103 mmol) in ethanol (1.5 ml) and 2M NaOH (aq.) (1.5 ml, 3.00 mmol) was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in water and washed with diethyl ether. The aqueous phase was acidified by adding 2M HCl (aq.) to pH <4. The resulting suspension was extracted with EtOAc (x 3), the combined organic phases were washed with brine, passed through a Biotage phase separator and concentrated in vacuo to give the title compound (49 mg, 95%). LCMS (method B): R _T= 1.37 min, m/z =499 [M+H] ⁺ .

Stage 3: 1-(((S)-1-((R)-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl )-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide: Prepared according to General Procedure 3 using 1-((( S )-1-(( R )-3-cyclobutyl- 2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (24 mg, 48, 1 µmol), dimethylamine (2M in THF, 36 µl, 72.2 µl), HATU (22.0 mg, 57.8 µl) and DIPEA (25 µl, 0.144 mmol) in DCM (1 ml), to give the indicated in the title compound (15 mg, 58%). LCMS (Method B): R _T =1.27 min, m/z =526 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84 (s, 1H), 7 .49-7.42(m, 1H), 7.39-7.32(m, 1H), 7.29-7.21(m, 2H), 6.46-6.41(m, 1H) , 4.91-4.84 (m, 1H), 4.53-4.38 (m, 1H), 3.86-3.61 (m, 2H), 3.32-3.19 (m, 2H (with signal overlap from HDO)), 3.01-2.67 (m, 7H), 2.25-2.12 (m, 1H), 2.03-1.88 (m, 2H), 1 .84-1.47 (m, 6H), 1.37-1.16 (m, 3H), 1.07-0.88 (m, 9H).

Example 236: 1-(((S)-1-((R)-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl )-5-(piperazine-1-carbonyl)pyridine-2(1H)-one

Stage 1: tert-butyl-4-(1-(((S)-1-((R)-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl) -4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate : Prepared according to General Procedure 3 using 1-((( S )-1-( ( R )-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3- carboxylic acid (Example 235, step 2) (24 mg, 48.1 µmol), tert-butylpiperazine-1-carboxylate (13.4 mg, 72.2 µmol), HATU (22.0 mg, 57.8 µmol) and DIPEA (25 μl, 0.144 mmol) in DCM (1 ml) to give the title compound (32 mg, quant.). LCMS (method B): R _T= 1.50 min, m/z =61 1 [M-butene+H] ⁺ .

Stage 2: 1-(((S)-1-((R)-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl )-5-(piperazine-1-carbonyl)pyridine-2(1H)-one: Prepared according to general procedure 7 using t-butyl-4-(1-(((S)-1-((R) -3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)piperazine -1-carboxylate (32 mg, 48.0 µmol), DCM (1 ml) and TFA (0.5 ml). The crude product was further purified by flash chromatography to give the title compound (20 mg, 71%). LCMS (Method B): R _T =0.86 min, m/z =567 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.81 (s, 1H), 7 .51-7.43(m, 1H), 7.40-7.34(m, 1H), 7.31-7.24(m, 2H), 6.46-6.41(m, 1H) , 4.92-4.79 (br s, 1H), 4.54-4.35 (m, 1H), 3.89-3.60 (m, 2H), 3.43-3.08 (m , 6H (with signal overlap from HDO)), 3.01-2.88 (m, 1H), 2.79-2.68 (m, 1H), 2.66-2.27 (m, 5H (s signal overlap from DMSO and solvent traces)), 2.24-2.13 (m, 1H), 2.01-1.89 (m, 2H), 1.83-1.47 (m, 6H), 1 .37-1.16 (m, 2H), 1.09-0.87 (m, 9H).

Example 237: 1-((2-((R)-3-cyclohexyl-2-methylpropanoyl)-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)methyl)-N,N-dimethyl-6- oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Step 1: tert-Butyl 5-((4-chloro-5-(ethoxycarbonyl)-2-oxopyridin-1(2H)-yl)methyl)-5-hydroxy-2-azaspiro[5.5]undecane-2-carboxylate : Solution of ethyl 4-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (86 mg, 0.427 mmol), epoxide 7 (120 mg, 0.427 mmol) and DIPEA (373 µl, 2.13 mmol) in NMP (1 ml) was stirred at 110°C for 136 hours. The reaction mixture was diluted with saturated NaHCO ₃ (aq) and extracted with DCM (x 3) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography to give the title compound (80 mg, 38%). LCMS (Method A): R _{T =} 2.08 min, m/z = all [M-butene+H] ⁺ .

Step 2: tert-Butyl 5-((5-(ethoxycarbonyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-5-hydroxy-2-azaspiro[5.5]undecane-2-carboxylate : Prepared according to general procedure 4 using tert-butyl-5-((4-chloro-5-(ethoxycarbonyl)-2-oxopyridin-1(2H)-yl)methyl)-5-hydroxy-2-azaspiro [5.5]undecane-2-carboxylate (80 mg, 0.166 mmol), phenylboronic acid (30.3 mg, 0.248 mmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (13.5 mg, 16.6 µmol) and sodium carbonate (43.9 mg, 0.414 mmol) in 1,4-dioxane (0.7 ml) and water (0.2 ml). The reaction mixture was heated under microwave irradiation at 150° C. for 10 minutes to give the title compound (74 mg, 85%). LCMS (Method A): R _T= 1.90 min, m/z =525 [M+H] ⁺ .

Step 3: Ethyl 1-((5-hydroxy-2-azaspiro[5.5]undecan-5-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate : tert-butyl solution -5-((5-(ethoxycarbonyl)-2-oxo-4-phenylpyridin-1(2H)-yl)methyl)-5-hydroxy-2-azaspiro[5.5]undecane-2-carboxylate (74 mg, 0.141 mmol ) in DCM (2 ml) and HCl (4M in 1,4-dioxane, 1 ml, 4.00 mmol) was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NaHCO ₃ (aq) and the aqueous phase was extracted with DCM (x 3) using a Biotage phase separator. The combined organic phases were concentrated in vacuo to give the title compound (51 mg, 85%). LCMS (Method A): R _T= 0.88 min, m/z =425 [M+H] ⁺ .

Stage 4. ethyl-1-((2-((R)-3-cyclohexyl-2-methylpropanoyl)-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)methyl)-6-oxo-4- phenyl 1,6-dihydropyridine-3-carboxylate : Prepared according to general procedure 3 using ethyl 1-((5-hydroxy-2-azaspiro[5.5]undecan-5-yl)methyl)-6-oxo- 4-phenyl-1,6-dihydropyridine-3-carboxylate (50 mg, 0.1-18 mmol), acid 1 (24.1 mg, 0.141 mmol), HATU (67.2 mg, 0.177 mmol), and DIPEA (82 μl, 0.471 mmol) in DCM (2 ml) to give the title compound (67 mg, 98%). LCMS (Method A): R _T= 1.82 min, m/z =577 [M+H] ⁺ .

Step 5: 1-((2-((R)-3-cyclohexyl-2-methylpropanoyl)-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)methyl)-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxylic acid : Ethyl-1-((2-((R)-3-cyclohexyl-2-methylpropanoyl)-5-hydroxy-2-azaspiro[5.5]undecan-5-yl) solution methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (67 mg, 0.1-16 mmol) in ethanol (1.5 ml) and 2M NaOH (aq.) (1.5 ml , 3.00 mmol) was stirred at 50°C for 1.5 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in water and washed with diethyl ether. The aqueous phase was acidified by adding 2M HCl (aq.) to pH <4. The resulting suspension was extracted with EtOAc (x 3), the combined organic phases were washed with brine, passed through a Biotage phase separator and concentrated in vacuo to give the title compound (63 mg, quant.). LCMS (method A): R _T= 1.72 min, m/z =549 [M+H] ⁺ .

Step 6: 1-((2-((R)-3-cyclohexyl-2-methylpropanoyl)-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)methyl)-N,N-dimethyl-6- oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide : Prepared according to general procedure 3 using 1-((2-((R)-3-cyclohexyl-2-methylpropanoyl)-5-hydroxy- 2-azaspiro[5.5]undecan-5-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (32 mg, 58.3 µmol), dimethylamine (2M in THF, 44 µmol, 87.5 ), HATU (26.6 mg, 70.0 µmol) and DIPEA (31 µl, 0.175 mmol) in DCM (2 ml) to give the title compound (26 mg, 75%). LCMS (method B): R _T= 1.56 min, m/z =576 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 7.80 (s, 1H), 7.47-7.42 (m, 3H), 7.41-7.35 (m, 2H), 6.48-6.42(m, 1H), 4.96-4.82(m, 1H), 4.67-4.52(m, 1H), 3.91-3.12(m, 4H (signal overlaps with HDO)), 2.96-2.84 (m, 1H), 2.75 (s, 3H), 2.63 (s, 3H (overlaps with DMSO satellite)), 1.73-0 .74 (m, 29H).

