New amide derivatives, pharmaceutical compositions containing them and their uses as sos1 inhibitors

Abstract

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Description

[0001] NEW AMIDE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USES AS SOS1 INHIBITORS FIELD OF THE INVENTIONThe present invention relates to new amide derivatives, to processes for their preparation, topharmaceutical compositions containing them and to their uses as Son Of Sevenless homolog 1(SOS1) inhibitors. The compounds of the present invention inhibit the activity of the SOS1 protein and may be of interest in the treatment of cancer, autoimmune diseases, diseases of immune system and genetic diseases. BACKGROUND OF THE INVENTIONRAS proteins play an important role in human cancer (Simanshu et al. Cell 2017, 170, 17-33;Malumbres et al. Nat. Rev. Cancer 2003, 3, 459-465). There are three RAS genes: KRAS,NRAS and HRAS that encode four RAS proteins, with two KRAS isoforms that arise from alternative RNA splicing (KRAS4A and KRAS4B). These proteins play a critical role in transmitting the growth signals from extracellular growth factor binding to intracellular downstream pathways. These growth factors can be, among others, epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and nerve growth factor (NGF) which when bound to their receptors will activate, via Ras activation, the mitogen-activated protein kinase (MAPK) / extracellular regulated kinase (ERK) pathway and phosphoinositide-3-kinase (PI3K) pathways hence regulating cellular division, survival and overall function in normal and altered states such as cancers. RAS proteins functions as guanosine triphosphatases (GTPases) that cycle between an inactive guanosine diphosphate (GDP)-bound state and an active guanosine triphosphate (GTP)-bound state. Mutations in Ras proteins can be found in about 30% of all tumors (Hobbs et al. J. CellSci.2016, 129, 1287-1292; Prior et al. Cancer Res.2020, 80, 2969-2974). These missense gain-of-function mutations in RAS genes lead to the hyperactivation of the signaling pathway thus driving tumor initiation and maintenance. These point mutations are typically found within the GTP-binding regions preventing the hydrolysis of bound GTP, leading to RAS constant activation.98% of these mutations are found at one of the three mutational hotspots: G12, G13 and Q61. Over the years, evidence has shown that amino acid substitutions at any one hotspot can have differential biochemical properties leading to differences in oncogenic potencies and functional consequences. Validating this further, it is known that some specific mutations on some isoforms are cancer-type specific. Recent studies have shown that despite being mutated, Ras still require nucleotide cycling for activation based on their intrinsic GTPase activity and sensitivity to extrinsic GTPases. As a consequence, mutant RAS proteins are sensitive to the inhibition of upstream factors such as SOS1 or SHP2. The molecular switch between the active and inactive state is tightly regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). GEFs function as activators of Ras by promoting the nucleotide exchange from GDP to GTP, whereas GAPsdeactivate Ras-GTP by catalyzing the hydrolysis of the bound GTP to GDP. There are threemain types of GEFs: two Son of Sevenless proteins (SOS1 and SOS2), four different isoforms of Ras guanine nucleotide releasing proteins (Ras-GRP1-4) and two Ras guanine nucleotide releasing factors (Ras-GRF1 and2). The most characterized GEFs are SOS proteins, as theyplay a critical role in cancer (Hillig et al. Adv. Cancer Res. 2022, 153, 169-203; Kessler et al.Curr. Opin. Chem. Biol. 2021, 62, 109-118).The SOS family is comprised of SOS1 and SOS2, which share about 70% sequence identity(Rojas et al. Genes Cancer 2011, 2, 298-305). SOS1 has been much more studied and isdescribed as the main RAS regulator. SOS are multidomain proteins belonging to the CDC25 homology domain containing GEF family. The N-terminal region contains two tandem histonefolds (HFs), a Dbl homology (DH) domain and a pleckstrin homology (PH) domain. The C-terminal region contains the RAS exchanger motif (REM) domain, CDC25 domain, andproline-rich (PR) region (Sondermann et al. Cell 2004, 393-405). Of importance, the N-terminaland C-terminal regions of SOS are joined by a helical linker, which acts as a hinge, allowing SOS to adopt both an active, membrane-bound conformation and an auto-inhibited cytosolic conformation. SOS proteins are recruited to phosphorylated RTKs through an interaction with growth factor receptor 2 (GRB2). Recruitment to the plasma membrane brings SOS and RAS together enabling RAS activation. SOS proteins display a catalytic site and an allosteric site. Through the catalytic site SOS promotes nucleotide exchange, whereas the allosteric site functions as a positive feedback loop, relieving steric occlusion of the catalytic site and is therefore required for full activation of the catalytic site. Out of the two SOS proteins, SOS1 is the most studied and characterized so far. Importantly, SOS1 but not SOS2 is a node in the negative feedback regulation of the KRAS pathway. Relief of SOS1 autoinhibition then sets up a positive feedback loop from mutant RASGTP through SOS1 to wild-type RAS that enhances activation of downstream effectors and is important for proliferation of KRAS mutantpancreatic cancer cells (Sheffels et al. Genes 2021, 12, 662). In addition, SOS1 mutations arefound in Noonan syndrome and several types of cancers including lung adenocarcinoma andendometrial cancers (Lepri et al. Hum. Mutat. 2011, 32, 760-772; Cai et al. Mol. Cancer Res.2019, 17, 1002-1012). Targeting Ras for cancer treatment has been long pursued (Moore et al. Nat. Rev. Drug Discov. 2020, 19, 533-552). For a long time, these proteins were considered undruggable. This was in part due to the scarcity of traditional pockets at the surface of the proteins and the high flexibility of the protein. One group of inhibitors that covalently binds to the cysteine of mutant form Kras G12C were recently discovered. These mutant specific inhibitors have the benefit to reach good target inhibition in a defined patient population. It also carries low risk of Kras WT-mediated toxicity. Other Kras mutant specific inhibitors are being pursued in preclinical studies but not all mutations will be addressed. In addition, one important caveat of this approach is the on-target acquired resistance developed in patient (Hofmann et al. Cancer Discov. 2022, 12, 924-937). Therefore, there is still a large unmet need for the treatment of Ras-dependent tumors and,particularly, there remains a need for novel therapeutics to disrupt Ras signaling. To this end,numerous SOS1 inhibitors have been recently developed and published in the literature (He etal., J. Med. Chem. 2022, 65, 13158-13171; Hillig et al., PNAS 2019, 116, 2551-2560; Liu et al.ACS Med. Chem. Lett. 2023, 14, 183-190; PCT / EP2018 / 086197) and, particularly, amidederivatives claimed as SOS1 inhibitors have been disclosed in PCT / KR2022 / 012254,PCT / US2021 / 063685 or PCT / US2023 / 012307. But so far, limited success has been achieved clinically. SUMMARY OF THE INVENTION The present invention provides potent selective SOS1 inhibitors of Formula (I) as defined below. We have shown that compounds of Formula (I) have a strong binding affinity on SOS1and are blocking the interaction between SOS1 and RAS-family members preventing therecycling of KRas into the active GTP-bound form. Therefore, the compounds of the invention could be of interest for a wide range of cancers, particularly Ras family member-associated cancers. In addition, the compounds of the present invention offer potential therapeutic benefit as inhibitors of SOS1-Ras proteins interaction in a cell for treating various forms of cancer, including Ras-associated cancer, SOS1-associated cancer and NF-1 / NF-2 associated cancer. Finally, the compounds of the present invention may provide also therapeutic benefit in genetic and immune diseases.In a first aspect of the invention, the present invention relates to compounds of Formula (I): wherein: ring A represents a heterocycloalkyl group,R1 represents a hydrogen atom or a halogen atom, R2 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group, a linear or branched halo(C1-C6)alkyl group, a linear or branched halo(C1-C6)alkoxy group, a linear or branched amino(C1-C6)alkyl group, a -CH(CH2-OH)CH2-Cl group, or R3 represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group, a linear or branched di(C1-C6)alkylphosphoryl group, a cycloalkyl group, an aryl group, or a heterocycloalkyl group, R4 represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, a linear orbranched halo(C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy(C1-C6)alkylgroup, a linear or branched hydroxy(C1-C6)alkyl group, a -CO-CH2-OH group, acycloalkyl group, a heterocycloalkyl group, or R5represents a hydrogen atom, a halogen atom, a hydroxy group, a linear or branched (C1-C6)alkyl group, a linear or branched halo(C1-C6)alkyl group, or a group selected from , R6 represents a hydrogen atom, a halogen atom, or a linear or branched (C1-C6)alkyl group, Wrepresents a bond, an oxygen atom, a -CO- group, a -O-CH2- group, or a -CH2-group, Cy1 represents an aryl group or a heteroaryl group, Cy2represents an aryl group, a heteroaryl group, or a heterocycloalkyl group, Cy3represents a cycloalkyl group, a heterocycloalkyl group, or a heteroaryl group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. In another aspect of the invention, the present invention relates to compounds of Formula (I): wherein: ring A represents a heterocycloalkyl group,R1 represents a hydrogen atom or a halogen atom, R2represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group, a linear or branched halo(C1-C6)alkyl group, a linear or branched halo(C1-C6)alkoxy group, a linear or branched amino(C1-C6)alkyl group, a -CH(CH2-OH)CH2-Cl group, or R3represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group, a cycloalkyl group, an aryl group, or a heterocycloalkyl group,R4 represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, a linear orbranched halo(C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy(C1-C6)alkylgroup, a linear or branched hydroxy(C1-C6)alkyl group, a -CO-CH2-OH group, acycloalkyl group, or group, R5represents a hydrogen atom, a halogen atom, a hydroxy group, a linear or branched (C1-C6)alkyl group, a linear or branched halo(C1-C6)alkyl group, or a group selected from , R6 represents a hydrogen atom, a halogen atom, or a linear or branched (C1-C6)alkyl group, Wrepresents a bond, an oxygen atom, a -CO- group, a -O-CH2- group, or a -CH2-group, Cy1represents an aryl group or a heteroaryl group, Cy2 represents an aryl group, a heteroaryl group, or a heterocycloalkyl group, Cy3represents a cycloalkyl group, a heterocycloalkyl group, or a heteroaryl group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.In another aspect, the invention provides compounds of Formula (I) as described herein, for usein the treatment of cancer, autoimmune diseases, diseases of immune system and geneticdiseases. In a further aspect, the invention provides a pharmaceutical composition comprising thecompounds of Formula (I) as described herein, and at least one pharmaceutically acceptableexcipient. DEFINITIONS Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid,camphoric acid, etc.Among the pharmaceutically acceptable bases there may be mentioned, without implying anylimitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.1-C6)alkyl hydrocarbon group having from 1 to 6 carbon atoms, and one or more halogen atoms. More preferably, halogen atoms are selected from fluorine, chlorine and bromine, more preferably fluorine. Among the haloalkyl groups, there may be mentioned, without implying anylimitation, -CH2F (or fluoromethyl), -CHF2 (or difluoromethyl), -CF3, -CH2-CH2F (or 2-fluoroethyl), -CH2-CHF2 (or 2,2-difluoroethyl), -CH2-CF3 (or 3,3,3-trifluoroethyl), -(CH2)2-CF3 (or 3,3,3-trifluoropropyl), -CH(CF3)-CH3, etc. 1-C6 -(C1-C6)alkyl-NH2 group. Among theamino(C1-C6)alkyl groups, there may be mentioned, without implying any limitation,-CH2-NH2, -CH2-CH2-NH2, and the like. halo(C1-C6)alkoxy means a linear or branched, saturated, monovalent (C1-C6)alkoxy group wherein one or more of the hydrogen atoms is replaced with a halogen atom.More preferably, halogen atoms are selected from fluorine, chlorine and bromine, morepreferably fluorine. Among the haloalkoxy radicals, there may be mentioned, without implyingany limitation, -O-CH2F, -O-CF3 (or trifluoromethoxy), -O-CH2-CHF2 (or 2,2-difluoroethoxy),-O-CH2-CF3 (or 2,2,2-trifluoroethoxy), and the likehydroxy(C1-C6 -(C1-C6)alkyl-OH group. Among thehydroxy(C1-C6)alkyl groups, there may be mentioned, without implying any limitation,-CH2-OH, -CH2-CH2-OH (or hydroxyethyl), -CH2-C(CH3)2-OH, and the like.The term1-C6)alkoxy(C1-C6-(C1-C6)alkyl-O-(C1-C6)alkyl group, wherein each (C1-C6)alkyl is independent. Among the (C1-C6)alkoxy(C1-C6)alkyl groups, there may be mentioned, without implying any limitation, -CH2-O-CH3 (ormethoxymethyl), -(CH2)2-O-CH3 (or methoxyethyl), -(CH2)3-O-CH3 (or methoxypropyl),-CH2-O-CH2CH3, -(CH2)2-O-CH2CH3, -(CH2)2-O-(CH2)2-CH3, and the like.1-C6 a monovalent -P(=O)[(C1-C6)alkyl]2 group, wherein each(C1-C6)alkyl is independent. Among the di(C1-C6)alkylphosphoryl groups, there may bementioned, without implying any limitation, -P(=O)(CH3)2, -P(=O)(CH2-CH3)2(or diethylphosphoryl), -P(=O)(CH3)(CH2-CH3), and the like. having at least one aromatic moiety. Among the aryl groups, there may be mentioned, without implying any limitation, phenyl, indanyl, naphthyl, etc. amonocyclic, a fused bicyclic, or a bridged bicyclic group composed offrom 5 to 12 ring members, having at least one aromatic moiety and containing from 1 to 4heteroatoms selected from oxygen, sulfur and nitrogen. Among the heteroaryl groups, theremay be mentioned, without implying any limitation, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyridazinyl,pyridinyl (or pyridyl), pyrimidinyl, pyrazinyl, pyridinonyl, indolyl, indazolyl, quinolinyl,isoquinolinyl, thienopyridinyl, imidazopyridinyl, furopyridinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolopyridinyl, pyranopyridinyl, thienopyrimidinyl, pyrrolopyridazinyl, quinoxalinyl, quinazolinonyl, benzofuranyl, benzopyranyl, benzodioxolyl, benzimidazolyl, benzothienyl, benzotriazolyl, benzothiazolyl, benzoxadiazolyl, dihydrobenzofuranyl, dihydroindolyl, dihydroquinolinyl, dihydroisoindolyl, dihydropyrrolizinyl, dihydrocyclopentathienyl, dihydroquinoxalinyl, dihydrobenzodioxinyl, dihydrothienodioxinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroindolizinyl, tetrahydroquinazolinyl,tetrahydroindazolyl, tetrahydronaphthyridinyl, tetrahydro-5,8-ethanoquinolinyl,tetrahydrobenzothienyl, cyclopentapyridinyl, cyclopentapyrimidinyl, hexahydropentalenopyridinyl, cycloheptapyridinyl, dioxino[2,3-b]pyridinyl, etc. amonocyclic, a fused bicyclic, a spiro bicyclic, or a bridged bicyclic non-aromatic carbocyclic group composed of from 3 to 10 ring members. Among the cycloalkylgroups, there may be mentioned, without implying any limitation, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, adamantyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptanyl, etc.a monocyclic, a fused bicyclic, or a spiro bicyclic non-aromaticgroup composed of from 3 to 10 ring members, containing from 1 to 3 heteroatoms selectedfrom oxygen, sulfur and nitrogen, and may have one double bond. Among the heterocycloalkylgroups, there may be mentioned, without implying any limitation, azetidinyl, azepanyl,tetrahydropyranyl, dihydropyranyl, tetrahydropyridinyl (or dihydro-2H-pyridinyl), piperidinyl(or piperidyl), piperazinyl, morpholinyl, pyrrolidinyl, dioxanyl, dihydrofuranyl,tetrahydrofuranyl, thianyl, dioxothianyl, oxetanyl, dioxothiazinyl (or diketothiazinanyl),thiazinanyl, azaspiro[3.3]heptanyl, oxazaspiro[3.3]heptanyl, oxazaspiro[2.5]octanyl,oxazaspiro[3.5]nonanyl, oxazaspiro[5.5]undecanyl, oxazaspiro[4,5]decanyl, 4-oxo- -oxaphosphinanyl, etc.As used -CN radical. -NH2 radical. Among the pharmaceutical compositions according to the invention there may be mentionedmore especially those that are suitable for oral, parenteral, nasal, per- or trans-cutaneous, rectal,perlingual, ocular or respiratory administration, especially tablets or dragées, sublingual tablets, sachets, paquets, capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels,and drinkable or injectable ampoules. The pharmaceutical compositions according to theinvention comprise one or more excipients or carriers selected from diluents (such as lactose,, lubricants (such as silica, talc,, binders (such asmagnesium aluminium silicate, starch, gelatin, tragacanth, methylcellulose, sodium ,disintegration agents (such as agar,, stabilizers, preservatives, absorbents,colorants, sweeteners, flavorings, etc. The administration route is preferably the oral route orthe intravenous route, and the corresponding pharmaceutical compositions may allow the instantaneous or delayed release of the active ingredients.Among the combinations of a compound of Formula (I) with an anticancer agent according tothe invention, there may be mentioned more especially those that are suitable for a simultaneousadministration or a sequential administration. The combinations according to the inventioncomprise a compound of Formula (I) combined to anti-cancer agents selected from genotoxicagents, mitotic poisons, anti-metabolites, proteasome inhibitors, enzymes inhibitors, signaling proteins inhibitors, transcription factor inhibitors, epigenetic factor inhibitors, kinase inhibitors, protein-protein interaction inhibitors, immunomodulators, E3 ligase inhibitors, chimeric antigen receptor T-cell therapy and antibodies. The compounds of the combination may moreover be administered in the form of two separate pharmaceutical compositions, each containing one of the active ingredients, or in the form of a single pharmaceutical composition, in which the active ingredients are in admixture. one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another physical parameter including those which may not be discernible by the patient. In yet another ting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. - dysregulation of a Ras gene, a Ras protein, or the expression or activity or level of any (e.g.,one or more) of the same (e.g., any of the types of dysregulation of a Ras gene, a Ras protein,or the expression or activity or level of any of the same, as described herein). Non-limiting examples of a Ras-associated cancer are described herein. In some embodiments, a Ras- associated cancer can be a KRas-associated cancer, a HRas-associated cancer, a NRas- associated cancer, or a combination thereof. - a dysregulation of a SOS1 gene, a SOS1-GEF (also called herein SOS1 protein), or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a SOS1 gene, a SOS1 protein, or the expression or activity or level of any of the same, as described herein). Non-limiting examples of a SOS1-associated cancer are described herein. -1 / NF-2- by or having a loss-of-function mutation in the neurofibromin (NF-1) gene or neurofibromin 2(NF-2) gene. Non-limiting examples of a NF-1 / NF-2-associated cancer are described herein.Among the treatment or the prevention of cancers envisaged, there may be mentioned, without implying any limitation, of Ras-associated cancer, SOS1-associated cancer and NF-1 / NF-2 associated cancer. These cancers may be, without implying any limitation hematological malignancies and solid tumors, more particularly, pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovariancancer, prostate cancer, glioblastoma, renal cancer, sarcomas, glioma and malignant peripheralnerve sheath tumors. In another aspect, the disease to be treated or prevented with compound of Formula (I) is aRASopathy. means a group of rare genetic diseases caused bymutations in certain genes that make proteins involved in the Ras / MAPK cell signalingpathway. Preferably, RASopathy is selected from the group consisting of neurofibromatosistype 1, Noonan syndrome, Noonan syndrome with multiple lengitines, capillary malformation- arteriovenous malformation syndrome, Costello syndrome, cardiofaciocutaneous syndrome, Legius syndrome and hereditary gingival fibromatosis. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, theduration of the treatment, other drugs, compounds and / or materials used in combination withthe particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A suitable daily dose of a compound of the invention will depend upon the factors described above and may range from 0.01 mg to 2.5 g per day in one or more administration(s). DETAILED DESCRIPTION Described below are a number of preferred and advantageous embodiments of the invention. It will be recognized that features specified in each preferred embodiment may be combined with other specified features to provide further preferred embodiments of the present invention. An advantageous possibility consists of compounds of Formula (I-a):wherein R1, R2, R3, R4, Cy1, Cy2 and A are as defined for Formula (I).Preferably, ring A represents a heterocycloalkyl group selected from, wherein R4 is as defined for Formula (I).More preferably, ring A represents a heterocycloalkyl group selected from, wherein R4 is as defined for Formula (I).Even more preferably, ring A represents a heterocycloalkyl group which is ,wherein R4is as defined for Formula (I).Another advantageous possibility consists of compounds of Formula (I-b): wherein R1, R2, R3, R4, Cy1and Cy2are as defined for Formula (I).In a preferred embodiment, R1 represents a hydrogen atom, a chlorine atom, or a fluorine atom.In another preferred embodiment, R1 represents a hydrogen atom or a fluorine atom. Morepreferably, R1 represents a fluorine atom.Advantageously, R2 represents a hydrogen atom, a bromine atom, a cyano group, a methylgroup, an ethyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a methoxygroup, an ethoxy group, an isopropyloxy group, an isobutyloxy group, a trifluoromethyl group,a difluoromethyl group, a 2,2,2-trifluoroethyl group, a trifluoromethoxy group, a 2,2-difluoroethoxy group, a -CH2-NH2group, a -CH(CH2-OH)CH2-Cl group, ora group.More advantageously, R2 represents an isopropyl group or a group. Preferably, R3 represents a hydrogen atom, a methyl group, a methoxy group, a cyclopropylgroup, a phenyl group, a diethylphosphoryl group, or a dihydrofuranyl group. Preferably, R3represents a hydrogen atom, a methyl group, a methoxy group, a cyclopropyl group, a phenylgroup, or a dihydrofuranyl group. More preferably, R3 represents a hydrogen atom, a methylgroup, or a methoxy group. Even more preferably, R3 represents a hydrogen atom.In one preferred embodiment, R4 represents a hydrogen atom, a methyl group, an ethyl group,an isopropyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group, a 3,3,3-trifluoropropylgroup, a methoxyethyl group, a hydroxyethyl group, a -CO-CH2-OH group, a cyclobutyl group,a tetrahydrofuranyl group, an oxetanyl group, or In one preferred embodiment, R4 represents a hydrogen atom, a methyl group, an ethyl group,an isopropyl group, a 2,2-difluoroethyl group, a 3,3,3-trifluoropropyl group, a methoxyethylgroup, a hydroxyethyl group, a -CO-CH2-OH group, a cyclobutyl group, or a group.In a more preferred embodiment, R4 represents a hydrogen atom, a methyl group,a In a more preferred embodiment, R4 represents a hydrogen atom or a methyl group. Even morepreferably, R4 represents a methyl group.Advantageously, R5 represents a hydrogen atom, a fluorine atom, a hydroxy group, a methylgroup, a fluoromethyl group, a difluoromethyl group, or a group selected from , More advantageously, R5 represents a hydrogen atom, a fluorine atom, a methyl group, or agroup selected from,Even more advantageously, R5 represents a hydrogen atom or group selected from. Even more advantageously, R5 represents a hydrogen atom.Preferably, R6 represents a hydrogen atom, a fluorine atom, or a methyl group. More preferably,R6represents a hydrogen atom.Preferably, W represents a bond, an oxygen atom, or a -O-CH2- group. More preferably, Wrepresents a bond. In one preferred embodiment, W represents an oxygen atom. In one preferredembodiment, W represents a -O-CH2- group.In a preferred embodiment, Cy1 represents a phenyl group or a pyridinyl group. In a more preferred embodiment, Cy1 represents a phenyl group.Preferably, Cy2 represents a phenyl group, a pyrazolyl group, a triazolyl group, a thienyl group,a pyridinyl group, pyrimidinyl group, a pyrazinyl group, a pyridonyl group, a quinolinyl group,an isoquinolinyl group, a thienopyridinyl group, an isoxazolopyridinyl group, abenzoxadiazolyl group, or a morpholinyl group. Preferably, Cy2 represents a phenyl group, apyrazolyl group, a triazolyl group, a pyridinyl group, pyrimidinyl group, a pyrazinyl group, apyridonyl group, a quinolinyl group, an isoquinolinyl group, a thienopyridinyl group, anisoxazolopyridinyl group, a benzoxadiazolyl group, or a morpholinyl group. More preferably,Cy2 represents a phenyl group, a pyrazolyl group, a triazolyl group, a pyridinyl group,pyrimidinyl group, a pyrazinyl group, a quinolinyl group, an isoquinolinyl group, athienopyridinyl group, an isoxazolopyridinyl group, a benzoxadiazolyl group, or a morpholinylgroup. Even more preferably, Cy2 represents a pyridinyl group, a pyrimidinyl group, anisoxazolopyridinyl group. In one preferred embodiment, Cy2 represents a pyridinyl group or apyrimidinyl group. In one preferred embodiment, Cy2 represents a pyridinyl group. In onepreferred embodiment, Cy2 represents a pyrimidinyl group.Advantageously, Cy3 represents a cyclopropyl group, a cyclopentyl group, a cyclohexyl group,a spiro[3.3]heptanyl group, an azetidinyl group, an oxetanyl group, a dihydrofuranyl group, atetrahydrofuranyl group, a pyrrolidinyl group, a morpholinyl group, a piperidinyl group, apiperazinyl group, a tetrahydropyranyl group, a dihydropyranyl group, a tetrahydropyridinylgroup, a dioxothiazinyl group, a dioxothianyl group, an oxazaspiro[3.3]heptanyl group, an oxazaspiro[2.5]octanyl group, an oxazaspiro[3.5]nonanyl group, an oxazaspiro[4,5]decanylgroup, a pyrazolyl group, a pyridinyl group, a pyridonyl group, or a 4-oxo- -oxaphosphinanyl group. Advantageously, Cy3 represents a cyclopropyl group, a cyclopentylgroup, a cyclohexyl group, a spiro[3.3]heptanyl group, an azetidinyl group, an oxetanyl group,a dihydrofuranyl group, a tetrahydrofuranyl group, a pyrrolidinyl group, a morpholinyl group,a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a dihydropyranyl group, atetrahydropyridinyl group, a dioxothiazinyl group, a dioxothianyl group, an oxazaspiro[3.3]heptanyl group, an oxazaspiro[2.5]octanyl group, an oxazaspiro[3.5]nonanylgroup, an oxazaspiro[4,5]decanyl group, a pyrazolyl group, a pyridinyl group, or a pyridonylgroup. More advantageously, Cy3 represents a cyclopentyl group, a cyclohexyl group, aspiro[3.3]heptanyl group, an azetidinyl group, an oxetanyl group, a dihydrofuranyl group, atetrahydrofuranyl group, a pyrrolidinyl group, a morpholinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a dihydropyranyl group, a tetrahydropyridinyl group, a dioxothiazinyl group, a dioxothianyl group, an oxazaspiro[3.3]heptanyl group, an oxazaspiro[2.5]octanyl group, an oxazaspiro[3.5]nonanyl group, an oxazaspiro[4,5]decanylgroup, a pyrazolyl group, a pyridinyl group, or a pyridonyl group. Even more advantageously,Cy3represents an oxetanyl group, a dihydrofuranyl group, a tetrahydrofuranyl group, a morpholinyl group, a piperazinyl group, a tetrahydropyridinyl group, a tetrahydropyranylgroup, a dihydropyranyl group, an oxazaspiro[2.5]octanyl group. In one preferred embodiment,Cy3 represents a tetrahydropyranyl group or a dihydropyranyl group. In one preferredembodiment, Cy3 represents a tetrahydropyranyl group. In one preferred embodiment, Cy3represents a dihydropyranyl group.Another advantageous possibility consists of compounds of Formula (I-c): wherein R2, R3, R4 and Cy2 are as defined for Formula (I).Another advantageous possibility consists of compounds of Formula (I-d): wherein R4, R5, R6, W, Cy2and Cy3are as defined for Formula (I).Preferred compounds according to the invention are:- N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-nicotinamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-(oxetan-3-ylmethoxy)nicotinamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-tetrahydropyran-4-yloxy-nicotinamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-3-isopropyl-isoxazolo[5,4-b]pyridine-5-carboxamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-tetrahydropyran-4-yl-nicotinamide; -5-(2,5-dihydrofuran-3-yl)-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]nicotinamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-[4-(oxetane-3-carbonyl)piperazino]nicotinamide; -N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-[4-(oxetane-3-carbonyl)piperazino]nicotinamide;- 5-[4-(cyclobutanecarbonyl)piperazino]-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]nicotinamide; -5-[1-(cyclobutanecarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]nicotinamide; -2-[1-[1-(fluoromethyl)cyclopropanecarbonyl]-3,6-dihydro-2H-pyridin-4-yl]-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]pyrimidine-4-carboxamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-[(3R)-tetrahydrofuran-3-yl]oxy-nicotinamide; -5-(3,6-dihydro-2H-pyran-4-yl)-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]nicotinamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-2-[(3R)-tetrahydrofuran-3-yl]oxy-pyrimidine-4- carboxamide; -5-[4-(cyclopropanecarbonyl)piperazino]-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]nicotinamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-2-tetrahydropyran-4-yl-pyrimidine-4-carboxamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-morpholino-nicotinamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-[2-(oxetan-3-ylmethyl)-2-azaspiro[3.3]heptan-6-ylidene]methyl]phenyl]ethyl]-2-tetrahydropyran-4-yl-pyrimidine-4-carboxamide. Pharmacological studies of the compounds of the invention have shown that they have strongbinding affinity on SOS1 and are blocking the interaction between SOS1 and RAS-familymembers preventing the recycling of KRas into the active GTP-bound form. Therefore, thecompounds of the invention could be of interest for a wide range of cancers, particularly Ras family member-associated cancers. In addition, the compounds of the present invention offerpotential therapeutic benefit as inhibitors of SOS1-Ras proteins interaction in a cell for treatingvarious forms of cancer, including Ras-associated cancer, SOS1-associated cancer and NF- 1 / NF-2 associated cancer. Finally, the compounds of the present invention may provide also therapeutic benefit in genetic and immune diseases. The present invention relates also to pharmaceutical compositions comprising at least one compound of Formula (I) or an addition salt thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients. In particular, these pharmaceutical compositions are interesting for use as SOS1 inhibitors, particularly, in the treatment of cancer (haematological malignancy and solid tumor), autoimmune diseases,diseases of immune system and genetic diseases. Preferably, said pharmaceutical compositionsare interesting for use as SOS1 inhibitors in the treatment or the prevention of Ras-associatedcancer, SOS1-associated cancer and NF-1 / NF-2 associated cancer. Particularly, these pharmaceutical compositions can be used in the treatment of cancer selected from pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renalcancer, sarcomas, glioma and malignant peripheral nerve sheath tumors. In one anotherembodiment, these pharmaceutical compositions can be used in the treatment of geneticdiseases, particularly in the treatment of neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lengitines, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardiofaciocutaneous syndrome, Legius syndrome and hereditary gingival fibromatosis.Furthermore, the present invention relates also to the combination of a compound of Formula (I)with small molecules including but not limited to anticancer agents selected from genotoxicagents, mitotic poisons, anti-metabolites, proteasome inhibitors, enzymes inhibitors, signaling proteins inhibitors, transcription factor inhibitors, epigenetic factor inhibitors, kinase inhibitors, protein-protein interaction inhibitors, immunomodulators, E3 ligase inhibitors, as well as chimeric antigen receptor T-cell therapy and antibodies. In one embodiment, the present invention relates also to pharmaceutical compositions comprising that type of combination and their use in the manufacture of medicaments for use in the treatment of cancer, especially pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladdercancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cellcarcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renalcancer, sarcomas, glioma and malignant peripheral nerve sheath tumors.EXAMPLES The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the inventioncan be synthesized using the methods described below, together with synthetic methods knownin the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. It is understood that at any moment considered appropriate during the processes synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis. Preferred methods include but are not limited to those methods described below. Compounds of the present invention can be synthesized by following the stepsoutlined in General Schemes 1 and 2 which comprise different sequences of preparingintermediates III, IV, VII and VIII. Starting materials I, II, V and VII are either commerciallyavailable or made by known procedures in the reported literature or as illustrated. General Scheme 1 wherein R1, Cy1and A are as defined in Formula (I) and PG1 represents a protecting group.The general way of preparing intermediate IV containing double bond moiety by usingintermediate II is outlined in General Scheme 1. Starting material I was transformed to providethe corresponding dialkylphosphonate derivative which underwent a Horner-Wadsworth-Emmons reaction with intermediate II using a strong base at low temperatures providingintermediate III. Bromination then -elimination using a strong base were finally performed toyield intermediate IV. General Scheme 2 wherein R1, R2, R3, Cy1, Cy2and A are as defined in Formula (I), PG1 and PG2 are protected ahydrogen atom, a linear or branched (C1-C6) alkyl group, or theform with the oxygen carrying them an optionally methylated ring. The general way of preparing compounds of Formula (I) is outlined in General Scheme 2. Thepreparation of intermediate VI was obtained through a Suzuki coupling using brominatedintermediate IV and boronate derivative V. After deprotection of the group PG2, amidationreaction was performed using carboxylic acid VII to yield intermediate VIII. Then, afterdeprotection of the protective group PG1, R4group was introduced according to classicalchemical reactions using the corresponding reactants to yiled compounds of Formula (I). A mixture of enantiomers, diastereoisomers resulting from the processes described above can be separated into their single components by chiral salt technique, chromatography using normal phase, reverse phase or chiral column, depending on the nature of the separation. GENERAL SYNTHETIC REMARKS All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from commercial sources and used without further drying. The reactions were monitored using LCMS instruments and / or TLC. Thin layer chromatography was conducted with 5 cm × 10 cm plates coated with Merck Type 60 F254 silica-gel.1H-NMR measurements were performed on Bruker Avance III HD 400 MHz spectrometer, using DMSO-d6 or CDCl3 as solvent (purchased from Eurisotop).1H NMR data is in the form of delta values, given in part per million (ppm), using the residual peak of the solvent (2.50 ppm for DMSO-d6and 7.26 ppm for CDCl3) as internal standard. Splitting patterns are designated as: s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), spt (septuplet), m (multiplet), br s (broad singlet), br d (broad doublet), br t (broad triplet), br m (broad multiplet), dd (doublet of doublets), br dd (broad doublet of doublets), td (triplet of doublets), dt (doublet of triplets), qd (quartet of doublets), tt (triplet of triplets), ddd (doublet of doublet of doublets), dtd (doublet of triplet of doublets). HRMS measurements were performed on a LTQ OrbiTrap Velos Pro mass spectrometer. The system was powered by Orbitrap Technology from ThermoFisher Scientific GmbH, (Bremen, Germany) coupled to an ultra-high pressure liquid chromatography (UHPLC) system (VANQUISH, ThermoFisher Scientific, Bremen, Germany) using a BEH C18 column (2.1 mm× 100 mm- 1.7 µm). Full-scan acquisition was performed over the range m / z 115 1500 at aresolving power of 30,000 (FWHM). A HESI (heated electrospray) ion source was operated in the positive mode. The parameters were as follows: electrospray voltage, 3.5 kV; heater temperature, 300 °C; capillary temperature, 300 °C; S-lens RF level, 55%. Nitrogen (N2) was used as the sheath and auxiliary gas, and helium (He) was used as the collision gas. ESI were determined on a Waters SQD UPLC. Chemical names were generated using Biovia Draw Version 18.1 by Dassault Systemes. GENERAL PROCEDURESGeneral Procedure 1: Boc To a stirred solution of the corresponding tert-butyl-N-carbamate (1.0 eq.) in dichloromethane or dioxane / water or acetonitrile or 1-methylpyrrolidin-2-one or in neat conditions was added aqueous hydrogen chloride (10 eq.) or trifluoroacetic acid (10 eq.) at room temperature. After complete conversion of the starting material, the mixture was concentrated under reduced pressure and the residues were purified by reverse phase chromatography or eluted through a PoraPak Rxn CX (polymer-based chromatography product using a strong cation-exchange sorbent) to give the expected amine.General Procedure 2: General Procedure 2A:A stock solution of the carboxylic acid (0.18 M in N-methyl-2-pyrrolidone) was loaded into a T-mixer and mixed with a stock solution of N-ethyl-N-isopropyl-propan-2-amine (1.2 M in dichloromethane). The resulting mixture was pumped continuously and mixed into a T-mixer with a stock solution of bis(trichloromethyl) carbonate (0.11 M in dichloromethane). Theresulting mixture was pumped into a 250 µL PFA (perfluoroalkoxy alkane) reactor coil at 20°C with a retention time of 0.03 min. A vial equipped with an automated injector and loaded with a solution of the amine (0.40 M in dichloromethane) was prepared. This solution was pumped and met the main stream in a T-mixer and injected into a 2nd PFA coil reactor (2.00 mL, retention time: 0.03 min) at 20 °C.The crude mixture was collected in the automated collector in a vial. The mixture was concentrated under reduced pressure to give the crude expected amide, which was engaged into the next step without further purification and considering a quantitative yield.General Procedure 2B:To a stirred solution of carboxylic acid (1.0 eq.) in N,N-dimethylformamide (0.1 M) ordichloromethane (0.1 M) were added N,N- -tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (1.3 eq.) and the amine (1 eq.) then the mixture was stirred to room temperature until completion of the reaction. The mixture was dissolved with water and dichloromethane and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residues were purified by silica gel column chromatography or reverse phase column chromatography to afford the expected amide.General Procedure 2C:To a stirred solution of carboxylic acid (1.0 eq.) in N,N-dimethylformamide (0.05 M) or dichloromethane (0.05 M) or N-methyl-2-pyrrolidone (0.1 M) were added N,N- diisopropylethylamine (3.0 eq.) and 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (2.0 eq.) and the amine (1 eq.) then the mixture was stirred to room temperature until completion of the reaction. The mixture was dissolved with water and dichloromethane and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residues were purified by silica gel column chromatography or reverse phase column chromatography to afford the expected amide.General Procedure 3: Phthalimide cleavageTo a stirred solution of the phthalimide-N-protected amine (1.0 eq.) in ethanol (0.1 M) was added hydrazine (5.0 eq.) at room temperature and the mixture was stirred until full conversion of the starting material. The mixture was concentrated under reduced pressure and the residues were purified by silica gel column chromatography or reverse phase chromatography to afford the corresponding amine.General Procedure 4: Suzuki couplingGeneral Procedure 4A:Vinyl bromide (1.0 eq.) was dissolved into a 4:1 toluene / ethanol mixture (0.15 M) which was degassed for 10 min with argon. Then, the boronic ester (1.2 eq.), sodium carbonate (3.0 eq.) and palladium triphenylphosphine (2 mol%) were added. The system was purged with argon and heated to 60 °C. The mixture was concentrated under reduced pressure and the residues were purified by silica gel column chromatography to afford the expected product.General Procedure 4B:Halogenated aryl (1.0 eq.) was dissolved into a 1:4 water / 1,4-dioxane mixture (0.15 M) which was degassed for 10 min with argon. Then, boronic acid (1.2 eq.), potassium fluoride (3.0 eq.) -Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1) (6 mol%) were added. The system was purged with argon and heated to 110 °C. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to afford the expected product.General Procedure 5: Miyaura borylation reactionHalogenated aryl (1.0 eq.) was dissolved into 1,4-dioxane (0.2 M) which was degassed for 10 -octamethyl- -bi-1,3,2-dioxaborolane (1.1 eq.),potassium acetate (2.0 eq.) and -Bis(diphenylphosphino)ferrocene]dichloropalladium(II)(1:1) (2 mol%) were added. The system was purged with argon and heated to 90 °C. The mixture was cooled to room temperature and triturated into heptane / ethyl acetate to give the corresponding boronate ester.General Procedure 6: Bromine eliminationTo a stirred mixture of the dibromoalkane in methanol or tetrahydrofuran (0.05 M) was added 2 N sodium hydroxide (15 eq.) and the mixture was heated to 45 °C until completion of the reaction. The mixture was concentrated under reduced pressure. The residues were dissolved in ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the expected vinylbromide which was engaged into the next step without further purification, considering a quantitative yield.General Procedure 7: SalificationThe crude amine (1.0 eq.) was dissolved into an acetonitrile / water mixture and aqueous 2 Nhydrogen chloride or 4 N dioxane hydrogen chloride (1.0 - 3.5 eq.) was added dropwise. Themixture was then freeze-dried to afford the corresponding hydrochloride salt.General Procedure 8: Reductive amination The amine (1.0 eq.) was dissolved in tetrahydrofuran (0.05 M) or in a 5:1dichloromethane / methanol mixture (0.05 M) before adding aqueous 37 wt.