Substituted pyridine and pyrazine compounds as pde4 inhibitors

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

0001Any and all priority claims identified in the Application Data Sheet, or any correction thereto, are hereby incorporated by reference under 37 CFR 1.57. For example, this application claims priority to and the benefit of <patcit id="pcit0001" dnum="US61786288A"><text>U.S. Application No. 61/786,288, filed on March 14, 2013</text></patcit>, the disclosure of which is incorporated herein in its entirety by reference.

FIELD OF THE INVENTION

0002The present invention relates to certain substituted pyridine and pyrazine compounds as inhibitors of PDE4 enzymes; derivatives of such compounds; compositions of such compounds; methods of making them; and their use in various methods, including detection and imaging techniques; enhancing neuronal plasticity; treating neurological disorders, including psychiatric, neurodegenerative, cerebrovascular, cognitive and motor disorders; providing neuroprotection; enhancing the efficiency of cognitive and motor training; facilitating neurorecovery and neurorehabilitation; and treating peripheral disorders, including inflammatory and renal disorders.

BACKGROUND OF THE INVENTION

0003The mammalian phosphodiesterases (PDEs) are a group of closely related enzymes divided into 11 families (PDE1-11) based on substrate specificity, inhibitor sensitivity and more recently, on sequence homology. The 11 families are coded by 21 genes, providing several of the families with multiple members. All mammalian PDEs share a conserved catalytic domain located in the COOH-terminal portion of the protein. In GAF-containing PDEs, one or both GAFs can provide dimerization contacts. In addition, one of the GAFs in each of these proteins provides for allosteric cGMP binding (PDE2, PDE5, PDE6, PDE11), allosteric cAMP binding (PDE10), and regulation of catalytic site functions (PDE2, PDE5, PDE6). The other families of PDEs have unique complements of various subdomains (UCR, NHR, PAS, membrane association) that contribute to regulation of activity. PDEs 1, 2, 3, and 4 are expressed in many tissues, whereas others are more restricted. In most cells, PDE3 and PDE4 provide the major portion of cAMP-hydrolyzing activity (<nplcit id="ncit0001" npl-type="s"><text>Francis, Physiological Reviews, 2011, 91, 651-690</text></nplcit>).

0004The PDE4 family includes four isoforms (PDE4A, B, C and D) with more than 20 splice variants, making it one of the largest PDE subfamilies (Bender and Beavo, 2006). PDE4 enzymes hydrolyze cAMP with a substrate apparent Km of 1-5 uM for cAMP. The PDE4 enzyme is reported to be regulated by two upper control region (UCR) domains. Depending on differential RNA splicing, PDE4 variants can be distinguished into two major subgroups: long and short forms (<nplcit id="ncit0002" npl-type="s"><text>Conti et al., J Biol Chem., 2003, 278, 5493-5496</text></nplcit>). Nine splice variants have been reported. PDE4D1, 4D2 and 4D6 all are shorter forms lacking UCRs. PDE4D3, 4D4, 4D5, 4D7, 4D8 and 4D9 are longer forms that contain both UCRs and N-terminal domains important for their subcellular localization (Bender and Beavo, 2006). Long form PDE4D3 activity is increased by PKA phosphorylation via Ser54 in the N-terminal UCR1 (<nplcit id="ncit0003" npl-type="s"><text>Alvarez et al., Mol Pharmacol., 1995, 48, 616-622</text></nplcit>; <nplcit id="ncit0004" npl-type="s"><text>Sette et al., J Biol Chem., 1996, 271, 16526-16534</text></nplcit>). Conversely, Erk2 phosphorylation of Ser597 in the C-terminus of PDE4D3 causes a reduction in catalytic activity. One or several PDE4D isoforms are expressed throughout most tissues tested, including cortex, hippocampus, cerebellum, heart, liver, kidney, lung and testis (<nplcit id="ncit0005" npl-type="s"><text>Richter et al., Biochem. J., 2005, 388, 803-811</text></nplcit>). The localization and regulation of PDE4D isoforms is thought to allow for tight and local regulation of cAMP levels, possibly limiting signal propagation in specific subcellular compartments.

0005Numerous studies have highlighted a role for PDEs generally, and PDE4 in particular, in modulating intracellular signaling pathways that regulate many physiological processes, including those underling neural plasticity, cognition, and memory. In particular, PDEs play an important role in intracellular signal transduction pathways involving the second messengers. cAMP and cGMP. These cyclic nucleotides function as ubiquitous intracellular signaling molecules in all mammalian cells. PDE enzymes hydrolyze cAMP and cGMP by breaking phosphodiester bonds to form the corresponding monophosphates (<nplcit id="ncit0006" npl-type="s"><text>Bender and Beavo, Pharmacol. Rev., 2006, 58 (3), 488-520</text></nplcit>). PDE activities are modulated in coordination with adenylyl cyclase (AC) and guanylyl cyclase (GC) activities through direct effectors and feedback pathways, thereby maintaining cAMP and cGMP levels within optimum ranges for responsiveness to signals. The ability of extracellular signals to modulate the intracellular concentration of cyclic nucleotides allows cells to respond to external stimuli across the boundary of the cell membrane.

0006The cyclic nucleotide signaling cascades have been adapted to respond to a host of transduction systems including G-protein coupled receptors (GPCRs) and voltage and ligand gated ion channels. Cyclic nucleotides transmit their signal in the cell through a variety of tertiary elements. The best described of these are cAMP dependent protein kinase (PKA) and cGMP dependent protein kinase (PKG). The binding of the cyclic nucleotide to each enzyme enables the phosphorylation of downstream enzymes and proteins functioning as effectors or additional elements in the signaling cascade. Of particular importance to memory formation is cAMP activation of PKA, which phosphorylates cAMP response element-binding protein (CREB). pCREB is an activated transcription factor, which binds to specific DNA loci and initiates transcription of multiple genes involved in neuronal plasticity. Both <i>in vitro</i> and <i>in vivo</i> studies have associated alterations in cyclic nucleotide concentrations with biochemical and physiological process linked to cognitive function (<nplcit id="ncit0007" npl-type="s"><text>Kelly and Brandon, Progress in Brain Research, 2009, 179, 67-73</text></nplcit>; <nplcit id="ncit0008" npl-type="s"><text>Schmidt, Current Topics in Medicinal Chemistry, 2010, 10, 222-230</text></nplcit>). Signal intensity and the levels of coincident activity at a synapse are established variables that can result in potentiation of transmission at a particular synapse. Long term potentiation (LTP) is the best described of these processes and is known to be modulated by both the cAMP and cGMP signaling cascades.

0007Focus on the role of PDE4 in memory stems from the discovery of the PDE4-like <i>Drosophila</i> learning mutant <i>dunce (</i>dnc <i>gene),</i> a cyclic nucleotide phosphodiesterase of the PDE4 subtype (<nplcit id="ncit0009" npl-type="s"><text>Yun and Davis, Nucleic Acids Research, 1989, 17(20), 8313-8326</text></nplcit>). The dnc mutant flies are defective in acquisition and/or short-term memory when tested in several different olfactory associative learning situations, with negative (<nplcit id="ncit0010" npl-type="s"><text>Dudai et al., Proc Natl Acad Sci., 1976, 73(5), 1684-1688</text></nplcit>; <nplcit id="ncit0011" npl-type="s"><text>Dudai Y., Proc Natl Acad Sci., 1983, 80(17), 5445-5448</text></nplcit>; <nplcit id="ncit0012" npl-type="s"><text>Tully and Quinn, Journal of Comparative Physiology, 1985, 157(2), 263-77</text></nplcit>) or positive reinforcement (<nplcit id="ncit0013" npl-type="s"><text>Tempel et al., Proc Natl Acad Sci., 1983, 80(5), 1482-1486</text></nplcit>). In mammals, PDE4D knockout animals display decreased immobility in the antidepressant tail-suspension and forced swim test models (<nplcit id="ncit0014" npl-type="s"><text>Zhang et al., Neuropsychopharmacology, 2002, 27(4), 587-595</text></nplcit>), enhanced in vitro LTP in hippocampal CA1 slices (<nplcit id="ncit0015" npl-type="s"><text>Rutten et al., Eur. J. Neurosci., 2008, 28(3), 625-632</text></nplcit>), and enhanced memory in radial maze, object recognition, and Morris water maze tasks (<nplcit id="ncit0016" npl-type="s"><text>Li et al., J. Neurosci., 2011, 31, 172-183</text></nplcit>).

0008Such observations highlight the interest in PDE-inhibition, including PDE4-inhibition, as a therapeutic target for numerous disorders and in cognitive enhancement. For example, by increasing cAMP levels, such inhibitors may be useful in treating cognitive deterioration in neurodegenerative disorders such Parkinson's Disease and Alzheimer's Disease, as well as generally improving cognition in normal, diseased, and aging subjects. Various small-molecule PDE4 enzyme inhibitors have been reported <i>e.g</i>., Aza-bridged bicycles (DeCODE Genetics; Intl. Pat. Appl. Publ. <patcit id="pcit0002" dnum="WO2010059836A"><text>WO 2010/059836, May 27, 2010</text></patcit>); <i>N</i>-substituted anilines (Memory Pharmaceuticals Corporation; Intl. Pat. Appl. Publ. <patcit id="pcit0003" dnum="WO2010003084A"><text>WO 2010/003084, January 7, 2010</text></patcit>); Biaryls (DeCODE Genetics; Intl. Pat. Appl. Publ. <patcit id="pcit0004" dnum="WO2009067600A"><text>WO 2009/067600, May 28, 2009</text></patcit>, <patcit id="pcit0005" dnum="WO2009067621A"><text>WO 2009/067621, May 28, 2009</text></patcit>); Benzothiazoles and benzoxazoles (DeCODE Genetics; U.S. Pat. Appl. Publ. <patcit id="pcit0006" dnum="US20090130076A"><text>US 2009/0130076, May 21, 2009</text></patcit>); Catechols (DeCODE Genetics; U.S. Pat. Appl. Publ. <patcit id="pcit0007" dnum="US20090131530A"><text>US 2009/0131530, May 21, 2009</text></patcit>), Pteridines (Boehringer Ingelheim International G.m.b.H.; <patcit id="pcit0008" dnum="US7674788B"><text>U.S. Pat. 7,674,788, Nov 29, 2007</text></patcit>); Heteroaryl pyrazoles (Memory Pharmaceuticals Corporation; Intl. Pat. Appl. Publ. <patcit id="pcit0009" dnum="WO2007123953A"><text>WO 2007/123953, November 1, 2007</text></patcit>); Naphthyridines (Glaxo Group Limited; Intl. Pat. Appl. Publ. <patcit id="pcit0010" dnum="WO2006053784A"><text>WO 2006/053784, May 26, 2006</text></patcit>); Piperazinyldihydrothienopyrimidines (Boehringer Ingelheim International G.m.b.H.; <patcit id="pcit0011" dnum="EP1874781A"><text>EP Pat. 1,874,781, Jun 24, 2009</text></patcit>); Nicotinamide derivatives (Pfizer; U.S. Pat. Appl. Publ. <patcit id="pcit0012" dnum="US20050020587A"><text>US 2005/0020587, January 27, 2005</text></patcit>); Heteroarylmethyl phenyl amines (Memory Pharmaceuticals Corporation; <patcit id="pcit0013" dnum="US7087625B"><text>U.S. Pat. 7,087,625, August 8, 2006</text></patcit>); Naphthyridines (Novartis AG; <patcit id="pcit0014" dnum="EP1443925A"><text>EP Pat. 1,443,925, December 26, 2007</text></patcit>; <patcit id="pcit0015" dnum="US7468370B"><text>U.S. Pat. 7,468,370, Dec 23, 2008</text></patcit>).

0009However, PDE4 inhibitors have generally been associated with numerous side effects - most notably emesis - that have typically limited their usefulness and tolerability (e.g., <nplcit id="ncit0017" npl-type="s"><text>Giembycz, Curr. Opin. Pharm. 2005, 5, 238-244</text></nplcit>). It is therefore desirable to develop improved PDE4 inhibitors such as those showing higher potency, greater specificity, and better side effect profiles. The present invention meets these and other needs in the art by disclosing substituted pyridine and pyrazine compounds as potent and well-tolerated PDE4 inhibitors.

SUMMARY OF THE INVENTION

0010The invention provides a chemical entity of Formula (I): <chemistry id="chem0001" num="0001"><img file="EP3345902A1_D0001.tif" /></chemistry> wherein R¹, R², R³, R⁴, Y and Z have any of the values described herein.

0011In one aspect the chemical entity is selected from the group consisting of compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically acceptable metabolites of compounds of Formula (I).

0012Chemical entities of compounds of Formula (I) are useful in wide range of methods as described herein. Isotopically-labeled compounds and prodrugs can be used in metabolic and reaction kinetic studies, detection and imaging techniques, and radioactive treatments. The chemical embodiments of the present invention can be used to inhibit PDE4, in particular; to treat a disorder mediated by PDE4, in particular; to enhance neuronal plasticity; to treat neurological disorders, including neurodegenerative disorders, cognitive disorders, and cognitive deficits associated with CNS disorders; to confer neuroprotection; and to treat peripheral disorders, including inflammatory and renal disorders. The chemical embodiments of the present invention are are also useful as augmenting agents to enhance the efficiency of cognitive and motor training, in stroke rehabilitation, to facilitate neurorecovery and neurorehabilitation, and to increase the efficiency of non-human animal training protocols. The invention is further directed to the general and specific embodiments defined, respectively, by the independent and dependent claims appended hereto, which are incorporated by reference herein.

DETAILED DESCRIPTION

0013The invention may be more fully appreciated by reference to the following description, including the examples. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described herein. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

0014For the sake of brevity, all publications, including patent applications, patents, and other citations mentioned herein, are incorporated by reference in their entirety. Citation of any such publication, however, shall not be construed as an admission that it is prior art to the present invention.

Abbreviations

0015The specification includes numerous abbreviations, whose meanings are listed in the following Table: <tables id="tabl0001" num="0001"><table frame="all"><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="42mm" /><colspec colnum="2" colname="col2" colwidth="90mm" /><thead><row><entry valign="top"><b>Abbreviation</b></entry><entry valign="top"><b>Meaning</b></entry></row></thead><tbody><row><entry>ACN</entry><entry>Acetonitrile</entry></row><row><entry>AcOH</entry><entry>Acetic Acid</entry></row><row><entry>AIBN</entry><entry>2,2'-Azobis(2-methylpropionitrile)</entry></row><row><entry>BOC</entry><entry><i>tert</i>-Butyl dicarbonate</entry></row><row><entry>n-BuLi</entry><entry><i>n</i>-Butyl lithium</entry></row><row><entry>DCM</entry><entry>Dichloromethane</entry></row><row><entry>Deoxo-Fluor®</entry><entry>Bis(2-methoxyethyl)aminosulfur trifluoride</entry></row><row><entry>Dess-Martin Reagent®</entry><entry>1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one</entry></row><row><entry>DIPEA, Hünig's base</entry><entry><i>N,N</i>-Ethyl-di<i>iso</i>propylamine or N,N-Di<i>iso</i>propylethyl amine</entry></row><row><entry>DMA</entry><entry><i>N, N</i>-Dimethylacetamide</entry></row><row><entry>DMF</entry><entry><i>N,N</i>-Dimethylformamide</entry></row><row><entry>DMSO</entry><entry>Dimethylsulfoxide</entry></row><row><entry>dppf</entry><entry>1,1'-Bis(diphenylphosphino)ferrocene</entry></row><row><entry>EtOAc, or EA</entry><entry>Ethyl Acetate</entry></row><row><entry>EtOH</entry><entry>Ethanol</entry></row><row><entry>HOAc or AcOH</entry><entry>Acetic Acid</entry></row><row><entry>HPLC</entry><entry>High-performance liquid chromatography</entry></row><row><entry>LAH</entry><entry>Lithium aluminum hydride</entry></row><row><entry>LCMS, LC/MS</entry><entry>Liquid chromatography-mass spectrometry</entry></row><row><entry>MeOH</entry><entry>Methanol</entry></row><row><entry>NBS</entry><entry>n-Bromosuccinimide,</entry></row><row><entry>PdCI₂(dppf)-DCM adduct</entry><entry>[1'1'-Bis(diphenylphosphino)ferrocene]palladium(ll)</entry></row><row><entry>Pd(PPh₃)₄</entry><entry>Tetrakis[triphenylphosphine]palladium(0)</entry></row><row><entry>TBAF</entry><entry>Tetrabutylammonium flouride</entry></row><row><entry>TEA, Et₃N</entry><entry>Triethylamine</entry></row><row><entry>TFA</entry><entry>Trifluoroacetic acid</entry></row><row><entry>THF</entry><entry>Tetrahydrofuran</entry></row><row><entry>TLC</entry><entry>Thin layer chromatography</entry></row><row><entry>XtalFluor®</entry><entry>(Diethylamino)difluorosulfonium tetrafluoroborate</entry></row></tbody></tgroup></table></tables>

TERMS AND DEFINITIONS

0016The use of subheadings such as "General," "Chemistry," "Compositions," "Formulations," <i>etc.,</i> in this section, as well as in other sections of this application, are solely for convenience of reference and not intended to be limiting.

General

0017As used herein, the term "about" or "approximately" means within an acceptable range for a particular value as determined by one skilled in the art, and may depend in part on how the value is measured or determined, e.g., the limitations of the measurement system or technique. For example, "about" can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% or less on either side of a given value. Alternatively, with respect to biological systems or processes, the term "about" can mean within an order of magnitude, within 5 fold, or within 2 fold on either side of a value. Numerical quantities given herein are approximate unless stated otherwise, meaning that the term "about" or "approximately" can be inferred when not expressly stated

0018To provide a more concise description, some of the quantitative expressions given herein are <b><i>not</i></b> qualified with the term "about". It is understood that, whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation of such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity for which that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.

0019As used herein, the terms "a," "an," and "the" are to be understood as meaning both singular and plural, unless explicitly stated otherwise. Thus, "a," "an," and "the" (and grammatical variations thereof where appropriate) refer to one or more.

0020A group of items linked with the conjunction "and" should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as "and/or" unless expressly stated otherwise. Similarly, a group of items linked with the conjunction "or" should not be read as requiring mutual exclusivity among that group, but rather should also be read as "and/or" unless expressly stated otherwise. Furthermore, although items, elements or components of the invention may be described or claimed in the singular, the plural is contemplated to be within the scope thereof unless limitation to the singular is explicitly stated.

0021The terms "comprising" and "including" are used herein in their open, non-limiting sense. Other terms and phrases used in this document, and variations thereof, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing: the term "example" is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; adjectives such as "conventional," "traditional," "normal," "criterion," "known," and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time, but instead should be read to encompass conventional, traditional, normal, or criterion technologies that may be available or known now or at any time in the future. Likewise, where this document refers to technologies that would be apparent or known to one of ordinary skill in the art, such technologies encompass those apparent or known to the skilled artisan now or at any time in the future.

0022The presence of broadening words and phrases such as "one or more," "at least," "but not limited to," or other like phrases in some instances shall not be read to mean that the narrower case is intended or required in instances where such broadening phrases may be absent. As will become apparent to one of ordinary skill in the art after reading this document, the illustrated embodiments and their various alternatives may be implemented without confinement to the illustrated examples.

Chemistry

0023The term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include, but are not limited to, methyl (Me, which also may be structurally depicted by the symbol, "<img file="EP3345902A1_D0002.tif" /> "), ethyl (Et), <i>n</i>-propyl, isopropyl, butyl, isobutyl, <i>sec</i>-butyl, <i>tert-butyl</i> (tBu), pentyl, isopentyl, <i>tert</i>-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. Alkyl groups may be optionally substituted with one or more substituents including, but not limited to, hydroxyl, alkoxy, cyano, thioalkoxy, amino, and amino alkyl.

0024The term "haloalkyl" refers to the alkyl moiety, which may be a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain substituted with a halo group. Examples of haloalkyl groups include, but are not limited to, -CF₃, -CHF₂, -CH₂F, -CH₂CF₃, - CH₂CHF₂, -CH₂CH₂F, -CH₂CH₂Cl, or -CH₂CF₂CF₃.

0025The term "cyano" refers to the group -CN.

0026The term "cycloalkyl" refers to a saturated or partially saturated carbocycle, such as monocyclic, fused polycyclic, bridged monocyclic, bridged polycyclic, spirocyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle. Where the term cycloalkyl is qualified by a specific characterization, such as monocyclic, fused polycyclic, bridged polycyclic, spirocyclic, and spiro polycyclic, then such term cycloalkyl refers only to the carbocycle so characterized. Illustrative examples of cycloalkyl groups include the following entities, in the form of properly bonded moieties: <chemistry id="chem0002" num="0002"><img file="EP3345902A1_D0003.tif" /></chemistry><chemistry id="chem0003" num="0003"><img file="EP3345902A1_D0004.tif" /></chemistry><chemistry id="chem0004" num="0004"><img file="EP3345902A1_D0005.tif" /></chemistry>

0027Those skilled in the art will recognize that the species of cycloalkyl groups listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.

0028The term "halogen" represents chlorine, fluorine, bromine or iodine. The term "halo" represents chloro, fluoro, bromo or iodo.

0029The term "heteroatom" used herein refers to, for example, O (oxygen), S (sulfur) and N (nitrogen).

0030The term "heteroaryl" refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. Illustrative examples of heteroaryl groups include the following entities, in the form of properly bonded moieties: <chemistry id="chem0005" num="0005"><img file="EP3345902A1_D0006.tif" /></chemistry><chemistry id="chem0006" num="0006"><img file="EP3345902A1_D0007.tif" /></chemistry><chemistry id="chem0007" num="0007"><img file="EP3345902A1_D0008.tif" /></chemistry><chemistry id="chem0008" num="0008"><img file="EP3345902A1_D0009.tif" /></chemistry>

0031The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents. Where the term "substituted" is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In cases where a specified moiety or group is not expressly noted as being optionally substituted or substituted with any specified substituent, it is understood that such a moiety or group is intended to be unsubstituted.

Formulas

0032Any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof, are considered within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. Furthermore, certain structures may exist as geometric isomers (i.e., <i>cis</i> and <i>trans</i> isomers), as tautomers, or as atropisomers.

0033The symbols <img file="EP3345902A1_D0010.tif" /> and <img file="EP3345902A1_D0011.tif" /> are used as meaning the same spacial arrangement in chemical structures shown herein. Analogously, the symbols <img file="EP3345902A1_D0012.tif" /> and <img file="EP3345902A1_D0013.tif" /> are used as meaning the same spacial arrangement in chemical structures shown herein.

Compounds

0034As used herein, a "compound" refers to any one of: (a) the actually recited form of such compound; and (b) any of the forms of such compound in the medium in which the compound is being considered when named. For example, reference herein to a compound such as R-COOH, encompasses reference to any one of, for example, R-COOH(s), R-COOH(sol), and R-COO-(sol). In this example, R-COOH(s) refers to the solid compound, as it could be for example in a tablet or some other solid pharmaceutical composition or preparation; R-COOH(sol) refers to the undissociated form of the compound in a solvent; and R-COO-(sol) refers to the dissociated form of the compound in a solvent, such as the dissociated form of the compound in an aqueous environment, whether such dissociated form derives from R-COOH, from a salt thereof, or from any other entity that yields R-COO- upon dissociation in the medium being considered.

0035As used herein, the term "chemical entity" collectively refers to a compound, along with the derivatives of the compound, including salts, chelates, solvates, conformers, non-covalent complexes, metabolites, and prodrugs.

0036In one aspect the chemical entity is selected from the group consisting of compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically acceptable metabolites of compounds of Formula (I).

0037In another example, an expression such as "exposing an entity to a compound of formula R-COOH" refers to the exposure of such entity to the form, or forms, of the compound R-COOH that exists, or exist, in the medium in which such exposure takes place. In still another example, an expression such as "reacting an entity with a compound of formula R-COOH" refers to the reacting of (a) such entity in the chemically relevant form, or forms, of such entity that exists, or exist, in the medium in which such reacting takes place, with (b) the chemically relevant form, or forms, of the compound R-COOH that exists, or exist, in the medium in which such reacting takes place. In this regard, if such entity is for example in an aqueous environment, it is understood that the compound R-COOH is in such same medium, and therefore the entity is being exposed to species such as R-COOH(aq) and/or R-COO-(aq), where the subscript "(aq)" stands for "aqueous" according to its conventional meaning in chemistry and biochemistry. A carboxylic acid functional group has been chosen in these nomenclature examples; this choice is not intended, however, as a limitation but it is merely an illustration. It is understood that analogous examples can be provided in terms of other functional groups, including but not limited to hydroxyl, basic nitrogen members, such as those in amines, and any other group that interacts or transforms according to known manners in the medium that contains the compound. Such interactions and transformations include, but are not limited to, dissociation, association, tautomerism, solvolysis, including hydrolysis, solvation, including hydration, protonation and deprotonation. No further examples in this regard are provided herein because these interactions and transformations in a given medium are known by any one of ordinary skill in the art.

0038In another example, a "zwitterionic" compound is encompassed herein by referring to a compound that is known to form a zwitterion, even if it is not explicitly named in its zwitterionic form. Terms such as zwitterion, zwitterions, and their synonyms zwitterionic compound(s) are standard IUPAC-endorsed names that are well known and part of standard sets of defined scientific names. In this regard, the name zwitterion is assigned the name identification CHEBI:27369 by the Chemical Entities of Biological Interest (ChEBI) dictionary of molecular entities. As is generally well known, a zwitterion or zwitterionic compound is a neutral compound that has formal unit charges of opposite sign. Sometimes these compounds are referred to by the term "inner salts". Other sources refer to these compounds as "dipolar ions", although the latter term is regarded by still other sources as a misnomer. As a specific example, aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH, and it exists in some media (in this case in neutral media) in the form of the zwitterion +H₃NCH₂COO-. Zwitterions, zwitterionic compounds, inner salts, and dipolar ions in the known and well established meanings of these terms are within the scope of this invention, as would in any case be so appreciated by those of ordinary skill in the art. Because there is no need to name each and every embodiment that would be recognized by those of ordinary skill in the art, no structures of the zwitterionic compounds that are associated with the compounds of this invention are given explicitly herein. They are, however, part of the embodiments of this invention. No further examples in this regard are provided herein because the interactions and transformations in a given medium that lead to the various forms of a given compound are known by any one of ordinary skill in the art.

0039Isotopes may be present in the compounds described. Each chemical element present in a compound either specifically or generically described herein may include any isotope of said element. Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, sulfur, fluorine, chlorine and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²⁵I, respectively.

0040When referring to any formula given herein, the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the same choice of the species for the variable appearing elsewhere. In other words, where a variable appears more than once, the choice of the species from a specified list is independent of the choice of species for the same variable elsewhere in the formula, unless otherwise stated.

0041By way of a first example on substituent terminology, if substituent S¹_example is one of S₁ and S₂, and substituent S²_example is one of S₃ and S₄, then these assignments refer to embodiments of this invention given according to the choices S¹_example is S₁ and S²_example is S₃; S¹_example is S₁ and S²_example is S₄; S¹_example is S₂ and S²_example is S₃; S¹_example is S₂ and S²_example is S₄; and equivalents of each one of such choices. The shorter terminology "S¹_example is one of S₁ and S₂ and "S²_example is one of S₃ and S₄ is accordingly used herein for the sake of brevity but not by way of limitation. The foregoing first example on substituent terminology, which is stated in generic terms, is meant to illustrate the various substituent assignments described herein. The foregoing convention given herein for substituents extends, when applicable, to members such as R¹, R², R³, R⁴ R^a, R^b, R^c, R^d, R^d1,R^e, R^e1, R^f, R^g, R^h, R^j, R^k R^m, Rⁿ and U, Y, Z, HAL, HET and any other generic substituent symbol used herein.

0042Furthermore, when more than one assignment is given for any member or substituent, embodiments of this invention comprise the various groupings that can be made from the listed assignments, taken independently, and equivalents thereof. By way of a second example on substituent terminology, if it is herein described that substituent S_example is one of S₁, S₂ and S₃, the listing refers to embodiments of this invention for which S_example is S₁; S_example is S₂; S_example is S₃; S_example is one of S₁ and S₂; S_example is one of S₁ and S₃; S_example is one of S₂ and S₃; S_example is one of S₁, S₂ and S₃; and S_example is any equivalent of each one of these choices. The shorter terminology "S_example is one of S₁, S₂ and S₃" is accordingly used herein for the sake of brevity, but not by way of limitation. The foregoing second example on substituent terminology, which is stated in generic terms, is meant to illustrate the various substituent assignments described herein. The foregoing convention given herein for substituents extends, when applicable, to members such as R¹, R², R³, R⁴ R^a, R^b, R^c, R^d, R^d1, R^e, R^e1, R^f, R^g, R^h, Rⁱ, R^k R^m, Rⁿ and U, Y, Z, HAL, HET and any other generic substituent symbol used herein.

0043The nomenclature "C_i-j" with j > i, when applied herein to a class of substituents, is meant to refer to embodiments of this invention for which each and every one of the number of carbon members, from i to j including i and j, is independently realized. By way of example, the term C_1-3 refers independently to embodiments that have one carbon member (C₁), embodiments that have two carbon members (C₂), and embodiments that have three carbon members (C₃).

0044The term C_n-malkyl refers to an aliphatic chain, whether straight or branched, with the total number N of carbon members in the chain that satisfies n≤ N≤ m, with m > n.

0045Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent -A-B-, where A ≠ B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second member and B attached to the first substituted member.

0046According to the foregoing interpretive considerations on assignments and nomenclature, it is understood that explicit reference herein to a set implies, where chemically meaningful and unless indicated otherwise, independent reference to embodiments of such set, and reference to each and every one of the possible embodiments of subsets of the set referred to explicitly.

0047The term "prodrug" means a precursor of a designated compound that, following administration to a subject, yields the compound <i>in vivo</i> via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (<i>e.g</i>., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)).

0048A "pharmaceutically acceptable prodrug" is a prodrug that is preferably non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "<nplcit id="ncit0018" npl-type="b"><text>Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985</text></nplcit>.

0049A "metabolite" means a pharmacologically active product of metabolism in the body of a compound of Formula (I) or salt thereof. Preferably, the metabolite is in an isolated form outside the body.

Compositions

0050The term "composition," as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula (I) and a pharmaceutically acceptable excipient.

0051The term "pharmaceutically acceptable," as used in connection with compositions of the invention, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to an animal (<i>e.g</i>., human). The term "pharmaceutically acceptable" may also mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals (<i>e.g</i>. mammals), and more particularly in humans.

0052A "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluents to facilitate administration of an agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. Suitable pharmaceutical carriers include those described in <nplcit id="ncit0019" npl-type="b"><text>Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams &amp; Wilkins (2005</text></nplcit>).

0053A "pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base of a compound represented by Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, <nplcit id="ncit0020" npl-type="b"><text>G.S. Paulekuhn et al., Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database, J. Med. Chem. 2007, 50, 6665-6672</text></nplcit>; <nplcit id="ncit0021" npl-type="b"><text>Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977, 66, 1-19</text></nplcit>; <nplcit id="ncit0022" npl-type="b"><text>Stahl and Wermuth (eds), Pharmaceutical Salts; Properties, Selection, and Use: 2nd Revised Edition, Wiley-VCS, Zurich, Switzerland (2011</text></nplcit>). Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. A compound of Formula (I) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

0054The term "carrier" refers to an adjuvant, vehicle, or excipients, with which the compound is administered. In preferred embodiments of this invention, the carrier is a solid carrier. Suitable pharmaceutical carriers include those described in <nplcit id="ncit0023" npl-type="b"><text>Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams &amp; Wilkins (2005</text></nplcit>).

0055The term "dosage form," as used herein, is the form in which the dose is to be administered to the subject or patient. The drug is generally administered as part of a formulation that includes nonmedical agents. The dosage form has unique physical and pharmaceutical characteristics. Dosage forms, for example, may be solid, liquid or gaseous. "Dosage forms" may include, for example, a capsule, tablet, caplet, gel caplet (gelcap), syrup, a liquid composition, a powder, a concentrated powder, a concentrated powder admixed with a liquid, a chewable form, a swallowable form, a dissolvable form, an effervescent, a granulated form, and an oral liquid solution. In a specific embodiment, the dosage form is a solid dosage form, and more specifically, comprises a tablet or capsule.

0056As used herein, the term "inert" refer to any inactive ingredient of a described composition. The definition of "inactive ingredient" as used herein follows that of the U.S. Food and Drug Administration, as defined in 21 C.F.R. 201.3(b)(8), which is any component of a drug product other than the active ingredient.

Methods and Uses

0057As used herein, the term "disorder" is used interchangeably with "disease" or "condition". For example, a CNS disorder also means a CNS disease or a CNS condition.

0058As used herein, the term "cognitive impairment" is used interchangeably with "cognitive dysfunction" or "cognitive deficit," all of which are deemed to cover the same therapeutic indications.

0059The terms "treating," "treatment," and "treat" cover therapeutic methods directed to a disease-state in a subject and include: (i) preventing the disease-state from occurring, in particular, when the subject is predisposed to the disease-state but has not yet been diagnosed as having it; (ii) inhibiting the disease-state, <i>e.g</i>., arresting its development (progression) or delaying its onset; and (iii) relieving the disease-state, <i>e.g</i>., causing regression of the disease state until a desired endpoint is reached. Treating also includes ameliorating a symptom of a disease (<i>e.g</i>., reducing the pain, discomfort, or deficit), wherein such amelioration may be directly affecting the disease (<i>e.g</i>., affecting the disease's cause, transmission, or expression) or not directly affecting the disease.

0060As used in the present disclosure, the term "effective amount" is interchangeable with "therapeutically effective amount" and means an amount or dose of a compound or composition effective in treating the particular disease, condition, or disorder disclosed herein, and thus "treating" includes producing a desired preventative, inhibitory, relieving, or ameliorative effect. In methods of treatment according to the invention, "an effective amount" of at least one compound according to the invention is administered to a subject (<i>e.g</i>., a mammal). An "effective amount" also means an amount or dose of a compound or composition effective to modulate activity of PDE4 or an associated signaling pathway, such as the CREB pathway and thus produce the desired modulatory effect. The "effective amount" will vary, depending on the compound, the disease, the type of treatment desired, and its severity, and age, weight, etc.

0061The term "animal" is interchangeable with "subject" and may be a vertebrate, in particular, a mammal, and more particularly, a human, and includes a laboratory animal in the context of a clinical trial or screening or activity experiment. Thus, as can be readily understood by one of ordinary skill in the art, the compositions and methods of the present invention are particularly suited to administration to any vertebrate, particularly a mammal, and more particularly, a human.

0062As used herein, a "control animal" or a "normal animal" is an animal that is of the same species as, and otherwise comparable to (<i>e.g</i>., similar age, sex), the animal that is trained under conditions sufficient to induce transcription-dependent memory formation in that animal.

0063By "enhance," "enhancing," or "enhancement" is meant the ability to potentiate, increase, improve or make greater or better, relative to normal, a biochemical or physiological action or effect. For example, enhancing long term memory formation refers to the ability to potentiate or increase long term memory formation in an animal relative to the normal long term memory formation of the animal or controls. As a result, long term memory acquisition is faster or better retained. Enhancing performance of a cognitive task refers to the ability to potentiate or improve performance of a specified cognitive task by an animal relative to the normal performance of the cognitive task by the animal or controls.

0064As used herein, the term "training protocol," or "training," refers to either "cognitive training" or "motor training." The phrase "in conjunction" means that a compound or composition of the present invention enhances CREB pathway function during cognitive or motor training.

0065Reference will now be made to the embodiments of the present invention, examples of which are illustrated by and described in conjunction with the accompanying drawings and examples. While certain embodiments are described herein, it is understood that the described embodiments are not intended to limit the scope of the invention. On the contrary, the present disclosure is intended to cover alternatives, modifications, and equivalents that can be included within the invention as defined by the appended claims.

COMPOUNDS

0066The present invention provides certain substituted pyridine and pyriazine derivatives, which are useful, for example, as inhibitors of PDE4 enzymatic activity. They are distinct from tri-substituted pyridines are disclosed in the following publications: <patcit id="pcit0016" dnum="US7399761B"><text>US Pat. 7,399,761</text></patcit>(Novartis AG, November 14, 2002, <nplcit id="ncit0024" npl-type="c"><text>CAS No. 1106203-18-2</text></nplcit>, 1106203-.16-0); Intl. Pat. Appl. Publ. <patcit id="pcit0017" dnum="WO2003050098A"><text>WO 2003050098</text></patcit>, (Maxia Pharmaceuticals, June 19, 2003,<nplcit id="ncit0025" npl-type="c"><text> CAS No. 544475-13-0</text></nplcit>, 544475-12-9) and <patcit id="pcit0018" dnum="JP4321737B"><text>JP Pat. 4,321,737</text></patcit> (Intl. Pat. Appl. Publ. <patcit id="pcit0019" dnum="WO9931062A"><text>WO 9931062</text></patcit>, Shionogi &amp; Co., Jun 24, 1999,<nplcit id="ncit0026" npl-type="c"><text> CAS No. 228096-03-5</text></nplcit>, 228096-04-6).