Example 238: 1-((2-((R)-3-cyclohexyl-2-methylpropanoyl)-5-hydroxy-2-azaspiro[5,5]-undecan-5-yl)methyl)-4-phenyl-5 -(piperazine-1-carbonyl)pyridine-2(1H)-one

Step 1: tert-Butyl-4-(1-((2-((R)-3-cyclohexyl-2-methylpropanoyl)-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)methyl)-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate: Prepared according to General Procedure 3 using 1-((2-(( R )-3-cyclohexyl-2-methylpropanoyl )-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (Example 237, step 5) (32 mg, 58.3 µmol), tert-butylpiperazine-1-carboxylate (16.3 mg, 87.5 µmol), HATU (26.6 mg, 70.0 µmol) and DIPEA (31 µl, 0.175 mmol) in DCM (2 ml) to give the title compound (39 mg, 93%). LCMS (method B): R _T= 1.75 min, m/z =661 [M-butene+H] ⁺ .

Stage 2: 1-((2-((R)-3-cyclohexyl-2-methylpropanoyl)-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)methyl)-4-phenyl-5-(piperazine -1-carbonyl)pyridin-2(1H)-one : Prepared according to general procedure 7 using tert-butyl-4-(1-((2-((R)-3-cyclohexyl-2-methylpropanoyl) -)5-hydroxy-2-azaspiro[5.5]undecan-5-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate (39 mg, 54, 4 µmol), DCM (1.5 ml) and TFA (0.5 ml). The crude product was further purified by flash chromatography to give the title compound (30 mg, 87%). LCMS (method B): R _T =1.04 min, m/z =617 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.79 (s, 1H), 7 .50-7.35 (m, 5H), 6.48-6.42 (m, 1H), 5.03-4.70 (br s, 1H), 4.66-4.49 (m, 1H ), 3.92-2.22 (m, 14H (with signal overlap from HDO, DMSO and solvent traces)), 2.01-0.73 (m, 29H).

Example 239: 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-5-(morpholine -4-carbonyl)-4-phenylpyridin-2(1H)-one

Prepared according to general procedure 3 using 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl )-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (Example 211, step 2) (33 mg, 61.7 µmol), morpholine (8 µg, 92.6 µg), HATU ( 28.2 mg, 74.1 µmol) and DIPEA (33 µl, 0.185 mmol) in DCM (2 ml) to give the title compound (26 mg, 67%). LCMS (method B): R _T =1.43 min, m/z =604 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.86 (s, 1H), 7 .51-7.45 (m, 3H), 7.45-7.38 (m, 2H), 6.49-6.42 (m, 1H), 5.08-4.77 (br s, 1H ), 4.69 (d, J =13.5 Hz, 0.65H), 4.56 (d, J =13.5 Hz, 0.35H), 3.79-2.77 (m, 12H ( with signal overlap from HDO)), 2.02-1.93 (m, 0.35H), 1.93-1.83 (m, 0.65H), 1.73-1.02 (m, 22H) , 1.00-0.91 (m, 3H), 0.91-0.74 (m, 2H).

Example 240: 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-5- (4-methylpiperazine-1-carbonyl)-4-phenylpyridine-2(1 H )-he

Prepared according to general procedure 3 using 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl )-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (Example 211, step 2) (33 mg, 61.7 µmol), 1-methylpiperazine (10 µmol, 92.6 µmol), HATU (28.2 mg, 74.1 µmol) and DIPEA (33 µl, 0.185 mmol) in DCM (2 ml) to give the title compound (28 mg, 72%). LCMS (method B): R _T =1.02 min, m/z =617 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 7.83 (s, 1H), 7 .50-7.36 (m, 5H), 6.49-6.43 (m, 1H), 5.06-4.79 (br s, 1H), 4.67 (d, J =13.5 Hz, 0.65H), 4.55(d, J =13.5Hz, 0.35H), 3.93-3.61(m, 2H), 3.57-2.76(m, 7H(s signal overlap from HDO)), 2.34-1.75 (m, 4H), 2.00 (s, 3H), 1.73-1.02 (m, 22H), 1.00-0.90 ( m, 3H), 0.90-0.75 (m, 2H).

Example 241: 1-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid

Acid 3 was purified by flash chromatography (0-15% MeOH in DCM) and lyophilized to give the title compound as a pale yellow solid. LCMS (Method A): R _T =1.53 min, m/z =509 [M+H] ⁺ , ¹H-NMR (500 MHz, DMSO- d ₆ ): δ 12.49 (br s, 1H) , 8.39 (s, 1H), 7.61-7.02 (m, 5H), 6.25-6.20 (m, 1H), 4.96 (s, 1H), 4.65-4 .45 (m, 1H), 4.12-3.50 (m, 2H), 3.28-2.80 (m, 3H, solvent peak overlap), 1.85-1.37 (m, 7H ), 1.34-0.63 (m, 18H).

Example 242: 1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-methoxy- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Sodium methoxide (6.2 mg, 0.115 mmol) was added to a stirred solution of 4-chloro-1-((7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decane -10-yl)methyl)-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (Example 144) (20.0 mg, 0.0385 mmol) in DMF (1.0 ml) in a 4 ml vial. The vial was sealed and heated to 60°C. After 1 hour the solvents were removed in vacuo and the remaining residue was partitioned between EtOAc and 1:1 brine/water. The resulting biphasic mixture was separated, extracted using EtOAc (x 2). The combined organic phase was dried (phase separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-15%, MeOH in DCM) to give the title compound (6.0 mg, 27%) as white solid. LCMS (method A): R _T =1.38 min, m/z =516 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.71-7.65 (m, 1H), 5.94-5.84 (m, 1H), 5.02-4.84 (m , 1H), 4.60-4.34 (m, 1H), 3.90-2.68 (m, 14H, overlap with solvent peak), 1.98-0.73 (m, 27H).

Example 243: 1-((7-(4,4-difluoro-2-methylbutanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6-oxo- 4-phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using amine 8 (10 mg, 24.4 µmol), 4,4-difluoro-2-methylbutanoic acid (3.4 mg, 24.4 µmol), HATU (9.3 mg, 24.4 µmol), DIPEA (17 µl, 97.7 µmol) and DCM (0.5 ml) to give the title compound (11.9 mg, 89%) as a colorless solid after lyophilization. LCMS (method B): R _T =1.11 min, m/z =530 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84 (s, 0.4H), 7.84 (s, 0.6H), 7.54-7.29 (m, 5H), 6.46 (s, 0.4H), 6.45 (s, 0.6H), 6.12-5.87 (m, 1H), 4.98 (s, 0.4H), 4.93 ( s, 0.6H), 4.73-4.58 (m, 1H), 4.57-4.49 (m, 0.4H), 4.01-3.05 (m, 3.6H (s signal overlap from HDO)), 3.05-2.93 (m, 1H), 2.75 (s, 3H), 2.63 (s, 3H), 2.27-2.12 (m, 1H) , 2.04-1.74 (m, 2H), 1.72-1.11 (m, 10H), 1.11-1.01 (m, 3H).

Example 244: 1-((7-(4,4-difluoro-2,2-dimethylbutanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6- oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using amine 8 (10 mg, 24.4 µmol), 4,4-difluoro-2,2-dimethylbutanoic acid (3.7 mg, 24.4 µmol), HATU (9, 3 mg, 24.4 µmol), DIPEA (17 µl, 97.7 µmol) and DCM (0.5 ml) to give the title compound (10.3 mg, 75%) as a colorless solid after lyophilization . LCMS (Method B): R _T =1.19 min, m/z =544 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.84 (s, 1H), 7.48-7.41 (m, 3H), 7.41-7.34 (m, 2H), 6.45 (s, 1H), 6.10 (tt, J =56.7, 4.4 Hz, 1H), 4.91 (s, 1H), 4.64 (d, J =13.5 Hz , 1H), 3.87-3.76 (m, 1H), 3.68 (d, J = 13.5 Hz, 1H), 3.54-3.41 (m, 2H), 3.38- 3.19 (m, 1H (with HDO overlap)), 2.75 (s, 3H), 2.63 (s, 3H), 2.12 (td, J =17.8, 4.5 Hz , 2H), 1.95-1.86 (m, 1H), 1.69-1.45 (m, 6H), 1.40-1.32 (m, 1H), 1.31-1.20 (m, 1H), 1.26 (s, 6H), 1.19-1.11 (m, 1H).