% formaldehyde (40eq.). The mixture was stirred at room temperature for 1 h and sodium triacetoxyborohydride (3.0 eq.) was added at 0 °C. The mixture was then allowed to reach room temperature. After completion of the reaction, the mixture was quenched with sat. NaHCO3 and dissolved with dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residues were purified by silica gel column chromatography or reverse phase chromatography to afford the expected methylated amine.General Procedure 9: General Procedure 9A:The ester (1.0 eq.) was dissolved in methanol (0.1 M) and 2 N sodium hydroxide (5.0 eq.) was added at room temperature. After completion of the reaction, water was added and the crude mixture was freeze-dried to afford the crude corresponding sodium carboxylate used into the next step without further purification.General Procedure 9B:The ester (1.0 eq.) was dissolved into a 2:1 tetrahydrofuran / water mixture and lithium hydroxide (3.0 eq.) was added at room temperature. After completion of the reaction, water was added and the crude mixture was freeze-dried to afford the crude corresponding lithium carboxylate used into the next step without further purification.General Procedure 10: Mitsunobu reactionTo a stirred solution of phenol (1.0 eq.) in dry tetrahydrofuran (0.2 M) was added alcohol (1.0 eq.), triphenylphosphine (1.5 eq.) and diisopropyl azodicarboxylate (1.5 eq.) at room temperature. After completion of the reaction, water was added to the mixture and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residues were purified by silica gel column chromatography to afford the expected product.General Procedure 11: Nucleophilic alkylation To a stirred solution of amine (1.0 eq.) in anhydrous acetonitrile (0.05 M) were added potassium carbonate (0.9 eq.) or N,N-diisopropylamine (2.0 eq.) and the electrophile (1.1 eq.) and the mixture was heated to 80 °C until completion of the reaction. Water was added to the mixture and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residues were purified by reverse phase column chromatography and freeze-dried to afford the expected alkylated amine.General Procedure 12: Buchwald couplingA stirred mixture of arylbromide (1.0 eq.) and amine (1.0 eq. - 2.0 eq.) in anhydrous toluene or1,4-dioxane (0.2 M) was degassed under argon for 10 min. Then, palladium acetate (II) (10 mol%), cesium carbonate (3.0 eq.) and XantPhos (4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene; 15 mol%) were added and the mixture was heated to 80 °C until completion of the reaction. The solvent was removed under reduced pressure and the residues were purified by silica gel column chromatography to afford the expected product.General Procedure 13: Diastereomeric / enantiomeric separationThe two diastereomers / enantiomers were separated by SFC / reverse phase to give the expected product.General Procedure 14: HydrogenationThe alkene (1.0 eq.) was dissolved in methanol (0.1 M) and the system was purged with argon. 10 wt.% Pd / C was added (20 wt.% / alkene) and the mixture was stirred at room temperature under hydrogen (1 atm.) until completion of the reaction. The mixture was filtered through a short pad of celite and reduced under reduced pressure. The residues were purified by silica gel column chromatography to give the corresponding reduced product.General Procedure 15: Nucleophilic substitutionGeneral Procedure 15A:To a stirred mixture of alcohol (3.0 eq.) in tetrahydrofuran (0.1 M) was added sodium hydride (60 wt.%, 3.3 eq.) at room temperature under argon and the mixture was stirred at room temperature for 20 min. Then, Ar-X (1.0 eq.) was added and the mixture was heated to refluxuntil completion of the reaction. The mixture was cooled to room temperature and acidifiedwith aqueous 1 M hydrogen chloride. Ethyl acetate was added and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the expected product. The product was engaged directly into the next step without further purification considering a quantitative yield.General Procedure 15B:Halogenated aryl (1.0 eq.) was dissolved into the amine (100 eq.) and the mixture was heated to 125 °C until completion of the reaction. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give the expected product. INTERMEDIATES Intermediate 1: 2-[(1R)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]ethyl]isoindoline-1,3-quinone quinone a - g, eq.) in acetic acid (2.42 L, 18 mL / g) was added isobenzofuran-1,3-dione (99.6 g, 672 mmol, 1.0 eq.) and the mixture was heated to reflux until completion of the reaction. The mixture was partiallyconcentrated under reduced pressure and water was added. The precipitated solid was filtered,washed with water and dried under vacuum to give 2-[(1R)-1-(4- bromophenyl)ethyl]isoindoline-1,3-quinone (204 g, 618 mmol). of Intermediate 1Intermediate 1 was prepared according to General Procedure 5 using 2-[(1R)-1-(4-bromophenyl)ethyl]isoindoline-1,3-quinone (151 g, 0.457 mol) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (128 g, 0.503 mol) to give the crude Intermediate 1 (101 g, 0.267 mol) which was used into the next step without further purification. Intermediate 2: 4-[[4-[ -1-aminoethyl]phenyl]-(4-fluorophenyl)methylene]piperidine- 1-carboxylic acid tert- ester Step A: Preparation of 1-(diethoxyphosphorylmethyl)-4-fluoro-benzene1-(diethoxyphosphorylmethyl)-4-fluoro-benzene 1-(bromomethyl)-4-fluoro-benzene (500 g, 2.65 mol, 1.0 eq.) was added to triethyl phosphite (571 g, 3.44 mol, 1.3 eq.) and the mixturewas heated to 130 °C until completion of the reaction. The mixture was then distilled underreduced pressure to give 1-(diethoxyphosphorylmethyl)-4-fluoro-benzene (603 g, 2.45 mol).Step B: Preparation of 4-(4-fluorobenzylidene)piperidine-1-carboxylic acid tert-butyl esterTo a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (150 g, 0.758 mol, 1.0 eq.) and 1-(diethoxyphosphorylmethyl)-4-fluoro-benzene (241 g, 0.979 mol, 1.3 eq.) in tetrahydrofuran (3.00 L, 20.0 mL / g), was slowly added 2-methylpropan-2-olate, potassium (110 g, 0.979 mol, 1.3 eq.) at 0 °C and the mixture was stirred at room temperature until completion of the reaction. Ethyl acetate was added and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude 4-(4-fluorobenzylidene)piperidine-1- carboxylic acid tert-butyl ester (358.5 g, 1.230 mol), which was used into the next step without further purification.Step C: Preparation of 4-bromo-4-[bromo-(4-fluorophenyl)methyl]piperidine-1-carboxylicacid tert-butyl ester To a stirred solution of tert-butyl 4-[(4-fluorophenyl)methylene]piperidine-1-carboxylate (208 g, 0.714 mol, 1.0 eq.) and potassium carbonate (44.4 g, 0.312 mol, 0.45 eq.) in dichloromethane (3.57 L, 5 M) at 0 °C was added dropwise a solution of bromine ( 125.5 g, 40.2 mL, 0.785 mol, 1.1 eq.) in dichloromethane (416 mL, 2 mL / g). The reaction mixture was stirred at room temperature until completion of the reaction. The reaction mixture was cooled to room temperature, quenched with a saturated aqueous thiosulfate solution and the mixturewas extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residues were crystallized in heptane to afford 4-bromo-4-[bromo-(4-fluorophenyl)methyl]piperidine-1- carboxylic acid tert-butyl ester (156.7 g, 0.347 mol). Step D: Preparation of 4-[bromo-(4-fluorophenyl)methylene]piperidine-1-carboxylic acidtert-butyl ester 4-[bromo-(4-fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to a modified General Procedure 6 using 4-bromo-4-[bromo-(4-fluorophenyl)methyl]piperidine-1-carboxylic acid tert-butyl ester (156 g, 0.346 mol) and 2 N sodium hydroxide (10 eq.) in tetrahydrofuran. The crude residues were triturated in hexane and filtered to give tert-butyl 4-[bromo-(4-fluorophenyl)methylene]piperidine-1-carboxylate (102 g, 0.274 mol), which was used into the next step without further purification. acid tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-phthalimidoethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to a modified General Procedure 4A using 4-[bromo-(4-fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester (84.4 g, 0.228 mol, 1.1 eq.), sodium carbonate (207 mL, 2 M, 2.0 eq.) and Intermediate 1 (78.2 g, 0.207 mol, 1.0 eq.) in dioxane (1.56 L, 0.13 M). The crude residues were purified by silica gel columnchromatography (n-heptane / ethyl acetate) to give 4-[(4-fluorophenyl)-[4-[(1R)-1- phthalimidoethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (60.0 g, 0.111 mol).Step F: Preparation of Intermediate 2Intermediate 2 was prepared according to General Procedure 3 using 4-[(4-fluorophenyl)-[4-[(1R)-1-phthalimidoethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (60.7 g, 0.109 mol) and hydrazine (26.4 mL, 0.543 mol). The crude residues were purified by silica gel column chromatography (dichloromethane / methanol / ammoniac) to giveIntermediate 2 (36.6 g, 0.0892 mol).Intermediate 3: 6-[[4-[(1R)-1-aminoethyl]phenyl]-(4-fluorophenyl)methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester Step A: Preparation of 6-(4-fluorobenzylidene)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester To a stirred solution of (4-fluorophenyl)methyl-triphenyl-phosphonium, chloride (4.20 g, 10.3 mmol, 1.1 eq.) in anhydrous tetrahydrofuran (15.0 mL), was added dropwise at 0 °C butyllithium (1.6 M solution in tetrahydrofuran, 6.60 mL, 11.0 mmol, 1.1 eq.) and the mixture was stirred at room temperature until completion of the reaction. A solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (2.00 g, 9.47 mmol, 1.0 eq.) in anhydroustetrahydrofuran (15.0 mL) was added dropwise and the mixture was allowed to stir at 65 °C. After completion of the reaction, the reaction mixture was cooled to room temperature,quenched with aqueous ammonium chloride and extracted with ethyl acetate. The combinedorganic layers were dried over anhydrous sodium sulfate, filtered , concentrated under reduced pressure and purified by silica gel column chromatography to give 6-(4- fluorobenzylidene)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.10 g, 3.63 mmol).Step B: Preparation of 6-bromo-6-[bromo-(4-fluorophenyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester To a stirred solution of 6-(4-fluorobenzylidene)-2-azaspiro[3.3]heptane-2-carboxylic acid tert- butyl ester (1.70 g, 5.50 mmol, 1.0 eq.) and potassium carbonate (0.840 g, 6.10 mmol, 1.1 eq.) in dichloromethane (10 mL) at 0 °C was added dropwise a solution of bromine (1.90 g, 0.620 mL, 12.0 mmol, 2.2 eq.) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature until completion of the reaction. The reaction mixture was cooled to room temperature and water was added. The layers were separated and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residues were purified by silica gel column chromatography (dichloromethane / ethanol / ammoniac) to afford 6-bromo-6-[bromo-(4-fluorophenyl)methyl]- 2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.20 g, 2.591 mmol).Step C: Preparation of 6-[bromo-(4-fluorophenyl)methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 6-[bromo-(4-fluorophenyl)methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butylester was prepared according to General Procedure 6 using 6-bromo-6-[bromo-(4-fluorophenyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.16 g, 2.504 m mol) in methanol to give 6-[bromo-(4-fluorophenyl)methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (0.89 g, 2.30 mmol) used into the next step without further purification. 2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 6-[(4-fluorophenyl)-[4-[(1R)-1-phthalimidoethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was prepared according to General Procedure 4A using 6-[bromo-(4-fluorophenyl)methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (2.60 g, 6.80 mmol) and Intermediate 1 (3.10 g, 8.20 mmol). The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 6-[(4-fluorophenyl)-[4- [(1R)-1-phthalimidoethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert- butyl ester (3.00 g, 5.43 mmol). [M+H]+=549.2.Step E: Preparation of Intermediate 3Intermediate 3 was prepared according to a modified General Procedure 3 using 6-[(4-fluorophenyl)-[4-[(1R)-1-phthalimidoethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (3.00 g, 5.429 mmol) and hydrazine (0.897 mL, 10.9 mmol, 2.0 eq.). The crude residues were purified by silica gel column chromatography (dichloromethane / methanol / ammoniac) to give Intermediate 3 (1.44 g, 3.41 mmol). [M+H]+=350.2. 2-azaspiro[3.3]heptan-6- 6-[bromo-(4-fluorophenyl)methylene]-2-azaspiro[3.3]heptane was prepared according to amodified General Procedure 1 using 6-[bromo-(4-fluorophenyl)methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.00 g, 2.616 mmol) in dichloromethane (0.3 M) and trifluoroacetic acid (1.31 mL, 2.0 eq.). The crude residues were eluted through a PoraPak Rxn CX to give 6-[bromo-(4-fluorophenyl)methylene]-2-azaspiro[3.3]heptane (730 mg, 2.587 mmol). [M+H]+=283.1.-2-methyl-2- 6-[bromo-(4-fluorophenyl)methylene]-2-methyl-2-azaspiro[3.3]heptane was preparedaccording to General Procedure 8 using 6-[bromo-(4-fluorophenyl)methylene]-2-azaspiro[3.3]heptane (700 mg, 2.48 mmol) in a 5:1 dichloromethane / methanol mixture. The crude residues were purified by silica gel column chromatography (dichloromethane / methanol / ammoniac) to give 6-[bromo-(4-fluorophenyl)methylene]-2-methyl-2-azaspiro[3.3]heptane (730 mg, 2.47 mmol). [M+H]+=297.0.Step C: Preparation of 2-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]isoindoline-1,3-quinone 2-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]isoindoline-1,3-quinone was prepared according to General Procedure 4A using 6-[bromo-(4-fluorophenyl)methylene]-2-methyl-2-azaspiro[3.3]heptane (730 mg, 2.46 mmol) and Intermediate 1 (1.12 g, 2.96 mmol). The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 2-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2- azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]isoindoline-1,3-quinone (750 mg, 1.61 mmol). [M+H]+=467.3. Step D: Preparation of Intermediate 4Intermediate 4 was prepared according to General Procedure 3 using 2-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]isoindoline- 1,3-quinone (750 mg, 1.608 mmol) and hydrazine (0.664 mL, 8.04 mmol). The crude residues were purified by silica gel column chromatography (dichloromethane / methanol / ammoniac) togive Intermediate 4 (360 mg, 1.070 mmol). 1H NMR (400 MHz, dmso-2H), 7.13 (m, 4H), 7.02 (m, 2H), 3.96 (q, 1H), 3.13 (s, 4H), 2.94 (br d, 4H), 2.15 (s, 3H), 2.03 (m, 2H), 1.24 (d, 3H) | [M+H]+=337.2. Intermediate 5: N-[ -1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]- 5-methoxy- Step A: Preparation of 4-[(4-fluorophenyl)-[4-[(1R)-1-[(5-methoxynicotinoyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-[(5-methoxynicotinoyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure 2Busing Intermediate 2 (300 mg, 0.731 mmol) and 5-methoxypyridine-3-carboxylic acid (112 mg, 0.731 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 4-[(4-fluorophenyl)-[4-[(1R)-1-[(5- methoxynicotinoyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (398 mg, 0.730 mmol).Step B: Preparation of Intermediate 5Intermediate 5 was prepared according to General Procedure 1 using 4-[(4-fluorophenyl)-[4-[(1R)-1-[(5-methoxynicotinoyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (398 mg, 0.730 mmol) and hydrogen chloride (7.30 mmol) to give Intermediate 5 (275 mg, 0.617 mmol). [M+H]+=446.4. Intermediate 6: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]- 5-isopropoxy-nicotinamide Step A: Preparation of 4-[(4-fluorophenyl)- -1-[(5-isopropoxynicotinoyl)amino]ethyl] phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-[(5-isopropoxynicotinoyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure 2Busing Intermediate 2 (300 mg, 0.731 mmol) and 5-isopropoxypyridine-3-carboxylic acid (133 mg, 0.731 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 4-[(4-fluorophenyl)-[4-[(1R)-1-[(5- isopropoxynicotinoyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (350 mg, 0.610 mmol). Step B: Preparation of Intermediate 6Intermediate 6 was prepared according to General Procedure 1 using 4-[(4-fluorophenyl)-[4-[(1R)-1-[(5-isopropoxynicotinoyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (350 mg, 0.610 mmol) and hydrogen chloride (6.10 mmol) to give Intermediate 6 (280 mg, 0.591 mmol). [M+H]+=474.6. Intermediate 7: 5-ethoxy-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]nicotinamide 1-carboxylic acid tert-butyl ester 4-[[4-[(1R)-1-[(5-ethoxynicotinoyl)amino]ethyl]phenyl]-(4- fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure 2B using Intermediate 2 (122 mg, 0.731 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 4-[[4-[(1R)-1-[(5-ethoxynicotinoyl)amino]ethyl]phenyl]-(4- fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester (409 mg, 0.731 mmol). Step B: Preparation of Intermediate 7Intermediate 7 was prepared according to General Procedure 1 using 4-[[4-[(1R)-1-[(5-ethoxynicotinoyl)amino]ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester (409 mg, 0.731 mmol) and hydrogen chloride (7.31 mmol) to give Intermediate 7 (280 mg, 0.834 mmol). [M+H]+=460.4. Intermediate 8: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]- 5-tetrahydropyran-4-yloxy-nicotinamide Step A: Preparation of 5-tetrahydropyran-4-yloxynicotinic acid methyl ester5-tetrahydropyran-4-yloxynicotinic acid methyl ester was prepared according to GeneralProcedure 10 using methyl 5-hydroxypyridine-3-carboxylate (500 mg, 3.26 mmol) andtetrahydropyran-4-ol (0.311 mL, 3.26 mmol). The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 5-tetrahydropyran-4-yloxynicotinicacid methyl ester (460 mg, 1.938 mmol). [M+H]+=238.1.Step B: Preparation of sodium;5-tetrahydropyran-4-yloxynicotinatesodium;5-tetrahydropyran-4-yloxynicotinate was prepared according to General Procedure 9A using 5-tetrahydropyran-4-yloxynicotinic acid methyl ester (460 mg, 1.93 mmol) to give sodium;5-tetrahydropyran-4-yloxynicotinate (475 mg, 1.93 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification. [M+H]+=224.2.Step C: Preparation of 4-[(4-fluorophenyl)-[4-[(1R)-1-[(5-tetrahydropyran-4-yloxynicotinoyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-[(5-tetrahydropyran-4-yloxynicotinoyl)amino]ethyl]phenyl] methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to GeneralProcedure 2B using Intermediate 2 (300 mg, 0.730 mmol) and sodium;5-tetrahydropyran-4-yloxynicotinate (179 mg, 0.730 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 4-[(4- fluorophenyl)-[4-[(1R)-1-[(5-tetrahydropyran-4-yloxynicotinoyl)amino]ethyl]phenyl] methylene]piperidine-1-carboxylic acid tert-butyl ester (333 mg, 0.540 mmol). [M+H]+=616.4.Step D: Preparation of Intermediate 8Intermediate 8 was prepared according to General Procedure 1 using 4-[(4-fluorophenyl)-[4-[(1R)-1-[(5-tetrahydropyran-4-yloxynicotinoyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (333 mg, 0.541 mmol), 4 N aqueous hydrochloric acid (1.35mL, 5.41 mmol) in dichloromethane (10.0 mL). The residues were eluted through a PoraPak Rxn CX and purified by reverse phase chromatography (acetonitrile / water / sodium bicarbonate) to give Intermediate 8 (155 mg, 0.301 mmol). [M+H]+=516.2. Intermediate 9: 5-piperazinonicotinic acid methyl ester Step A: Preparation of 4-(5-carbomethoxy-3-pyridyl)piperazine-1-carboxylic acid tert-butylester 4-(5-carbomethoxy-3-pyridyl)piperazine-1-carboxylic acid tert-butyl ester was preparedaccording to General Procedure 12 using methyl 5-bromopyridine-3-carboxylate (2.00 g, 9.26mmol) and tert-butyl piperazine-1-carboxylate (2.07 g mL, 11.1 mmol, 1.2 eq.) in 1,4- dioxane. The crude residues were purified by silica gel column chromatography (n- heptane / ethyl acetate) to give tert-butyl 4-(5-methoxycarbonyl-3-pyridyl)piperazine-1- carboxylate (2.58 g, 7.22 mmol).Step B: Preparation of Intermediate 9Intermediate 9 was prepared according to General Procedure 1 using 4-(5-carbomethoxy-3-pyridyl)piperazine-1-carboxylic acid tert-butyl ester (600 mg, 1.87 mmol) and trifluoroacetic acid (1.43 mL, 18.7 mmol) in neat conditions. The crude residues were eluted through a PoraPak Rxn CX to give Intermediate 9 (378 mg, 1.708 mmol) which was used into the next step without further purification. Intermediate 11: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-(1,2,3,6-tetrahydropyridin-4-yl)nicotinamide Step A: Preparation of lithium;5-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)nicotinate Lithium;5-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)nicotinate was preparedaccording to General Procedure 9B using 5-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)nicotinic acid methyl ester (1.00 g, 3.14 mmol) to give the crude lithium;5-(1-tert- butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)nicotinate (974 mg, 3.14 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification.Step B: Preparation of 4-[5-[[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]carbamoyl]-3-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 4-[5-[[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl] ethyl]carbamoyl]-3-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester wasprepared according to General Procedure 2B using lithium;5-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)nicotinate (922 mg, 2.97 mmol) and Intermediate 4 (1.00 g, 2.97 mmol) in N,N-dimethylformamide (30.0 mL, 0.1 M). The crude residues were purified by silica gel column chromatography (dichloromethane / methanol / ammoniac) to give 4-[5- [[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl] ethyl]carbamoyl]-3-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.09 g, 1.75 mmol).Step C: Preparation of Intermediate 11Intermediate 11 was prepared according to General Procedure 1 using 4-[5-[[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]carbamoyl]-3- pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.09 g, 1.75 mmol) and trifluoroacetic acid (1.34 mL, 17.5 mmol) in neat conditions. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude residues were dissolved intomethanol and eluted through a PoraPak Rxn CX to give Intermediate 11 (915 mg, 1.75mmol). Intermediate 12: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-(4-piperidyl)nicotinamide Step A: Preparation of lithium;5-(1-tert-butoxycarbonyl-4-piperidyl)nicotinateLithium;5-(1-tert-butoxycarbonyl-4-piperidyl)nicotinate was prepared according to GeneralProcedure 9B using 5-(1-tert-butoxycarbonyl-4-piperidyl)nicotinic acid methyl ester (1.10 g,3.40 mmol) to give the crude lithium;5-(1-tert-butoxycarbonyl-4-piperidyl)nicotinate (1.09 g, 3.40 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification.Step B: Preparation of 4-[5-[[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]carbamoyl]-3-pyridyl]piperidine-1-carboxylic acid tert-butyl ester 4-[5-[[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl] ethyl]carbamoyl]-3-pyridyl]piperidine-1-carboxylic acid tert-butyl ester was preparedaccording to General Procedure 2B using lithium;5-(1-tert-butoxycarbonyl-4- piperidyl)nicotinate (928 mg, 2.97 mmol) and Intermediate 4 (1.00 g, 2.97 mmol) in N,N- dimethylformamide (30.0 mL, 0.1 M). The crude residues were purified by silica gel column chromatography (dichloromethane / methanol / ammoniac) to give 4-[5-[[(1R)-1-[4-[(4- fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]carbamoyl]-3- pyridyl]piperidine-1-carboxylic acid tert-butyl ester (1.36 g, 2.18 mmol).Step C: Preparation of Intermediate 12Intermediate 12 was prepared according to General Procedure 1 using 4-[5-[[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]carbamoyl]-3- pyridyl]piperidine-1-carboxylic acid tert-butyl ester (1.36 g, 2.18 mmol) and trifluoroacetic acid (1.67 mL, 21.8 mmol) in neat conditions. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude residues were dissolved into methanol and eluted through a PoraPak Rxn CX to give Intermediate 12 (1.14 g, 2.17 mmol). heptan-6- 4-carboxylateLithium;2-(4-tert-butoxycarbonylpiperazino)pyrimidine-4-carboxylate was preparedaccording to General Procedure 9B using 2-(4-tert-butoxycarbonylpiperazino)pyrimidine-4-carboxylic acid methyl ester (951 mg, 2.95 mmol) to give the crude lithium;2-(4-tert- butoxycarbonylpiperazino)pyrimidine-4-carboxylate (927 mg, 2.95 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification. 6- 2-yl]piperazine-1-carboxylic acid tert- butyl ester 4-[4-[[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]carbamoyl]pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure 2B using lithium;2-(4-tert-butoxycarbonylpiperazino)pyrimidine-4-carboxylate (934 mg, 2.97 mmol) and Intermediate 4 (1.00 g, 2.97 mmol) in N,N-dimethylformamide (30.0 mL, 0.1 M). The crude residues were purified by silica gel column chromatography (dichloromethane / methanol / ammoniac) to give 4-[4-[[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]carbamoyl]pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (1.22 g, 1.95 mmol).Step C: Preparation of Intermediate 13Intermediate 13 was prepared according to General Procedure 1 using 4-[4-[[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]carbamoyl] pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (1.22 g, 1.95 mmol) and trifluoroacetic acid (1.49 mL, 19.5 mmol) in neat conditions. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude residues were dissolved into methanol and eluted through a PoraPak Rxn CX to give Intermediate 13 (1.00 g, 1.90 mmol). Intermediate 14: 6-[[4-[(1R)-1- -(5-fluoro-2- -2- acid tert-butyl ester Step A: Preparation of tributyl-[(5-fluoro-2-pyridyl)methyl]phosphonium;bromideTo a stirred solution 2-(bromomethyl)-5-fluoropyridine (2.10 g, 11.1 mmol, 1.0 eq.) in acetonitrile (25.0 mL), was added tri-n-butylphosphine (2.73 mL, 11.1 mmol, 1.0 eq.) and the reaction mixture was stirred at 80 °C until completion of the reaction. The reaction mixture was concentrated under reduced pressure to give the crude tributyl-[(5-fluoro-2- pyridyl)methyl]phosphonium;bromide (4.12 g, 5.29 mmol) which was used into the next step without further purification.Step B: Preparation of 6-[(5-fluoro-2-pyridyl)methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester To a stirred solution of tributyl-[(5-fluoro-2-pyridyl)methyl]phosphonium;bromide (4.12 g, 10.5 mmol, 1.0 eq.) and tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (2.22 g, 10.5 mmol, 1.0 eq.) in acetonitrile (50.0 mL), was slowly added at 0 °C potassium tert-butoxide (1 M solution in tetrahydrofuran, 21.0 mL, 21.0 mmol, 2.0 eq.) and the mixture was stirred at room temperature until completion of the reaction. The reaction mixture was quenched withaqueous ammonium chloride solution and extracted with ethyl acetate. The combined organiclayers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude 6-[(5-fluoro-2-pyridyl)methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (3.20 g, 10.5 mmol), which was used into the next step without further purification. of 6-bromo-6- (5-fluoro-2- -2- 2-carboxylic acid tert-butyl ester To a stirred solution of 6-[(5-fluoro-2-pyridyl)methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (3.13 g, 10.3 mmol, 1.0 eq.) in dichloromethane (35 mL) at 0 °C was added potassium carbonate (0.710 g, 5.14 mmol, 0.5 eq.) and bromine (0.580 mL, 11.3 mmol, 1.1 eq.) and the reaction mixture was stirred at room temperature until completion of the reaction. The reaction mixture was partitioned between water and dichloromethane and the layers were separated. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude 6-bromo-6-[bromo- (5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (4.51 g, 6.32 mmol), which was used into the next step without further purification. -2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 6-[Bromo-(5-fluoro-2-pyridyl)methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butylester was prepared according to a modified General Procedure 6 using 6-bromo-6-[bromo-(5- fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (4.50 g, 0.457 mol) in tetrahydrofuran at room temperature. The crude residues were purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 6-[bromo-(5-fluoro-2- pyridyl)methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.54 g, 3.42 mmol). 2-carboxylic acid tert-butyl ester A stirred solution of tert-butyl 6-(bromo(5-fluoropyridin-2-yl)methylene)-2- azaspiro[3.3]heptane-2-carboxylate (1.54 g, 4.02 mmol) and (R)-2-(1-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)ethyl)isoindoline-1,3-dione (1.52 g, 4.02 mmol) and potassium phosphate (2.56 g, 12.1 mmol) in a tetrahydrofuran / water (15.0 mL / 3.00 mL) waspurged with argon. Chloro(2-dicyclohexylphosphino- -triisopropyl- -biphenyl)[2- -amino- -biphenyl)]palladium(II) (0.316 g, 0.402 mmol) was added and the reactionmixture was heated to 70 °C until completion of the reaction. The mixture was cooled to room temperature, water and ethyl acetate were added and the mixture was filtered through a short pad of celite. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate and the mixture was concentrated under reduced pressure. The crude residues were purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give tert-butyl (R)-6-((4-(1-(1,3-dioxoisoindolin-2-yl)ethyl)phenyl)(5- fluoropyridin-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carboxylate (1.72 g, 2.73 mmol).Step F: Preparation of Intermediate 14Intermediate 14 was prepared according to a modified General Procedure 3 using 6-[(5-fluoro-2-pyridyl)-[4-[(1R)-1-phthalimidoethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (1.72 g, 3.11 mmol, 1.0 eq.) and hydrazine (0.718 g, 9.32 mmol, 3.0 eq.). The crude residues were purified by silica gel column chromatography (dichloromethane / methanol) to give Intermediate 14 (1.03 g, 1.97 mmol). EXAMPLES Example 1: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-3-isopropyl-isoxazolo[5,4-b]pyridine-5-carboxamide;hydrochloride ( Step A: Preparation of 4-[(4-fluorophenyl)- -1-[(3-isopropylisoxazolo[5,4-b]pyridine- 5-carbonyl)amino]ethyl]phenyl]methylene] 1-carboxylic acid tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-[(3-isopropylisoxazolo[5,4-b]pyridine-5- carbonyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester wasprepared according to General Procedure 2A using Intermediate 2 (83.1 mg, 0.202 mmol, 1.1eq.) and 3-isopropylisoxazolo[5,4-b]pyridine-5-carboxylic acid (37.9 mg, 0.184 mmol) in dichloromethane to give the crude 4-[(4-fluorophenyl)-[4-[(1R)-1-[(3-isopropylisoxazolo[5,4- b]pyridine-5-carbonyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (110 mg, 0.184 mmol), which was engaged into the next step without further purification, considering a quantitative yield.Step B: Preparation of Example 1Example 1 was prepared according to a modified General Procedure 1 using 4-[(4-fluorophenyl)-[4-[(1R)-1-[(3-isopropylisoxazolo[5,4-b]pyridine-5- carbonyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (110 mg, 0.184 mmol) in dichloromethane (0.3 M) and hydrogen chloride (5.0 eq.). The crude residues were purified by SFC (carbon dioxide / methanol / diethylamine). The residues weremixed with aqueous hydrogen chloride (10 eq.) and the mixture was freeze-dried to giveExample 1 (22.0 mg, 0.0385 mmol). 1H NMR (400 MHz, dmso-d6) ppm 9.17 (m, 1H), 9.12(s, 1H), 8.95 (s, 1H), 8.85 (m, 2H), 7.4 (m, 2H), 7.18 (s, 4H), 7.11 (s, 1H), 5.21 (m, 1H), 3.48(m, 1H), 3.12 (m, 4H), 2.42 (m, 4H), 1.53 (m, 3H), 1.44 (d, 6H) | [M+H]+=499.2504 Example 2: N-[ -1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5,6- dimethoxy- tert- ester: To a solution of 5,6-dimethoxypyridine-3-carboxylic acid (300 mg, 1.64 mmol) in tetrahydrofuran (5.0 mL, 4.5 M) was added di(imidazol-1-yl)methanone (319 mg, 1.97 mmol, 1.2 eq.) and the mixture was stirred at room temperature for 1 h then Intermediate 2 (807 mg, 1.97 mmol, 1.2 eq.) was added and the mixture was stirred at room temperature untilcompletion of the reaction. Ethyl acetate was added and the mixture was washed with waterand brine. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residues were purified by silica gel column chromatography (ethyl acetate / cyclohexane) to give 4-[[4-[(1R)-1-[(5,6- dimethoxynicotinoyl)amino]ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester (606 mg, 1.05 mmol). 1H NMR (400 MHz, dmso-d6) ppm8.73 (m, 1H), 8.3 (m, 1H), 7.7 (m, 1H), 7.35 (m, 2H), 7.15 (m, 4H), 7.07 (m, 2H), 5.17 (m, 1H), 3.87 (m, 6H), 3.4 (m, 4H), 2.23 (m, 4H), 1.49 (m, 3H), 1.4 (s, 9H).Step B: Preparation of Example 2To a solution of tert-butyl 4-[[4-[(1R)-1-[(5,6-dimethoxypyridine-3- carbonyl)amino]ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1-carboxylate (300 mg, 0.521 mmol, 1.0 eq.) and 2,6-dimethylpyridine (223 mg, 2.08 mmol, 4.0 eq.) in dichloromethane (10 M), was added dropwise trimethylsilyl trifluoromethanesulfonate (347 mg, 0.283 mL, 1.56 mmol, 3.0 eq.) and the mixture was stirred at room temperature until completion of the reaction. The mixture was quenched with sat. NaHCO3 and dissolved with dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude residues were purified by reverse phase column chromatography (acetonitrile / water / ammonium bicarbonate) to afford Example 2 (132 mg, 0.278 mmol).1HNMR (400 MHz, dmso-d6) ppm 8.74 (d, 1H), 8.27 (d, 1H), 7.66 (d, 1H), 7.32 (d, 2H), 7.09(m, 6H), 5.17 (t, 1H), 3.91 (s, 3H), 3.83 (s, 3H), 2.75 (br s, 4H), 2.15 (s, 1H), 2.15 (m, 4H), 1.47 (d, 3H) | [M+H]+=476.2354 Example 3: N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]quinoline-3-carboxamide;hydrochloride Step A: Preparation of 4-[(4-fluorophenyl)-[4-[(1R)-1-(quinoline-3-carbonylamino)ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-(quinoline-3-carbonylamino)ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure 2Ausing Intermediate 2 (326 mg, 0.794 mmol, 1.1 eq.) and quinoline-3-carboxylic acid (125 mg, 0.722 mmol) in dichloromethane to give the expected product (408 mg, 0.722 mmol), which was engaged into the next step without further purification, considering a quantitative yield.Step B: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]quinoline-3-carboxamide N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]quinoline-3-carboxamide was prepared according to a modified General Procedure 1 using 4-[(4-fluorophenyl)-[4-[(1R)-1-(quinoline-3-carbonylamino)ethyl]phenyl]methylene]piperidine-1- carboxylic acid tert-butyl ester (408 mg, 0.722 mmol) in dichloromethane (0.3 M) and 2 N hydrogen chloride (7.21 mL, 14.4 mmol, 20 eq.). The crude residues were eluted through a PoraPak Rxn CX and the mixture was concentrated under reduced pressure. The residues were purified by a reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]quinoline-3- carboxamide (33.0 mg, 0.0709 mmol). Example 3 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]quinoline-3-carboxamide (33 mg, 0.0709 mmol) and hydrogen chloride (0.177 mmol) to give Example 3 (34.2 mg, 0.0681 mmol). 1H NMR (500 MHz, dmso-d6) ppm 9.36 (d, 1H), 9.25 (d, 1H), 8.99 (br d, 3H), 8.14(m, 2H), 7.92 (s, 1H), 7.74 (s, 1H), 7.43 (d, 2H), 7.17 (m, 4H), 7.12 (d, 2H), 5.08 (m, 1H), 3.11 (br d, 4H), 2.43 (m, 4H), 1.53 (d, 3H). [M+H]+=466.2295 fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester 4-[[4-[(1R)-1-[(5-bromonicotinoyl)amino]ethyl]phenyl]-(4-fluorophenyl)methylene] piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure 2Ausing Intermediate 2 (324 mg, 0.789 mmol, 1.1 eq.) and 5-bromopyridine-3-carboxylic acid (145 mg, 0.718 mmol) in dichloromethane to give the crude 4-[[4-[(1R)-1-[(5- bromonicotinoyl)amino]ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester (427 mg, 0.718 mmol), which was engaged into the next step without further purification, considering a quantitative yield. -(4-piperidylidene)methyl]phenyl]ethyl]nicotinamide 5-bromo-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]nicotinamide was prepared according to a modified General Procedure 1 using the product obtained inprevious step1 (427 mg, 0.718 mmol) in dichloromethane (0.3 M) and 2 N hydrogen chloride (7.10 mL, 14.3 mmol, 20 eq.). The crude residues were eluted through a PoraPak Rxn CX and the mixture was concentrated under reduced pressure. The residues were purified by a reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give 5-bromo-N-[(1R)- 1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]nicotinamide (33.0 mg, 0.0668 mmol). Step C: Preparation of Example 4Example 4 was prepared according to General Procedure 7 using 5-bromo-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]nicotinamide (33.0 mg, 0.0668 mmol) and hydrogen chloride (0.167 mmol) to give Example 4 (34.6 mg, 0.0610 mmol).1H NMR (500 MHz, dmso-d6) ppm 9.12 (m, 1H), 9 (d, 1H), 8.86 (br d, 3H), 8.49 (s, 1H), 7.37 (d, 2H), 7.17 (m, 4H), 7.11 (d, 2H), 5.11 (m, 1H), 3.11 (m, 4H), 2.43 (m, 4H), 1.48 (d, 3H) | [M+H]+=494.1257 Example 5: N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]isoquinoline-7-carboxamide;hydrochloride butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-(isoquinoline-7-carbonylamino)ethyl]phenyl]methylene] piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure 2Ausing Intermediate 2 (130 mg, 0.318 mmol, 1.1 eq.) and quinoline-6-carboxylic acid (50.0 mg, 0.289 mmol) in dichloromethane to give the crude 4-[(4-fluorophenyl)-[4-[(1R)-1- (isoquinoline-7-carbonylamino)ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert- butyl ester (163 mg, 0.289 mmol), which was engaged into the next step without further purification, considering a quantitative yield.Step B: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]isoquinoline-7-carboxamide N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]isoquinoline-7-carboxamide was prepared according to General Procedure 1 using 4-[(4-fluorophenyl)-[4-[(1R)-1-(isoquinoline-7-carbonylamino)ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (163 mg, 0.289 mmol) in dichloromethane (0.3 M) and hydrogen chloride. The crude residues were eluted through a PoraPak Rxn CX and the mixture was concentrated under reduced pressure. The residues were purified by a reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]isoquinoline-7-carboxamide (100 mg, 0.215 mmol).Step C: Preparation of Example 5Example 5 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]isoquinoline-7-carboxamide (100 mg, 0.215 mmol) and hydrogen chloride (0.644 mmol) to give Example 5 (114 mg, 0.212 mmol).1H NMR (400 MHz, dmso-d6) ppm 9.19 (m, 1H), 9.13 (m, 3H), 8.79 (m, 1H), 8.7 (d, 1H),8.34 (dd, 1H), 8.22 (d, 1H), 7.82 (dd, 1H), 7.42 (d, 2H), 7.17 (m, 4H), 7.12 (d, 2H), 5.25 (m, 1H), 3.11 (br s, 4H), 2.45 (br dd, 4H), 1.53 (d, 3H) | [M+H]+=466.2290 Example 6: 3-cyano-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]benzamide;hydrochloride 1-carboxylic acid tert-butyl ester 4-[[4-[(1R)-1-[(3-cyanobenzoyl)amino]ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine- 1-carboxylic acid tert-butyl ester was prepared according to General Procedure 2A usingIntermediate 2 (154 mg, 0.374 mmol, 1.1 eq.) and 3-cyanobenzoic acid (50.0 mg, 0.339 mmol) in dichloromethane to give the crude 4-[[4-[(1R)-1-[(3- cyanobenzoyl)amino]ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester (183 mg, 0.339 mmol), which was engaged into the next step without further purification, considering a quantitative yield. -(4- 3-cyano-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]benzamide was prepared according to General Procedure 1 using 4-[[4-[(1R)-1-[(3-cyanobenzoyl)amino]ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester (183 mg, 0.339 mmol) in dichloromethane (0.3 M) and hydrogen chloride. The crude residues were eluted through a PoraPak Rxn CX and the mixture was concentrated under reduced pressure. The residues were purified by a reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give 3-cyano-N-[(1R)-1-[4-[(4-fluorophenyl)- (4-piperidylidene)methyl]phenyl]ethyl]benzamide (114 mg, 0.259 mmol). Step C: Preparation of Example 6Example 6 was prepared according to General Procedure 7 using 3-cyano-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]benzamide (114 mg, 0.259 mmol) and hydrogen chloride (0.649 mmol) to give Example 6 (120 mg, 0.252 mmol). 1H NMR (400MHz, dmso-d6) ppm 9.03 (d, 1H), 8.95 (m, 2H), 8.35 (m, 1H), 8.18 (m, 1H), 8.01 (dt, 1H), 7.69 (m, 1H), 7.37 (m, 2H), 7.17 (s, 4H), 7.09 (m, 2H), 5.16 (m, 1H), 3.11 (m, 4H), 2.42 (m, 4H), 1.48 (d, 3H) | [M+H]+=440.2123 tert- ester 4-[[4-[(1R)-1-(benzofurazan-5-carbonylamino)ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure 2Ausing Intermediate 2 (183 mg, 0.445 mmol, 1.2 eq.) and 2,1,3-benzoxadiazole-5-carboxylic acid (64.0 mg, 0.371 mmol) in dichloromethane to give the crude 4-[[4-[(1R)-1- (benzofurazan-5-carbonylamino)ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1- carboxylic acid tert-butyl ester (206 mg, 0.371 mmol), which was engaged into the next step without further purification, considering a quantitative yield.Step B: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]benzofurazan-5-carboxamide N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]benzofurazan-5-carboxamide was prepared according to General Procedure 1 using 4-[[4-[(1R)-1-(benzofurazan-5-carbonylamino)ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1- carboxylic acid tert-butyl ester (206 mg, 0.371 mmol) in dichloromethane (0.3 M) and 2 N hydrogen chloride (20 eq.). The crude residues were eluted through a PoraPak Rxn CX and the mixture was concentrated under reduced pressure. The residues were purified by a reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give N-[(1R)-1-[4-[(4- fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]benzofurazan-5-carboxamide (48.7 mg, 0.107 mmol).Step C: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]benzofurazan-5-carboxamide;hydrochlorideExample 7 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]benzofurazan-5-carboxamide (48.7 mg, 0.107 mmol) and hydrogen chloride (0.267 mmol) to give Example 7 (52.4 mg, 0.106 mmol). 1H NMR (400 MHz, dmso-d6) ppm 9.22 (d, 1H), 8.8 (br s, 2H), 8.61 (s, 1H), 8.13 (dd, 1H),7.95 (dd, 1H), 7.4 (d, 2H), 7.16 (m, 6H), 5.18 (t, 1H), 3.12 (br s, 4H), 2.43 (m, 4H), 1.5 (d, 3H) | [M+H]+=457.2045 1-carboxylic acid tert-butyl ester 4-[[4-[(1R)-1-[[5-(2,2-difluoroethoxy)nicotinoyl]amino]ethyl]phenyl]-(4-fluorophenyl) methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure 2A using Intermediate 2 (183 mg, 0.445 mmol, 1.2 eq.) and 5-(2,2-difluoroethoxy)pyridine-3-carboxylic acid (79.0 mg, 0.369 mmol) in dichloromethane to give the crude 4-[[4- [(1R)-1-[[5-(2,2-difluoroethoxy)nicotinoyl]amino]ethyl]phenyl]-(4-fluorophenyl)methylene] piperidine-1-carboxylic acid tert-butyl ester (220 mg, 0.369 mmol), which was engaged intothe next step without further purification, considering a quantitative yield. -(4- 5-(2,2-difluoroethoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl] ethyl]nicotinamide was prepared according to General Procedure 1 using 4-[[4-[(1R)-1-[[5-(2,2-difluoroethoxy)nicotinoyl]amino]ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1- carboxylic acid tert-butyl ester (220 mg, 0.369 mmol) in dichloromethane (0.3 M) and 2 N hydrogen chloride (20 eq.). The crude residues were eluted through a PoraPak Rxn CX and the mixture was concentrated under reduced pressure. The residues were purified by a reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give 5-(2,2- difluoroethoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]nicotinamide (43.0 mg, 0.0868 mmol).Step C: Preparation of Example 8Example 8 was prepared according to General Procedure 7 using 5-(2,2-difluoroethoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]nicotinamide (43.0 mg, 0.0868 mmol) and hydrogen chloride (0.217 mmol) to give Example 8 (49.0 mg, 0.0862mmol). 