0067In its many embodiments, the invention is directed to a chemical entity of Formula (I): <chemistry id="chem0009" num="0009"><img file="EP3345902A1_D0014.tif" /></chemistry> wherein: <ul id="ul0001" list-style="none" compact="compact"><li>Z is CH or N; <ul id="ul0002" list-style="none" compact="compact"><li>i) wherein when Z is CH, then; <ul id="ul0003" list-style="none" compact="compact"><li>R¹ is a member selected from the group consisting of: -H, -C_1-3alkyl and -C_1-3haloalkyl;</li><li>Y is -C(R^a)₂-, where each R^a is independently selected from the group consisting of: -H, -F, - CH₃, -OH and -N(R^b)₂;</li><li>R² is a member selected from the group consisting of: <ol id="ol0001" compact="compact"><li>A) phenyl unsubstituted or substituted with one or two R^c members, where each R^c is independently selected from the group consisting of: halo, -CN, -CO₂R^b, -CONH₂, - SO₂CH₃, -C(R^b)₂OH, -CH₂NH₂, -CH₂CONH₂, -CH₂CO₂C_1-3alkyl, -NHCONH₂, - NHCONH-oxetane, -CONH-oxetane, <chemistry id="chem0010" num="0010"><img file="EP3345902A1_D0015.tif" /></chemistry></li><li>B) six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of: halo, -C_1-3alkyl, -C_1-3haloalkyl, -CN, -OH, - C(R^b)₂OH, -CH₂NH₂, -C(R^b)₂CN, -C(R^b)₂CONH₂, -OCH₂CONH₂, -OC_1-3alkyl, - OCH₂C(R^b)₂OH, -OCH₂cyclopropyl, -OC_1-3haloalkyl, -CO₂H, -CON(R^b)₂, -N(R^b)₂, - NHCH₂CF₃, -NHCH(CH₃)₂, -NHCH₂CH₂N(CH₃)₂, -NHCH₂CH₂OH, - NHcyclopropyl, -NHCOCH₃, morpholinyl, pyrrolidin-3-ol, and azetidin-3-ol;</li><li>C) five-membered monocyclic heteroaromatic ring containing two, three, or four nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of halo, -C_1-3alkyl, -C_1-3haloalkyl, -C(R^b)₂OH, -N(R^b)₂, -NO₂, -CN, -CH₂CN, -OC_1-3alkyl, -CH₂OCH₃, -CH₂CH₂OH, - CH₂NH₂, -CH₂CONH₂, -CO₂C_1-3alkyl, -CO₂H, -CONH₂, -NHCOCH₃, and cyclopropyl; and</li><li>D) five or six-membered ring selected from: 1,2-dihydro-pyridin-2-one, thiazole or 1,2-oxazole unsubstituted or substituted with one or two members each independently selected from the group consisting of -CH₃, and -NH₂;</li></ol></li><li>R³ is phenyl or pyridine, substituted with one or two members each independently selected from the group consisting of: -halo, -C_1-3alkyl, -OC_1-3alkyl, -Ocyclopropyl, -O-oxetane, -C₁-₃haloalkyl, -OC_1-3haloalkyl, -CN, -CH₂OH, -SO₂CH₃, or -N(CH₃)₂;</li><li>R⁴ is a member selected from the group consisting of -C_1-3alkyl and -C_1-3haloalkyl; and</li><li>each R^b is independently selected from -H or -CH₃;</li></ul></li><li>ii) wherein when Z is N, then; <ul id="ul0004" list-style="none" compact="compact"><li>R¹ is -H;</li><li>Y is -CH₂-;</li><li>R² is a member selected from the group consisting of: <ol id="ol0002" compact="compact"><li>A) phenyl substituted with one or two R^d members, where each R^d is independently selected from the group consisting of: -CN, -CONH₂, and -CO₂C_1-3alkyl;</li><li>B) six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with a member selected from the group consisting of: -CN, -OC_1-3alkyl, -CONH₂, -NHCH₂CH₂OH, -N(R^b)₂, and -NH-cyclopropyl;</li><li>C) five-membered monocyclic heteroaromatic ring containing two or three nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of -C_1-3alkyl, -C_1-3haloalkyl, -CH₂OR^b, -N(R^b)₂, - NO₂, -CO₂CH₃, -CO₂N(R^b)₂, or cyclopropyl; and</li><li>D) 1,2-oxazole optionally substituted with one or two R^b members;</li></ol></li><li>R³ phenyl substituted with one or two members each independently selected from the group consisting of: -Cl, -OC_1-3alkyl, or -OC_1-3haloalkyl;</li><li>R⁴ is -C_1-3alkyl; and</li><li>each R^b is independently selected from -H or -CH₃.</li></ul></li></ul></li></ul>

0068In certain embodiments of compounds of Formula (I), Z is CH.

0069In certain embodiments of compounds of Formula (I), Z is N.

0070Some embodiments are given by compounds of Formula (I) where Z is CH, and R¹ -H, -CH₃, or -CF₃.

0071In some of these embodiments, R¹ is -H.

0072In certain embodiments of compounds of Formula (I), Y is -CH₂-, -CH(F)-, -CH(OH)-, -C(OH)(CH₃)-, or -CH(CH₃)-, and Z is CH.

0073In some of these embodiments, Y is -CH₂- and Z is N.

0074In certain embodiments of compounds of Formula (I), R² is <chemistry id="chem0011" num="0011"><img file="EP3345902A1_D0016.tif" /></chemistry> and R^c is halo, -CN, -CO₂H, -(CH₂)_0-1CONH₂, -SO₂CH₃, -C(R^b)₂OH, -CH₂NH₂, -CH₂CO₂C_1-6alkyl, - NHCONH₂, -NHCONH-oxetane, -CONH-oxetane, <chemistry id="chem0012" num="0012"><img file="EP3345902A1_D0017.tif" /></chemistry>

0075In some of these embodiments, R² is <chemistry id="chem0013" num="0013"><img file="EP3345902A1_D0018.tif" /></chemistry> and R^c is -F, -(CH₂)_0-1CONH₂, - CH₂NH₂, -C(CH₃)₂OH, -SO₂CH₃, or -NHCONH₂.

0076In certain embodiments of compounds of Formula (I), Z is N and R² is 4-cyanophenyl, 4-phenylamide or 4-phenylcarboxylic acid methyl ester.

0077Some embodiments are given by compounds of Formula (I) where R² is pyridine, unsubstituted or substituted with one or two members each independently selected from: -F, -C_1-6alkyl, -C_1-3haloalkyl, -OC_1-6alkyl, -OCH₂cyclopropyl, -CN, -N(R^b)₂, -CH₂NH₂, -CO₂H, - CON(R^b)₂, or -C(R^b)₂OH.

0078In some of these embodiments, R² is <chemistry id="chem0014" num="0014"><img file="EP3345902A1_D0019.tif" /></chemistry> and R^d is -C_1-6alkyl, -CF₃, -CN, - N(R^b)₂, -CO₂H, -CON(R^b)₂, -OC_1-3alkyl, -CH₂NH₂, -C(R^b)₂OH, -OCH₂cyclopropyl, or - OCH(CH₃)₂.

0079In some of these embodiments, R² is <chemistry id="chem0015" num="0015"><img file="EP3345902A1_D0020.tif" /></chemistry> and R^d is -CH₃, -CF₃, -NH₂, -NHCH₃, - N(CH₃)₂, -CONH₂, -CONHCH₃, -CON(CH₃)₂, -OC_1-3alkyl, -CH₂OH, -C(CH₃)₂OH, or - OCH₂cyclopropyl.

0080In some of these embodiments, Z is N, and R² is <chemistry id="chem0016" num="0016"><img file="EP3345902A1_D0021.tif" /></chemistry>

0081R^d1 is -CN or -CONH₂.

0082Some embodiments are given by compounds of Formula (I), where R² is selected from the group consisting of pyrazine, pyridazine and pyrimidine; where pyrazine is optionally unsubstituted or substituted with -C_1-3alkyl, -OC_1-3alkyl, -N(R^b)₂, or -NHCH₂CH₂OH; pyridazine is optionally unsubstituted or substituted with -C_1-3alkyl; and pyrimidine is optionally substituted with a group consisting of: -H, halo, -C_1-3alkyl, -CN, -OH, -OC_1-3alkyl, -OC_1-3haloalkyl, -CO₂H, -CON(R^b)₂, -C(R^b)₂CONH₂, -C(R^b)₂OH, -C(R^b)₂CN, -CH₂CH₂N(CH₃)₂, - OCH₂C(R^b)₂OH, -OCH₂CONH₂, -N(R^b)₂, -NHCH₂CF₃, -NHCH(CH₃)₂, -NHCH₂CH₂OH, - NHcyclopropyl, -NHCOCH₃, morpholinyl, pyrrolidin-3-ol, and azetidin-3-ol.

0083In some of these embodiments, R² is <chemistry id="chem0017" num="0017"><img file="EP3345902A1_D0022.tif" /></chemistry> unsubstituted or substituted with one or two R^e members, where each R^e is independently -H, -Cl, -C_1-3alkyl, -CN, -OCH₃, -OC_1-3haloalkyl, -CO₂H, -CONH₂, -C(R^b)₂CONH₂, -C(R^b)₂OH, -C(R^b)₂CN, -CH₂CH₂N(CH₃)₂, - OCH₂C(R^b)₂OH, -OCH₂CONH₂, -N(R^b)₂, -NHCH₂CF₃, -NHCH(CH₃)₂, -NHCH₂CH₂OH, - NHcyclopropyl, -NHCOCH₃, morpholinyl, pyrrolidin-3-ol, and azetidin-3-ol.

0084In some of these embodiments, Z is N, and R² is <chemistry id="chem0018" num="0018"><img file="EP3345902A1_D0023.tif" /></chemistry> unsubstituted or substituted with R^e1, where R^e1 is -CN, -OCH₃, -CONH₂, -NH₂, -NHCH₃, -NHCH₂CH₂OH, or - NHcyclopropyl.

0085In some of these embodiments, R² is <chemistry id="chem0019" num="0019"><img file="EP3345902A1_D0024.tif" /></chemistry> and R^e is -H, halo, -CH₃, -CN, -OH, - OCH₃, -OCHF₂, -NH₂, -NHCH₃, -N(CH₃)₂, -NHCH₂CF₃, -NHcyclopropyl, -C(CH₃)₂OH, - CONH₂, -CONHCH₃, or -CON(CH₃)₂.

0086Some embodiments are given by compounds of Formula (I) where R² is imidazole, pyrazole, triazole, and tetrazole, unsubstituted or substituted with one or two members each independently selected from the group consisting of: -Cl, -CH₃, -CHF₂, -CF₃, -CH₂OH, - CH₂CN, -CH₂CONH₂, -CH₂CH₂OH, -NH₂, -NO₂, -CN, -CO₂C_1-3alkyl, -CO₂H, -CONH₂, or - NHCOCH₃.

0087In some of these embodiments, R² is <chemistry id="chem0020" num="0020"><img file="EP3345902A1_D0025.tif" /></chemistry> and R^f is -H, -Cl, -CH₃, -NO₂, -NH₂, - NHCOCH₃, -CH₂OH, -CN, -CONH₂, -CO₂H, or -CO₂CH₂CH₃.

0088In some of these embodiments, R² is <chemistry id="chem0021" num="0021"><img file="EP3345902A1_D0026.tif" /></chemistry> and R^f is -H, -NH₂, or -CH₂OH.

0089In some of these embodiments, R² is <chemistry id="chem0022" num="0022"><img file="EP3345902A1_D0027.tif" /></chemistry> where R^g is -H, -CH₃, -CH₂OH, - CONH₂, or -NH₂.

0090Some embodiments are given by compounds of Formula (I) where R² is 1H-tetrazole, 2H-tetrazole, 1,2-oxazole, 1,3-thiazole, each independently unsubstituted or substituted with - CH₃, -CH₂OH, -CH₂CH₂OH or -NH₂.

0091Some embodiments are given by compounds of Formula (I) where R² is 1,2,3-triazole and 1,2,4-triazole, each independently unsubstituted or substituted with -CH₃, -CH₂F, -CHF₂, - CF₃, -OCH₃, -OCH₂CH₃, -CN, -CH₂CN, -CH₂CONH₂, -C(R^b)OH, -CH₂OCH₃, N(R^b)₂, -NO₂, - CO₂CH₃, -CONH₂, cyclopropyl or -CH₂NH₂.

0092In some of these embodiments, R² is <chemistry id="chem0023" num="0023"><img file="EP3345902A1_D0028.tif" /></chemistry> and R^h is -H, -CH₃, -CF₃, -CH₂F, - CHF₂, -OCH₃, -OCH₂CH₃, -CH₂OH, -C(CH₃)₂OH, -CH₂OCH₃, -NO₂, -NH₂, -NHCH₃, - N(CH₃)₂, -CN, -CH₂CN, -CH₂CONH₂, -CONH₂, -CO₂CH₃, or -cyclopropyl.

0093In some of these embodiments, R² is <chemistry id="chem0024" num="0024"><img file="EP3345902A1_D0029.tif" /></chemistry> and R^j is -H, -CH₃, -CF₃, -OCH₃, - CH₂(OH), -C(CH₃)₂OH, -CH₂OCH₃, -CO₂CH₃, or -NO₂.

0094In some of these embodiments, R² is <chemistry id="chem0025" num="0025"><img file="EP3345902A1_D0030.tif" /></chemistry> and R^k is -H, -CH₃, -CF₃, -CH₂F, -CHF₂, -OCH₃, -OCH₂CH₃, -CH₂OH, -C(CH₃)₂OH, -CH₂OCH₃, -NO₂, -NH₂, -NHCH₃, -N(CH₃)₂, -CN, -CONH₂, -CO₂CH₃, or -cyclopropyl.

0095Some embodiments are given by compounds of Formula (I) where R³ is <chemistry id="chem0026" num="0026"><img file="EP3345902A1_D0031.tif" /></chemistry> and R^m is -Cl, -F, -CH₃, -CHF₂, -CN, -OCH₃, -CH₂OH, -OCH₂CH₃, -OCF₃, -OCHF₂, -N(CH₃)₂, -SO₂CH₃, -OCH(CH₃)₂, <chemistry id="chem0027" num="0027"><img file="EP3345902A1_D0032.tif" /></chemistry>

0096In some of these embodiments, R³ is a member selected from the group consisting of: 3-chlorophenyl, 3-cyanophenyl, 3-fluorophenyl, 3-methylphenyl, 3-(trifluoromethyl)phenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3-(trifluoromethoxy)phenyl, 3-(difluoromethoxy)phenyl, 3-(difluoromethyl)phenyl, 3-(dimethylamino)phenyl, 4-fluorophenyl, 4-chlorophenyl, 5-chloropyridin-3-yl, 3,4-difluorophenyl, 3,5-difluorophenyl, (3-fluoro-5-methoxyphenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methoxyphenyl or 3-ethoxy-4-fluorophenyl.

0097Some embodiments are given by compounds of Formula (I) where R³ is <chemistry id="chem0028" num="0028"><img file="EP3345902A1_D0033.tif" /></chemistry> and Rⁿ is H, -Cl, -CH₃, -CF₃, -OCH₃, -OCH₂CH₃, -OCHF₂, -OCF₃, or -CN.

0098Some embodiments are given by compounds of Formula (I) where R⁴ is -CH₃, - CH₂CH₃, -CH(CH₃)₂, or -CHF₂.

0099Further embodiments are provided by pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically active metabolites of compounds of Formula (I).

0100In certain embodiments, a compound, or a pharmaceutically acceptable salt thereof, of Formula (I), is selected from the group consisting of: <tables id="tabl0002" num="0002"><table frame="all"><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="30mm" /><colspec colnum="2" colname="col2" colwidth="136mm" /><thead><row><entry align="center" valign="middle"><b>Ex #</b></entry><entry align="center" valign="middle"><b>Compound Name</b></entry></row></thead><tbody><row><entry align="center" valign="middle">1</entry><entry valign="middle">5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile;</entry></row><row><entry align="center" valign="middle">2</entry><entry valign="middle">2-Chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine;</entry></row><row><entry align="center" valign="middle">3</entry><entry valign="middle">{2-[(5-{[5-(3-Chlorophenyl)-6-methoxypyndin-3-yl]methyl}pyrimidin-2-yl)amino] ethyl} dimethylamine;</entry></row><row><entry align="center" valign="middle">4</entry><entry valign="middle">2-Methoxy-3-(6-methoxypyridm-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">5</entry><entry valign="middle">2-Methoxy-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">6</entry><entry valign="middle">2-Methoxy-3-(5-methylpyridin-3-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">7</entry><entry valign="middle">2-Methoxy-3-(2-methylpyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">8</entry><entry valign="middle">{3-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]phenyl}methanol;</entry></row><row><entry align="center" valign="middle">9</entry><entry valign="middle">3-(3-Methanesulfonylphenyl)-2-methoxy-5-(1 H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">10</entry><entry valign="middle">2-Methoxy-3-(4-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">11</entry><entry valign="middle">2-Methoxy-3-(6-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">12</entry><entry valign="middle">2-(Difluoromethoxy)-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">13</entry><entry valign="middle">5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">14</entry><entry valign="middle">[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol;</entry></row><row><entry align="center" valign="middle">15</entry><entry valign="middle">1-[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]-1-(4-fluorophenyl)ethan-1-ol;</entry></row><row><entry align="center" valign="middle">16</entry><entry valign="middle">[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](5-fluoropyridin-2-yl)methanol;</entry></row><row><entry align="center" valign="middle">17</entry><entry valign="middle">{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl} (methyl)amine;</entry></row><row><entry align="center" valign="middle">18</entry><entry valign="middle">[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanamine;</entry></row><row><entry align="center" valign="middle">19</entry><entry valign="middle">{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl} dimethylamine;</entry></row><row><entry align="center" valign="middle">20</entry><entry valign="middle">3-(3-Chlorophenyl)-5-[fluoro(4-fluorophenyl)methyl]-2-methoxypyridine;</entry></row><row><entry align="center" valign="middle">21</entry><entry valign="middle">4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzoic acid;</entry></row><row><entry align="center" valign="middle">22</entry><entry valign="middle">5-{[6-(3-Chlorophenyl)-5- methoxypyrazin-2- yl]methyl} pyrimidine-2-carbonitrile;</entry></row><row><entry align="center" valign="middle">23</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxylic acid;</entry></row><row><entry align="center" valign="middle">24</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">25</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">26</entry><entry valign="middle">(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)urea;</entry></row><row><entry align="center" valign="middle">27</entry><entry valign="middle">4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzamide;</entry></row><row><entry align="center" valign="middle">28</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-pyrazol-4-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">29</entry><entry valign="middle">5-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">30</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine;</entry></row><row><entry align="center" valign="middle">31</entry><entry valign="middle">1-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)-3-(oxetan-3-yl)urea;</entry></row><row><entry align="center" valign="middle">32</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxypyridin-3-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">33</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-amine;</entry></row><row><entry align="center" valign="middle">34</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyridin-2-amine;</entry></row><row><entry align="center" valign="middle">35</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carbonitrile;</entry></row><row><entry align="center" valign="middle">36</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1,3-thiazol-2-amine;</entry></row><row><entry align="center" valign="middle">37</entry><entry valign="middle">(2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanol;</entry></row><row><entry align="center" valign="middle">38</entry><entry valign="middle">5-([5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">39</entry><entry valign="middle">5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carbonitrile;</entry></row><row><entry align="center" valign="middle">40</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">41</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-(propan-2-yloxy)pyridin-3-yl]methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">42</entry><entry valign="middle">5-{[6-(Difluoromethoxy)-5-[3-(propan-2-yloxy)phenyl]pyridin-3-yl] methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">43</entry><entry valign="middle">5-{[6-(Difluoromethoxy)-5-[3-(oxetan-3-yloxy)phenyl]pyridin-3-yl] methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">44</entry><entry valign="middle">N-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide;</entry></row><row><entry align="center" valign="middle">45</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methanesulfonylphenyl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">46</entry><entry valign="middle">5-{[6-(Difluoromethoxy)-5-(2-methoxypyridin-4-yl)pyridin-3-yl] methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">47</entry><entry valign="middle">5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">48</entry><entry valign="middle">2-[5-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-yl]propan-2-ol;</entry></row><row><entry align="center" valign="middle">49</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyridine;</entry></row><row><entry align="center" valign="middle">50</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{ [6-(propan-2-yloxy)pyridin-3-yl]methyl}pyridine;</entry></row><row><entry align="center" valign="middle">51</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-propoxypyridin-3-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">52</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1-methyl-1,2-dihydropyridin-2-one;</entry></row><row><entry align="center" valign="middle">53</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-(pyridin-4-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">54</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxylic acid;</entry></row><row><entry align="center" valign="middle">55</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-[(2-methoxypyrimidin-5-yl)methyl]pyrazine;</entry></row><row><entry align="center" valign="middle">56</entry><entry valign="middle">5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-methylpyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">57</entry><entry valign="middle">5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-cyclopropylpyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">58</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyrazine;</entry></row><row><entry align="center" valign="middle">59</entry><entry valign="middle">(4- {[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanamine;</entry></row><row><entry align="center" valign="middle">60</entry><entry valign="middle">4-5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine;</entry></row><row><entry align="center" valign="middle">61</entry><entry valign="middle">3-(3-Chlorophenyl)-5-[(2,6-dimethylpyridin-4-yl)methyl]-2-methoxypyridine;</entry></row><row><entry align="center" valign="middle">62</entry><entry valign="middle">4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carbonitrile;</entry></row><row><entry align="center" valign="middle">63</entry><entry valign="middle">4-{[5-(3-chlorophenyl)-6- methoxypyridin-3- yl]methyl} pyridine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">64</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-(pyridin-3-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">65</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-(1,3-thiazol-5-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">66</entry><entry valign="middle">3-(3-Chlorophenyl)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]-2-methoxypyridine;</entry></row><row><entry align="center" valign="middle">67</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxy-5-methylpyridin-3-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">68</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-5-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">69</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">70</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-3-carboxamide;</entry></row><row><entry align="center" valign="middle">71</entry><entry valign="middle">(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-3-yl)methanamine;</entry></row><row><entry align="center" valign="middle">72</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-methylpyridin-3-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">73</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(2-methyl-1,3-thiazol-5-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">74</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-2-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">75</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methylpyrimidine;</entry></row><row><entry align="center" valign="middle">76</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-methoxypyridm-3-yl]methyl}-2-methoxypyrimidine;</entry></row><row><entry align="center" valign="middle">77</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(propan-2-yl)pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">78</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine;</entry></row><row><entry align="center" valign="middle">79</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">80</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-4-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">81</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-methoxypyridm-3-yl]methyl}-N-methylpyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">82</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-cyclopropylpyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">83</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">84</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">85</entry><entry valign="middle">Methyl4-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl] methyl} benzoate;</entry></row><row><entry align="center" valign="middle">86</entry><entry valign="middle">4-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzonitrile;</entry></row><row><entry align="center" valign="middle">87</entry><entry valign="middle">5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">88</entry><entry valign="middle">3-(3-Chlorophenyl)-5-[(4-fluorophenyl)methyl]-2-methoxypyridine;</entry></row><row><entry align="center" valign="middle">89</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">90</entry><entry valign="middle">5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyridine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">91</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-cyclopropylpyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">92</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-2-methoxypyrimidine;</entry></row><row><entry align="center" valign="middle">93</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methylpyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">94</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">95</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-(1,2-oxazol-4-ylmethyl)pyrazine;</entry></row><row><entry align="center" valign="middle">96</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-(1,2-oxazol-4-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">97</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,2-oxazol-4-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">98</entry><entry valign="middle">3-(3-Chlorophenyl)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]-2-methoxypyrazine;</entry></row><row><entry align="center" valign="middle">99</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">100</entry><entry valign="middle">Methyl 2-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetate;</entry></row><row><entry align="center" valign="middle">101</entry><entry valign="middle">Ethyl 1-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxylate;</entry></row><row><entry align="center" valign="middle">102</entry><entry valign="middle">3-(3-Chlorophenyl)-5-{[6-(cyclopropylmethoxy)pyridin-3-yl]methyl}-2-(difluoromethoxy)pyridine;</entry></row><row><entry align="center" valign="middle">103</entry><entry valign="middle">5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carbonitrile;</entry></row><row><entry align="center" valign="middle">104</entry><entry valign="middle">5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">105</entry><entry valign="middle">5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">106</entry><entry valign="middle">5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl} methyl)pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">107</entry><entry valign="middle">5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile;</entry></row><row><entry align="center" valign="middle">108</entry><entry valign="middle">5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2- yl]methyl} pyrimidine-2-carbonitrile;</entry></row><row><entry align="center" valign="middle">109</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(pyridin-2-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">110</entry><entry valign="middle">2-{ [5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrazine;</entry></row><row><entry align="center" valign="middle">111</entry><entry valign="middle">6-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridazin-3-amine;</entry></row><row><entry align="center" valign="middle">112</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-6-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">113</entry><entry valign="middle">4-{ [6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl} benzamide;</entry></row><row><entry align="center" valign="middle">114</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">115</entry><entry valign="middle">5-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">116</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">117</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">118</entry><entry valign="middle">5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">119</entry><entry valign="middle">5-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">120</entry><entry valign="middle">5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">121</entry><entry valign="middle">5-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">122</entry><entry valign="middle">5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">123</entry><entry valign="middle">5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">124</entry><entry valign="middle">5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">125</entry><entry valign="middle">5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl} methyl)pyrimidine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">126</entry><entry valign="middle">5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">127</entry><entry valign="middle">Methyl 1-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate;</entry></row><row><entry align="center" valign="middle">128</entry><entry valign="middle">3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-(difluoromethoxy)pyridine;</entry></row><row><entry align="center" valign="middle">129</entry><entry valign="middle">3-(3-Fluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">130</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyrazine;</entry></row><row><entry align="center" valign="middle">131</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">132</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyrazine;</entry></row><row><entry align="center" valign="middle">133</entry><entry valign="middle">3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyrazine;</entry></row><row><entry align="center" valign="middle">134</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">135</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(propan-2-yloxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">136</entry><entry valign="middle">3-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]benzonitrile;</entry></row><row><entry align="center" valign="middle">137</entry><entry valign="middle">2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine;</entry></row><row><entry align="center" valign="middle">138</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-4H-1,2,4-triazol-4-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">139</entry><entry valign="middle">3-(3,5-Difluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">140</entry><entry valign="middle">Methyl 1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-5-carboxylate;</entry></row><row><entry align="center" valign="middle">141</entry><entry valign="middle">Methyl 1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carboxylate;</entry></row><row><entry align="center" valign="middle">142</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">143</entry><entry valign="middle">3-[3-(Difluoromethyl)phenyl]-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">144</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyridme;</entry></row><row><entry align="center" valign="middle">145</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1 -yl]methyl}pyridine;</entry></row><row><entry align="center" valign="middle">146</entry><entry valign="middle">3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridine;</entry></row><row><entry align="center" valign="middle">147</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">148</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-{[4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}pyridine;</entry></row><row><entry align="center" valign="middle">149</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[1-(1H-1,2,4-triazol-1-yl)ethyl]pyridine;</entry></row><row><entry align="center" valign="middle">150</entry><entry valign="middle">3-(3-Fluorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">151</entry><entry valign="middle">3-(3-Chlorophenyl)-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</entry></row><row><entry align="center" valign="middle">152</entry><entry valign="middle">3-(3-Chlorophenyl)-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</entry></row><row><entry align="center" valign="middle">153</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methyl-1H-imidazol-1-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">154</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1 -yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">155</entry><entry valign="middle">1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carbonitrile;</entry></row><row><entry align="center" valign="middle">156</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</entry></row><row><entry align="center" valign="middle">157</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</entry></row><row><entry align="center" valign="middle">158</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</entry></row><row><entry align="center" valign="middle">159</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</entry></row><row><entry align="center" valign="middle">160</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,3,4-tetrazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">161</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(2H-1,2,3,4-tetrazol-2-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">162</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</entry></row><row><entry align="center" valign="middle">163</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</entry></row><row><entry align="center" valign="middle">164</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</entry></row><row><entry align="center" valign="middle">165</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</entry></row><row><entry align="center" valign="middle">166</entry><entry valign="middle">5-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-methoxypyridine;</entry></row><row><entry align="center" valign="middle">167</entry><entry valign="middle">1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide;</entry></row><row><entry align="center" valign="middle">168</entry><entry valign="middle">Ethyl 1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylate;</entry></row><row><entry align="center" valign="middle">169</entry><entry valign="middle">1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carbonitrile;</entry></row><row><entry align="center" valign="middle">170</entry><entry valign="middle">2-Methoxy-3-(pyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">171</entry><entry valign="middle">N-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)acetamide;</entry></row><row><entry align="center" valign="middle">172</entry><entry valign="middle">3-(3-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyridine;</entry></row><row><entry align="center" valign="middle">173</entry><entry valign="middle">2-(Difluoromethoxy)-3-(3-fluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">174</entry><entry valign="middle">2-(Difluoromethoxy)-3-(3-methoxyphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">175</entry><entry valign="middle">2-(Difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine;</entry></row><row><entry align="center" valign="middle">176</entry><entry valign="middle">1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1,2-dihydropyridin-2-one;</entry></row><row><entry align="center" valign="middle">177</entry><entry valign="middle">5-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-(3-chlorophenyl)-2-methoxypyridine;</entry></row><row><entry align="center" valign="middle">178</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">179</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-[(4-nitro-1H-pyrazol-1-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">180</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-[(4-nitro-1H-pyrazol-1-yl)methyl]pyrazine;</entry></row><row><entry align="center" valign="middle">181</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyrazine;</entry></row><row><entry align="center" valign="middle">182</entry><entry valign="middle">3-(3-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyrazine;</entry></row><row><entry align="center" valign="middle">183</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyrazine;</entry></row><row><entry align="center" valign="middle">184</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyrazine;</entry></row><row><entry align="center" valign="middle">185</entry><entry valign="middle">5-[(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-ethoxypyrazine;</entry></row><row><entry align="center" valign="middle">186</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-methyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine;</entry></row><row><entry align="center" valign="middle">187</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1 -yl]methyl}pyrazine;</entry></row><row><entry align="center" valign="middle">188</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine;</entry></row><row><entry align="center" valign="middle">189</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine;</entry></row><row><entry align="center" valign="middle">190</entry><entry valign="middle">Methyl 1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate;</entry></row><row><entry align="center" valign="middle">191</entry><entry valign="middle">Methyl 1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-5-carboxylate;</entry></row><row><entry align="center" valign="middle">192</entry><entry valign="middle">3-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine;</entry></row><row><entry align="center" valign="middle">193</entry><entry valign="middle">3-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((5-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine;</entry></row><row><entry align="center" valign="middle">194</entry><entry valign="middle">Methyl 1-{ [6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-5-carboxylate;</entry></row><row><entry align="center" valign="middle">195</entry><entry valign="middle">Methyl 1-({6-[3-(difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,4-triazole-3-carboxylate;</entry></row><row><entry align="center" valign="middle">196</entry><entry valign="middle">Methyl 1-{[6-(3-chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate;</entry></row><row><entry align="center" valign="middle">197</entry><entry valign="middle">1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazole-4-carboxamide;</entry></row><row><entry align="center" valign="middle">198</entry><entry valign="middle">(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">199</entry><entry valign="middle">(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">200</entry><entry valign="middle">[1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;</entry></row><row><entry align="center" valign="middle">201</entry><entry valign="middle">[1-( {5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl} methyl)-1H-1,2,4-triazol-3-yl]methanol;</entry></row><row><entry align="center" valign="middle">202</entry><entry valign="middle">(1-((5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">203</entry><entry valign="middle">(1-{[6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">204</entry><entry valign="middle">[1-( {5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;</entry></row><row><entry align="center" valign="middle">205</entry><entry valign="middle">[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;</entry></row><row><entry align="center" valign="middle">206</entry><entry valign="middle">(1-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">207</entry><entry valign="middle">[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;</entry></row><row><entry align="center" valign="middle">208</entry><entry valign="middle">[1-( {6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl} methyl)-1H-1,2,4-triazol-5-yl]methanol;</entry></row><row><entry align="center" valign="middle">209</entry><entry valign="middle">(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-5-yl)methanol;</entry></row><row><entry align="center" valign="middle">210</entry><entry valign="middle">[1-( {6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl} methyl)-1H-1,2,4-triazol-3-yl]methanol;</entry></row><row><entry align="center" valign="middle">211</entry><entry valign="middle">(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">212</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">213</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methoxy-1H-1,2,4-triazol-1 -yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">214</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(5-methoxy-1H-1,2,4-triazol-1 -yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">215</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-ethoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">216</entry><entry valign="middle">1-( {5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl} methyl)-1H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">217</entry><entry valign="middle">1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">218</entry><entry valign="middle">1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">219</entry><entry valign="middle">1-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">220</entry><entry valign="middle">1-{[6-Methoxy-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">221</entry><entry valign="middle">1-{[6-Methoxy-5-(3-methylphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">222</entry><entry valign="middle">3-{5-[(3-Amino-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridin-3-yl}benzonitrile;</entry></row><row><entry align="center" valign="middle">223</entry><entry valign="middle">1-{[5-(3-Ethoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">224</entry><entry valign="middle">1-{[5-(3-Cyclopropoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">225</entry><entry valign="middle">1-( {5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl} methyl)- 1H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">226</entry><entry valign="middle">1-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">227</entry><entry valign="middle">1-{[5-(5-Chloropyridin-3-yl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">228</entry><entry valign="middle">1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">229</entry><entry valign="middle">1-( {5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl} methyl)-1H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">230</entry><entry valign="middle">1-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl} -1 H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">231</entry><entry valign="middle">1-( {5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl} methyl)-1H-pyrazol-3-amine;</entry></row><row><entry align="center" valign="middle">232</entry><entry valign="middle">1-( {5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl} methyl)-1H-pyrazol-5-amine;</entry></row><row><entry align="center" valign="middle">233</entry><entry valign="middle">4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-amine;</entry></row><row><entry align="center" valign="middle">234</entry><entry valign="middle">4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-amine;</entry></row><row><entry align="center" valign="middle">235</entry><entry valign="middle">1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-pyrazol-4-amine;</entry></row><row><entry align="center" valign="middle">236</entry><entry valign="middle">1-((6-(3-(Difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">237</entry><entry valign="middle">1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methyl-1H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">238</entry><entry valign="middle">1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N,N-dimethyl-1H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">239</entry><entry valign="middle">(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanamine;</entry></row><row><entry align="center" valign="middle">240</entry><entry valign="middle">1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carboxamide;</entry></row><row><entry align="center" valign="middle">241</entry><entry valign="middle">4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(oxetan-3-yl)benzamide;</entry></row><row><entry align="center" valign="middle">242</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methylpyridine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">243</entry><entry valign="middle">1-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxamide;</entry></row><row><entry align="center" valign="middle">244</entry><entry valign="middle">2-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetamide;</entry></row><row><entry align="center" valign="middle">245</entry><entry valign="middle">2-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)propan-2-ol;</entry></row><row><entry align="center" valign="middle">246</entry><entry valign="middle">2-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-5-yl)propan-2-ol;</entry></row><row><entry align="center" valign="middle">247</entry><entry valign="middle">2-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)propan-2-ol;</entry></row><row><entry align="center" valign="middle">248</entry><entry valign="middle">2-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol;</entry></row><row><entry align="center" valign="middle">249</entry><entry valign="middle">2-(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol;</entry></row><row><entry align="center" valign="middle">250</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine;</entry></row><row><entry align="center" valign="middle">251</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}pyridine;</entry></row><row><entry align="center" valign="middle">252</entry><entry valign="middle">2-(Difluoromethoxy)-3-(3-ethoxyphenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</entry></row><row><entry align="center" valign="middle">253</entry><entry valign="middle">3-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1 -yl]methyl} -2-methoxypyridine;</entry></row><row><entry align="center" valign="middle">254</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine;</entry></row><row><entry align="center" valign="middle">255</entry><entry valign="middle">3-(3-Chlorophenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyrazine;</entry></row><row><entry align="center" valign="middle">256</entry><entry valign="middle">3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</entry></row><row><entry align="center" valign="middle">257</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1 -yl]methyl} -2-ethoxypyridine;</entry></row><row><entry align="center" valign="middle">258</entry><entry valign="middle">3-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine;</entry></row><row><entry align="center" valign="middle">259</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,3-triazol-1-ylmethyl)pyridine;</entry></row><row><entry align="center" valign="middle">260</entry><entry valign="middle">[1-( {5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl} methyl)-1H-1,2,3-triazol-4-yl]methanol;</entry></row><row><entry align="center" valign="middle">261</entry><entry valign="middle">(1-((6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol;</entry></row><row><entry align="center" valign="middle">262</entry><entry valign="middle">[1-( {6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl} methyl)-1H-1,2,3-triazol-4-yl]methanol;</entry></row><row><entry align="center" valign="middle">263</entry><entry valign="middle">(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methanol;</entry></row><row><entry align="center" valign="middle">264</entry><entry valign="middle">[1-( {6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl} methyl)-1H-1,2,3-triazol-4-yl]methanol;</entry></row><row><entry align="center" valign="middle">265</entry><entry valign="middle">(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methanol;</entry></row><row><entry align="center" valign="middle">266</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-5-{[4-(difluoromethyl)-1H-1,2,3-triazol-1 -yl]methyl} -2-ethoxypyridine;</entry></row><row><entry align="center" valign="middle">267</entry><entry valign="middle">1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylic acid;</entry></row><row><entry align="center" valign="middle">268</entry><entry valign="middle">1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxamide;</entry></row><row><entry align="center" valign="middle">269</entry><entry valign="middle">[1-( {5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl} methyl)-1 H-pyrazol-4-yl]methanol;</entry></row><row><entry align="center" valign="middle">270</entry><entry valign="middle">(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-5-yl)methanol;</entry></row><row><entry align="center" valign="middle">271</entry><entry valign="middle">(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-4-yl)methanol;</entry></row><row><entry align="center" valign="middle">272</entry><entry valign="middle">[1-( {5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl} methyl)-1 H-pyrazol-3-yl]methanol;</entry></row><row><entry align="center" valign="middle">273</entry><entry valign="middle">(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)methanol;</entry></row><row><entry align="center" valign="middle">274</entry><entry valign="middle">(4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-yl)methano 1;</entry></row><row><entry align="center" valign="middle">275</entry><entry valign="middle">(4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-yl)methano 1;</entry></row><row><entry align="center" valign="middle">276</entry><entry valign="middle">4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}benzoic acid;</entry></row><row><entry align="center" valign="middle">277</entry><entry valign="middle">(1-((6-Ethoxy-5-(2-fluorophenyl)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">278</entry><entry valign="middle">5-((5-(3,4-Difluorophenyl)-6-propoxypyridin-3-yl)methyl)pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">279</entry><entry valign="middle">5-((5-(3-Chloro-4-fluorophenyl)-6-ethoxypyridin-3-yl)methyl)pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">280</entry><entry valign="middle">2-(4-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)acetamide;</entry></row><row><entry align="center" valign="middle">281</entry><entry valign="middle">2-(5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide;</entry></row><row><entry align="center" valign="middle">282</entry><entry valign="middle">5-{[5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">283</entry><entry valign="middle">2-[(5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-ol;</entry></row><row><entry align="center" valign="middle">284</entry><entry valign="middle">2-(5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)-2-methylpropanenitrile;</entry></row><row><entry align="center" valign="middle">285</entry><entry valign="middle">2-(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)acetonitrile;</entry></row><row><entry align="center" valign="middle">286</entry><entry valign="middle">3-(3-Chlorophenyl)-5-[(5-ethoxypyridin-2-yl)methyl]-2-methoxypyridine;</entry></row><row><entry align="center" valign="middle">287</entry><entry valign="middle">5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-amine;</entry></row><row><entry align="center" valign="middle">288</entry><entry valign="middle">5-((5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-amine;</entry></row><row><entry align="center" valign="middle">289</entry><entry valign="middle">2-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-5-ethoxypyrazine;</entry></row><row><entry align="center" valign="middle">290</entry><entry valign="middle">2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-yl)amino) ethanol;</entry></row><row><entry align="center" valign="middle">291</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-((5-methyl-1<i>H</i>-tetrazol-1-yl)methylpyridine;</entry></row><row><entry align="center" valign="middle">292</entry><entry valign="middle">4-(5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)pyrimidin-2-yl)morpholine;</entry></row><row><entry align="center" valign="middle">293</entry><entry valign="middle">5-((6-(3,4-difluorophenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">294</entry><entry valign="middle">2-((5-((6-(3,4-difluorophenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidin-2-yl)amino)ethanol;</entry></row><row><entry align="center" valign="middle">295</entry><entry valign="middle">2-(1-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-tetrazol-5-yl)ethanol;</entry></row><row><entry align="center" valign="middle">296</entry><entry valign="middle">2-Ethoxy-3-(4-fluorophenyl)-5-((5-methyl-1H-tetrazol-1-yl)methyl)pyridine;</entry></row><row><entry align="center" valign="middle">297</entry><entry valign="middle">2'-(Difluoromethoxy)-5-((4-(difluoromethyl)-2-methyl-1H-imidazol-1-yl)methyl)-2-methoxy-3,4'-bipyridine;</entry></row><row><entry align="center" valign="middle">298</entry><entry valign="middle">2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)acetamide;</entry></row><row><entry align="center" valign="middle">299</entry><entry valign="middle">(5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)methanol;</entry></row><row><entry align="center" valign="middle">300</entry><entry valign="middle">(1-((5-(3-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">301</entry><entry valign="middle">5-((2'-(Difluoromethoxy)-2-methoxy-[3,4'-bipyridin]-5-yl)methyl)-3-fluoropyridin-2-amine;</entry></row><row><entry align="center" valign="middle">302</entry><entry valign="middle">5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-ol;</entry></row><row><entry align="center" valign="middle">303</entry><entry valign="middle">2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)ethanol;</entry></row><row><entry align="center" valign="middle">304</entry><entry valign="middle">5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-2-(difluoromethoxy)pyrimidine;</entry></row><row><entry align="center" valign="middle">305</entry><entry valign="middle">5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-3-methylpyridazine;</entry></row><row><entry align="center" valign="middle">306</entry><entry valign="middle">3-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-fluoropyridin-3-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">307</entry><entry valign="middle">1-{[5-(2-Cyanopyridin-4-yl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide;</entry></row><row><entry align="center" valign="middle">308</entry><entry valign="middle">1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide;</entry></row><row><entry align="center" valign="middle">309</entry><entry valign="middle">1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazole-3-carboxamide;</entry></row><row><entry align="center" valign="middle">310</entry><entry valign="middle">1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-imidazole-4-carboxamide;</entry></row><row><entry align="center" valign="middle">311</entry><entry valign="middle">1-( {5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl} methyl)-1H-imidazole-4-carboxamide;</entry></row><row><entry align="center" valign="middle">312</entry><entry valign="middle">1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-imidazole-4-carboxamide;</entry></row><row><entry align="center" valign="middle">313</entry><entry valign="middle">1-{[6-(3-Chlorophenyl)-5-ethoxypyrazm-2-yl]methyl}-1H-pyrazole-3-carboxamide;</entry></row><row><entry align="center" valign="middle">314</entry><entry valign="middle">1-{[6-(3,4-Difluorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-imidazole-4-carboxamide;</entry></row><row><entry align="center" valign="middle">315</entry><entry valign="middle">[1-( {5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-2-methyl-1H-imidazo l-4-yl] methanol;</entry></row><row><entry align="center" valign="middle">316</entry><entry valign="middle">[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-5-methyl-1H-pyrazol-3-yl]methanol;</entry></row><row><entry align="center" valign="middle">317</entry><entry valign="middle">1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-5-methyl-1H-pyrazol-3-amine;</entry></row><row><entry align="center" valign="middle">318</entry><entry valign="middle">1-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)oxy]-2-methylpropan-2-ol;</entry></row><row><entry align="center" valign="middle">319</entry><entry valign="middle">(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-5-yl)methanol;</entry></row><row><entry align="center" valign="middle">320</entry><entry valign="middle">(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-3-methyl-1H-pyrazol-5-yl)methanol;</entry></row><row><entry align="center" valign="middle">321</entry><entry valign="middle">(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</entry></row><row><entry align="center" valign="middle">322</entry><entry valign="middle">(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</entry></row><row><entry align="center" valign="middle">323</entry><entry valign="middle">(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl] methyl}-5-methyl-1H-pyrazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">324</entry><entry valign="middle">(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</entry></row><row><entry align="center" valign="middle">325</entry><entry valign="middle">(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-5-methyl-1H-pyrazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">326</entry><entry valign="middle">(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</entry></row><row><entry align="center" valign="middle">327</entry><entry valign="middle">(1-{[6-Ethoxy-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">328</entry><entry valign="middle">(1-{[5-(4-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">329</entry><entry valign="middle">(1-{[5-(5-Chloropyridin-3-yl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">330</entry><entry valign="middle">(1-{[5-(3,4-Dichlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">331</entry><entry valign="middle">(1-{[6-Ethoxy-5-(4-fluoro-3-methylphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">332</entry><entry valign="middle">[1-( {6-Ethoxy-5-[3-(trifluoromethyl)phenyl]pyridin-3-yl} methyl)-1H-1,2,4-triazol-3-yl]methanol;</entry></row><row><entry align="center" valign="middle">333</entry><entry valign="middle">[1-( {6-Ethoxy-5-[3-(trifluoromethoxy)phenyl]pyridin-3-yl} methyl)-1H-1,2,4-triazol-3-yl]methanol;</entry></row><row><entry align="center" valign="middle">334</entry><entry valign="middle">(1-{[6-Ethoxy-5-(3-ethoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">335</entry><entry valign="middle">[1-({5-[3-(Dimethylamino)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;</entry></row><row><entry align="center" valign="middle">336</entry><entry valign="middle">(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">337</entry><entry valign="middle">(1-{[5-(3-Chloro-4-fluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">338</entry><entry valign="middle">(1-{[5-(3,5-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">339</entry><entry valign="middle">[1-( {6-Ethoxy-5-[2-(trifluoromethyl)pyridin-4-yl]pyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;</entry></row><row><entry align="center" valign="middle">340</entry><entry valign="middle">(1-{[5-(3,4-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">341</entry><entry valign="middle">(1-{[6-Ethoxy-5-(3-fluorophenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">342</entry><entry valign="middle">(1-{[6-Ethoxy-5-(4-fluorophenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</entry></row><row><entry align="center" valign="middle">343</entry><entry valign="middle">(1-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</entry></row><row><entry align="center" valign="middle">344</entry><entry valign="middle">(1-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</entry></row><row><entry align="center" valign="middle">345</entry><entry valign="middle">(1-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</entry></row><row><entry align="center" valign="middle">346</entry><entry valign="middle">(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</entry></row><row><entry align="center" valign="middle">347</entry><entry valign="middle">4-{5-[(2-Aminopyrimidin-5-yl)methyl]-2-methoxypyridin-3-yl}pyridine-2-carbonitrile;</entry></row><row><entry align="center" valign="middle">348</entry><entry valign="middle">2-(5-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetonitrile;</entry></row><row><entry align="center" valign="middle">349</entry><entry valign="middle">5-{[5-(2-Ethoxypyridin-4-yl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">350</entry><entry valign="middle">5-6-Ethoxy-5-(4-fluorophenyl)pyridin-3-yl]methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">351</entry><entry valign="middle">5-{ [5-(4-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">352</entry><entry valign="middle">5-{[6-Ethoxy-5-(4-fluoro-3-methylphenyl)pyridin-3-yl] methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">353</entry><entry valign="middle">5-{[5-(3,4-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">354</entry><entry valign="middle">5- {[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl] methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">355</entry><entry valign="middle">5-{[5-(3-Ethoxy-4-fluorophenyl)-6-methoxypyridin-3-yl] methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">356</entry><entry valign="middle">3-{5-[(2-Aminopyrimidin-5-yl)methyl]-2-methoxypyridin-3-yl} benzonitrile;</entry></row><row><entry align="center" valign="middle">357</entry><entry valign="middle">5-{[5-(4-Fluoro-3-methylphenyl)-6-methoxypyridin-3-yl] methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">358</entry><entry valign="middle">2-(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetonitrile;</entry></row><row><entry align="center" valign="middle">359</entry><entry valign="middle">5-{[5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl] methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">360</entry><entry valign="middle">5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">361</entry><entry valign="middle">5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">362</entry><entry valign="middle">5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;</entry></row><row><entry align="center" valign="middle">363</entry><entry valign="middle">2-(4-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide;</entry></row><row><entry align="center" valign="middle">364</entry><entry valign="middle">2-(4- {[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide;</entry></row><row><entry align="center" valign="middle">365</entry><entry valign="middle">2-(4-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide;</entry></row><row><entry align="center" valign="middle">366</entry><entry valign="middle">2-(5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide;</entry></row><row><entry align="center" valign="middle">367</entry><entry valign="middle">2-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)-2-methylpropanamide;</entry></row><row><entry align="center" valign="middle">368</entry><entry valign="middle">2-(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide;</entry></row><row><entry align="center" valign="middle">369</entry><entry valign="middle">2-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide;</entry></row><row><entry align="center" valign="middle">370</entry><entry valign="middle">2-(5-{ [5-(3-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetamide;</entry></row><row><entry align="center" valign="middle">371</entry><entry valign="middle">2-(5-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetamide;</entry></row><row><entry align="center" valign="middle">372</entry><entry valign="middle">2-(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)acetamide;</entry></row><row><entry align="center" valign="middle">373</entry><entry valign="middle">5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">374</entry><entry valign="middle">5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide;</entry></row><row><entry align="center" valign="middle">375</entry><entry valign="middle">2-[(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-ol;</entry></row><row><entry align="center" valign="middle">376</entry><entry valign="middle">(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrazin-2-yl)methanol;</entry></row><row><entry align="center" valign="middle">377</entry><entry valign="middle">2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-5-methylpyrazine;</entry></row><row><entry align="center" valign="middle">378</entry><entry valign="middle">6-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-3-carbonitrile;</entry></row><row><entry align="center" valign="middle">379</entry><entry valign="middle">5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrazin-2-amine;</entry></row><row><entry align="center" valign="middle">380</entry><entry valign="middle">3-(3-Chlorophenyl)-2-methoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">381</entry><entry valign="middle">(2-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol;</entry></row><row><entry align="center" valign="middle">382</entry><entry valign="middle">(1-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5 -yl)methano 1;</entry></row><row><entry align="center" valign="middle">383</entry><entry valign="middle">(2-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol;</entry></row><row><entry align="center" valign="middle">384</entry><entry valign="middle">(1-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol;</entry></row><row><entry align="center" valign="middle">385</entry><entry valign="middle">(2-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol;</entry></row><row><entry align="center" valign="middle">386</entry><entry valign="middle">(1-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol;</entry></row><row><entry align="center" valign="middle">387</entry><entry valign="middle">(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol;</entry></row><row><entry align="center" valign="middle">388</entry><entry valign="middle">(2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol;</entry></row><row><entry align="center" valign="middle">389</entry><entry valign="middle">1-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)pyrrolidin-3-ol;</entry></row><row><entry align="center" valign="middle">390</entry><entry valign="middle">1-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)azetidin-3-ol;</entry></row><row><entry align="center" valign="middle">391</entry><entry valign="middle">2-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-ol;</entry></row><row><entry align="center" valign="middle">392</entry><entry valign="middle">2-Ethoxy-3-(4-fluorophenyl)-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">393</entry><entry valign="middle">3-(3,4-Difluorophenyl)-2-ethoxy-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">394</entry><entry valign="middle">3-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">395</entry><entry valign="middle">3-(3,4-Difluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">396</entry><entry valign="middle">3-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">397</entry><entry valign="middle">3-(4-Chloro-3-fluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">398</entry><entry valign="middle">3-(3-Chloro-4-fluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">399</entry><entry valign="middle">3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">400</entry><entry valign="middle">2-Ethoxy-3-(2-ethoxypyridin-4-yl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">401</entry><entry valign="middle">2-Ethoxy-3-(3-ethoxyphenyl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">402</entry><entry valign="middle">2-Ethoxy-3-(3-fluoro-5-methoxyphenyl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</entry></row><row><entry align="center" valign="middle">403</entry><entry valign="middle">3-(3-Chlorophenyl)-5-{[4-(difluoromethyl)-2-methyl-1H-imidazol-1-yl]methyl}-2-ethoxypyrazine;</entry></row><row><entry align="center" valign="middle">404</entry><entry valign="middle">(5-{[6-(2,2-Difluoroethoxy)-5-(2-ethoxypyridin-4-yl)pyridin-3-yl]methyl}-3-fluoropyridin-2-yl)methanol;</entry></row><row><entry align="center" valign="middle">405</entry><entry valign="middle">[5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-3-fluoropyridin-2-yl]methanol;</entry></row><row><entry align="center" valign="middle">406</entry><entry valign="middle">(1-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</entry></row><row><entry align="center" valign="middle">407</entry><entry valign="middle">1-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</entry></row><row><entry align="center" valign="middle">Intermediate 49</entry><entry valign="middle">Ethyl 2-(4-{[5-(3,4-difluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetate;</entry></row><row><entry align="center" valign="middle">Intermediate 50</entry><entry valign="middle">Ethyl 2-(4-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetate; and</entry></row></tbody></tgroup></table></tables>