Example 245: 1-((10-hydroxy-7-(4-(trifluoromethyl)thiazole-2-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6-oxo -4-phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using amine 8 (10 mg, 24.4 µmol), 4-(trifluoromethyl)thiazole-2-carboxylic acid (4.8 mg, 24.4 µmol), HATU (9.3 mg, 24.4 µmol), DIPEA (17 µl, 97.7 µmol) and DCM (0.5 ml) to give the title compound (13 mg, 88%) as a colorless solid after lyophilization. LCMS (Method B): R _T =1.30 min, m/z =589 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 8.78 (s, 0.6H), 8.76 (s, 0.4H), 7.85 (s, 1H), 7.52- 7.27 (m, 5H), 6.48 (s, 0.6H), 6.46 (s, 0.4H), 5.07 (s, 0.6H), 5.04 (s, 0, 4H), 4.72-4.64 (m, 1H), 4.51-4.45 (m, 0.4H), 4.26-4.19 (m, 0.6H), 4.11- 4.04(m, 0.6H), 4.01-3.92(m, 1H), 3.77-3.69(m, 1H), 3.67-3.61(m, 0.4H ), 3.60-3.50 (m, 1H), 2.75 (s, 3H), 2.63 (s, 3H), 2.01-1.89 (m, 1H), 1.78- 1.35 (m, 8H), 1.28-1.20 (m, 1H).

Example 246: 1-((10-hydroxy-7-(2-(trifluoromethyl)thiazole-4-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-6-oxo -4-phenyl-1,6-dihydropyridine-3-carboxamide

Prepared according to general procedure 3 using amine 8 (10 mg, 24.4 µmol), 2-(trifluoromethyl)thiazole-4-carboxylic acid (4.8 mg, 24.4 µmol), HATU (9.3 mg, 24.4 µmol), DIPEA (17 µl, 97.7 µmol) and DCM (0.5 ml) to give the title compound (12.7 mg, 85%) as a colorless solid after lyophilization. LCMS (Method B): R _T =1.22 min, m/z =589 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 8.55 (s, 0.5H), 8.50 (s, 0.5H), 7.84 (s, 1H), 7.55- 7.27 (m, 5H), 6.48 (s, 0.5H), 6.43 (s, 0.5H), 5.02 (s, 0.5H), 5.01 (s, 0, 5H), 4.72-4.61 (m, 1H), 3.99-3.92 (m, 0.5H), 3.77-3.67 (m, 1.5H), 3.64- 3.41 (m, 3H), 2.75 (s, 3H), 2.69-2.57 (m, 3H), 2.01-1.87 (m, 1H), 1.79-1, 44 (m, 6H), 1.41-1.17 (m, 3H).

Example 247: 1-(((S)-10-hydroxy-7-((S)-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl) methyl)-N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide

Stage 1: ethyl-1-(((S)-10-hydroxy-7-((S)-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decane-10- yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate: Prepared according to General Procedure 3 using amine 10 (66.8 mg, 0.163 mmol), acid 14 (28.0 mg, 0.163 mmol), HATU (74.2 mg, 0.195 mmol), DIPEA (114 μl, 0.651 mmol) and DCM (2.0 ml) to give the title compound (69.8 mg, 76%) in form of a white solid. LCMS (method A): R _T= 1.43 min, m/z =565 [M+H] ⁺ .

Step 2: 1-(((S)-10-hydroxy-7-((S)-4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid : A solution of ethyl 1-(((S)-10-hydroxy-7-((S)-4,4,4-trifluoro-2- (hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate (69.8 mg, 0.124 mmol) in 1M NaOH (aq.) (0.618 ml, 0.618 mmol) and 1,4-dioxane (10.5 ml) were stirred at 50°C for 2 hours. The reaction mixture was allowed to cool to room temperature and the pH was adjusted to ~2 with 1M HCl (aq.). The resulting mixture was extracted with DCM (x 3) using a Biotage phase separator and the combined organic phases were concentrated in vacuo to give the title crude compound (70.2 mg, >100%) as a white solid. LCMS (method A): R _T= 1.11 min, m/z =537 [M+H] ⁺ .

Step 3: 1-(((S)-10-hydroxy-7-((S)-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl) methyl)-N,N-dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide : Prepared according to General Procedure 3 using 1-(((S)-10-hydroxy-7 -((S)-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxylic acid (30.0 mg, 0.0559 mmol), 2M dimethylamine in THF (55.9 µl, 0.112 mmol), HATU (25.5 mg, 0.0671 mmol), DIPEA (39.1 µl , 0.224 mmol) and DCM (1.5 mL) to give the title compound (19.9 mg, 63%) as a white solid after lyophilization. LCMS (method A): R _T =1.12 min, m/z =564 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.86-7.81 (m, 1H), 7.48-7.35 (m, 5H), 6.48-6.43 (m , 1H), 5.02-4.87 (m, 2H), 4.69-4.44 (m, 1H), 4.10-3.60 (m, 2H), 3.59-2.94 (m, 5H, overlap with solvent peak), 2.81-2.57 (m, 7H), 2.47-2.32 (m, 1H), 2.05-1.06 (m, 11H).

Example 248: 1-(((S)-10-hydroxy-7-((S)-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl-7-azaspiro[4,5]decan-10-yl )methyl)-5-(morpholine-4-carbonyl)-4-phenylpyridin-2(1H)-one

Prepared according to general procedure 3 using 1-(((S)-10-hydroxy-7-((S)-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5] decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (10.0 mg, 18.6 µmol), morpholine (3.3 µl, 37.3 µmol ), HATU (8.5 mg, 22.4 µmol) DIPEA (13.0 µl, 74.6 µmol) and DCM (1.0 ml) to give the title compound (8.9 mg, 79%) as a white solid after lyophilization. LCMS (method A): R _T =1.10 min, m/z =606 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.85 (s, 1H), 7.53-7.35 (m, 5H), 6.49-6.42 (m, 1H), 5.10-4.75 (m, 2H), 4.72-4.42 (m, 1H), 4.10-2.30 (m, 17H, solvent peak overlap), 2.06-1, 06 (m, 11H).

Example 249: 1-(((S)-10-hydroxy-7-((S)-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl) methyl)-4-phenyl-5-(piperazine-1-carbonyl)pyridin-2(1H)-one

Step 1: tert-butyl-4-(1-(((S)-10-hydroxy-7-((S)-4,4,4-trifluoro-2-(hydroxymethyl)butanoy-azaspiro[4.5]decan- 10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate : Prepared according to general procedure 3 using 1-(((S)-10 -hydroxy-7)-((S)-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxylic acid (30.0 mg, 0.0559 mmol), tert-butylpiperazine-1-carboxylate (10.4 mg, 0.0559 mmol), HATU (25.5 mg, 0.0559 mmol), 0671 mmol), DIPEA (39.1 μl, 0.224 mmol) and DCM (1.5 ml) to give the title compound (27.5 mg, 70%) as a white solid. LCMS (method A): R _T= 1.41 min, m/z =705 [M+H] ⁺ .

Step 2: 1-((((S)-10-hydroxy-7-((S)-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl )methyl)-4-phenyl-5-(piperazine-1-carbonyl)pyridine-2(1H)-one : Solution of tert-butyl-4-(1-(((S)-10-hydroxy-7-)( (S)-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3 -carbonyl)piperazine-1-carboxylate (27.5 mg, 0.0390 mmol) in TFA (0.5 ml) and DCM (1.0 ml) was stirred for 1 hour, then the reaction mixture was purified using a Biotage SCX cartridge -2 (5 g) (pre-equilibrated and then washed with 1:1 DCM/MeOH before eluting with 1:1 DCM/7M NH ₃ in MeOH). The main eluents were concentrated in vacuo and the remaining residue was purified by flash chromatography (0-10% MeOH in DCM) and lyophilized to give the title compound (17.0 mg, 72%) as a white solid. LCMS (method A): R _T =0.72 min, m/z =605 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.82 (s, 1H), 7.51-7.33 (m, 5H), 6.48-6.41 (m, 1H), 5.09-4.78 (m, 2H), 4.71-4.43 (m, 1H), 4.10-1.08 (m, 29H, overlap with solvent peak).

Example 250: 1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- 5-(morpholine-4-carbonyl)-4-phenylpyridin-2(1H)-one

Prepared according to general procedure 3 using 1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan- 10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (Example 216, step 2) (29.0 mg, 55.7 µmol), morpholine (5.4 µl , 61.3 µmol), HATU (25.4 mg, 66.9 µmol), DIPEA (29.2 µl, 167 µmol) and DCM (1.5 ml) to give the title compound (25.0 mg , 76%) as a white solid after lyophilization. LCMS (method A): R _T =1.31 min, m/z =590 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.85 (s, 1H), 7.53-7.35 (m, 5H), 6.50-6.43 (m, 1H), 5.12-4.73 (m, 1H), 4.70-4.46 (m, 1H), 4.04-2.64 (m, 14H, solvent peak overlap), 2.32-2, 19 (m, 1H), 2.06-1.83 (m, 1H), 1.80-0.78 (m, 13H).