1H NMR (400 MHz, dmso-d6) ppm 9.03 (m, 3H), 8.72 (d, 1H), 8.52 (d, 1H), 7.94(m, 1H), 7.38 (d, 2H), 7.15 (m, 6H), 6.44 (tt, 1H), 5.18 (quin, 1H), 4.5 (td, 2H), 3.11 (br s, 4H), 2.43 (m, 4H), 1.49 (d, 3H) Example 9: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-isopropoxy-nicotinamide [(4-fluorophenyl)-[4-[(1R)-1-[(5- 2-carboxylic acid tert-butyl ester 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-isopropoxynicotinoyl)amino]ethyl]phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was prepared according to General Procedure 2B using Intermediate 3 (250 mg, 0.592 mmol) and 5-isopropoxypyridine-3- carboxylic acid (107 mg, 0.592 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (dichloromethane / ethyl acetate) to give 6-[(4- fluorophenyl)-[4-[(1R)-1-[(5-isopropoxynicotinoyl)amino]ethyl]phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (347 mg, 0.593 mmol). [M+H]+=586.3.Step B: Preparation of N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-isopropoxy-nicotinamide N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5- isopropoxy-nicotinamide was prepared according to a modified General Procedure 1 using 6- [(4-fluorophenyl)-[4-[(1R)-1-[(5-isopropoxynicotinoyl)amino]ethyl]phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (347 mg, 0.593 mmol) in dichloromethane (0.3 M) and trifluoroacetic acid (0.296 mL, 1.19 mmol, 2.0 eq.). The crude residues were purified by silica gel column chromatography (dichloromethane / methanol / ammoniac) to give N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6- ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-isopropoxy-nicotinamide (80.0 mg, 0.165 mmol). [M+H]+=486.4.Step C: Preparation of Example 9Example 9 was prepared according to General Procedure 8 using N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-isopropoxy- nicotinamide (80.0 mg, 0.165 mmol) in a 5:1 dichloromethane / methanol mixture. The crude residues were purified by reverse phase column chromatography(acetonitrile / water / ammonium bicarbonate) to give Example 9 (45.0 mg, 0.090 mmol). 1HNMR (400 MHz, dmso-d6) ppm 8.94 (d, 1H), 8.62 (d, 1H), 8.38 (d, 1H), 7.75 (m, 1H), 7.34(d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.18 (t, 1H), 4.77 (dt, 1H), 3.13 (s, 4H), 2.95 (br d, 4H), 2.15 (s, 3H), 1.49 (d, 3H), 1.3 (dd, 6H) Example 10: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-methoxy-nicotinamideStep A: Preparation of 6-[(4-fluorophenyl)- -1-[(5-methoxynicotinoyl)amino]ethyl] phenyl]methylene]-2-azaspiro[3.3]heptane- acid tert-butyl ester 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-methoxynicotinoyl)amino]ethyl]phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was prepared according to GeneralProcedure 2B using Intermediate 3 (250 mg, 0.592 mmol) and 5-methoxypyridine-3-carboxylic acid (90.6 mg, 0.592 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (dichloromethane / ethyl acetate) to give 6-[(4- fluorophenyl)-[4-[(1R)-1-[(5-methoxynicotinoyl)amino]ethyl]phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (250 mg, 0.449 mmol). [M+H]+=558.3.Step B: Preparation of N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-methoxy-nicotinamide N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-methoxy-nicotinamide was prepared according to a modified General Procedure 1 using 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-methoxynicotinoyl)amino]ethyl]phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (250 mg, 0.448 mmol) in dichloromethane (0.3 M) and trifluoroacetic acid (0.224 mL, 0.897 mmol, 2 eq.). The crude residues were purified by silica gel column chromatography (dichloromethane / methanol / ammoniac) to give N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6- ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-methoxy-nicotinamide (125 mg, 0.273mmol). [M+H]+=458.4.Step C: Preparation of Example 10Example 10 was prepared according to General Procedure 8 using N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-methoxy-nicotinamide (125.0 mg, 0.273 mmol) in a 5:1 dichloromethane / methanol mixture. The crude residues were purified by reverse phase column chromatography (acetonitrile / water / ammonium bicarbonate)to give Example 10 (60.0 mg, 0.127 mmol). 1H NMR (400 MHz, dmso-d6) ppm 8.97 (d,1H), 8.66 (d, 1H), 8.42 (d, 1H), 7.77 (dd, 1H), 7.35 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.18 (quin, 1H), 3.88 (s, 3H), 3.15 (s, 4H), 2.95 (br d, 4H), 2.16 (s, 3H), 1.49 (d, 3H) Example 11: 5-ethoxy-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan- 6-ylidene)methyl]phenyl]ethyl]nicotinamide - tert- ester 6-[[4-[(1R)-1-[(5-ethoxynicotinoyl)amino]ethyl]phenyl]-(4-fluorophenyl)methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was prepared according to GeneralProcedure 2B using Intermediate 3 (250 mg, 0.592 mmol) and 5-ethoxypyridine-3-carboxylicacid (98.9 mg, 0.592 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (dichloromethane / ethyl acetate) to give 6-[[4-[(1R)-1-[(5- ethoxynicotinoyl)amino]ethyl]phenyl]-(4-fluorophenyl)methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (338 mg, 0.591 mmol). [M+H]+=572.4.of 5-ethoxy-N-[(1R)-1-[4-[1-(4- -2-oxa-7- nonan-1- 5-ethoxy-N-[(1R)-1-[4-[1-(4-fluorophenyl)-2-oxa-7-azadispiro[2.1.35.13]nonan-1-yl]phenyl]ethyl]nicotinamide was prepared according to a modified General Procedure 1 using 6-[[4-[(1R)-1-[(5-ethoxynicotinoyl)amino]ethyl]phenyl]-(4-fluorophenyl)methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (338 mg, 0.591 mmol) in dichloromethane (0.3 M) and trifluoroacetic acid (0.226 mL, 2.96 mmol, 5 eq.). The crude residues were eluted through a PoraPak Rxn CX to give 5-ethoxy-N-[(1R)-1-[4-[1-(4- fluorophenyl)-2-oxa-7-azadispiro[2.1.35.13]nonan-1-yl]phenyl]ethyl]nicotinamide (150 mg,0.318 mmol). 1H NMR (400 / 500 MHz, dmso-d6) ppm 8.96 (d, 1H), 8.64 (s, 1H), 8.41 (s,1H), 7.75 (s, 1H), 7.34 (d, 1H), 7.14 (m, 2H), 7.1 (m, 1H), 5.17 (m, 1H), 4.16 (q, 1H), 3.6 (br s, 1H), 3 (2br s, 1H), 1.49 (d, 1H), 1.36 (t, 1H) | [M+H]+=472.2394.Step C: Preparation of Example 11Example 11 was prepared according to General Procedure 8 using 5-ethoxy-N-[(1R)-1-[4-[1-(4-fluorophenyl)-2-oxa-7-azadispiro[2.1.35.13]nonan-1-yl]phenyl]ethyl]nicotinamide (150 mg, 0.318 mmol) in a 5:1 dichloromethane / methanol mixture. The crude residues were purified by reverse phase column chromatography (acetonitrile / water / ammonium bicarbonate)to give Example 11 (75.0 mg, 0.154 mmol). 1H NMR (400 MHz, dmso-d6) ppm 8.95 (d,1H), 8.64 (d, 1H), 8.4 (d, 1H), 7.76 (dd, 1H), 7.34 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.18 (quin, 1H), 4.16 (q, 2H), 3.13 (s, 4H), 2.95 (br d, 4H), 2.15 (s, 3H), 1.49 (d, 3H), 1.36 (t, 3H) Example 12: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-3- pyrazol-1-yl-benzamide;hydrochloride Step A: Preparation of 4-[(4-fluorophenyl)-[4-[ -1-[(3-pyrazol-1- ylbenzoyl)amino]ethyl]phenyl]methylene] 1-carboxylic acid tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-[(3-pyrazol-1-ylbenzoyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure 2A using Intermediate 2 (184 mg, 0.448 mmol, 1.2 eq.) and 3-pyrazol-1-ylbenzoic acid (74.0 mg, 0.374 mmol) in dichloromethane to give the crude 4-[(4-fluorophenyl)-[4-[(1R)-1-[(3- pyrazol-1-ylbenzoyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (217 mg, 0.374 mmol), which was engaged into the next step without further purification, considering a quantitative yield.Step B: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-3-pyrazol-1-yl-benzamide N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-3-pyrazol-1-yl-benzamide was prepared according to a modified General Procedure 1 using 4-[(4-fluorophenyl)-[4-[(1R)-1-[(3-pyrazol-1-ylbenzoyl)amino]ethyl]phenyl]methylene]piperidine- 1-carboxylic acid tert-butyl ester (217 mg, 0.374 mmol) in dichloromethane (0.3 M) and 2 Nhydrogen chloride (20 eq.). The crude residues were eluted through a PoraPak Rxn CX andthe mixture was concentrated under reduced pressure. The residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give N-[(1R)-1-[4-[(4- fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-3-pyrazol-1-yl-benzamide (49.0 mg, 0.102 mmol).Step C: Preparation of Example 12Example 12 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-3-pyrazol-1-yl-benzamide (49.0 mg, 0.102 mmol) and hydrogen chloride (0.316 mmol) to give Example 12 (55.9 mg, 0.101mmol). 1H NMR (400 MHz, dmso-d6) ppm 8.99 (d, 1H), 8.81 (br s, 2H), 8.57 (d, 1H), 8.33(s, 1H), 7.99 (br d, 1H), 7.81 (d, 1H), 7.79 (d, 1H), 7.59 (t, 1H), 7.39 (m, 2H), 7.17 (m, 4H), 7.11 (m, 2H), 6.58 (t, 1H), 5.2 (t, 1H), 3.12 (br s, 4H), 2.43 (m, 4H), 1.5 (d, 3H) Example 13: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5- (trifluoromethoxy)nicotinamide;hydrochlorideStep A: Preparation of 4-[(4-fluorophenyl)- (trifluoromethoxy)nicotinoyl] amino]ethyl]phenyl]methylene]piperidine- tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-[[5-(trifluoromethoxy)nicotinoyl]amino]ethyl]phenyl] methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to GeneralProcedure 2A using Intermediate 2 (183 mg, 0,446 mmol, 1.2 eq.) and 5-(trifluoromethoxy)pyridine-3-carboxylic acid (77.0 mg, 0.372 mmol) in dichloromethane to give the crude 4-[(4- fluorophenyl)-[4-[(1R)-1-[[5-(trifluoromethoxy)nicotinoyl]amino]ethyl]phenyl]methylene] piperidine-1-carboxylic acid tert-butyl ester (223 mg, 0.372 mmol), which was engaged into the next step without further purification, considering a quantitative yield.Step B: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5-(trifluoromethoxy)nicotinamide N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5-(trifluoromethoxy)nicotinamide was prepared according to a modified General Procedure 1 using 4-[(4-fluorophenyl)-[4-[(1R)-1-[[5-(trifluoromethoxy)nicotinoyl]amino]ethyl]phenyl]methylene] piperidine-1-carboxylic acid tert-butyl ester (223 mg, 0.372 mmol) in dichloromethane (0.3 M) and 2 N hydrogen chloride (20 eq.). The crude residues were eluted through a PoraPak Rxn CX and the mixture was concentrated under reduced pressure. The residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give N- [(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5- (trifluoromethoxy)nicotinamide (58.0 mg, 0.116 mmol).Step C: Preparation of Example 13Example 13 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5-(trifluoromethoxy)nicotinamide (58.0 mg, 0.116 mmol) and hydrogen chloride (0.290 mmol) to give Example 13 (65.9 mg,0.115 mmol). 1H NMR (400 MHz, dmso-d6) ppm 9.19 (m, 1H), 9.11 (s, 1H), 8.98 (br s,2H), 8.84 (d, 1H), 8.28 (br s, 1H), 7.38 (m, 2H), 7.17 (d, 4H), 7.11 (m, 2H), 5.18 (t, 1H), 3.11 (br s, 4H), 2.43 (m, 4H), 1.49 (d, 3H) Example 14: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-3- piperazino-benzamide;2,2,2-trifluoroacetic acid Step A: Preparation of 4-[3-[[(1R)-1-[4-[(1-tert-butoxycarbonyl-4-piperidylidene)-(4-fluorophenyl)methyl]phenyl]ethyl]carbamoyl]phenyl]piperazine-1-carboxylic acid tert-butyl ester 4-[3-[[(1R)-1-[4-[(1-tert-butoxycarbonyl-4-piperidylidene)-(4- fluorophenyl)methyl]phenyl]ethyl]carbamoyl]phenyl]piperazine-1-carboxylic acid tert-butylester was prepared according to General Procedure 2A using Intermediate 2 (182 mg, 0,443mmol, 1.2 eq.) and 3-(4-tert-butoxycarbonylpiperazin-1-yl)benzoic acid (113 mg, 0.369 mmol) in dichloromethane to give the crude 4-[3-[[(1R)-1-[4-[(1-tert-butoxycarbonyl-4- piperidylidene)-(4-fluorophenyl)methyl]phenyl]ethyl]carbamoyl]phenyl]piperazine-1- carboxylic acid tert-butyl ester (258 mg, 0.369 mmol), which was engaged into the next step without further purification, considering a quantitative yield.Step B: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-3-piperazino-benzamide N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-3-piperazino-benzamide was prepared according to a modified General Procedure 1 using 4-[3-[[(1R)-1-[4-[(1-tert-butoxycarbonyl-4-piperidylidene)-(4-fluorophenyl)methyl]phenyl]ethyl]carbamoyl] phenyl]piperazine-1-carboxylic acid tert-butyl ester (258 mg, 0.369 mmol) in dichloromethane (0.3 M) and 2 N hydrogen chloride (20 eq.). The crude residues were eluted through a PoraPak Rxn CX and the mixture was concentrated under reduced pressure. The residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]- 3-piperazino-benzamide (81.0 mg, 0.163 mmol).Step C: Preparation of Example 14The crude N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-3- piperazino-benzamide (81.0 mg, 0.163 mmol) was purified by reverse phase chromatography(acetonitrile / water / trifluoroacetic acid) to give Example 14 (71.6 mg, 0.135 mmol). 1H NMR(400 MHz, dmso-d6) ppm 8.74 (br d, 4H), 7.37 (m, 5H), 7.15 (m, 7H), 5.17 (m, 1H), 3.34 (m, 12H), 2.41 (s, 1H), 2.41 (m, 4H), 1.47 (d, 3H). Example 15: N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4- fluorophenyl)methyl]phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-nicotinamide Step A: Preparation of 5-[(3S)-tetrahydrofuran-3-yl]oxynicotinic acid methyl ester5-[(3S)-tetrahydrofuran-3-yl]oxynicotinic acid methyl ester was prepared according toGeneral Procedure 10 using methyl 5-hydroxypyridine-3-carboxylate (500 mg, 3.27 mmol)and (3R)-tetrahydrofuran-3-ol (0.262 mL, 3.27 mmol). The residues were purified by silica gel column chromatography (heptane / ethyl acetate) to give 5-[(3S)-tetrahydrofuran-3- yl]oxynicotinic acid methyl ester (728 mg, 3.26 mmol).Step B: Preparation of sodium;5-[(3S)-tetrahydrofuran-3-yl]oxypyridine-3-carboxylatesodium;5-[(3S)-tetrahydrofuran-3-yl]oxypyridine-3-carboxylate was prepared according toGeneral Procedure 9A using 5-[(3S)-tetrahydrofuran-3-yl]oxynicotinic acid methyl ester (728mg, 3.26 mmol) to give sodium;5-[(3S)-tetrahydrofuran-3-yl]oxypyridine-3-carboxylate (750 mg, 3.24 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification. 3- 2-carboxylic acid tert-butyl ester 6-[(4-fluorophenyl)-[4-[(1R)-1-[[5-[(3S)-tetrahydrofuran-3-yl]oxynicotinoyl]amino]ethyl] phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was preparedaccording to General Procedure 2B using Intermediate 3 (500 mg, 1.18 mmol) and sodium;5-[(3S)-tetrahydrofuran-3-yl]oxypyridine-3-carboxylate (274 mg, 1.18 mmol) in N,N- dimethylformamide. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 6-[(4-fluorophenyl)-[4-[(1R)-1-[[5-[(3S)-tetrahydrofuran-3- yl]oxynicotinoyl]amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (509 mg, 0.829 mmol).Step D: Preparation of Example 15Example 15 was prepared according to General Procedure 1 using (509 mg, 0.829 mmol) indichloromethane (0.3 M) and trifluoroacetic acid. The crude residues were purified by reverse phase column chromatography (acetonitrile / water / ammonium bicarbonate) to give Example15 (200 mg, 0.389 mmol). 1H NMR (500 MHz, dmso-d6) ppm 8.98 (d, 1H), 8.67 (br s, 1H),8.41 (t, 1H), 7.76 (br s, 1H), 7.35 (d, 2H), 7.14 (m, 2H), 7.13 (m, 2H), 7.07 (d, 2H), 5.2 (m, 1H), 5.17 (m, 1H), 3.9 (m, 1H), 3.85 (m, 2H), 3.83 (m, 2H), 3.83 (m, 2H), 3.78 (m, 1H), 3.08 (m, 4H), 2.27 (m, 1H), 2 (m, 1H), 1.48 (d, 3H). [M+H]+=514.2497 Example 16: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-(oxetan-3-yloxy)nicotinamideStep A: Preparation of 5-(oxetan-3-yloxy)nicotinic acid methyl ester5-(oxetan-3-yloxy)nicotinic acid methyl ester was prepared according to General Procedure10 using methyl 5-hydroxypyridine-3-carboxylate (500 mg, 3.27 mmol) and oxetan-3-ol (242 mg, 3.27 mmol). The crude residues were purified by silica gel column chromatography (n- heptane / ethyl acetate) to give 5-(oxetan-3-yloxy)nicotinic acid methyl ester (367 mg, 1.75mmol). 1H NMR (400 MHz, dmso-d6) ppm 8.73 (d, 1H), 8.47 (d, 1H), 7.57 (dd, 1H), 5.49(m, 1H), 4.96 (m, 2H), 4.58 (m, 2H), 3.89 (s, 3H). [M+H]+=210.1.Step B: Preparation of sodium;5-(oxetan-3-yloxy)nicotinatesodium;5-(oxetan-3-yloxy)nicotinate was prepared according to General Procedure 9A using5-(oxetan-3-yloxy)nicotinic acid methyl ester (367 mg, 1.75 mmol) to give sodium;5-(oxetan- 3-yloxy)nicotinate (380 mg, 1.75 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification.[M+H]+=196.1.Step C: Preparation of 6-[(4-fluorophenyl)-[4-[(1R)-1-[[5-(oxetan-3-yloxy)nicotinoyl]amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 6-[(4-fluorophenyl)-[4-[(1R)-1-[[5-(oxetan-3-yloxy)nicotinoyl]amino]ethyl]phenyl] methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was prepared accordingto General Procedure 2B using Intermediate 3 (300 mg, 0.710 mmol) and sodium;5-(oxetan-3-yloxy)pyridine-3-carboxylate (154 mg, 0.710 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (dichloromethane / ethyl acetate) to give 6-[(4-fluorophenyl)-[4-[(1R)-1-[[5-(oxetan-3-yloxy)nicotinoyl]amino]ethyl]phenyl] methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (186 mg, 0.310 mmol).Step D: Preparation of N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-(oxetan-3-yloxy)nicotinamide N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-(oxetan-3-yloxy)nicotinamide was prepared according to General Procedure 1 using tert-butyl6-[(4-fluorophenyl)-[4-[(1R)-1-[[5-(oxetan-3-yloxy)pyridine-3-carbonyl]amino]ethyl]phenyl] methylene]-2-azaspiro[3.3]heptane-2-carboxylate (186 mg, 0.310 mmol), trifluoroacetic acid (0.119 mL, 1.55 mmol) in dichloromethane (10.0 mL). The residues were eluted through a PoraPak Rxn CX and purified by silica gel column chromatography (dichloromethane / methanol-ammoniac) to give N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6- ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-(oxetan-3-yloxy)pyridine-3-carboxamide (96.0 mg, 0.192 mmol), used into the next step without further purification.Step E: Preparation of Example 16Example 16 was prepared according to General Procedure 8 using (96.0 mg, 0.192 mmol) in a5:1 dichloromethane / methanol mixture. The crude residues were purified by reverse phase column chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 16(55.0 mg, 0.107 mmol). 1H NMR (400 MHz, dmso-d6) ppm 8.97 (d, 1H), 8.7 (d, 1H), 8.33(d, 1H), 7.59 (m, 1H), 7.34 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.45 (m, 1H), 5.17 (quin, 1H), 4.95 (t, 2H), 4.58 (m, 2H), 3.13 (s, 4H), 2.95 (br d, 4H), 2.15 (s, 3H), 1.49 (d, 3H) Example 17: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-nicotinamide Example 17 was prepared according to General Procedure 8 using Example 15 (145 mg,0.282 mmol) in a 5:1 dichloromethane / methanol mixture. The crude residues were purified by reverse phase column chromatography (acetonitrile / water / ammonium bicarbonate) to giveExample 17 (85.0 mg, 0.161 mmol). 1H NMR (400 MHz, dmso-d6) ppm 8.96 (d, 1H), 8.67(d, 1H), 8.41 (d, 1H), 7.75 (dd, 1H), 7.34 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.19 (m, 2H), 3.84 (m, 4H), 3.15 (s, 4H), 2.95 (br d, 4H), 2.27 (m, 1H), 2.16 (s, 3H), 1.99 (m, 1H), 1.49 (d, 3H) Example 18: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-(oxetan-3-ylmethoxy)nicotinamide Step A: Preparation of 5-(oxetan-3-ylmethoxy)nicotinic acid methyl ester5-(oxetan-3-ylmethoxy)nicotinic acid methyl ester was prepared according to GeneralProcedure 10 using methyl 5-hydroxypyridine-3-carboxylate (500 mg, 3.27 mmol) andoxetan-3-ylmethanol (288 mg, 3.27 mmol) to give 5-(oxetan-3-ylmethoxy)nicotinic acidmethyl ester (1.40 g, 3.10 mmol). [M+H]+=224.1.Step B: Preparation of sodium;5-(oxetan-3-ylmethoxy)nicotinatesodium;5-(oxetan-3-ylmethoxy)nicotinate was prepared according to General Procedure 9Ausing 5-(oxetan-3-ylmethoxy)nicotinic acid methyl ester (1.10 g, 4.90 mmol) to give sodium;5-(oxetan-3-ylmethoxy)nicotinate (725 mg, 3.14 mmol) which was used into the next step without further purification. [M+H]+=210.1.Step C: Preparation of Example 18Example 18 was prepared according to General Procedure 2B using Intermediate 4 (110 mg,0.327 mmol) and sodium;5-(oxetan-3-ylmethoxy)nicotinate (75.6 mg, 0.327 mmol) in N,N- dimethylformamide. The crude residues were purified by reverse phase column chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 18 (34.0 mg,0.0644 mmol). 1H NMR (400 MHz, dmso-d6) ppm 8.96 (m, 1H), 8.66 (d, 1H), 8.44 (d, 1H), 7.83 (dd, 1H), 7.35 (d, 2H), 7.13 (m, 5H), 7.07 (d, 2H), 5.18 (m, 1H), 4.63 (m, 4H), 4.35 (d, 2H), 3.43 (m, 1H), 3.27 (m, 4H), 2.97 (m, 4H), 2.24 (m, 3H), 1.47 (m, 3H). [M+H]+=528.2668 Example 19: N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4- piperidylidene)methyl]phenyl]ethyl]-5-methoxy-nicotinamide;hydrochloride Step A: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-methoxy-nicotinamide N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-methoxy-nicotinamide was prepared according to General Procedure 8 using Intermediate 5 (170 mg,0.382 mmol) in a 5:1 dichloromethane / methanol mixture. The crude residues were purified by reverse phase column chromatography (acetonitrile / water / ammonium bicarbonate) to give N- [(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-methoxy- nicotinamide (98.0 mg, 0.213 mmol).Step B: Preparation of Example 19Example 19 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-methoxy-nicotinamide (98.0 mg, 0.213 mmol) and hydrogen chloride (0.213 mmol) to give Example 19 (100 mg,0.202 mmol). 1H NMR (400 MHz, dmso-d6) ppm 10.51 (m, 1H), 9.04 (m, 1H), 8.68 (m,1H), 8.43 (m, 1H), 7.86 (m, 1H), 7.39 (m, 2H), 7.16 (s, 4H), 7.1 (m, 2H), 5.18 (m, 1H), 3.9 (s, 3H), 3.42 (m, 2H), 3 (m, 2H), 2.73 (, 3H), 2.73 (d, 3H), 2.51 (m, 4H) | [M+H]+=460.2380. Example 20: N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4- piperidylidene)methyl]phenyl]ethyl]-5-isopropoxy-nicotinamide;hydrochloride Step A: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-isopropoxy-nicotinamide N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-isopropoxy-nicotinamide was prepared according to General Procedure 8 using Intermediate 6(200 mg, 0.422 mmol) in a 5:1 dichloromethane / methanol mixture. The crude residues were purified by reverse phase column chromatography (acetonitrile / water / ammonium bicarbonate) to give N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5- isopropoxy-nicotinamide (69.0 mg, 0.142 mmol).Step B: Preparation of Example 20Example 20 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-isopropoxy-nicotinamide (69.0 mg, 0.142 mmol) and hydrogen chloride (0.142 mmol) to give Example 20 (60.0 mg,0.115 mmol). 1H NMR (400 MHz, dmso-d6) ppm 10.88 (s, 1H), 9.16 (d, 1H), 8.72 (d, 1H),8.5 (d, 1H), 8 (m, 1H), 7.39 (d, 2H), 7.15 (m, 6H), 5.18 (quin, 1H), 4.85 (spt, 1H), 4.42 (br s, 1H), 3.41 (br d, 2H), 3 (m, 2H), 2.72 (d, 3H), 2.52 (m, 4H), 1.5 (d, 3H), 1.31 (dd, 6H). [M+H]+=488.2683 Example 21: 5-ethoxy-N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4- piperidylidene)methyl]phenyl]ethyl]nicotinamide;hydrochlorideStep A: Preparation of 5-ethoxy-N-[ -1-[4-[(4-fluorophenyl)-(1-methyl-4- piperidylidene)methyl]phenyl]ethyl] 5-ethoxy-N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4- piperidylidene)methyl]phenyl]ethyl]nicotinamide was prepared according to GeneralProcedure 8 using Intermediate 7 (180 mg, 0.392 mmol) in a 5:1 dichloromethane / methanolmixture. The crude residues were purified by reverse phase column chromatography (acetonitrile / water / ammonium bicarbonate) to give 5-ethoxy-N-[(1R)-1-[4-[(4-fluorophenyl)- (1-methyl-4-piperidylidene)methyl]phenyl]ethyl]nicotinamide (105 mg, 0.222 mmol).Step B: Preparation of Example 21Example 21 was prepared according to General Procedure 7 using 5-ethoxy-N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]nicotinamide (105 mg, 0.222 mmol) and hydrogen chloride (0.222 mmol) to give Example 21 (110 mg, 0.216 mmol).1HNMR (400 MHz, dmso-d6) ppm 10.62 (m, 1H), 9.06 (m, 1H), 8.67 (m, 1H), 8.46 (m, 1H),7.84 (m, 1H), 7.37 (s, 2H), 7.16 (m, 4H), 7.1 (d, 2H), 5.18 (m, 1H), 4.18 (d, 2H), 3.43 (m, 2H), 3 (m, 2H), 2.73 (d, 3H), 2.51 (m, 4H), 1.49 (d, 3H), 1.36 (t, 3H). [M+H]+=474.2563. Example 22: 5-[1-(chloromethyl)-2-hydroxy-ethoxy]-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]nicotinamide;hydrochlorideStep A: Preparation of 4-[(4-fluorophenyl)-[4-[(1R)-1- (oxetan-3- yloxy)nicotinoyl]amino]ethyl]phenyl]methylene] 1-carboxylic acid tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-[[5-(oxetan-3-yloxy)nicotinoyl]amino]ethyl]phenyl] methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure 2B using Intermediate 2 (300 mg, 0.731 mmol) and sodium;5-(oxetan-3- yloxy)nicotinate (159 mg, 0.731 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 4-[(4- fluorophenyl)-[4-[(1R)-1-[[5-(oxetan-3-yloxy)nicotinoyl]amino]ethyl]phenyl]methylene] piperidine-1-carboxylic acid tert-butyl ester (275 mg, 0.469 mmol [M+H]+=588.3.Step B: Preparation of 5-[1-(chloromethyl)-2-hydroxy-ethoxy]-N-[ -1-[4-[(4- fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]nicotinamide 5-[1-(chloromethyl)-2-hydroxy-ethoxy]-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]nicotinamide was prepared according to General Procedure 1 using 4-[(4-fluorophenyl)-[4-[(1R)-1-[[5-(oxetan-3- yloxy)nicotinoyl]amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (275 mg, 0.468 mmol) in dichloromethane (0.3 M) and hydrogen chloride. The crude residues were purified by reverse phase column chromatography (acetonitrile / water / ammonium bicarbonate) to give 5-[1-(chloromethyl)-2-hydroxy-ethoxy]-N-[(1R)-1-[4-[(4-fluorophenyl)- (4-piperidylidene)methyl]phenyl]ethyl]nicotinamide (190 mg, 0.363 mmol).Step C: Preparation of 5-[1-(chloromethyl)-2-hydroxy-ethoxy]-N-[ -1-[4-[(4- fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]Example 22 was prepared according to General Procedure 7 using 5-[1-(chloromethyl)-2-hydroxy-ethoxy]-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]nicotinamide (75.0 mg, 0.143 mmol) and hydrogenchloride (0.286 mmol) to give Example 22 (80.0 mg, 0.134 mmol). 1H NMR (400 MHz,dmso-d6) ppm 9.09 (m, 1H), 9.03 (br s, 2H), 8.7 (s, 1H), 8.52 (d, 1H), 8 (s, 1H), 7.38 (d, 2H), 7.17 (m, 4H), 7.11 (d, 2H), 5.18 (quin, 1H), 4.77 (m, 1H), 3.98 (br d, 1H), 3.87 (br s, 1H), 3.67 (dd, 2H), 3.11 (br s, 4H), 2.44 (m, 4H), 1.49 (d, 3H) | [M+H]+=524.2118 Example 23: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5- [(3R)-tetrahydrofuran-3-yl]oxy-nicotinamide;hydrochloride Step A: Preparation of 5-[(3R)-tetrahydrofuran-3-yl]oxynicotinic acid methyl ester5-[(3R)-tetrahydrofuran-3-yl]oxynicotinic acid methyl ester was prepared according toGeneral Procedure 10 using methyl 5-hydroxypyridine-3-carboxylate (500 mg, 3.27 mmol)and (3S)-tetrahydrofuran-3-ol (288 mg, 3.27 mmol). The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 5-[(3R)-tetrahydrofuran-3-yl]oxynicotinic acid methyl ester (1.00 g, 2.69 mmol). [M+H]+=224.1.Step B: Preparation of sodium;5-[(3R)-tetrahydrofuran-3-yl]oxynicotinatesodium;5-[(3R)-tetrahydrofuran-3-yl]oxynicotinate was prepared according to GeneralProcedure 9A using 5-[(3R)-tetrahydrofuran-3-yl]oxynicotinic acid methyl ester (600 mg,2.69 mmol) to give sodium;5-[(3R)-tetrahydrofuran-3-yl]oxynicotinate (621 mg, 2.69 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification. [M+H]+=210.1.Step C: Preparation of 4-[(4-fluorophenyl)-[4-[(1R)-1- -tetrahydrofuran-3- yl]oxynicotinoyl]amino]ethyl]phenyl]methylene] carboxylic acid tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-[[5-[(3R)-tetrahydrofuran-3- yl]oxynicotinoyl]amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl esterwas prepared according to General Procedure 2B using Intermediate 2 (300 mg, 0.731 mmol)and sodium;5-[(3R)-tetrahydrofuran-3-yl]oxynicotinate (169 mg, 0.731 mmol) in N,N- dimethylformamide. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 4-[(4-fluorophenyl)-[4-[(1R)-1-[[5-[(3R)-tetrahydrofuran-3- yl]oxynicotinoyl]amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester(327 mg, 0.544 mmol). [M+H]+=602.4.Step D: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5-[(3R)-tetrahydrofuran-3-yl]oxy-nicotinamide N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5-[(3R)-tetrahydrofuran-3-yl]oxy-nicotinamide was prepared according to General Procedure 1 using4-[(4-fluorophenyl)-[4-[(1R)-1-[[5-[(3R)-tetrahydrofuran-3- yl]oxynicotinoyl]amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (327 mg, 0.544 mmol) in dichloromethane (0.3 M) and hydrogen chloride. The crude residues were purified by reverse phase column chromatography (acetonitrile / water / ammonium bicarbonate) to give N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]- 5-[(3R)-tetrahydrofuran-3-yl]oxy-nicotinamide (175 mg, 0.349 mmol).Step E: Preparation of Example 23Example 23 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5-[(3R)-tetrahydrofuran-3-yl]oxy- nicotinamide (65.0 mg, 0.129 mmol) and hydrogen chloride (0.259 mmol) to give Example23 (70.0 mg, 0.122 mmol). 1H NMR (400 MHz, dmso-d6) ppm 9.19 (br d, 3H), 8.76 (d,1H), 8.53 (d, 1H), 8.01 (m, 1H), 7.38 (d, 2H), 7.17 (m, 4H), 7.11 (d, 2H), 5.27 (dd, 1H), 5.18 (quin, 1H), 3.85 (m, 4H), 3.1 (br s, 4H), 2.44 (m, 4H), 2.28 (dt, 1H), 2 (m, 1H), 1.5 (d, 3H) | [M+H]+=502.2507 Example 24: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5- [(3S)-tetrahydrofuran-3-yl]oxy-nicotinamide;hydrochlorideStep A: Preparation of 4-[(4-fluorophenyl)- -tetrahydrofuran-3- yl]oxynicotinoyl]amino]ethyl]phenyl] acid tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-[[5-[(3S)-tetrahydrofuran-3-yl]oxynicotinoyl]amino]ethyl] phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure 2B using Intermediate 2 (300 mg, 0.731 mmol) and sodium;5-[(3S)- tetrahydrofuran-3-yl]oxynicotinate (169 mg, 0.731 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 4-[(4-fluorophenyl)-[4-[(1R)-1-[[5-[(3S)-tetrahydrofuran-3-yl]oxynicotinoyl]amino] ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (344 mg, 0.572 mmol). [M+H]+=602.4.Step B: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-nicotinamide N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5-[(3S)- tetrahydrofuran-3-yl]oxy-nicotinamide was prepared according to General Procedure 1 using 4-[(4-fluorophenyl)-[4-[(1R)-1-[[5-[(3S)-tetrahydrofuran-3-yl]oxynicotinoyl]amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (344 mg, 0.572 mmol) indichloromethane (0.3 M) and hydrogen chloride. The crude residues were purified by reverse phase column chromatography (acetonitrile / water / ammonium bicarbonate) to give N-[(1R)-1- [4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3- yl]oxy-nicotinamide (175 mg, 0.349 mmol).Step C: Preparation of Example 24Example 24 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy- nicotinamide (75.0 mg, 0.149 mmol) and hydrogen chloride (0.299 mmol) to give Example24 (80.0 mg, 0.139 mmol). 1H NMR (400 MHz, dmso-d6) ppm 9.19 (br d, 3H), 8.76 (d,1H), 8.53 (d, 1H), 8.01 (m, 1H), 7.38 (d, 2H), 7.17 (m, 4H), 7.11 (d, 2H), 5.27 (dd, 1H), 5.18 (quin, 1H), 3.85 (m, 4H), 3.1 (br s, 4H), 2.44 (m, 4H), 2.28 (m, 1H), 2 (m, 1H), 1.5 (d, 3H) | [M+H]+=502.2506 Example 25: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5- tetrahydropyran-4-yloxy-nicotinamide;hydrochloride Example 25 was prepared according to General Procedure 7 using Intermediate 8 (75.0 mg,0.145 mmol) and hydrogen chloride (0.290 mmol) to give Example 25 (80.0 mg, 0.135mmol). 1H NMR (400 MHz, dmso-d6) ppm 9.13 (m, 3H), 8.72 (d, 1H), 8.55 (d, 1H), 8.01(s, 1H), 7.38 (d, 2H), 7.15 (m, 6H), 5.17 (quin, 2H), 4.83 (br d, 1H), 3.86 (m, 2H), 3.51 (m, 2H), 3.1 (br s, 4H), 2.44 (m, 4H), 2 (br d, 2H), 1.61 (m, 2H), 1.49 (d, 3H) | [M+H]+=516.2626 Example 26: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5- methoxy-nicotinamide;hydrochloride Example 26 was prepared according to a modified General Procedure 7 using Intermediate 5(100 mg, 0.225 mmol) and hydrogen chloride (0.112 mL, 0.449 mmol). The residues were purified by SFC (ethanol / diethylamine / carbon dioxide) to give Example 26 (45.0 mg, 0.0868 mmol). Example 27: 5-[1-(chloromethyl)-2-hydroxy-ethoxy]-N-[(1R)-1-[4-[(4-fluorophenyl)-(1- methyl-4-piperidylidene)methyl]phenyl]ethyl]nicotinamide;hydrochloride Step A: Preparation of 5-[1-(chloromethyl)-2-hydroxy-ethoxy]-N-[ -1-[4-[(4- fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]nicotinamide 5-[1-(chloromethyl)-2-hydroxy-ethoxy]-N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4- piperidylidene)methyl]phenyl]ethyl]nicotinamide was prepared according to General Procedure 8 using 5-[1-(chloromethyl)-2-hydroxy-ethoxy]-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]nicotinamide (110 mg, 0.209 mmol) in tetrahydrofuran (0.05 M). The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give 5-[1-(chloromethyl)-2-hydroxy-ethoxy]- N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4- piperidylidene)methyl]phenyl]ethyl]nicotinamide (71.0 mg, 0.132 mmol).Step B: Preparation of Example 27Example 27 was prepared according to General Procedure 7 using 5-[1-(chloromethyl)-2-hydroxy-ethoxy]-N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4- piperidylidene)methyl]phenyl]ethyl]nicotinamide (71.0 mg, 0.132 mmol) and hydrogenchloride (0.132 mmol) to give Example 27 (70.0 mg, 0.121 mmol). 1H NMR (400 MHz,dmso-d6) ppm 10.47 (br s, 1H), 9.07 (d, 1H), 8.7 (s, 1H), 8.52 (d, 1H), 7.99 (m, 1H), 7.39 (d, 2H), 7.16 (m, 4H), 7.1 (d, 2H), 5.18 (quin, 1H), 4.77 (quin, 1H), 3.95 (br dd, 1H), 3.87 (m, 1H), 3.67 (dd, 2H), 3.42 (br d, 2H), 3.01 (m, 2H), 2.74 (d, 3H), 2.49 (br s, 4H), 1.49 (d, 3H) | [M+H]+ = 538.2233 Example 28: N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4- piperidylidene)methyl]phenyl]ethyl]-5-[(3R)-tetrahydrofuran-3-yl]oxy- nicotinamide;hydrochloride Step A: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-[(3R)-tetrahydrofuran-3-yl]oxy-nicotinamide N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-[(3R)- tetrahydrofuran-3-yl]oxy-nicotinamide was prepared according to General Procedure 8 using N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5-[(3R)- tetrahydrofuran-3-yl]oxy-nicotinamide (110 mg, 0.219 mmol) in tetrahydrofuran (0.05 M). The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give N-[(1R)-1-[4-[(4-fluorophenyl)-(1- methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-[(3R)-tetrahydrofuran-3-yl]oxy-nicotinamide (110 mg, 0.213 mmol).Step B: Preparation of Example 28Example 28 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-[(3R)-tetrahydrofuran-3- yl]oxy-nicotinamide (72.0 mg, 0.139 mmol) and hydrogen chloride (0.290 mmol) to giveExample 28 (75.0 mg, 0.135 mmol). 1H NMR (400 MHz, dmso-9.06 (d, 1H), 8.7 (d, 1H), 8.46 (d, 1H), 7.86 (m, 1H), 7.38 (d, 2H), 7.16 (m, 4H), 7.1 (d, 2H), 5.23 (m, 1H), 5.18 (m, 1H), 3.81 (m, 4H), 3.42 (br d, 2H), 3.01 (m, 2H), 2.74 (d, 3H), 2.51 (br s, 4H), 2.27 (m, 1H), 1.99 (m, 1H), 1.49 (d, 3H) | [M+H]+=516.2663. Example 29: 3-(aminomethyl)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]benzamide;hydrochloride phenyl]-(4- fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester 4-[[4-[(1R)-1-[[3-[(tert-butoxycarbonylamino)methyl]benzoyl]amino]ethyl]phenyl]-(4- fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared accordingto a modified General Procedure 2C using 3-[(tert-butoxycarbonylamino)methyl]benzoic acid(93.0 mg, 0,370 mmol) and Intermediate 2 (182.3 mg, 0,444 mmol, 1.2 eq.) in N- methylpyrrolidin-2-one to give the crude 4-[[4-[(1R)-1-[[3-[(tert- butoxycarbonylamino)methyl]benzoyl]amino]ethyl]phenyl]-(4-fluorophenyl)methylene] piperidine-1-carboxylic acid tert-butyl ester (238 mg, 0.370 mmol), which was used into the next step without further purification, considering a quantitative yield.Step B: Preparation of 3-(aminomethyl)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]benzamide 3-(aminomethyl)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]benzamide was prepared according to General Procedure 1 using 4-[[4-[(1R)-1-[[3-[(tert-butoxycarbonylamino)methyl]benzoyl]amino]ethyl]phenyl]-(4-fluorophenyl)methylene] piperidine-1-carboxylic acid tert-butyl ester (283 mg, 0.440 mmol) and hydrogen chloride in dichloromethane (0.3 M). The crude residues were purified by silica gel column chromatography (dichloromethane / methanol / ammoniac) to give 3-(aminomethyl)-N-[(1R)-1- [4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]benzamide (45.0 mg, 0.104 mmol).Step C: Preparation of Example 29Example 29 was prepared according to General Procedure 7 using 3-(aminomethyl)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]benzamide (43.0 mg, 0.0969 mmol) and hydrogen chloride (0.139 mmol) to give Example 29 (49.1 mg, 0.0951 mmol).1HNMR (400 MHz, dmso-7.89 (m, 1H), 7.62 (m, 1H), 7.52 (m, 1H), 7.38 (br d, 2H), 7.16 (m, 4H), 7.1 (m, 2H), 5.16 (m, 1H), 4.07 (m, 2H), 3.1 (m, 4H), 2.4 (m, 4H), 1.48 (m, 3H) | [M+H]+=444.2453 Example 30: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5- isopropoxy-nicotinamide;hydrochloride Example 30 was prepared according to General Procedure 7 using Intermediate 6 (100 mg,0.211 mmol) and hydrogen chloride (0.422 mmol) to give Example 30 (55.0 mg, 0.100mmol). 1H NMR (400 MHz, dmso-8.44 (d, 1H), 7.87 (br s, 1H), 7.37 (d, 2H), 7.17 (m, 4H), 7.11 (d, 2H), 5.17 (quin, 1H), 4.8 (dt, 1H), 3.11 (br s, 4H), 2.43 (m, 4H), 1.48 (d, 3H), 1.3 (dd, 6H) | [M+H]+=474.2565 Example 31: 5-ethoxy-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]nicotinamide;hydrochlorideExample 31 was prepared according to General Procedure 7 using Intermediate 7 (100 mg,0.217 mmol) and hydrogen chloride (0.435 mmol) to give Example 31 (45.0 mg, 0.0845mmol). 1H NMR (400 MHz, dmso-s, 1H), 7.38 (d, 2H), 7.17 (m, 4H), 7.11 (d, 2H), 5.18 (quin, 1H), 4.2 (m, 2H), 3.11 (br s, 4H), 2.44 (m, 4H), 1.49 (d, 3H), 1.37 (t, 3H) | [M+H]+=460.2404 Example 32: N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4- piperidylidene)methyl]phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy- nicotinamide;hydrochloride Step A: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-nicotinamide N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-nicotinamide was prepared according to General Procedure 8 usingN-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5-[(3S)- tetrahydrofuran-3-yl]oxy-nicotinamide (100 mg, 0.199 mmol) in tetrahydrofuran (0.05 M). The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give N-[(1R)-1-[4-[(4-fluorophenyl)-(1- methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-nicotinamide (90.0 mg, 0.174 mmol).Step B: Preparation of Example 32Example 32 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3- yl]oxy-nicotinamide (50.0 mg, 0.0969 mmol) and hydrogen chloride (0.193 mmol) to giveExample 32 (40.0 mg, 0.0679 mmol). 1H NMR (400 MHz, dmso-d6) ppm 10.73 (br s, 1H),9.12 (d, 1H), 8.73 (d, 1H), 8.49 (d, 1H), 7.93 (m, 1H), 7.39 (d, 2H), 7.16 (m, 4H), 7.1 (d, 2H), 5.25 (dd, 1H), 5.18 (quin, 1H), 3.84 (m, 4H), 3.42 (br d, 2H), 3 (m, 2H), 2.73 (d, 3H), 2.51 (m, 4H), 2.27 (m, 1H), 2 (m, 1H), 1.49 (d, 3H) | [M+H]+=516.267. Example 33: N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl] ethyl]-5-tetrahydropyran-4-yloxy-nicotinamide;hydrochloride Step A: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-tetrahydropyran-4-yloxy-nicotinamide N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-tetrahydropyran-4-yloxy-nicotinamide was prepared according to General Procedure 8 usingIntermediate 8 (80.0 mg, 0.155 mmol) in tetrahydrofuran (0.05 M). The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5- tetrahydropyran-4-yloxy-nicotinamide (50.0 mg, 0.0944 mmol).Step B: Preparation of Example 33Example 33 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-5-tetrahydropyran-4-yloxy- nicotinamide (50.0 mg, 0.0944 mmol) and hydrogen chloride (0.188 mmol) to give Example33 (50.0 mg, 0.0829 mmol). 1H NMR (400 MHz, dmso-1H), 8.7 (d, 1H), 8.53 (d, 1H), 7.96 (s, 1H), 7.39 (d, 2H), 7.16 (m, 4H), 7.1 (d, 2H), 5.18 (quin, 1H), 4.8 (tt, 1H), 3.86 (m, 2H), 3.51 (m, 2H), 3.42 (br d, 2H), 3.01 (m, 2H), 2.73 (d, 3H), 2.51 (m, 4H), 2 (br d, 2H), 1.61 (m, 2H), 1.49 (d, 3H) | [M+H]+=530.2820 Example 34: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5- (oxetan-3-yloxy)nicotinamide Example 34 was prepared according to General Procedure 1 using 4-[(4-fluorophenyl)-[4-[(1R)-1-[[5-(oxetan-3-yloxy)nicotinoyl]amino]ethyl]phenyl]methylene]piperidine-1- carboxylic acid tert-butyl ester (209 mg, 0.355 mmol) and hydrogen chloride in dichloromethane (0.3 M). The crude residues were purified by reverse phase chromatography(water / acetonitrile / ammonium bicarbonate) to give Example 34 (80.0 mg, 0.164 mmol). 1HNMR (400 MHz, dmso-7.32 (d, 2H), 7.11 (m, 4H), 7.05 (d, 2H), 5.44 (t, 1H), 5.16 (t, 1H), 4.95 (t, 2H), 4.57 (br t, 2H), 2.71 (m, 4H), 2.13 (m, 5H), 1.47 (d, 3H) | [M+H]+=488.2356 Example 35: N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4- fluorophenyl)methyl]phenyl]ethyl]-1-methyl-pyrazole-4-carboxamideStep A: Preparation of 6-[(4-fluorophenyl)- -1-[(1-methylpyrazole-4-carbonyl) amino]ethyl]phenyl]methylene]-2-azaspiro 2-carboxylic acid tert-butyl ester 6-[(4-fluorophenyl)-[4-[(1R)-1-[(1-methylpyrazole-4-carbonyl)amino]ethyl]phenyl] methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was prepared accordingto General Procedure 2B using Intermediate 3 (300 mg, 0.71 mmol) and 1-methylpyrazole-4-carboxylic acid (89.5 mg, 0.709 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (ethyl acetate) to give 6-[(4-fluorophenyl)-[4- [(1R)-1-[(1-methylpyrazole-4-carbonyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3] heptane-2-carboxylic acid tert-butyl ester (377 mg, 0.710 mmol). [M+H]+=530.3.Step B: Preparation of Example 35Example 35 was prepared according to General Procedure 1 using 6-[(4-fluorophenyl)-[4-[(1R)-1-[(1-methylpyrazole-4-carbonyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3] heptane-2-carboxylic acid tert-butyl ester (370 mg, 0.697 mmol) and hydrogen chloride in dichloromethane (0.3 M). The crude residues were purified by reverse phase chromatography(water / acetonitrile / ammonium bicarbonate) to give Example 35 (94.0 mg, 0.218 mmol). 1HNMR (400 MHz, dmso-(m, 4H), 7.05 (m, 2H), 5.11 (quin, 1H), 3.79 (m, 8H), 3 (m, 4H), 1.43 (d, 3H). [M+H]+=431.2246 Example 36: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5- (oxetan-3-ylmethoxy)nicotinamideStep A: Preparation of 4-[(4-fluorophenyl)- -1-[[5-(oxetan-3-ylmethoxy)nicotinoyl] amino]ethyl]phenyl]methylene]piperidine- acid tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-[[5-(oxetan-3-ylmethoxy)nicotinoyl]amino]ethyl]phenyl] methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure 2B using Intermediate 2 (500 mg, 1.21 mmol) and sodium;5-(oxetan-3-ylmethoxy) nicotinate (281 mg, 1.21 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 4-[(4-fluorophenyl)-[4- [(1R)-1-[[5-(oxetan-3-ylmethoxy)nicotinoyl]amino]ethyl]phenyl]methylene]piperidine-1- carboxylic acid tert-butyl ester (237 mg, 0.393 mmol). [M+H]+=602.4.Step B: Preparation of Example 36Example 36 was prepared according to General Procedure 1 using 4-[(4-fluorophenyl)-[4-[(1R)-1-[[5-(oxetan-3-ylmethoxy)nicotinoyl]amino]ethyl]phenyl]methylene]piperidine-1- carboxylic acid tert-butyl ester (237 mg, 0.393 mmol) and hydrogen chloride in dichloromethane (0.3 M). The crude residues were purified by reverse phase chromatography(water / acetonitrile / ammonium bicarbonate) to give Example 36 (80.0 mg, 0.159 mmol). 1HNMR (400 MHz, dmso-7.35 (d, 2H), 7.14 (d, 4H), 7.08 (d, 2H), 5.17 (t, 1H), 4.72 (dd, 2H), 4.44 (t, 2H), 4.34 (d, 2H), 3.41 (m, 2H), 2.95 (br s, 4H), 2.31 (m, 4H), 1.48 (d, 3H) | [M+H]+=502.2475 Example 37: N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4- piperidylidene)methyl]phenyl]ethyl]-5-(oxetan-3-ylmethoxy)nicotinamideExample 37 was prepared according to General Procedure 8 using N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5-(oxetan-3-ylmethoxy)nicotinamide (50.0 mg, 0.0996 mmol) in a 5:1 dichloromethane / methanol mixture. The crude residues were purified by SFC (carbon dioxide / methanol / diethylamine) to give Example 37 (42.0 mg,0.0814 mmol). 1H NMR (400 MHz, dmso-7.82 (dd, 1H), 7.34 (d, 2H), 7.12 (m, 4H), 7.06 (m, 2H), 5.17 (quin, 1H), 4.72 (dd, 2H), 4.44(t, 2H), 4.34 (d, 2H), 3.41 (m, 2H), 2.39 (br s, 3H), 2.25 (m, 4H), 2.21 (m, 3H), 1.48 (d, 3H) |[M+H]+=516.2657 Example 38: N-[ -1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl] ethyl]-1-methyl-pyrazole-4-carboxamide Example 38 was prepared according to General Procedure 8 using Example 35 (70.0 mg,0.162 mmol) in a 5:1 dichloromethane / methanol mixture. The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give Example38 (50.0 mg, 0.112 mmol). 