Isotopically-Labeled Compounds

0101The invention also includes isotopically-labeled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of carbon, chlorine, fluorine, hydrogen, iodine, nitrogen, oxygen, phosphorous, sulfur, and technetium including ¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ²H, ³H, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, and ^99mTc.

0102Compounds of the present invention (and derivatives of such compounds, such as pharmaceutically acceptable salts and prodrugs) that contain the aforementioned isotopes or other isotopes of other atoms are within the scope of the invention. Isotopically-labeled compounds of the present invention are useful in drug and substrate tissue distribution and target occupancy assays. For example, isotopically labeled compounds are particularly useful in SPECT (single photon emission computed tomography) and in PET (positron emission tomography), as discussed further herein.

Derivatives

0103The present invention also provides derivatives of a chemical entity of Formula (I), which include, but are not limited to, any salt, solvate, conformer, or crystalline form/polymorph.

Salts

0104Accordingly, in one embodiment the invention includes pharmaceutically acceptable salts of the compounds represented by Formula (I), and methods using such salts.

0105Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, borate, nitrate, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, besylate, mesylate and mandelates.

0106When the compound of Formula (I) contains a basic nitrogen, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid, glutaric acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

0107When the compound of Formula (I) is an acid, such as a carboxylic acid or sulfonic acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology. Illustrative examples of suitable salts include organic salts derived from amino acids, such as N-methyl-O-glucamine, lysine, choline, glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as tromethamine, benzylamines, pyrrolidines, piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

Solvates

0108In other embodiments, the invention provides a solvate of a compound of Formula (I), and the use of such solvates in methods of present invention. Certain compounds of Formula (I) or pharmaceutically acceptable salts of compounds of Formula (I) may be obtained as solvates. In some embodiments, the solvent is water and the solvates are hydrates.

0109More particularly, solvates include those formed from the interaction or complexes of compounds of the invention with one or more solvents, either in solution or as a solid or crystalline form. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, <i>e.g</i>., water, ethanol, ethylene glycol, and the like. Other solvents may be used as intermediate solvates in the preparation of more desirable solvates, such as MeOH, methyl <i>t</i>-butyl ether, ethyl acetate, methyl acetate, (<i>S</i>)-propylene glycol, (<i>R</i>)-propylene glycol, 1,4-butyne-diol, and the like. Hydrates include compounds formed by an incorporation of one or more water molecules.

Conformers and Crystalline Forms/Polymorphs

0110In other embodiments, the invention provides conformer and crystalline form of a compound of Formula (I), and the use of these derivatives in methods of present invention. A conformer is a structure that is a conformational isomer. Conformational isomerism is the phenomenon of molecules with the same structural formula but different conformations (conformers) of atoms about a rotating bond.

0111A polymorph is a composition having the same chemical formula, but a different solid state or crystal structure. In certain embodiments of the invention, compounds of Formula (I) were obtained in crystalline form. In addition, certain crystalline forms of compounds of Formula (I) or pharmaceutically acceptable salts of compounds of Formula (I) may be obtained as co-crystals. In still other embodiments, compounds of Formula (I) may be obtained in one of several polymorphic forms, as a mixture of crystalline forms, as a polymorphic form, or as an amorphous form.

Prodrugs

0112The invention also relates to prodrugs of the compounds of Formula (I), and the use of such pharmaceutically acceptable prodrugs in methods of the present invention, particularly therapeutic methods. Exemplary prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (<i>e.g</i>., two, three or four) amino acid residues, covalently joined through an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of a compound of Formula (I). Examples of amino acid residues include the twenty naturally occurring amino acids, commonly designated by three letter symbols, as well as 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.

0113Additional types of prodrugs may be produced, for instance, by derivatizing free carboxyl groups of structures of Formula (I) as amides or alkyl esters. Examples of amides include those derived from ammonia, primary C_1-6alkyl amines and secondary di(C_1-6alkyl) amines. Secondary amines include 5- or 6-membered heterocycloalkyl or heteroaryl ring moieties. Examples of amides include those that are derived from ammonia, C_1-3alkyl primary amines, and di(C_1-2alkyl)amines. Examples of esters of the invention include C_1-6alkyl, C_1-6cycloalkyl, phenyl, and phenyl(C_1-6alkyl) esters. Preferred esters include methyl esters. Prodrugs may also be prepared by derivatizing free hydroxy groups using groups including hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, following procedures such as those outlined in <nplcit id="ncit0027" npl-type="s"><text>Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130</text></nplcit>.

0114Carbamate derivatives of hydroxy and amino groups may also yield prodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters of hydroxy groups may also provide prodrugs. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group may be an alkyl ester, optionally substituted with one or more ether, amine, or carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, is also useful to yield prodrugs. Prodrugs of this type may be prepared as described in <nplcit id="ncit0028" npl-type="s"><text>Robinson et al., J. Med. Chem. 1996, 39, 10-18</text></nplcit>. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including ether, amine, and carboxylic acid functionalities.

0115Prodrugs may be determined using routine techniques known or available in the art (<i>e.g.</i>, <nplcit id="ncit0029" npl-type="b"><text>Bundgard (ed.), 1985, Design of prodrugs, Elsevier</text></nplcit>; <nplcit id="ncit0030" npl-type="b"><text>Krogsgaard-Larsen et al., (eds.), 1991, Design and Application of Prodrugs, Harwood Academic Publishers</text></nplcit>).

Metabolites

0116The present invention also relates to a metabolite of a compound of Formula (I), as defined herein, and salts thereof. The present invention further relates to the use of such metabolites, and salts thereof, in methods of present invention, including therapeutic methods.

0117Metabolites of a compound may be determined using routine techniques known or available in the art. For example, isolated metabolites can be enzymatically and synthetically produced (<i>e.g.</i>, <nplcit id="ncit0031" npl-type="s"><text>Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016</text></nplcit>; <nplcit id="ncit0032" npl-type="s"><text>Shan et al., J. Pharm. Sci. 1997, 86, 765-767</text></nplcit>; <nplcit id="ncit0033" npl-type="s"><text>Bagshawe, Drug Dev. Res. 1995, 34, 220-230</text></nplcit>; and <nplcit id="ncit0034" npl-type="s"><text>Bodor, Adv Drug Res. 1984, 13, 224-231</text></nplcit>).

COMPOSITIONS

0118In some embodiments Compounds of Formula (I) and pharmaceutically acceptable salts thereof are used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions. A pharmaceutical composition of the invention comprises: (a) an effective amount of at least one active agent in accordance with the invention; and (b) a pharmaceutically acceptable excipient.

Formulations and Administration

0119Numerous standard references are available that describe procedures for preparing various formulations suitable for administering the compounds according to the invention. Examples of potential formulations and preparations are contained, for example, in the <nplcit id="ncit0035" npl-type="b"><text>Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current editi</text></nplcit>on); <nplcit id="ncit0036" npl-type="b"><text>Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc.</text></nplcit>, as well as <nplcit id="ncit0037" npl-type="b"><text>Remington's Pharmaceutical Sciences (Osol, ed.),1980, 1553-1593</text></nplcit>.

0120Any suitable route of administration may be employed for providing an animal, especially a human, with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.

0121Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent, or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to an animal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (<i>e.g.</i>, PEG400, PEG300), etc. and mixtures thereof. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (<i>i.e.</i>, a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (<i>i.e.</i>, medicament).

0122The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (<i>i.e.</i>, a compound of the present invention or stabilized form of the compound (<i>e.g</i>., complex with a cyclodextrin derivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable and appropriate dosage of the drug.

0123The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways, depending upon the method used to administer the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

0124The present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

0125The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.

0126The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

0127The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

0128Sterile injectable solutions are typically prepared by incorporating the active compound in the required amount in the appropriate solvent with a variety of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, common methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

0129For topical administration, the present compounds may be applied in pure form, <i>i.e.</i>, when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.

0130Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.

0131Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

Dosages

0132Useful dosages of the compounds of Formula (I) can be determined by comparing their <i>in vitro</i> activity and <i>in vivo</i> activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art. Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and <i>in vivo</i> activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art (<i>e.g.</i>, <patcit id="pcit0020" dnum="US4938949A"><text>U.S. Pat. No. 4,938,949</text></patcit>). Useful dosages of PDE4 inhibitors are known to the art (<i>e.g.</i>, <patcit id="pcit0021" dnum="US7829713B"><text>U.S. Pat. No. 7,829,713</text></patcit>; <patcit id="pcit0022" dnum="US8338405B"><text>U.S. Pat. No. 8,338,405</text></patcit>).

0133Optimal dosages to be administered in the therapeutic methods of the present invention may be determined by those skilled in the art and will depend on multiple factors, including the particular composition in use, the strength of the preparation, the mode and time of administration, and the advancement of the disease or condition. Additional factors may include characteristics on the subject being treated, such as age, weight, gender, and diet.

0134In general, however, a suitable dose will be in the range from about 0.01 to about 100 mg/kg, more specifically, from about 0.1 to about 100 mg/kg, such as 10 to about 75 mg/kg of body weight per day, 3 to about 50 mg per kilogram body weight of the recipient per day, 0.5 to 90 mg/kg/day, or 1 to 60 mg/kg/day (or any other value or range of values therein). The compound is conveniently administered in a unit dosage form; for example, containing about 1 to 1000 mg, particularly about 10 to 750 mg, and more particularly, about 50 to 500 mg of active ingredient per unit dosage form.

0135Preferably, the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 µM, preferably, about 1 to 50 µM, and more preferably, about 2 to about 30 µM. This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1 to 100 mg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.01 to 5.0 mg/kg/hr or by intermittent infusions containing about 0.4 to 15 mg/kg of the active ingredient(s).

0136The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, <i>e.g</i>., into a number of temporally-distinct administrations used according to the compositions and methods of the present invention.

0137Effective amounts or doses of the active agents of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, <i>e.g.</i>, the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful composition is such that an effective dosage level will be obtained. An exemplary dose is in the range from about 0.001 to about 200 mg of active agent per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, or about 0.1 to 10 mg/kg/daily in single or divided dosage units (<i>e.g</i>., BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from 1 to 200 mg/day, or about 5 to 50 mg/day.

Methods and Uses

Uses of Isotopically-Labeled Compounds

0138In one aspect, the present invention provides a method of using isotopically labeled compounds and prodrugs of the present invention in: (i) metabolic studies (preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H); (ii) detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays; or (iii) in radioactive treatment of patients.

0139Isotopically labeled compounds and prodrugs of the invention thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. An ¹⁸F or ¹¹C labeled compound may be particularly preferred for PET, and an I¹²³ labeled compound may be particularly preferred for SPECT studies. Further substitution with heavier isotopes such as deuterium (<i>i.e.</i>, ²H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased <i>in vivo</i> half-life or reduced dosage requirements.

Therapeutic Methods

Generally

0140In certain embodiments the present invention provides therapeutic methods of using a compound of Formula (I) and its pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites, whether alone or in combination (collectively, "active agents") of the present invention are useful as inhibiting PDE4 in the methods of the invention. Such methods for inhibiting PDE4 comprising administering to an animal an effective amount of at least one chemical entity selected from compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically active metabolites of compounds of Formula (I). Embodiments of this invention inhibit PDE4. The invention further includes the use of such compounds and compositions therof in the methods described herein. In one aspect of such methods disclosed herein, the animal is healthy. In another aspect of such methods, the animal has a disorder. In another aspect of all such methods the animal is an aged animal. In preferred embodiments the animal in such methods is a human.

0141In one aspect, such chemical entites are useful as inhibitors of PDE4 enzymes. Accordingly, the present invention provides a method for inhibiting PDE4, comprising administering to an animal an effective amount of a chemical entity of Formula (I) or composition therof.

0142Chemical entities of the present invention may be administered as a mono-therapy or as part of a combination therapy. In one aspect, one or more of the compounds (or salts, produgs, or metabolites thereof) of the present invention may be co-administered or used in combination with one or more additional therapies known in the art.

0143Compounds of the present invention may also be used as adjunct therapy, for example, with other PDE inhibitors.

0144The present invention also includes methods of treating a disease, disorder, or condition mediated by PDE4. Accordingly, in one embodiment, the invention provides a method of treating a disorder mediated by PDE4 in particular, comprising administering to an animal in need of such treatment an effective amount of a chemical entity of Formula (I) or composition of the present invention.

0145In certain embodiments, the present invention includes the use of a chemical entity of Formula (I) in the manufacture of a medicament for treating a disease, condition, or disorder by inhibiting PDE4 The present invention further provides a method of administering a therapeutically effective amount of a medicament of the present invention to a patient in need of such treatment to treat the disorder.

0146In one aspect, the compounds of the present invention are useful in enhancing neuronal plasticity - an essential property of the brain that can be augmented in healthy animals and can be impaired in numerous CNS disorders. For example, by inhibiting PDE4, a compound of the present invention can increase levels of cAMP, modulating cyclic nucleotide signaling cascades.

0147More particularly, the ability of extracellular signals to modulate the intracellular concentration of cyclic nucleotides allows cells to respond to external stimuli across the boundary of the cell membrane. The cyclic nucleotide signaling cascades have been adapted to respond to a host of transduction systems including G-protein coupled receptors (GPCRs) and voltage and ligand gated ion channels. Cyclic nucleotides transmit their signal in the cell through a variant of tertiary elements. The best described of these are cAMP dependent protein kinase (PKA) and cGMP dependent protein kinase (PKG). The binding of the cyclic nucleotide to each enzyme enables the phosphorylation of downstream enzymes and proteins functioning as effectors or additional elements in the signaling cascade. Of particular importance to memory formation is cAMP-dependent activation of PKA, which phosphorylates CREB. pCREB is an activated transcription factor, which binds to specific DNA loci and initiates transcription of multiple genes involved in neuronal plasticity (<i>e.g</i>.,<nplcit id="ncit0038" npl-type="s"><text>Tully et al., Nat. Rev. Drug. Discov. 2003, 2, 267-277</text></nplcit>; and <nplcit id="ncit0039" npl-type="s"><text>Alberini, Physiol. Rev. 2009, 89, 121-145</text></nplcit>).

0148Consistent with these observations, both <i>in vitro</i> and <i>in vivo</i> studies have associated alterations in cyclic nucleotide concentrations with biochemical and physiological process linked to cognitive function (<nplcit id="ncit0040" npl-type="s"><text>Kelly and Brandon, Progress in Brain Research, 2009, 179, 67-73</text></nplcit>; <nplcit id="ncit0041" npl-type="s"><text>Schmidt, Current Topics in Medicinal Chemistry, 2010, 10, 222-230</text></nplcit>). Moreover, signal intensity and the levels of coincident activity at a synapse are established variables that can result in potentiation of transmission at a particular synapse. Long term potentiation (LTP) is the best described of these processes and is known to be modulated by both the cAMP and cGMP signaling cascades.

0149Accordingly, the present invention provides a method of enhancing neuronal plasticity, comprising administering to an animal in need thereof an effective amount of a chemical entity or composition of the present invention.

0150In another embodiment, the present invention provides a method of treating a disease mediated by PDE4, comprising administering to an animal in need of such treatment an effective amount of a compound or composition of the present invention. PDE4-related indications that can be treated by compounds and compositions of the present invention include, but are not limited to neurological disorders, inflammatory disorder, renal disorder, and other disorders involving PDE4.

0151Chemical entities and compositions of the present invention are also useful as neuroprotective agents, as described in greater detail herein. Accordingly, the present invention provides a method of neuroprotection, comprising administering to an animal in need thereof an effective amount of at least one chemical entity or composition of the present invention.

0152Chemical entities and compositions of the present invention are also useful as agents in neurorehabilitation and neurorecovery, as described in greater detail herein. Accordingly, the present invention provides a method of neurorehabilitation or neurorecovery, comprising administering to an animal in need thereof an effective amount of at least one chemical entity or composition of the present invention.

0153In addition, such compounds can be administered in conjunction with training protocols to treat cognitive or motor deficits associated with CNS disorders, as described in more detail herein. In addition, such compounds can be used to enhance the efficiency of training protocols in non-human animals, in particular healthy non-human animals, as described herein.

Neurological Disorders

0154In some embodiments, the present invention provides a method of treating a neurological disorder, comprising administering to an animal in need of such treatment an effective amount of a compound or composition described herein.

0155A neurological disorder (or condition or disease) is any disorder of the body's nervous system. Neurological disorders can be categorized according to the primary location affected, the primary type of dysfunction involved, or the primary type of cause. The broadest division is between central nervous system (CNS) disorders and peripheral nervous system (PNS) disorders.

0156Neurological disorders include structural, biochemical, or electrical abnormalities in the brain, spinal cord or other nerves, abnormalities that can result in a range of symptoms. Examples of such symptoms include paralysis, muscle weakness, poor coordination, loss of sensation, seizures, confusion, pain, altered levels of consciousness, and cognitive deficits, including memory impairments. There are many recognized neurological disorders, some relatively common, but many rare. They may be assessed by neurological examination, and studied and treated within the specialties of neurology and clinical neuropsychology.

0157Neurological disorders and their sequelae (direct consequences) affect as many as one billion people worldwide, as estimated by the World Health Organization in 2006. Interventions for neurological disorders may include, in addition to medications, preventative measures, lifestyle changes, physiotherapy or other therapies, neurorehabilitation, pain management, and surgery.

0158Neurological disorders include, but are not limited to the following (which are not necessarily mutually exclusive): psychiatric disorders, such as mood disorders, psychotic disorders, and anxiety disorders; personality disorders; substance-related disorders; dissociative disorders; eating disorders; sleep disorders; developmental disorders; neurodegenerative disorders, including movement disorders; trauma-related disorders; pain disorders; and cognitive disorders, a category that includes memory disorders such as AAMI and MCI, as well as cognitive deficits (particularly memory deficits) associated with CNS disorders.

Psychiatric Disorders

0159In one embodiment, the invention provides a method of treating a psychiatric disorder, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. Psychiatric disorders include mood (or affective) disorders, psychotic disorders, and anxiety (or neurotic) disorders.

Mood Disorders

0160In some embodiments, the psychiatric disorder is a mood (or affective) disorder. Accordingly, the present invention provides a method of treating a mood disorder, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. In a specific aspect, the mood disorder is a depressive disorder, including a dysthymic disorder, major depressive disorder (recurrent and single episode), mania, bipolar disorders (I and II), and cyclothymic disorder. Long-standing research underscores a role for PDE4 in mood disorders, including depressive disorders, bipolar disorders, and substance induced mood disorders is known in the literature.

0161A specific embodiment of the invention is a method of treating a substance induced mood disorder, comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound or pharmaceutical composition described herein. The utility of PDE4 inhibitors in the treatment of substance induced mood disorders is known in the literature.

Psychotic Disorders

0162In some embodiments, the psychiatric disorder is a psychotic disorder. Accordingly, the present invention provides a method of treating a psychotic disorder, comprising an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. In a specific aspect, the psychotic disorder is one or more of the following: schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder; shared psychotic disorder; substance-induced psychotic disorders, such as a psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; and personality disorders at times of stress (including paranoid personality disorder, schizoid personality disorder, and borderline personality disorder).

0163A specific embodiment of the invention is a method of treating a delusional disorder, comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound or pharmaceutical composition described herein. The utility of PDE4 inhibitors in the treatment of delusional disorders is known in the literature.

0164A particular embodiment of the invention is a method of treating schizophrenia, comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound or pharmaceutical composition described herein. The utility of PDE4 inhibitors in the treatment of schizophrenia, including schizophreniform disorder and schizoaffective disorder, is known in the literature.

Anxiety Disorders

0165In some embodiments, the psychiatric disorder is an anxiety (or neurotic) disorder. Accordingly, the present invention provides a method of treating an anxiety disorder, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. More particularly, the anxiety disorder is one or more of the following: panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, generalized anxiety disorder, post-traumatic stress disorder; and acute stress disorder. The use of PDE4 inhibitors in the treatment of anxiety is known in the literature.

Personality Disorders

0166In some embodiments, the neurological disorder is a personality disorder. Accordingly, the present invention provides a method of treating a personality disorder, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. In particular embodiments, the personality disorder is one or more of the following: includes those of Cluster A (odd or eccentric), such as paranoid or schizoid personality disorder; those of Cluster B (dramatic, emotional, or erratic), such as antisocial, borderline, or narcissistic personality disorder; and those of Cluster C (anxious or fearful), such as avoidant, dependent, or obsessive-compulsive personality disorder.

Substance Related Disorders

0167In some embodiments, the neurological disorder is a substance-related disorder. Accordingly, a specific embodiment of the invention is a method of treating a substance-related disorder, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein.

0168More particularly, the substance-related disorder includes one or more of the following: an alcohol-related disorder, such as abuse, dependence, and withdrawal; an amphetamine (or amphetamine-related) disorder, such as abuse, dependence and withdrawal, a cocaine-related disorder, such as abuse, dependence and withdrawal; a hallucinogen-related disorder, such as abuse, dependence and withdrawal; an inhalant-related disorder, such as dependent and withdrawal; a nicotine-related disorder, such as dependence and withdrawal; an opioid-related disorder, such as abuse, dependence and withdrawal; a phencyclidine (or phencyclidine-like) related disorder, such as abuse and dependence; and a sedative-, hypnotic-, or anxiolytic-related disorder, such as abuse, dependence, and withdrawal.