Example 251: 1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- 5-(4-methylpiperazin-1-carbonyl)-4-phenylpyridin-2(1H)-one

Prepared according to general procedure 3 using 1-(((S)-10-hydroxy-7-((R)-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan- 10-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid (Example 216, step 2) (29.0 mg, 55.7 µmol), 1-methylpiperazine (6, 8 µl, 61.33 µmol) HATU (25.4 mg, 66.9 µmol), DIPEA (29.2 µl, 167 µmol) and DCM (1.5 ml) to give the title compound (21.6 mg, 64%) as a white solid after lyophilization. LCMS (Method A): R _T = 0.87 min, m/z = 603 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 7.83 (s, 1H), 7.51-7.33 (m, 5H), 6.49-6.42 (m, 1H), 5.11-4.77 (m, 1H), 4.70-4.43 (m, 1H), 4.06-2.64 (m, 10H, solvent peak overlap), 2.34-0, 74 (m, 22H).

Example 252: ethyl 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6- oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate

Ethyl 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxylate (Example 211, step 1) was purified by flash chromatography using a KP-NH column (1 g) (0-50% EtOAc in cyclohexane) and lyophilized to give the title compound as a white solid. LCMS (Method A): R _T =1.93 min, m/z =563 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 8.46-8.39 (m, 1H), 7.46-7.35 (m, 3H), 7.32-7.21 (m , 2H), 6.33-6.25 (m, 1H), 5.00-4.89 (m, 1H), 4.83-4.64 (m, 1H), 4.04-3.94 (m, 2H), 3.92-3.59 (m, 2H), 3.52-3.08 (m, 2H, solvent peak overlap), 2.94-2.80 (m, 1H), 2.05-1.83 (m, 1H), 1.74-0.74 (m, 29H).

Example 253: 1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo- 4-phenyl-1,6-dihydropyridine-3-carboxylic acid

1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxylic acid (Example 211, step 2) was purified by flash chromatography (0-10% MeOH in DCM) and lyophilized to give the title compound as a white solid. LCMS (method A): R _T =1.61 min, m/z =535 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 12.47 (br s, 1H), 8.43 (s, 1H), 7.54-7.12 (m, 5H), 6, 28-6.20 (m, 1H), 5.03-4.91 (m, 1H), 4.80-4.60 (m, 1H), 4.16-3.96 (m, 1H), 3.92-3.58 (m, 2H), 3.54-3.30 (m, 1H, solvent overlay), 2.94-2.80 (m, 1H), 2.03-1.83 (m, 1H), 1.80-0.65 (m, 26H).

USP19 activity assay

USP19 activity was monitored in a homogeneous fluorescent polarization (FP) assay using the isopeptide substrate Ubiquitin-Lys-TAMRA (AUB-101, Almac Sciences Scotland Limited or U-558, Boston Biochem, both of which give identical results). Full length USP19 was purchased from Boston Biochem (E-576). Unless otherwise noted, all other reagents were purchased from Sigma. Enzymatic reactions were performed in black 384-well flat bottom polystyrene plates (Nunc) with a total volume of 30 μl. USP19 (2.5 nM, 10 µl) was incubated in assay buffer (50 mM HEPES (pH 7.4), 150 mM NaCl, 5 mM DTT, 0.05% BSA (w/v), 0.05 % CHAPS) in the presence or absence of inhibitor (10 μl). Inhibitors were stored as 10 mM stock solutions in DMSO in an inert environment (low humidity, darkness, low oxygen, room temperature) using a Storage Pod System, and serial dilutions were prepared in buffer immediately prior to assay (from 200 μM to 2 pM, based on 8-18 points for the curve). After incubation at room temperature for 30 minutes, enzymatic reactions were initiated by dosing Ub substrate (500 nM, 10 μl). FP was measured every 15 minutes for 90 minutes (within the linear range of the assay) using a Synergy 4 (BioTek) plate reader with excitation at 530 nm and measuring parallel and perpendicular light intensity at 575 nm. The FP signal was normalized to control (no compound). The data were plotted on a graph and a curve was plotted by points. Concentrations resulting in 50% inhibition (IC ₅₀ ) were calculated using a non-linear regression curve fitting model using GraphPad (Prism) software. The IC ₅₀ values for the inhibitors of the invention are summarized in Table 1 and are the average of at least two replicate experiments.

Claims (378)

1. Compound of formula (I):

where: R ₁ is: C1-C6 alkyl, where when alkyl is C1 alkyl it is optionally substituted and the optional substituent is cyclobutyloxy or cyclohexyloxy, when alkyl is C2 alkyl it is optionally substituted and each of one or more optional substituents is independently selected from OH, F, methyl, ethyl, phenyl, fluorophenyl, C3-C7 cycloalkyl, cyclohexyloxy, pyrazole, piperidine, morpholine, tetrahydrofuran, methoxymethyl, and ethoxy, when alkyl is C3 alkyl it is optionally substituted and each of the one or more optional substituents is independently selected from OH, methyl, phenyl, cyclobutyl, cyclohexyl, difluoro, trifluoro, trifluoromethyl, trifluoroethyl, benzyloxy and hydroxymethyl, when alkyl is C4 alkyl it is optionally substituted and each of the one or more optional substituents is methyl, when alkyl is C5 alkyl it is optionally substituted and each of the one or more optional substituents is ethyl; optionally substituted butenyl, where each of the one or more optional substituents is cyclohexylmethyl; optionally substituted C3-C6 cycloalkyl, where when the cycloalkyl is cyclopropyl, the cyclopropyl is substituted with one or more substituents independently selected from phenyl, isobutyl, thiophene and difluoroethyl, when cycloalkyl is cyclobutyl, cyclobutyl is substituted with trifluoromethyl, when cycloalkyl is cyclopentyl, each of the one or more optional substituents is independently selected from C1-C6 alkyl, F, and trifluoromethyl, when cycloalkyl is cyclohexyl, each of the one or more optional substituents is independently selected from C1-C6 alkyl and methenyl; bicyclopentane, bicylcoheptane, spiropentane; optionally substituted alkylcycloalkyl selected from ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl, ethylcyclohexyl, ethylcycloheptyl, where when the alkylcycloalkyl is ethylcyclopropyl, each of the one or more optional substituents is C1-C6 alkyl, when the alkylcycloalkyl is ethylcyclobutyl, each of the one or more optional substituents is independently selected from C1-C6 alkyl optionally substituted with OH, when the alkylcycloalkyl is ethylcyclohexyl, each of the one or more optional substituents is independently selected from OH, F, C1-C6 alkyl optionally substituted with OH, propenyl, benzyloxymethyl and methoxymethyl, when the alkylcycloalkyl is ethylcycloheptyl, each of the one or more optional substituents is C1-C6 alkyl; ethylcyclopentyl, propylcyclohexyl, or an optionally substituted alkylheterocycloalkyl selected from ethylpiperidine and ethylmorpholine, wherein one or more optional substituents are each C1-C6 alkyl; ethyltetrahydrofuran, tetrahydronaphthalenemethyl, optionally substituted ethylbenzene, where each of the one or more optional substituents is independently selected from OH, F, C1-C6 alkyl, difluoromethyl, and trifluoromethyl; optionally substituted heteroaryl selected from pyrazole, pyrrole, oxazole and thiazole, wherein when heteroaryl is pyrazole, each of the one or more optional substituents is cyclohexyl, when heteroaryl is pyrrole substituted with benzyl, when heteroaryl is oxazole, each of the one or more optional substituents is independently selected from phenyl and cyclopropyl, when heteroaryl is a thiazole, each of the one or more optional substituents is trifluoromethyl; indazole, indole or optionally substituted ethylpyrazole, where each of one or more optional substituents is C1-C6 alkyl; R ₂ is H, R ₃ is H, R ₄ is H or C1-C6 alkyl group, R ₅ represents H or C1-C6 alkyl group, R ₂ and R ₄ may be combined with each other to form 3-azabicyclo[3.2.1]octane including the carbon to which they are attached, or alternatively R ₄ and R ₅ may be combined with each other to form C4-C6 cycloalkyl or oxane, including the carbon atoms to which they are attached; R ₆ is H or a C1-C6 alkyl group; W is C or N; X is N or CR ₈ where R ₈ is H or C1-C6 alkyl, Y is N or CR _9, Z is CH or NH, where R ₉ represents H or optionally substituted C1-C6 alkyl, where each of one or more optional substituents is independently selected from oxo and dimethylamine; optionally substituted phenyl, where each of the one or more optional substituents is independently selected from amido, acetamido, methylamine, and cyano; heteroaryl selected from furan, pyridine, pyrimidine and oxazole; optionally substituted pyrazole, where each of the one or more optional substituents is independently selected from C1-C6 alkyl; optionally substituted pyrrolidine, where the optional substituent is oxo; halogen, C(O)R ₁₀ where R ₁₀ is selected from OH and ethoxy; C(O)NR'R'', where R' and R'' are independently selected from H, C1-C6 alkyl, optionally substituted with OH, cyclohexane, methoxy, cyclopropylmethyl, phenyl and benzyl, or where R' and R'' are connected with each other to form a heterocycloalkyl which includes the N to which they are attached, wherein the heterocycloalkyl is selected from piperidine, hydroxypiperidine (hydroxymethyl)piperidine, pyrrolidine, methylpyrrolidine, 1,4-dioxa-8-azaspiro[4.5]decane, morpholine, piperazine, methylpiperazine, acetylpiperazine, boc-piperazine and (hydroxymethyl)piperazine; methylamine disubstituted with methyl; or cyano; R ₇ is hydrogen, halogen or ethenyl substituted with methyl; substituted amino, where each of the one or more optional substituents is independently selected from C1-C6 alkyl; optionally substituted phenyl, where each of the one or more optional substituents is independently selected from F, C1-C6 alkyl, methoxy, dioxolane, trifluoromethoxy, cyano, acetamido, hydroxymethyl, and aminomethyl; naphthalene, cyclopropyl, cyclohexenyl, methoxy, phenoxy substituted with F; heteroaryl selected from furan, thiophene and pyrimidine, or optionally substituted heteroaryl selected from indazole and pyrazole, where each of one or more optional substituents is C1-C6 alkyl; or connection