1H NMR (400 MHz, dmso-d6) ppm 8.33 (d, 1H), 8.15 (s, 1H),7.87 (s, 1H), 7.3 (m, 2H), 7.13 (m, 4H), 7.05 (m, 2H), 5.11 (quin, 1H), 3.84 (s, 3H), 3.24 (m, 4H), 2.97 (br d, 4H), 2.22 (s, 3H), 1.43 (d, 3H) | [M+H]+=445.2401 Example 39: 1-ethyl-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]pyrazole-4-carboxamide;hydrochloride fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester 4-[[4-[(1R)-1-[(1-ethylpyrazole-4-carbonyl)amino]ethyl]phenyl]-(4-fluorophenyl) methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to a modifiedGeneral Procedure 2A using 1-ethylpyrazole-4-carboxylic acid (52.0 mg, 0,371 mmol) andIntermediate 2 (183 mg, 0,445 mmol, 1.2 eq.) in 1-methylpyrrolidin-2-one to give the crude 4-[[4-[(1R)-1-[(1-ethylpyrazole-4-carbonyl)amino]ethyl]phenyl]-(4-fluorophenyl)methylene] piperidine-1-carboxylic acid tert-butyl ester (197 mg, 0.371 mmol), which was used into the next step without further purification, considering a quantitative yield.Step B: Preparation of 1-ethyl-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]pyrazole-4-carboxamide 1-ethyl-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]pyrazole-4-carboxamide was prepared according to General Procedure 1 using 4-[[4-[(1R)-1-[(1-ethylpyrazole-4-carbonyl)amino]ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1- carboxylic acid tert-butyl ester (198 mg, 0,37 mmol) and hydrogen chloride in dichloromethane (0.3 M). The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give 1-ethyl-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]pyrazole-4-carboxamide (35.0 mg, 0.0809 mmol).Step C: Preparation of Example 39Example 39 was prepared according to General Procedure 7 using 1-ethyl-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]pyrazole-4-carboxamide (35.0 mg, 0.0809 mmol) and hydrogen chloride (0.242 mmol) to give Example 39 (40.2 mg, 0.0795mmol). 1H NMR (400 MHz, dmso-(s, 1H), 7.32 (m, 2H), 7.16 (d, 4H), 7.08 (m, 2H), 5.1 (quin, 1H), 4.13 (q, 2H), 3.11 (br s, 4H), 2.43 (m, 4H), 1.42 (d, 3H), 1.36 (t, 3H). [M+H]+=433.2407 Example 40: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1- isopropyl-pyrazole-4-carboxamide;hydrochloride Step A: Preparation of 4-[(4-fluorophenyl)-[4-[ -1-[(1-isopropylpyrazole-4- carbonyl)amino]ethyl]phenyl]methylene] 1-carboxylic acid tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-[(1-isopropylpyrazole-4- carbonyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester wasprepared according to a modified General Procedure 2A using 1-isopropylpyrazole-4-carboxylic acid (57.0 mg, 0,369 mmol) and Intermediate 2 (182 mg, 0,442 mmol, 1.2 eq.) in 1-methylpyrrolidin-2-one to give the crude 4-[(4-fluorophenyl)-[4-[(1R)-1-[(1- isopropylpyrazole-4-carbonyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (202 mg, 0.369 mmol), which was used into the next step without further purification, considering a quantitative yield.Step B: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-isopropyl-pyrazole-4-carboxamide N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-isopropyl-pyrazole-4-carboxamide was prepared according to General Procedure 1 using 4-[(4-fluorophenyl)-[4-[(1R)-1-[(1-isopropylpyrazole-4-carbonyl)amino]ethyl]phenyl]methylene]piperidine-1- carboxylic acid tert-butyl ester (202 mg, 0,37 mmol) and hydrogen chloride in dichloromethane (0.3 M). The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]-1-isopropyl-pyrazole-4-carboxamide (32.0 mg, 0.0716 mmol).Step C: Preparation of Example 40Example 40 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-isopropyl-pyrazole-4-carboxamide (32.0 mg, 0.0716 mmol) and hydrogen chloride (0.250 mmol) to give Example 40 (35.1 mg,0.0676 mmol). 1H NMR (400 MHz, dmso-1H), 7.88 (s, 1H), 7.33 (m, 2H), 7.16 (d, 4H), 7.08 (m, 2H), 5.1 (quin, 1H), 4.49 (quin, 1H), 3.11 (m, 4H), 2.43 (m, 4H), 1.41 (m, 9H) | [M+H]+=447.2563 Example 41: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1- isobutyl-pyrazole-4-carboxamide;hydrochloride Step A: Preparation of 4-[(4-fluorophenyl)-[4-[(1R)-1-[(1-isobutylpyrazole-4-carbonyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-[(1-isobutylpyrazole-4-carbonyl)amino]ethyl]phenyl] methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to a modifiedGeneral Procedure 2A using 1-isobutylpyrazole-4-carboxylic acid (62.0 mg, 0,368 mmol) andIntermediate 2 (181.6 mg, 0,442 mmol, 1.2 eq.) in 1-methylpyrrolidin-2-one to give the crude 4-[(4-fluorophenyl)-[4-[(1R)-1-[(1-isobutylpyrazole-4-carbonyl)amino]ethyl]phenyl] methylene]piperidine-1-carboxylic acid tert-butyl ester (206 mg, 0.369 mmol), which was used into the next step without further purification, considering a quantitative yield.Step B: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-isobutyl-pyrazole-4-carboxamide N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-isobutyl-pyrazole-4-carboxamide was prepared according to General Procedure 1 using 4-[(4-fluorophenyl)-[4-[(1R)-1-[(1-isobutylpyrazole-4-carbonyl)amino]ethyl]phenyl]methylene]piperidine-1- carboxylic acid tert-butyl ester (207 mg, 0,369 mmol) and hydrogen chloride in dichloromethane (0.3 M). The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]-1-isobutyl-pyrazole-4-carboxamide (36.0 mg, 0.0781 mmol).Step C: Preparation of Example 41Example 41 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-isobutyl-pyrazole-4-carboxamide (36.0 mg, 0.0781 mmol) and hydrogen chloride (0.273 mmol) to give Example 41 (36.4 mg,0.0682 mmol). 1H NMR (400 MHz, dmso-1H), 7.9 (s, 1H), 7.33 (m, 2H), 7.16 (m, 4H), 7.09 (m, 2H), 5.1 (quin, 1H), 3.91 (d, 2H), 3.49 (m, 1H), 3.11 (br s, 4H), 2.43 (m, 4H), 2.09 (m, 1H), 1.43 (d, 3H), 0.83 (d, 6H). [M+H]+=461.2715 Example 42: 1-(difluoromethyl)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]pyrazole-4-carboxamide;hydrochlorideStep A: Preparation of 4-[[4-[(1R)-1-[[1-(difluoromethyl)pyrazole-4-carbonyl]amino]ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester 4-[[4-[(1R)-1-[[1-(difluoromethyl)pyrazole-4-carbonyl]amino]ethyl]phenyl]-(4- fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared accordingto a modified General Procedure 2A using 1-(difluoromethyl)pyrazole-4-carboxylic acid (60.0mg, 0,370 mmol) and Intermediate 2 (182 mg, 0,444 mmol, 1.2 eq.) in 1-methylpyrrolidin-2- one to give the crude 4-[[4-[(1R)-1-[[1-(difluoromethyl)pyrazole-4- carbonyl]amino]ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1-carboxylic acid tert- butyl ester (205 mg, 0.370 mmol), considering a quantitative yield.Step B: Preparation of 1-(difluoromethyl)-N-[ -1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]pyrazole- 1-(difluoromethyl)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]pyrazole-4-carboxamide was prepared according toGeneral Procedure 1 using 4-[[4-[(1R)-1-[[1-(difluoromethyl)pyrazole-4-carbonyl]amino]ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1-carboxylic acid tert- butyl ester (205 mg, 0,369 mmol) and hydrogen chloride in dichloromethane (0.3 M). The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give 1-(difluoromethyl)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]pyrazole-4-carboxamide (47 mg, 0.103 mmol).Step C: Preparation of Example 42Example 42 was prepared according to General Procedure 7 using 1-(difluoromethyl)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]pyrazole-4-carboxamide (47.0 mg, 0.103 mmol) and hydrogen chloride (0.361 mmol) to give Example 42 (49.4 mg,0.0912 mmol). 1H NMR (400 MHz, dmso- 1H), 8.19 (s, 1H), 7.85 (m, 1H), 7.34 (d, 2H), 7.15 (m, 6H), 5.11 (quin, 1H), 3.11 (br s, 4H), 2.43 (m, 4H), 1.44 (d, 3H) | [M+H]+=455.2058 Example 43: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1- (2,2,2-trifluoroethyl)pyrazole-4-carboxamide;hydrochloride Step A: Preparation of 4-[(4-fluorophenyl)-[4-[(1R)-1-[[1-(2,2,2-trifluoroethyl)pyrazole-4-carbonyl]amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-[[1-(2,2,2-trifluoroethyl)pyrazole-4-carbonyl]amino]ethyl] phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to amodified General Procedure 2A using 1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylic acid (72.0mg, 0,370 mmol) and Intermediate 2 (183 mg, 0,445 mmol, 1.2 eq.) in 1-methylpyrrolidin-2- one to give the crude 4-[(4-fluorophenyl)-[4-[(1R)-1-[[1-(2,2,2-trifluoroethyl)pyrazole-4- carbonyl]amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (217 mg, 0.370 mmol), considering a quantitative yield.Step B: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide was prepared according to General Procedure 1 using4-[(4-fluorophenyl)-[4-[(1R)-1-[[1-(2,2,2-trifluoroethyl)pyrazole-4- carbonyl]amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (217 mg, 0,369 mmol) and hydrogen chloride in dichloromethane (0.3 M). The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-(2,2,2- trifluoroethyl)pyrazole-4-carboxamide (45.0 mg, 0.0925 mmol).Step C: Preparation of Example 43Example 43 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-(2,2,2-trifluoroethyl)pyrazole-4- carboxamide (45.0 mg, 0.0925 mmol) and hydrogen chloride (0.323 mmol) to give Example43 (45.2 mg, 0.0808 mmol). 1H NMR (400 MHz, dmso-1H), 8.33 (s, 1H), 8.03 (s, 1H), 7.33 (d, 2H), 7.16 (m, 4H), 7.09 (d, 2H), 5.19 (quad, 2H), 5.11 (quin, 1H), 3.11 (m, 4H), 2.43 (m, 4H), 1.43 (d, 3H) | [M+H]+=487.2051 (4-fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester 4-[[4-[(1R)-1-[(1-tert-butylpyrazole-4-carbonyl)amino]ethyl]phenyl]-(4-fluorophenyl) methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to a modifiedGeneral Procedure 2A using 1-tert-butylpyrazole-4-carboxylic acid (63.0 mg, 0,374 mmol)and Intermediate 2 (186 mg, 0,449 mmol, 1.2 eq.) in 1-methylpyrrolidin-2-one to give the crude 4-[[4-[(1R)-1-[(1-tert-butylpyrazole-4-carbonyl)amino]ethyl]phenyl]-(4-fluorophenyl) methylene]piperidine-1-carboxylic acid tert-butyl ester (210 mg, 0.374 mmol), which was used into the next step without further purification, considering a quantitative yield. -(4- 1-tert-butyl-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]pyrazole-4-carboxamide was prepared according to General Procedure 1 using 4-[[4-[(1R)-1-[(1-tert-butylpyrazole-4-carbonyl)amino]ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1- carboxylic acid tert-butyl ester (210 mg, 0,374 mmol) and hydrogen chloride in dichloromethane (0.3 M). The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give 1-tert-butyl-N-[(1R)-1-[4-[(4- fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]pyrazole-4-carboxamide (38.0 mg, 0.0825 mmol).Step C: Preparation of Example 44Example 44 was prepared according to General Procedure 7 using 1-tert-butyl-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]pyrazole-4-carboxamide (38.0 mg, 0.0825 mmol) and hydrogen chloride (0.288 mmol) to give Example 44 (36.1 mg, 0.0677mmol). 1H NMR (400 MHz, dmso-(d, 2H), 7.16 (m, 4H), 7.09 (d, 2H), 5.09 (quin, 1H), 3.11 (m, 4H), 2.42 (m, 4H), 1.52 (s, 9H), 1.43 (m, 3H). [M+H]+=461.2720 1-carboxylic acid tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-[(1-tetrahydropyran-4-ylpyrazole-4- carbonyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester wasprepared according to a modified General Procedure 2A using 1-tetrahydropyran-4-ylpyrazole-4-carboxylic acid (73.0 mg, 0,372 mmol) and Intermediate 2 (183 mg, 0,446 mmol, 1.2 eq.) in 1-methylpyrrolidin-2-one to give the crude 4-[(4-fluorophenyl)-[4-[(1R)-1- [(1-tetrahydropyran-4-ylpyrazole-4-carbonyl)amino]ethyl]phenyl]methylene]piperidine-1- carboxylic acid tert-butyl ester (219 mg, 0.372 mmol), which was used into the next step without further purification, considering a quantitative yield.Step B: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide was prepared according to General Procedure 1 using 4-[(4-fluorophenyl)-[4-[(1R)-1-[(1-tetrahydropyran-4-ylpyrazole-4- carbonyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (219 mg, 0,372 mmol) and hydrogen chloride in dichloromethane (0.3 M). The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give 1-tert-butyl-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]pyrazole- 4-carboxamide (46.0 mg, 0.0941 mmol).Step C: Preparation of Example 45Example 45 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-tetrahydropyran-4-yl-pyrazole-4- carboxamide (46.0 mg, 0.0941 mmol) and hydrogen chloride (0.329 mmol) to give Example45 (43.1 mg, 0.0768 mmol). 1H NMR (400 MHz, dmso-1H), 8.29 (s, 1H), 7.92 (s, 1H), 7.33 (d, 2H), 7.16 (m, 4H), 7.09 (d, 2H), 5.1 (quin, 1H), 4.42 (m, 1H), 3.94 (m, 2H), 3.43 (m, 2H), 3.11 (m, 4H), 2.41 (m, 4H), 1.93 (2m, 4H), 1.43 (d, 3H). [M+H]+=489.2672 Example 46: 1-cyclopentyl-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]pyrazole-4-carboxamide;hydrochloride A: Preparation of 4-[[4-[(1R)-1-[(1-cyclopentylpyrazole-4-carbonyl)amino]ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1-carboxylic acid tert- butyl ester 4-[[4-[(1R)-1-[(1-cyclopentylpyrazole-4-carbonyl)amino]ethyl]phenyl]-(4- fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to a modified General Procedure 2A using 1-cyclopentylpyrazole-4-carboxylic acid (67.0 mg,0,371 mmol) and Intermediate 2 (183 mg, 0,446 mmol, 1.2 eq.) in 1-methylpyrrolidin-2-one to give the crude 4-[[4-[(1R)-1-[(1-cyclopentylpyrazole-4-carbonyl)amino]ethyl]phenyl]-(4- fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester (213 mg, 0.371 mmol), which was used into the next step without further purification, considering a quantitative yield. 1-cyclopentyl-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]pyrazole-4-carboxamide was prepared according to General Procedure 1 using 4-[[4-[(1R)-1-[(1-cyclopentylpyrazole-4-carbonyl)amino]ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1-carboxylic acid tert- butyl ester (219 mg, 0,372 mmol) and hydrogen chloride in dichloromethane (0.3 M). The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammoniumbicarbonate) to give 1-cyclopentyl-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]pyrazole-4-carboxamide (35.0 mg, 0.074 mmol). Step C: Preparation of Example 46Example 46 was prepared according to General Procedure 7 using 1-cyclopentyl-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]pyrazole-4-carboxamide (35.0 mg, 0.0740 mmol) and hydrogen chloride (0.259 mmol) to give Example 46 (35.3 mg, 0.0647 mmol). 1H NMR (400 MHz, dmso-(s, 1H), 7.33 (d, 2H), 7.16 (m, 4H), 7.08 (d, 2H), 5.1 (quin, 1H), 4.67 (quin, 1H), 3.11 (m, 4H), 2.41 (m, 4H), 2.1 (m, 2H), 1.9 (m, 2H), 1.77 (m, 2H), 1.64 (m, 2H), 1.42 (d, 3H). [M+H]+=473.2663 Example 47: N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-hydroxyethyl)-4- piperidylidene]methyl]phenyl]ethyl]-5-methoxy-nicotinamide;hydrochloride Step A: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-hydroxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]-5-methoxy-nicotinamide N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-hydroxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]-5-methoxy-nicotinamide was prepared according to General Procedure 11 using Intermediate5 (75.0 mg, 0.168 mmol, 1.0 eq.) and 2-bromoethanol (23.1 mg, 0.0100 mL, 0.185 mmol, 1.1 eq.) in acetonitrile. The crude residues were purified by silica gel column chromatography (dichloromethane / methanol / ammoniac) to give N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2- hydroxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]-5-methoxy-nicotinamide (70.0 mg, 0.143 mmol).Step B: Preparation of Example 47Example 47 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-hydroxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]-5-methoxy- nicotinamide (70.0 mg, 0.143 mmol) and hydrogen chloride (0.285 mmol) to give Example47 (70.0 mg, 0.124 mmol). 1H NMR (400 MHz, dmso-1H), 8.69 (d, 1H), 8.47 (d, 1H), 7.87 (m, 1H), 7.39 (d, 2H), 7.17 (m, 4H), 7.1 (d, 2H), 5.18 (m, 1H), 3.9 (s, 3H), 3.76 (br s, 2H), 3.53 (br d, 2H), 3.15 (br d, 2H), 3.05 (m, 2H), 2.54 (m, 4H), 1.49 (d, 3H) | [M+H]+=490.2513 Example 48: N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-methoxyethyl)-4- piperidylidene]methyl]phenyl]ethyl]-5-methoxy-nicotinamide;hydrochlorideStep A: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-methoxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]-5-methoxy-nicotinamide N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-methoxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]-5-methoxy-nicotinamide was prepared according to General Procedure 11 using Intermediate5 (75.0 mg, 0.168 mmol, 1.0 eq.) and 1-bromo-2-methoxy-ethane (25.7 mg, 0.174 mmol, 1.0 eq.) in acetonitrile. The crude residues were purified by silica gel column chromatography (dichloromethane / methanol) to give N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-methoxyethyl)-4- piperidylidene]methyl]phenyl]ethyl]-5-methoxy-nicotinamide (70.0 mg, 0.139 mmol).Step B: Preparation of Example 48Example 48 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-methoxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]-5-methoxy- nicotinamide (70.0 mg, 0.139 mmol) and hydrogen chloride (0.278 mmol) to give Example48 (70.0 mg, 0.121 mmol). 1H NMR (400 MHz, dmso-1H), 8.7 (d, 1H), 8.48 (d, 1H), 7.89 (br s, 1H), 7.39 (d, 2H), 7.17 (m, 4H), 7.1 (d, 2H), 5.18 (quin, 1H), 3.91 (s, 3H), 3.69 (m, 2H), 3.5 (br d, 2H), 3.29 (s, 3H), 3.27 (br d, 2H), 3.05 (m, 2H), 2.52 (m, 4H), 1.49 (d, 3H) | [M+H]+=504.2666 Example 49: N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4- piperidylidene)methyl]phenyl]ethyl]-1-methyl-pyrazole-4-carboxamide;hydrochlorideStep A: Preparation of 4-[(4-fluorophenyl)-[4-[(1R)-1-[(1-methylpyrazole-4-carbonyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-[(1-methylpyrazole-4- carbonyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester wasprepared according to General Procedure 2B using Intermediate 2 (1.00 g, 2.43 mmol) and 1-methylpyrazole-4-carboxylic acid (307 mg, 2.43 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (ethyl acetate) to give 4- [(4-fluorophenyl)-[4-[(1R)-1-[(1-methylpyrazole-4- carbonyl)amino]ethyl]phenyl]methylene]piperidine-1-carboxylic acid tert-butyl ester (1.26 g, 2.43 mmol). [M+H]+=519.2.Step B: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-methyl-pyrazole-4-carboxamide N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-methyl-pyrazole-4-carboxamide was prepared according to a modified General Procedure 1 using 4-[(4-fluorophenyl)-[4-[(1R)-1-[(1-methylpyrazole-4-carbonyl)amino]ethyl]phenyl]methylene] piperidine-1-carboxylic acid tert-butyl ester (1.26 g, 2.43 mmol) and hydrogen chloride in dichloromethane (0.3 M). After completion of the reaction, the precipitated solid was filtered, washed with dichloromethane and dried under vacuum to give N-[(1R)-1-[4-[(4- fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-methyl-pyrazole-4-carboxamide(1.19 g, 2.42 mmol). [M+H]+=419.3.Step C: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-1-methyl-pyrazole-4-carboxamide N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-1-methyl-pyrazole-4-carboxamide was prepared according to General Procedure 8 using N-[(1R)-1-[4- [(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-methyl-pyrazole-4-carboxamide (250 mg, 0.508 mmol) in tetrahydrofuran (0.05 M). The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give N-[(1R)-1- [4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-1-methyl-pyrazole-4- carboxamide (167 mg, 0.386 mmol).Step D: Preparation of Example 49Example 49 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-1-methyl-pyrazole-4- carboxamide (167 mg, 0.386 mmol) and hydrogen chloride (0.772 mmol) to give Example 49(160 mg, 0.316 mmol). 1H NMR (400 MHz, dmso-8.15 (s, 1H), 7.87 (s, 1H), 7.33 (m, 2H), 7.16 (m, 4H), 7.07 (m, 2H), 5.1 (quin, 1H), 3.84 (s, 3H), 3.42 (br d, 2H), 3.01 (m, 2H), 2.74 (d, 3H), 2.51 (m, 4H), 1.42 (d, 3H) | [M+H]+=433.2410. Example 50: N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-hydroxyethyl)-4- piperidylidene]methyl]phenyl]ethyl]-5-isopropoxy-nicotinamide;hydrochloride Step A: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-hydroxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]-5-isopropoxy-nicotinamide N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-hydroxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]-5-isopropoxy-nicotinamide was prepared according to General Procedure 11 usingIntermediate 6 (85.0 mg, 0.179 mmol, 1.0 eq.) and 2-bromoethanol (24.6 mg, 10.0 µL, 0.197 mmol, 1.1 eq.) in acetonitrile. The crude residues were purified by silica gel column chromatography (dichloromethane / methanol) to give N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2- hydroxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]-5-isopropoxy-nicotinamide (48.0 mg, 0.0927 mmol).Step B: Preparation of Example 50Example 50 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-hydroxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]-5-isopropoxy- nicotinamide (48.0 mg, 0.0927 mmol) and hydrogen chloride (0.185 mmol) to give Example50 (47.0 mg, 0.0795 mmol). 1H NMR (400 MHz, dmso-1H), 8.66 (d, 1H), 8.44 (d, 1H), 7.86 (br s, 1H), 7.43 (m, 1H), 7.38 (d, 1H), 7.18 (s, 1H), 7.16 (m, 4H), 7.09 (s, 1H), 5.18 (m, 1H), 4.8 (m, 2H), 3.76 (m, 2H), 3.53 (m, 2H), 3.15 (m, 2H), 3.03 (m, 2H), 2.51 (br s, 4H), 1.49 (d, 3H), 1.3 (dd, 6H). [M+H]+=518.2825. 5-ethoxy-N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-hydroxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]nicotinamide was prepared according to General Procedure 11 usingIntermediate 7 (85.0 mg, 0.184 mmol, 1.0 eq.) and 2-bromoethanol (25.4 mg, 0.0100 mL, 0.203 mmol, 1.1 eq.) in acetonitrile. The crude residues were purified by silica gel column chromatography (dichloromethane / methanol / ammoniac) to give 5-ethoxy-N-[(1R)-1-[4-[(4- fluorophenyl)-[1-(2-hydroxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]nicotinamide (58.0 mg, 0.115 mmol).Step B: Preparation of Example 51Example 51 was prepared according to General Procedure 7 using 5-ethoxy-N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-hydroxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]nicotinamide (48.0 mg, 0.0953 mmol) and hydrogen chloride (0.190 mmol) to give Example 51 (48.0 mg, 0.0832mmol). 1H NMR (400 MHz, dmso-(m, 1H), 7.87 (br s, 1H), 7.38 (m, 2H), 7.16 (m, 4H), 7.1 (m, 2H), 5.2 (m, 1H), 4.18 (m, 2H), 3.75 (m, 2H), 3.53 (m, 2H), 3.16 (m, 2H), 3.03 (m, 2H), 2.57 (m, 4H), 1.49 (d, 3H), 1.36 (t, 3H) | [M+H]+=504.2665 -2- 1-carboxylic acid tert-butyl ester 4-[(4-fluorophenyl)-[4-[(1R)-1-[(2-methoxypyrimidine-4-carbonyl)amino]ethyl]phenyl] methylene]piperidine-1-carboxylic acid tert-butyl ester was prepared according to a modifiedGeneral Procedure 2A using 2-methoxypyrimidine-4-carboxylic acid (50.0 mg, 0,324 mmol)and Intermediate 2 (146 mg, 0,356 mmol, 1.1 eq.) in dichloromethane to give the crude 4-[(4- fluorophenyl)-[4-[(1R)-1-[(2-methoxypyrimidine-4-carbonyl)amino]ethyl]phenyl]methylene] piperidine-1-carboxylic acid tert-butyl ester (177 mg, 0.323 mmol), which was used into the next step without further purification, considering a quantitative yield. B: Preparation of Example 52Example 52 was prepared according to General Procedure 1 using the crude 4-[(4-fluorophenyl)-[4-[(1R)-1-[(2-methoxypyrimidine-4-carbonyl)amino]ethyl]phenyl]methylene] piperidine-1-carboxylic acid tert-butyl ester (177 mg, 0.323 mmol) and hydrogen chloride in dichloromethane (0.3 M. The crude residues were purified by reverse phase chromatography(water / acetonitrile / ammonium bicarbonate) to give Example 52 (62.0 mg, 0.446 mmol). 1HNMR (400 MHz, dmso-(m, 4H), 7.04 (d, 2H), 5.16 (quin, 1H), 4.02 (s, 3H), 2.71 (m, 4H), 2.25 (m, 1H), 2.13 (q, 4H), 1.52 (d, 3H) | [M+H]+=447.2194 Example 53: N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-methoxyethyl)-4- piperidylidene]methyl]phenyl]ethyl]-5-isopropoxy-nicotinamide;hydrochloride Example 53 was prepared according to General Procedure 11 using Intermediate 6 (85.0 mg,0.179 mmol, 1.0 eq.) and 1-bromo-2-methoxy-ethane (27.4 mg, 0.197 mmol, 1.1 eq.) inacetonitrile. The crude residues were purified by silica gel column chromatography (dichloromethane / methanol) then mixed with 4 N hydrogen chloride (2.0 eq.) in dioxane togive Example 53 (58.0 mg, 0.115 mmol). 1H NMR (400 MHz, dmso-1H), 9.05 (d, 1H), 8.66 (d, 1H), 8.44 (d, 1H), 7.87 (m, 1H), 7.38 (m, 2H), 7.17 (m, 4H), 7.1 (m, 2H), 5.18 (quin, 1H), 4.81 (quin, 1H), 3.7 (m, 2H), 3.5 (m, 2H), 3.3 (s, 3H), 3.27 (br d, 2H), 3.04 (m, 2H), 2.52 (m, 4H), 1.49 (d, 3H), 1.3 (dd, 6H) | [M+H]+=532.2983 Example 54: N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-hydroxyethyl)-4- piperidylidene]methyl]phenyl]ethyl]-1-methyl-pyrazole-4-carboxamide;hydrochloride Example 54 was prepared according to General Procedure 11 using N-[(1R)-1-[4-[(4- fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-methyl-pyrazole-4-carboxamide (150 mg, 0.305 mmol), potassium carbonate (90.8 mg, 0.915 mmol, 3.0 eq.) and 2-bromoethanol (42.0 mg, 0.335 mmol, 1.0 eq.). The crude residues were purified by silica gel column chromatography (dichloromethane / methanol / ammoniac) then mixed with hydrogen chloride(2.0 eq.) in dioxane to give Example 54 (110 mg, 0.237 mmol). 1H NMR (400 MHz, dmso-d6) ppm 10.26 (br s, 1H), 8.37 (d, 1H), 7.88 (s, 1H), 7.33 (m, 2H), 7.16 (d, 4H), 7.08 (m, 2H), 5.1 (quin, 1H), 4.5 (m, 2H), 3.84 (s, 3H), 3.76 (br t, 2H), 3.52 (m, 2H), 3.51 (s, 1H), 3.14 (m, 2H), 3.05 (m, 2H), 2.6 (m, 4H), 1.43 (d, 3H) | [M+H]+=463.2498 Example 55: N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-methoxyethyl)-4- piperidylidene]methyl]phenyl]ethyl]-1-methyl-pyrazole-4-carboxamide;hydrochloride Example 55 was prepared according to General Procedure 11 using N-[(1R)-1-[4-[(4- fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1-methyl-pyrazole-4-carboxamide (150 mg, 0.305 mmol), potassium carbonate (90.8 mg, 0.915 mmol, 3.0 eq.) and 1-bromo-2- methoxy-ethane (46.7 mg, 0.335 mmol, 1.1 eq.). The crude residues were purified by silica gel column chromatography (dichloromethane / methanol) then mixed with 4 N hydrogenchloride (2.0 eq.) in dioxane to give Example 55 (110 mg, 0.237 mmol). 1H NMR (400 MHz,dmso-d6) ppm 10.5 (br s, 1H), 8.38 (d, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 7.33 (m, 2H), 7.16 (m, 4H), 7.07 (m, 2H), 5.1 (quin, 1H), 3.84 (s, 3H), 3.7 (t, 2H), 3.5 (br d, 2H), 3.29 (s, 3H), 3.26 (br d, 2H), 3.04 (m, 2H), 2.53 (m, 4H), 1.43 (d, 3H) | [M+H]+=477.2665 Example 56: 5-ethoxy-N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-methoxyethyl)-4- piperidylidene]methyl]phenyl]ethyl]nicotinamide;hydrochloride Example 56 was prepared according to General Procedure 11 using Intermediate 7 (85.0 mg,0.184 mmol), potassium carbonate (20.2 mg, 0.203 mmol, 1.1 eq.) and 1-bromo-2-methoxy- ethane (28.3 mg, 0.203 mmol, 1.1 eq.). The crude residues were purified by silica gel column chromatography (dichloromethane / methanol) then mixed with 4 N hydrogen chloride (2.0eq.) in dioxane to give Example 56 (60.0 mg, 0.115 mmol). 1H NMR (400 MHz, dmso-d6)ppm 10.31 (br s, 1H), 9.07 (d, 1H), 8.69 (d, 1H), 8.46 (d, 1H), 7.88 (s, 1H), 7.38 (d, 2H), 7.15 (m, 6H), 5.18 (quin, 1H), 4.19 (q, 2H), 3.72 (m, 2H), 3.51 (m, 2H), 3.29 (s, 3H), 3.27 (br d, 2H), 3.04 (m, 2H), 2.52 (br s, 4H), 1.49 (d, 3H), 1.36 (t, 3H). [M+H]+=518.2779 Example 57: N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4- fluorophenyl)methyl]phenyl]ethyl]-5-tetrahydropyran-4-yloxy-nicotinamideStep A: Preparation of 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-tetrahydropyran-4-yloxynicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-tetrahydropyran-4- yloxynicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was prepared according to General Procedure 2B using Intermediate 3 (630 mg, 1.49 mmol) and sodium;5-tetrahydropyran-4-yloxynicotinate (365 mg, 1.49 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (dichloromethane / ethyl acetate) to give 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5- tetrahydropyran-4-yloxynicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (593 mg, 0.945 mmol). [M+H]+=629.4.Step B: Preparation of Example 57Example 57 was prepared according to a modified General Procedure 1 using 6-[(4- fluorophenyl)-[4-[(1R)-1-[(5-tetrahydropyran-4-yloxynicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (314 mg, 0.500 mmol)and hydrogen chloride in dichloromethane (0.3 M). The crude residues were purified by silicagel column chromatography (dichloromethane / methanol / ammoniac) to give Example 57 (229mg, 0.434 mmol). 1H NMR (500 MHz, dmso-d6) ppm 8.98 (d, 1H), 8.67 (br s, 1H), 8.41 (t,1H), 7.76 (br s, 1H), 7.35 (d, 2H), 7.14 (m, 2H), 7.13 (m, 2H), 7.07 (d, 2H), 5.2 (m, 1H), 5.17 (m, 1H), 3.9 (m, 1H), 3.85 (m, 2H), 3.83 (m, 2H), 3.83 (m, 2H), 3.78 (m, 1H), 3.08 (m, 4H), 2.27 (m, 1H), 2 (m, 1H), 1.48 (m, 3H). [M+H]+ = 528.2627 Example 58: N-[(1R)-1-[4-[(4-fluorophenyl)-[2-(2-methoxyethyl)-2-azaspiro[3.3]heptan- 6-ylidene]methyl]phenyl]ethyl]-5-tetrahydropyran-4-yloxy-nicotinamideExample 58 was prepared according to General Procedure 11 using Example 57 (70.0 mg,0.132 mmol), potassium carbonate (14.5 mg, 0.145 mmol, 1.1 eq.) and 1-bromo-2-methoxy- ethane (20.3 mg, 0.145 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give Example 58 (25.0 mg,0.0426 mmol). 1H NMR (400 MHz, dmso-7.8 (dd, 1H), 7.34 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.17 (quin, 1H), 4.75 (tt, 1H), 3.86 (m, 2H), 3.5 (m, 2H), 3.28 (m, 6H), 3.2 (s, 3H), 2.98 (br d, 4H), 2.58 (m, 2H), 1.99 (m, 2H), 1.61 (m, 2H), 1.49 (d, 3H) | [M+H]+=586.3095 Example 59: N-[ -1-[4-[(4-fluorophenyl)-(1-isopropyl-4- piperidylidene) phenyl]ethyl]-5-tetrahydropyran-4-yloxy-nicotinamide Example 59 was prepared according to General Procedure 11 using Intermediate 8 (100 mg,0.193 mmol), potassium carbonate (21.1 mg, 0.213 mmol, 1.1 eq.) and 2-iodopropane (36.3 mg, 0.213 mmol, 1.1 eq.). The crude residues were purified by silica gel column chromatography (dichloromethane / methanol) to give Example 59 (80.0 mg, 0.143 mmol).1HNMR (400 MHz, dmso-d6) ppm 8.95 (d, 1H), 8.64 (d, 1H), 8.45 (d, 1H), 7.79 (m, 1H), 7.33(d, 2H), 7.12 (m, 4H), 7.06 (d, 2H), 5.16 (quin, 1H), 4.75 (tt, 1H), 3.85 (m, 2H), 3.49 (m, 2H), 2.7 (m, 1H), 2.49 (br s, 4H), 2.24 (br s, 4H), 1.99 (br d, 2H), 1.61 (m, 2H), 1.48 (d, 3H), 0.97 (br s, 6H) | [M+H]+=558.3123 Example 60: N-[(1R)-1-[4-[(1-ethyl-4-piperidylidene)-(4- fluorophenyl)methyl]phenyl]ethyl]-5-tetrahydropyran-4-yloxy-nicotinamide Example 60 was prepared according to General Procedure 11 using Intermediate 8 (100 mg,0.193 mmol), potassium carbonate (21.1 mg, 0.213 mmol, 1.1 eq.) and iodoethane (33.3 mg, 0.213 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give Example 60 (20.0 mg, 0.0367 mmol).1HNMR (400 MHz, dmso-d6) ppm 8.93 (d, 1H), 8.64 (d, 1H), 8.45 (d, 1H), 7.79 (m, 1H), 7.33(d, 2H), 7.09 (m, 6H), 5.16 (quin, 1H), 4.74 (tt, 1H), 3.85 (m, 2H), 3.49 (m, 2H), 2.29 (m, 10H), 1.98 (br d, 2H), 1.61 (m, 2H), 1.48 (d, 3H), 0.98 (t, 3H) | [M+H]+=544.2969 Example 61: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-1- (trifluoromethyl)pyrazole-4-carboxamide;hydrochloride Example 61 was prepared according to General Procedure 7 using Intermediate 2 (139 mg,0.294 mmol) and hydrogen chloride (0.367 mL, 0.735 mmol) to give Example 61 (156 mg,0.285 mmol). 1H NMR (400 MHz, dmso- 1H), 8.33 (s, 1H), 7.35 (d, 2H), 7.17 (d, 4H), 7.1 (d, 2H), 5.12 (quin, 1H), 3.11 (m, 4H), 2.43 (m, 4H), 1.45 (d, 3H) | [M+H]+=473.1955 Example 62: N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4- Step A: Preparation of 5-(1,1-diketothian-4-yl)oxynicotinic acid methyl ester5-(1,1-diketothian-4-yl)oxynicotinic acid methyl ester was prepared according to GeneralProcedure 10 using methyl 5-hydroxypyridine-3-carboxylate (500 mg, 3.26 mmol) and 1,1-dioxothian-4-ol (0.449 mL, 3.26 mmol). The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 5-(1,1-diketothian-4-yl)oxynicotinicacid methyl ester (931 mg, 3.26 mmol). [M+H]+=286.1.Step B: Preparation of sodium;5-(1,1-diketothian-4-yl)oxynicotinateSodium;5-(1,1-diketothian-4-yl)oxynicotinate was prepared according to General Procedure 9A using 5-(1,1-diketothian-4-yl)oxynicotinic acid methyl ester (931 mg, 3.26 mmol) to givesodium;5-(1,1-diketothian-4-yl)oxynicotinate (950 mg, 3.23 mmol). [M+H]+=272.1.Step C: Preparation of 6- diketothian-4-yl)oxynicotinoyl]amino]ethyl] phenyl]-(4-fluorophenyl) - [3.3]heptane-2-carboxylic acid tert-butyl ester 6-[[4-[(1R)-1-[[5-(1,1-diketothian-4-yl)oxynicotinoyl]amino]ethyl]phenyl]-(4- fluorophenyl)methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester wasprepared according to General Procedure 2B using Intermediate 3 (500 mg, 1.18 mmol) andsodium;5-(1,1-diketothian-4-yl)oxynicotinate (347 mg, 1.18 mmol, 1.0 eq.) in N,N- dimethylformamide. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 6-[[4-[(1R)-1-[[5-(1,1-diketothian-4- yl)oxynicotinoyl]amino]ethyl]phenyl]-(4-fluorophenyl)methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (331 mg, 0.489 mmol). [M+H]+=576.2. Example 62 was prepared according to General Procedure 1 using 6-[[4-[(1R)-1-[[5-(1,1-diketothian-4-yl)oxynicotinoyl]amino]ethyl]phenyl]-(4-fluorophenyl)methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (331 mg, 0.489 mmol) and hydrogen chloride in dichloromethane (0.3 M). The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give Example 62 (150 mg, 0.260 mmol). 1H NMR (400 / 500 MHz, dmso-d6) ppm 8.96 (d, 1H), 8.68 (s, 1H), 8.53 (m,1H), 7.86 (br s, 1H), 7.35 (d, 2H), 7.14 (m, 2H), 7.12 (m, 2H), 7.07 (d, 2H), 5.18 (quin, 1H), 4.89 (m, 1H), 3.86 (br s, 1H), 3.5 (br s, 3H), 3.2 (m, 4H), 3.05 (m, 1H), 2.99 (m, 3H), 2.24 (m, 4H), 1.48 (d, 3H) | [M+H]+=576.2326 A: Preparation of 3-morpholinobenzoic acid3-Morpholinobenzoic acid was prepared according to General Procedure 9A using methyl 3-morpholinobenzoate (500 mg, 2.25 mmol) to give 3-morpholinobenzoic acid (400 mg, 1.93 mmol). [M+H]+=208.1. 2-carboxylic acid tert-butyl ester 6-[(4-Fluorophenyl)-[4-[(1R)-1-[(3-morpholinobenzoyl)amino]ethyl]phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was prepared according to GeneralProcedure 2B using Intermediate 3 (500 mg, 1.18 mmol) and 3-morpholinobenzoic acid (245mg, 1.18 mmol, 1.0 eq.) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 6-[(4-fluorophenyl)-[4- [(1R)-1-[(3-morpholinobenzoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (720 mg, 1.17 mmol). [M+H]+=612.3.Step C: Preparation of Example 63Example 63 was prepared according to General Procedure 1 using 6-[(4-fluorophenyl)-[4-[(1R)-1-[(3-morpholinobenzoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (700 mg, 1.14 mmol) and trifluoroacetic acid in dichloromethane (0.3 M). The crude residues were purified by reverse phase chromatography(water / acetonitrile / ammonium bicarbonate) to give Example 63 (400 mg, 0.639 mmol). 1HNMR (400 MHz, dmso-7.12 (m, 7H), 5.17 (quin, 1H), 4.03 (br t, 4H), 3.75 (br s, 4H), 3.15 (m, 8H), 1.48 (d, 3H) | [M+H]+=512.2695 Example 64: N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4- fluorophenyl)methyl]phenyl]ethyl]-5-isobutoxy-nicotinamide Step A: Preparation of 5-isobutoxynicotinic acid methyl ester5-Isobutoxynicotinic acid methyl ester was prepared according to General Procedure 10 usingmethyl 5-hydroxypyridine-3-carboxylate (500 mg, 3.26 mmol) and 2-methylpropan-1-ol (0.301 mL, 3.26 mmol). The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 5-isobutoxynicotinic acid methyl ester (680mg, 3.24 mmol). [M+H]+=210.1.Step B: Preparation of sodium;5-isobutoxynicotinateSodium;5-isobutoxynicotinate was prepared according to General Procedure 9A using 5-isobutoxynicotinic acid methyl ester (683 mg, 3.26 mmol) to give sodium;5-isobutoxynicotinate (700 mg, 3.22 mmol). [M+H]+=196.1.Step C: Preparation of 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-isobutoxynicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 6-[(4-Fluorophenyl)-[4-[(1R)-1-[(5-isobutoxynicotinoyl)amino]ethyl]phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was prepared according to GeneralProcedure 2B using Intermediate 3 (500 mg, 1.18 mmol) and sodium;5-isobutoxynicotinate(257 mg, 1.18 mmol, 1.0 eq.) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 6-[(4-fluorophenyl)-[4- [(1R)-1-[(5-isobutoxynicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (368 mg, 0.613 mmol). [M+H]+=600.1.Step D: Preparation of Example 64Example 64 was prepared according to General Procedure 1 using 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-isobutoxynicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (368 mg, 0.613mmol) and trifluoroacetic acid in dichloromethane (0.3 M). The crude residues were purified by reverse phase chromatography(water / acetonitrile / ammonium bicarbonate) to give Example 64 (400 mg, 0.320 mmol). 1HNMR (400 MHz, dmso-7.35 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.18 (quin, 1H), 3.88 (d, 2H), 3.67 (m, 4H), 2.97 (br d, 4H), 2.05 (m, 1H), 1.49 (d, 3H), 1 (d, 6H) | [M+H]+=500.2691 Example 65: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-tetrahydropyran- nicotinamide Example 65 was prepared according to General Procedure 8 using Example 57 (229 mg,0.434 mmol) in a 5:1 dichloromethane / methanol mixture. The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give Example65 (95.0 mg, 0.175 mmol). 1H NMR (400 MHz, dmso-8.46 (d, 1H), 7.79 (dd, 1H), 7.34 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.17 (quin, 1H), 4.75 (tt, 1H), 3.85 (m, 2H), 3.5 (m, 2H), 3.14 (s, 4H), 2.95 (br d, 4H), 2.15 (s, 3H), 1.99 (br d, 2H), 1.61 (m, 2H), 1.49 (d, 3H) Example 66: N-[(1R)-1-[4-[(4-fluorophenyl)-[2-(2-hydroxyethyl)-2-azaspiro[3.3]heptan- 6-ylidene]methyl]phenyl]ethyl]-5-tetrahydropyran-4-yloxy-nicotinamide Example 66 was prepared according to General Procedure 11 using Example 57 (120 mg,0.227 mmol), potassium carbonate (24.8 mg, 0.250 mmol, 1.1 eq.) and 2-bromoethanol (31.3 mg, 0.250 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (water / acetonitrile / ammonium bicarbonate) to give Example 66 (20.0 mg, 0.0349 mmol).1HNMR (400 MHz, dmso-d6) ppm 8.95 (d, 1H), 8.65 (d, 1H), 8.46 (d, 1H), 7.79 (dd, 1H),7.34 (d, 2H), 7.11 (m, 6H), 5.17 (t, 1H), 4.75 (tt, 1H), 4.31 (br s, 1H), 3.86 (m, 2H), 3.5 (br d, 2H), 3.26 (br s, 2H), 3.16 (s, 4H), 2.95 (br d, 4H), 2.38 (m, 2H), 1.99 (br d, 2H), 1.61 (m, 2H), 1.49 (d, 3H) | [M+H]+=572.2912 Example 67: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-spiro[3.3]heptan-2-yloxy-nicotinamide Step A: Preparation of 5-spiro[3.3]heptan-2-yloxynicotinic acid methyl ester5-Spiro[3.3]heptan-2-yloxynicotinic acid methyl ester was prepared according to GeneralProcedure 10 using methyl 5-hydroxypyridine-3-carboxylate (350 mg, 2.28 mmol) andspiro[3.3]heptan-2-ol (0.232 mL, 2.28 mmol). The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 5-spiro[3.3]heptan-2-yloxynicotinicacid methyl ester (514 mg, 2.07 mmol). [M+H]+=248.1.Step B: Preparation of sodium;5-spiro[3.3]heptan-2-yloxynicotinateSodium;5-spiro[3.3]heptan-2-yloxynicotinate was prepared according to General Procedure 9A using 5-spiro[3.3]heptan-2-yloxynicotinic acid methyl ester (514 mg, 2.08 mmol) to give sodium;5-spiro[3.3]heptan-2-yloxynicotinate (530 mg, 2.08 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification. [M+H]+=234.1. 2- 2-carboxylic acid tert-butyl ester 6-[(4-Fluorophenyl)-[4-[(1R)-1-[(5-spiro[3.3]heptan-2- yloxynicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acidtert-butyl ester was prepared according to General Procedure 2B using Intermediate 3 (500mg, 1.18 mmol) and sodium;5-spiro[3.3]heptan-2-yloxynicotinate (302 mg, 1.18 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5- spiro[3.3]heptan-2-yloxynicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane- 2-carboxylic acid tert-butyl ester (400 mg, 0.627 mmol). [M+H]+=638.5.Step D: Preparation of N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-spiro[3.3]heptan-2-yloxy-nicotinamide N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-spiro[3.3]heptan-2-yloxy-nicotinamide was prepared according to General Procedure 1 using6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-spiro[3.3]heptan-2-yloxynicotinoyl)amino]ethyl]phenyl] methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (400 mg, 0.627 mmol) in dichloromethane (0.3 M) and trifluoroacetic acid. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give N-[(1R)-1-[4-[2- azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-spiro[3.3]heptan-2-yloxy-nicotinamide (140 mg, 0.260 mmol). 1H NMR (400 MHz, dmso-d6) ppm 8.95 (d,1H), 8.64 (d, 1H), 8.32 (d, 1H), 7.61 (dd, 1H), 7.34 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.17 (m, 1H), 4.74 (quin, 1H), 3.5 (s, 4H), 2.98 (m, 4H), 2.59 (m, 2H), 2.02 (m, 6H), 1.82 (m, 2H), 1.49 (d, 3H) | [M+H]+=538.2835Step E: Preparation of Example 67Example 67 was prepared according to General Procedure 8 using N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-spiro[3.3]heptan-2- yloxy-nicotinamide (90.0 mg, 0.167 mmol) in tetrahydrofuran. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to giveExample 67 (30.0 mg, 0.0544 mmol). 1H NMR (400 MHz, dmso-d6) ppm 8.94 (d, 1H),8.64 (d, 1H), 8.32 (d, 1H), 7.61 (dd, 1H), 7.34 (d, 2H), 7.11 (m, 6H), 5.17 (t, 1H), 4.74 (quin, 1H), 3.13 (s, 4H), 2.95 (br d, 4H), 2.59 (m, 2H), 2.15 (s, 3H), 2.02 (m, 6H), 1.82 (m, 2H), 1.48 (d, 3H) | [M+H]+=552.3035 Example 68: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-isopropyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-tetrahydropyran-4-yloxy-nicotinamideExample 68 was prepared according to General Procedure 11 using Example 57 (100 mg,0.189 mmol), potassium carbonate (20.7 mg, 0.208 mmol, 1.1 eq.) and 2-iodopropane (35.4 mg, 0.208 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography(acetonitrile / water / ammonium bicarbonate) to give Example 68 (70 mg, 0.123 mmol). 1HNMR (400 MHz, dmso-7.34 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.17 (t, 1H), 4.75 (tt, 1H), 3.85 (m, 2H), 3.5 (m, 2H), 3.09 (s, 4H), 2.94 (br d, 4H), 2.14 (quin, 1H), 1.99 (br d, 2H), 1.61 (m, 2H), 1.49 (d, 3H), 0.8 (d, 6H) | [M+H]+=570.3116 Example 69: N-[(1R)-1-[4-[(2-ethyl-2-azaspiro[3.3]heptan-6-ylidene)-(4- fluorophenyl)methyl]phenyl]ethyl]-5-tetrahydropyran-4-yloxy-nicotinamide Example 69 was prepared according to General Procedure 11 using Example 57 (150 mg,0.284 mmol), potassium carbonate (31.0 mg, 0.313 mmol, 1.1 eq.) and bromoethane (34.1 mg, 0.313 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography(acetonitrile / water / ammonium bicarbonate) to give Example 69 (50.0 mg, 0.0899 mmol). 1HNMR (400 MHz, dmso-7.34 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.17 (t, 1H), 4.75 (m, 1H), 3.86 (m, 2H), 3.5 (m, 2H), 3.12 (s, 4H), 2.95 (br d, 4H), 2.32 (q, 2H), 1.99 (br d, 2H), 1.61 (m, 2H), 1.49 (d, 3H), 0.83 (t, 3H) Example 70: 5-(1,1-diketothian-4-yl)oxy-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2- azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]nicotinamide Example 70 was prepared according to General Procedure 8 using Example 62 (94.0 mg,0.163 mmol) in tetrahydrofuran. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 70 (60.0 mg,0.102 mmol). 1H NMR (400 MHz, dmso-7.86 (m, 1H), 7.34 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.18 (quin, 1H), 4.89 (br d, 1H), 3.21 (m, 4H), 3.14 (s, 4H), 2.95 (br d, 4H), 2.23 (br d, 4H), 2.16 (s, 3H), 1.49 (d, 3H) | [M+H]+=590.2493 Example 71: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-3-morpholino-benzamide;2,2,2-trifluoroacetic acid Example 71 was prepared according to General Procedure 8 using Example 63 (150 mg,0.240 mmol) in tetrahydrofuran. The crude residues were purified by reverse phase chromatography (acetonitrile / water / trifluoracetic acid) to give Example 71 (100 mg, 0.156mmol). 1H NMR (400 MHz, dmso- (m, 4H), 7.12 (m, 7H), 5.17 (t, 1H), 4.29 (m, 2H), 4.01 (m, 2H), 3.75 (m, 4H), 3.15 (m, 8H), 2.79 (d, 3H), 1.48 (d, 3H) | [M+H]+=526.2875 Example 72: N-[ -1-[4-[[2-(2,2-difluoroethyl)-2-azaspiro[3.3]heptan-6-ylidene]-(4- fluorophenyl) phenyl]ethyl]-5-tetrahydropyran-4-yloxy-nicotinamide;2,2,2- trifluoroacetic acid Example 72 was prepared according to General Procedure 11 using Example 57 (150 mg,0.284 mmol), N,N-diisopropylamine (91.9 mg, 0.711 mmol, 2.5 eq.) and 1,1-difluoro-2-iodo- ethane (60.0 mg, 0.313 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 72 (80 mg,0.113 mmol). 1H NMR (400 MHz, dmso-1H), 8.47 (d, 1H), 7.8 (m, 1H), 7.36 (d, 2H), 7.17 (m, 4H), 7.08 (br d, 2H), 6.35 (br t, 1H), 5.17 (t, 1H), 4.75 (tt, 1H), 4.29 (br s, 4H), 3.86 (m, 2H), 3.77 (m, 2H), 3.64 (br s, 12H), 3.49 (m, 2H), 3.15 (br s, 5H), 1.99 (br d, 2H), 1.61 (m, 2H), 1.49 (d, 3H) | [M+H]+=592.2793 Example 73: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-isobutoxy-nicotinamide