0169In a specific embodiment, the compounds and compositions of the present invention are useful as an aid to a treatment of smoking cessation. Accordingly, the present invention provides a method of treating smoking addiction, comprising administering to an animal in need thereof an effective amount of a compound or composition of the present invention.

Dissociative Disorders

0170In some embodiments, the neurological disorder is a dissociative disorder. Accordingly, a specific embodiment of the invention is a method of treating a dissociative disorder, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. More particularly, the dissociative disorder includes one or more of the following: depersonalization disorder, dissociative amnesia, and dissociative identity disorder.

Eating Disorders

0171In some embodiments, the neurological disorder is an eating disorder. Accordingly, a specific embodiment of the invention is a method of treating an eating disorder, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. More particularly, the eating disorder is anorexia nervosa or bulimia nervosa. The utility of PDE4 inhibitors in the treatment of eating disorders is known in the literature.

Sleep Disorders

0172In some embodiments, the neurological disorder is a sleep disorder. Accordingly, a specific embodiment of the invention is a method of treating a sleep disorder, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. More particularly, the sleep disorder includes a primary sleep disorder, such as primary hypersomnia, primary insomnia, and narcolepsy; a parasomnia, such as a nightmare or sleep terror disorder; and other sleep disorders. The utility of PDE4 inhibitors in the treatment of sleep disorders is known in the literature.

0173In other embodiments, the sleep disorder is restless leg syndrome. Restless legs syndrome (RLS) is a disorder of the part of the nervous system that affects the legs and causes an urge to move them. People with restless legs syndrome have uncomfortable sensations in their legs (and sometimes arms or other parts of the body) and an irresistible urge to move their legs to relieve the sensations. The sensations are usually worse at rest, especially when lying or sitting. The sensations can lead to sleep deprivation and stress. Because it usually interferes with sleep, it also is considered a sleep disorder. Accordingly, the present invention provides a method of treating restless leg syndrome, comprising administering to an animal in need thereof an effective amount of a compound or composition of the present invention.

Developmental Disorders

0174In some embodiments, the neurological disorder is a developmental disorder. Accordingly, a specific embodiment of the invention is a method of treating a developmental disorder, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein.

0175More particularly, the developmental disorder is one or more of the following: mental retardation, including mild, moderate, and severe forms; a learning disorder, such as that affecting reading, mathematics, or written expression; a motor skill disorder, such as developmental coordination disorder; a communication disorder; a pervasive developmental disorder, such as an autistic disorder, Rhett's disorder, childhood disintegrative disorder, and Asperger's disorder; an attention-deficit or disruptive disorder, such as attention-deficit hyperactivity disorder; and a tic disorder, such as Tourette's disorder, chronic motor disorder, or vocal tic disorder.

0176A specific embodiment of the invention is a method of treating an autistic disorder, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. In another embodiment, the invention provides a method of treating an attention-deficit hyperactivity disorder, comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound or pharmaceutical composition described herein. The utility of PDE4 inhibitors in the treatment of attention-deficit hyperactivity disorder is known in the literature.

Neurodegenerative Disorders

0177In particular embodiments, the invention provides a method of treating a oneurodegenerative disorder, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein.

0178In one aspect, neurodegenerative disorders include Alzheimer's disease, Amyotrophic lateral sclerosis, corticobasal degeneration, chronic traumatic encephalopathy, and a disorder associated with repetitive head injury.

Alzheimer's Disease

0179In a specific embodiment, the invention provides a method of treating Alzheimer's disease, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. A detailed set of criteria for the diagnosis of <nplcit id="ncit0042" npl-type="b"><text>Alzheimer's is set forth in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, text revision (2000</text></nplcit>), also known as the DSM-IV-TR). First, multiple cognitive deficits must be present, one of which must be memory impairment. Second, one or more of the following must be present: aphasia (deterioration of language abilities); apraxia (difficulty executing motor activities - even though movement, senses, and the ability to understand what is being asked are still intact); or agnosia (impaired ability to recognize or identify objects - even though sensory abilities are intact).

Amyotrophic Lateral Sclerosis

0180In another specific embodiment, the invention provides a method of treating amyotrophic lateral sclerosis, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein.

0181Amyotrophic lateral sclerosis (ALS), often referred to as "Lou Gehrig's Disease," is a progressive neurodegenerative disease that affects nerve cells. Motor neurons reach from the brain to the spinal cord and from the spinal cord to the muscles throughout the body. As motor neurons degenerate, they can no longer send impulses to the muscle fibers that normally result in muscle movement.

0182Early symptoms of ALS often include increasing muscle weakness, especially involving the arms and legs, speech, swallowing or breathing. The progressive degeneration of the motor neurons in ALS eventually leads to their death. When the motor neurons die, the ability of the brain to initiate and control muscle movement is lost. With voluntary muscle action progressively affected, patients in the later stages of the disease may become totally paralyzed.

Movement Disorders

0183In other embodiments, the invention provides a method of treating a movement disorder, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. In one aspect, the movement disorder includes one or more of the following: Huntington's disease, Parkinson's disease, an essential tremor, a Lewy body disease, hypokinetic disease, Multiple Sclerosis, various types of Peripheral Neuropathy, dystonia, a basal ganglia disorder, hypokinesia (including akinesia), and dyskinesia. In addition, Tourette's syndrome and other tic disorders can be included as categories of movement disorders. The utility of PDE4 inhibitors in the treatment of movement disorders is known in the literature.

0184In related embodiment, the invention provides a method of treating chorea, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. Chorea can occur in a variety of conditions and disorders, and is a primary feature of Huntington's disease, a progressive neurological disorder.

Huntington's Disease

0185In a specific embodiment, the present invention provides a method of treating Huntington's disease, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein.

0186Huntington's Disease (HD, or Huntington chorea) is a disorder passed down through families in which nerve cells in certain parts of the brain waste away, or degenerate. It is caused by a genetic defect on chromosome 4, causing a CAG repeat, to occur many more times than normal. The CAG element is normally repeated 10 to 28 times, but in persons with Huntington's disease, is repeated 36 to 120 times.

0187There are two forms of Huntington's disease: adult-onset Huntington's disease - which is the most common form and usually begins in the mid 30s and 40s; and early-onset Huntington's disease, which accounts for a small number of cases and begins in childhood or adolescence.

0188Symptoms of Huntington's disease include behavioral changes, abnormal and unusual movements, and worsening dementia. Behavioral changes may include behavioral disturbances, hallucinations, irritability, moodiness, restlessness or fidgeting, paranoia, and psychosis. Abnormal and unusual movements include facial movements, such as grimaces; head turning to shift eye position; quick, sudden, sometimes wild jerking movements of the arms, legs, face, and other body parts; slow, uncontrolled movements; and unsteady gait. Worsening dementia includes; disorientation or confusion; loss of judgment; loss of memory; personality changes; and speech changes (<i>e.g.,</i><nplcit id="ncit0043" npl-type="b"><text>Dumas et al., Front Biosci (Schol Ed) 2013, 5, 1-18</text></nplcit>). The utility of PDE4 inhibitors in treating Huntington's disease is known in the art.

Parkinson's Disease

0189In a specific embodiment, the present invention provides a method of treating Parkinson's disease, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein.

0190In another embodiment, the invention provides a method of treating myoclonus, Gilles de Ia Tourette' s syndrome, dystonia, or tics, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. The utility of PDE4 inhibitors in the treatment of myoclonus, Tourette's syndrome, dystonia and tics is known in the literature.

0191In a specific aspect, a movement disorder also includes multiple sclerosis, basal ganglia disorders, hypokinesia, and dyskinesia.

Lewy Body Diseases

0192In one embodiment, the present embodiment, the invention provides a method of treating a Lewy Body Disease, comprising administering to an animal in need of such treatment an effective amount of a compound or composition of the present invention. Lewy bodies appear as spherical masses that displace other cell components. The two morphological types are classical (brain stem) Lewy bodies and cortical Lewy bodies. A classical Lewy body is an eosinophilic cytoplasmic inclusion consisting of a dense core surrounded by a halo of 10-nm-wide radiating fibrils, the primary structural component of which is alpha-synuclein. In contrast, a cortical Lewy body is less well defined and lacks the halo. Nonetheless, it is still made up of alpha-synuclein fibrils. Cortical Lewy bodies are a distinguishing feature of Dementia with Lewy bodies (DLB), but may occasionally be seen in ballooned neurons characteristic of Pick's disease and corticobasal degeneration, as well as in patients with other tauopathies.

0193More particularly, the Lewy Body disorder is selected from the group consisting of multiple system atrophy, particularly the Parkinsonian variant; Parkinson disease without or with dementia (PDD); dementia with LBs (DLB) alone or in association with Alzheimer disease (AD); multiple system atrophy, particularly the Parkinsonian variant, as well as Pick's disease and corticobasal degeneration.

Multiple sclerosis

0194In one embodiment, the present invention provides a method of treating a motor symptom associated with multiple sclerosis (MS), compring administering to animal in need of such treatment an effective amount of a compound or composition of the present invention. MS is an autoimmune, demyelinating disease that affects the brain and spinal cord of the CNS. It affects women more than men and is most commonly diagnosed between ages 20 and 40, but can be seen at any age.

0195MS is caused by damage to the myelin sheath, the protective covering that surrounds nerve cells. When this nerve covering is damaged, nerve signals slow down or stop. Because nerves in any part of the brain or spinal cord may be damaged, patients with multiple sclerosis can have symptoms in many parts of the body. Symptoms vary, because the location and severity of each attack can be different. Episodes can last for days, weeks, or months. These episodes alternate with periods of reduced or no symptoms (remissions).

0196Muscle symptoms associated with MS include loss of balance; muscle spasms; numbness, tingling, or abnormal sensation in any area; problems moving arms or legs; problems walking; problems with coordination and making small movements; tremor in one or more arms or legs; and weakness in one or more arms or legs.

Basal Ganglia Disorders

0197In particular embodiments, the present invention provides a method of treating a basal ganglia disorder. Basal ganglia disorders refer to a group of physical dysfunctions that occur when the group of nuclei in the brain known as the basal ganglia fail to properly suppress unwanted movements or to properly prime upper motor neuron circuits to initiate motor function (<nplcit id="ncit0044" npl-type="s"><text>Leisman and Mello, Rev. Neurosci. 2013, 24, 9-25</text></nplcit>).

0198Increased output of the basal ganglia inhibits thalamocortical projection neurons. Proper activation or deactivation of these neurons is an integral component for proper movement. If something causes too much basal ganglia output, then the thalamocortical projection neurons become too inhibited and one cannot initiate voluntary movement. These disorders are known as <b><i>hypokinetic</i></b> disorders. However, a disorder leading to abnormally low output of the basal ganglia leads to relatively no inhibition of the thalamocortical projection neurons. This situation leads to an inability to suppress unwanted movements. These disorders are known as <b><i>hyperkinetic</i></b> disorders (<nplcit id="ncit0045" npl-type="s"><text>Wichmann and DeLong, Curr. Opin. Neurobiol 1996, 6, 751-758</text></nplcit>).

Hypokinesia

0199In particular embodiments, the present invention provides a method of treating hypokinesia. Hypokinesia refers to decreased bodily movements, and they may be associated with basal ganglia diseases (such as Parkinson's disease), mental health disorders and prolonged inactivity due to illness, amongst other diseases.

0200More generally, hypokinesia describes a spectrum of disorders, including: (i) Akinesia, which refers to the inability to initiate movement due to difficulty selecting or activating motor programs in the central nervous system. Akinesia is a result of severely diminished dopaminergic cell activity in the direct pathway of movement and is common in severe cases of Parkinson's disease; (ii) Bradykinesia, which is characterized by slowness of movement and has been linked to Parkinson's disease and other disorders of the basal ganglia. Rather than being a slowness in initiation (akinesia), bradykinesia describes a slowness in the execution of movement. It is one of the 3 key symptoms of parkinsonism, which are bradykinesia, tremor and rigidity. Bradykinesia is also the cause of what is normally referred to as "stone face" (expressionless face) among those with Parkinson's; (iii) Freezing, which is characterized by an inability to move muscles in any desired direction; and (iv) Rigidity, which is characterized by an increase in muscle tone causing resistance to externally imposed joint movements; and (v) Postural instability, which is the loss of ability to maintain an upright posture.

Dyskinesia

0201In particular embodiments, the present invention provides a method of treating dyskinesia. Dyskinesia is a movement disorder which consists of adverse effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or chorea.

0202Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but can also be seen in the lower extremities. Discoordination can also occur internally especially with the respiratory muscles and it often goes unrecognized. Dyskinesia is a symptom of several medical disorders, distinguished by the underlying cause and generally corresponding to one of three types: acute dyskinesia, chronic (or tardive) dyskinesia, and non-motor dyskinesia.

0203More specifically, a dyskinesia can include one or more the following: paroxysmal dyskinesias, e.g., primary and secondary paroxysmal dyskinesias; paroxysmal kinesigenic dyskinesias (PKD); paroxysmal non-kinesigenic dyskinesias (PNKD); paroxysmal exercise-induced (exertion-induced) dyskinesias (PED); and paroxysmal hypnogenic dyskinesias (PHD).

Trauma-Related Disorders

0204In specific embodiments, the present invention provides a method of treating a trauma-related disorder, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition of the present invention.

0205In specific embodiments, trauma-related disorders comprise brain trauma; head trauma (closed and penetrating); head injury; tumors, especially cerebral tumors affecting the thalamic or temporal lobe head injuries; cerebrovascular disorders (diseases affecting the blood vessels in the brain), such as stroke, ischemia, hypoxia, and viral infection (<i>e.g</i>., encephalitis); excitotoxicity; and seizures.

0206Conditions within the scope of the invention that are amenable to neuroprotection include: Stroke; traumatic brain injury (TB); Dementia; Alzheimer's disease; Parkinson's disease; Huntington's disease; Cerebral palsy; Post-polio syndrome; Guillain-Barre syndrome, and Multiple Sclerosis; and other developmental syndromes, genetic conditions, and progressive CNS diseases affecting cognitive function, such as autism spectrum disorders, fetal alcohol spectrum disorders (FASD), Rubinstein-Taybi syndrome, Down syndrome, and other forms of mental retardation.

Pain Disorders

0207In specific embodiments, the invention provides methods of treating pain, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. The utility of PDE4 inhibitors in the treatment of pain is known in the literature.

0208In particular embodiments, the pain disorder includes one or more of the following: dental pain, cancer pain, myofascial pain, perioperative pain, acute pain, chronic pain, posttraumatic pain, trigeminal neuralgia, migraine severe pain, intractable pain, neuropathic pain, post-traumatic pain, cancer pain, non-cancer pain. Pain also encompasses a pain disorder associated with psychological factors, a pain disorder associated with a general medical condition, and a pain disorder associated with both psychological factors and a general medical condition.

Cognitive Disorders

0209In particular embodiments of the invention, the neurological disorder is a cognitive disorder. Accordingly, the present invention provides a method of treating a cognitive disorder, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. The utility of PDE4 inhibitors in the treatment of cognitive disorders is known in the literature (<i>e.g</i>., U.S. Pat. No. <patcit id="pcit0023" dnum="US7829713B"><text>US 7,829,713</text></patcit>; U.S. Pat. No. <patcit id="pcit0024" dnum="US8338405B"><text>US8,338,405</text></patcit>).

0210Cognitive disorders can significantly impair social and occupational functioning, adversely impacting the autonomy and quality of life of the affected individual. An estimated four to five million Americans (about 2% of all ages and 15% of those older than 65) have some form and degree of cognitive impairment (<nplcit id="ncit0046" npl-type="b"><text>Abrams et al., Merck Manual of Geriatrics, 1995, Whitehouse Station (NJ), Medical Services</text></nplcit>).

0211Cognitive disorders reflect problems in cognition, <i>i.e.</i>, the general processes by which knowledge is acquired, retained and used. Accordingly, cognitive disorders can encompass impairments in such functions as concentration, perception, attention, information processing, learning, memory, or language. Cognitive disorders can also encompass impairments in psychomotor learning abilities, which include physical skills, such as movement and coordination; fine motor skills such as the use of precision instruments or tools; and gross motor skills, such as dance, musical, or athletic performance.

0212Cognitive disorders also encompass impairments in executive functions, which include abilities underlying the planning and execution of goal-oriented behaviors. Such abilities include flexibility, <i>i.e.</i>, the capacity for quickly switching to the appropriate mental mode; anticipation and prediction based on pattern recognition; reasoning and problem-solving; decision making; working memory, <i>i</i>.<i>e</i>., the capacity to hold and manipulate internally- or externally-derived information in real time; emotional self-regulation, including the ability to recognize and manage one's emotions for good performance; sequencing, such as the ability to dissect complex actions into manageable units and prioritize them in the right order; and self-inhibition, <i>i.e.</i>, the ability to withstand distraction and internal urges.

0213Cognitive disorders also comprise cognitive impairments (deficits or dysfunctions) that are associated with (due to) to CNS disorders. In one aspect, a cognitive impairment can be a direct result of a CNS disorder. For example, impairments in speech and language can directly result from a stroke or head-injury that damages the brain regions controlling speech and language, as in aphasia.

0214In another aspect, a cognitive impairment is associated with a complex CNS disorder, condition, or disease. For example, a cognitive impairment can comprise a deficit in executive control that accompanies autism or mental retardation; a deficit in memory associated with schizophrenia or Parkinson's disease; or a cognitive deficit arising from multiple sclerosis. In the case of multiple sclerosis (MS), for example, about one-half of MS patients will experience problems with cognitive function, such as slowed thinking, decreased concentration, or impaired memory. Such problems typically occur later in the course of MS - although in some cases they can occur much earlier, if not at the onset of disease.

0215Cognitive impairments can be due to many, non-exclusive categories of CNS disorders, including the following (and as described herein): <ol id="ol0003" compact="compact"><li>(1) dementias, such as those associated with Alzheimer's disease, Parkinson's disease; Huntington's disease, Pick's disease, Creutzfeldt-Jakob, AIDS Dementia, and other neurodegenerative disorders; and cognitive disabilities associated with progressive diseases involving the nervous system, such as multiple sclerosis.</li><li>(2) psychiatric disorders, which include affective (mood) disorders, such as depression and bipolar disorders; psychotic disorders, such as schizophrenia and delusional disorder; and neurotic and anxiety disorders, such as phobias, panic disorders, obsessive-compulsive disorder, generalized anxiety disorder; eating disorders; and posttraumatic stress disorders.</li><li>(3) developmental syndromes, genetic conditions, and progressive CNS diseases affecting cognitive function, such as autism spectrum disorders; fetal alcohol spectrum disorders (FASD); Rubinstein-Taybi syndrome; Down syndrome, and other forms of mental retardation; and multiple sclerosis.</li><li>(4) trauma-dependent losses of cognitive functions, <i>i.e</i>., impairments in memory, language, or motor skills resulting from brain trauma; head trauma (closed and penetrating); head injury; tumors, especially cerebral tumors affecting the thalamic or temporal lobe; cerebrovascular disorders (diseases affecting the blood vessels in the brain), such as stroke, ischemia, hypoxia, and viral infection (<i>e.g</i>., encephalitis); excitotoxicity; and seizures. Such trauma-dependent losses also encompass cognitive impairments resulting from extrinsic agents such as alcohol use, long-term drug use, and neurotoxins, <i>e.g.</i>, lead, mercury, carbon monoxide, and certain insecticides (<i>e.g.</i>, <nplcit id="ncit0047" npl-type="s"><text>Duncan et al., Drug Discover. Ther. 2012, 6, 112-122</text></nplcit>).</li><li>(5) age-associated cognitive deficits, including age-associated memory impairment (AAMI; also referred to herein as age-related memory impairment (AMI)), and deficits affecting patients in early stages of cognitive decline, as in Mild Cognitive Impairment (MCI); and</li><li>(6) learning, language, or reading disabilities, such as perceptual handicaps, dyslexia, and attention deficit disorders.</li></ol>

0216Accordingly, the invention provides a method of treating a cognitive impairment associated with a CNS disorder selected from one or more of the group comprising: dementias, including those associated with neurodegenerative disorders; psychiatric disorders; developmental syndromes, genetic conditions, and progressive CNS diseases and genetic conditions; trauma-dependent losses of cognitive function, age-associated cognitive deficits; and learning, language, or reading disorders.

Dementias

0217In a specific embodiment, the invention provides a method of treating a cognitive deficit associated with dementia, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein.

0218Dementias are neurodegenerative diseases characterized by learning and cognitive deficiencies and are typically accompanied by behavioral symptoms, psychological symptoms and motor symptoms. More particularly, dementia symptoms can include difficulty with many areas of mental function, including emotional behavior or personality, language, memory, perception, and thinking and judgment.

0219Dementias include, but are not limited to, the following: dementia due to Alzheimer's disease (with early or late onset), dementia due to Parkinson's disease, dementia due to Pick's disease, dementia due to Creutzfeldt-Jakob disease, dementia due to HIV disease, dementia due to head trauma; dementia due to a vascular disease ("vascular dementia"), Lewy body dementia, fronto-temporal dementia, Pick's disease and corticobasal degeneration.

0220In one embodiment, dementia is due to Alzheimer's disease. Accordingly, the present invention provides a method of treating dementia due to Alzheimer's disease, comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound or pharmaceutical composition described herein. The utility of PDE4 inhibitors in the treatment of Alzheimer's disease is known in the literature. Accordingly, the invention provides a method of treating dementia due to Alzheimer's disease, comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound or pharmaceutical composition described herein.

0221In another embodiment, dementia is due to Parkinson's disease. Accordingly, the invention provides a method of treating dementia due to Parkinson's disease, comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound or pharmaceutical composition described herein. Dementia has been reported to occur in approximately 20%-60% of individuals with Parkinson's disease and is more likely to be present in older individuals or those with more severe or advanced disease. The dementia associated with Parkinson's disease is characterized by cognitive and motoric slowing; problems with executive functioning, such as planning tasks, organizing projects, or carrying out goals in the proper sequence; and impairment in memory retrieval. Declining cognitive performance in individuals with Parkinson's disease is frequently exacerbated by depression. The utility of PDE4 inhibitors in treating Parkinson's disease is known in the literature.

0222Dementia has been reported to occur in approximately 20%-60% of individuals with Parkinson's disease and is more likely to be present in older individuals or those with more severe or advanced disease. The dementia associated with Parkinson's disease is characterized by cognitive and motoric slowing, executive dysfunction, and impairment in memory retrieval. Declining cognitive performance in individuals with Parkinson's disease is frequently exacerbated by depression. For a review, <nplcit id="ncit0048" npl-type="s"><text>Davie, Br. Med. Bull. 2008, 86, 109-127</text></nplcit>. The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of this cell death is unknown. Early in the course of the disease, the most obvious symptoms are movement-related. Four motor symptoms are considered cardinal in PD: shaking (tremors), rigidity, slowness of movement, and postural instability, <i>i.e.</i>, difficulty with walking and gait (<i>e.g.</i>, <nplcit id="ncit0049" npl-type="s"><text>Jankovic, J. Neurol. Neurosurg. Psychiatr. 2008, 79, 368-376</text></nplcit>). Later, cognitive and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease. Other symptoms include sensory, sleep and emotional problems. PD is more common in the elderly, with most cases occurring after the age of 50.

0223In another aspect, a cognitive impairment is associated with a complex CNS syndrome, condition, or disease. For example, a cognitive impairment can comprise a deficit in executive control that accompanies autism or mental retardation; a deficit in memory associated with schizophrenia or Parkinson's disease; or a cognitive deficit arising from multiple sclerosis. In the case of multiple sclerosis (MS), for example, about one-half of MS patients will experience problems with cognitive function, such as slowed thinking, decreased concentration, or impaired memory. Such problems typically occur later in the course of MS - although in some cases they can occur much earlier, if not at the onset of disease.

0224In one aspect, a cognitive impairment can be a direct result of a CNS disorder. For example, impairments in speech and language can directly result from a stroke or head-injury that damages the brain regions controlling speech and language, as in aphasia.

Psychiatric Disorders

0225In a specific embodiment, the invention provides a method of treating a cognitive deficit associated with a psychiatric disorder, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. Psychiatric disorders include affective disorders (mood disorders), such as depression and bipolar disorders; psychotic disorders, such as schizophrenia and delusional disorder; and neurotic and anxiety disorders, such as phobias, panic disorders, obsessive-compulsive disorder, generalized anxiety disorder, eating disorders, and posttraumatic stress disorders.

Developmental Syndromes, Genetic Disorders, and Progressive Diseases

0226In a specific embodiment, the invention provides a method of treating a cognitive deficit associated with a developmental syndrome, genetic disorder, or progressive disease, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. In a specific aspect, the cognitive deficit is associated with an autism spectrum disorder; a fetal alcohol spectrum disorder (FASD); Rubinstein-Taybi syndrome; Down syndrome, and other forms of mental retardation; and multiple sclerosis.

Trauma-Related Disorders

0227In a specific embodiment, the invention provides a method of treating a cognitive deficit associated with trauma. Such trauma-dependent losses of cognitive function include, but are not limited to, those due to cerebrovascular diseases, including stroke and ischemia; brain trauma, including subdural hematoma and brain tumor; traumatic brain injury (TBI) and head injury.

0228Such trauma-dependent losses also encompass cognitive impairments resulting from extrinsic agents such as alcohol use, long-term drug use, and neurotoxins such as lead, mercury, carbon monoxide, and certain insecticides.

Stroke

0229In some embodiments, chemical entities and compositions of the present invention are useful in treating stroke, and in more specific embodiments, treating motor or cognitive impairments during post-stroke rehabilitation. Stroke care is a temporal continuum that includes immediate (acute) treatments and subsequent rehabilitative therapy.

0230Acute treatments directly target the initial damage, such as that triggered by ischemic or hemorrhagic stroke; they usually involve using agents to dissolve clots and restore blood flow to reduce tissue damage and stabilize the patient. The efficacy of acute treatments is typically limited to a short time window extending only a few hours from stroke onset.

0231Rehabilitation becomes the therapeutic focus after the patient has been medically stabilized. Rehabilitation (also referred to as "stroke rehabilitation" or "post-stroke rehabilitation") is directed to cognitive and motor deficits that persist after the initial stroke injury, the goal being to restore and recover neurological function as much as possible to compensate for the permanent tissue loss. (<i>e.g.</i>, 1995 Clinical Guideline by the Department of Health and Human Services on Post-Stroke Rehabilitation.)

0232Stroke rehabilitation is typically a comprehensive program coordinated by a team of medical professionals. A physical therapist on the team, for example, may focus on maintaining and restoring range of motion and strength in affected limbs, maximizing mobility in walking, improving manual dexterity, and rehabilitating other motor and sensorimotor functions. A mental health professional may be involved in the treatment of loss of cognitive skills. Rehabilitation services can occur in multiple environments, such as a rehabilitation hospital, long-term care facility, outpatient clinic, or at home.

0233Neurological functions impacted by stroke (and which can be targeted during rehabilitation) include impairments in cognitive and motor functions. Cognitive function impairments, for example, can manifest as deficits in understanding speech or writing (aphasia); knowing the right words but having trouble saying them clearly (dysarthria); as well as deficits in other cognitive functions, such as attention, reasoning, planning, execution, and learning and memory. Motor function impairments, for example, can manifest as weakness (hemiparesis) or paralysis (hemiplegia) on one side of the body that may affect the whole side or just the arm or leg; by problems with balance or coordination; deficits in gross motor skills such as gait and walking speed; deficits in fine motor skills or manual dexterity; and deficits in upper and lower extremity function.

0234Accordingly, the present invention provides the use of a PDE4 inhibitor in the treatment of stroke, including methods of post stroke rehabilitation. In certain embodiments, chemical entities of the present invention are useful during stroke rehabilitation to treat stroke deficits (or "post-stroke deficits") resulting from impaired neurological functions. In some embodiments, the present invention provides methods of post-stroke rehabilitation comprising: (a) administering to a subject in need thereof a PDE4 inhibitor during recovery of the subject from stroke; (b) providing training to the subject under conditions sufficient to improve performance of a neurological function whose impairment is due to said stroke; and (c) repeating steps (a) and (b) one or more times, whereby the amount of training sufficient to improve the performance is reduced relative to that produced by training alone.

0235In one aspect, the PDE4 inhibitor is a chemical entity of the present invention. In some embodiments, the deficit is a motor deficit. In other embodiments, the deficit is a cognitive deficit, particularly, a deficit in memory formation, and more specifically, a deficit in long-term memory formation. In still other embodiments, the deficit may include a cognitive and motor deficit. In another aspect, training comprises a battery of tasks directed to the neurological function. In a specific aspect, the reduction in the amount of training is a reduction in the number of training sessions.

0236In a further embodiment, one or more training steps are separated by a discrete interval. In one aspect, each training step is provided daily. In other aspects, the interval between one or more training steps can be less than one day or more than one day <i>e.g.</i>, such as once a week, twice a week, three times a week, or longer.

0237In a further embodiment, said administering step (a) is in conjunction with said training step (b). In one aspect, the subject is a human. In another aspect, the subject has undergone neuronal stem cell manipulation. In other aspects, the compound is administered before and during each training session.

Age-Associated Cognitive Deficits

AAMI

0238In a specific embodiment, the invention provides a method of treating an age-associated cognitive deficit. In one aspect, the age-associated cognitive deficit is age-related memory impairment (AAMI). Accordingly, the invention provides a method of treating age-associated memory impairment (AAMI), comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein.

0239AAMI is a decline in various cognitive abilities, in particular memory abilities, associated with normal aging. For example, AAMI subjects show a decline in the ability to encode new memories of events or facts, as well as working memory (<nplcit id="ncit0050" npl-type="s"><text>Hedden and Gabrieli, Nat. Rev. Neurosci. 2004, 5, 87-96</text></nplcit>). In addition, AAMI subjects, when compared with age-matched controls, appeared to be impaired in tests of executive functions associated with frontal lobe function. These and other studies suggest an important role for frontal lobe dysfunction in the memory loss of elderly people. More generally, studies comparing the effects of aging on episodic memory, semantic memory, short-term memory and priming find that episodic memory is especially impaired in normal aging; but some types of short-term memory can also be impaired (<nplcit id="ncit0051" npl-type="s"><text>Nilsson, Acta Neurol. Scand. Suppl. 2003, 179, 7-13</text></nplcit>)

0240In general, an AAMI diagnosis identifies persons with subjectively and objectively evidenced memory loss without cognitive decline impaired enough to warrant the diagnosis of dementia. According to criteria established by the NIH working group (<nplcit id="ncit0052" npl-type="s"><text>Crook et al., Devel. Neuropsychol. 1986, 2, 261-276</text></nplcit>) a diagnosis of AAMI includes the following in a person aged 50 or older: <ol id="ol0004" compact="compact"><li>(i) the presence of subjective memory decline, <i>e.g.</i>, complaints of memory loss reflected in such everyday problems as difficulty remembering names of individuals introduced to the subject, misplacing objects, difficulty remembering a list of items to be purchased or a list of tasks to be performed;</li><li>(ii) objective evidence of memory loss (<i>e.g.</i>, a score at least one standard deviation below the mean of younger adults in a well standardized memory test);</li><li>(iii) evidence of adequate intellectual function (<i>e.g..</i>, a raw score of at least 32) on the Vocabulary subtest of the Wechsler Adult Intelligence Scale., and</li><li>(iv) the absence of dementia (or other memory-affecting disease, such as stroke), <i>e.g.</i>, based on the Global Deterioration Scale for assessment of dementia, individuals with AAMI have very mild cognitive decline (level 2) (<nplcit id="ncit0053" npl-type="s"><text>Reisberg et al., Am. J. Psych. 1982, 139,1136-1139</text></nplcit>).</li></ol>

0241Individuals with AAMI have been shown to have a three-fold greater risk for development of dementia than individuals who do not meet AAMI criteria (<nplcit id="ncit0054" npl-type="s"><text>Goldman and Morris, Alzheimer Dis. Assoc. Disord. 2002, 15:72-79</text></nplcit>).

MCI

0242In a specific embodiment, the invention provides a method of treating mild cognitive impairment (MCI), comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein.

0243MCI may be diagnosed when an individual's memory declines below the level considered normal for that age group. In other words, MCI is a condition in which people face memory problems more often than that of the average person their age. These symptoms, however, do not prevent them from carrying out normal activities and are not as severe as the symptoms for Alzheimer's disease. Symptoms often include misplacing items, forgetting events or appointments, and having trouble thinking of desired words.

0244According to recent research, MCI has been called the transitional state between cognitive changes of normal aging and Alzheimer's disease (AD). Many people who experience mild cognitive impairment are at a high risk of developing Alzheimer's disease. Indeed, research suggests that: about 12% of people aged 65 or older diagnosed with MCI go on to develop Alzheimer's disease within a year; and that about 40% develop Alzheimer's within three years. This is a much higher rate than in the general population, wherein only about 1% of people aged 65 or older develop Alzheimer's each year.

0245Thus, people with MCI are considered at heightened risk to develop Alzheimer's disease. These symptoms, however, do not prevent them from carrying out normal activities and are not as severe as the symptoms for Alzheimer's disease. Symptoms often include misplacing items, forgetting events or appointments, and having trouble thinking of desired words (<i>e.g</i>., <nplcit id="ncit0055" npl-type="s"><text>Arnáiz and Almkvist, Acta Neurol. Scand. Suppl. 2003, 179, 34-41</text></nplcit>). Some patients with MCI, however, never progress to AD.

Learning and Related Disabilities

0246In a specific embodiment, the invention provides a method of treating a learning, language, or reading disability, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein.

Neuroprotection

0247In specific embodiments, the invention provides a method of neuroprotection, comprising administering to animal in need thereof an effective amount of a chemical entity or composition of the present invention.

0248Like neuroplasticity, neuroprotection reflects an endogenous neurobiological process that is central to protection of the nervous system. More specifically, neuroprotection refers to the ability to halt or slow the loss of neurons, thereby preventing or slowing disease progression and secondary injuries. In a particular aspect, neuroprotection targets neuronal damage arising from oxidative stress and excitotoxicity - both of which are highly associated with CNS disorders, despite differences in symptoms or injuries.

0249The utility of PDE4 inhibitors in the treatment of neuronal damage is known in the literature. In addition to neurodegenerative diseases, neuronal damage can also result from other sources of trauma, such as cerebrovascular diseases, including stroke and ischemia; brain trauma, including subdural hematoma and brain tumor; and head injury.

Augmented Cognitive and Motor Training

0250In certain embodiments, a compound or composition herein is used as an augmenting agent in methods to enhance the efficiency of cognitive or motor training (collectively "training"). Such enhancement methods are collectively known as "augmented training," comprising "augmented cognitive training" or "augmented motor training."

0251Training generally requires multiple sessions to attain the desired benefits, for example, to rehabilitate a motor deficit or language deficit following stroke. This can be costly and time-consuming, deterring subject compliance and the realization of real world benefits that endure over time. The efficiency of such training protocols can be improved by administering certain agents (known as augmenting agents) in conjunction with the training protocol (<i>e.g.</i>, <patcit id="pcit0025" dnum="US7868015B"><text>U.S. 7,868,015</text></patcit>; <patcit id="pcit0026" dnum="US7947731B"><text>U.S. 7,947,731</text></patcit>; <patcit id="pcit0027" dnum="US20080188525A"><text>US 2008-0188525</text></patcit>). Augmented training comprises a specific training protocol for a particular brain function, such as that underlying declarative memory, performance of a fine motor skill, locomotion, language acquisition, an executive function, etc., and a general administration of CREB pathway-enhancing drugs. The training protocol (cognitive or motor training) induces neuronal activity in specific brain regions and produces improved performance of a specific brain (cognitive or motor) function. In other words, the use of augmenting agents achieves cognitive training effects with less repetition, <i>i.e.</i>, fewer training sessions.

0252In some embodiments, the invention provides methods of treating a cognitive disorder, and more particularly, methods for improving a cognitive deficit associated with a central nervous system (CNS) disorder or condition in an animal, comprising treating the animal with an augmenting agent that enhances CREB pathway function in conjunction with cognitive training, wherein the augmenting agent is a compound or composition of the present invention. Exemplary compounds of the present inventions, for example, have been shown to activate CREB in cell-based assays.

0253In one aspect, the method comprises: (a) providing cognitive training to a subject in need of treatment of a cognitive deficit under conditions sufficient to produce an improvement in performance by said animal of a cognitive function whose impairment is associated with said cognitive deficit; (b) administering a compound or composition of the present invention to the animal in conjunction with said cognitive training; repeating steps (a) and (b) one or more times; and (d) reducing the number of training sessions sufficient to produce the improvement in performance, relative to the same improvement in performance produced by cognitive training alone.

0254In another aspect, the method comprises: (a) providing cognitive training to a subject in need of treatment of a cognitive deficit under conditions sufficient to produce an improvement in performance by said animal of a cognitive function whose impairment is associated with said cognitive deficit; (b) administering a compound or composition of the present invention to the animal in conjunction with said cognitive training; repeating steps (a) and (b) one or more times; and (d) producing a long-lasting improvement in performance of said function relative to the improvement in performance of said function produced by cognitive training alone.

0255In one aspect, a compound or composition of the present invention can be used as an augmenting agent in conjunction with any psychotherapeutic approach intended to modulate cognitive function in the brain, thereby enhancing the efficacy of such therapy by reducing the number of sessions necessary to attain benefits.