. 2. The compound according to claim 1, where R ₁ is an optionally substituted cyclohexylethane, where each of the one or more optional substituents is independently selected from OH, F, C1-C6 alkyl optionally substituted with OH, propenyl and methoxymethyl; or optionally substituted ethylbenzene, where each of the one or more optional substituents is independently selected from OH, F, and C1-C6 alkyl; or optionally substituted 3,3,3-trifluoropropane, where each of the one or more optional substituents is independently selected from OH, methyl, and hydroxymethyl. 3. The compound according to claim 1 or 2, where R ₇ is an optionally substituted phenyl, where each of the one or more optional substituents is independently selected from F, C1-C6 alkyl, methoxy, dioxolane, trifluoromethoxy, cyano, acetamide, hydroxymethyl and aminomethyl ; naphthalenyl, optionally substituted indazole, wherein one or more optional substituents are each C1-C6 alkyl; pyrimidine, thiophene or optionally substituted pyrazole, where each of one or more optional substituents is C1-C6 alkyl. 4. The connection according to any one of paragraphs. 1-3, where R ₂ and R ₃ are H, and R ₄ and R ₅ are methyl. 5. Connection according to any one of paragraphs. 1-3, where R ₂ and R ₃ are H and R ₄ and R ₅ are connected to each other to form a C4-C6 cycloalkyl which includes the carbon to which they are attached, optionally a C4 or C5 cycloalkyl which includes a carbon, to which they are attached. 6. The connection according to any one of paragraphs. 1-3, where R ₂ and R ₄ are connected to each other to form 3-azabicyclo[3.2.1]octane, including the carbon atoms to which they are attached, and where R ₃ represents H, and where R ₅ and R ₆ are independently H or C1-C6 alkyl. 7. Connection according to any one of paragraphs. 1-6 where W is N and X is CR ₈ where R ₈ is H or methyl. 8. Connection according to any one of paragraphs. 1-7 where Y is N or CR ₉ where R ₉ is H, C1-C6 alkyl, C(O)NR'R'', cyano, carboxyl, halogen, optionally substituted phenyl or heteroaryl, where heteroaryl is selected from furan, pyridine, pyrimidine, oxazole and pyrazole, and one or more optional phenyl substituents selected from methylamine, amido and cyano, where R' and R" are independently selected from H, C1-C6 alkyl, optionally substituted OH, cyclohexane, cyclopropylmethyl, benzyl, phenyl and methoxy, or where R' and R" are connected to each other to form a heterocycle that includes N, to to which they are attached, wherein the heterocycle is piperidine, hydroxypiperidine (hydroxymethyl)piperidine, pyrrolidine, methylpyrrolidine, morpholine, piperazine, methylpiperazine, acetylpiperazine, and (hydroxymethyl)piperazine. 9. Connection according to any one of paragraphs. 1-8, where Y is N or CR ₉ where R ₉ is phenyl, optionally substituted with amido, cyano or methylamine; pyridine; oxazole, pyrazole; carboxyl or C(O)NR'R"; where R' and R" are independently selected from H, C1-C6 alkyl, cyclohexyl, or where R' and R" are connected to each other to form a heterocycloalkyl that includes the N to which they are attached, where heterocycloalkyl is piperidine, hydroxypiperidine ( hydroxymethyl)piperidine, pyrrolidine, methylpyrrolidine, morpholine, piperazine, methylpiperazine, acetylpiperazine and (hydroxymethyl)piperazine. 10. Connection according to claim 1, where R ₁ is selected from optionally substituted ethylcyclohexane, where each of the one or more optional substituents is independently selected from C1-C6 alkyl, optionally substituted with OH, propenyl and methoxymethyl, optionally substituted ethylbenzene, where each of the one or more optional substituents is C1-C6 alkyl , and optionally substituted 3,3,3-trifluoropropane, where each of one or more optional substituent is selected from methyl and hydroxymethyl, R ₂ and R ₃ is H, R ₄ and R ₅ are independently selected from H, methyl or connected to each other to form C4-C6 cycloalkyl or oxane which includes the carbon to which they are attached, optionally C4 or C5 cycloalkyl which includes the carbon to which they are attached, R ₆ is H or methyl, R ₇ is selected from indazole, optionally substituted phenyl, where each of the one or more optional substituents is independently selected from F, C1-C6 alkyl, methoxy, dioxolane, cyano, acetamide, hydroxymethyl and aminomethyl, optionally substituted thiophene, or pyrazole, where each of one or more optional substituents is methyl, W is N or C, X is CH or N, Z is C or NH, Y is N or CR ₉ where R ₉ is phenyl optionally substituted with amido, cyano or methylamine; pyridine; oxazole; or pyrazole; C(O)NR'R"; where R' and R" are independently selected from H, C1-C6 alkyl, cyclohexyl, or where R' and R" are connected to each other to form a heterocycloalkyl that includes the N to which they are attached, where heterocycloalkyl is piperidine, hydroxypiperidine ( hydroxymethyl)piperidine, pyrrolidine, methylpyrrolidine, morpholine, piperazine, methylpiperazine, acetylpiperazine and (hydroxymethyl)piperazine. 11. The compound according to claim 1, which is: ( R )-5-bromo-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2( 1H )-one; 6-(2-fluorophenyl)-3-((4-hydroxy-1-(3-phenylpropanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one; 3-((1-(3-cyclobutylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one; 3-((1-(3-cyclopentylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one; ( R , S )-6-(2-fluorophenyl)-3-((4-hydroxy-1-(2-methyl-3-phenylpropanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one ; ( R ) -N- (3-(1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3- yl)phenyl)acetamide; ( R )-3-(1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)6-oxo-4-phenyl-1,6-dihydropyridin-3-yl)benzamide; ( R )-5-(furan-2-yl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2( 1H )-one; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(1-methyl- 1H -pyrazol-5-yl)-4-phenylpyridin-2 (1 H )-he; ( R )-4-chloro-1-((4-hydroxy-1(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-phenylpyridin-2( 1H )-one; ( R )-4-(dimethylamino)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-phenylpyridin-2( 1H )-one; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-phenyl-4-(prop-1-en-2-yl)pyridine-2(1 H )-he; ( R )-ethyl 1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate; ( R,S )-4-(2-fluorophenyl)-1-((4-hydroxy-1-(2-methyl-1,2,3,4-tetrahydronaphthalene-2-carbonyl)piperidin-4-yl)methyl ) -N -isopropyl- N -methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; ( R , S )-1-((1-(3-cyclobutyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-phenyl-5-(piperidine-1-carbonyl)pyridine-2( 1 H )-he; ( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(1-methyl- 1H -indazol-7-yl)pyrimidin-4( 3H )-he; ( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(2-methoxyphenyl)pyrimidin-4( 3H )-one; ( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-2-methyl-6-phenylpyrimidin-4( 3H )-one; ( R )-2-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5,6-diphenylpyridazin-3( 2H )-one; ( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(naphthalen-1-yl)pyrimidin-4( 3H )-one; ( R )-6-(3-(1,3-dioxolan-2-yl)phenyl)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3 H )-he; ( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(thiophen-3-yl)pyrimidin-4( 3H )-one; 4-(2-fluorophenyl)-1-((4-hydroxy-1-(1-methylcyclopentan-1-carbonyl)piperidin-4-yl)methyl) -N -isopropyl- N -methyl-6-oxo-1, 6-dihydropyridine-3-carboxamide; 3-((1-(1-ethylcyclohexane-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one; 3-((1-(2-(cyclohexylmethyl)-3-methylbutanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidine-4(3 H )- he; ( R )-6-(furan-2-yl)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2( 1H )-one; ( R )-6-(cyclohex-1-en-1-yl)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one ; ( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(prop-1-en-2-yl)pyrimidin-4( 3H )-one ; ( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(2-(trifluoromethoxy)phenyl)pyrimidin-4( 3H )-one; 3-(((1 R ,5 S )-3-(( R )-3-cyclohexyl-2-methylpropanoyl)-8-hydroxy-3-azabicyclo[3.2.1]octan-8-yl)methyl)-6 -(2-fluorophenyl)pyrimidin-4( 3H )-one; ( R )-6-(2-fluorophenyl)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one; ( R )-5-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-2-phenylpyrimidin-4( 3H )-one; 3-((4-hydroxy-1-(3-phenylpropanoyl)piperidin-4-yl)methyl)-2-methyl-6-phenylpyrimidin-4( 3H )-one; ( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(isobutylamino)pyrimidin-4( 3H )-one; ( R )-1-((1-(3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-phenyl-5-(piperidine-1-carbonyl)pyridine-2( 1H )-he; ( R )-2-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-phenylpyridazin-3( 2H )-one; ( R )-4-(2-cyanophenyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl) -N -isopropyl- N -methyl-6-oxo-1, 6-dihydropyridine-3-carboxamide; ( R )-3-((1-(3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one; 3-((1-(2-(cyclohexylmethyl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one; rac- 6-(2-fluorophenyl)-3-((4-hydroxy-1-( cis -2-phenylcyclopropanecarbonyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one; 