[0002] Example 73 was prepared according to General Procedure 8 using Example 64 (100 mg,0.200 mmol) in tetrahydrofuran. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 73 (75.0 mg,0.146 mmol). 1H NMR (400 MHz, dmso-d6) ppm 8.95 (d, 1H), 8.64 (d, 1H), 8.42 (d, 1H),7.76 (dd, 1H), 7.34 (d, 2H), 7.11 (m, 6H), 5.18 (t, 1H), 3.88 (d, 2H), 3.21 (br s, 4H), 2.96 (br d, 4H), 2.2 (s, 3H), 2.05 (dt, 1H), 1.49 (d, 3H), 1 (d, 6H) | [M+H]+=514.2871 Example 74: N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4- fluorophenyl)methyl]phenyl]ethyl]-5-[(3R)-tetrahydrofuran-3-yl]oxy-nicotinamide Step A: Preparation of 6-[(4-fluorophenyl)- -tetrahydrofuran-3- yl]oxynicotinoyl]amino]ethyl]phenyl] - heptane-2-carboxylic acid tert-butyl ester 6-[(4-fluorophenyl)-[4-[(1R)-1-[[5-[(3R)-tetrahydrofuran-3- yl]oxynicotinoyl]amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was prepared according to General Procedure 2B using Intermediate 3 (1 g, 2.37 mmol) and sodium;5-[(3R)-tetrahydrofuran-3-yl]oxynicotinate (547 mg, 2.37 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (dichloromethane / ethyl acetate) to give 6-[(4-fluorophenyl)-[4-[(1R)-1-[[5- [(3R)-tetrahydrofuran-3-yl]oxynicotinoyl]amino]ethyl]phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.00 g, 1.63 mmol). [M+H]+=614.4.Step B: Preparation of Example 74Example 74 was prepared according to a modified General Procedure 1 using 6-[(4-fluorophenyl)-[4-[(1R)-1-[[5-[(3R)-tetrahydrofuran-3- yl]oxynicotinoyl]amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (274 mg, 0.447 mmol) in dichloromethane (0.3 M) and trifluoroacetic acid (0.223 mL, 0.893 mmol, 2.0 eq.). The crude residues were purified by silica gel columnchromatography (dichloromethane / methanol) to give Example 74 (198 mg, 0.386 mmol). 1HNMR (400 MHz, dmso-7.35 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.19 (m, 2H), 3.84 (m, 4H), 3.5 (s, 4H), 2.97 (br d, 4H), 2.26 (m, 1H), 1.99 (m, 1H), 1.49 (d, 3H) | [M+H]+ = 514.2503 Example 75: N-[(1R)-1-[4-[(4-fluorophenyl)-[2-(2-hydroxyethyl)-2-azaspiro[3.3]heptan- 6-ylidene]methyl]phenyl]ethyl]-5-[(3R)-tetrahydrofuran-3-yl]oxy-nicotinamide Example 75 was prepared according to General Procedure 11 using Example 74 (110 mg,0.214 mmol), potassium carbonate (32.6 mg, 0.236 mmol, 1.1 eq.) and 2-bromoethanol (29.4 mg, 0.236 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography(acetonitrile / water / ammonium bicarbonate) to give Example 75 (20.0 mg, 0.0359 mmol). 1HNMR (400 MHz, dmso-7.34 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.19 (m, 2H), 4.31 (t, 1H), 3.84 (m, 4H), 3.29 (m, 2H), 3.16 (s, 4H), 2.95 (br d, 4H), 2.38 (t, 2H), 2.26 (m, 1H), 1.98 (m, 1H), 1.49 (d, 3H) | [M+H]+=558.2768 Example 76: N-[(1R)-1-[4-[(4-fluorophenyl)-[2-(2-hydroxyethyl)-2-azaspiro[3.3]heptan- 6-ylidene]methyl]phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-nicotinamide Example 76 was prepared according to General Procedure 11 using Example 15 (90.0 mg,0.175 mmol), potassium carbonate (26.6 mg, 0.193 mmol, 1.1 eq.) and 2-iodoethanol (33.2 mg, 0.193 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography(acetonitrile / water / ammonium bicarbonate) to give Example 76 (40.0 mg, 0.0717 mmol). 1HNMR (400 MHz, dmso-d6) ppm 8.96 (d, 1H), 8.66 (d, 1H), 8.41 (d, 1H), 7.75 (dd, 1H),7.34 (d, 2H), 7.11 (m, 6H), 5.19 (m, 2H), 4.32 (t, 1H), 3.84 (m, 4H), 3.29 (br s, 2H), 3.18 (s, 4H), 2.95 (br d, 4H), 2.4 (m, 2H), 2.26 (m, 1H), 1.99 (m, 1H), 1.49 (d, 3H) | [M+H]+=558.2770 Example 77: N-[ -1-[4-[(4-fluorophenyl)-[2-(3,3,3-trifluoropropyl)-2-azaspiro[3.3] heptan-6- phenyl]ethyl]-5-[ -tetrahydrofuran-3-yl]oxy-nicotinamide Example 77 was prepared according to General Procedure 11 using Example 74 (110 mg,0.214 mmol), potassium carbonate (32.6 mg, 0.236 mmol, 1.1 eq.) and 1,1,1-trifluoro-3-iodo- propane (52.8 mg, 0.236 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 77 (45.0 mg,0.0738 mmol). 1H NMR (400 MHz, dmso-d6) ppm 8.95 (m, 1H), 8.66 (d, 1H), 8.41 (d,1H), 7.75 (dd, 1H), 7.35 (m, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.19 (m, 2H), 3.83 (m, 4H), 3.17 (s, 4H), 2.95 (m, 4H), 2.52 (br s, 2H), 2.25 (m, 3H), 1.98 (m, 1H), 1.49 (d, 3H) | [M+H]+=610.2682 Example 78: N-[ -1-[4-[(4-fluorophenyl)-[2-(3,3,3-trifluoropropyl)-2-azaspiro[3.3] heptan-6- phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-nicotinamide Example 78 was prepared according to General Procedure 11 using Example 15 (80.0 mg,0.156 mmol), potassium carbonate (23.68 mg, 0.171 mmol, 1.1 eq.) and 1,1,1-trifluoro-3- iodo-propane (38.4 mg, 0.171 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 78 (52.0mg, 0.0853 mmol). 1H NMR (400 MHz, dmso-d6) ppm 8.95 (m, 1H), 8.66 (d, 1H), 8.41 (d,1H), 7.75 (dd, 1H), 7.35 (m, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.19 (m, 2H), 3.83 (m, 4H), 3.17 (s, 4H), 2.95 (m, 4H), 2.52 (br s, 2H), 2.25 (m, 3H), 1.98 (m, 1H), 1.49 (d, 3H) | [M+H]+=610.2683 Example 79: N-[(1R)-1- azaspiro[3.3]heptan-6-ylidene-(4- fluorophenyl)methyl] -5-morpholino-nicotinamide;2,2,2-trifluoroacetic acidStep A: Preparation of 5-morpholinonicotinic acid methyl ester5-Morpholinonicotinic acid methyl ester was prepared according to General Procedure 12using methyl 5-bromopyridine-3-carboxylate (1.00 g, 4.63 mmol) and morpholine (0.607 mL, 6.94 mmol, 1.5 eq.) in toluene. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 5-morpholinonicotinic acid methyl ester(1.00 g, 4.50 mmol). [M+H]+=223.1.Step B: Preparation of sodium;5-morpholinonicotinateSodium;5-morpholinonicotinate was prepared according to General Procedure 9A using 5-morpholinonicotinic acid methyl ester (1.00 g, 4.50 mmol) to give sodium;5-morpholinonicotinate (1.05 g, 4.56 mmol). [M+H]+=209.1.Step C: Preparation of 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-morpholinonicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 6-[(4-Fluorophenyl)-[4-[(1R)-1-[(5-morpholinonicotinoyl)amino]ethyl]phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was prepared according to GeneralProcedure 2B using Intermediate 3 (500 mg, 1.18 mmol) and sodium;5-morpholinonicotinate(272 mg, 1.18 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 6-[(4-fluorophenyl)-[4-[(1R)-1- [(5-morpholinonicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (414 mg, 0.676 mmol). [M+H]+=613.4.Step D: Preparation of Example 79Example 79 was prepared according to General Procedure 1 using 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-morpholinonicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (414 mg, 0.677 mmol) in dichloromethane (0.3 M) and trifluoroacetic acid. The crude residues were purified by reverse phase chromatography(acetonitrile / water / ammonium bicarbonate) to give Example 79 (150 mg, 0.239 mmol). 1HNMR (400 MHz, dmso-d6) ppm 8.95 (d, 1H), 8.55 (br s, 2H), 8.5 (d, 1H), 8.45 (d, 1H), 7.75(s, 1H), 7.36 (d, 2H), 7.15 (m, 4H), 7.08 (d, 2H), 5.18 (m, 1H), 4.03 (br t, 4H), 3.77 (br d, 4H), 3.25 (m, 4H), 3.14 (br d, 4H), 1.49 (d, 3H) | [M+H]+=513.2668 Example 80: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-glycoloyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-[(3R)-tetrahydrofuran-3-yl]oxy-nicotinamide Example 80 was prepared according to General Procedure 11 using Example 74 (150 mg,0.292 mmol), potassium carbonate (36.33 mg, 0.263 mmol, 0.9 eq.) and 2-bromoacetamide (44.3 mg, 0.321 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 80 (45.0 mg,0.0787 mmol). 1H NMR (400 MHz, dmso-7.75 (m, 1H), 7.35 (d, 2H), 7.15 (d, 4H), 7.09 (d, 2H), 5.19 (m, 2H), 4.82 (t, 1H), 4.08 (m, 4H), 3.85 (m, 6H), 3.09 (br d, 4H), 2.26 (m, 1H), 1.98 (m, 1H), 1.49 (d, 3H) | [M+H]+ = 572.2564 Example 81: N-[(1R)-1-[4-[(4-fluorophenyl)-[2-(2-methoxyethyl)-2-azaspiro[3.3]heptan- 6-ylidene]methyl]phenyl]ethyl]-5-[(3R)-tetrahydrofuran-3-yl]oxy-nicotinamideExample 81 was prepared according to General Procedure 11 using Example 74 (100 mg,0.195 mmol), potassium carbonate (24.2 mg, 0.175 mmol, 0.90 eq.) and 1-bromo-2-methoxy- ethane (29.8 mg, 0.214 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 81 (80.0 mg,0.140 mmol). 1H NMR (400 MHz, dmso-d6) ppm 8.96 (d, 1H), 8.66 (d, 1H), 8.41 (d, 1H),7.75 (dd, 1H), 7.34 (d, 2H), 7.11 (m, 6H), 5.19 (m, 2H), 3.84 (m, 4H), 3.22 (m, 1H), 3.19 (m, 8H), 2.95 (br d, 4H), 2.46 (m, 2H), 2.26 (m, 1H), 1.99 (br dd, 1H), 1.49 (d, 3H) | [M+H]+=572.2918 Example 82: N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl] ethyl]-2-methyl-morpholine-4-carboxamide;hydrochloride Step A: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-2-methyl-morpholine-4-carboxamide N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-2-methyl-morpholine-4-carboxamide was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-2-methyl-morpholine-4- carboxamide (89.0 mg, 0.203 mol) and hydrogen chloride (0.407 mmol) to give N-[(1R)-1-[4- [(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-2-methyl-morpholine-4-carboxamide (75.6 mg, 0.159 mol). 1H NMR (400 MHz, dmso-d6) ppm 9 (m, 2H), 7.28 (m,2H), 7.17 (m, 4H), 7.07 (m, 2H), 6.78 (d, 1H), 4.83 (quin, 1H), 3.85 (br d, 3H), 3.36 (m, 2H), 3.11 (br s, 4H), 2.7 (m, 1H), 2.35 (m, 5H), 1.34 (d, 3H), 1.06 (dd, 3H). [M+H]+=438.2554Step B: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-2-methyl-morpholine-4-carboxamide N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-2-methyl-morpholine-4-carboxamide was prepared according to a modified General Procedure 8 usingN-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-2-methyl-morpholine-4-carboxamide (40.3 mg, 0.0850 mmol), aqueous 37 wt.% formaldehyde (213mg, 0.195 mL, 2.55 mmol) in a 5:1 dichloromethane / methanol mixture. After completion of the reaction, the mixture was quenched with sat. sodium bicarbonate and dissolved with dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4- piperidylidene)methyl]phenyl]ethyl]-2-methyl-morpholine-4-carboxamide (38.4 mg, 0.0850 mmol), considering a quantitative yield and engaged into the next step without further purification.Step C: Preparation of Example 82Example 82 was prepared according to General Procedure 7 using N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4-piperidylidene)methyl]phenyl]ethyl]-2-methyl-morpholine-4- carboxamide (38.0 mg, 0.0850 mol) and hydrogen chloride (0.213 mmol) to give Example 82(37.5 mg, 0.0768 mol). 1H NMR (400 MHz, dmso-d6) ppm 10.51 (br s, 1H), 7.29 (m, 2H),7.17 (m, 4H), 7.06 (m, 2H), 6.78 (d, 1H), 4.83 (m, 1H), 3.82 (m, 3H), 3.38 (m, 4H), 3 (br d, 2H), 2.74 (d, 3H), 2.69 (m, 1H), 2.51 (m, 4H), 2.38 (m, 1H), 1.35 (d, 3H), 1.06 (dd, 3H) | [M+H]+=452.2680 Example 83: N-[(1R)-1-[4-[(4-fluorophenyl)-[2-(2-methoxyethyl)-2-azaspiro[3.3]heptan- 6-ylidene]methyl]phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-nicotinamideExample 83 was prepared according to General Procedure 11 using Example 15 (170 mg,0.331 mmol), potassium carbonate (41.2 mg, 0.298 mmol, 0.90 eq.) and 1-bromo-2-methoxy- ethane (50.6 mg, 0.364 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 83 (70.0 mg,0.122 mmol). 1H NMR (400 MHz, dmso-7.75 (m, 1H), 7.34 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.19 (m, 2H), 3.84 (m, 4H), 3.24 (t, 2H), 3.19 (s, 3H), 3.16 (s, 4H), 2.95 (br d, 4H), 2.46 (m, 2H), 2.27 (m, 1H), 1.99 (m, 1H), 1.49 (d, 3H) | [M+H]+=572.2923 Example 84: N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-methoxyethyl)-4- piperidylidene]methyl]phenyl]ethyl]-5-[(3R)-tetrahydrofuran-3-yl]oxy-nicotinamide Example 84 was prepared according to General Procedure 11 using N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-5-[(3R)-tetrahydrofuran-3-yl]oxy- nicotinamide (209 mg, 0.417 mmol), potassium carbonate (46.1 mg, 0.333 mmol, 0.80 eq.) and 1-bromo-2-methoxy-ethane (63.7 mg, 0.458 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to giveExample 84 (150 mg, 0.268 mmol). 1H NMR (400 MHz, dmso-(d, 1H), 8.41 (d, 1H), 7.75 (m, 1H), 7.33 (d, 2H), 7.11 (m, 4H), 7.05 (d, 2H), 5.18 (m, 2H), 3.84 (m, 4H), 3.41 (m, 2H), 3.21 (s, 3H), 2.46 (m, 6H), 2.23 (m, 5H), 1.98 (m, 1H), 1.48 (d, 3H) | [M+H]+=560.2892 Example 85: N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-hydroxyethyl)-4- piperidylidene]methyl]phenyl]ethyl]-5-tetrahydropyran-4-yloxy-nicotinamide Example 85 was prepared according to General Procedure 11 using Intermediate 8 (176 mg,0.341 mmol), potassium carbonate (42.5 mg, 0.307 mmol, 0.9 eq.) and 2-bromoethanol (46.9 mg, 0.376 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography(acetonitrile / water / ammonium bicarbonate) to give Example 85 (110 mg, 0.197 mmol). 1HNMR (400 MHz, dmso-7.33 (d, 2H), 7.11 (m, 4H), 7.05 (d, 2H), 5.16 (quin, 1H), 4.74 (tt, 1H), 4.36 (t, 1H), 3.85 (m, 2H), 3.49 (m, 4H), 2.45 (br s, 4H), 2.39 (t, 2H), 2.23 (m, 4H), 1.99 (br d, 2H), 1.61 (m, 2H), 1.48 (d, 3H) | [M+H]+=560.2925 Example 86: N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4- fluorophenyl)methyl]phenyl]ethyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide4- 2-carboxylic acid tert-butyl ester 6-[(4-fluorophenyl)-[4-[(1R)-1-[[1-(2,2,2-trifluoroethyl)pyrazole-4- carbonyl]amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was prepared according to General Procedure 2C using Intermediate 3 (239 mg, 0.565 mmol, 1.1 eq.) and 1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylic acid (105 mg, 0.514 mmol) in dichloromethane (0.15 M) to give the crude 6-[(4-fluorophenyl)-[4-[(1R)-1-[[1-(2,2,2- trifluoroethyl)pyrazole-4-carbonyl]amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (307 mg, 0.514 mmol), considering a quantitative yield.Step B: Preparation of Example 86Example 86 was prepared according to General Procedure 1 using the crude 6-[(4-fluorophenyl)-[4-[(1R)-1-[[1-(2,2,2-trifluoroethyl)pyrazole-4- carbonyl]amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (307 mg, 0.513 mmol) in dichloromethane (0.3 M) and trifluoroacetic acid. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammoniumbicarbonate) to give Example 86 (108 mg, 0.217 mmol). 1H NMR (400 MHz, dmso-d6)ppm 8.53 (d, 1H), 8.33 (s, 1H), 8.03 (s, 1H), 7.31 (d, 2H), 7.13 (m, 4H), 7.07 (s, 2H), 5.19 (d, 2H), 5.1 (m, 1H), 3.49 (br s, 4H), 2.96 (br d, 4H), 1.44 (d, 3H) | [M+H]+=499.2086 6- Step A: Preparation of 5-(2-oxa-8-azaspiro[3.5]nonan-8-ylmethyl)nicotinic acid methyl ester5-(2-Oxa-8-azaspiro[3.5]nonan-8-ylmethyl)nicotinic acid methyl ester was preparedaccording to a modified General Procedure 11 using methyl 5-(bromomethyl)pyridine-3-carboxylate (500 mg, 2.17 mmol), potassium carbonate (474 mg, 3.26 mmol, 1.5 eq.) and 2- oxa-8-azaspiro[3.5]nonane (304 mg, 2.39 mmol, 1.1 eq.) at room temperature. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give 5-(2-oxa-8-azaspiro[3.5]nonan-8-ylmethyl)nicotinic acid methyl ester(517 mg, 1.87 mmol). 1H NMR (400 MHz, dmso-(t, 1H), 4.23 (d, 2H), 4.16 (d, 2H), 3.9 (s, 3H), 3.61 (s, 2H), 2.49 (m, 2H), 2.3 (m, 2H), 1.63 (br s, 2H), 1.44 (quin, 2H). [M+H]+=277.1.Step B: Preparation of sodium;5-(2-oxa-8-azaspiro[3.5]nonan-8-ylmethyl)nicotinateSodium;5-(2-oxa-8-azaspiro[3.5]nonan-8-ylmethyl)nicotinate was prepared according toGeneral Procedure 9A using 5-(2-oxa-8-azaspiro[3.5]nonan-8-ylmethyl)nicotinic acid methylester (610 mg, 2.21 mmol) to give sodium;5-(2-oxa-8-azaspiro[3.5]nonan-8- ylmethyl)nicotinate (627 mg, 2.21 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification. [M+H]+=263.1.Step C: Preparation of Example 87Example 87 was prepared according to General Procedure 2B using Intermediate 4 (150mg,0.446 mmol) and sodium;5-(2-oxa-8-azaspiro[3.5]nonan-8-ylmethyl)nicotinate (127 mg, 0.446 mmol) in N,N-dimethylformamide. The crude residues were dissolved into methanol and eluted through a PoraPak Rxn CX and purified by reverse phase column chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 87 (75.0 mg, 0.108 mmol). [M+H]+=581.3264 5- 2-carboxylic acid tert- butyl ester 6-[(4-fluorophenyl)-[4-[(1R)-1-[(3-isopropylisoxazolo[5,4-b]pyridine-5-carbonyl)amino] ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was prepared according to a modified General Procedure 2C using Intermediate 3 (225 mg, 0.532mmol, 1.1 eq.) and 3-isopropylisoxazolo[5,4-b]pyridine-5-carboxylic acid (105 mg, 0.484 mmol) in dichloromethane (0.15 M) to give the crude 6-[(4-fluorophenyl)-[4-[(1R)-1-[(3- isopropylisoxazolo[5,4-b]pyridine-5-carbonyl)amino]ethyl]phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (295 mg, 0.484 mmol), considering a quantitative yield. B: Preparation of Example 88Example 88 was prepared according to General Procedure 1 using the crude 6-[(4-fluorophenyl)-[4-[(1R)-1-[(3-isopropylisoxazolo[5,4-b]pyridine-5-carbonyl)amino] ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (295 mg, 0.483 mmol) in dichloromethane (0.3 M) and trifluoroacetic acid. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 88 (61.4 mg, 0.117 mmol). 1H NMR (400 MHz, dmso-(d, 1H), 7.38 (d, 2H), 7.12 (m, 6H), 5.24 (quin, 1H), 3.85 (m, 1H), 3.49 (m, 5H), 2.97 (br d, 4H), 1.54 (d, 3H), 1.45 (d, 6H). [M+H]+=511.2503. -4- nicotinamideExample 89 was prepared according to General Procedure 11 using Intermediate 8 (100 mg,0.194 mmol), potassium carbonate (21.1 mg, 0.213 mmol, 1.1 eq.) and 1-bromo-2-methoxy- ethane (29.6 mg, 0.213 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 89 (25.0 mg,0.0436 mmol). 1H NMR (400 MHz, dmso-7.78 (s, 1H), 7.33 (d, 2H), 7.09 (m, 6H), 5.16 (t, 1H), 4.74 (tt, 1H), 3.85 (m, 2H), 3.49 (br t, 2H), 3.41 (t, 2H), 3.21 (s, 3H), 2.44 (m, 6H), 2.22 (m, 4H), 1.99 (m, 2H), 1.61 (m, 2H), 1.48 (d, 3H) | [M+H]+=574.3068 Example 90: N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-methoxyethyl)-4- piperidylidene]methyl]phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-nicotinamide Step A: Preparation of 4-[bromo-(4-fluorophenyl)methylene]piperidine4-[bromo-(4-fluorophenyl)methylene]piperidine was prepared according to GeneralProcedure 1 using 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-spiro[3.3]heptan-2- yloxynicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (5.00 g, 13.5 mmol) in dichloromethane (0.3 M) and hydrogen chloride to give the crude N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4- fluorophenyl)methyl]phenyl]ethyl]-5-spiro[3.3]heptan-2-yloxy-nicotinamide (3.60 g, 13 mmol), which was used into the next step without further purification. [M+H]+=272.0. 4-[Bromo-(4-fluorophenyl)methylene]-1-(2-methoxyethyl)piperidine was prepared according to General Procedure 11 using 4-[bromo-(4-fluorophenyl)methylene]piperidine (1.90 g, 7.03mmol), potassium carbonate (0.780 g, 5.64 mmol, 0.80 eq.) and 1-bromo-2-methoxy-ethane (1.10 g, 7.73 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give 4-[bromo-(4- fluorophenyl)methylene]-1-(2-methoxyethyl)piperidine (2.12 g, 6.46 mmol). [M+H]+=330.0.methoxyethyl)-4- 2-[(1R)-1-[4-[(4-Fluorophenyl)-[1-(2-methoxyethyl)-4-piperidylidene]methyl]phenyl] ethyl]isoindoline-1,3-quinone was prepared according to General Procedure 4A using 4-[bromo-(4-fluorophenyl)methylene]-1-(2-methoxyethyl)piperidine (2.12 g, 6.46 mmol) and 2- [(1R)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]isoindoline-1,3-dione (2.92 g, 7.75 mmol). The crude residues were purified by silica gel column chromatography (dichloromethane / methanol / ammoniac) to give 2-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2- methoxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]isoindoline-1,3-quinone (2.86 g, 5.74 mmol). [M+H]+=499.2. -[1-(2-methoxyethyl)-4- [(1R)-1-[4-[(4-Fluorophenyl)-[1-(2-methoxyethyl)-4-piperidylidene]methyl]phenyl] ethyl]amine was prepared according to General Procedure 3 using 2-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2-methoxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]isoindoline-1,3- quinone (2.86 g, 2.50 mmol) and hydrazine (2.37 mL, 28.7 mmol). The crude residues were purified by silica gel column chromatography (dichloromethane / methanol / ammoniac) to give [(1R)-1-[4-[(4-fluorophenyl)-[1-(2-methoxyethyl)-4- piperidylidene]methyl]phenyl]ethyl]amine (1.40 g, 0.235 mmol). [M+H]+=369.1. Step E: Preparation of Example 90:Example 90 was prepared according to General Procedure 2B using [(1R)-1-[4-[(4-fluorophenyl)-[1-(2-methoxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]amine (250 mg, 0.678 mmol) and sodium;5-[(3S)-tetrahydrofuran-3-yl]oxynicotinate (157 mg, 0.678 mmol) in N,N-dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 90 (150 mg, 0.268 mmol). 1H NMR (400 MHz, dmso-7.75 (m, 1H), 7.33 (d, 2H), 7.09 (m, 6H), 5.18 (m, 2H), 3.84 (m, 4H), 3.41 (t, 2H), 3.21 (s, 3H), 2.45 (m, 6H), 2.24 (m, 5H), 1.99 (m, 1H), 1.48 (d, 3H) | [M+H]+=560.2915 2-carboxylic acid tert-butyl ester 6-[(4-Fluorophenyl)-[4-[(1R)-1-[[1-(trifluoromethyl)pyrazole-4- carbonyl]amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was prepared according to a modified General Procedure 2C using Intermediate 3 (401 mg, 0.948 mmol, 1.1 eq.) and 1-(trifluoromethyl)pyrazole-4-carboxylic acid (160 mg, 0.862 mmol) in dichloromethane (0.15 M) to give the crude 6-[(4-fluorophenyl)-[4-[(1R)-1-[[1- (trifluoromethyl)pyrazole-4-carbonyl]amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane- 2-carboxylic acid tert-butyl ester (504 mg, 0.862 mmol), considering a quantitative yield.Step B: Preparation of Example 91Example 91 was prepared according to General Procedure 1 using the crude 6-[(4-fluorophenyl)-[4-[(1R)-1-[[1-(trifluoromethyl)pyrazole-4- carbonyl]amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (504 mg, 0.860 mmol) in dichloromethane (0.3 M) and trifluoroacetic acid. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammoniumbicarbonate) to give Example 91 (153 mg, 0.316 mmol). 1H NMR (400 MHz, dmso-ppm 8.98 (s, 1H), 8.72 (d, 1H), 8.56 (m, 2H), 8.33 (s, 1H), 7.34 (d, 2H), 7.15 (m, 4H), 7.07 (d, 2H), 5.12 (m, 1H), 4.04 (s, 4H), 3.14 (br d, 4H), 1.46 (d, 3H) | [M+H]+=485.1958 Example 92: 5-(3,3-difluorocyclopentoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]pyridine-3-carboxamide, diastereoisomer 1 Step A: Preparation of 5-(3,3-difluorocyclopentoxy)nicotinic acid methyl ester, racemic5-(3,3-Difluorocyclopentoxy)nicotinic acid methyl ester was prepared according to GeneralProcedure 10 using methyl 5-hydroxypyridine-3-carboxylate (630 mg, 4.11 mmol) and 3,3-difluorocyclopentanol (502 mg, 4.11 mmol). The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 5-(3,3-difluorocyclopentoxy)nicotinic acid methyl ester, racemic (517 mg, 2.01 mmol). 1H NMR(400 MHz, dmso- 3H), 2.69 (m, 1H), 2.14 (m, 5H). [M+H]+=258.1.Step B: Preparation of methyl 5-(3,3-difluorocyclopentoxy)pyridine-3-carboxylate,enantiomer 1 methyl 5-(3,3-difluorocyclopentoxy)pyridine-3-carboxylate, enantiomer 1 was preparedaccording to General Procedure 13 using 5-(3,3-difluorocyclopentoxy)nicotinic acid methylester, racemic (500 mg, 1.94 mmol) by reverse phase (ethanol / acetonitrile / diethylamine) to give methyl 5-(3,3-difluorocyclopentoxy)pyridine-3-carboxylate, enantiomer 1 (132 mg,0.513 mmol). 1H NMR (400 MHz, dmso-5.18 (m, 1H), 3.9 (m, 3H), 2.69 (m, 1H), 2.14 (m, 5H). [M+H]+=258.1.Step C: Preparation of sodium;5-(3,3-difluorocyclopentoxy)nicotinate, enantiomer 1Sodium;5-(3,3-difluorocyclopentoxy)nicotinate, enantiomer 1 was prepared according toGeneral Procedure 9A using 5-[(1S)-3,3-difluorocyclopentoxy]nicotinic acid methyl ester,enantiomer 1 (132 mg, 0.513 mmol) to give sodium;5-(3,3-difluorocyclopentoxy)nicotinate, enantiomer 1 (627 mg, 0.513 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification. [M+H]+=244.0. pyridine-3- diastereoisomer 1 tert-butyl 4-[[4-[(1R)-1-[[5-(3,3-difluorocyclopentoxy)pyridine-3-carbonyl]amino]ethyl] phenyl]-(4-fluorophenyl)methylene]piperidine-1-carboxylate, diastereoisomer 1 was preparedaccording to General Procedure 2B using Intermediate 2 (210 mg, 0.512 mmol) andsodium;5-(3,3-difluorocyclopentoxy)nicotinate, enantiomer 1 (136 mg, 0.512 mmol) in N,N- dimethylformamide. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give tert-butyl 4-[[4-[(1R)-1-[[5-(3,3-difluorocyclopentoxy) pyridine-3-carbonyl]amino]ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1- carboxylate, diastereoisomer 1 (285 mg, 0.448 mmol). [M+H]+=636.1.Step E: Preparation of Example 92Example 92 was prepared according to General Procedure 1 using tert-butyl 4-[[4-[(1R)-1-[[5-(3,3-difluorocyclopentoxy)pyridine-3-carbonyl]amino]ethyl]phenyl]-(4- fluorophenyl)methylene]piperidine-1-carboxylate, diastereoisomer 1 (285 mg, 0.448 mmol) in dichloromethane (0.3 M) and hydrogen chloride. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 92 (145mg, 0.271 mmol). 1H NMR (400 MHz, dmso-1H), 7.73 (m, 1H), 7.33 (m, 2H), 7.1 (s, 4H), 7.04 (m, 2H), 5.15 (m, 2H), 2.74 (m, 4H), 2.64 (m, 1H), 2.17 (m, 9H), 1.48 (d, 3H) | [M+H]+=536.2505 Example 93: 5-(3,3-difluorocyclopentoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4- piperidylidene)methyl]phenyl]ethyl]pyridine-3-carboxamide, diastereoisomer 2 Step A: Preparation of methyl 5-(3,3-difluorocyclopentoxy)pyridine-3-carboxylate,enantiomer 2 methyl 5-(3,3-difluorocyclopentoxy)pyridine-3-carboxylate, enantiomer 2 was preparedaccording to General Procedure 13 using 5-(3,3-difluorocyclopentoxy)nicotinic acid methylester, racemic (500 mg, 1.94 mmol) by reverse phase (ethanol / acetonitrile / diethylamine) to give methyl 5-(3,3-difluorocyclopentoxy)pyridine-3-carboxylate, enantiomer 2 (136 mg,0.529 mmol). 1H NMR (400 MHz, dmso-5.18 (m, 1H), 3.9 (m, 3H), 2.69 (m, 1H), 2.14 (m, 5H). rt [M+H]+=258.1.Step B: Preparation of sodium;5-(3,3-difluorocyclopentoxy)nicotinate, enantiomer 2Sodium;5-(3,3-difluorocyclopentoxy)nicotinate, enantiomer 2 was prepared according toGeneral Procedure 9A using 5-[(1R)-3,3-difluorocyclopentoxy]nicotinic acid methyl ester,enantiomer 2 (137 mg, 0.533 mmol) to give sodium;5-(3,3-difluorocyclopentoxy)nicotinate, enantiomer 2 (141 mg, 0.533 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification. [M+H]+=244.0.3- diastereoisomer 2 tert-butyl 4-[[4-[(1R)-1-[[5-(3,3-difluorocyclopentoxy)pyridine-3-carbonyl]amino]ethyl] phenyl]-(4-fluorophenyl)methylene]piperidine-1-carboxylate, diastereoisomer 2 was preparedaccording to General Procedure 2B using Intermediate 2 (220 mg, 0.536 mmol) andsodium;5-(3,3-difluorocyclopentoxy)nicotinate, enantiomer 2 (142 mg, 0.536 mmol) in N,N- dimethylformamide. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give tert-butyl 4-[[4-[(1R)-1-[[5-(3,3-difluorocyclopentoxy) pyridine-3-carbonyl]amino]ethyl]phenyl]-(4-fluorophenyl)methylene]piperidine-1- carboxylate, diastereoisomer 2 (280 mg, 0.441 mmol). [M+H]+=636.1. D: Preparation of Example 93Example 93 was prepared according to General Procedure 1 using tert-butyl 4-[[4-[(1R)-1-[[5-(3,3-difluorocyclopentoxy)pyridine-3-carbonyl]amino]ethyl]phenyl]-(4- fluorophenyl)methylene]piperidine-1-carboxylate, diastereoisomer 2 (280 mg, 0.441 mmol) in dichloromethane (0.3 M) and hydrogen chloride. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 93 (135mg, 0.252 mmol). 1H NMR (400 MHz, dmso-1H), 7.73 (m, 1H), 7.33 (m, 2H), 7.1 (s, 4H), 7.04 (m, 2H), 5.15 (m, 2H), 2.74 (m, 4H), 2.64 (m, 1H), 2.17 (m, 9H), 1.48 (d, 3H) | [M+H]+=536.2509 Example 94 was prepared according to General Procedure 11 using Example 74 (200 mg,0.389 mmol), potassium carbonate (43.1 mg, 0.312 mmol, 0.80 eq.) and iodoethane (66.8 mg, 0.428 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography(acetonitrile / water / ammonium bicarbonate) to give Example 94 (105 mg, 0.194 mmol). 1HNMR (400 MHz, dmso-7.33 (s, 2H), 7.13 (m, 4H), 7.07 (m, 2H), 5.17 (m, 2H), 3.83 (m, 4H), 3.14 (s, 4H), 2.96 (m, 4H), 2.36 (m, 2H), 2.23 (m, 1H), 2.01 (m, 1H), 1.49 (d, 3H), 0.84 (m, 3H) | [M+H]+=542.2805 Example 95: 5-(3,3-difluorocyclopentoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4- piperidylidene)methyl]phenyl]ethyl]nicotinamide, diastereoisomer 1 Example 95 was prepared according to a modified General Procedure 8 using Example 92(118 mg, 0.220 mmol) in tetrahydrofuran. The crude residues were dissolved into methanoland eluted through a PoraPak Rxn CX to give Example 95 (95.0 mg, 0.173 mmol). 1H NMR(400 MHz, dmso-d6) ppm 8.94 (d, 1H), 8.66 (d, 1H), 8.4 (d, 1H), 7.75 (dd, 1H), 7.33 (d, 2H), 7.12 (m, 4H), 7.05 (m, 2H), 5.14 (m, 2H), 2.69 (m, 1H), 2.29 (m, 12H), 2.16 (s, 3H), 1.97 (m, 1H), 1.49 (d, 3H). [M+H]+=550.2670 Example 96: 5-(3,3-difluorocyclopentoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-(1-methyl-4- piperidylidene)methyl]phenyl]ethyl]nicotinamide, diastereoisomer 2Example 96 was prepared according to a modified General Procedure 8 using Example 93(108 mg, 0.202 mmol) in tetrahydrofuran. The crude residues were dissolved into methanoland eluted through a PoraPak Rxn CX to give Example 96 (70.0 mg, 0.127 mmol). 1H NMR(400 MHz, dmso- 2H), 7.12 (m, 4H), 7.05 (m, 2H), 5.14 (m, 2H), 2.69 (m, 1H), 2.29 (m, 12H), 2.16 (s, 3H), 1.97 (m, 1H), 1.49 (d, 3H). [M+H]+=550.2671 Example 97: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide Example 97 was prepared according to a modified General Procedure 8 using Example 86(60.0 mg, 0.120 mmol), aqueous 37 wt.% formaldehyde (301 mg, 0.276 mL, 3.61 mmol) in a5:1 dichloromethane / methanol mixture. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give N-[(1R)-1-[4-[(4- fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide (40.9 mg, 0.0798 mmol). 1H NMR (400 MHz, dmso- 5.2 (q, 2H), 5.11 (m, 1H), 3.13 (s, 4H), 2.94 (m, 4H), 2.15 (s, 3H), 1.44 (d, 3H) | [M+H]+=513.2266 Example 98: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-3-isopropyl-isoxazolo[5,4-b]pyridine-5-carboxamide Example 98 was prepared according to a modified General Procedure 8 using Example 88(36.0 mg, 0.0705 mmol) and aqueous 37 wt.% formaldehyde (176 mg, 0.162 mL, 2.12 mmol)in a 5:1 dichloromethane / methanol mixture. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 98 (22.3mg, 0.0425 mmol). 1H NMR (400 MHz, dmso-(m, 2H), 7.14 (m, 4H), 7.08 (m, 2H), 5.19 (m, 1H), 3.5 (m, 1H), 3.14 (s, 4H), 2.95 (m, 4H), 2.15 (s, 3H), 1.53 (d, 3H), 1.45 (d, 6H) | [M+H]+=525.2656 Example 99: N-[(1R)-1-[4-[(4-fluorophenyl)-[2-(2-methoxyethyl)-2-azaspiro[3.3]heptan- 6-ylidene]methyl]phenyl]ethyl]-1-(trifluoromethyl)pyrazole-4-carboxamide;2,2,2- trifluoroacetic acid N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-1- (trifluoromethyl)pyrazole-4-carboxamide was prepared according to General Procedure 1 using the crude tert-butyl 6-[(4-fluorophenyl)-[4-[(1R)-1-[[1-(trifluoromethyl)pyrazole-4- carbonyl]amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (503 mg, 0.860 mmol) in dichloromethane (0.3 M) and trifluoroacetic acid. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-1- (trifluoromethyl)pyrazole-4-carboxamide (153 mg, 0.316 mmol).Step B: Preparation of Example 99Example 99 was prepared according to General Procedure 11 using N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-1-(trifluoromethyl) pyrazole-4-carboxamide (50 mg, 0.103 mmol), potassium carbonate (12.8 mg, 0.093 mmol, 0.90 eq.) and 1-bromo-2-methoxy-ethane (16.4 mg, 0.114 mmol, 1.1 eq.). The crude residueswere purified by reverse phase chromatography (acetonitrile / water / trifluoracetic acid) to giveExample 99 (29.2 mg, 0.0538 mmol). 1H NMR (400 MHz, dmso-d6) ppm 9.83 (m, 1H),8.98 (s, 1H), 8.71 (d, 1H), 8.33 (s, 1H), 7.34 (d, 2H), 7.16 (br d, 4H), 7.05 (m, 2H), 5.1 (m, 1H), 4.17 (m, 4H), 3.49 (m, 2H), 3.33 (m, 2H), 3.27 (s, 3H), 3.13 (m, 4H), 1.46 (d, 3H) | [M+H]+=543.2370 Example 100: N-[(1R)-1- [2-azaspiro[3.3]heptan-6-ylidene-(4- fluorophenyl)methyl] ethyl]-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinamide Step A: Preparation of 5-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinic acid methyl ester5-(4-Oxa-7-azaspiro[2.5]octan-7-yl)nicotinic acid methyl ester was prepared according toGeneral Procedure 12 using methyl 5-bromopyridine-3-carboxylate (0.500 g, 2.31 mmol) and 4-oxa-7-azaspiro[2.5]octane, hydrogen chloride (1:1) (416 mg, 2.78 mmol, 1.2 eq.) in 1,4- dioxane. The crude residues were purified by silica gel column chromatography (dichloromethane / methanol) to give 5-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinic acid methylester (323 mg, 1.17 mmol). 1H NMR (400 MHz, dmso-7.65 (m, 1H), 3.87 (s, 3H), 3.8 (m, 2H), 3.31 (s, 4H), 3.24 (s, 2H), 0.7 (m, 4H). [M+H]+=249.0.Step B: Preparation of sodium;5-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinateSodium;5-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinate was prepared according to GeneralProcedure 9A using 5-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinic acid methyl ester (320 mg,1.29 mmol) to give sodium;5-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinate (330 mg, 1.29 mmol, considering a quantitative yield. The compound was engaged into the next step without further purification. [M+H]+=235.0. 7- tert- butyl ester 6-[(4-Fluorophenyl)-[4-[(1R)-1-[[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinoyl]amino]ethyl] phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was preparedaccording to General Procedure 2B using Intermediate 3 (300 mg, 0.710 mmol) andsodium;5-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinate (182 mg, 0.710 mmol) in N,N- dimethylformamide. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 6-[(4-fluorophenyl)-[4-[(1R)-1-[[5-(4-oxa-7- azaspiro[2.5]octan-7-yl)nicotinoyl]amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (289 mg, 0.452 mmol). [M+H]+=639.3.Step D: Preparation of Example 100Example 100 was prepared according to General Procedure 1 using 6-[(4-fluorophenyl)-[4-[(1R)-1-[[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinoyl]amino]ethyl]phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (289 mg, 0.452 mmol) and trifluoroacetic acid (0.693 mL, 9.05 mmol, 20 eq.) in neat conditions. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to giveExample 100 (137 mg, 0.254 mmol). 1H NMR (400 MHz, dmso-(d, 1H), 8.41 (d, 1H), 7.63 (s, 1H), 7.34 (d, 2H), 7.11 (m, 6H), 5.18 (t, 1H), 3.82 (m, 2H), 3.49 (m, 4H), 3.36 (m, 2H), 3.22 (m, 3H), 2.98 (m, 4H), 1.49 (d, 3H), 0.7 (m, 4H) | [M+H]+=539.2812. Example 101: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinamide Example 101 was prepared according to a modified General Procedure 8 using Example 100(100 mg, 0.186 mmol) in tetrahydrofuran. The crude residues were dissolved into methanoland eluted through a PoraPak Rxn CX to give Example 101 (83.0 mg, 0.150 mmol). 1H NMR(400 MHz, dmso- 2H), 7.13 (m, 4H), 7.06 (d, 2H), 5.18 (t, 1H), 3.82 (m, 2H), 3.29 (m, 2H), 3.22 (s, 2H), 3.17 (s, 4H), 2.95 (br d, 4H), 2.17 (s, 3H), 1.49 (d, 3H), 0.7 (m, 4H) | [M+H]+=553.2969 Example 102: N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]-3- (6-keto-1-methyl-3-pyridyl)-4-methyl-benzamide;2,2,2-trifluoroacetic acid Step A: Preparation of 3-(6-keto-1-methyl-3-pyridyl)-4-methyl-benzoic acid 3-(6-Keto-1-methyl-3-pyridyl)-4-methyl-benzoic acid was prepared according to a modifiedGeneral Procedure 4B using 5-bromo-1-methylpyridin-2(1H)-one (500 mg, 2.66 mmol),potassium phosphate (1.41 g, 6.65 mmol) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoic acid (383 mg, 2.127 mmol) to give 3-(6-keto-1-methyl-3-pyridyl)- 4-methyl-benzoic acid (330 mg, 1.36 mmol). [M+H]+=240.0.Step B: Preparation of 4-[(4-fluorophenyl)-[4-[(1R)-1- (6-keto-1-methyl-3-pyridyl)-4- methyl-benzoyl]amino]ethyl]phenyl]methylene] 1-carboxylic acid tert-butyl ester To a stirred solution of tert-butyl (R)-4-((4-(1-aminoethyl)phenyl)(4-fluorophenyl)methylene) piperidine-1-carboxylate (320 mg, 0.779 mmol) and 4-methyl-3-(1-methyl-6-oxo-1,6-dihydro pyridin-3-yl)benzoic acid (284 mg, 1.17 mmol) in dichloromethane (10.0 mL) was added N,N-diisopropylethylamine (302 mg, 2.34 mmol) and the solution was cooled to 0 °C. A 50 wt.% propylphosphonic anhydride solution in ethyl acetate (372 mg, 1.17 mmol) was added and the mixture was stirred at room temperature until completion of the reaction. The mixture was partitioned between ethyl acetate and water. The layers were separated and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residues were purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give tert-butyl (R)-4-((4-fluorophenyl)(4-(1-(4-methyl-3-(1- methyl-6-oxo-1,6-dihydropyridin-3-yl)benzamido)ethyl)phenyl)methylene) piperidine-1- carboxylate (320 mg, 0.503 mmol). LCMS: 636.6 [M+H]+Step C: Preparation of Example 102Example 102 was prepared according to General Procedure 1 using 4-[(4-fluorophenyl)-[4-[(1R)-1-[[3-(6-keto-1-methyl-3-pyridyl)-4-methyl-benzoyl]amino]ethyl]phenyl]methylene] piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.315 mmol) in dichloromethane (0.3 M) and trifluoroacetic acid (1.0 eq.). The crude residues were purified by reverse phase chromatography (acetonitrile / water / trifluoroacetic acid) to give Example 102 (35.0 mg, 0.065mmol). 1H-NMR (400 MHz, DMSO- ), 7.80-7.76(m, 3H), 7.52 (dd, J = 2.80, 9.40 Hz, 1H), 7.39-7.35 (m, 3H), 7.17 (d, J = 7.20 Hz, 4H), 7.17 (d, J = 7.20 Hz, 2H), 6.47 (d, J = 9.20 Hz, 1H), 5.18 (t, J = 7.20 Hz, 1H), 3.49 (s, 3H), 3.13 (s, 4H), 2.44-2.39 (m, 4H), 2.31 (s, 3H), 1.47 (d, J = 6.80 Hz, 3H). [M+H]+=536.3. Example 103: 3-(1,1-diketo-1,4-thiazinan-4-yl)-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl- 2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]benzamide Step A: Preparation of 3-(1,1-diketo-1,4-thiazinan-4-yl)benzoic acid methyl ester3-(1,1-Diketo-1,4-thiazinan-4-yl)benzoic acid methyl ester was prepared according to GeneralProcedure 12 using methyl 3-bromobenzoate (477 mg, 2.22 mmol) and 1,4-thiazinane 1,1-dioxide (300 mg, 2.21 mmol, 1.0 eq.) in 1.4-dioxane. The crude residues were purified by silica gel column chromatography (ethyl acetate / cyclohexane) to give 3-(1,1-diketo-1,4-thiazinan-4-yl)benzoic acid methyl ester (285 mg, 1.06 mmol). 1H NMR (400 MHz, dmso-3.15 (m, 4H). [M+H]+=270.0.Step B: Preparation of 3-(1,1-diketo-1,4-thiazinan-4-yl)benzoate3-(1,1-Diketo-1,4-thiazinan-4-yl)benzoate was prepared according to General Procedure 9Ausing 3-(1,1-diketo-1,4-thiazinan-4-yl)benzoic acid methyl ester (285 mg, 1.06 mmol) to give3-(1,1-diketo-1,4-thiazinan-4-yl)benzoate (360 mg, 1.30 mmol). 1H NMR (400 MHz, dmso-[M+H]+=255.4.Step C: Preparation of Example 103Example 103 was prepared according to General Procedure 2B using Intermediate 4 (170 mg,0.377 mmol) and 3-(1,1-diketo-1,4-thiazinan-4-yl)benzoate (105 mg, 0.377 mmol) in N,N-dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 103 (45.0 mg, 0.078 mmol).1HNMR (400 MHz, dmso- 7.13 (m, 4H), 7.06 (d, 1H), 5.18 (t, 1H), 3.81 (m, 4H), 3.15 (m, 4H), 3.13 (s, 4H), 2.94 (br d, 4H), 2.15 (s, 3H), 1.49 (d, 3H) | [M+H]+=574.2529 Example 104: 5-(3,3-difluorocyclopentoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2- methoxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]pyridine-3-carboxamide;2,2,2- trifluoroacetic acid, diastereoisomer 1 5-(3,3-Difluorocyclopentoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl] phenyl]ethyl]nicotinamide, diastereoisomer 1 was prepared according to General Procedure 1using 4-[[4-[(1R)-1-[[5-(3,3-difluorocyclopentoxy)nicotinoyl]amino]ethyl]phenyl]-(4- fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester, diastereoisomer 1 (250 mg, 0.393 mmol) and trifluoroacetic acid (0.602 mL, 7.87 mmol, 20 eq.) in neat conditions. The crude residues were dissolved into methanol and eluted through a PoraPak Rxn CX to give 5-(3,3-difluorocyclopentoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl] phenyl]ethyl]nicotinamide, diastereoisomer 1 (192 mg, 0.359 mmol). [M+H]+=536.1.Step B: Preparation of Example 104Example 104 was prepared according to General Procedure 11 using 5-(3,3-difluorocyclopentoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl] ethyl]nicotinamide, diastereoisomer 1 (95.0 mg, 0.177 mmol), potassium carbonate (22.1 mg,0.160 mmol, 0.90 eq.) and 1-bromo-2-methoxy-ethane (27.1 mg, 0.195 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammoniumbicarbonate) to give Example 104 (92.0 mg, 0.130 mmol). 1H NMR (400 MHz, dmso-ppm 9.57 (m, 1H), 8.97 (d, 1H), 8.67 (d, 1H), 8.42 (d, 1H), 7.77 (t, 1H), 7.38 (d, 2H), 7.17 (m, 4H), 7.1 (d, 2H), 5.17 (quin, 1H), 5.13 (m, 1H), 3.64 (t, 2H), 3.51 / 3.05 (2m, 4H), 3.3 (m+s, 5H), 2.68 (m, 1H), 2.5 (m, 4H), 2.28 (m, 4H), 1.96 (m, 1H), 1.48 (d, 3H) | [M+H]+=594.2932 Example 105: 5-(3,3-difluorocyclopentoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2- hydroxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]pyridine-3-carboxamide, diastereoisomer 1 Example 105 was prepared according to General Procedure 11 using 5-(3,3-difluorocyclopentoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl] ethyl]nicotinamide, diastereoisomer 1 (95 mg, 0.177 mmol), potassium carbonate (22.1 mg, 0.160 mmol, 0.90 eq.) and 2-bromoethanol (24.4 mg, 0.195 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammoniumbicarbonate) to give Example 105 (65.0 mg, 0.112 mmol). 1H NMR (400 MHz, dmso-ppm 8.94 (d, 1H), 8.66 (d, 1H), 8.4 (d, 1H), 7.75 (dd, 1H), 7.33 (d, 2H), 7.11 (m, 4H), 7.05 (d, 2H), 5.15 (m, 2H), 4.35 (t, 1H), 3.48 (m, 2H), 2.68 (m, 1H), 2.45 (br d, 4H), 2.38 (t, 2H), 2.26 (m, 8H), 1.97 (br dd, 1H), 1.48 (d, 3H) | [M+H]+=580.2777 Example 106: 5-(3,3-difluorocyclopentoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2- methoxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]pyridine-3-carboxamide, diastereoisomer 2 5-(3,3-difluorocyclopentoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]nicotinamide, diastereoisomer 2 was prepared according to General Procedure 1using 4-[[4-[(1R)-1-[[5-(3,3-difluorocyclopentoxy)nicotinoyl]amino]ethyl]phenyl]-(4- fluorophenyl)methylene]piperidine-1-carboxylic acid tert-butyl ester, diastereoisomer 2 (380 mg, 0.598 mmol) and trifluoroacetic acid (0.96 mL, 12.0 mmol, 20 eq.) in neat conditions. The crude residues were dissolved into methanol and eluted through a PoraPak Rxn CX to give 5-(3,3-difluorocyclopentoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl]ethyl]nicotinamide, diastereoisomer 2 (290 mg, 0.541 mmol). [M+H]+=536.1.Step B: Preparation of Example 106Example 106 was prepared according to General Procedure 11 using 5-(3,3-difluorocyclopentoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl] ethyl]nicotinamide, diastereoisomer 2 (140 mg, 0.261 mmol), potassium carbonate (32.5 mg, 0.235 mmol, 0.90 eq.) and 1-bromo-2-methoxy-ethane (40 mg, 0.288 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammoniumbicarbonate) to give Example 106 (37.0 mg, 0.0623 mmol). 1H NMR (400 MHz, dmso-ppm 8.95 (d, 1H), 8.67 (d, 1H), 8.4 (d, 1H), 7.75 (t, 1H), 7.33 (d, 2H), 7.11 (m, 4H), 7.05 (d, 2H), 5.17 (quin, 1H), 5.13 (m, 1H), 3.42 (t, 2H), 3.22 (s, 3H), 2.67 (m, 1H), 2.46 (t+m, 7H), 2.22 (m, 8H), 1.96 (m, 1H), 1.48 (d, 3H) | [M+H]+=594.2934 Example 107: 5-(3,3-difluorocyclopentoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(2- hydroxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]pyridine-3-carboxamide, diastereoisomer 2 Example 107 was prepared according to General Procedure 11 using 5-(3,3- difluorocyclopentoxy)-N-[(1R)-1-[4-[(4-fluorophenyl)-(4-piperidylidene)methyl]phenyl] ethyl]nicotinamide, diastereoisomer 2 (140 mg, 0.261 mmol), potassium carbonate (32.5 mg, 0.235 mmol, 0.90 eq.) and 2-bromoethanol (35.9 mg, 0.288 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammoniumbicarbonate) to give Example 107 (96.0 mg, 0.166 mmol). 1H NMR (400 MHz, dmso-ppm 8.94 (d, 1H), 8.67 (d, 1H), 8.4 (d, 1H), 7.75 (m, 1H), 7.33 (d, 2H), 7.09 (m, 6H), 7.08 (s, 1H), 5.16 (m, 2H), 4.35 (br s, 1H), 3.48 (br d, 2H), 2.68 (qd, 1H), 2.4 (m, 6H), 2.25 (m, 8H), 1.48 (d, 3H) | [M+H]+=580.2777 Example 108: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-tetrahydropyran-4-yl-nicotinamide Step A: Preparation of 5-(3,6-dihydro-2H-pyran-4-yl)nicotinic acid methyl ester 5-(3,6-Dihydro-2H-pyran-4-yl)nicotinic acid methyl ester was prepared according to GeneralProcedure 4B using methyl 5-bromopyridine-3-carboxylate (500 mg, 2.31 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (584 mg, 2.78 mmol). Thecrude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) togive 5-(3,6-dihydro-2H-pyran-4-yl)nicotinic acid methyl ester (446 mg, 2.03 mmol). [M+H]+=220.0.Step B: Preparation of 5-tetrahydropyran-4-ylnicotinic acid methyl ester5-Tetrahydropyran-4-ylnicotinic acid methyl ester was prepared according to a modifiedGeneral Procedure 14 using 5-(3,6-dihydro-2H-pyran-4-yl)nicotinic acid methyl ester (446mg, 2.03 mmol) to give the crude 5-tetrahydropyran-4-ylnicotinic acid methyl ester (415 mg,1.86 mmol) which was used into the next step without further purification. [M+H]+=222.0.Step C: Preparation of sodium;5-tetrahydropyran-4-ylnicotinateSodium;5-tetrahydropyran-4-ylnicotinate was prepared according to General Procedure 9Ausing 5-tetrahydropyran-4-ylnicotinic acid methyl ester (415 mg, 1.88 mmol) to give sodium;5-tetrahydropyran-4-ylnicotinate (429 mg, 1.88 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification. [M+H]+=208.0.Step D: Preparation of Example 108Example 108 was prepared according to General Procedure 2B using Intermediate 4 (250 mg,0.743 mmol) and sodium;5-tetrahydropyran-4-ylnicotinate (170 mg, 0.743 mmol) in N,N- dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 108 (60.0 mg, 0.114 mmol).1HNMR (400 MHz, dmso-(d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.19 (t, 1H), 3.97 (m, 2H), 3.45 (m, 2H), 3.13 (s, 4H), 2.95 (br d, 5H), 2.15 (s, 3H), 1.74 (m, 4H), 1.5 (d, 3H) | [M+H]+=526.2861 Example 109: N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4- fluorophenyl)methyl]phenyl]ethyl]-5-(3-pyridyl)nicotinamide;2,2,2-trifluoroacetic acidStep A: Preparation of 5-(3-pyridyl)nicotinic acid methyl ester5-(3-Pyridyl)nicotinic acid methyl ester was prepared according to General Procedure 4Busing methyl 5-bromopyridine-3-carboxylate (500 mg, 2.31 mmol) and 3-pyridylboronic acid (341 mg, 2.78 mmol). The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 5-(3-pyridyl)nicotinic acid methyl ester (495 mg, 2.31 mmol). [M+H]+=215.0.Step B: Preparation of sodium;5-(3-pyridyl)nicotinateSodium;5-(3-pyridyl)nicotinate was prepared according to General Procedure 9A using 5-(3-pyridyl)nicotinic acid methyl ester (495 mg, 2.31 mmol) to give sodium;5-(3- pyridyl)nicotinate (513 mg, 2.31 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification. [M+H]+=201.1. 2-carboxylic acid tert-butyl ester 6-[(4-Fluorophenyl)-[4-[(1R)-1-[[5-(3-pyridyl)nicotinoyl]amino]ethyl]phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was prepared according to GeneralProcedure 2B using Intermediate 3 (500 mg,1.18 mmol) and sodium;5-(3-pyridyl)nicotinate(263 mg, 1.18 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (ethyl acetate / methanol) to give 6-[(4-fluorophenyl)-[4-[(1R)-1- [[5-(3-pyridyl)nicotinoyl]amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (473 mg, 0.782 mmol). [M+H]+=605.2.Step D: Preparation of Example 109Example 109 was prepared according to General Procedure 1 using 6-[(4-fluorophenyl)-[4-[(1R)-1-[[5-(3-pyridyl)nicotinoyl]amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (470 mg, 0.777 mmol) and trifluoroacetic acid (1.19 mL, 15.5 mmol, 20 eq.) in neat conditions. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 109 (295 mg,0.477 mmol). 1H NMR (400 MHz, dmso-8.55 (br s, 2H), 8.29 (dt, 1H), 7.61 (dd, 1H), 7.39 (d, 2H), 7.15 (m, 4H), 7.09 (d, 2H), 5.22 (m, 1H), 4.03 (br t, 4H), 3.14 (br d, 4H), 1.52 (d, 3H) | [M+H]+=505.2394 Example 110: N-[(1R)-1-[4-[(4-fluorophenyl)-[2-(2-methoxyethyl)-2-azaspiro[3.3] heptan-6-ylidene]methyl]phenyl]ethyl]-5-morpholino-nicotinamide;2,2,2-trifluoroacetic acid Step A: Preparation of N- -1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4- fluorophenyl)methyl] -5-morpholino-nicotinamide N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-morpholino-nicotinamide was prepared according to General Procedure 1 using 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-morpholinonicotinoyl)amino]ethyl]phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (332 mg, 0.542 mmol) and trifluoroacetic acid (0.830 mL, 10.8 mmol, 20 eq.) in neat conditions. The crude residues were dissolved into methanol and eluted through a PoraPak Rxn CX to give N-[(1R)-1-[4-[2- azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-morpholino-nicotinamide (233 mg, 0.455 mmol). [M+H]+=513.1.Step B: Preparation of Example 110Example 110 was prepared according to General Procedure 11 using N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-morpholino- nicotinamide (110 mg, 0.215 mmol), potassium carbonate (26.7 mg, 0.193 mmol, 0.90 eq.) and 1-bromo-2-methoxy-ethane (32.8 mg, 0.236 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to giveExample 110 (65.0 mg, 0.0945 mmol). 1H NMR (400 MHz, dmso-8.94 (br d, 1H), 8.49 (t, 1H), 8.45 (d, 1H), 7.74 (s, 1H), 7.36 (dd, 2H), 7.13 (m, 6H), 5.18 (m, 1H), 4.2 (m, 4H), 3.77 (br d, 4H), 3.65 (m, 1H), 3.49 (m, 2H), 3.32 (br s, 2H), 3.27 (s, 3H), 3.25 (m, 4H), 3.13 (m, 4H), 1.49 (dd, 3H) | [M+H]+=571.3073 nicotinamide;2,2,2-trifluoroacetic acid Example 111 was prepared according to General Procedure 11 using N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-morpholino- nicotinamide (110 mg, 0.215 mmol), potassium carbonate (26.7 mg, 0.193 mmol, 0.90 eq.) and 2-bromoethanol (29.5 mg, 0.236 mmol, 1.1 eq.). The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example111 (25.0 mg, 0.0373 mmol). 1H NMR (400 MHz, dmso-d, 1H), 8.47 (m, 2H), 7.75 (s, 1H), 7.36 (dd, 2H), 7.13 (m, 6H), 5.18 (br dd, 2H), 4.22 (m, 4H), 3.77 (br s, 4H), 3.57 (m, 2H), 3.21 (m, 11H), 1.49 (dd, 3H) | [M+H]+=557.2919. Example 112: N-[ -1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl] ethyl]-5-(3-pyridyl)nicotinamideExample 112 was prepared according to a modified General Procedure 8 using Example 109(150 mg, 0.243 mmol) in tetrahydrofuran. The crude residues were dissolved into methanoland eluted through a PoraPak Rxn CX to give Example 112 (105 mg, 0.203 mmol). 1H NMR(400 MHz, dmso- 1H), 8.58 (t, 1H), 8.24 (dt, 1H), 7.57 (ddd, 1H), 7.38 (d, 2H), 7.13 (m, 4H), 7.08 (d, 2H), 5.23 (quin, 1H), 3.15 (s, 4H), 2.95 (br d, 4H), 2.16 (s, 3H), 1.52 (d, 3H) | [M+H]+=519.2549 Example 113: 5-(2,5-dihydrofuran-3-yl)-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2- azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]nicotinamide Step A: Preparation of 5-(2,5-dihydrofuran-3-yl)nicotinic acid methyl ester5-(2,5-Dihydrofuran-3-yl)nicotinic acid methyl ester was prepared according to GeneralProcedure 4B using methyl 5-bromopyridine-3-carboxylate (1.00 g, 4.63 mmol) and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.09 g, 5.55 mmol). The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 5-(2,5-dihydrofuran-3-yl)nicotinic acid methyl ester (929 mg, 4.53 mmol).Step B: Preparation of sodium;5-(2,5-dihydrofuran-3-yl)nicotinateSodium;5-(2,5-dihydrofuran-3-yl)nicotinate was prepared according to General Procedure 9Ausing 5-(2,5-dihydrofuran-3-yl)nicotinic acid methyl ester (200 mg, 0.975 mmol) to give sodium;5-(2,5-dihydrofuran-3-yl)nicotinate (207 mg, 0.971 mmol).Step C: Preparation of Example 113Example 113 was prepared according to General Procedure 2B using sodium;5-(2,5-dihydrofuran-3-yl)nicotinate (190 mg, 0.892 mmol) and Intermediate 4 (300 mg, 0.892 mmol) in N,N-dimethylformamide. The crude residues were dissolved into methanol and eluted through a PoraPak Rxn CX and purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 113 (70 mg, 0.137 mmol).1HNMR (400 MHz, dmso-(d, 2H), 7.11 (m, 6H), 6.75 (s, 1H), 5.2 (t, 1H), 4.97 (td, 2H), 4.77 (m, 2H), 3.13 (s, 4H), 2.95 (br d, 4H), 2.15 (s, 3H), 1.5 (d, 3H) | [M+H]+=510.2548 Example 114: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-tetrahydrofuran-3-yl-nicotinamide, diastereoisomer 1 Step A: Preparation of 5-tetrahydrofuran-3-ylnicotinic acid methyl ester5-Tetrahydrofuran-3-ylnicotinic acid methyl ester was prepared according to GeneralProcedure 14 using 5-(2,5-dihydrofuran-3-yl)nicotinic acid methyl ester (929 mg, 4.53mmol). The crude residues were purified by silica gel column chromatography (n- heptane / ethyl acetate) to give 5-tetrahydrofuran-3-ylnicotinic acid methyl ester (500 mg, 2.41mmol). 1H NMR (400 MHz, dmso-(m, 1H), 3.97 (m, 1H), 3.89 (s, 3H), 3.81 (m, 1H), 3.63 (m, 1H), 3.54 (m, 1H), 2.37 (m, 1H), 1.95 (m, 1H). [M+H]+=208.0.Step B: Preparation of 5-tetrahydrofuran-3-ylnicotinic acid methyl ester, enantiomer 15-Tetrahydrofuran-3-ylnicotinic acid methyl ester, enantiomer 1 was prepared according toGeneral Procedure 13 using 5-tetrahydrofuran-3-ylnicotinic acid methyl ester (500 mg, 2.41mmol) by SFC (carbon dioxide / ethanol / diethylamine) to give 5-tetrahydrofuran-3-ylnicotinicacid methyl ester, enantiomer 1 (175 mg, 0.844 mmol). 1H NMR (400 MHz, dmso-8.95 (m, 1H), 8.77 (m, 1H), 8.16 (m, 1H), 4.05 (m, 1H), 3.97 (m, 1H), 3.89 (s, 3H), 3.81 (m, 1H), 3.63 (m, 1H), 3.54 (m, 1H), 2.37 (m, 1H), 1.95 (m, 1H). [M+H]+=208.0.Step C: Preparation of sodium;5-tetrahydrofuran-3-ylnicotinate, enantiomer 1Sodium;5-tetrahydrofuran-3-ylnicotinate, enantiomer 1 was prepared according to GeneralProcedure 9A using 5-tetrahydrofuran-3-ylnicotinic acid methyl ester (175 mg, 0.845 mmol)to give sodium;5-tetrahydrofuran-3-ylnicotinate, enantiomer 1 (181 mg, 0.841 mmol).Step D: Preparation of 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-tetrahydrofuran-3-ylnicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert- butyl ester, diastereoisomer 1 6-[(4-Fluorophenyl)-[4-[(1R)-1-[(5-tetrahydrofuran-3-ylnicotinoyl)amino]ethyl]phenyl] methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester, diastereoisomer 1 wasprepared according to General Procedure 2B using sodium;5-tetrahydrofuran-3-ylnicotinate,enantiomer 1 (178 mg, 0.828 mmol) and Intermediate 3 (350 mg, 0.828 mmol) in N,N- dimethylformamide. The crude residues were purified on silica gel column chromatography (n-heptane / ethyl acetate) to give 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-tetrahydrofuran-3- ylnicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert- butyl ester, diastereoisomer 1 (307 mg, 0.514 mmol).Step E: Preparation of N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-tetrahydrofuran-3-yl-nicotinamide, diastereoisomer 1 N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5- tetrahydrofuran-3-yl-nicotinamide, diastereoisomer 1 was prepared according to GeneralProcedure 1 using 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-tetrahydrofuran-3-ylnicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert- butyl ester, diastereoisomer 1 (110 mg, 0.184 mmol) and 2,2,2-trifluoroacetic acid (1.17 g, 10.3 mmol, 20 eq.) in neat conditions. The crude residues were dissolved into methanol and eluted through a PoraPak Rxn CX to give N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4- fluorophenyl)methyl]phenyl]ethyl]-5-tetrahydrofuran-3-yl-nicotinamide, diastereoisomer 1 (198 mg, 0.398 mmol).Step F: Preparation of Example 114Example 114 was prepared according to a modified General Procedure 8 using N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-tetrahydrofuran-3- yl-nicotinamide, diastereoisomer 1 (90.0 mg, 0.181 mmol) in tetrahydrofuran (0.02 M). The crude residues were dissolved into methanol and eluted through a PoraPak Rxn CX to giveExample 114 (73.0 mg, 0.143 mmol). 1H NMR (400 MHz, dmso-8.89 (m, 1H), 8.64 (m, 1H), 8.1 (m, 1H), 7.34 (m, 2H), 7.13 (m, 4H), 7.07 (m, 2H), 5.17 (m, 1H), 4.06 (m, 1H), 3.98 (m, 1H), 3.81 (m, 1H), 3.62 (m, 1H), 3.49 (m, 1H), 3.13 (s, 4H), 2.95 (m, 4H), 2.36 (m, 1H), 2.15 (s, 3H), 1.95 (m, 1H), 1.49 (m, 3H) | [M+H]+=512.2714 Example 115: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-tetrahydrofuran-3-yl-nicotinamide, diastereoisomer 2 Step A: Preparation of 5-tetrahydrofuran-3-ylnicotinic acid methyl ester, enantiomer 25-Tetrahydrofuran-3-ylnicotinic acid methyl ester, enantiomer 2 was prepared according toGeneral Procedure 13 using 5-tetrahydrofuran-3-ylnicotinic acid methyl ester (500 mg, 2.41mmol) by SFC (carbon dioxide / ethanol / diethylamine) to give 5-tetrahydrofuran-3-ylnicotinicacid methyl ester, enantiomer 2 (182 mg, 0.876 mmol). 1H NMR (400 MHz, dmso- 8.95 (m, 1H), 8.77 (m, 1H), 8.16 (m, 1H), 4.05 (m, 1H), 3.97 (m, 1H), 3.89 (s, 3H), 3.81 (m, 1H), 3.63 (m, 1H), 3.54 (m, 1H), 2.37 (m, 1H), 1.95 (m, 1H). [M+H]+=208.0.Step B: Preparation of sodium;5-tetrahydrofuran-3-ylnicotinate, enantiomer 2Sodium;5-tetrahydrofuran-3-ylnicotinate, enantiomer 2 was prepared according to GeneralProcedure 9A using 5-tetrahydrofuran-3-ylnicotinic acid methyl ester, enantiomer 2 (182 mg,0.878 mmol) to give sodium;5-tetrahydrofuran-3-ylnicotinate, enantiomer 2 (188 mg, 0.874 mmol).Step C: Preparation of 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-tetrahydrofuran-3-ylnicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert- butyl ester, diastereoisomer 2 6-[(4-Fluorophenyl)-[4-[(1R)-1-[(5-tetrahydrofuran-3-ylnicotinoyl)amino]ethyl]phenyl] methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester, diastereoisomer 2 wasprepared according to General Procedure 2B using sodium;5-tetrahydrofuran-3-ylnicotinate,enantiomer 2 (178 mg, 0.828 mmol) and Intermediate 3 (350 mg, 0.828 mmol) in N,N- dimethylformamide. The crude residues were purified on silica gel column chromatography (n-heptane / ethyl acetate) to give 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-tetrahydrofuran-3- ylnicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert- butyl ester, diastereoisomer 2 (356 mg, 0.596 mmol).Step D: Preparation of N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-tetrahydrofuran-3-yl-nicotinamide, diastereoisomer 2 N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5- tetrahydrofuran-3-yl-nicotinamide, diastereoisomer 2 was prepared according to GeneralProcedure 1 using 6-[(4-fluorophenyl)-[4-[(1R)-1-[(5-tetrahydrofuran-3-ylnicotinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester, diastereoisomer 2 (356 mg, 0.596 mmol) and 2,2,2-trifluoroacetic acid (1.36 g, 11.9 mmol, 20 eq.) in neat conditions. The crude residues were dissolved into methanol and eluted through a PoraPak Rxn CX to give N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl) methyl]phenyl]ethyl]-5-tetrahydrofuran-3-yl-nicotinamide, diastereoisomer 2 (207 mg, 0.416 mmol).Step E: Preparation of Example 115Example 115 was prepared according to a modified General Procedure 8 using N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-tetrahydrofuran-3- yl-nicotinamide, diastereoisomer 2 (100 mg, 0.201 mmol) in tetrahydrofuran (0.02 M). The crude residues were dissolved into methanol and eluted through a PoraPak Rxn CX to giveExample 115 (85.0 mg, 0.166 mmol). 1H NMR (400 MHz, dmso-8.89 (m, 1H), 8.64 (m, 1H), 8.1 (m, 1H), 7.34 (m, 2H), 7.13 (m, 4H), 7.07 (m, 2H), 5.17 (m, 1H), 4.06 (m, 1H), 3.98 (m, 1H), 3.81 (m, 1H), 3.62 (m, 1H), 3.49 (m, 1H), 3.13 (s, 4H), 2.95 (m, 4H), 2.36 (m, 1H), 2.15 (s, 3H), 1.95 (m, 1H), 1.49 (m, 3H) | [M+H]+=512.2695 Example 116: N-[(1R)-1-[4-[(4-fluorophenyl)-[2-(2-hydroxyethyl)-2-azaspiro[3.3]heptan- 6-ylidene]methyl]phenyl]ethyl]-5-tetrahydrofuran-3-yl-nicotinamide;2,2,2- trifluoroacetic acid, diastereoisomer 1 Example 116 was prepared according to General Procedure 11 using N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-tetrahydrofuran-3-yl- nicotinamide, diastereoisomer 1 (100 mg, 0.201 mmol), potassium carbonate (25.0 mg, 0.181mmol, 0.90 eq.) and 2-bromoethanol (27.6 mg, 0.221 mmol, 1.1 eq.). The crude residues weredissolved into methanol and eluted through a PoraPak Rxn CX and purified by reverse phase chromatography (water / acetonitrile / trifluoroacetic acid) to give Example 116 (49.0 mg,0.0747 mmol). 1H NMR (400 MHz, dmso-8.64 (d, 1H), 8.12 (d, 1H), 7.37 (m, 2H), 7.16 (m, 4H), 7.08 (t, 2H), 5.19 (td, 2H), 4.22 (m, 2H), 4.14 (m, 2H), 4.06 (t, 1H), 3.98 (m, 1H), 3.82 (q, 1H), 3.62 (m, 1H), 3.56 (m, 2H), 3.5 (m, 1H), 3.17 (m, 6H), 2.36 (m, 1H), 1.97 (qd, 1H), 1.5 (dd, 3H). [M+H]+=542.2796 trifluoroacetic acid, diastereoisomer 2 Example 117 was prepared according to General Procedure 11 using N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-tetrahydrofuran-3-yl- nicotinamide, diastereoisomer 2 (100 mg, 0.201 mmol), potassium carbonate (25.0 mg, 0.181 mmol, 0.90 eq.) and 2-bromoethanol (27.6 mg, 0.221 mmol, 1.1 eq.) The crude residues were dissolved into methanol and eluted through a PoraPak Rxn CX and purified by reverse phasechromatography (water / acetonitrile / trifluoroacetic acid) to give Example 117 (27.0 mg,0.0412 mmol). 1H NMR (400 MHz, dmso-1H), 8.64 (d, 1H), 8.12 (d, 1H), 7.37 (m, 2H), 7.15 (m, 4H), 7.08 (m, 2H), 5.19 (td, 1H), 4.22 (m, 2H), 4.13 (m, 2H), 4.06 (t, 1H), 3.98 (td, 1H), 3.82 (q, 1H), 3.62 (m, 1H), 3.56 (m, 2H), 3.5 (m, 1H), 3.17 (m, 6H), 2.36 (m, 1H), 1.98 (m, 1H), 1.51 (m, 3H). [M+H]+=542.2797 4- 4-carboxamideStep A: Preparation of 1-(oxetan-3-ylmethyl)pyrazole-4-carboxylic acid ethyl ester1-(Oxetan-3-ylmethyl)pyrazole-4-carboxylic acid ethyl ester was prepared according to amodified General Procedure 11 using ethyl 1H-pyrazole-4-carboxylate (300 mg, 2.14 mmol),cesium carbonate (698 mg, 2.14 mmol) and 3-(bromomethyl)oxetane (404 mg, 2.57 mmol, 1.2 eq.) to give 1-(oxetan-3-ylmethyl)pyrazole-4-carboxylic acid ethyl ester (425 mg, 2.02mmol) used into the next step without further purification. 1H NMR (400 MHz, dmso-ppm 8.37 (s, 1H), 7.85 (s, 1H), 4.62 (dd, 2H), 4.45 (d, 2H), 4.4 (t, 2H), 4.21 (q, 2H), 3.41 (m, 1H), 1.26 (t, 3H).Step B: Preparation of 1-(oxetan-3-ylmethyl)pyrazole-4-carboxylic acid1-(Oxetan-3-ylmethyl)pyrazole-4-carboxylic acid was prepared according to GeneralProcedure 9B using 1-(oxetan-3-ylmethyl)pyrazole-4-carboxylic acid ethyl ester (425 mg,2.02 mmol) to give 1-(oxetan-3-ylmethyl)pyrazole-4-carboxylic acid (307 mg, 1.69 mmol).1H NMR (400 MHz, dmso-2H), 4.44 (d, 2H), 4.4 (t, 2H), 3.41 (m, 1H).Step C: Preparation of Example 118Example 118 was prepared according to General Procedure 2C using 1-(oxetan-3-ylmethyl)pyrazole-4-carboxylic acid (100 mg, 0.521 mmol) and [(1R)-1-[4-[(4-fluorophenyl)- [1-(2-methoxyethyl)-4-piperidylidene]methyl]phenyl]ethyl]amine (211 mg, 0.574 mmol, 1.1 eq.) in dichloromethane. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 118 (153 mg, 0.288 mmol).1HNMR (400 MHz, dmso- 4H), 7.03 (d, 2H), 5.1 (s, 1H), 4.62 (m, 2H), 4.4 (m, 4H), 3.41 (m, 3H), 3.21 (s, 3H), 2.46 (m, 6H), 2.22 (m, 4H), 1.42 (d, 3H). [M+H]+=533.2927 Example 119: 5-(1,1-diketo-1,4-thiazinan-4-yl)-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl- 2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]nicotinamide;2,2,2-trifluoroacetic acid Step A: Preparation of 5-(1,1-diketo-1,4-thiazinan-4-yl)nicotinic acid methyl ester5-(1,1-Diketo-1,4-thiazinan-4-yl)nicotinic acid methyl ester was prepared according toGeneral Procedure 12 using methyl 5-bromopyridine-3-carboxylate (320 mg, 1.48 mmol) and1,4-thiazinane 1,1-dioxide (200 mg, 1.48 mmol) in 1,4-dioxane. The crude residues were purified by silica gel chromatography(cyclohexane / ethyl acetate) to give 5-(1,1-diketo-1,4-thiazinan-4-yl)nicotinic acid methyl ester (226 mg, 0.835 mmol). 1H NMR (400 MHz, dmso-d, 4H), 3.88 (s, 3H), 3.17 (m, 4H). [M+H]+=271.8.Step B: Preparation of 5-(1,1-diketo-1,4-thiazinan-4-yl)nicotinate5-(1,1-Diketo-1,4-thiazinan-4-yl)nicotinate was prepared according to General Procedure 9Ausing 5-(1,1-diketo-1,4-thiazinan-4-yl)nicotinic acid methyl ester (225 mg, 0.832 mmol) togive 5-(1,1-diketo-1,4-thiazinan-4-yl)nicotinate (326 mg, 1.17 mmol). 1H NMR (400 MHz,dmso- [M+H]+=257.0.Step C: Preparation of Example 119Example 119 was prepared according to General Procedure 2C using 5-(1,1-diketo-1,4-thiazinan-4-yl)nicotinate (99.0 mg, 0.210 mmol, 1.1 eq.) and Intermediate 4 (65.0 mg, 0.190 mmol) in N,N-dimethylformamide. The crude was purified by reverse phase chromatography (acetonitrile / water / trifluoroacetic acid) to give Example 119 (42.0 mg, 0.0610 mmol).1HNMR (400 MHz, dmso-7.77 (br s, 1H), 7.36 (d, 2H), 7.13 (m, 6H), 5.19 (br t, 1H), 4.3 (br d, 2H), 4.01 (m, 2H), 3.89 (br s, 4H), 3.19 (m, 4H), 3.14 (br d, 4H), 2.8 (d, 3H), 1.5 (d, 3H) | [M+H]+=575.2433 Example 120: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-6-[(3R)-tetrahydrofuran-3-yl]oxy-pyrazinamide Step A: Preparation of 6-[(3R)-tetrahydrofuran-3-yl]oxypyrazinoic acid6-[(3R)-tetrahydrofuran-3-yl]oxypyrazinoic acid was prepared according to a modifiedGeneral Procedure 15A using (3R)-tetrahydrofuran-3-ol (229 mg, 2.61 mmol) and methyl 6-chloropyrazine-2-carboxylate (150 mg, 0.951 mmol). The crude was purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give 6-[(3R)-tetrahydrofuran- 3-yl]oxypyrazinoic acid (93.0 mg, 0.208 mmol). [M+H]+=210.9.Step B: Preparation of Example 120Example 120 was prepared according to General Procedure 2B using 6-[(3R)-tetrahydrofuran-3-yl]oxypyrazinoic acid (86.4 mg, 0.193 mmol) and Intermediate 4 (65.0 mg, 0.193 mmol) inN,N-dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 120 (22.0 mg, 0.0416 mmol).1HNMR (400 MHz, dmso-(m, 4H), 7.07 (d, 2H), 5.88 (br dd, 1H), 5.22 (m, 1H), 3.97 (dd, 1H), 3.83 (m, 3H), 3.13 (s, 4H), 2.95 (br d, 4H), 2.32 (m, 1H), 2.15 (s, 3H), 2.06 (m, 1H), 1.55 (d, 3H) | [M+H]+=529.2566 Example 121: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-(7-oxa-2-azaspiro[4.5]decan-2-yl)nicotinamide Step A: Preparation of 5-(7-oxa-2-azaspiro[4.5]decan-2-yl)nicotinic acid methyl ester5-(7-oxa-2-azaspiro[4.5]decan-2-yl)nicotinic acid methyl ester was prepared according to amodified General Procedure 12 using methyl 5-bromopyridine-3-carboxylate (300 mg, 1.39mmol), BINAP ( -bis(diphenylphosphino)- -binaphthyl; 86.5 mg, 0.139 mmol, 0.10 eq.)and 7-oxa-2-azaspiro[4.5]decane;hydrochloride (0.296 mg, 1.39 mmol, 1.2 eq.) in 1,4-dioxane. The crude residues were purified by silica gel column chromatography (n- heptane / ethyl acetate) to give 5-(7-oxa-2-azaspiro[4.5]decan-2-yl)nicotinic acid methyl ester (383 mg, 1.39 mmol).Step B: Preparation of sodium;5-(7-oxa-2-azaspiro[4.5]decan-2-yl)nicotinateSodium;5-(7-oxa-2-azaspiro[4.5]decan-2-yl)nicotinate was prepared according to GeneralProcedure 9A using 5-(7-oxa-2-azaspiro[4.5]decan-2-yl)nicotinic acid methyl ester (383 mg,1.39 mmol) to give sodium;5-(7-oxa-2-azaspiro[4.5]decan-2-yl)nicotinate (394 mg, 1.39 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification.Step C: Preparation of Example 121Example 121 was prepared according to General Procedure 2B using sodium;5-(7-oxa-2-azaspiro[4.5]decan-2-yl)nicotinate (169 mg, 0.594 mmol) and Intermediate 4 (200 mg, 0.594 mmol) in N,N-dimethylformamide. The crude residues were dissolved into methanol and eluted through a PoraPak Rxn CX and purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 121 (100 mg, 0.172 mmol).1HNMR (400 MHz, dmso- (m, 1H), 7.13 (m, 4H), 7.06 (d, 2H), 5.18 (quin, 1H), 3.62 (m, 1H), 3.54 (m, 1H), 3.38 (m, 5H), 3.13 (s, 4H), 3.07 (m, 1H), 2.95 (br d, 4H), 2.15 (s, 3H), 1.93 (dt, 1H), 1.76 (m, 1H), 1.63 (m, 4H), 1.49 (m, 3H) | [M+H]+=581.3256 Example 122: 5-[4-(1-fluorocyclopropanecarbonyl)piperazino]-N-[(1R)-1-[4-[(4- fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]nicotinamide Step A: Preparation of 4-(5-carbomethoxy-3-pyridyl)piperazine-1-carboxylic acid tert-butylester 4-(5-Carbomethoxy-3-pyridyl)piperazine-1-carboxylic acid tert-butyl ester was preparedaccording to a modified General Procedure 12 using methyl 5-bromopyridine-3-carboxylate(1.00 g, 4.63 mmol), BINAP (288 mg, 0.463 mmol, 0.10 eq.) and tert-butyl piperazine-1- carboxylate (1.03 g, 5.55 mmol, 1.2 eq.) in 1,4-dioxane. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 4-(5-carbomethoxy-3- pyridyl)piperazine-1-carboxylic acid tert-butyl ester (1.33 g, 3.72 mmol).Step B: Preparation of sodium;5-(4-tert-butoxycarbonylpiperazino)nicotinateSodium;5-(4-tert-butoxycarbonylpiperazino)nicotinate was prepared according to GeneralProcedure 9A using 4-(5-carbomethoxy-3-pyridyl)piperazine-1-carboxylic acid tert-butylester (500 mg, 1.56 mmol) to give sodium;5-(4-tert-butoxycarbonylpiperazino)nicotinate (512 mg, 1.56 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification.Step C: Preparation of 4-[5-[[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]carbamoyl]-3-pyridyl]piperazine-1-carboxylic acid tert-butyl ester 4-[5-[[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]carbamoyl]-3-pyridyl]piperazine-1-carboxylic acid tert-butylester was prepared according to General Procedure 2B using sodium;5-(4-tert-butoxycarbonylpiperazino)nicotinate (489 mg, 1.49 mmol) and Intermediate 4 (500 mg, 1.49 mmol) in N,N-dimethylformamide. The crude product was dissolved into methanol and elutedthrough a PoraPak Rxn CX and purified on silica gel column chromatography(dichloromethane / methanol / ammoniac) to give 4-[5-[[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl- 2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]carbamoyl]-3-pyridyl]piperazine-1- carboxylic acid tert-butyl ester (453 mg, 0.724 mmol).Step D: Preparation of N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-piperazino-nicotinamide N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-piperazino-nicotinamide was prepared according to GeneralProcedure 1 using 4-[5-[[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]carbamoyl]-3-pyridyl]piperazine-1-carboxylic acid tert-butyl ester (453 mg, 0.724 mmol) in neat conditions in 2,2,2-trifluoroacetic acid (1.65 g, 14.5 mmol, 20 eq.). The crude residues were dissolved into methanol and eluted through a PoraPak Rxn CX to give N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-piperazino-nicotinamide (283 mg, 0.744 mmol).Step E: Preparation of Example 122Example 122 was prepared according to General Procedure 2B using 1-fluorocyclopropanecarboxylic acid (27.7 mg, 0.266 mmol) and N-[(1R)-1-[4-[(4- fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-piperazino- nicotinamide (140 mg, 0.266 mmol) in N,N-dimethylformamide. The crude residues were dissolved into methanol and eluted through a PoraPak Rxn CX and purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 122 (62.0 mg,0.101 mmol). 1H NMR (400 MHz, dmso- 7.72 (dd, 1H), 7.34 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.19 (quin, 1H), 3.76 (br s, 4H), 3.34 (br s, 4H), 3.15 (s, 4H), 2.95 (br d, 4H), 2.16 (s, 3H), 1.49 (d, 3H), 1.25 (m, 4H) | [M+H]+=612.3141. Example 123: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-2-[(3R)-tetrahydrofuran-3-yl]oxy-isonicotinamide Step A: Preparation of 2-[(3R)-tetrahydrofuran-3-yl]oxyisonicotinic acid2-[(3R)-tetrahydrofuran-3-yl]oxyisonicotinic acid was prepared according to GeneralProcedure 15A using (3R)-tetrahydrofuran-3-ol (252 mg, 2.86 mmol) and 2-chloropyridine-4-carboxylic acid (150 mg, 0.952 mmol) to give 2-[(3R)-tetrahydrofuran-3-yl]oxyisonicotinic acid (200 mg, 0.956 mmol). [M+H]+=210.0.Step B: Preparation of Example 123Example 123 was prepared according to General Procedure 2B using 2-[(3R)-tetrahydrofuran-3-yl]oxyisonicotinic acid (200 mg, 0.287 mmol) and Intermediate 4 (96.5 mg, 0.287 mmol) in N,N-dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 123 (23.3 mg, 0.0442 mmol).1HNMR (400 MHz, dmso-1H), 7.13 (m, 4H), 7.06 (d, 2H), 5.54 (dd, 1H), 5.14 (t, 1H), 3.92 (dd, 1H), 3.8 (m, 3H), 3.13 (s, 4H), 2.94 (br d, 4H), 2.23 (m, 1H), 2.15 (s, 3H), 2.01 (m, 1H), 1.46 (d, 3H) | [M+H]+=528.2654 Example 124: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-[4-(oxetane-3-carbonyl)piperazino]nicotinamide;2,2,2- trifluoroacetic acid Example 124 was prepared according to General Procedure 2B using oxetane-3-carboxylic acid (71.9 mg, 0.704 mmol) and N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2- azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-piperazino-nicotinamide (370 mg, 0.704 mmol) in N,N-dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / trifluoroacetic acid) to give Example 124 (75.0 mg, 0.104mmol). 1H NMR (400 MHz, dmso-(d, 1H), 7.74 (br s, 1H), 7.36 (d, 2H), 7.13 (m, 6H), 5.18 (br t, 1H), 4.7 (m, 4H), 4.29 (m, 2H),4.18 (m, 1H), 4.01 (br dd, 2H), 3.65 (m, 2H), 3.29 (m, 6H), 3.16 (br dd, 4H), 2.8 (d, 3H), 1.49 (d, 3H). [M+H]+=610.3179 Example 125: 5-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-N-[(1R)-1-[4-[(4-fluorophenyl)- (2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]nicotinamide Step A: Preparation of 5-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)nicotinic acid methyl ester5-(1-Acetyl-3,6-dihydro-2H-pyridin-4-yl)nicotinic acid methyl ester was prepared accordingto General Procedure 4B using methyl 5-bromopyridine-3-carboxylate (250 mg, 1.16 mmol)and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone (349 mg, 1.39 mmol). The crude residues were purified by silica gel column chromatography (ethyl acetate / methanol) to give 5-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)nicotinic acid methyl ester (300 mg, 1.15 mmol).Step B: Preparation of sodium;5-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)nicotinateSodium;5-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)nicotinate was prepared according toGeneral Procedure 9A using 5-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)nicotinic acid methylester (300 mg, 1.15 mmol) to give sodium;5-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)nicotinate (309 mg, 1.15 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification.Step C: Preparation of Example 125Example 125 was prepared according to General Procedure 2B using sodium;5-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)nicotinate (159 mg, 0.594 mmol) and Intermediate 4 (350 mg, 0.594 mmol) in N,N-dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 125 (62.0 mg,0.110 mmol). 1H NMR (400 MHz, dmso-8.24 (m, 1H), 7.36 (d, 2H), 7.12 (m, 6H), 6.39 (br dd, 1H), 5.2 (quin, 1H), 4.16 (br dd, 2H), 3.67 (m, 2H), 3.47 (br s, 4H), 3.02 (br d, 4H), 2.62 (m, 1H), 2.54 (m, 1H), 2.36 (s, 3H), 2.07 (d, 3H), 1.5 (d, 3H) | [M+H]+=565.2970 Example 126 was prepared according to General Procedure 11 using Example 91 (73.0 mg,0.122 mmol), potassium carbonate (15.2 mg, 0.110 mmol, 0.90 eq.) and 2-bromoethanol (0.0951 mL, 0.134 mmol, 1.1 eq.) and purified by reverse phase chromatography(acetonitrile / water / ammonium bicarbonate) to give Example 126 (20.3 mg, 0.0354 mmol). 1HNMR (400 MHz, dmso-(m, 4H), 7.07 (d, 2H), 5.13 (quin, 1H), 4.71 (m, 1H), 3.66 (m, 4H), 3.42 (br d, 2H), 3.04 (br d, 4H), 2.76 (m, 2H), 1.46 (d, 3H) | [M+H]+=529.2220 Example 127: 3-(4,4-difluoropiperidino)-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2- azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]benzamide Step A: Preparation of 3-(4,4-difluoropiperidino)benzoic acid methyl ester3-(4,4-Difluoropiperidino)benzoic acid methyl ester was prepared according to GeneralProcedure 12 using methyl 3-bromobenzoate (136 mg, 0.635 mmol) and 4,4-difluoropiperidine;hydrochloride (100 mg, 0.635 mmol) in 1,4-dioxane. The crude product was purified by silica gel column chromatography (dichloromethane / ethanol) to give 3-(4,4-difluoropiperidino)benzoic acid methyl ester (113 mg, 0.443 mmol). 1H NMR (400 MHz,dmso-d6) ppm 7.51 (s, 1H), 7.38 (q, 2H), 7.3 (m, 1H), 3.84 (s, 3H), 3.38 (m, 4H), 2.06 (m, 4H) | [M+H]+=256.5.Step B: Preparation of 3-(4,4-difluoropiperidino)benzoate3-(4,4-Difluoropiperidino)benzoate was prepared according to General Procedure 9A using 3-(4,4-difluoropiperidino)benzoic acid methyl ester (193 mg, 0.756 mmol) to give 3-(4,4-difluoropiperidino)benzoate (225 mg, 0.855 mmol). 1H NMR (400 MHz, dmso-d6) ppm 7.5(dd, 1H), 7.32 (d, 1H), 7.1 (t, 1H), 6.9 (m, 1H), 3.32 (m, 2H), 3.28 (br d, 2H), 2.05 (m, 4H) | [M+H]+=243.2.Step C: Preparation of Example 127Example 127 was prepared according to General Procedure 2C using 3-(4,4-difluoropiperidino)benzoate (111 mg, 0.253 mmol) and Intermediate 4 (85.0 mg, 0.253 mmol) in N,N-dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 127 (18.5 mg,0.0331 mmol). 1H NMR (400 MHz, dmso-d6) ppm 8.71 (d, 1H), 7.45 (s, 1H), 7.33 (m, 3H),7.3 (m, 1H), 7.16 (m, 1H), 7.13 (m, 4H), 7.06 (d, 2H), 5.18 (quin, 1H), 3.37 (m, 4H), 3.13 (s, 4H), 2.94 (br d, 4H), 2.15 (s, 3H), 2.07 (ddd, 4H), 1.48 (d, 3H) | [M+H]+=560.2881 Example 128: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-3-[(3R)-tetrahydrofuran-3-yl]oxy-benzamide Step A: Preparation of 3-[(3R)-tetrahydrofuran-3-yl]oxybenzoic acid methyl ester3-[(3R)-tetrahydrofuran-3-yl]oxybenzoic acid methyl ester was prepared according to GeneralProcedure 10 using methyl 3-hydroxybenzoate (500 mg, 3.29 mmol) and (3S)-tetrahydrofuran-3-ol (0.262 mL, 3.29 mmol). The crude residues were purified by silica gel column chromatography (dichloromethane / ethyl acetate) to give 3-[(3R)-tetrahydrofuran-3-yl]oxybenzoic acid methyl ester (619 mg, 2.79 mmol). 1H NMR (400 MHz, dmso-7.55 (d, 1H), 7.45 (t, 1H), 7.42 (br d, 1H), 7.22 (dd, 1H), 5.11 (br dd, 1H), 3.89 (m, 1H), 3.85 (s, 3H), 3.81 (m, 2H), 3.76 (m, 1H), 2.23 (m, 1H), 1.97 (m, 1H). [M+H]+=269.3.Step B: Preparation of 3-[(3R)-tetrahydrofuran-3-yl]oxybenzoate3-[(3R)-tetrahydrofuran-3-yl]oxybenzoate was prepared according to General Procedure 9Ausing 3-[(3R)-tetrahydrofuran-3-yl]oxybenzoic acid methyl ester (619 mg, 2.78 mmol) to give3-[(3R)-tetrahydrofuran-3-yl]oxybenzoate (700 mg, 3.04 mmol). 1H NMR (400 MHz, dmso-1H), 3.79 (m, 2H), 3.74 (m, 1H), 2.19 (m, 1H), 1.96 (m, 1H). [M+H]+=190.8.Step C: Preparation of Example 128Example 128 was prepared according to General Procedure 2C using 3-[(3R)-tetrahydrofuran-3-yl]oxybenzoate (123.0 mg, 0.2675 mmol) and Intermediate 4 (90.0 mg, 0.2675 mmol) inN,N-dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 128 (31.8 mg, 0.0604 mmol).1HNMR (400 MHz, dmso-(d, 2H), 7.12 (m, 5H), 7.06 (d, 2H), 5.16 (quin, 1H), 5.09 (br dd, 1H), 3.9 (m, 1H), 3.81 (m, 2H), 3.75 (m, 1H), 3.13 (s, 4H), 2.94 (br d, 4H), 2.23 (m, 1H), 2.15 (s, 3H), 1.96 (m, 1H), 1.47 (d, 3H) | [M+H]+=527.2703 Example 129: 5-[(4,4-dimethyloxetan-2-yl)methoxy]-N-[(1R)-1-[4-[(4-fluorophenyl)-(2- methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]nicotinamide, diastereoisomer 2 Step A: Preparation of 5-[(4,4-dimethyloxetan-2-yl)methoxy]nicotinic acid methyl ester,enantiomer 2 5-[(4,4-Dimethyloxetan-2-yl)methoxy]nicotinic acid methyl ester was prepared according toGeneral Procedure 10 using methyl 5-hydroxypyridine-3-carboxylate (500 mg, 3.27 mmol)and (4,4-dimethyloxetan-2-yl)methanol (0.344 mL, 3.27 mmol). The crude residues were purified by silica gel column chromatography (methyl tert-butyl ether / ethyl acetate). The two enantiomers were separated by chiral SFC (carbon dioxide / ethanol) to give 5-[(4,4- dimethyloxetan-2-yl)methoxy]nicotinic acid methyl ester, enantiomer 2 (195 mg, 0.774mmol). 1H NMR (400 MHz, dmso-(m, 1H), 4.24 (m, 2H), 3.89 (s, 3H), 2.38 (m, 2H), 1.41 (s, 3H), 1.35 (s, 3H). [M+H]+=253.4.Step B: Preparation of 5-[(4,4-dimethyloxetan-2-yl)methoxy]nicotinate, enantiomer 25-[(4,4-Dimethyloxetan-2-yl)methoxy]nicotinate, enantiomer 2 was prepared according toGeneral Procedure 9A using 5-[(4,4-dimethyloxetan-2-yl)methoxy]nicotinic acid methylester, enantiomer 2 (194 mg, 0.772 mmol) to give 5-[(4,4-dimethyloxetan-2-yl)methoxy]nicotinate, enantiomer 2 (204 mg, 0.785 mmol). 1H NMR (400 MHz, dmso-ppm 8.57 (d, 1H), 8.19 (d, 1H), 7.68 (dd, 1H), 4.8 (m, 1H), 4.12 (m, 2H), 2.38 (m, 2H), 1.36 (m, 6H). [M+H]+=239.2.Step C: Preparation of Example 129Example 129 was prepared according to General Procedure 2C using 5-[(4,4-dimethyloxetan-2-yl)methoxy]nicotinate, enantiomer 2 (61.65 mg, 0.238 mmol) and Intermediate 4 (80.0 mg, 0.238 mmol) in N,N-dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 129 (28.8 mg,0.0518 mmol). 1H NMR (400 MHz, dmso-7.81 (m, 1H), 7.35 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.18 (quin, 1H), 4.82 (m, 1H), 4.21 (d, 2H), 3.13 (s, 4H), 2.95 (br d, 4H), 2.38 (m, 2H), 2.15 (s, 3H), 1.49 (d, 3H), 1.38 (m, 6H) | [M+H]+=556.2966. Example 130: 5-[(4,4-dimethyloxetan-2-yl)methoxy]-N-[(1R)-1-[4-[(4-fluorophenyl)-(2- methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]nicotinamide, diastereoisomer 1 Step A: Preparation of 5-[(4,4-dimethyloxetan-2-yl)methoxy]nicotinic acid methyl ester,enantiomer 1 5-[(4,4-dimethyloxetan-2-yl)methoxy]nicotinic acid methyl ester, enantiomer 1 was preparedaccording to General Procedure 10 using methyl 5-hydroxypyridine-3-carboxylate (500 mg,3.27 mmol) and (4,4-dimethyloxetan-2-yl)methanol (0.344 mL, 3.27 mmol). The crude residues were purified by silica gel column chromatography (methyl tert-butyl ether / ethyl acetate). The two enantiomers were separated by chiral SFC (carbon dioxide / ethanol) to give 5-[(4,4-dimethyloxetan-2-yl)methoxy]nicotinic acid methyl ester, enantiomer 1 (183 mg,0.728 mmol). 1H NMR (400 MHz, dmso-4.82 (m, 1H), 4.24 (m, 2H), 3.89 (s, 3H), 2.38 (m, 2H), 1.41 (s, 3H), 1.35 (s, 3H). [M+H]+=253.3.Step B: Preparation of 5-[(4,4-dimethyloxetan-2-yl)methoxy]nicotinate, enantiomer 15-[(4,4-Dimethyloxetan-2-yl)methoxy]nicotinate, enantiomer 1 was prepared according toGeneral Procedure 9A using 5-[(4,4-dimethyloxetan-2-yl)methoxy]nicotinic acid methylester, enantiomer 1 (183 mg, 0.728 mmol) to give 5-[(4,4-dimethyloxetan-2-yl)methoxy]nicotinate (201 mg, 0.775 mmol). 1H NMR (400 MHz, dmso-1H), 7.68 (dd, 1H), 4.8 (m, 1H), 4.12 (m, 2H), 2.38 (m, 2H), 1.36 (m, 6H). [M+H]+=239.2.Step C: Preparation of Example 130Example 130 was prepared according to a modified General Procedure 2C using 5-[(4,4-dimethyloxetan-2-yl)methoxy]pyridine-3-carboxylate, sodium(1+) (1:1) (61.7 mg, 0.238mmol, 1.0 eq.) and Intermediate 4 (80.0 mg, 0.238 mmol) in N,N-dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammoniumbicarbonate) to give Example 130 (30.2 mg, 0.0543 mmol). 1H NMR (400 MHz, dmso-ppm 8.96 (d, 1H), 8.66 (s, 1H), 8.45 (d, 1H), 7.81 (br s, 1H), 7.35 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.18 (m, 1H), 4.82 (m, 1H), 4.22 (m, 2H), 3.14 (s, 4H), 2.95 (br d, 4H), 2.38 (m, 2H), 2.15 (s, 3H), 1.49 (d, 3H), 1.39 (m, 6H) | [M+H]+=556.2965 6- -3-isopropyl-isoxazolo[5,4-b]pyridine-5-carboxamideStep A: Preparation of N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-3-isopropyl-isoxazolo[5,4-b]pyridine-5- carboxamide;2,2,2-trifluoroacetic acid N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-3- isopropyl-isoxazolo[5,4-b]pyridine-5-carboxamide;2,2,2-trifluoroacetic acid was preparedaccording to General Procedure 1 using 6-[(4-fluorophenyl)-[4-[(1R)-1-[(3-isopropylisoxazolo[5,4-b]pyridine-5-carbonyl)amino]ethyl]phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (450 mg, 0.737 mmol) in neat conditions in 2,2,2-trifluoroacetic acid (1.68 g, 14.7 mmol, 20 eq.). The residues was purified by reverse phase chromatography (acetonitrile / water / trifluoroacetic acid) to give N-[(1R)-1- [4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-3-isopropyl- isoxazolo[5,4-b]pyridine-5-carboxamide;2,2,2-trifluoroacetic acid (154.5 mg, 0.284 mmol).Step B: Preparation of Example 131Example 131 was prepared according to General Procedure 11 using N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-3-isopropyl- isoxazolo[5,4-b]pyridine-5-carboxamide;2,2,2-trifluoroacetic acid (155 mg, 0.209 mmol), potassium carbonate (54.9 mg, 0.397 mmol, 1.9 eq.) and 2-bromoethanol (0.0163 mL, 0.230 mmol, 1.1 eq.). The crude residues were purified by SFC chromatography (carbondioxide / methanol / diethylamine) to give Example 131 (48.8 mg, 0.0880 mmol). 1H NMR (400MHz, dmso- 4.33 (br t, 1H), 3.48 (m, 1H), 3.28 (br s, 2H), 3.19 (s, 4H), 2.96 (br d, 4H), 2.41 (m, 2H), 1.53 (d, 3H), 1.45 (d, 6H) | [M+H]+=555.2763 Example 132: N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4- fluorophenyl)methyl]phenyl]ethyl]-4-methoxy-picolinamide;2,2,2-trifluoroacetic acid Step A: Preparation of 6-[(4-fluorophenyl)- -1-[(4-methoxypicolinoyl)amino]ethyl] phenyl]methylene]-2-azaspiro[3.3]heptane- acid tert-butyl ester 6-[(4-Fluorophenyl)-[4-[(1R)-1-[(4-methoxypicolinoyl)amino]ethyl]phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was prepared according to a modifiedGeneral Procedure 2C using 4-methoxypyridine-2-carboxylic acid (200 mg, 1.24 mmol) andIntermediate 3 (577 mg, 1.36 mmol, 1.1 eq.) in dichloromethane. The crude residues were purified by silica gel column chromatography (dichloromethane / methanol) to give 6-[(4- fluorophenyl)-[4-[(1R)-1-[(4-methoxypicolinoyl)amino]ethyl]phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (601 mg, 1.08 mmol).Step B: Preparation of Example 132Example 132 was prepared according to General Procedure 1 using 6-[(4-fluorophenyl)-[4-[(1R)-1-[(4-methoxypicolinoyl)amino]ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (601 mg, 1.08 mmol) in neat conditions in 2,2,2-trifluoroacetic acid (2.46 g, 21.6 mmol, 20 eq.). The residues were purified by reverse phase chromatography(acetonitrile / water / trifluoroacetic acid) to give Example 132 (358 mg, 0.522 mmol). 1H NMR(400 MHz, dmso- 2H), 7.15 (m, 5H), 7.06 (d, 2H), 5.16 (quin, 1H), 4.03 (br t, 4H), 3.9 (s, 3H), 3.14 (br d, 4H), 1.52 (d, 3H) | [M+H]+=458.2221. Example 133: 5-(4-acetylpiperazino)-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2- azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]nicotinamideStep A: Preparation of 5-(4-acetylpiperazino)nicotinic acid methyl ester5-(4-Acetylpiperazino)nicotinic acid methyl ester was prepared according to a modified General Procedure 12 using methyl 5-bromopyridine-3-carboxylate (1.00 g, 4.63 mmol),BINAP (288 mg, 0.463 mmol, 0.10 eq.) and 1-piperazin-1-ylethanone (712 mg, 5.55 mmol, 1.2 eq.) in 1,4-dioxane. The crude residues were purified by silica gel column chromatography (dichloromethane / methanol) to give 5-(4-acetylpiperazino)nicotinic acid methyl ester (1.18 g, 4.03 mmol). Step B: Preparation of sodium;5-(4-acetylpiperazino)nicotinateSodium;5-(4-acetylpiperazino)nicotinate was prepared according to General Procedure 9Ausing 5-(4-acetylpiperazino)nicotinic acid methyl ester (500 mg, 1.90 mmol) to give sodium;5-(4-acetylpiperazino)nicotinate (515 mg, 1.90 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification. Step C: Preparation of Example 133Example 133 was prepared according to General Procedure 2B using sodium;5-(4-acetylpiperazino)nicotinate (137 mg, 0.505 mmol) and Intermediate 4 (170 mg, 0.505 mmol) in N,N-dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 133 (40.0 mg, 0.0705 mmol). 1H NMR (400 MHz, dmso-7.7 (s, 1H), 7.34 (d, 2H), 7.13 (m, 4H), 7.07 (d, 2H), 5.18 (m, 1H), 3.59 (br d, 4H), 3.23 (m, 4H), 3.13 (s, 4H), 2.95 (br d, 4H), 2.15 (s, 3H), 2.05 (s, 3H), 1.49 (d, 3H) | [M+H]+=568.3056 Example 134 was prepared according to General Procedure 2B using oxetane-3-carboxylicacid (23.3 mg, 0.229 mmol) and Intermediate 12 (120 mg, 0.229 mmol) in N,N- dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 134 (25.0 mg, 0.0411 mmol).1HNMR (400 MHz, dmso-7.34 (m, 2H), 7.12 (s, 4H), 7.06 (m, 2H), 5.19 (m, 1H), 4.7 (m, 4H), 4.56 (m, 1H), 4.14 (m, 1H), 3.47 (m, 1H), 3.13 (s, 4H), 3.05 (m, 1H), 2.95 (m, 4H), 2.89 (m, 1H), 2.68 (m, 1H), 2.15 (s, 3H), 1.82 (m, 2H), 1.59 (m, 2H), 1.49 (d, 3H) | [M+H]+=609.3212 Example 135: 5-[1-(1-fluorocyclopropanecarbonyl)-4-piperidyl]-N-[(1R)-1-[4-[(4- fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]nicotinamide Example 135 was prepared according to General Procedure 2B using 1-fluorocyclopropanecarboxylic acid (23.8 mg, 0.229 mmol) and Intermediate 12 (120 mg, 0.229 mmol) in N,N-dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 135 (38.0 mg,0.0622 mmol). 1H NMR (400 MHz, dmso- 8.12 (t, 1H), 7.34 (d, 2H), 7.11 (m, 6H), 5.19 (t, 1H), 4.39 (br d, 2H), 3.37 (m, 2H), 3.13 (s, 4H), 2.96 (m, 5H), 2.15 (s, 3H), 1.89 (br d, 2H), 1.67 (m, 2H), 1.49 (d, 3H), 1.23 (m, 4H) | [M+H]+=611.3167 Example 136: 5-(1-acetyl-4-piperidyl)-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2- azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]nicotinamide Step A: Preparation of 5-(4-piperidyl)nicotinic acid methyl ester5-(4-Piperidyl)nicotinic acid methyl ester was prepared according to General Procedure 1using 5-(1-tert-butoxycarbonyl-4-piperidyl)nicotinic acid methyl ester (580 mg, 1.81 mmol) and 2,2,2-trifluoroacetic acid (1.39 g, 18.1 mmol, 10 eq.) in neat conditions. The crude residues were dissolved into methanol and eluted through a PoraPak Rxn CX to give 5-(4- piperidyl)nicotinic acid methyl ester (393 mg, 1.78 mmol).Step B: Preparation of 5-(1-acetyl-4-piperidyl)nicotinic acid methyl esterTo a stirred solution of 5-(4-piperidyl)nicotinic acid methyl ester (200 mg, 0.908 mmol, 1.0 eq.) in dichloromethane (0.15 M) were added N,N-diethylethanamine (0.253 mL, 1.82 mmol,2.0 eq.) and acetyl chloride (82.5 mg, 0.999 mmol, 1.1 eq.) and the mixture was stirred atroom temperature until completion of the reaction. Water was added to the mixture and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5-(1-acetyl-4-piperidyl)nicotinic acid methyl ester (238 mg, 0.907 mmol).Step C: Preparation of sodium;5-(1-acetyl-4-piperidyl)nicotinateSodium;5-(1-acetyl-4-piperidyl)nicotinate was prepared according to General Procedure 9Ausing 5-(1-acetyl-4-piperidyl)nicotinic acid methyl ester (238 mg, 0.907 mmol) to give sodium;5-(1-acetyl-4-piperidyl)nicotinate (245 mg, 0.907 mmol), considering a quantitative yield. The compound was engaged into the next step without further purification.Step D: Preparation of Example 136Example 136 was prepared according to General Procedure 2B using sodium;5-(1-acetyl-4-piperidyl)nicotinate (241 mg, 0.892 mmol) and Intermediate 4 (300 mg, 0.892 mmol) in N,N-dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 136 (135 mg, 0.238 mmol).1HNMR (400 MHz, dmso-(d, 2H), 7.11 (m, 6H), 5.19 (quin, 1H), 4.56 (br d, 1H), 3.95 (br d, 1H), 3.13 (m, 5H), 2.93 (m, 5H), 2.58 (m, 1H), 2.15 (s, 3H), 2.03 (s, 3H), 1.81 (m, 2H), 1.53 (m, 5H). [M+H]+=567.3104 Example 137: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-1-(trifluoromethyl)pyrazole-4-carboxamide Example 137 was prepared according to General Procedure 8 using N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-1- (trifluoromethyl)pyrazole-4-carboxamide (40.0 mg, 0.0826 mmol) in a 5:1 dichloromethane / methanol. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) mixture to give Example 137(26.1 mg, 0.0524 mmol). 1H NMR (400 MHz, dmso-8.32 (s, 1H), 7.32 (d, 2H), 7.13 (m, 4H), 7.06 (d, 2H), 5.13 (s, 1H), 3.13 (s, 4H), 2.94 (m, 4H), 2.15 (s, 3H), 1.46 (d, 3H) | [M+H]+=499.2107 6- Step A: Preparation of 6-(7-oxa-2-azaspiro[4.5]decan-2-yl)nicotinic acid methyl ester6-(7-Oxa-2-azaspiro[4.5]decan-2-yl)nicotinic acid methyl ester was prepared according to amodified General Procedure 12 using methyl 6-bromopyridine-3-carboxylate (300 mg, 1.39mmol), BINAP (86.5 mg, 0.139 mmol, 0.10 eq.) and 7-oxa-2- azaspiro[4.5]decane;hydrochloride (296 mg, 1.67 mmol, 1.2 eq.) in 1,4-dioxane. The crude residues were purified by silica gel column chromatography (n-heptane / ethyl acetate) to give 6-(7-oxa-2-azaspiro[4.5]decan-2-yl)nicotinic acid methyl ester (200 mg, 0.724 mmol).Step B: Preparation of sodium;6-(7-oxa-2-azaspiro[4.5]decan-2-yl)nicotinateSodium;6-(7-oxa-2-azaspiro[4.5]decan-2-yl)nicotinate was prepared according to GeneralProcedure 9A using 6-(7-oxa-2-azaspiro[4.5]decan-2-yl)nicotinic acid methyl ester (200 mg,0.724 mmol) to give sodium;6-(7-oxa-2-azaspiro[4.5]decan-2-yl)nicotinate (245 mg, 0.862 mmol).Step C: Preparation of Example 138Example 138 was prepared according to General Procedure 2B using sodium;6-(7-oxa-2-azaspiro[4.5]decan-2-yl)nicotinate (211 mg, 0.743 mmol) and Intermediate 4 (250 mg, 0.743 mmol) in N,N-dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 138 (55.0 mg,0.0947 mmol). 1H NMR (400 MHz, dmso-1H), 7.32 (d, 2H), 7.12 (m, 4H), 7.05 (d, 2H), 6.46 (d, 1H), 5.15 (quin, 1H), 3.62 (m, 1H), 3.5 (m, 4H), 3.38 (m, 2H), 3.17 (m, 5H), 2.95 (br d, 4H), 2.17 (s, 3H), 1.91 (m, 1H), 1.75 (m, 1H), 1.66 (m, 2H), 1.58 (m, 2H), 1.45 (d, 3H). [M+H]+=581.3281 Example 139: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-5-(pyrrolidine-1-carbonyl)nicotinamide Step A: Preparation of 5-(pyrrolidine-1-carbonyl)nicotinic acid methyl ester5-(Pyrrolidine-1-carbonyl)nicotinic acid methyl ester was prepared according to GeneralProcedure 2B using 5-methoxycarbonylpyridine-3-carboxylic acid (300 mg, 1.66 mmol) andpyrrolidine (118 mg, 1.66 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (dichloromethane / methanol) to give 5- (pyrrolidine-1-carbonyl)nicotinic acid methyl ester (388 mg, 1.66 mmol).Step B: Preparation of sodium;5-(pyrrolidine-1-carbonyl)nicotinateSodium;5-(pyrrolidine-1-carbonyl)nicotinate was prepared according to General Procedure 9A using 5-(pyrrolidine-1-carbonyl)nicotinic acid methyl ester (388 mg, 1.66 mmol) to give sodium;5-(pyrrolidine-1-carbonyl)nicotinate (400 mg, 1.65 mmol).Step C: Preparation of Example 139Example 139 was prepared according to General Procedure 2B using sodium;5-(pyrrolidine-1-carbonyl)nicotinate (144 mg, 0.5945 mmol) and Intermediate 4 (200 mg, 0.5945 mmol) inN,N-dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 139 (70.0 mg, 0.130 mmol).1HNMR (400 MHz, dmso-(d, 2H), 7.14 (m, 2H), 7.12 (br s, 2H), 7.07 (d, 2H), 5.19 (quin, 1H), 3.41 (m, 4H), 3.13 (s, 4H), 2.95 (br d, 4H), 2.15 (s, 3H), 1.84 (m, 4H), 1.49 (d, 3H) | [M+H]+=539.2811 Example 140: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-4-methoxy-picolinamide;2,2,2-trifluoroacetic acidExample 140 was prepared according to General Procedure 8 using Example 132 (100 mg,0.146 mmol) in tetrahydrofuran (0.02 M). The crude residues were purified by reverse phase chromatography (acetonitrile / water / trifluoroacetic acid) to give Example 140 (45.9 mg,0.0656 mmol). 1H NMR (400 MHz, dmso-1H), 7.53 (d, 1H), 7.39 (d, 2H), 7.16 (m, 5H), 7.07 (m, 2H), 5.16 (m, 1H), 4.29 (m, 2H), 4 (m, 2H), 3.9 (s, 3H), 3.16 (m, 4H), 2.79 (d, 3H), 1.52 (d, 3H). [M+H]+=472.2392 Example 141: N-[(1R)-1-[4-[(4-fluorophenyl)-[1-(oxetan-3-ylmethyl)-4- piperidylidene]methyl]phenyl]ethyl]-5-tetrahydropyran-4-yloxy-nicotinamide Example 141 was prepared according to a modified General Procedure 8 using Intermediate 8(80.0 mg, 0.155 mmol), oxetane-3-carboxaldehyde (20.0 mg, 0.233 mmol, 1.5 eq.), acetic acid (0.0178 mL, 0.310 mmol, 2.0 eq.) and sodium triacetoxyborohydride (69.0 mg, 0.329 mmol, 2.1 eq.) in dichloromethane (0.05 M). The crude residues were purified by SFC (carbon dioxide / methanol / diethylamine) to give Example 141 (20.0 mg, 0.0342 mmol).1HNMR (400 MHz, dmso-(d, 2H), 7.11 (m, 4H), 7.04 (d, 2H), 5.16 (t, 1H), 4.74 (tt, 1H), 4.61 (dd, 2H), 4.23 (t, 2H), 3.85 (m, 2H), 3.5 (m, 2H), 3.15 (dt, 1H), 2.61 (m, 2H), 2.35 (m, 4H), 2.21 (m, 4H), 1.99 (br d, 2H), 1.6 (m, 2H), 1.47 (d, 3H) | [M+H]+=586.3071 Example 142: N-[(1R)-1-[4-[(1-cyclobutyl-4-piperidylidene)-(4- fluorophenyl)methyl]phenyl]ethyl]-5-tetrahydropyran-4-yloxy-nicotinamide Example 142 was prepared according to a modified General Procedure 8 using Intermediate 8(100 mg, 0.194 mmol), cyclobutanone (20.4 mg, 0.291 mmol, 1.5 eq.), acetic acid (0.0222 mL, 0.388 mmol, 2.0 eq.) and sodium triacetoxyborohydride (87.1 mg, 0.411 mmol, 2.1 eq.) in dichloromethane (0.05M). The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 142 (37.0 mg,0.0650 mmol). 1H NMR (400 MHz, dmso-7.78 (m, 1H), 7.33 (d, 2H), 7.11 (m, 4H), 7.05 (d, 2H), 5.16 (quin, 1H), 4.74 (tt, 1H), 3.85 (m, 2H), 3.49 (br t, 2H), 2.67 (br d, 1H), 2.24 (m, 8H), 1.96 (m, 4H), 1.77 (m, 2H), 1.61 (m, 4H), 1.47 (d, 3H) | [M+H]+=570.3123 Example 143: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-6-[ -tetrahydrofuran-3-yl]oxy-picolinamide Step A: Preparation of 6-[(3R)-tetrahydrofuran-3-yl]oxypicolinic acid6-[(3R)-tetrahydrofuran-3-yl]oxypicolinic acid was prepared according to General Procedure 15A using (3R)-tetrahydrofuran-3-ol (852 mg, 9.67 mmol) and methyl 6-fluoropyridine-2- carboxylate (500 mg, 3.22 mmol) to give 6-[(3R)-tetrahydrofuran-3-yl]oxypicolinic acid (674 mg, 3.22 mmol).Step B: Preparation of Example 143Example 143 was prepared according to General Procedure 2B using 6-[(3R)-tetrahydrofuran-3-yl]oxypicolinic acid (311 mg, 1.49 mmol) and Intermediate 4 (500 mg, 1.49 mmol) in N,N- dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 143 (192 mg, 0.364 mmol).1HNMR (400 MHz, dmso-(m, 7H), 5.8 (td, 1H), 5.18 (m, 1H), 3.96 (dd, 1H), 3.8 (m, 3H), 3.13 (s, 4H), 2.95 (br d, 4H), 2.29 (m, 1H), 2.15 (s, 3H), 2.02 (m, 1H), 1.54 (d, 3H) | [M+H]+=528.2640 Example 144: N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]-6-methoxy-picolinamide Example 144 was prepared according to General Procedure 2B using 6-[(3R)-tetrahydrofuran-3-yl]oxypicolinic acid (311 mg, 1.49 mmol) and Intermediate 4 (500 mg, 1.49 mmol) in N,N- dimethylformamide. The crude residues were purified by reverse phase chromatography (acetonitrile / water / ammonium bicarbonate) to give Example 144 (110 mg, 0.233 mmol).1HNMR (400 MHz, dmso-(m, 7H), 5.19 (quin, 1H), 3.99 (s, 3H), 3.13 (s, 4H), 2.94 (br d, 4H), 2.15 (s, 3H), 1.54 (d, 3H) | [M+H]+=528.2658 Example 145: N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4- fluorophenyl)methyl]phenyl]ethyl]-5-[4-(oxetane-3-carbonyl)piperazino]nicotinamide Step A: Preparation of 5-[4-(oxetane-3-carbonyl)piperazino]nicotinic acid methyl ester5-[4-(Oxetane-3-carbonyl)piperazino]nicotinic acid methyl ester was prepared according toGeneral Procedure 2B using oxetane-3-carboxylic acid (369 mg, 3.62 mmol) and Intermediate9 (800 mg, 3.62 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (dichloromethane / methanol) to give 5-[4-(oxetane-3- carbonyl)piperazino]nicotinic acid methyl ester (777 mg, 2.55 mmol). [M+H]+=306.0.Step B: Preparation of lithium;5-[4-(oxetane-3-carbonyl)piperazino]nicotinateLithium;5-[4-(oxetane-3-carbonyl)piperazino]nicotinate was prepared according to GeneralProcedure 9B using 5-[4-(oxetane-3-carbonyl)piperazino]nicotinic acid methyl ester (777 mg,2.55 mmol) to give lithium;5-[4-(oxetane-3-carbonyl)piperazino]nicotinate (756 mg, 2.54 mmol). [M+H]+=292.0.Step C: Preparation of 6-[(4-fluorophenyl)-[4- (oxetane-3- carbonyl)piperazino]nicotinoyl]amino]ethyl] -2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester 6-[(4-Fluorophenyl)-[4-[(1R)-1-[[5-[4-(oxetane-3-carbonyl)piperazino]nicotinoyl]amino] ethyl]phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester wasprepared according to General Procedure 2B using lithium;5-[4-(oxetane-3-carbonyl)piperazino]nicotinate (141 mg, 0.473 mmol) and Intermediate 3 (200 mg, 0.473 mmol) in N,N-dimethylformamide. The crude residues were purified by silica gel column chromatography (dichloromethane / methanol) to give 6-[(4-fluorophenyl)-[4-[(1R)-1-[[5-[4- (oxetane-3-carbonyl)piperazino]nicotinoyl]amino]ethyl]phenyl]methylene]-2-azaspiro[3.3] heptane-2-carboxylic acid tert-butyl ester (89.0 mg, 0.128 mmol). [M+H]+=696.3.Step D: Preparation of Example 145Example 145 was prepared according to a modified General Procedure 1 using 6-[(4-fluorophenyl)-[4-[(1R)-1-[[5-[4-(oxetane-3-carbonyl)piperazino]nicotinoyl]amino]ethyl] phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (89.0 ...