0256In another aspect, the cognitive deficit treated by these methods is or includes memory impairment, and more particularly, a defect in long-term memory. Long-term memory (LTM) generally comprises two main biological properties. First, formation of long-term memory requires synthesis of new proteins. Second, it involves cAMP-responsive transcription and is mediated through the cAMP-response element binding protein (CREB) family transcription factors. Compounds of the present invention can act as CREB-augmenting agents and are therefore useful in enhancing memory formation in an animal, and more particularly, transcription-dependent memory. Indeed, exemplary compounds of the present invention activate CREB in cell-based assays.

0257In some embodiments, the invention provides methods of treating a motor disorder, and more particularly, methods for improving a motor deficit associated with a central nervous system (CNS) disorder or condition in an animal comprising treating the animal with an augmenting agent that enhances CREB pathway function in conjunction with motor training. Methods are also provided herein for providing sustained improvement in a motor deficit associated with a central nervous system (CNS) disorder or condition in an animal in need of said treatment comprising administering to the animal a compound or composition of the present invention; and detecting said sustained improvement

0258In one aspect, the method comprises: (a) providing motor training to a subject in need of treatment of a motor deficit under conditions sufficient to produce an improvement in performance by said animal of a motor function whose impairment is associated with said cognitive deficit; (b) administering a compound or composition of the present invention to the animal in conjunction with said motor training; repeating steps (a) and (b) one or more times; and (d) reducing the number of training sessions sufficient to produce the improvement in performance, relative to the same improvement in performance produced by motor training alone.

0259In another aspect, the method comprises: (a) providing motor training to a subject in need of treatment of a motor deficit under conditions sufficient to produce an improvement in performance by said animal of a motor function whose impairment is associated with said cognitive deficit; (b) administering a compound or composition of the present invention to the animal in conjunction with said motor training; repeating steps (a) and (b) one or more times; and (d) producing a long-lasting improvement in performance of said function relative to the improvement in performance of said function produced by motor training alone.

0260In other embodiments, the invention provides methods for enhancing a specific aspect of cognitive performance in an otherwise healthy animal (particularly in a human or other mammal or vertebrate) comprising (a) administering to the animal an augmenting agent of the present invention; and (b) training the animal under conditions sufficient to produce an improvement in performance of a particular cognitive task by the animal. In other embodiments, the present invention provides methods of enhancing cognitive or motor performance, as well as methods for repeated stimulation of neuronal activity or a pattern of neuronal activity, such as that underlying a specific neuronal circuit(s).

Augmenting Agents

0261Augmenting agents, including the compounds and compositions herein, are able to enhance CREB pathway function. By enhancing CREB pathway function in conjunction with training, such augmented training can decrease the number of training sessions required to improve performance of a cognitive or motor function, relative to the improvement observed by training alone (<i>e.g.</i>, <patcit id="pcit0028" dnum="US20070203154A"><text>U.S. 2007-0203154</text></patcit>, <patcit id="pcit0029" dnum="US20110160248A"><text>U.S. 2011-0160248</text></patcit>, <patcit id="pcit0030" dnum="US20100317648A"><text>U.S. 2010-0317648</text></patcit>, and <patcit id="pcit0031" dnum="US8222243B"><text>U.S. Pat. No. 8,222,243</text></patcit>).

0262The augmenting agent can be administered before, during or after one or more of the training sessions. In a particular embodiment, the augmenting agent is administered before and during each training session. Treatment with an augmenting agent in connection with each training session is also referred to as the "augmenting treatment".

Training Protocols

0263Training protocols are generally employed in rehabilitating individuals who have some form and degree of cognitive or motor dysfunction. For example, training protocols are commonly employed in stroke rehabilitation and in age-related memory loss rehabilitation. Because multiple training sessions are often required before an improvement or enhancement of a specific aspect of cognitive (or motor) performance (ability or function) is obtained in the individuals, training protocols are often very costly and time-consuming. Augmented training methods are more efficacious and therefore more cost-effective.

0264For example, human brain injury often results in motor and cognitive impairments. While advances in critical care medicine and patient management have led to improvements in patient outcome following traumatic brain injury (TBI), there is currently no known treatment to prevent the neuronal cell death and dysfunction that follows TBI. Although multiple treatments have proven neuroprotective in pre-clinical models of TBI, most have failed to show efficacy in humans.

0265Once a patient is stabilized following TBI, the standard of care dictates extensive motor or cognitive rehabilitation. During this rehabilitation the patient often regains lost skills, finally resulting in improved functional outcome. It would be beneficial if pharmaceutical treatments could be developed to enhance motor or cognitive rehabilitation following TBI, and thus improve functional outcome.

0266Cognitive and motor training protocols and the underlying principles are well known in the art (<i>e.g.</i>, <nplcit id="ncit0056" npl-type="s"><text>Allen et al., Parkinsons Dis. 2012, 1-15</text></nplcit>; <nplcit id="ncit0057" npl-type="s"><text>Jaeggi et al., Proc. Natl. Acad. Sci. USA 2011, 108, 10081-10086</text></nplcit>; <nplcit id="ncit0058" npl-type="s"><text>Chein et al., Psychon. Bull. Rev. 2010, 17, 193-199</text></nplcit>; <nplcit id="ncit0059" npl-type="s"><text>Klingberg, Trends Cogn. Sci. 2010, 14, 317-324</text></nplcit>; <nplcit id="ncit0060" npl-type="s"><text>Owen et al., Nature 2010, 465, 775-778</text></nplcit>;<nplcit id="ncit0061" npl-type="s"><text> Tsao et al., J. Pain 2010, 11, 1120-1128</text></nplcit>; <nplcit id="ncit0062" npl-type="s"><text>Lustig et al., Neuropsychol. Rev. 2009, 19, 504-522</text></nplcit>; <nplcit id="ncit0063" npl-type="s"><text>Park and Reuter-Lorenz, Ann. Rev. Psych. 2009, 60, 173-196</text></nplcit>; <nplcit id="ncit0064" npl-type="s"><text>Oujamaa et al., Ann. Phys. Rehabil. Med. 2009, 52, 269-293</text></nplcit>; <nplcit id="ncit0065" npl-type="s"><text>Frazzitta et al., Movement Disorders 2009, 8, 1139-1143</text></nplcit>; <nplcit id="ncit0066" npl-type="s"><text>Jaeggi et al., Proc. Natl. Acad. Sci. USA 2008, 105, 6829-6833</text></nplcit>; <nplcit id="ncit0067" npl-type="s"><text>Volpe et al., Neurorehabil. Neural Repair 2008, 22, 305-310</text></nplcit>; <nplcit id="ncit0068" npl-type="s"><text>Fischer et al., Top. Stroke Rehab. 2007, 14, 1-12</text></nplcit>; <nplcit id="ncit0069" npl-type="s"><text>Jonsdottir et al., Neurorehabil. Neural Repair 2007, 21, 191-194</text></nplcit>; <nplcit id="ncit0070" npl-type="s"><text>Stewart et al., J. Neurol. Sci. 2006, 244, 89-95</text></nplcit>; <nplcit id="ncit0071" npl-type="s"><text>Krakauer, Curr. Opin. Neurol. 2006, 19, 84-90</text></nplcit>;<nplcit id="ncit0072" npl-type="s"><text> Belleville et al., Dement. Geriatr. Cogn. Disord. 2006, 22, 486-499</text></nplcit>; <nplcit id="ncit0073" npl-type="s"><text>Klingberg et al., J. Am. Acad. Child. Adolesc. Psychiatry 2005, 44, 177-186</text></nplcit>;<nplcit id="ncit0074" npl-type="s"><text> Dean et al., Arch. Phys. Med. Rehabil. 2000, 81, 409-417</text></nplcit>;<nplcit id="ncit0075" npl-type="s"><text> Whitall et al., Stroke 2000, 31, 2390-2395</text></nplcit>; <nplcit id="ncit0076" npl-type="s"><text>Hummelsheim and Eickhof, Scand. J. Rehabil. Med. 1999, 31, 250-256</text></nplcit>; <nplcit id="ncit0077" npl-type="s"><text>Merzenich et al., Science 1996, 271, 77-81</text></nplcit>; <nplcit id="ncit0078" npl-type="s"><text>Merzenich et al., Cold Spring Harb. Symp. Quant. Biol. 1996, 61, 1-8</text></nplcit>; <nplcit id="ncit0079" npl-type="s"><text>Rider and Abdulahad, Percept. Mot. Skills 1991, 73, 219-224</text></nplcit>; <nplcit id="ncit0080" npl-type="s"><text>Wek and Husak, Percept. Mot. Skills, 1989, 68, 107-113</text></nplcit>;

0267Cognitive training protocols are directed to numerous cognitive dimensions, including memory, concentration and attention, perception, learning, planning, sequencing, and judgment. Motor training protocols can be directed to numerous motor domains, such as the rehabilitation of arm or leg function after a stroke or head injury. One or more protocols (or modules) underling a training program can be provided to a subject.

0268In some embodiments, the protocols can be used to treat, or rehabilitate, cognitive or motor impairments in afflicted subjects. Such protocols may be restorative or remedial, intended to reestablish prior skills and functions, or they may be focused on delaying or slowing cognitive or motor decline due to neurological disease. Other protocols may be compensatory, providing a means to adapt to a cognitive or motor deficit by enhancing function of related and uninvolved brain domains. In other embodiments, the protocols can be used to improve particular skills or cognitive or motor functions in otherwise healthy individuals. For example, a cognitive training program might include modules focused on delaying or preventing cognitive decline that normally accompanies aging; here the program is designed to maintain or improve cognitive health.

0269In general, a training protocol (or module) comprises a set of distinct exercises that can be process-specific or skill-based: Process-specific training focuses on improving a particular domain such as attention, memory, language, executive function, or motor function. Here the goal of training is to obtain a general improvement that transfers from the trained activities to untrained activities associated with the same cognitive or motor function or domain. For example, an auditory cognitive training protocol can be used to treat a student with impaired auditory attention. At the end of training, the student should show a generalized improvement in auditory attention, manifested by an increased ability to attend to and concentrate on verbal information presented in class-and therefore to remember to write down and complete homework assignments. Similarly, a cognitive training protocol may be directed to impaired executive function in an autistic subject, preventing the subject from carrying out instructions to complete an activity, such as making a meal, cleaning one's room, or preparing for school in the morning. Cognitive training allows the subject to focus his attention and concentration and as a result, complete the sequence of tasks required for such activities.

0270Skill-based training is aimed at improving performance of a particular activity or ability. Here the goal of training is to obtain a general improvement in the skill or ability. For example, a training protocol may focus on learning a new language, performing a musical instrument, improving memory, or learning a fine motor skill. The different exercises within such a protocol will focus on core components underlying the skill. Modules for increasing memory, for example, may include tasks directed to the recognition and use of fact, and the acquisition and comprehension of explicit knowledge rules.

0271Some rehabilitation programs may rely on a single strategy (such as computer-assisted cognitive training) targeting either an isolated cognitive function or multiple functions concurrently. For example, the CogState testing method comprises a customizable range of computerized cognitive tasks able to measure baseline and change in cognitive domains underlying attention, memory, executive function, as well as language and social-emotional cognition (<i>e.g.</i>, <nplcit id="ncit0081" npl-type="s"><text>Yoshida et al., PloS ON, 2011, 6, e20469</text></nplcit>;<nplcit id="ncit0082" npl-type="s"><text> Frederickson et al., Neuroepidemiology 2010, 34, 65-75</text></nplcit>). Other rehabilitation programs may use an integrated or interdisciplinary approach. Cognitive and motor training programs may involve computer games, handheld game devices, interactive exercises, and may employ feedback and adaptive models.

Neurorehabilitation and Neurorecovery

0272In other embodiments, the invention further relates to the use of compounds and compositions of the present invention in neurorecovery and neurorehabilitation - endogenous neurobiological processes that are central to recovery of cognitive and motor impairments of the nervous system (<i>e.g.</i>, <nplcit id="ncit0083" npl-type="s"><text>Harkema et al., Arch. Phys. Med. Rehabil. 2012, 93, 1588-1597</text></nplcit>; <nplcit id="ncit0084" npl-type="s"><text>Muresanu et al., J. Cell. Mol. Med. 2012, 16, 2861-2871</text></nplcit>).

0273Neurorehabilitation or neurorecovery generally refers to a collection process that focuses on aiding a person's recovery from a neurological disorder, or helping that individual to live a more normal, active, and independent life. For example, the quality of life of a person can be greatly affected by a brain or spinal cord injury, or a medical condition which affects the mobility, cognitive functions, or other physical or psychological processes that have been affected by changes in the nervous system. The goal of neurorehabilitation is to combat those changes and improve quality of life by various therapies.

0274Conditions within the scope of the invention that are treated by neurorehabilitation and neurorecovery include: Stroke; traumatic brain injury (TB); Dementia; Alzheimer's disease; Parkinson's disease; Huntington's disease; Cerebral palsy; Post-polio syndrome; Guillain-Barre syndrome, and Multiple Sclerosis; and other developmental syndromes, genetic conditions, and progressive CNS diseases affecting cognitive function, such as autism spectrum disorders, fetal alcohol spectrum disorders (FASD), Rubinstein-Taybi syndrome, Down syndrome, and other forms of mental retardation.

0275By focusing on all aspects of a person's well-being, neurorehabilitation or neurorecovery offers a series of therapies from the psychological to occupational, teaching or re-training patients on mobility skills, communication processes, and other aspects of that person's daily routine. Neurorehabilitation or neurorecovery also provides focuses on nutrition, psychological, and creative parts of a person's recovery.

0276In one embodiment, the present invention provides a method of augmenting neurorehabilitation or neurorecovery from a cognitive impairment, comprising (a) providing cognitive training to a subject in need of treatment of a cognitive deficit under conditions sufficient to produce an improvement in performance by said animal of a cognitive function whose impairment is associated with said cognitive deficit; (b) administering a compound or composition of the present invention to the animal in conjunction with said cognitive training; repeating steps (a) and (b) one or more times; and (d) producing a long-lasting improvement in performance of said function relative to the improvement in performance of said function produced by cognitive training alone.

0277In another embodiment, the present invention provides a method of augmenting neurorehabilitation or neurorecovery from a motor impairment, comprising: (a) providing motor training to a subject in need of treatment of a motor deficit under conditions sufficient to produce an improvement in performance by said animal of a motor function whose impairment is associated with said cognitive deficit; (b) administering a compound or composition of the present invention to the animal in conjunction with said motor training; repeating steps (a) and (b) one or more times; and (d) reducing the number of training sessions sufficient to produce the improvement in performance, relative to the same improvement in performance produced by motor training alone.

Non-Human Animal Training Protocols

0278Aside from applications for humans, compounds and compositions of the present invention have additional uses for non-human animals, namely in enhancing (augmenting) the efficiency of training protocols directed to numerous cognitive and motor functions.

0279Conditions, under which non-human animals would benefit, include enhanced (augmented) training procedures for specific purposes, (<i>e.g</i>. hunting dogs, guide dogs, police dogs etc, or animals used in movie industry).

0280Enhanced training protocols can also benefit animals that have been exposed to stressful or traumatic conditions and are in need of training to treat the resulting cognitive impairments. Such a need may arise, for example, after such an animal has been captured or transported, subjected to new housing conditions (as in a change of domicile or owner), or has developed analogous disorders and is distressed or aggressive, or displays stereotypic behavior, obsessive-compulsive behavior, or anxiety. Animals which are subject to stress would also include animals used in racing (eg. dogs, horses, camels) or other sports, performing animals (such as circus animals and those appearing on stage, television or in the movies) and horses that perform dressage and other highly disciplined routines.

0281Compounds of the present invention can also enhance the efficiency of rehabilative protocols following physical injury to a non-human animal, such as limb amputation. For example, administering an augmenting agent of the present invention in conjunction with a trainin protocol can increase the efficiency of a rehabilitative program by decreasing the number of training sessions necessary to achieve an improvement in motor function.

0282In particular embodiments, compounds and compositions of the present invention are used in methods of training service animals. By combining augmenting agents of the present invention with training protocols, the efficiency of training non-human animals for service in both the public and private sectors will be enhanced. Service animals are typically dogs. However, other non-human animals can also be trained to perform services, such as assisting blind or disabled people. For example, miniature horses can be trained to guide the blind, to pull wheelchairs, or to provide support for Parkinson's patients. As another example, capuchin monkeys can be trained to assist disabled perform manual tasks, such as grasping items, operating knobs and switches, turning the pages of a book.

0283In specific embodiments, augmented training with compounds and compositions of the present invention can be used to reduce the number of training sessions necessary to teach an animal skills that are useful in public service, such as in law enforcement. In dogs, for example, such skills include, but are not limited to, the following: (i) public order maintenance, <i>e.g</i>., chasing, holding, or detaining suspects; (ii) search and rescue, <i>e.g</i>., locating suspects, missing persons, or objects; and (iii) contraband detection, <i>e.g</i>., detecting illicit substances such as drugs, narcotics, explosives, weapons, and even human remains. Such methods can therefore be applied to police dogs, bomb-sniffing dogs, drug-sniffing dogs, search and rescue dogs, etc.

0284In other embodiments, augmented training (with compounds and compositions of the present invention) can be used to reduce the number of training sessions required to teach animals skills that are useful in the private sector, such as security and medical care. In dogs, for example, such skills can include, but are not limited to, the following: (i) private security, <i>e.g</i>., guarding property or protecting an individual; (ii) handicap assistance, <i>e.g</i>., providing eyes for the visually impaired, ears for the hearing-impaired, arms and legs for the physically-disabled; (iii) health care, <i>e.g</i>., detecting cancer or altering a caregiver to seizures in a subject; (iv) psychiatric assistance, <i>e.g</i>., calming a phobic person under stress-triggering conditions, or alerting an autistic person to distracting repetitive movements such as hand flapping; and (v) pest control, <i>e.g</i>., identifying source of infestations by bedbugs or termites.

0285In some embodiments, the training protocol can be directed to a single skill or task, such as the detection of a single drug. In other embodiments, the training protocol can be directed to a complex set of skills, such as those underlying search and rescue. For a complex set of skills, training will therefore comprise more than one task.

0286In another aspect, when training is carried out with a wide enough scope of tasks, a generalized "rehabilitation" effect is expected, resulting in generalized improved function of one or more cognitive domains. This results in improved performance of the animal of related tasks (involving the same cognitive domains) that are not specifically part of the training protocol.

0287Accordingly, the present invention provides a method of reducing the time necessary to teach an animal one or more skills, wherein said reducing comprising: a) administering an augmenting agent of the present invention to the animal; b) providing a training protocol to said dog under conditions to improve performance of one or more tasks, wherein said training protocol comprises multiple training sessions; and c) decreasing the number of training sessions required to improve performance of said one or more tasks relative to the number of said training sessions required to produce said improvement in performance by the training protocol alone.

0288The training protocol can be provided to the animal under conditions to improve performance of a single task; a complex set of tasks; or a wide scope of tasks, resulting in generalized improved function of one or more cognitive domains. The tasks can relate to a skill involved in public service, such as public order maintenance, search and rescue, and contraband detection. The tasks can also relate to a skill involved in private service, such as private security, handicap assistance, health care, psychiatric assistance, and pest control.

Peripheral Disorders

0289PDE4 enzymes are located in a number of peripheral tissues. For example, one or several PDE4D isoforms are expressed throughout most tissues tested, including cortex, hippocampus, cerebellum, heart, liver, kidney, lung and testis (<nplcit id="ncit0085" npl-type="s"><text>Richter et al., Biochem. J., 2005, 388, 803-811</text></nplcit>). The localization and regulation of PDE4D isoforms is thought to allow for tight and local regulation of cAMP levels, possibly limiting signal propagation in specific subcellular compartments.

0290Thus, in one embodiment, the invention provides a method of treating a peripheral disorder associated with PDE4, by administering to an animal in need thereof a therapeutically effective amount of a compound or pharmaceutical composition described herein.

0291The peripheral disorder may include, but is not limited to, such PDE4-associated disorders as inflammatory bowel disease (<nplcit id="ncit0086" npl-type="s"><text>Banner and Trevethick, 2004, Trends Pharmacol. Sci. 25, 430-436</text></nplcit>); rheumatoid arthritis (<nplcit id="ncit0087" npl-type="s"><text>Kobayashi et al., 2007, Mediators Inflamm. 2007, 58901</text></nplcit>); chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis, pulmonary artery hypertension (<nplcit id="ncit0088" npl-type="s"><text>DeFranceschi et al., 2008, FASEB J., 22, 1849-1860</text></nplcit>); renal diseases (<nplcit id="ncit0089" npl-type="s"><text>Conti et al., 2003, J. Biol. Chem., 278, 5493</text></nplcit>); allergic skin diseases and psoriasis (<nplcit id="ncit0090" npl-type="s"><text>Baumer et al., 2007, Inflamm. Allergy Drug Targets, 6, 17-26</text></nplcit>).

EXAMPLES

0292The present disclosure will be further illustrated by the following non-limiting Examples. These Examples are understood to be exemplary only, and they are not to be construed as limiting the scope of the invention herein, and as defined by the appended claims.

PREPARATIVE EXAMPLES

0293Exemplary compounds useful in methods of the invention will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples to follow.

Synthetic Schemes

0294One skilled in the art will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Unless otherwise specified, the variables are as defined above in reference to Formula (I). Reactions may be performed between -78 °C and the reflux temperature of the solvent. Reactions may be heated employing conventional heating or microwave heating. Reactions may also be conducted in sealed pressure vessels above the normal reflux temperature of the solvent. <chemistry id="chem0029" num="0029"><img file="EP3345902A1_D0034.tif" /></chemistry>

0295According to Scheme A, commercially available or synthetically accessible 3-bromo-5-methylpyridin-2-ol (II) is difluoromethylated with 2,2-difluoro-2-(fluorosulfonyl)acetic acid or the silyl ester of 2-fluorosulfonyldiflouroacetate, preferably 2,2-difluoro-2-(fluorosulfonyl)acetic acid, in an aprotic solvent, such as ACN, a base, such as Na₂CO₃, NaH, and the like, preferably Na₂CO₃, at temperatures ranging from room temperature to the reflux temperature of the solvent, preferably room temperature, to afford a compound of formula (VI) where Z is CH and R₄ is CHF₂ (<nplcit id="ncit0091" npl-type="s"><text>Chen et al., J. Flourine Chem., 1989, 44, 433-440</text></nplcit>).

0296According to Scheme A, a compound of formula (VI), where Z is CH, U is -CH₃, R⁴ is - C_1-3alkyl or -C_1-3haloalkyl, is prepared from a commercially available or synthetically accessible compound of formula (III), where U is -CH₃. Reaction of 3-bromo-2-chloro-5-methylpyridine, with an alkoxide, such as sodium ethoxide, sodium methoxide and the like, in a suitable solvent, such as the alcohol used to generate the alkoxide, at a temperature ranging from room temperature to the reflux temperature of the solvent, for a period of 4 to 48 h provides a bromopyridyl ether compound of formula (VI). Alternatively, a compound of formula (VI), where R⁴ is -C_1-3alkyl or -C_1-3haloalkyl, may be prepared by reaction of 3-bromo-2-chloro-5-methylpyridine with a suitably substituted primary or secondary alcohol, in the presence of a base such as NaH, in a solvent, such as DMA, 1,4-dioxane, THF, and the like, at temperatures ranging from room temperature to the reflux temperature of the solvent.

0297According to Scheme A, a compound of formula (VI), where Z is CH, U is -CH₂OH, R⁴ is -C_1-3alkyl or -C_1-3haloalkyl, is prepared in two steps from a commercially available or synthetically accessible compound of formula (III), where U is -CO₂H or -CO₂C_1-3alkyl. For example, 5-bromo-6-chloronicotinic acid is reacted with a suitably substituted alcohol, in the presence of a base such as NaH, Cs₂CO₃, and the like, with our without a solvent, such as DMA, 1,4-dioxane, THF, and the like, at temperatures ranging from room temperature to the reflux temperature of the solvent, employing conventional or microwave heating, for a period of 30 minutes to 8 h, to provide a compound of formula (VI), where R⁴ is -C_1-3alkyl or -C_1-3haloalkyl. In an alternate method, a compound of formula (VI), where U is -CO₂C_1-3alkyl, and R⁴ is -C_1-3alkyl or -C_1-3haloalkyl, is prepared from a compound of formula (III), where U is -CO₂H, where the acid is activated, with a suitable activating agent, followed by reaction with a suitable alcohol. For example 5-bromo-6-chloronicotinic acid is reacted with a chlorinating agent such as oxalyl chloride, in a solvent such as DMF, to provide the acid chloride. Subsequent reaction with an alkoxide, in a suitable solvent, such as the alcohol used to generate the alkoxide, provides a compound of formula (VI), where U is -CO₂C_1-3alkyl, and R⁴ is -C_1-3alkyl or -C_1-3haloalkyl. In a subsequent reaction, a compound of formula (VI), where U is -CO₂C_1-3alkyl, and R⁴ is -C_1-3alkyl or -C_1-3haloalkyl, is reduced with a reducing agent such as NaBH₄, LiBH₄, or a mixture thereof, in a solvent such as THF, and the like, at temperatures ranging from 0 °C to rt, to provide a compound of formula (VI), where U is -CH₂OH.

0298According to Scheme A, a compound of formula (VI), where Z is CH, U is -CH₂Cl, and R⁴ is -C_1-3alkyl or -C_1-3haloalkyl is prepared from a compound of formula (VI), where Z is CH, U is -CH₂OH, and R⁴ is -C_1-3alkyl or -C_1-3haloalkyl. For example (5-bromo-6-ethoxypyridin-3-yl)methanol is reacted with a halogenating agent such as thionyl chloride, in a solvent such as DCM, and the like, at temperatures ranging from 0 °C to rt, to provide 3-bromo-5-(chloromethyl)-2-ethoxypyridine.

0299A compound of formula (VI), where Z is CH, U is -CH(=O), and R⁴ is -C_1-3alkyl or -C_1-3haloalky, for example 5-bromo-6-methoxynicotinaldehyde, is prepared from 6-methoxynicotinaldehyde, employing a bromination reaction conditions known to one skilled in the art. For example, 6-methoxynicotinaldehyde is reacted with Br₂, NaOAc, in a solvent such as HOAc, at temperatures ranging from rt to 90 °C, to provide 5-bromo-6-methoxynicotinaldehyde.

0300According to Scheme A, commercially available or synthetically accessible 5-methylpyrazin-2-amine (IV), where R¹ is H, U is CH₃, and Z is N, is brominated under conditions known to one skilled in the art, for example, by reaction with a suitable halogenating agent such as NBS, Br₂, and the like, in an appropriate solvent such as DCM, 1,4-dioxane, THF, CHCl₃, preferably DCM, at temperatures ranging from 0 °C to room temperature, for a period of 8 to 16 h to afford 3-bromo-5-methylpyrazin-2-amine. Subsequent reaction of 3-bromo-5-methylpyrazin-2-amine (V) with an oxidizing agent, such as, but not limited to, <i>tert-butyl</i> nitrite, in the presence of an anhydrous acid source, for example, HCl in 1,4-dioxane, in an alcoholic solvent such as MeOH, EtOH, and the like, at temperatures ranging from 0 °C to 60 °C, for a period of 8 to 16 h affords compounds of formula (VI), where Z is N, U is -CH₃, and R₄ is -C_1-3alkyl.

0301According to Scheme A, commercially available or synthetically accessible 6-amino-2-methylnicotinonitrile (IV), where R¹ is -CH₃, U is -CN, and Z is CH is prepared in two steps (bromination and diazotization/alcohol addition) by the methods previously described to provide compounds of formula (VI) where R¹ is -CH₃, U is -CN, and Z is CH. <chemistry id="chem0030" num="0030"><img file="EP3345902A1_D0035.tif" /></chemistry>

0302According to Scheme B, 2-(difluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)pyridine (IX) is obtained in 2 steps from commercially available 4-bromo-2-hydroxypyridine (VII). Alkylation of 4-bromo-2-hydroxypyridine (VII), with 2-chloro-2,2-difluoroacetate in a solvent such as ACN, THF, 1,4-dioxane, or a mixture thereof, at temperatures ranging from room temperature to the reflux temperature of the solvent, for a period of 6-12 h (also described in <patcit id="pcit0032" dnum="WO2010056195A"><text>WO2010/056195, May 20, 2010</text></patcit>) provides 4-bromo-2-(difluoromethoxy)pyridine (VIII). A boronate ester is prepared using methods known to one skilled in the art, for example, 2-difluoromethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (IX) is prepared from 4-bromo-2-(difluoromethoxy)pyridine (VIII) by reaction with KOAc, K₃PO₄, and the like, a catalyst such as Pd(dppl)Cl₂, Pd(PPh₃)₄, and the like, bis(pinacolato)diboron, and the like, in a solvent such as 1,4-dioxane, 1-2-dimethoxyethane, DMF, DMSO, and the like, at temperatures ranging from 60 to 150 °C, for a period of 6-24 h. <chemistry id="chem0031" num="0031"><img file="EP3345902A1_D0036.tif" /></chemistry>

0303As shown in Scheme C, a compound of formula (VI), where U is -CH₃, -CN, -CH₂OH, - CH(=O), or -NH₂, Z is CH or N; R¹ is H or -CH₃, and R⁴ is -C_1-3alkyl or -C_1-3haloalkyl; under Suzuki reaction conditions known to one skilled in the art, is reacted with commercially available or synthetically accessible aromatic or heteroaromatic boronic acids or esters, or synthetically accessible heteroaromatic boronic esters, such as compound (IX), in a solvent such as ACN, toluene, EtOH, H₂O, or a mixture thereof, in the presence of a base such as, NaHCO₃ Na₂CO₃, K₂CO₃, Cs₂CO₃, and the like, and a palladium catalyst such as Pd(dppf)₂, Pd(PPh₃)₄, and the like, employing conventional or microwave heating, at temperatures ranging from 80 to 120 °C, to provide a compound of formula (X). A compound of formula (X) where R³ is aryl or heteroaryl optionally substituted with -OH, under standard alkylating conditions known to one skilled in the art, is treated with commercially available or synthetically accessible alkyl groups with appropriate leaving groups, such as halides, for example -Cl, -Br or -I, or sulfonates, such as methanesulfonyl, <i>p</i>-toluenesulfonyl and the like, in the presence of a base, such as but not limited to, NaH, K₂CO₃, Cs₂CO₃, and the like, in a solvent such as DMF, DMSO, 1,-4-dioxane, and the like, at temperatures ranging from 60 °C to the reflux temperature of the solvent for a period of 8 to 24 h, to provide a aryl or heteroaryl O-alkyl compound of formula (X).

0304Halogenation of a compound of formula (X), where U is -CH₃ or -CH₂OH, Z is CH or N; R¹ is H or -CH₃, R₃ is aryl or heteroaryl, and R⁴ is -C_1-3alkyl or -C_1-3haloalkyl, under free-radical halogenation conditions. For example, a compound of formula (X), where U is -CH₃, is reacted with NBS, a radical initiator such as AIBN or benzoyl peroxide, in a solvent such as CCl₄, at temperatures ranging from 60 °C to the reflux temperature of the solvent, for a period of 4 to 24 h, provides a compound of formula (XI), where HAL is -Br. In an alternate method, a compound of formula (X), where U is -CH₂OH, is reacted with a chlorinating agent such as thionyl chloride, employing methods previously described, to provide a compound of formula (X), where HAL is -Cl.

0305A nitrile compound of formula (X), where U is -CN, Z is CH; R¹ is -CH₃, R₃ is aryl or heteroaryl, and R⁴ is -CH₃, is reduced to the corresponding aldehyde with a reducing agent such as DIBAL, and the like, in a solvent such as DCM, THF, toluene, and the like, at low temperature, preferably -78 °C, for a period of 1 to 3 h. Subsequent reduction of the aldehyde moiety to the corresponding alcohol, is accomplished with a reducing agent, such as sodium or lithium borohydride, and the like, in a solvent such as MeOH, THF, and the like, at temperatures ranging from 0 °C to room temperature. Activation of the alcohol using methanesulfonyl chloride, in a suitable solvent, such as DCM, in the presence of an alkylamine base, such as Hünig's base, TEA, and the like, provides a compound of formula (XI), where U is -CN, Z is CH; R¹ is -CH₃, R⁴ is -CH₃ and HAL is -Cl.

0306According to Scheme C, 5-bromo-6-methoxypyridin-3-amine, where U is -NH₂, Z is CH; R¹ is H, R⁴ is -CH₃, is reacted under standard Suzuki reaction conditions as previously described, to provide compounds of formula (X), where U is -NH₂, Z is CH; R¹ is H, R³ is aryl or heteroaryl, and R⁴ is -CH₃. Alternately, a compound of formula (X), may be prepared from commercially available or synthetically accessible suitably substituted pyridine amines, such as, 5-bromo-6-ethoxypyridin-3-amine, as outlined in the procedures described above, where U is - NH₂, Z is CH; R¹ is H, R³ is aryl or heteroaryl, and R⁴ is -C_1-3alkyl. <chemistry id="chem0032" num="0032"><img file="EP3345902A1_D0037.tif" /></chemistry>

0307According to Scheme D, a compound of formula (XII), under Sandmeyer conditions known to one skilled in the art, are reacted with an oxidizing agent, such as, but not limited to, <i>tert-butyl</i> nitrite, in the presence of a halogenating agent, for example copper(II)bromide, in an appropriate solvent, such as ACN and the like, at a suitable temperature, preferably 60 °C, affords a compound of formula (XIII). Lithiation of a compound of formula (XIII) with a suitable metallo-base, such as <i>n</i>-BuLi or the like, in a non-protic solvent, such as THF, Et₂O or the like, at a low temperature, preferably -78 °C, for a period of 30-60 minutes, prior to addition of an appropriate aryl or heteroarylcarbonyl compound, followed by additional stirring at temperatures ranging from -78 °C to ambient temperature, provides a compound of Formula (I), where Y is CHOH, Z is CH, R² and R³ are monocyclic aromatic or heteroaromatic rings, and R⁴ is -CH₃.

0308A fluoro compound of Formula (I), where Y is -C(R^a)₂-, and R^a is -H or -F; is prepared by the reaction of an alcohol of Formula (I), where Y is CH(OH), employing fluorinating conditions such, but not limited to, reaction with Deoxo-Fluor®, XtalFluor® and the like, in a solvent such as DCM and the like, at room temperature, for a period of 1 to 24 h.

0309A compound of Formula (I), where Y is -C(R^a)₂-, and R^a is -H is prepared by treating an alcohol of Formula (I), where Y is CH(OH), with a reducing agent, such as but not limited to triethylsilane in the presence of an acid source, such as trifluoroacetic acid, triflic acid and the like, in a solvent such as DCM and the like, at room temperature, for a period up to 24 h.

0310An amine compound of Formula (I), where Y is -CHNH2-, -CHNH(CH₃)-, or -CHN (CH₃)₂-, is prepared in two steps by the reaction of an alcohol of Formula (I), where Y is - CH(OH), with a chlorinating agent, such as thionyl chloride, oxalyl chloride and the like, with or without a catalytic amount of DMF, in a solvent such as DCM, and the like, at temperatures ranging from 0 °C to room temperature to provide the chloro intermediate which is then reacted with the appropriate amine, such as, but not limited to ammonia, methylamine and the like, with or without a catalytic amount of sodium iodide, in solvent such as ACN, at a temperature ranging from room temperature to 80 °C. <chemistry id="chem0033" num="0033"><img file="EP3345902A1_D0038.tif" /></chemistry>

0311As described in Scheme E, a compound of Formula (I) can be obtained from a compound of formula (IX) thru a reaction such as, but not limited to, Suzuki or Negishi coupling reactions, and substitution reactions with nitrogen heteroaryls. A compound of formula (IX) is reacted, employing standard Suzuki coupling conditions, known to those skilled in the art and previously described herein, with commercially available aromatic or heteroaromatic boronic acids, boronic esters, trifluoroborates or synthetically accessible heteroaromatic boronic esters, such as compound (IV), to give a compound of Formula (I). In an alternate method, a compound of formula (IX), where HAL is -Cl, is reacted with dipinacol diboron, a suitable base such as K₂CO₃, a palladium catalyst such as Pd(PPh₃)₄, and the like, in a solvent such as dioxane, to provide the corresponding boronate ester. Subsequent reaction of the boronate ester with a suitably halo substituted heteroaryl compound employing Suzuki reaction conditions previously described, provides a compound of Formula (I).

0312A compound of formula (IX) is reacted, employing standard Negishi coupling conditions, known to those skilled in the art. An example of Negishi reaction conditions are: coupling commercially available halogen containing aromatic or heteroaromatic intermediates, with a preformed zincate obtained from reacting compounds of formula (IX) with zinc, pretreated with activators such as trimethylsilyl chloride and 1,2-dibromoethane, in an appropriate solvent, such as THF, 1,4-dioxane, and the like, at a temperature ranging from room temperature to reflux temperature, preferably reflux temperature, for a period of 12 to 24 h. Combining the zincate intermediate with commercially available halogen containing aromatic or heteroaromatic compounds in the presence of a palladium catalyst, such as Pd(PPh₃)₄ and the like, in a suitable solvent, such as THF, 1,4-dioxane, and the like, at temperatures ranging from 50 °C to the reflux temperature of the solvent, for a period of 12 to 48 h, affords a compound of Formula (I), where R² is a six membered heteroaryl ring containing one to two nitrogen members.