6-(2-fluorophenyl)-3-((4-hydroxy-1-(1-methylcyclohexanecarbonyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one; 3-(( S )-1-(1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)propyl)-6-phenylpyrimidin-4( 3H )-one; 3-(( R )-1-(1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)propyl)-6-phenylpyrimidin-4( 3H )-one; ( R , S )-3-((1-(3-cyclohexyl-2-hydroxypropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbaldehyde; ( R )-5-((dimethylamino)methyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2( 1H )-one; 3-(( R )-1-(4-hydroxy-1-(( R )-3-phenylbutanoyl)piperidin-4-yl)ethyl)-6-phenylpyrimidin-4( 3H )-one; 3-(( S )-1-(4-hydroxy-1-(( R )-3-phenylbutanoyl)piperidin-4-yl)ethyl)-6-phenylpyrimidin-4( 3H )-one; ( R )-6-(2-fluorophenyl)-3-((4-hydroxy-1-(4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H ) -he; ( R , S )-3-((1-(3-cyclohexyl-2-fluyliopropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one; 3-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-phenylpyrimidine-4(3 H ) -he; 3-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-phenylpyrimidine-4(3 H ) -he; 3-((( R )-6-(( R )-3-cyclohexyl-2-methylpropanoyl)-9-hydroxy-6-azaspiro[3.5]nonan-9-yl)methyl)-6-(2-fluorophenyl) pyrimidin-4(3 H )-one; 3-((( S )-6-(( R )-3-cyclohexyl-2-methylpropanoyl)-9-hydroxy-6-azaspiro[3.5]nonan-9-yl)methyl)-6-(2-fluorophenyl) pyrimidin-4(3 H )-one; ( R )-5-(3-(aminomethyl)phenyl)-1-((1-(3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-(2-fluorophenyl)pyridine -2(1 H )-he; 3-((( S )-4-hydroxy-3,3-dimethyl-1-(( R )-3-phenylbutanoyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4( 3H )-one; 3-((( R )-4-hydroxy-3,3-dimethyl-1-(( R )-3-phenylbutanoyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4( 3H )-one; ( R )-6-(4-fluorophenoxy)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(2-oxopyrrolidin-1-yl)-4-phenylpyridin-2( 1H )- he; 6-(2-fluorophenyl)-3-((4-hydroxy-1-(1-methyl-4-methylenecyclohexanecarbonyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one; ( R , S )-3-((1-(3-cyclobutyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one; ( R,S )-3-((1-(3-cycloheptyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one; 3-((1-(3-cyclobutyl-2,2-dimethylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one; 6-(2-fluorophenyl)-3-(((1 R ,5 S )-8-hydroxy-3-(( R )-3-phenylbutanoyl)-3-azabicyclo[3.2.1]octan-8-yl) methyl)pyrimidin-4( 3H )-one; 3-((( R )-4-hydroxy-2,2-dimethyl-1-(( R )-3-phenylbutanoyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4( 3H )-one; 3-((( S )-4-hydroxy-2,2-dimethyl-1-(( R )-3-phenylbutanoyl)piperidin-4-yl)methyl)-6-phenylpyrimidin-4( 3H )-one; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(4-hydroxypiperidine-1-carbonyl)-4-phenylpyridine-2( 1H )- he; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-5-(pyrrolidin-1-carbonyl)pyridin-2( 1H )-one ; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-5-(1,4-dioxa-8-azaspiro[4.5]decan-8 -carbonyl)pyridine-2(1 H )-one; ( R ) -N -cyclohexyl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-( cis -2-phenylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)pyrimidin-4(3 H ) -he; ( R , S )-3-((1-(3-cyclohexyl-1H-pyrazole-4-carbonyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl) pyrimidin-4(3 H )-one; ( R , S )-6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(3-phenylpropanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H ) -he; ( R , S )-6-(2-fluorophenyl)-3-((4-hydroxy-1-(1-isobutylcyclopropane-1-carbonyl)-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4 (3 H )-he; ( R,S ) - 6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(3-methyl-3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4 (3 H )-he; ( S )-1-((1-(4,4-difluoro-3-phenylbutanoyl)-4-hydroxypiperidin-4-yl)methyl)- N -isopropyl- N -methyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide; 1-((4-hydroxy-1-(1-(thiophen-2-yl)cyclopropan-1-carbonyl)piperidin-4-yl)methyl) -N -isopropyl- N -methyl-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxamide; 1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N -isopropyl- N -methyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl) -N -isopropyl- N -methyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; ( R )-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-(2-(hydroxymethyl)phenyl)pyrimidin-4( 3H )-one; ( R ) -N , N -diethyl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3- carboxamide; 3-((1-(3-cyclohexylbutanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(morpholine-4-carbonyl)-4-phenylpyridin-2( 1H )-one; ( R , S )-3-((1-(3-cyclohexylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidine-4( 3H )- he; ( R , S )-1-((1-(3-cyclobutylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl) -N -isopropyl- N -methyl-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxamide; ( R , S )-1-((1-(2-ethylhexanoyl)-4-hydroxypiperidin-4-yl)methyl)- N -isopropyl- N -methyl-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxamide; ( R,S )-6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(1-methylcyclohexane-1-carbonyl)piperidin-4-yl)methyl)pyrimidin-4 (3 H )-he; 6-(2-fluorophenyl)-3-((1-(3-(4-fluorophenyl)propanoyl)-4-hydroxypiperidin-4-yl)methyl)pyrimidin-4( 3H )-one; ( R , S )-3-((1-(3-cyclopropylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidine-4( 3H )- he; 1-((1-(2,2-dimethylbutanoyl)-4-hydroxypiperidin-4-yl)methyl)- N -isopropyl- N -methyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide ; ( R ) -N- (2-(1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-1,6-dihydropyrimidin-4-yl)phenyl) acetamide; ( R )-5-(4-(aminomethyl)phenyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2( 1H )-one ; ( R )-1-((1-(3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)methyl)- N -isopropyl- N -methyl-6-oxo-4-phenyl-1,6 -dihydropyridine-3-carboxamide; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-5-(piperidine-1-carbonyl)pyridin-2( 1H )-one ; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl) -N -isopropyl-4-(2-methoxyphenyl) -N -methyl-6-oxo-1, 6-dihydropyridine-3-carboxamide; ( R )-4-(2-fluorophenyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl) -N -isopropyl- N -methyl-6-oxo-1, 6-dihydropyridine-3-carboxamide; ( R )-1'-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4'-phenyl-[2,3'-bipyridine]-6'( 1'H ) -he; 1-((1-(3-cyclohexylpropanoyl)-4-hydroxypiperidin-4-yl)methyl) -N -isopropyl- N -methyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; ( R )-tert-Butyl- 4- (1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3 -carbonyl)piperazine-1-carboxylate; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-5-(piperazin-1-carbonyl)pyridine-2( 1H )-one ; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3- carboxamide; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl) -N -isopropyl- N -methyl-6-oxo-4-(p-tolyl)-1, 6-dihydropyridine-3-carboxamide; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)- N -methoxy- N -methyl-6-oxo-4-phenyl-1,6-dihydropyridine- 3-carboxamide; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4,5-diphenylpyridin-2( 1H )-one; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-[3,3'-bipyridin]-6( 1H )-one; ( R )-5-(3-(aminomethyl)phenyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenylpyridin-2( 1H )-one ; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)- N -isopropyl- N -methyl-6-oxo-4-phenyl-1,6-dihydropyridine- 3-carboxamide; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl) -N -isopropyl- N -methyl-6-oxo-4-( m -tolyl)-1, 6-dihydropyridine-3-carboxamide; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-phenyl-5-(pyrimidin-5-yl)pyridin-2( 1H )-one ; ( R ) -N- (cyclopropylmethyl)-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3- carboxamide; ( R )- N -benzyl-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)- N -methyl-6-oxo-4-phenyl-1,6-dihydropyridine- 3-carboxamide; ( R )-2-(1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridin-3-yl)benzonitrile ; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)- N -methyl-6-oxo- N ,4-diphenyl-1,6-dihydropyridine-3- carboxamide; 3-(1-(1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxypiperidin-4-yl)ethyl)-6-phenylpyrimidin-4( 3H )-one; (R) -1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(1-methyl-1H-pyrazol-4-yl)-4-phenylpyridin-2( 1H)-he; ( R )-3-((1-(2-(cyclohexylmethyl)pent-4-enoyl)-4-hydroxypiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one ; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-methyl-4-phenylpyridin-2( 1H )-one; ( R )-6-(1,5-dimethyl- 1H -pyrazol-4-yl)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3 H )-he; 3-(((1 R ,5 S )-3-(3-cyclohexylpropanoyl)-8-hydroxy-3-azabicyclo[3.2.1]octan-8-yl)methyl)-6-(2-fluorophenyl)pyrimidine- 4( 3H )-he; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonitrile; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)- N- (2-hydroxyethyl)-6-oxo-4-phenyl-1,6-dihydropyridine- 3-carboxamide; 1-((4-hydroxy-1-(( R )-3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(( S )-2-methylpyrrolidin-1-carbonyl)-4-phenylpyridine-2( 1 H )-he; ( R )-1-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5-(4-(hydroxymethyl)piperidine-1-carbonyl)-4-phenylpyridine-2(1 