Claims

CLAIMSwherein: ring A represents a heterocycloalkyl group,R1 represents a hydrogen atom or a halogen atom, R2 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched(C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group, a linear or branched halo(C1-C6)alkyl group, a linear or branched halo(C1-C6)alkoxy group, a linear or branched amino(C1-C6)alkyl group, a -CH(CH2-OH)CH2-Cl group, orR3 represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group, a linear or branched di(C1-C6)alkylphosphoryl group, a cycloalkyl group, an aryl group, or a heterocycloalkyl group, R4 represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, a linear orbranched halo(C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy(C1-C6)alkylgroup, a linear or branched hydroxy(C1-C6)alkyl group, a -CO-CH2-OH group, acycloalkyl group, a heterocycloalkyl group, orR5 represents a hydrogen atom, a halogen atom, a hydroxy group, a linear or branched (C1-C6)alkyl group, a linear or branched halo(C1-C6)alkyl group, or a group selected from ,R6 represents a hydrogen atom, a halogen atom, or a linear or branched (C1-C6)alkyl group, Wrepresents a bond, an oxygen atom, a -CO- group, a -O-CH2- group, or a -CH2-group, Cy1represents an aryl group or a heteroaryl group,Cy2 represents an aryl group, a heteroaryl group, or a heterocycloalkyl group, Cy3represents a cycloalkyl group, a heterocycloalkyl group, or a heteroaryl group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

2. Compound of Formula (I):wherein: ring A represents a heterocycloalkyl group,R1represents a hydrogen atom or a halogen atom, R2represents a halogen atom, a cyano group, a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group, a linear or branched halo(C1-C6)alkyl group, a linear or branched halo(C1-C6)alkoxy group, a linear or branched amino(C1-C6)alkyl group, a -CH(CH2-OH)CH2-Cl group, orR3represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group, a cycloalkyl group, an aryl group, or a heterocycloalkylgroup, R4 represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, a linear orbranched halo(C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy(C1-C6)alkylgroup, a linear or branched hydroxy(C1-C6)alkyl group, a -CO-CH2-OH group, acycloalkyl group, or a group,R5 represents a hydrogen atom, a halogen atom, a hydroxy group, a linear or branched (C1-C6)alkyl group, a linear or branched halo(C1-C6)alkyl group, or a group selected from ,R6represents a hydrogen atom, a halogen atom, or a linear or branched (C1-C6)alkyl group, Wrepresents a bond, an oxygen atom, a -CO- group, a -O-CH2- group, ora -CH2- group,Cy1 represents an aryl group or a heteroaryl group,Cy2 represents an aryl group, a heteroaryl group, or a heterocycloalkyl group, Cy3represents a cycloalkyl group, a heterocycloalkyl group, or a heteroaryl group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

3. Compound according to claim 1 or 2, which is a compound of Formula (I-a):wherein R1, R2, R3, R4, Cy1, Cy2 and A are as defined in claim 1.

4. Compound according to claim 1 or 2, wherein ring A represents a heterocycloalkyl groupselected from: ,wherein R4is as defined in claim 1.

5. Compound according to claim 1 or 2, wherein ring A represents a heterocycloalkyl groupselected from:.wherein R4 is as defined in claim 1.

6. Compound according to claim 1 or 2, which is a compound of Formula (I-b):wherein R1, R2, R3, R4, Cy1and Cy2are as defined in claim 1.

7. Compound according to claim 1 or 2, wherein R1 represents a hydrogen atom, a chlorineatom, or a fluorine atom.

8. Compound according to claim 1 or 2, wherein R1 represents a hydrogen atom or a fluorineatom.

9. Compound according to claim 1 or 2, wherein R2 represents a bromine atom, a cyano group,a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a tert-butyl group,a methoxy group, an ethoxy group, an isopropyloxy group, an isobutyloxy group, atrifluoromethyl group, a difluoromethyl group, a 2,2,2-trifluoroethyl group, atrifluoromethoxy group, a 2,2-difluoroethoxy group, a -CH2-NH2 group, a-CH(CH2-OH)CH2-Cl group, or10. Compound according to claim 1 or 2, wherein R3 represents a hydrogen atom, a methylgroup, a methoxy group, a cyclopropyl group, a phenyl group, a diethylphosphoryl group,or a dihydrofuranyl group.

11. Compound according to claim 1 or 2, wherein R3 represents a hydrogen atom, a methylgroup, a methoxy group, a cyclopropyl group, a phenyl group, or a dihydrofuranyl group.

12. Compound according to claim 1 or 2, wherein R4 represents a hydrogen atom, a methylgroup, an ethyl group, an isopropyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group, a 3,3,3-trifluoropropyl group, a methoxyethyl group, a hydroxyethyl group, a -CO-CH2- OH group, a cyclobutyl group, a tetrahydrofuranyl group, an oxetanyl group, or13. Compound according to claim 1 or 2, wherein R4 represents a hydrogen atom, a methylgroup, an ethyl group, an isopropyl group, a 2,2-difluoroethyl group, a 3,3,3- trifluoropropyl group, a methoxyethyl group, a hydroxyethyl group, a -CO-CH2-OH group,a cyclobutyl group, orgroup.

14. Compound according to claim 1 or 2, wherein R5 represents a hydrogen atom, a fluorineatom, a hydroxy group, a methyl group, a fluoromethyl group, a difluoromethyl group, or a group selected from ,15. Compound according to claim 1 or 2, wherein R6 represents a hydrogen atom, a fluorineatom, or a methyl group.

16. Compound according to claim 1 or 2, wherein W represents a bond, an oxygen atom, ora -O-CH2- group.

17. Compound according to claim 1 or 2, wherein Cy1 represents a phenyl group or a pyridinylgroup.

18. Compound according to claim 1 or 2, wherein Cy2 represents a phenyl group, a pyrazolylgroup, a triazolyl group, a thienyl group, a pyridinyl group, pyrimidinyl group, a pyrazinylgroup, a pyridonyl group, a quinolinyl group, an isoquinolinyl group, a thienopyridinylgroup, an isoxazolopyridinyl group, a benzoxadiazolyl group, or a morpholinyl group.

19. Compound according to claim 1 or 2, wherein Cy2 represents a phenyl group, a pyrazolylgroup, a triazolyl group, a pyridinyl group, pyrimidinyl group, a pyrazinyl group, apyridonyl group, a quinolinyl group, an isoquinolinyl group, a thienopyridinyl group, an isoxazolopyridinyl group, a benzoxadiazolyl group, or a morpholinyl group.

20. Compound according to claim 1 or 2, wherein Cy3 represents a cyclopropyl group, acyclopentyl group, a cyclohexyl group, a spiro[3.3]heptanyl group, an azetidinyl group, anoxetanyl group, a dihydrofuranyl group, a tetrahydrofuranyl group, a pyrrolidinyl group, a morpholinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a tetrahydropyridinyl group, a dihydropyranyl group, a dioxothiazinyl group, a dioxothianyl group, an oxazaspiro[3.3]heptanyl group, an oxazaspiro[2.5]octanyl group, anoxazaspiro[3.5]nonanyl group, an oxazaspiro[4,5]decanyl group, a pyrazolyl group, apyridinyl group, a pyridonyl group, or a 4-oxo- -oxaphosphinanyl group.

21. Compound according to claim 1 or 2, wherein Cy3 represents a cyclopropyl group, acyclopentyl group, a cyclohexyl group, a spiro[3.3]heptanyl group, an azetidinyl group, anoxetanyl group, a dihydrofuranyl group, a tetrahydrofuranyl group, a pyrrolidinyl group, a morpholinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a tetrahydropyridinyl group, a dihydropyranyl group, a dioxothiazinyl group, a dioxothianyl group, an oxazaspiro[3.3]heptanyl group, an oxazaspiro[2.5]octanyl group, anoxazaspiro[3.5]nonanyl group, an oxazaspiro[4,5]decanyl group, a pyrazolyl group, apyridinyl group, or a pyridonyl group.

22. Compound according to claim 1 or 2, which is a compound of Formula (I-c):wherein R2, R3, R4 and Cy2 are as defined in claim 1.

23. Compounds according to claim 1 or 2, which are:- N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-nicotinamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-(oxetan-3-ylmethoxy)nicotinamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-tetrahydropyran-4-yloxy-nicotinamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-3-isopropyl-isoxazolo[5,4-b]pyridine-5-carboxamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-tetrahydropyran-4-yl-nicotinamide; -5-(2,5-dihydrofuran-3-yl)-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]nicotinamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-[4-(oxetane-3-carbonyl)piperazino]nicotinamide; -N-[(1R)-1-[4-[2-azaspiro[3.3]heptan-6-ylidene-(4-fluorophenyl)methyl]phenyl]ethyl]-5-[4-(oxetane-3-carbonyl)piperazino]nicotinamide;- 5-[4-(cyclobutanecarbonyl)piperazino]-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]nicotinamide; -5-[1-(cyclobutanecarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]nicotinamide; -2-[1-[1-(fluoromethyl)cyclopropanecarbonyl]-3,6-dihydro-2H-pyridin-4-yl]-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6- ylidene)methyl]phenyl]ethyl]pyrimidine-4-carboxamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-[(3R)-tetrahydrofuran-3-yl]oxy-nicotinamide; -5-(3,6-dihydro-2H-pyran-4-yl)-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]nicotinamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-2-[(3R)-tetrahydrofuran-3-yl]oxy-pyrimidine-4- carboxamide; -5-[4-(cyclopropanecarbonyl)piperazino]-N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]nicotinamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-2-tetrahydropyran-4-yl-pyrimidine-4-carboxamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-(2-methyl-2-azaspiro[3.3]heptan-6-ylidene)methyl]phenyl]ethyl]-5-morpholino-nicotinamide; -N-[(1R)-1-[4-[(4-fluorophenyl)-[2-(oxetan-3-ylmethyl)-2-azaspiro[3.3]heptan-6-ylidene]methyl]phenyl]ethyl]-2-tetrahydropyran-4-yl-pyrimidine-4-carboxamide.

24. Pharmaceutical composition comprising a compound of Formula (I) according to any oneof claims 1 to 23 or an addition salt thereof with a pharmaceutically acceptable acid or basein combination with one or more pharmaceutically acceptable excipients.

25. Pharmaceutical composition according to claim 24 for use as SOS1 inhibitors.

26. Pharmaceutical composition according to claim 24 for use in the treatment of cancer,autoimmune diseases, diseases of immune system and genetic diseases.

27. Pharmaceutical composition according to claim 26 wherein cancer is selected frompancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamouscell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, sarcomas, glioma and malignant peripheral nerve sheathtumors.

28. Pharmaceutical composition according to claim 27 wherein genetic disease is selected fromneurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lengitines, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardiofaciocutaneous syndrome, Legius syndrome and hereditary gingival fibromatosis.

29. Compound of Formula (I) according to any one of claims 1 to 23, or an addition salt thereofwith a pharmaceutically acceptable acid or base, for use as SOS1 inhibitor.

30. Compound of Formula (I) according to any one of claims 1 to 23, or an addition salt thereofwith a pharmaceutically acceptable acid or base, for use in the treatment of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cellcarcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, sarcomas, glioma, malignant peripheral nerve sheath tumors,neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lengitines, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardiofaciocutaneous syndrome, Legius syndrome and hereditary gingival fibromatosis.