0313A compound of formula (IX) when combined with the appropriate heterocycle (HET) with an acidic proton, such as but not limited to, 1H-1,2,4-triazole or imidazole, in an aprotic solvent, for example DMF, acetone, ACN, and the like, with a suitable base, such as Cs₂CO₃, K₂CO₃, and the like, at temperatures ranging from room temperature to 60 °C, for period of 2 to 24 h, provides a compound of Formula (I), where R² is a five membered heteroaryl ring containing two to three nitrogen members.

0314A compound of Formula (I), where Y is -CH₂, and R² is an optionally substituted 1,2,3-triazole is obtained using "Click Chemistry" (for example, copper-catalyzed azide-alkyne cycloaddition) under conditions known to one skilled in the art, for example, by treating a compound of formula (IX) with sodium azide in a suitable solvent, such as DMF, acetone, DMSO, and the like, and base such as K₂CO₃, and the like, at temperatures ranging from room temperature to 100 °C, affords the azido intermediate which is then combined with a commercially available or synthetically accessible alkyne, such as but not limited to ethynyltrimethylsilane, and the like, in a solvent such as DMSO, 1,4-dioxane, THF, ACN, <i>t-</i>butanol, and water or a mixture thereof, in the presence of a catalyst, for example copper(II)iodide, copper(II)bromide, copper(I)sulfate, and the like, and base, such as DIPEA, and the like, at temperatures ranging from room temperature to 100 °C, for a period of 2 to 12 h, provide a compound of Formula (I),where R² is an optionally substituted 1,2,3-triazole.

0315A compound of Formula (I), where R² is substituted with an amide (-CONH₂), is prepared from the corresponding nitriles (-CN) or esters (-CO₂C_1-3alkyl) using methods known to those skilled in the art. For example, an amide of Formula (I) is obtained by reaction of a nitrile compound of Formula (I) with a base, such as NaOH or KOH, preferably NaOH, and a peroxide, such as H₂O₂, in a solvent such as MeOH, and the like, at a temperatures ranging from 0 to 50 °C, for a period of 8 to 24 h. Optionally, a carboxylic acid compound of Formula (I) are obtained when nitrile compound of Formula (I) are treated as described above at a temperature of 50 °C, for a period of 2 to 4 h. An ester compound of Formula (I) is converted to an amide of Formula (I) by treating with an appropriate amine, such as ammonia, methylamine or the like, in a solvent, such as MeOH, 1,4-dioxane, and the like, at temperatures ranging from room temperature to the reflux temperature of the solvent.

0316A compound of Formula (I), where R² is substituted with a primary (-(CH₂)_1-2OH) or tertiary (-C(CH₃)₂OH) alcohol is prepared from a corresponding aldehyde or ester compound of Formula (I), using methods known to those skilled in the art. Reduction of an aldehyde compound of Formula (I) with a reducing agent, such as NaBH₄ or NaBH₃CN, and the like, in a solvent such as MeOH, THF, DMF and the like, at temperatures ranging from 0 °C to room temperature, for a period of 0.2 to 2 h, affords a primary alcohol compound of Formula (I), where R² is substituted with -CH₂OH. A compound of Formula (I), where R² is substituted with an ester moiety, is reduced, with a reducing agent, such as NaBH₄, LiBH₄, LAH, DIBAL and the like, with our without KF, in a solvent such as MeOH, THF, Et₂O and the like, at temperatures ranging from 0 °C to room temperature, for a period of 2 to 24 h, to afford a primary alcohol compound of Formula (I), where R² is substituted with -CH₂OH.

0317A compound of Formula (I), where R² is substituted with -CH₂OH or -CHO, is fluorinated, employing fluorinating conditions such as, but not limited to, reaction with Deoxo-Fluor®, XtalFluor® and the like, in a solvent such as DCM and the like, room temperature, for a period of 2 to 24 h, to provide a fluoroalkyl compound of Formula (I), where R² is substituted with -CH₂F or -CHF₂.

0318A compound of Formula (I), where R² is substituted with an ester moiety, is reacted under Grignard conditions known to one skilled in the art, with a Grignard reagent such as, but not limited to, methylmagnesium bromide, in a solvent such as THF, Et₂O, and the like, at temperatures ranging from 0 °C to room temperature, for a period of 0.3 to 2 h, to provide a compound of Formula (I), where R² is substituted with a tertiary alcohol (-C(CH₃)₂OH).

0319A compound of Formula (I), where R² is substituted with -CN, is reduced with a reducing agent, such as DIBAL and the like, in a solvent such as Et₂O, THF, and the like, at low temperatures, preferably -78 °C, for a period of 1 to 4 h, to provide a primary amine compound of Formula (I), where R² is substituted with primary amine (-CH₂NH₂).

0320A compound of Formula (I), where R² is substituted with -CN, is reacted with acetyl chloride, in an alcoholic solvent such as MeOH, EtOH, and the like, a at low temperature, preferably 0 °C, for a period of 30 min. to 2 h, provides a compound of Formula (I), where R² is substituted with CO₂C_1-3alkyl.

0321A compound of Formula (I), where R² is substituted with -CH₂CN, is reacted under alkylating conditions, known to one skilled in the art, to provide a compound of Formula (I), where R² is substituted with -C(CH₃)₂CN. For example, reaction with an alkylating agent such as MeI, a base such as NaOH, a solvent such as DMSO, water, or a mixture thereof, at low temperatures such as 0 °C, for a period of 30 min. to 2 h.

0322A compound of Formula (I), where R² is substituted with an ester moiety, is reacted under standard hydrolysis conditions known to one skilled in the art, with a base such as, but not limited to, KOH, LiOH, NaOH and the like, in a solvent such as THF, 1,4-dioxane, MeOH, H₂O or a mixture thereof, at temperatures ranging from room temperature to the reflux temperature of the solvent, for a period of 1 to 4 h, to provide a compound of Formula (I), where R² is substituted with carboxylic acid (-CO₂H).

0323A compound of Formula (I), where R² is substituted with an amide (-CONH₂) is prepared in two steps from a compound of Formula (I), where R² is substituted with carboxylic acid (-CO₂H). Halogenation to the acid chloride employing known methods, followed by reaction with an ammonia source such as ammonia in dioxane, provides a compound of Formula (I), where R² is substituted with an amide (-CONH₂).

0324A compound of Formula (I), where R² is an optionally substituted pyrimidine or pyrazine substituted with -Cl or -Br is reacted with alkyl or heteroalkyl oxygen or nitrogen nucleophiles, such as <i>N1</i>,<i>N1</i>-dimethylethane-1,2-diamine, 2-aminoethanol, morpholine, and the like, in a solvent such as ACN, THF, EtOH, DMF, toluene, and the like, a base such as DIPEA, TEA, NaH, K₂CO₃, and the like, at temperature ranging from 50 to 180 °C, employing conventional or microwave heating conditions, for a period of 1 to 4 h, to provide a compound of Formula (I), where R² is an optionally substituted pyrimidine or pyrazine.

0325A compound of Formula (I), where R² is substituted with -NO₂, is reduced with a reducing agent, such as, but not limited to zinc or iron, in a solvent such as acetic acid, water, or a mixture thereof, at temperatures ranging from room temperature to 50 °C, for a period of 1 to 4 h, to provide a primary amine compound of Formula (I), where R² is substituted with primary amine (-NH₂).

0326A compound of Formula (I), where R² is substituted with primary amine (-NH₂) is reacted with <i>tert</i>-butyl nitrite, in a solvent such as DMF, water, or a mixture thereof, at temperatures ranging from 0 °C to 60 °C, for a period of 8 to 16 h, affords a compound of Formula (I), where R² is substituted with -OH.

0327A compound of Formula (I), where R² is substituted with (-NHR^b) or (-N(R^b)₂) is prepared from the corresponding amine compounds of Formula (I), employing methods known to one skilled in the art, such as but not limited to a reductive amination reaction. For example, a compound of Formula (I) where R² is substituted with (-NH₂), is reacted with an appropriate carbonyl intermediate, such as but not limited to, formaldehyde and the like, in a solvent such as THF, DCM, MeOH and the like, with a reducing agent, such as NaBH(OAc)₃, NaBH₃CN and the like, at temperatures ranging from 0 to 50 °C, for a period of 1 to 4 h, to provide an alkyl amine compound of Formula (I), where R^b is -CH₃.

0328A compound of Formula (I), where R² is substituted with (-NHCOCH₃) is prepared from the corresponding amine compound of Formula (I), employing methods known to one skilled in the art, such as but not limited to, treatment with an acyl chloride or anhydride. For example, a compound of Formula (I) where R² is substituted with (-NH₂), is treated with an appropriately activated acylating agent, such as but not limited to, acetyl chloride, acetic anhydride and the like, in a solvent such as, DCM, DMF and the like, with a base, such as TEA, DIPEA, and the like, at temperatures ranging from 0 °C to room temperature, for a period of up to 24 h, provides an acyl subsituted amine compound of Formula (I), where R² is (-NHCOCH₃).

0329A compound of Formula (I), where R² is substituted with (-NHCONH₂) is prepared from a corresponding amine compound of Formula (I), employing methods known to one skilled in the art, such as but not limited to, treatment with potassium cyanate and the like, in a solvent such as, acetic acid and water or a mixture thereof, at temperatures ranging from room temperature to 60 °C, for 0.2 to 4 h, to provide a urea subsituted compound of Formula (I), where R² is (-NHCONH₂). Optionally, a compound of Formula (I), where R² is substituted with (-NHCONH-oxetane) is prepared from the corresponding carboxylic acid compounds of Formula (I), using the Curtuis rearrangement employing methods known to one skilled in the art. For example, a compound of Formula (I) where R² is substituted with (-CO₂H), are treated with, but not limited to, diphenylphosphoryl azide and the like, in the presence of a base, such as TEA, DIPEA, and the like, in an appropriate solvent such as, toluene, 1,-4-dioxane, and the like, at the reflux temperature of the solvent, for a period of up to 1 h. The intermediate acyl azide is then reacted with an appropriate amine, in the presence of a base, such as TEA, DIPEA, and the like, to afford a compound of Formula (I) where R² is substituted with (-NHCONH-oxetane).

0330A compound of Formula (I), where R² is substituted with -NO₂, is reacted with a commercially available or synthetically accessible metallo-alkoxide, for example, sodium methoxide, sodium ethoxide and the like, in a solvent such as, but not limited to, MeOH, EtOH, 1,4-dioxane and the like, at temperatures ranging from room temperature to the reflux temperature of the solvent, for a period of 24 h, to provide a compound of Formula (I) where R² is substituted with (-OC_1-3alkyl).

0331A compound of Formula (I), wherein R² is 1,2,3-triazole optionally substituted with -H, is synthesized from the corresponding 4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl) compounds of Formula (I), by reacting with a desilylating agent, such as but not limited to, tetrabutylammonium fluoride, in a solvent such as THF, DMF, and the like, at temperatures ranging from room temperature to 50 °C, for a period of 8 to 24 h.

0332A compound of Formula (I), where R² is substituted with -CHO, is prepared from the corresponding alcohols or esters, previously described using methods known to those skilled in the art. For example, treating an alcohol of Formula (I) with an oxidizing agent, such as but not limited to Dess-Martin® reagent, in an appropriate solvent, such as DCM or THF and the like, at room temperature for 3 to 8 h give the desired aldehyde. The desired aldehyde of Formula (I) is also obtained by treating the corresponding ester of Formula (I) with a reducing agent, such as DIBAL, in an appropriate solvent, such as THF, Et₂O and the like, at low temperature, preferably -78 °C, for 1 to 4 h.

0333Removal of the <i>tert</i>-butylcarbamate (BOC) or paramethoxybenzyl (PMB) in a compound of Formula (I) where R² is optionally substituted with (-NH-BOC), (-HET-N-BOC), (-NH-PMB) is accomplished by using methods known to one skilled in the art, such as, HCI, TFA, or <i>p</i>-toluenesulfonic acid, in a solvent such as CH₃OH, dioxane, or CH₂CI₂. In a preferred embodiment, a compound of formula is treated with TFA in DCM or HCI to afford a compound of Formula (I) where R² is optionally substituted with (-NH₂) or (-HET-NH₂). <chemistry id="chem0034" num="0034"><img file="EP3345902A1_D0039.tif" /></chemistry>

0334According to Scheme F, a compound of formula (VI) where U is -CH₃; R¹ is H, R⁴ is - C_1-3alkyl or -C_1-3haloalkyl, is halogenated according to methods previously described to provide the corresponding alkylbromide compound. Subsequent reaction with HET, where HET is an optionally substituted five membered heteroaryl ring selected from, but not limited to, 1H-1,2,4-triazole or imidazole, according to methods previously described, provides a compound of formula (XII) where HET is an optionally substituted five membered heteroaryl ring.

0335According to Scheme F, a compound of formula (XII) where HET is an optionally substituted five membered heteroaryl ring is prepared from a compound of formula (VI) where U is -CH₂Cl, R¹ is H, R⁴ is -C_1-3alkyl or -C_1-3haloalkyl, employing methods previously described. For example, reaction of (5-bromo-6-ethoxypyridin-3-yl)methanol with an optionally substituted five membered heteroaryl ring, a base such as K₂CO₃, Cs₂CO₃, and the like, with or without NaI, in a solvent such as DCM, CHCl₃, ACN, and the like, at temperatures ranging from rt to the reflux temperature of the solvent, provides a compound of formula (XII).

0336A compound of formula (XII), where HET is five membered heteroaryl ring optionally substituted with a -CO₂C_1-3alkyl or C(=O)H moiety, is reduced, employing methods known to one skilled in the art or previously described, to provide a compound of formula (XII), where the HET is substituted with -CH₂OH. For example, methyl 1-((5-bromo-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate is reacted with a reducing agent such as LiBH₄, NaBH₄, and the like, in a solvent such as THF, MeOH, and the like, at temperatures ranging from 0 °C to rt, for a period of 1 to 5 h, to provide a compound of formula (XII) where HET is substituted with -CH₂OH.

0337A compound of formula (XII), where HET is five membered heteroaryl ring optionally substituted with a -NO₂ moiety, is reduced, employing methods known to one skilled in the art or previously described, to provide a compound of formula (XII), where the HET is substituted with -NH₂.

0338A compound of formula (XII) is reacted, employing standard Suzuki coupling conditions, known to those skilled in the art and previously described herein, with commercially available aromatic or heteroaromatic boronic acids or esters, or synthetically accessible heteroaromatic boronic esters, such as compound (IV), to give a compound of Formula (I).

0339Optionally, a compound of Formula (I), where R³ is substituted with pyrazole is prepared from the corresponding compounds of formula (XII), employing methods known to one skilled in the art, such as but not limited to, Buchwald coupling conditions. For example, a compound of formula (XII) is reacted with the appropriate heterocycle (HET) with an acidic proton, such as but not limited to, pyrazole, in a solvent, such as toluene, 1,4-dioxane, and the like, with a suitable base, such as sodium <i>tert</i>-butoxide, sodium methoxide, a palladium catalyst such as but not limited to, Pd₂(dba)₃, Pd(OAc)₂ and the like, and a phosphine ligand, such as (2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, tri(<i>tert</i>-butyl)phosphine and the like, at temperatures ranging from room temperature to the reflux temperature of the solvent, for period of 4 to 48 h, to provide a compound of Formula (I), where insert R³ is an optionally substituted pyrazole.

0340Compounds of Formula (I) may be converted to their corresponding salts using methods known to those skilled in the art. For example, compounds of Formula (I) may be treated with TFA, HCl, maleic acid, or citric acid in a solvent such as Et₂O, DCM, THF, or MeOH to provide the corresponding salt forms.

0341Compounds prepared according to the schemes described above may be obtained as single enantiomers, diastereomers, or regioisomers, by enantio-, diastereo-, or regiospecific synthesis, or by resolution. Where compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Compounds prepared according to the schemes above may alternately be obtained as racemic (1:1) or non-racemic (not 1:1) mixtures of mixtures as diastereomers or regioisomers. Where racemic and non-racemic mixtures of enantiomers are obtained, single enantiomers may be isolated using conventional separation methods known to one skilled in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation, or enzymatic transformation. Where regioisomeric or diastereomeric mixtures are obtained, single isomers may be separated using conventional methods such as chromatography or crystallization.

0342The following examples are provided to further illustrate the invention and various preferred embodiments.

EXAMPLES

Chemistry:

0343In obtaining the compounds described in the examples below, and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

0344Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature (rt) under nitrogen atmosphere. Where solutions were "dried", they were generally dried over a drying agent such as Na₂SO₄ or MgSO₄. Where mixtures, solutions, and extracts were "concentrated", they were typically concentrated on a rotary evaporator under reduced pressure.

0345Reactions under microwave irradiation conditions were carried out in a CEM Discover-SP with Activent microwave reaction apparatus, model number 909150, or Biotage Initiator, model number 355302.

0346Normal-phase flash column chromatography (FCC) was performed on silica gel (SiO₂) using packed or prepackaged cartridges, eluting with the indicated solvents.

0347LC/MS were obtained on a Waters 2695 Separations Unit, 2487 Dual Absorbance Detector, Micromass ZQ fitted with ESI Probe, or a Waters Acquity™ Ultra performance LC (UPLC) with PDA eλ and SQ detectors.

0348Nuclear magnetic resonance (NMR) spectra were obtained in a Varian 400 MHz or Bruker 400 MHz NMR. Samples were analyzed in either deuterated chloroform (CDCl₃), methanol-<i>d4</i> (CD₃OD), or dimethyl sulfoxide-<i>d</i>₆ (DMSO-<i>d</i>₆). For CDCl₃ samples, tetramethylsilane (TMS) was used as an internal standard with the TMS resonance set to a chemical shift of 0.00 ppm for ¹H NMR spectra. For CD₃OD the residual central resonance peak at 3.31 for ¹H was used for chemical shift assignment and for DMSO-<i>d</i>₆ the residual central resonance peak at 2.50 ppm for ¹H was used for chemical shift assignment. The format of the ¹H NMR data below is: chemical shift in ppm downfield the tetramethylsilane reference (multiplicity, coupling constant <i>J</i> in Hz, integration).

0349Chemical names were generated using ChemDraw Ultra 12.0 (CambridgeSoft Corp., Cambridge, MA) or ChemAxon.

Intermediate 1. 5-(Bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine.

0350<chemistry id="chem0035" num="0035"><img file="EP3345902A1_D0040.tif" /></chemistry><ul id="ul0005" list-style="none" compact="compact"><li>Step 1. 3-Bromo-5-methylpyrazin-2-amine. To a cooled, 0 °C, solution of 5-methylpyrazin-2-amine (5.00 g, 0.05 mol) in DCM (230 mL) was added 1-bromopyrrolidine-2,5-dione (8.97 g, 0.05 mol) all at once. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction was quenched with 1 N sodium thiosulfate (50 mL), the layers were separated and the organic phase was extracted with water (2 X 50 mL). The combined organic layers were dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 0 - 50%, EtOAc/hexanes) afforded the title compound as a yellow solid (8.61 g, 65%). [M+H] = 188.9/190.11</li><li>Step 2. 3-Bromo-2-ethoxy-5-methylpyrazine. To a solution of 3-bromo-5-methylpyrazin-2-amine (4.00 g, 21.27 mmol) in EtOH (42 mL), at 0 °C, was added <i>tert-butyl</i> nitrite (7.65 mL, 63.82 mmol) followed by 4 N HCl in 1,4-dioxane (1.91 mL, 7.66 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 8 h. The mixture was concentrated under reduced pressure. The residue was diluted with aq. NaHCO₃ and extracted into DCM. The combined organic layers were dried, and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 0 - 20%, EtOAc/hexanes) afforded the title compound as a white solid (2.5 g, 54%). [M+H] = 217.06/219.05.</li><li>Step 3. 3-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-methylpyrazine. A solution of 3-bromo-2-ethoxy-5-methylpyrazine (1.80 g, 8.29 mmol), 3-(difluoromethoxy)phenyl)boronic acid (2.03 g, 10.78 mmol), Pd(PPh₃)₄ (958.25 mg, 0.83 mmol), Na₂CO₃ (21.63 mL, 1.15 mol/L, 24.88 mmol), in EtOH (22 mL) and toluene (118 mL), under nitrogen, was heated at 88 °C for 1h. The reaction mixture was extracted with EtOAc. The combined organic layers were dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 0 - 50%, EtOAc/hexanes) afforded the title compound as a colorless oil (2.09 g, 90%). [M+H] = 281.19. Step 4. 5-(Bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine. To a solution of 3-(3-(difluoromethoxy)phenyl)-2-ethoxy-5-methylpyrazine (2.00 g, 0.01 mol), 1-bromopyrrolidine-2,5-dione (1.27 g, 0.01 mol) in carbon tetrachloride (24 mL), was added benzoylperoxide (0.26 g, 1.07 mmol). The mixture was heated at 88 °C for 8 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried (Na₂SO₄) and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 0 - 5%, EtOAc/hexanes) afforded the title compound contaminated with ∼10% starting material (1.5 g, 59 %). [M+H] = 459.13/361.13.</li></ul>

0351Intermediates 2-3 were prepared in a manner analogous to Intermediate 1, Steps 3-4, with the appropriated starting material substitutions.

Intermediate 2. 5-(Bromomethyl)-3-(3-chlorophenyl)-2-methoxypyridine.

0352<chemistry id="chem0036" num="0036"><img file="EP3345902A1_D0041.tif" /></chemistry> M+H] = 312.05/314.04

Intermediate 3. 5-(Bromomethyl)-3-(3-chlorophenyl)-2-methoxypyrazine.

0353<chemistry id="chem0037" num="0037"><img file="EP3345902A1_D0042.tif" /></chemistry> [M+H] = 313.17/315.19

Intermediate 4. 3-Bromo-2-(difluoromethoxy)-5-methylpyridine.

0354<chemistry id="chem0038" num="0038"><img file="EP3345902A1_D0043.tif" /></chemistry>

03553-Bromo-2-(difluoromethoxy)-5-methylpyridine. To a solution of 3-bromo-5-methylpyridin-2-ol (25.0 g, 0.13 mol) in ACN (100 mL) was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (23.7 g, 0.13 mol) and Na₂CO₃ (28.2 g, 0.270 mol). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was extracted with DCM. The combined organic layers were dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 0 - 10%, EtOAc/hexanes) afforded the title compound as an off-white solid (22 g, 70%). [M+H] = 238.09/240.09.

Intermediate 5. 5-((1H-1,2,4-Triazol-1-yl)methyl)-3-bromo-2-(difluoromethoxy)pyridine.

0356<chemistry id="chem0039" num="0039"><img file="EP3345902A1_D0044.tif" /></chemistry><ul id="ul0006" list-style="none" compact="compact"><li>Step 1. 3-Bromo-5-(bromomethyl)-2-(difluoromethoxy)pyridine. To a solution of 3-bromo-2-(difluoromethoxy)-5-methylpyridine (0.50 g, 2.1 mmol) in carbon tetrachloride (13 mL), was added 1-bromopyrrolidine-2,5-dione (0.521 g, 2.93 mmol), and azobisisobutyronitrile (44 mg, 0.26 mmol). The reaction mixture was stirred at 80 °C for 8 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 10 - 90%, EtOAc/hexanes) afforded the title compound (400 mg, 60 %). [M+H] = 317.88.</li><li>Step 2. 5-((1H-1,2,4-Triazol-1-yl)methyl)-3-bromo-2-(difluoromethoxy)pyridine. To a solution of 3-bromo-5-(bromomethyl)-2-(difluoromethoxy)pyridine (Intermediate 4, 0.50 g, 1.57 mmol), in acetone (12 mL), was added 1H-1,2,4-triazole (202 mg, 2.9 mmol), and K₂CO₃ (650 mg, 4.7 mmol). The reaction mixture stirred at room temperature for 2 h, then filtered and concentrated under reduced pressure. Purification (FCC, SiO₂, 30 - 70%, EtOAc/hexanes) afforded the title compound (431 mg, 90 %). [M+H] = 304.91/306.91.</li></ul>

Intermediate 6. 3-Bromo-2-ethoxy-5-methylpyridine.

0357<chemistry id="chem0040" num="0040"><img file="EP3345902A1_D0045.tif" /></chemistry>

0358To a solution of 3-bromo-2-chloro-5-methylpyridine (4.00 g, 19.37 mmol) in ethanol (100 mL) was added sodium ethoxide (6.59 g, 96.9 mmol) in three portions. The mixture was stirred under nitrogen at 100 °C for 2 days. The reaction was cooled to room temperature, diluted with water and extracted with DCM. The combined organic layers were dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 20%, EtOAc/hexanes) afforded the title compound (3.00 g, 72%). ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 7.94 (dd, <i>J</i> = 0.8, 2.3 Hz, 1H), 7.89 - 7.82 (m, 1H), 4.31 (q, <i>J</i> = 7.0 Hz, 2H), 2.18 (t, <i>J</i> = 0.8 Hz, 3H), 1.30 (t, <i>J</i> = 7.0 Hz, 3H).

Intermediate 7. 5-Bromo-3-(3-chlorophenyl)-2-methoxypyridine.

0359<chemistry id="chem0041" num="0041"><img file="EP3345902A1_D0046.tif" /></chemistry><ul id="ul0007" list-style="none" compact="compact"><li>Step 1. 5-(3-Chlorophenyl)-6-methoxypyridin-3-amine. A 10 mL microwave vial was charged with 5-bromo-6-methoxypyridin-3-amine (2.00 g, 10 mmol) (3-chlorophenyl)boronic acid (1.87 g, 12 mmol), Pd(dppf)Cl₂ · DCM (365 mg, 0.45 mmol), ACN (6 mL) and sat. aq. NaHCO₃ (3 mL). The vial was sealed, purged with nitrogen and heated at 110 °C for 15 min. The layers were separated and the aq. phase extracted with EtOAc. The combined organic layers were dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 0 - 50%, EtOAc/hexanes) afforded the title compound (1.95 g, 84%) which was taken on directly to the next step.</li><li>Step 2. 5-Bromo-3-(3-chlorophenyl)-2-methoxypyridine. A solution of 5-(3-chlorophenyl)-6-methoxypyridin-3-amine (1.95 g, 8.39 mmol), copper (II) bromide (3.72 g, 16.7 mmol), <i>tert-</i>butyl nitrite (1.7 g, 16.7 mmol) in ACN (50 mL), under nitrogen, was heated at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure. Purification (FCC, SiO₂, 0 - 10%, EtOAc/hexanes) afforded the title compound as an orange solid (1.53 g, 61%). [M+H] = 298.20/300.21.</li></ul>

Intermediate 8. 3-(Chloromethyl)-5-(3-chlorophenyl)-6-methoxy-2-methylpyridine.

0360<chemistry id="chem0042" num="0042"><img file="EP3345902A1_D0047.tif" /></chemistry><ul id="ul0008" list-style="none" compact="compact"><li>Step 1. 6-Amino-5-bromo-2-methylnicotinonitrile. A solution of 6-amino-2-methylnicotinonitrile (5 g, 37.6 mmol), NBS (7.36 g, 41.3 mmol) and DCM (100 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. Purification (FCC, SiO₂, 1:1 EtOAc/DCM) afforded the title compound as tan solid (4.5 g, 56%). [M+H] = 211.95/213.96.</li><li>Step 2. 5-Bromo-6-methoxy-2-methylnicotinonitrile. A solution of 6-amino-5-bromo-2-methylnicotinonitrile (4.5 g, 21.2 mmol), HCl (2 mL 4 N HCl in 1,4-dioxane), <i>tert</i>-butyl nitrite (6.56 g, 63.7 mmol) and methanol (50 mL) was heated at 60 °C for 12 h. The solvent was removed under reduced pressure. Purification (FCC, SiO₂, 0 - 25%, EtOAc/hexanes) afforded the title compound (2.5 g, 51%). [M+H] = 226.96/228.96.</li><li>Step 3. 5-(3-Chlorophenyl)-6-methoxy-2-methylnicotinonitrile. A 20 mL microwave vial was charged with 5-bromo-6-methoxy-2-methylnicotinonitrile (1.2 g, 5.28 mmol), (3-chlorophenyl)boronic acid (990 mg, 6.3 mmol), Pd(dppl)Cl₂ · DCM (191 mg, 0.26 mmol), ACN (10 mL) and sat. aq. NaHCO₃ (3 mL). The vial was sealed, purged with nitrogen and heated at 100 °C under microwave irradiation for 10 min. The layers were separated and the aq. phase extracted with EtOAc. The combined organic layers were dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 0 - 50%, EtOAc/hexanes) afforded the title compound as an off white solid (995 mg, 74 %). [M+H] = 259.06.</li><li>Step 4. 5-(3-Chlorophenyl)-6-methoxy-2-methylnicotinaldehyde. To a cooled solution, -78 °C, of 5-(3-chlorophenyl)-6-methoxy-2-methylnicotinonitrile (500 mg, 1.9 mmol) in DCM (15 mL), under nitrogen, was added DIBAL (1 M in hexanes, 4.8 mL, 4.8 mmol) drop-wise, over 3 minutes. The reaction mixture was stirred at -78 °C for 1 h. The reaction was carefully quenched by addition of saturated sodium fluoride (1 mL). After stirring for 30 minutes the suspension was filtered and the filtrate concentrated under reduced pressure. Purification (FCC, SiO₂, 0 - 50%, EtOAc/hexanes) afforded the title compound (358 mg, 72 %). [M+H] = 262.05.</li><li>Step 5. (5-(3-Chlorophenyl)-6-methoxy-2-methylpyridin-3-yl)methanol. To a solution of 5-(3-chlorophenyl)-6-methoxy-2-methylnicotinaldehyde (350 mg, 1.34 mmol) in methanol (3 mL) was added NaBH₄ (52 mg, 1.3 mmol). The solution was stirred at room temperature for 20 minutes then concentrated under reduced pressure. Purification (FCC, SiO₂, 0 - 50%, EtOAc/hexanes) afforded the title compound (322 mg, 91 %). [M+H] = 264.06.</li><li>Step 6. 3-(Chloromethyl)-5-(3-chlorophenyl)-6-methoxy-2-methylpyridine. Into a scintillation vial containing (5-(3-chlorophenyl)-6-methoxy-2-methylpyridin-3-yl)methanol (340 mg, 1.29 mmol) in DCM (5 mL), was added diisopropylethylamine (199 mg, 1.54 mmol), and methanesulfonyl chloride (147 mg, 1.29 mmol). The solution was stirred at room temperature for 1 h. The reaction mixture was extracted with water (3 x). The combined organic layers were dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 0 - 30%, EtOAc/hexanes) afforded the title compound (87 mg, 24 %). [M+H] = 282.03</li></ul>

Intermediate 9. 2-Difluoromethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine.

0361<chemistry id="chem0043" num="0043"><img file="EP3345902A1_D0048.tif" /></chemistry><ul id="ul0009" list-style="none" compact="compact"><li>Step 1. 4-Bromo-2-(difluoromethoxy)pyridine. To a stirring solution of 2-chloro-2,2-difluoroacetate (6.00 g, 39.4 mmol) in ACN (200 mL) was added 4-bromopyridin-2(1H)-one (4.90 g, 28.1 mmol). The mixture was refluxed for 8 h. The resulting mixture was filtered and the filtrate was extracted with hexanes (6 × 20 mL). The combined organic layers were dried (Na₂SO₄), and concentrated at room temperature to give the title compound as a liquid (2.60 g, 42% yield). ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.19-8.20 (s, 1H), 7.48 (s, 1H), 7.52 (s, 1H), 7.54 -7.88 (m, 1H).</li><li>Step 2. 2-Difluoromethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine. To a solution of 4-bromo-2-(difluoromethoxy)pyridine (7.20 g, 32.1 mmol), in 1,4-dioxane (230 mL), was added bis(pinacolato)diboron (8.80 g, 34.6 mmol), and potassium acetate (7.10 g, 71.9 mmol). The flask was fitted with a reflux condenser and vacuum/nitrogen inlet, and it was degassed/backfilled with nitrogen (3 X). The catalyst, Pd(dppf)Cl₂ (2.35 g, 3.2 mmol) was added, and the reaction mixture was refluxed for 8 h. The resulting mixture was filtered, and concentrated under reduced pressure. Purification (FCC, SiO₂, 1:1 petroleum ether/hexanes) afforded the title compound (6.10 g, 70%) as a liquid. ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.31-8.32 (d, <i>J</i> = 4.8 Hz, 1H), 7.52-7.89 (m, 1H), 7.42-7.44 (d, <i>J</i> = 4.8 Hz, 1H), 7.156 (s, 1H), 1.32 (s, 12H).</li></ul>

Intermediate 10. 5-(Bromomethyl)-2-(difluoromethoxy)-3-(3-(oxetan-3-yloxy)phenyl)pyridine.

0362<chemistry id="chem0044" num="0044"><img file="EP3345902A1_D0049.tif" /></chemistry><ul id="ul0010" list-style="none" compact="compact"><li>Step 1. 3-(2-(Difluoromethoxy)-5-methylpyridin-3-yl)phenol. A 20 mL microwave vial was charged with 3-bromo-2-(difluoromethoxy)-5-methylpyridine (Intermediate 4, 1.90 g, 7.98 mmol), 3-hydroxyphenylboronic acid (1.32 g, 9.58 mmol), Pd(dppl)Cl₂ (330 mg, 0.40 mmol), Na₂CO₃ (2.12 g, 19.96 mmol), water (4.0 mL), and ACN (12 mL). The vial was sealed, purged with nitrogen, and heated under microwave irradiation at 100 °C for 15 min. The reaction mixture was diluted with water and extracted with DCM (3 X). The combined organic phase was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Purification (FCC, SiO₂, 0-40% EtOAc/hexanes) afforded the title compound (1.81 g, 91%) as a colorless waxy solid. [M+H] = 252.12.</li><li>Step 2. 2-(Difluoromethoxy)-5-methyl-3-(3-(oxetan-3-yloxy)phenyl)pyridine. To a solution of 3-(2-(difluoromethoxy)-5-methylpyridin-3-yl)phenol (502.5 mg, 2.0 mmol), in DMF, was added oxetan-3-yl 4-methylbenzenesulfonate (685 mg, 3.0 mmol), and K₂CO₃ (553 mg, 4.00 mmol). The reaction mixture was stirred at 60 °C for 8 h. LC-MS suggested about 50 % conversion. The temperature was raised to 90 °C and the reaction mixture was stirred an additional 4 h. Sat. aq. NaCl was added, and the mixture was extracted with DCM (3 X). The combined organic layers were dried (Na₂SO₄), filtered and concentrated under reduced pressure. Purification (FCC, SiO₂, 10-30% EtOAc/hexanes) afforded the title compound (310 mg, 50%) as a colorless solid. [M+H] = 308.11</li><li>Step 3. 5-(Bromomethyl)-2-(difluoromethoxy)-3-(3-(oxetan-3-yloxy)phenyl)pyridine. To a solution of 2-(difluoromethoxy)-5-methyl-3-(3-(oxetan-3-yloxy)phenyl)pyridine (310 mg, 1.0 mmol) in carbon tetrachloride (10 mL), was added 1-bromopyrrolidine-2,5-dione (180 mg, 1.0 mmol), and benzoylperoxide (37 mg, 0.15 mmol). The reaction mixture was stirred at 80 °C for 8 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 10 - 30%, EtOAc/hexanes) afforded the title compound (140 mg, 36 %). [M+H] = 387.21</li></ul>

Intermediate 11. 5-(Bromomethyl)-2-(difluoromethoxy)-3-(3-isopropoxyphenyl)pyridine.

0363<chemistry id="chem0045" num="0045"><img file="EP3345902A1_D0050.tif" /></chemistry>

0364The title compound was prepared in a manner analogous to Intermediate 10, using 2-bromopropane for step 2, followed by bromination according to step 3. [M+H] = 373.24.

Intermediate 12. 5-(Bromomethyl)-3-(3-chlorophenyl)-2-(difluoromethoxy)pyridine.

0365<chemistry id="chem0046" num="0046"><img file="EP3345902A1_D0051.tif" /></chemistry>

0366The title compound was prepared in a manner analogous to Intermediate 10, using Intermediate 4 and 3-chlorophenyl boronic acid in Step 1, followed by bromination according to Step 3. [M+H] = 348.17/350.15

Intermediate 13. 5-((1H-1,2,4-Triazol-1-yl)methyl)-3-bromo-2-methoxypyridine.

0367<chemistry id="chem0047" num="0047"><img file="EP3345902A1_D0052.tif" /></chemistry>

0368The title compound was prepared in a manner analogous to Intermediate 5, with the appropriate starting material substitutions. [M+H] = 269.21/271.23

Intermediate 14. Ethyl 5-bromo-6-ethoxynicotinate.