H )-he; 3-((1-(2-(cyclohexylmethyl)butanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one; 3-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3 H )-he; 1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl) -N -isopropyl- N -methyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo -4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo -4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-phenyl-5-(pyrrolidin- 1-carbonyl)pyridine-2(1 H )-one; 1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-phenyl-5-(piperazin- 1-carbonyl)pyridine-2(1 H )-one; 1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-phenyl-5-(piperazin- 1-carbonyl)pyridine-2(1 H )-one; 3-((1-(2-(cyclohexyloxy)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4( 3H )-one; 1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-1 ,6-dihydropyridine-3-carboxamide; 1-((1-(( R )-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxamide; 1-((1-(( R )-3-cyclopropyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxamide; 1-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-[4,5'-bipyrimidine]-6(1 H )-he; 3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(1-methyl- 1H -pyrazol-5 -yl)pyrimidin-4(3 H )-one; 3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(1 H -pyrazol-4-yl)pyrimidine -4( 3H )-he; 3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(1 H -pyrazol-5-yl)pyrimidine -4( 3H )-he; 3-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)pyrimidin-4( 3H )-one; 3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(thiophen-3-yl)pyrimidin-4( 3 H )-he; 1-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(oxazol-2-yl)-4-phenylpyridine -2(1 H )-he; 3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-(hydroxymethyl)phenyl)pyrimidin-4 (3 H )-he; 3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(3-(hydroxymethyl)phenyl)pyrimidin-4 (3 H )-he; 3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(4-(hydroxymethyl)phenyl)pyrimidin-4 (3 H )-he; 6-(4-(aminomethyl)phenyl)-3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4 (3 H )-he; 6-(2-(Aminomethyl)phenyl)-3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4 (3 H )-he; 6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(2,4,4-trimethylpentanoyl)piperidin-4-yl)methyl)pyrimidin-4( 3H )-one ; 6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(4,4,4-trifluoro-2-methylbutanoyl)piperidin-4-yl)methyl)pyrimidin-4(3 H )-he; 4-chloro-1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6 -oxo-1,6-dihydropyridine-3-carboxamide; 1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(dimethylamino)- N , N -dimethyl -6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((1-(( S )-3-(benzyloxy)-2-(cyclohexylmethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6- oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-isobutyryl-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide ; 1-((10-hydroxy-7-(( R )-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide; 1-((7-(( R )-3-cyclopropyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxamide; 6-(2-fluorophenyl)-3-((4-hydroxy-3,3-dimethyl-1-(2-methyl-3-(1 H -pyrazol-1-yl)propanoyl)piperidin-4-yl)methyl )pyrimidin-4(3 H )-one; 1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-(hydroxymethyl)phenyl)- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((( S )-1-(( S )-3-cyclohexyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( R )-1-(( S )-3-cyclohexyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1'-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4'-(2-fluorophenyl)-[2, 3'-bipyridine]-6'(1' H )-one; 1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4 -(thiophen-3-yl)-1,6-dihydropyridine-3-carboxamide; 1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(3-(hydroxymethyl)phenyl)- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((7-(3-cyclohexyl-2-hydroxypropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-(2-methyl-3-(piperidin-1-yl)propanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6- oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 6-(3-(Aminomethyl)phenyl)-3-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrimidin-4 (3 H )-he; 1-((( S )-1-(( S )-3-cyclohexyl-2-(methoxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 4-(2-(aminomethyl)phenyl)-1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(4-(hydroxymethyl)phenyl)- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-(2-methyl-3-morpholinepropanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide; 1-((( S )-1-(( S )-2-(cyclohexylmethyl)-4-hydroxybutanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( R )-1-(( S )-2-(cyclohexylmethyl)-4-hydroxybutanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( S )-1-(( S )-3-cyclobutyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( R )-1-(( S )-3-cyclobutyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(morpholine-4-carbonyl)-4-phenylpyridine -2(1 H )-he; 5-(4-acetylpiperazin-1-carbonyl)-1-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4 -phenylpyridin-2(1 H )-one; 1-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(4-methylpiperazin-1-carbonyl)-4 -phenylpyridin-2(1 H )-one; 1-((10-hydroxy-7-(4,4,4-trifluoro-3-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-(4,4,4-trifluorobutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-(3-(tetrahydrofuran-3-yl)propanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-((1 R ,2 S )-2-phenylcyclopropane-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-(1-methylcyclohexane-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide; 1-((7-(3-fluorocyclopentan-1-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide; 1-((7-(1-(2,2-difluoroethyl)cyclopropane-1-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6- oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((7-(bicyclo[2.2.1]heptane-1-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxamide; 1-((7-(( S )-4,4-difluoro-3-phenylbutanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo -4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((7-(( R )-4,4-difluoro-3-phenylbutanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo -4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((7-(3-ethoxypropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxamide; 1-((10-hydroxy-7-(( S )-3-phenylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide; 1-((7-(3-(4-fluorophenyl)propanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-(( R )-3-phenylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-(1-methylcyclopentan-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-(1 H -pyrazole-3-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-(1 H -indazole-3-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxamide; 1-((7-(3-cyclohexyl- 1H -pyrazole-4-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo- 4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-(1 H -indole-3-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl- 1,6-dihydropyridine-3-carboxamide; 1-((7-(bicyclo[1.1.1]pentan-1-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-(5-phenyloxazole-4-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide; 1-((7-(5-cyclopropyloxazole-4-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide; 1-((7-(2-(cyclohexyloxy)acetyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1, 6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-(spiro[2.2]pentan-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-(3-(trifluoromethyl)cyclopentane-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxamide; 1-((7-(2,4-dimethylpentanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6 -dihydropyridine-3-carboxamide; 1-((7-(1-benzyl-1 H --pyrrole-2-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo -4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((7-(2-(cyclohexyloxy)propanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1, 6-dihydropyridine-3-carboxamide; 3-((1-(( S )-3-cyclobutyl-2-(hydroxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-(2-fluorophenyl)pyrimidin-4 (3 H )-he; 1-((7-(2-cyclobutoxyacetyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxamide; 1-((7-(3,3-difluorocyclopentan-1-carbonyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-(2-hydroxy-3-phenylpropanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1 ,6-dihydropyridine-3-carboxamide; 1-((( S )-4-hydroxy-3,3-dimethyl-1-(( R )-4,4,4-trifluoro-2-methylbutanoyl)piperidin-4-yl)methyl)- N , N - dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl) -N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)-5 -(piperazine-1-carbonyl)pyridine-2(1 H )-one; ( S )-1-((4-hydroxy-3,3-dimethyl-1-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)piperidin-4-yl)methyl) - N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(( S )-2- (hydroxymethyl)piperazin-1-carbonyl)-4-phenylpyridin-2( 1H )-one; 1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl-5-( piperazine-1-carbonyl)pyridine-2(1 H )-one; 1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl-5-( piperazine-1-carbonyl)pyridine-2(1 H )-one; 1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(( R )-3- methylpiperazin-1-carbonyl)-4-phenylpyridin-2(1 H )-one; 1-((( S )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( S )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl-5-( piperazine-1-carbonyl)pyridine-2(1 H )-one; 1-((( S )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( S )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl -5-(piperazin-1-carbonyl)pyridine-2(1 H )-one; ( S )-1-((10-hydroxy-7-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl ) -N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; ( S )-1-((10-hydroxy-7-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl )-4-phenyl-5-(piperazin-1-carbonyl)pyridin-2(1 H )-one; 1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-cyclopropyl- N , N -dimethyl -6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-cyclopropyl-5-(piperazin- 1-carbonyl)pyridine-2(1 H )-one; 1-((( S )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl) - N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 4-(2-fluorophenyl)-1-((( S )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decane-10- yl)methyl) -N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((( S )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl) -5-(piperazin-1-carbonyl)pyridine-2(1 H )-one; 4-(2-fluorophenyl)-1-((( S )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decane-10- yl)methyl)-5-(piperazin-1-carbonyl)pyridin-2(1 H )-one; 1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl) - N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl) -5-(piperazin-1-carbonyl)pyridine-2(1 H )-one; 1-((( S )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(4-hydroxypiperidin-1- carbonyl)-4-phenylpyridin-2(1 H )-one; 1-((10-hydroxy-7-(3-(trifluoromethyl)cyclobutane-1-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( S )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((( S )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl-5-( piperazine-1-carbonyl)pyridine-2(1 H )-one; 1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl-5-( piperazine-1-carbonyl)pyridine-2(1 H )-one; 1-((2-(( R )-3-cyclohexyl-2-methylpropanoyl)-5-hydroxy-9-oxa-2-azaspiro[5.5]undecan-5-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( S )-1-(( R )-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl) -N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((( S )-1-(( R )-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)-5 -(piperazine-1-carbonyl)pyridine-2(1 H )-one; 1-((2-(( R) -3-cyclohexyl-2-methylpropanoyl)-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)methyl)- N , N -dimethyl-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxamide; 1-((2-(( R )-3-cyclohexyl-2-methylpropanoyl)-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)methyl)-4-phenyl-5-(piperazin-1- carbonyl)pyridine-2(1 H )-one; 1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-5-(morpholin-4- carbonyl)-4-phenylpyridin-2(1 H )-one; 1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-5-(4-methylpiperazin- 1-carbonyl)-4-phenylpyridin-2(1 H )-one; 1-((1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-6-oxo-4-phenyl-1,6-dihydropyridine -3-carboxylic acid; 1-((7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-methoxy- N , N -dimethyl-6 -oxo-1,6-dihydropyridine-3-carboxamide; 1-((7-(4,4-difluoro-2-methylbutanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxamide; 1-((7-(4,4-difluoro-2,2-dimethylbutanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-(4-(trifluoromethyl)thiazole-2-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxamide; 1-((10-hydroxy-7-(2-(trifluoromethyl)thiazole-4-carbonyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4- phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( S )-10-hydroxy-7-(( S )-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( S )-10-hydroxy-7-(( S )-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- 5-(morpholine-4-carbonyl)-4-phenylpyridin-2(1 H )-one; 1-((( S )-10-hydroxy-7-(( S )-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- 4-phenyl-5-(piperazin-1-carbonyl)pyridin-2( 1H )-one; 1-((( S )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-5-( morpholine-4-carbonyl)-4-phenylpyridin-2(1 H )-one; 1-((( S )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-5-( 4-methylpiperazin-1-carbonyl)-4-phenylpyridin-2(1 H )-one; ethyl-1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxylate; 1-((( S )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxylic acid; 1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-phenyl-5-(pyrrolidin- 1-carbonyl)pyridine-2(1 H )-one; 1-((( R )-1-(( S )-3-cyclohexyl-2-(methoxymethyl)propanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)- N , N -dimethyl- 6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( R )-4-hydroxy-3,3-dimethyl-1-(( R )-4,4,4-trifluoro-2-methylbutanoyl) piperidin-4-yl) methyl) - N , N - dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)-5 -(piperazine-1-carbonyl)pyridine-2(1 H )-one; ( R )-1-((4-hydroxy-3,3-dimethyl-1-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)piperidin-4-yl)methyl) - N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(( S )-2- (hydroxymethyl)piperazin-1-carbonyl)-4-phenylpyridin-2( 1H )-one; 1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(( R )-3- methylpiperazin-1-carbonyl)-4-phenylpyridin-2(1 H )-one; 1-((( R )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6 -oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( R )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl-5-( piperazine-1-carbonyl)pyridine-2(1 H )-one; 1-((( R )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( R )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenyl -5-(piperazin-1-carbonyl)pyridine-2(1 H )-one; ( R )-1-((10-hydroxy-7-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl ) -N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; ( R )-1-((10-hydroxy-7-(4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl )-4-phenyl-5-(piperazin-1-carbonyl)pyridin-2(1 H )-one; 1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-cyclopropyl- N , N -dimethyl -6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-cyclopropyl-5-(piperazin- 1-carbonyl)pyridine-2(1 H )-one; 1-((( R )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl) - N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 4-(2-fluorophenyl)-1-((( R )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decane-10- yl)methyl) -N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((( R )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl) -5-(piperazin-1-carbonyl)pyridine-2(1 H )-one; 4-(2-fluorophenyl)-1-((( R )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decane-10- yl)methyl)-5-(piperazin-1-carbonyl)pyridin-2(1 H )-one; 1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl) - N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-(2-fluorophenyl) -5-(piperazin-1-carbonyl)pyridine-2(1 H )-one; 1-((( R )-1-(( R )-3-cyclohexyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-5-(4-hydroxypiperidin-1- carbonyl)-4-phenylpyridin-2(1 H )-one; 1-((( R )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((( R )-7-(( R )-3-cyclobutyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl-5-( piperazine-1-carbonyl)pyridine-2(1 H )-one; 1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-cyclopropyl-5-( piperazine-1-carbonyl)pyridine-2(1 H )-one; 1-((( R )-1-(( R )-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)- N , N -dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-((( R )-1-(( R )-3-cyclobutyl-2-methylpropanoyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)-4-(2-fluorophenyl)-5 -(piperazine-1-carbonyl)pyridine-2(1 H )-one; 1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-5-(morpholine-4- carbonyl)-4-phenylpyridin-2(1 H )-one; 1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-5-(4-methylpiperazin- 1-carbonyl)-4-phenylpyridin-2(1 H )-one; 1-((( R )-10-hydroxy-7-(( S )-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- N , N -dimethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxamide; 1-((( R )-10-hydroxy-7-(( S )-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- 5-(morpholine-4-carbonyl)-4-phenylpyridin-2(1 H )-one; 1-((( R )-10-hydroxy-7-(( S )-4,4,4-trifluoro-2-(hydroxymethyl)butanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)- 4-phenyl-5-(piperazin-1-carbonyl)pyridin-2( 1H )-one; 1-((( R )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-5-( morpholine-4-carbonyl)-4-phenylpyridin-2(1 H )-one; 1-((( R )-10-hydroxy-7-(( R )-4,4,4-trifluoro-2-methylbutanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-5-( 4-methylpiperazin-1-carbonyl)-4-phenylpyridin-2(1 H )-one; ethyl-1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4 -phenyl-1,6-dihydropyridine-3-carboxylate; or 1-((( R )-7-(( R )-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-6-oxo-4-phenyl -1,6-dihydropyridine-3-carboxylic acid. 12. Connection according to any one of paragraphs. 1-11 which is an inhibitor of USP19, preferably human USP19. 13. Connection according to any one of paragraphs. 1-12 for use in a method for treating or preventing Parkinson's disease. 14. A method of treating Parkinson's disease, comprising administering to a subject an effective amount of a compound according to any one of paragraphs. 1-12.

Images