0369<chemistry id="chem0048" num="0048"><img file="EP3345902A1_D0053.tif" /></chemistry>

0370Step 1. 5-Bromo-6-chloronicotinoyl chloride. To a solution of 5-bromo-6-chloronicotinic acid (10.00 g, 42.29 mmol) in DCM (211.46 mL) was added oxalyl dichloride (42.29 mL, 84.58 mmol) and a few drops of DMF. The reaction mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure to afford the crude title compound (9.0 g, 83%). The crude material was used without further purification. [M+H] = 253.2/255.2/257.2. Step 2. Ethyl 5-bromo-6-ethoxynicotinate. To a slurry of 5-bromo-6-chloronicotinoyl chloride (5.00 g, 19.62 mmol) in EtOH (100 mL) was added sodium ethoxide (22.0 mL, 21.00 %w/w, 58.85 mmol). The reaction mixture was stirred in room temperature for 75 minutes. The product crystallized out after the addition of 2 volumes of water in an ice bath. The solid was filtered, washed with hexanes and water to obtain the title compound (4.5 g, 84%). ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.66 (br s, 1H), 8.34 (br s, 1H), 4.48 - 4.37 (m, 2H), 4.37 - 4.16 (m, 2H), 1.32 (td, <i>J</i> = 6.9, 18.7 Hz, 6H); [M+H] = 274.3/276.3.

Intermediate 15. Methyl 5-bromo-6-methoxynicotinate.

0371<chemistry id="chem0049" num="0049"><img file="EP3345902A1_D0054.tif" /></chemistry>

0372To a slurry of methyl 5-bromo-6-chloronicotinate (10.00 g, 39.92 mmol) in MeOH (80.00 mL) was added sodium methoxide (2.59 g, 47.91 mmol). The reaction mixture was stirred in rt for 2 h. The product crystallized out. The slurry was cooled to 0 °C and water (80 mL) was added and stirred for 30 min., then filtered. The solid cake was washed with water and dried to afford the title compound (9.05 g, 92 %). [M+H] = 246.2.

Intermediate 16. (5-Bromo-6-ethoxypyridin-3-yl)methanol.

0373<chemistry id="chem0050" num="0050"><img file="EP3345902A1_D0055.tif" /></chemistry>

0374A solution of ethyl 5-bromo-6-ethoxynicotinate (Intermediate 14, 1.06 g, 3.85 mmol) in 2-methoxy-2-methylpropane (10.50 mL) was cooled to 0 °C and DIBAL (9 mL, 9.00 mmol) was slowly added while keeping the temperature under 25 °C. After the addition was complete, the mixture was stirred at room temperature for 45 minutes. The reaction was cooled to 0 °C, then quenched with aq NaOH (5.78 mL, 11.56 mmol) and stirred at room temperature for 1 h. The mixture was diluted with MTBE and water, then extracted into MTBE. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure to afford the title compound (0.87 g, 97%) as a white solid. The crude material was used without further purification. [M+H] = 232.3/234.3.

Intermediate 17. 3-Bromo-5-(chloromethyl)-2-ethoxypyridine.

0375<chemistry id="chem0051" num="0051"><img file="EP3345902A1_D0056.tif" /></chemistry>

0376A solution of (5-bromo-6-ethoxypyridin-3-yl)methanol (13.44 g, 57.91 mmol) in DCM (250 mL) was cooled to 0 °C and thionyl chloride (6.74 mL, 92.63 mmol) was slowly added. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM (250 mL), and the pH was adjusted to basic pH with a sat. aq. solution of NaHCO₃. The crude product was extracted into DCM (3 x 250 mL) and the combined organic extracts were washed with water (100 mL). The organics were dried (Na₂SO₄), filtered and concentrated under reduced pressure to afford the title compound (13.6 g, 94%). The crude material was used without further purification. [M+H] = 250.2/252.2.

Intermediate 18. Methyl 1-((5-bromo-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate.

0377<chemistry id="chem0052" num="0052"><img file="EP3345902A1_D0057.tif" /></chemistry>

0378A solution of 3-bromo-5-(chloromethyl)-2-ethoxypyridine (13.60 g, 54.29 mmol), CHCl₃ (250 mL), 18-Crown-6 (12.20 g, 46.14 mmol), K₂CO₃ (15.01 g, 108.57 mmol) and methyl 1H-1,2,4-triazole-3-carboxylate (10.70 g, 84.18 mmol) was stirred at 35 °C for 17 h. Celite® was added to the reaction and the mixture concentrated in vacuo to give the crude material fused to Celite®. Purification (FCC, SiO₂, 10-100% EtOAc/hexanes) afforded the title compound (11.76 g, 64%). [M+H] = 341.3/343.3.

Intermediate 19. (1-((5-Bromo-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol.

0379<chemistry id="chem0053" num="0053"><img file="EP3345902A1_D0058.tif" /></chemistry>

0380(1-((5-Bromo-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol. A solution of methyl 1-((5-bromo-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate (11.76 g, 34.47 mmol) in THF (100 mL) was cooled to 0 °C, LiBH₄ (787.00 mg, 36.13 mmol) added and the mixture was warmed to 25 °C over 3 h. Water (10 mL), IN NaOH (10 mL) and Celite® were added to the reaction and the mixture concentrated in vacuo to give the crude material fused to Celite®. Purification (FCC, SiO₂, 0-15% MeOH/DCM) afforded the title compound (9.36 g, 87%) as a white solid. [M+H] = 313.3/315.3.

Intermedate 20. (5-Bromo-6-propoxypyridin-3-yl)methanol.

0381<chemistry id="chem0054" num="0054"><img file="EP3345902A1_D0059.tif" /></chemistry><ul id="ul0011" list-style="none" compact="compact"><li>Step 1. 5-Bromo-6-propoxynicotinic acid. A mixture of 5-bromo-6-chloronicotinic acid (2.00 g, 8.46 mmol), propan-1-ol (10 mL, 133.69 mmol) and Cs₂CO₃ (5.51 g, 16.92 mmol) were irradiated in a microwave at 120 °C for 1h. The mixture was additionally irradiated a further 8 h at 120 °C. The mixture was diluted with DCM (100 mL) and water (100 mL). The aqueous layer was made acidic with 1 N aq. HCl, and extracted into DCM (3 x 100 mL). The combined organic extracts were washed with sat. aq. NaCl (100 mL), dried (Na₂SO₄), filtered and concentrated under reduced pressure to afford the title compound (2.04 g, 93%) as a cream solid. The crude material was used without further purification. ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 13.30 (s, 1H), 8.59 - 8.76 (m, 1H), 8.35 (d, <i>J</i> = 1.96 Hz, 1H), 4.28 - 4.45 (m, 2H), 1.61 - 1.86 (m, 2H), 0.99 (t, <i>J</i> = 7.43 Hz, 3H); [M+H] = 260.3/262.3.</li><li>Step 2. (5-Bromo-6-propoxypyridin-3-yl)methanol. A mixture of 5-bromo-6-propoxynicotinic acid (1.61 g, 6.19 mmol), THF (15.06 mL) and TEA (1.73 mL, 12.38 mmol) was cooled to 0 °C, methyl chloroformate (0.72 mL, 9.29 mmol) added and the mixture stirred at 0 °C for 2 h. The mixture was filtered, (the solid) rinsed with more THF (20 mL), cooled to 0 °C, NaBH₄ (0.47 g, 12.38 mmol) added and the mixture stirred at 0 °C for 90 min. LiBH₄ (0.18 g, 8.05 mmol) was added and the mixture stirred at room temperature for 17 h. The reaction mixture was diluted with DCM (100 mL) and water (100 mL), the layers separated and the aqueous layer extracted into DCM (3 x 80 mL). The extracts were dried (Na₂SO₄), filtered, Celite® added and the solvent removed to give the crude alcohol fused to Celite®. Purification (FCC, SiO₂, 5-40% EtOAc/hexanes) afforded the title compound (966 mg, 63%). [M+H] = 246.3/248.3.</li></ul>

Intermediate 21. (5-(3,4-Difluorophenyl)-6-propoxypyridin-3-yl)methanol.

0382<chemistry id="chem0055" num="0055"><img file="EP3345902A1_D0060.tif" /></chemistry>

0383Nitrogen gas was bubbled through a solution of (5-bromo-6-propoxypyridin-3-yl)methanol (Intermeidate 20, 483 mg, 1.96 mmol), (3,4-difluorophenyl)boronic acid (464.8 mg, 2.94 mmol), K₂CO₃ (813.7 mg, 5.89 mmol) in water (2.9 mL), Pd(dppf)Cl₂ (215.4 mg, 0.29 mmol) added and the mixture irradiated with stirring in a microwave at 120 °C for 20 minutes. Celite® was added to the reaction and the mixture concentrated in vacuo to give the crude material fused to Celite®. Purification (FCC, SiO₂, 5-100% EtOAc/hexanes) afforded the title compound (547 mg, 100%). [M+H] = 280.4.

Intermediate 22. 5-(Chloromethyl)-3-(3,4-difluorophenyl)-2-propoxypyridine.

0384<chemistry id="chem0056" num="0056"><img file="EP3345902A1_D0061.tif" /></chemistry>

0385The title compound was prepared in a manner analogous to Intermediate 17, substituting (5-(3,4-difluorophenyl)-6-propoxypyridin-3-yl)methanol (Intermediate 21) for (5-bromo-6-ethoxypyridin-3-yl)methanol. [M+H] = 298.4.

Intermediate 23. (5-Bromo-6-methoxypyridin-3-yl)methanol.

0386<chemistry id="chem0057" num="0057"><img file="EP3345902A1_D0062.tif" /></chemistry>

0387To a solution of methyl 5-bromo-6-methoxynicotinate (8.00 g, 32.51 mmol) in THF (162.56 mL) was added LiBH₄ (1.06 g, 48.77 mmol). MeOH (40.64 mL) was slowly added to the reaction, with vigorous stirring. The reaction was allowed to stir at room temperature for 2 h. 2N NaOH was added to the reaction mixture the mixture was stirred at room temp for 1 h. The crude mixture was added to EtoAc and H₂O, the organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Purification (FCC, SiO₂) afforded the title compound (6.00 g, 84%). [M+H] = 218.2.

Intermediate 24. (5-(4-Fluorophenyl)-6-methoxypyridin-3-yl)methanol.

0388<chemistry id="chem0058" num="0058"><img file="EP3345902A1_D0063.tif" /></chemistry>

0389A solution of (5-bromo-6-methoxypyridin-3-yl)methanol (Intermediate 23, 2.45 g, 11.24 mmol), (4-fluorophenyl)boronic acid (1.97 g, 14.05 mmol), Na₂CO₃ (29.31 mL, 1.15 mol/L, 33.71 mmol) and Pd(dppl)Cl₂ (822.15 mg, 1.12 mmol) in ACN (74.91 mL) was heated under microwave conditions at 120 °C for 20 min. The aq. layer was removed and the organic layer was dried (Na₂SO₄). The Na₂SO₄ was washed with EtOAc (3 x 15 mL). Purification (FCC, SiO₂, 10% MeOH /90% EtOAc) afforded the title compound (2.0 g, 76%). [M+H] = 234.50.

Intermediate 25. 3-Bromo-5-(chloromethyl)-2-methoxypyridine

0390<chemistry id="chem0059" num="0059"><img file="EP3345902A1_D0064.tif" /></chemistry>

0391The title compound was prepared in a manner analogous to Intermediate 17 using Intermediate 23. [M+H] = 235.9/237.9.

Intermediate 26. 3-(3-Chloro-4-fluorophenyl)-5-(chloromethyl)-2-methoxypyridine.

0392<chemistry id="chem0060" num="0060"><img file="EP3345902A1_D0065.tif" /></chemistry>

0393The title compound was prepared in a manner analogous to Intermediate 17. [M+H] = 286.25.

Intermediate 27. 5-(Chloromethyl)-3-(3-chlorophenyl)-2-methoxypyridine.

0394<chemistry id="chem0061" num="0061"><img file="EP3345902A1_D0066.tif" /></chemistry>

0395To a mixture of 6-methoxy nicotinaldehyde (24 g, 0.175 mol) and NaOAc (28.7 g, 0.35 mol) in HOAc (180 mL) was added Br₂ (42 g, 0.263 mol) over 20 min. The mixture was stirred and heated to 90 °C for 5 h. The mixture was cooled to rt and poured to iced water. The resultant mixture was neutralized to pH 9 with saturated aq. NaOH (10 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was washed with brine (100 mL), filtered, dried (Na₂SO₄), filtered, and concentrated under reduced pressure to provide the title compound (7 g, 22%). The title compound was used crude in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 9.93 (s, 1H), 8.57 (s, 1H), 8.31 (s, 1H), 4.12 (s, 3H).

Intermediate 28. 5-(3-Chlorophenyl)-6-methoxynicotinaldehyde.

0396<chemistry id="chem0062" num="0062"><img file="EP3345902A1_D0067.tif" /></chemistry>

0397The title compound was prepared in a manner analogous to Intermediate 1, Step 3, employing 5-bromo-6-methoxynicotinaldehyde and 3-chlorophenylboronic acid in THF/water, at 75 °C under N₂ overnight. ¹H NMR (400 MHz, CDCl₃) δ 10.03 (s, 1 H), 8.65 (d, <i>J</i> = 2.4 Hz, 1 H), 8.09 (d, <i>J</i> = 2.4 Hz, 1 H), 7.57, (d, <i>J</i> = 0.88 Hz, 1 H), 7.42-7.46 (m, 1 H), 7.36-7.41 (m, 2 H), 4.09 (s, 3 H).

Intermediate 29. (5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methanol.

0398<chemistry id="chem0063" num="0063"><img file="EP3345902A1_D0068.tif" /></chemistry>

0399To a solution of 5-(3-chlorophenyl)-6-methoxynicotinaldehyde (18 g, 0.072 mol) in EtOH (150 mL) was added NaBH₄ (5.5 g, 0.144 mol) at 0 °C. The reaction mixture was stirred at room temperature under N₂ for 2 h. To the mixture was added HCl (1 M, 5 mL) dropwise, followed by water (100 mL) at 0 °C. The mixture was extracted with EtOAc (2 x 100 mL). The organic layers were combined, washed with brine (100 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure to afford the title compound (16.2 g, 90 %) as a yellow solid, which was used for next step without further purified.

Intermediate 30. 5-(Chloromethyl)-3-(3-chlorophenyl)-2-methoxypyridine.

0400<chemistry id="chem0064" num="0064"><img file="EP3345902A1_D0069.tif" /></chemistry>

0401The title compound was prepared in a manner analogous to Intermediate 17, employing (5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methanol. ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, <i>J</i> = 2.0 Hz, 1H), 7.66 (d, <i>J</i> = 2.0 Hz, 1H), 7.55-7.66 (d, <i>J</i> = 2.0 Hz, 1H) 7.35-7.44 (m, 3H), 4.61 (s, 2H), 3.99 (s, 3H).

Intermediate 31. 3-(3-Chlorophenyl)-2-methoxy-5-((4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2-yl)methyl)pyridine.

0402<chemistry id="chem0065" num="0065"><img file="EP3345902A1_D0070.tif" /></chemistry>

0403The title compound was prepared in a manner analogous to Intermediate 9, employing 5-(chloromethyl)-3-(3-chlorophenyl)-2-methoxypyridine, substituting K₂CO₃ and Pd(PPh₃)₄ (114 mg, 0.10 mmol) for potassium acetate and Pd(dppl)Cl₂. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, <i>J</i> = 2.35 Hz, 1H), 7.55 (t, <i>J</i> = 1.76 Hz, 1H), 7.42-7.47 (m, 2H), 7.29-7.37 (m, 2H), 3.95 (s, 3H), 2.24 (s, 2H), 1.26 (s, 12H).

Intermediate 32. 3-Bromo-2-ethoxy-5-((5-methyl-1H-tetrazol-1-yl)methyl)pyridine.

0404<chemistry id="chem0066" num="0066"><img file="EP3345902A1_D0071.tif" /></chemistry>

0405A solution of 3-bromo-5-(chloromethyl)-2-ethoxypyridine (2.84 g, 11.34 mmol), NaI (169.93 mg, 1.13 mmol), K₂CO₃ (3.13 g, 22.67 mmol) and 5-methyl-2H-tetrazole (1.91 g, 22.67 mmol) in ACN (50 mL) was stirred at rt for 72 h. The reaction mixture was filtered and concentrated under reduced pressure. Purification (FCC, SiO₂, hexanes/EtOAc, 0-100%) provided the title compound as an oil (1.83 g, 54%). ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, <i>J</i> = 2.35 Hz, 1H), 7.74 (d, <i>J</i> = 2.35 Hz, 1H), 5.40 (s, 2H), 4.44 (q, <i>J</i> = 7.04 Hz, 2H), 2.54 (s, 3H), 1.43 (t, <i>J</i> = 7.04 Hz, 3H).

Intermediate 33. Ethyl 2-(2-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-tetrazol-5-yl)acetate.

0406<chemistry id="chem0067" num="0067"><img file="EP3345902A1_D0072.tif" /></chemistry>

0407The title compound was prepared in a manner analogous to Intermediate 32, with the appropriate starting material substitutions. ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, <i>J</i> = 2.35 Hz, 1H), 7.55 (d, <i>J</i> = 2.35 Hz, 1H), 7.50-7.52 (m, 1H), 7.34-7.38 (m, 3H), 5.59 (s, 2H), 4.20 (q, <i>J</i> = 7.30 Hz, 2H), 4.00 (s, 3H), 3.97 (s, 2H), 1.27 (t, <i>J</i> = 7.24 Hz, 3H).

Intermediate 34. 3-Bromo-2-ethoxy-5-((5-methyl-2H-tetrazol-2-yl)methyl)pyridine.

0408<chemistry id="chem0068" num="0068"><img file="EP3345902A1_D0073.tif" /></chemistry>

0409Isolated from Intermediate 32 reaction. White solid (1.32 g, 39%) ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, <i>J</i> = 2.35 Hz, 1H), 7.87 (d, <i>J</i> = 1.96 Hz, 1H), 5.61 (s, 2H), 4.44 (q, <i>J</i> = 7.04 Hz, 2H), 2.53 (s, 3H), 1.39-1.49 (m, 3H).

Intermediate 35. (1-((5-Bromo-6-methoxypyridin-3-yl)methyl)-2-methyl-1H-imidazol-4-yl)methanol.

0410<chemistry id="chem0069" num="0069"><img file="EP3345902A1_D0074.tif" /></chemistry><ul id="ul0012" list-style="none" compact="compact"><li>Step 1. 1-((5-Bromo-6-methoxypyridin-3-yl)methyl)-2-methyl-1H-imidazole-4-carbaldehyde. 3-Bromo-5-(chloromethyl)-2-methoxypyridine (Intermediate 25, 630 mg, 2.66 mmol) in acetone (10 mL) was added Cs₂CO₃ (1.32 g, 4.0 mmol) and NaI (39.93 mg, 0.27 mmol). The reaction mixture was allowed to stir for 3 h. The mixture was diluted with DCM and filtered. The filtrate was dried (Na₂SO₄), filtered, and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 20 - 100%, EtOAc/hexanes) afforded the title compound as which was directly taken into the next step.</li><li>Step 2. (1-((5-Bromo-6-methoxypyridin-3-yl)methyl)-2-methyl-1H-imidazol-4-yl)methanol. 1-((5-Bromo-6-methoxypyridin-3-yl)methyl)-2-methyl-1H-imidazole-4-carbaldehyde (347 mg, 1.12 mmol) in MeOH (5 mL) was added NaBH₄ (42.33 mg, 1.22 mmol). The reaction mixture was allowed to stir at room temperature for 0.5 h. The mixture was diluted with water and extracted into DCM. The organic fractions were dried (Na₂SO₄), filtered, and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 50 - 100%, EtOAc/hexanes) afforded the title compound.</li></ul>

Intermediate 36. 1-((5-Bromo-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-amine.

0411<chemistry id="chem0070" num="0070"><img file="EP3345902A1_D0075.tif" /></chemistry><ul id="ul0013" list-style="none" compact="compact"><li>Step 1. 3-Bromo-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine. The title compound was prepared in a manner analogous to Intermediate 5 with the appropriate starting material substitutions.</li><li>Step 2. 1-((5-Bromo-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-amine. To a solution of 3-bromo-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine (1.0 g, 3.18 mmol) in AcOH (15 mL), and water (4 mL) was added zinc (2.07 g, 31.8 mmol). The mixture was stirred at 50 °C for 1 hr. The solvent was removed under reduced pressure to afford a white solid. The crude solid was dissolved in DCM (50 mL), sonicated and filtered (repeated twice). The combined DCM extracts were washed with sat. aq. NaHCO₃ and the layers separated. The organic layers were combined, dried (Na₂SO₄) and concentrated under reduced pressure. The resulting solid was triturated with hexanes to give the title compound.</li></ul>

Intermediate 37. 5-(Chloromethyl)-2-methoxy-[3,4'-bipyridine]-2'-carbonitrile.

0412<chemistry id="chem0071" num="0071"><img file="EP3345902A1_D0076.tif" /></chemistry><ul id="ul0014" list-style="none" compact="compact"><li>Step 1. 2'-Chloro-2-methoxy-[3,4'-bipyridine]-5-carbaldehyde. The title compound was prepared in a manner analogous to Intermediate 8 Step 3, employing 5-bromo-6-methoxynicotinaldehyde (Intermediate 27) and (2-chloropyridin-4-yl)boronic acid. [M+H] = 249.25.</li><li>Step 2. 5-Formyl-2-methoxy-[3,4'-bipyridine]-2'-carbonitrile. Into a 10 mL microwave vial were added 2'-chloro-2-methoxy-[3,4'-bipyridine]-5-carbaldehyde (684 mg, 2.75 mmol), dicyanozinc (226 mg, 1.93 mmol), Pd(PPh₃)₄ (318 mg, 0.28 mmol), and DMF (15 mL). The vial was capped, purged with nitrogen, then heated at 150 °C for 15 min. The reaction mixture was diluted with EtOAc and extracted with water. The remaining organic phase was treated with brine, dried (NaSO₄), filtered and concentrated. Purification (FCC, SiO₂, 0-75% EtOAc/hexanes) afforded the title compound (602.00 mg, 91%). [M+H] = 240.28.</li><li>Step 3. 5-(Hydroxymethyl)-2-methoxy-[3,4'-bipyridine]-2'-carbonitrile. Into a 100 mL round bottomed flask containing 5-formyl-2-methoxy-[3,4'-bipyridine]-2'-carbonitrile (602 mg, 2.52 mmol) was added MeOH (25 mL) followed by NaBH₄ (95 mg, 2.52 mmol). The rxn mixture was stirred at rt for 10 min. The reaction was was quenched with HCl (1 mL), then concentrated. The residue was diluted with sat. aq. NaHCO₃ and EtOAc. The layers were separated, and the organic phase was extracted with EtOAc. The combined organic phase was dried (Na₂SO₄), filtered and concentrated to afford the title compound (219 mg, 36%) as a white solid. The crude material was used without further purification. [M+H] = 242.30.</li><li>Step 4. 5-(Chloromethyl)-2-methoxy-[3,4'-bipyridine]-2'-carbonitrile. To a solution of 5-(hydroxymethyl)-2-methoxy-[3,4'-bipyridine]-2'-carbonitrile (219.3 mg, 0.91 mmol) in DCM (10 mL) was added thionyl chloride (130 µL, 1.82 mmol). The reaction mixture was stirred at rt for 2.5 h then concentrated to afford the title compound as a yellow solid (0.2225 g, 94%). [M+H] = 260.27.</li></ul>

Intermediate 38. 5-(Chloromethyl)-2'-ethoxy-2-methoxy-3,4'-bipyridine.

0413<chemistry id="chem0072" num="0072"><img file="EP3345902A1_D0077.tif" /></chemistry><ul id="ul0015" list-style="none" compact="compact"><li>Step 1. (2'-chloro-2-methoxy-[3,4'-bipyridin]-5-yl)methanol. The title compound was prepared in a manner analogous to Intermediate 8, Step 3, employing (5-bromo-6-methoxypyridin-3-yl)methanol (Intermediate 23) and (2-chloropyridin-4-yl)boronic acid. [M+H] = 251.30.</li><li>Step 2. (2'-Ethoxy-2-methoxy-[3,4'-bipyridin]-5-yl)methanol. A solution of (2'-chloro-2-methoxy-[3,4'-bipyridin]-5-yl)methanol (925 mg, 3.69 mmol) in 21% w/w NaOEt in EtOH (22 mL) was heated at 75 °C for 8 h under nitrogen. The rxn mixture was cooled to rt, diluted with EtOAc, washed with 1M citric acid (2 X), dried (Na₂SO₄), filtered and concentrated. Purification (FCC, SiO₂, 0-75% EtOAc/hexanes afforded (0.499 g, 52 %) of the title compound as an amber oil. [M+H] = 261.39.</li><li>Step 3. 5-(Chloromethyl)-2'-ethoxy-2-methoxy-3,4'-bipyridine. A solution of (2'-ethoxy-2-methoxy-[3,4'-bipyridin]-5-yl)methanol (499.30 mg, 1.92 mmol) in DCM (10 mL) and tetrahydrofuran (5 mL) was cooled in an ice-water bath for 5 min. Thionyl chloride (0.35 mL, 4.8 mmol) was added dropwise over 1 min. A white ppt formed immediately. The rxn mixture was stirred for 1 h at rt, then quenched with sat. aq. NaHCO₃. The layers were separated, and the aq. phase was extracted with DCM. The combined organic phase was dried (NaSO₄), filtered and concentrated to give (543 mg, 101 %) of the title compound as an amber oil. [M+H] = 278.38.</li></ul>

Intermediate 39. 5-(Chloromethyl)-2-(2,2-difluoroethoxy)-2'-ethoxy-3,4'-bipyridine.

0414<chemistry id="chem0073" num="0073"><img file="EP3345902A1_D0078.tif" /></chemistry>

0415The title compound was prepared in a manner analogous to Intermediate 38, employing (5-bromo-6-(2,2-difluoroethoxy)pyridin-3-yl)methanol and (2-chloropyridin-4-yl)boronic acid in Step 1. [M+H] = 329.37.

Intermediate 40. 5-(Chloromethyl)-3-(3-chlorophenyl)-2-(2,2-difluoroethoxy)pyridine.

0416<chemistry id="chem0074" num="0074"><img file="EP3345902A1_D0079.tif" /></chemistry>

0417The title compound was prepared in a manner analogous to Intermediate 38, employing (5-bromo-6-(2,2-difluoroethoxy)pyridin-3-yl)methanol and (2-chlorophenyl)boronic acid in Step 1. [M+H] = 318.30.

Intermediate 41. 5-(Chloromethyl)-3-(3-chlorophenyl)-2-(2,2,2-trifluoroethoxy)pyridine.

0418<chemistry id="chem0075" num="0075"><img file="EP3345902A1_D0080.tif" /></chemistry><ul id="ul0016" list-style="none" compact="compact"><li>Step 1. Methyl 5-bromo-6-(2,2,2-trifluoroethoxy)nicotinate. To a solution of methyl 5-bromo-6-chloronicotinate (3.00 g, 11.98 mmol) in THF (5 mL) was added 2,2,2-trifluoroethanol (1.44 g, 14.37 mmol). The solution was cooled in an ice-water bath under nitrogen for 5 minutes, then potassium <i>tert</i>-butoxide (12.58 mL, 1.00 mol/L, 12.58 mmol) was added dropwise over 5 minutes. The reaction mixture was stirred for 16 h, then diluted with NaHCO₃ and EtOAc. The layers were separated, and the organic phase was washed with water, and brine. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Purification (FCC, SiO₂, 0-15% EtOAc/hexanes) afforded the title compound (2.355 g, 63%) as a white solid. [M+H] = 314.22/317.22.</li><li>Step 2. (5-Bromo-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol. To a cooled solution, 0 °C, of 5-bromo-6-(2,2,2-trifluoroethoxy)nicotinate (2.36 g, 7.50 mmol) in THF (20 mL) under nitrogen, was added DIBAL (15.00 mL, 1.00 mol/L, 15.00 mmol) over 2 min. The reaction mixture was allowed to warm to rt where it was stirred for 8 h. The rxn mixture was concentrated then diluted with DCM and stirred 48 h with 1M NaOH (25 mL). The layers were separated, and the aq. phase was extracted with DCM. The combined organic phase was dried (Na₂SO₄), filtered, and concentrated to yield (2.778 g, 130 %) of the title compound as a colorless oil. [M+H] = 286.23/288.23.</li><li>Step 3. (5-(3-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol. To a solution of (5-bromo-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (1.50 g, 5.24 mmol) in ACN (10.0 mL) was added 3-chloro-phenyl-boronic acid (902.02 mg, 5.77 mmol), Pd(dppl)Cl₂.DCM (42.82 mg, 0.05 mmol), and 2 M aq. Na₂CO₃ (10.0 mL). The reaction mix was purged with nitrogen and heated under microwave irradiation for 30 min at 100 °C. The layers were separated, and the aqueous phase was extracted with EtOAc. Purification (FCC, SiO₂, 0-50% EtOAc/ hexanes) provided the title compound (1.0937 g, 6₆) as an amber oil. [M+H] = 318.30. Step 4. 5-(Chloromethyl)-3-(3-chlorophenyl)-2-(2,2,2-trifluoroethoxy)pyridine. To a cooled, 0 °C, solution of (5-(3-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (1.09 g, 3.4 mmol) in DCM (15.0 mL), was added thionyl chloride (0.63 mL, 8.6 mmol) dropwise over 1 min. A white ppt formed immediately. After stirring 1 h at rt, more thionyl chloride (300 µL) was added, and the reaction mixture was stirred for additional 8 h. The reaction was quenched with sat. aq. NaHCO₃, the layers were separated, and the aq. phase was extracted with DCM. The combined organic phase was dried (NaSO₄), filtered and concentrated to afford (0.9143 g, 79 %) of the title compound as an amber oil. [M+H] = 336.24.</li></ul>

Intermediate 42. 5-(Chloromethyl)-2'-(difluoromethoxy)-2-methoxy-3,4'-bipyridine.

0419<chemistry id="chem0076" num="0076"><img file="EP3345902A1_D0081.tif" /></chemistry>

0420The title compound was prepared in a manner analogous to Intermediate 38, Steps 1 and Step 3, employing 2-(difluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and (5-bromo-6-methoxypyridin-3-yl)methanol (Intermediate 23) in Step 1. [M+H] = 301.04.

Intermediate 43. 5-(Chloromethyl)-2'-(difluoromethoxy)-2-ethoxy-3,4'-bipyridine.

0421<chemistry id="chem0077" num="0077"><img file="EP3345902A1_D0082.tif" /></chemistry>

0422The title compound was prepared in a manner analogous to Intermediate 38. [M+H] = 315.05.

Intermediate 44. Methyl 5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine-2-carboxylate.

0423<chemistry id="chem0078" num="0078"><img file="EP3345902A1_D0083.tif" /></chemistry><ul id="ul0017" list-style="none" compact="compact"><li>Step 1. 5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine-2-carbonitrile. The title compound was prepared analogous to Intermediate 7, Step 1, employing 5-(chloromethyl)-3-(3-chlorophenyl)-2-methoxypyridine (Intermediate 30) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile, and substituting Pd(PPh₃)₄ for Pd(dppf)Cl₂ · DCM. [M+H] = 337.34.</li><li>Step 2. Methyl 5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine-2-carboxylate. To a cooled, 0 °C, solution of wet MeOH was added acetyl chloride (2.0 mL) dropwise over 5 min. The reaction mix was stirred an additional 35 min. at 0 °C, then added to 5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine-2-carbonitrile (278.4 mg, 0.83 mmol). The reaction mix was heated to 50 °C for 2.5 h. The rxn mixture was concentrated, diluted with EtOAc, neutralized with sat. aq. NaHCO₃. The layers organic phase was separated, washed with brine, dried (Na₂SO₄), filtered and concentrated under reduced pressure to afford (277.5 mg, 91%) of the title compound as a colorless oil that contains some of the corresponding carboxylic acid. The title compound was used crude in the next step. [M+H] = 370.37.</li></ul>

Intermediate 45. Methyl 5-((2-(2,2-difluoroethoxy)-2'-ethoxy-[3,4'-bipyridin]-5-yl)methyl)-3-fluoropicolinate.

0424<chemistry id="chem0079" num="0079"><img file="EP3345902A1_D0084.tif" /></chemistry>

0425Prepared in the same manner as Interemediate 44 using intermediate Intermediate 39. [M+H] = 448.39.

Intermediate 46. 5-(Bromomethyl)-3-(3,4-difluorophenyl)-2-ethoxypyrazine.

0426<chemistry id="chem0080" num="0080"><img file="EP3345902A1_D0085.tif" /></chemistry>

0427The title compound was prepared in a manner analogous to Intermediate 1.

Intermediate 47. 5-(Chloromethyl)-3-(4-fluorophenyl)-2-methoxypyridine.

0428<chemistry id="chem0081" num="0081"><img file="EP3345902A1_D0086.tif" /></chemistry>

0429The title compound was prepared in a manner analogous to Intermediate 17, employing (5-(4-fluorophenyl)-6-methoxypyridin-3-yl)methanol.

Intermediate 48. 2-Chloro-5-((6-(3,4-difluorophenyl)-5-ethoxypyrazin-2-yl)methyl) pyrimidine.

0430<chemistry id="chem0082" num="0082"><img file="EP3345902A1_D0087.tif" /></chemistry>

0431The title compound was prepared in a manner analogous to Intermediate 1, Step 3, employing 5-(bromomethyl)-3-(3,4-difluorophenyl)-2-ethoxypyrazine (Intermediate 46) and (2-chloropyrimidin-5-yl)boronic acid, substituting aq. NaHCO₃ for Na₂CO₃. ¹H NMR (400 MHz, CDCl₃) d 8.66 (s, 2H), 7.98-8.05 (m, 2H), 7.87-7.93 (m, 1H), 7.20-7.26 (m, 1H), 4.50 (q, <i>J</i> = 7.04 Hz, 2H), 4.10 (s, 2H), 1.47 (t, <i>J</i> = 7.04 Hz, 3H). [M+H] = 363.4.

Intermediate 49. Ethyl 2-(4-{[5-(3,4-difluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetate.

0432<chemistry id="chem0083" num="0083"><img file="EP3345902A1_D0088.tif" /></chemistry>

0433The title compound was prepared in a manner analogous to Intermediate 24, employing 5-(chloromethyl)-3-(3,4-difluorophenyl)-2-methoxypyridine and (4-(2-ethoxy-2-oxoethyl)phenyl)boronic acid. [M+H] = 398.41.

Intermediate 50. Ethyl 2-(4-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetate.

0434<chemistry id="chem0084" num="0084"><img file="EP3345902A1_D0089.tif" /></chemistry>

0435The title compound was prepared in a manner analogous to Intermediate 24, employing Intermediate 30 and (4-(2-ethoxy-2-oxoethyl)phenyl)boronic acid. [M+H] = 396.32.

Intermediate 51. 2-Chloro-5-((5-(4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine.

0436<chemistry id="chem0085" num="0085"><img file="EP3345902A1_D0090.tif" /></chemistry>

0437The title compound was prepared in a manner analogous to Intermediate 24, employing Intermediate 47 and (2-chloropyrimidin-5-yl)boronic acid. [M+H] = 330.40.

Intermediate 52. 5-((5-Bromo-6-ethoxypyridin-3-yl)methyl)pyrimidin-2-amine.

0438<chemistry id="chem0086" num="0086"><img file="EP3345902A1_D0091.tif" /></chemistry>

0439The title compound was prepared in a manner analogous to Intermediate 21, from 3-bromo-5-(chloromethyl)-2-ethoxypyridine (Intermediate 17) and 2-aminopyrimidine-5-boronic acid.

Intermediate 53. 2-(5-((5-(4-Fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)acetonitrile.

0440<chemistry id="chem0087" num="0087"><img file="EP3345902A1_D0092.tif" /></chemistry>

0441The title compound was prepared in a manner analogous to Intermediate 7, from 5-(chloromethyl)-3-(4-fluorophenyl)-2-methoxypyridine (Intermediate 47) and 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)acetonitrile.

Intermediate 54. 2-(5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)acetonitrile.

0442<chemistry id="chem0088" num="0088"><img file="EP3345902A1_D0093.tif" /></chemistry>

0443The title compound was prepared in a manner analogous to Intermediate 10, Step 1, employing Intermediate 30 and 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pynmidm-2-yl)acetonitrile, omitting water as a co-colvent.

Intermediate 55.

tert

-Butyl (5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-yl)carbamate.

0444<chemistry id="chem0089" num="0089"><img file="EP3345902A1_D0094.tif" /></chemistry>

0445A solution of 3-(3-chlorophenyl)-2-methoxy-5-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)pyridine (Intermediate 31, 127.7 mg, 0.36 mmol), <i>tert-</i>butyl (5-bromopyrazin-2-yl)carbamate (126.53 mg, 0.46 mmol), K₂CO₃ (98 mg, 0.70 mmol) and Pd(PPh₃)₄ (32.8 mg, 0.03 mmol) in dioxane (3.00 mL) and water (600.00 µl) was heated at 110 °C overnight.

Intermediate 56.

tert

-Butyl (5-((5-(3-chloro-4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-yl)carbamate.

0446<chemistry id="chem0090" num="0090"><img file="EP3345902A1_D0095.tif" /></chemistry>

0447The title compound was prepared in a manner analogous to Intermediate 21, employing 3-(3-chloro-4-fluorophenyl)-5-(chloromethyl)-2-methoxypyridine (Intermediate 26) and <i>tert</i>-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl) carbamate.

Intermediate 57. 2-Bromo-5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazine.

0448<chemistry id="chem0091" num="0091"><img file="EP3345902A1_D0096.tif" /></chemistry>

0449The title compound was prepared in a manner analogous to Intermediate 55, employing 3-(3-chlorophenyl)-2-methoxy-5-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)pyridine (Intermediate 31) and 2-bromo-5-iodopyrazine. ¹H NMR (400 MHz, CDCl₃) δ 8.62 (d, <i>J</i> = 1.57 Hz, 1H), 8.29 (d, <i>J</i> = 0.78 Hz, 1H), 8.10 (d, <i>J</i> = 2.35 Hz, 1H), 7.47-7.56 (m, 2H), 7.31-7.43 (m, 3H), 4.10 (s, 2H), 3.97 (s, 3H).

Intermediate 58. 5-((6-Chloro-5-fluoropyridin-3-yl)methyl)-2'-(difluoromethoxy)-2-methoxy-3,4'-bipyridine.

0450<chemistry id="chem0092" num="0092"><img file="EP3345902A1_D0097.tif" /></chemistry>

0451The title compound was prepared in a manner analogous to Intermediate 1, using Intermediate 39, employing microwave heating, substituting sodium bicarbonate for sodium carbonate.

Examples:

Example 1. 5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile.

0452<chemistry id="chem0093" num="0093"><img file="EP3345902A1_D0098.tif" /></chemistry>

0453Into a 5 mL microwave vial was combined 5-(bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine (Intermediate 1, 176.00 mg, 0.49 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (124.55 mg, 0.54 mmol), EtOH (2.45 mL), benzene (7.00 mL), Pd(PPh₃)₄ (56.63 mg, 0.05 mmol), and aq. NaHCO₃ (1.38 mL, 1.15 mol/L, 1.59 mmol). The vial was sealed, purged with nitrogen and heated to 125 °C under microwave conditions for 15 minutes. Water was removed from the reaction with a pipette, and the crude reaction mixture was filtered thru CELITE®, and washed with EtOAc (3 x 5 mL). The combined organic layers were dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 0 - 30%, EtOAc/hexanes) afforded the title compound as a white solid (100 mg, 53 %). ¹H NMR (400MHz, CD₃OD) δ 8.94 (s, 2H), 8.17 (s, 1H), 7.95 - 7.90 (m, 1H), 7.85 (t, <i>J</i> = 1.8 Hz, 1H), 7.46 (t, <i>J</i> = 8.2 Hz, 1H), 7.19 (dd, <i>J</i> = 2.3, 7.8 Hz, 1H), 7.04 - 6.61 (m, 1H), 4.49 (q, <i>J</i> = 7.0 Hz, 2H), 4.30 - 4.25 (m, 2H), 1.44 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 384.15.

Example 2. 2-Chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine.

0454<chemistry id="chem0094" num="0094"><img file="EP3345902A1_D0099.tif" /></chemistry>

0455To a solution of 5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyridine (Intermediate 2, 100 mg, 0.321 mmol), (2-chloropyrimidin-5-yl)boronic acid (76 mg, 0.481 mmol) in ACN (3.2 mL) was added NaHCO₃ (417 mg, 1.282 mmol) and PdCI₂(dppf)-DCM (23 mg, 0.032 mmol). The reaction was heated under microwave conditions, at 120 °C for 12 minutes. Water was removed from the reaction with a pipette, and the crude reaction mix was filtered thru CELITE®, and washed with EtOAc. The combined organics were dried (Na₂SO₄), filtered and concentrated onto silica. Purification (FCC, SiO₂, 30-70% EtOAc/hexanes) afforded the title compound (61 mg, 55%). ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.34 (s, 2H), 8.11 (d, <i>J</i> = 2.0 Hz, 1H), 7.70 (d, <i>J</i> = 2.0 Hz, 1H), 7.58 (t, <i>J</i> = 1.8 Hz, 1H), 7.53 - 7.36 (m, 3H), 3.83 (s 2H), 3.73 (s, 3H). [M+H] = 346.11.

Example 3. {2-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethyl} dimethylamine.

0456<chemistry id="chem0095" num="0095"><img file="EP3345902A1_D0100.tif" /></chemistry>

0457To a solution of 2-chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine (Example 2, 50.00 mg, 0.14 mmol) in ACN (1.44 mL), was added <i>N1</i>,<i>N1</i>-dimethylethane-1,2-diamine (0.03 mL, 0.29 mmol), and DIPEA (77.13 µL, 0.43 mmol). The reaction mixture was heated at 180 °C for 15 minutes. EtOAc (5 mL) was added to the reaction mixture, and the reaction mixture was extracted with water (3 X). The combined organic layers were dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 0-15% MeOH/DCM) afforded the title compound (15.6 mg, 28 %). ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.21 (s, 2H), 8.09 (s, 1H), 7.67 (br s, 2H), 7.58 (s, 1H), 7.51 - 7.34 (m, 2H), 6.79 (br s, 1H), 3.84 (s, 3H), 3.72 (s, 2H), 2.42 - 2.37 (m, 4H), 2.17 (s, 6H). [M+H] = 398.20.

Example 4. 2-Methoxy-3-(6-methoxypyndin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine.

0458<chemistry id="chem0096" num="0096"><img file="EP3345902A1_D0101.tif" /></chemistry>

0459A solution of 5-((1H-1,2,4-triazol-1-yl)methyl)-3-bromo-2-(difluoromethoxy)pyridine (Intermediate 13,50 mg, 0.16 mmol), (6-methoxypyridin-2-yl)boronic acid (46 mg, 0.30 mmol), in EtOH (2.45 mL), benzene (7.00 mL), was combined with Pd(PPh₃)₄ (27 mg, 0.02 mmol), and 4 M aq. Na₂CO₃ (3 mL) in a microwave vial. The vial was sealed, purged with nitrogen and heated under microwave conditions to 120 °C for 12 minutes. Water was removed from the reaction with a pipette, and the crude reaction mix was filtered thru CELITE®, and washed with EtOAc (3 x 5 mL). The combined organic layers were dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 30-70% EtOAc/hexanes) afforded the title compound (11.9 mg, 25 %). ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 7.88 (s, 1H), 7.58 (d, <i>J</i> = 2.7 Hz, 1H), 7.41 (d, <i>J</i> = 2.3 Hz, 1H), 7.24 (s, 1H), 6.91 - 6.84 (m, 2H), 5.93 (d, <i>J</i> = 4.3 Hz, 1H), 4.69 (s, 2H), 3.97 (s, 3H), 3.14 (s, 3H). [M+H] = 298.02.

Examples 5-12 were prepared analogous to procedures described in Examples 1 or 2, with the appropriate starting materials and reagent substitutions.

Example 5. 2-Methoxy-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine.

0460<chemistry id="chem0097" num="0097"><img file="EP3345902A1_D0102.tif" /></chemistry>

0461¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.65 (s, 1H), 8.18 - 8.15 (m, 1H), 7.95 (s, 1H), 7.70 (d, <i>J</i> = 2.3 Hz, 1H), 7.31 - 7.27 (m, 3H), 7.19 - 7.14 (m, 1H), 5.41 (s, 2H), 3.85 (s, 3H), 2.33 (s, 3H). [M+H] = 281.36.

Example 6. 2-Methoxy-3-(5-methylpyridin-3-yl)-5-(1H-1,2,4-tnazol-1-ylmethyl)pyridine.

0462<chemistry id="chem0098" num="0098"><img file="EP3345902A1_D0103.tif" /></chemistry>

0463¹H NMR (400 MHz,DMSO-<i>d</i>₆) δ 8.93 (s, 1H), 8.77 (s, 2H), 8.57 (s, 1H), 8.35 (d, <i>J</i> = 2.0 Hz, 1H), 8.04 (s, 2H), 5.45 (s, 2H), 3.91 (s, 3H), 2.50 (s, 3H). [M+H] = 282.09.

Example 7. 2-Methoxy-3-(2-methylpyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine.

0464<chemistry id="chem0099" num="0099"><img file="EP3345902A1_D0104.tif" /></chemistry>

0465¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.77 - 8.63 (m, 2H), 8.37 (d, <i>J</i> = 2.3 Hz, 1H), 8.04 (d, <i>J</i> = 2.0 Hz, 1H), 8.00 - 7.85 (m, 2H), 7.58 - 7.43 (m, 1H), 5.45 (s, 2H), 3.92 (s, 3H), 2.68 (s, 3H). [M+H] = 282.20.

Example 8. {3-[2-Methoxy-5-(1H-1,2,4-tnazol-1-ylmethyl)pyridin-3-yl]phenyl}methanol.

0466<chemistry id="chem0100" num="0100"><img file="EP3345902A1_D0105.tif" /></chemistry>

0467¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.65 (s, 1H), 8.18 (d, <i>J</i> = 2.0 Hz, 1H), 7.95 (s, 1H), 7.70 (d, <i>J</i> = 2.3 Hz, 1H), 7.45 - 7.26 (m, 4H), 5.41 (s, 2H), 5.22 (t, <i>J</i> = 5.7 Hz, 1H), 4.51 (d, <i>J</i> = 5.9 Hz, 2H), 3.85 (s, 3H). [M+H] = 297.23.

Example 9. 3-(3-Methanesulfonylphenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine.

0468<chemistry id="chem0101" num="0101"><img file="EP3345902A1_D0106.tif" /></chemistry>

0469¹H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H), 8.24 (d, <i>J</i> = 1.96 Hz, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 7.94 (d, <i>J</i> = 7.83 Hz, 1H), 7.89 (d, <i>J</i> = 7.83 Hz, 1H), 7.83 (d, <i>J</i> = 1.56 Hz, 1H), 7.65-7.72 (m, 1H), 5.46 (s, 2H), 3.96 (s, 3H), 3.15 (s, 3H). [M+H] = 345.21.

Example 10. 2-Methoxy-3-(4-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine.

0470<chemistry id="chem0102" num="0102"><img file="EP3345902A1_D0107.tif" /></chemistry>

0471¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 8.44 (d, <i>J</i> = <i>5</i>.1 Hz, 1H), 8.26 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 8.01 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.98 (s, 1H), 7.70 (s, 1H), 7.22 (d, <i>J</i> = <i>5</i>.1 Hz, 1H), 5.46 (s, 2H), 3.99 (s, 3H), 2.42 (s, 3H). [M+H] = 282.31.

Example 11. 2-Methoxy-3-(6-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine.

0472<chemistry id="chem0103" num="0103"><img file="EP3345902A1_D0108.tif" /></chemistry>

0473¹H NMR (400 MHz, CD₃OD) δ 8.50 (s, 1H), 8.32 - 8.27 (m, 1H), 8.22 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.89 (s, 1H), 7.68 - 7.62 (m, 1H), 7.56 (d, <i>J</i> = <i>2</i>.7 Hz, 1H), 7.26 (dd, <i>J</i> = <i>5</i>.1, 7.8 Hz, 1H), 5.37 (s, 2H), 3.82 (s, 3H), 2.04 (s, 3H). [M+H] = 282.39.

Example 12. 2-(Difluoromethoxy)-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine.

0474<chemistry id="chem0104" num="0104"><img file="EP3345902A1_D0109.tif" /></chemistry>

0475As a mixture of compounds, ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.72 - 8.61 (m, 1H), 8.00 - 7.96 (m, 1H), 7.94 - 7.86 (m, 1H), 7.73 - 7.68 (m, 1H), 7.55 -7.51 (m, 1H), 7.40 - 7.33 (m, 1H), 7.32 - 7.27 (m, 1H), 7.24 (d, <i>J</i> = 7.8 Hz, 1H), 5.75 (s, 1H), 5.49 (s, 1H), 5.44 (s, 1H), 2.35 (s, 3H). [M+H] = 317.15.

Example 13. 5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide.

0476<chemistry id="chem0105" num="0105"><img file="EP3345902A1_D0110.tif" /></chemistry>

0477To a solution of 5-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidine-2-carbonitrile (Example 1, 100.00 mg, 0.26 mmol) in MeOH (1.3 mL) was added aq. NaOH (0.78 mL, 0.78 mmol), followed by H₂O₂ (0.78 mL, 0.79 mmol). The reaction mixture was stirred at rt for 8 h. The reaction mixture was concentrated, and the precipitate filtered and washed with water to obtain the title compound as a white solid (70 mg, 67%). ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.93 (s, 2H), 8.27 (s, 1H), 8.12 (br s, 1H), 7.91 - 7.84 (m, 1H), 7.81 (t, <i>J</i> = 1.8 Hz, 1H), 7.72 (br s, 1H), 7.52 (s, 1H), 7.44 - 7.02 (m, 2H), 4.42 (q, <i>J</i> = 7.0 Hz, 2H), 4.25 (s, 2H), 1.35 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 402.26.

Example 14. [5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol.

0478<chemistry id="chem0106" num="0106"><img file="EP3345902A1_D0111.tif" /></chemistry>

0479To a cooled solution, -78 °C, of 5-bromo-3-(3-chlorophenyl)-2-methoxypyridine (Intermediate 7, 1.5 g, 5 mmol) in THF (25 mL), under nitrogen, was added <i>n</i>BuLi (4.8 mL, 5.5 mmol) dropwise over 2 minutes. The reaction mixture was stirred at -78 °C for 40 min. A solution of 4-fluorobenzaldehyde (744 mg, 6 mmol) in THF (2 mL) was added, and the reaction mixture was stirred an additional 30 min at -78 °C. The reaction was quenched with sat. Na₂SO₄, filtered, and concentrated under reduced pressure. Purification (FCC, SiO₂, 0-25% EtOAc/hexanes) afforded the title compound as a colorless solid (1.65 g, 96%). ¹H NMR (400 MHz, CD₃OD) δ 8.11 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.63 (d, <i>J</i> = <i>2</i>.0 Hz, 1H), 7.51 (s, 1H), 7.47 - 7.29 (m, 5H), 7.07 (t, <i>J</i> = <i>8</i>.6 Hz, 2H), 5.84 (s, 1H), 3.93 (s, 3H). [M+H] = 344.18.

0480Examples 15-16 were prepared in a manner analogous to Example 14, with the appropriate starting materials and reagent substitutions.

Example 15. 1-[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]-1-(4-fluorophenyl)ethan-1-ol.

0481<chemistry id="chem0107" num="0107"><img file="EP3345902A1_D0112.tif" /></chemistry>

0482¹H NMR (400 MHz, CD₃OD) δ 8.16 (d, <i>J</i> = <i>2</i>.7 Hz, 1H), 7.68 (d, <i>J</i> = <i>2</i>.7 Hz, 1H), 7.53 - 7.43 (m, 3H), 7.42 - 7.28 (m, 3H), 7.04 (t, <i>J</i> = <i>8</i>.8 Hz, 2H), 3.93 (s, 3H), 1.94 (s, 3H). [M+H] = 358.21.

Example 16. [5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](5-fluoropyridin-2-yl)methanol.

0483<chemistry id="chem0108" num="0108"><img file="EP3345902A1_D0113.tif" /></chemistry>

0484¹H NMR (400 MHz, CD₃OD) δ 8.38 (d, <i>J</i> = <i>2</i>.7 Hz, 1H), 8.16 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.77 - 7.58 (m, 3H), 7.52 (s, 1H), 7.45 - 7.28 (m, 3H), 5.87 (s, 1H), 3.93 (s, 3H). [M+H] = 345.19.

Example 17. {[5-(3-Chlorophenyl)-6-methoxypyridm-3-yl](4-fluorophenyl)methyl}(methyl)amine.

0485<chemistry id="chem0109" num="0109"><img file="EP3345902A1_D0114.tif" /></chemistry><ul id="ul0018" list-style="none" compact="compact"><li>Step 1. 5-(Chloro(4-fluorophenyl)methyl)-3-(3-chlorophenyl)-2-methoxypyridine. To a cooled solution, 0 °C, of [5-(3-chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol (Example 14, 1.43 g, 4.17 mmol), in DCM (10 mL), was added thionyl chloride (744 mg, 6.25 mmol) dropwise. The solution was allowed to warm up to room temperature, and stirred for 1 h. The reaction mixture was concentrated under reduced pressure. Purification (FCC, SiO₂, 0-10% EtOAc/hexanes) afforded the title compound, which was used directly for the next step.</li><li>Step 2. {[5-(3-chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}(methyl)amine. To a solution of 5-(chloro(4-fluorophenyl)methyl)-3-(3-chlorophenyl)-2-methoxypyridine (70 mg, 0.193 mmol) in ACN (2 mL) was added K₂CO₃ (53 mg, 0.39 mmol), NaI (5 mg, 0.03 mmol), and methylamine (0.5 mL, 0.97 mmol). The reaction was sealed and heated at 45 °C for 12 h. The reaction mixture was concentrated. Purification (FCC, SiO₂, 0-10% MeOH/DCM) afforded the title compound (23 mg, 33%). ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.71 (s, 1H), 7.50 - 7.42 (m, 3H), 7.40 - 7.27 (m, 3H), 7.18 (t, <i>J</i> = <i>8</i>.8 Hz, 2H), 5.54 - 5.49 (m, 1H), 3.90 (s, 3H), 2.63 (s, 3H). [M⁺; loss ofNHMe]= 326.14.</li></ul>

0486Examples 18-19 were prepared in a manner analogous to Example 17, with the appropriate starting materials and reagent substitutions.

Example 18. [5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanamine.

0487<chemistry id="chem0110" num="0110"><img file="EP3345902A1_D0115.tif" /></chemistry>¹H NMR (400 MHz, CD₃OD) δ 8.17 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.72 (d, <i>J</i> = <i>2</i>.7 Hz, 1H), 7.55 (s, 1H), 7.49 - 7.34 (m, 5H), 7.18 (m, 2H), 5.58 (s, 1H), 3.96 (s, 3H). [M⁺; loss of NH₂] = 326.14.

Example 19. {[5-(3-Chlorophenyl)-6-methoxypyridm-3-yl](4-fluorophenyl)methyl}dimethylamine.

0488<chemistry id="chem0111" num="0111"><img file="EP3345902A1_D0116.tif" /></chemistry>

0489¹H NMR (400 MHz, CD₃OD) δ 8.28 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.86 (s, 1H), 7.57 (dd, <i>J</i> = <i>5</i>.1, 8.6 Hz, 2H), 7.50 (t, <i>J</i> = <i>1</i>.6 Hz, 1H), 7.43 - 7.28 (m, 3H), 7.18 (m, 2H), 5.51 - 5.38 (m, 1H), 3.90 (s, 3H), 2.88 - 2.74 (m, 6H). [M+H] = 371.20.

Example 20. 3-(3-Chlorophenyl)-5-[fluoro(4-fluorophenyl)methyl]-2-methoxypyridine.

0490<chemistry id="chem0112" num="0112"><img file="EP3345902A1_D0117.tif" /></chemistry>

0491To a solution of [5-(3-chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol (Example 14, 70 mg, 0.18 mmol) in DCM (1 mL) was added Deoxo-Fluor® (79 mg, 0.36 mmol). The solution was stirred at room temperature for 1 h then concentrated under reduced pressure. Purification (FCC, SiO₂, 0-10% EtOAc/hexanes) afforded the title compound (21 mg, 34%). ¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 1H), 7.62 (d, <i>J</i> = <i>2</i>.0 Hz, 1H), 7.52 (s, 1H), 7.47 - 7.31 (m, 5H), 7.15 (t, <i>J</i> = <i>8</i>.8 Hz, 2H), 6.70 - 6.52 (m, 1H), 3.96 (s, 3H). [M+H] = 346.17.

Example 21. 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzoic acid.

0492<chemistry id="chem0113" num="0113"><img file="EP3345902A1_D0118.tif" /></chemistry><ul id="ul0019" list-style="none" compact="compact"><li>Step 1. Methyl 4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)benzoate was prepared in a manner analogous to Example 2 with the appropriate starting material substitution. Purification (FCC, SiO₂, 0-50% EtOAc/hexanes) afforded the title compound. [M+H] = 368.11</li><li>Step 2. 4-{[5-(3-Chlorophenyl)-6-methoxypyndm-3-yl]methyl}benzoic acid. To a solution of methyl 4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)benzoate (91 mg, 0.248 mmol) in MeOH (2 mL) was added 2 N aq. NaOH (2.0 mL). The reaction mixture was stirred at rt for 2 h. Solvent was removed under reduced pressure, and the resulting solid was triturated with diethyl ether. The resulting white solid was dissolved in DCM and filtered to remove inorganic solids. The filtrated was concentrated under reduced pressure to afford the title compound (74 mg, 85%). ¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, <i>J</i> = 2.0 Hz, 1H), 7.96 (d, <i>J</i> = 7.8 Hz, 2H), 7.60 (d, <i>J</i> = 2.3 Hz, 1H), 7.52 (s, 1H), 7.43 - 7.30 (m, 5H), 4.05 (s, 2H), 3.95 (s, 3H). [M+H] = 354.13.</li></ul>

Example 22. 5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile.

0493<chemistry id="chem0114" num="0114"><img file="EP3345902A1_D0119.tif" /></chemistry>

0494Example 22 was prepared in a manner analogous to Example 1, with the appropriate starting materials and reagent substitutions. [M+H] = 338.10

Example 23. 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxylic acid.

0495<chemistry id="chem0115" num="0115"><img file="EP3345902A1_D0120.tif" /></chemistry>

0496A solution of 5-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile (Example 22, 30 mg, 0.0845 mmol) in MeOH (1.54 mL) was heated to 50 °C until the starting material dissolved. 1 N aq. NaOH (0.23 mL, 0.23 mmol) was added followed by H₂O₂ (0.23 mL, 1.00 mol/L, 0.23 mmol) and the solution was heated at 50 °C for an additional 2 h. Water (5 mL) was added and the reaction was filtered and washed with water (3 X 5 mL). A mixture of products were observed; 5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxylic acid (the title compound) and 5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide (Example 24, 4 mg, 13%). The filtrated contained the acid, and the water layer was acidified with concentrated HCl (3 drops) and extracted with DCM (3 X 20 mL). The organic layers were combined, dried (Na₂SO₄), and concentrated under reduced pressure to afford the title compound (23 mg, 74%). ¹H NMR (400 MHz, CD₃OD) δ 8.86 (br s, 2H), 8.11 (d, <i>J</i> = 1.96 Hz, 1H), 7.66 (d, <i>J</i> = 1.96 Hz, 1H), 7.55 (s, 1H), 7.49 - 7.27 (m, 3H), 4.14 (br s, 2H), 3.94 (s, 3H). [M+H] = 356.13

Example 24. 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide.

0497<chemistry id="chem0116" num="0116"><img file="EP3345902A1_D0121.tif" /></chemistry>

0498The title compound was made in a manner analogous to Example 13. ¹H NMR (400 MHz, CD₃OD) δ 8.83 (s, 2H), 8.11 (d, <i>J</i> = <i>2</i>.0 Hz, 1H), 7.65 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.54 (s, 1H), 7.47 - 7.29 (m, 3H), 4.12 (s, 2H), 3.94 (s, 3H). [M+H] = 355.21.

0499Examples 25, 27-30, 32-35, 37-43, 45-89, 91-108 were prepared analogous to procedures described in Examples 1 or 2, with the appropriate starting materials and reagent substitutions.

Example 25. 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine.

0500<chemistry id="chem0117" num="0117"><img file="EP3345902A1_D0122.tif" /></chemistry>

0501¹H NMR (400 MHz, CD₃OD) δ 8.18 (s, 2H), 8.02 (d, <i>J</i> = <i>2.</i>3 Hz, 1H), 7.58 - 7.51 (m, 2H), 7.44 - 7.31 (m, 3H), 3.93 (s, 3H), 3.82 (s, 2H). [M+H] = 327.21.

Example 26. (4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)urea.

0502<chemistry id="chem0118" num="0118"><img file="EP3345902A1_D0123.tif" /></chemistry><ul id="ul0020" list-style="none" compact="compact"><li>Step 1. 3-(3-Chlorophenyl)-2-methoxy-5-(4-nitrobenzyl)pyridine. The title compound was prepared in a manner analogous to Example 1, from Intermediate 2 and 4-nitrophenyl boronic acid to afford a tan solid. [M+H] = 355.07.</li><li>Step 2. 4-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)aniline. A solution of 3-(3-chlorophenyl)-2-methoxy-5-(4-nitrobenzyl)pyridine (162 mg, 0.45 mmol), HOAc (3 mL), water (1 mL), and zinc (292.5 mg, 4.5 mmol) was heated at 60 °C for 1 h, then filtered hot through a 1 cm pad of Celite® and used directly for the next step.</li><li>Step 3. (4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)urea. 4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)aniline solution from Step 2 was added KCNO (73 mg, 0.9 mmol). The mixture was sonicated for 20 min to afford a gummy ppt. The reaction mixture was diluted with water, neutralized with aq. Na₂CO₃ to pH 7, then extracted with EtOAc (3 x 5 mL). The combined organic layers were concentrated under reduced pressure to afford a solid, which was triturated with DCM to give (55 mg, 34%) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.41 (s, 1H), 8.06 (d, <i>J</i> = 2.3 Hz, 1H), 7.64 - 7.53 (m, 2H), 7.49 - 7.37 (m, 3H), 7.28 (d, <i>J</i> = 8.2 Hz, 2H), 7.10 (d, <i>J</i> = 8.6 Hz, 2H), 5.75 (s, 2H), 3.85 - 3.81 (m, 5H). [M+H] = 368.27.</li></ul>

Example 27. 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzamide.

0503<chemistry id="chem0119" num="0119"><img file="EP3345902A1_D0124.tif" /></chemistry>

0504¹H NMR (400 MHz, CD₃OD) δ 8.02 (d, <i>J</i> = 2.0 Hz, 1H), 7.81 (d, <i>J</i> = 8.2 Hz, 2H), 7.56 - 7.49 (m, 2H), 7.42 - 7.29 (m, 5H), 4.03 (s, 2H), 3.92 (s, 3H). [M+H] = 353.13.

Example 28. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-pyrazol-4-ylmethyl)pyridine.

0505<chemistry id="chem0120" num="0120"><img file="EP3345902A1_D0125.tif" /></chemistry>

0506¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 12.61 (br s, 1H), 7.92 - 7.43 (m, 9H), 3.84 (s, 2 H). [M+H] = 336.18.

Example 29. 5-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine.

0507<chemistry id="chem0121" num="0121"><img file="EP3345902A1_D0126.tif" /></chemistry>

0508¹H NMR (400 MHz, CD₃OD) δ 8.19 (s, 2H), 8.07 (d, <i>J</i> = 2.35 Hz, 1H), 7.71 (d, <i>J</i> = 1.96 Hz, 1H), 7.57 (s, 1H), 7.30 - 7.38 (m, 1H), 7.02 - 7.10 (m, 2H), 6.95 (dd, <i>J</i> = 8.22, 1.57 Hz, 1H), 3.82 (s, 3H), 3.87 (s, 2H). [M+H] = 359.28.

Example 30. 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine.

0509<chemistry id="chem0122" num="0122"><img file="EP3345902A1_D0127.tif" /></chemistry>

0510¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, <i>J</i> = 2.0 Hz, 1H), 7.80 (d, <i>J</i> = 2.0 Hz, 1H), 7.52 (d, <i>J</i> = 2.0 Hz, 2H), 7.43 - 7.29 (m, 4H), 6.55 (d, <i>J</i> = 8.6 Hz, 1H), 3.92 (s, 3H), 3.81 (s, 2H). [M+H] = 326.26.

Example 31. 1-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)-3-(oxetan-3-yl)urea.

0511<chemistry id="chem0123" num="0123"><img file="EP3345902A1_D0128.tif" /></chemistry>

0512To a solution of 4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)benzoic acid (Example 21,90 mg, 0.25 mmol) in toluene (5 mL) was added DIPEA (33 mg, 0.25 mmol) and DPPA (77 mg, 0.28 mmol). The mixture was stirred at 80 °C for 30 minutes. The LCMS confirmed the disappearance of the starting acid. A solution of oxetan-3-amine hydrochloride (41.5 mg, 0.38 mmol), DIPEA (49 mg, 0.38 mmol) and DCM (2 mL) was added to the reaction mixture and stirred at room temperature for 2 h. The LCMS confirmed the presence of the product. All solvents were removed under reduced pressure. Purification (FCC, SiO₂, 0 - 5%, MeOH/DCM) afforded the title compound (50 mg, 46%). ¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, <i>J</i> = 2.3 Hz, 1H), 7.49 (d, <i>J</i> = 2.3 Hz, 2H), 7.41 - 7.24 (m, 5H), 7.14 (d, <i>J</i> = 8.6 Hz, 2H), 4.87 (br s, 3H), 4.55 (s, 2H), 3.91 (s, 3H), 3.90 (s, 2 H). [M+H] = 424.20.

Example 32. 3-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxypyridin-3-yl)methyl]pyridine.

0513<chemistry id="chem0124" num="0124"><img file="EP3345902A1_D0129.tif" /></chemistry>

0514¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.10 (dd, <i>J</i> = 2.0, 6.3 Hz, 2H), 7.67 (d, <i>J</i> = 2.3 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.50 - 7.36 (m, 3H), 6.72 (d, <i>J</i> = 8.2 Hz, 1H), 3.86 (s, 2H), 3.84 (s, 3H), 3.78 (s, 3H). [M+H] = 341.19.

Example 33. 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-amine.

0515<chemistry id="chem0125" num="0125"><img file="EP3345902A1_D0130.tif" /></chemistry>

0516¹H NMR (400 MHz, CD₃OD) δ 8.06 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.77 (dd, <i>J</i> = <i>2</i>.0, 9.4 Hz, 1H), 7.73 - 7.64 (m, 2H), 7.51 - 7.30 (m, 5H), 6.89 (d, <i>J</i> = <i>9</i>.4 Hz, 1H), 3.88 (s, 2H). [M+H] = 362.31.

Example 34. 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-

N

,

N

-dimethylpyridin-2-amine.

0517<chemistry id="chem0126" num="0126"><img file="EP3345902A1_D0131.tif" /></chemistry>

0518¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, <i>J</i> = <i>2</i>.0 Hz, 1H), 7.94 (d, <i>J</i> = <i>2</i>.0 Hz, 1H), 7.51 (d, <i>J</i> = <i>1</i>.6 Hz, 2H), 7.43 - 7.29 (m, 4H), 6.63 (d, <i>J</i> = <i>9</i>.0 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 2H), 3.04 (s, 6H). [M+H] = 354.22.

Example 35. 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carbonitrile.

0519<chemistry id="chem0127" num="0127"><img file="EP3345902A1_D0132.tif" /></chemistry>

0520¹H NMR (400 MHz, CD₃OD) δ 8.85 (s, 2H), 8.18 (s, 1H), 7.85 (d, <i>J</i> = 2.3 Hz, 1H), 7.80 - 7.38 (m, 5H), 4.21 - 4.17 (m, 2H). [M+H] = 373.14.

Example 36. 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1,3-thiazol-2-amine.

0521<chemistry id="chem0128" num="0128"><img file="EP3345902A1_D0133.tif" /></chemistry><ul id="ul0021" list-style="none" compact="compact"><li>Step 1. 3-(3-Chlorophenyl)-5-(dibromomethyl)-2-(difluoromethoxy)pyridine was prepared in a manner analogous to Intermediate 1, Steps 4, with the appropriate starting material substitutions. [M+H] = 426.1, 428.1, 430.1.</li><li>Step 2. 5-(3-Chlorophenyl)-6-(difluoromethoxy)nicotinaldehyde. To a solution of 3-(3-chlorophenyl)-5-(dibromomethyl)-2-(difluoromethoxy)pyridine (700 mg, 1.65 mmol) in ACN (2 mL) was added a solution of Na₂CO₃ (525 mg, 5.0 mmol) in water (4 mL) and the mixture was stirred at 70 °C for 16 h. The LCMS showed complete conversion. All solvents were removed under reduced pressure. The residue was dissolved in DCM, washed with water, dried (Na₂SO₄), filtered and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 0 - 20%, EtOAc/hexanes) afforded 5-(3-chlorophenyl)-6-(difluoromethoxy)nicotinaldehyde (355 mg, 76%). [M+H] = 284.1.</li><li>Step 3. <i>tert</i>-Butyl (5-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)(hydroxy)methyl)thiazol-2-yl)carbamate. A solution of <i>tert</i>-butyl (5-bromothiazol-2-yl)carbamate (100 mg, 0.36 mmol) in THF (2 mL) was cooled to -78 °C and <i>n</i>-butyllithium (0.51 mL of 1.4 M solution in hexanes, 0.72 mmol) was added dropwise and the mixture was stirred for 30 minutes at -78 °C. A solution of 5-(3-chlorophenyl)-6-(difluoromethoxy)nicotinaldehyde (112 mg, 0.39 mmol) in THF (2 mL) was added dropwise to the reaction and this mixture was stirred for 30 minutes at -78 °C. The LCMS confirmed the product. A saturated aqueous solution of ammonium chloride was added and the mixture was extracted into EtOAc. The combined extracts were dried (Na₂SO₄), filtered and solvent was removed under reduced pressure. Purification (FCC, SiO₂, 10 - 80%, EtOAc/hexanes) afforded <i>tert</i>-butyl (5-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)(hydroxy)methyl)thiazol-2-yl)carbamate (73 mg, 42%). [M(-<i>t</i>Bu)+H] = 428.1.</li><li>Step 4. 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1,3-thiazol-2-amine. To a solution of <i>tert</i>-butyl (5-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)(hydroxy)methyl)thiazol-2-yl)carbamate (73 mg, 0.15 mmol) in DCM (3 mL) was added TES (52.2 mg, 0.45 mmol) and TFA (102 mg, 0.90 mmol) and the mixture was stirred at room temperature for 16 h. The LCMS showed complete conversion. All solvents were removed in vacuo. The residue was dissolved in DCM and sat. aq. NaHCO₃, the layers shaken and separated and the aqueous layer extracted into DCM. The combined organic extracts were washed with brine, dried (Na₂SO₄), filtered and solvent under reduced pressure. Purification (FCC, SiO₂, 20 - 100%, EtOAc/hexanes) gave the title compound (34.4 mg, 62%). ¹H NMR (400 MHz, CD₃OD) δ 8.02 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.71 - 7.30 (m, 6H), 6.68 (s, 1H), 3.94 (s, 2H). [M+H] = 368.06.</li></ul>

Example 37. (2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanol.

0522<chemistry id="chem0129" num="0129"><img file="EP3345902A1_D0134.tif" /></chemistry>

0523¹H NMR (400 MHz, CD₃OD) δ 7.94 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.49 (m, 2H), 7.44 - 7.14 (m, 7H), 4.63 (s, 2H), 4.07 (s, 2H), 3.91 (s, 3H). [M+H] = 340.13.

Example 38. 5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine.

0524<chemistry id="chem0130" num="0130"><img file="EP3345902A1_D0135.tif" /></chemistry>

0525¹H NMR (400 MHz, CD₃OD) δ 8.17 (s, 2H), 8.02 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.57 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.43 - 7.25 (m, 3H), 7.09 - 7.02 (m, 1H), 3.93 (s, 3H), 3.81 (s, 2H). [M+H] = 311.00.

Example 39. 5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carbonitrile.

0526<chemistry id="chem0131" num="0131"><img file="EP3345902A1_D0136.tif" /></chemistry>

0527¹H NMR (400 MHz, CLOROFORM-d) δ 8.71 (s, 2H), 8.06 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.55 (s, 1H), 7.42 - 7.35 (m, 2H), 7.26 - 7.23 (m, 1H), 7.10 - 7.03 (m, 1H), 4.05 (s, 2H), 3.98 (s, 3H). [M+H] = 321.17.

Example 40. 5-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine.

0528<chemistry id="chem0132" num="0132"><img file="EP3345902A1_D0137.tif" /></chemistry>

0529¹H NMR (400 MHz, CD₃OD) δ 8.18 (s, 2H), 7.99 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.56 (d, <i>J</i> = <i>2</i>.3 Hz, 2H), 7.47 - 7.30 (m, 3H), 4.38 (d, <i>J</i> = <i>7</i>.0 Hz, 2H), 3.81 (s, 2H), 1.33 (t, <i>J</i> = <i>7</i>.0 Hz, 3H). [M+H] = 341.04.

Example 41. 5- {[5-(3-Chlorophenyl)-6-(propan-2-yloxy)pyridin-3-yl]methyl}pyrimidin-2-amine.

0530<chemistry id="chem0133" num="0133"><img file="EP3345902A1_D0138.tif" /></chemistry>

0531¹H NMR (400 MHz, CD₃OD) δ 8.18 (s, 2H), 8.01 - 7.98 (m, 1H), 7.58 - 7.53 (m, 2H), 7.46 - 7.29 (m, 3H), 5.35 (m, 1H), 3.80 (s, 2H), 1.30 (d, <i>J</i> = <i>6</i>.3 Hz, 6H). [M+H] = 355.21.

Example 42. 5- {[6-(Difluoromethoxy)-5-[3-(propan-2-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine.

0532<chemistry id="chem0134" num="0134"><img file="EP3345902A1_D0139.tif" /></chemistry>¹H NMR (400 MHz, CD₃OD) δ 8.19 (s, 2H), 8.06 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.78 - 7.29 (m, 3H), 7.06 - 7.00 (m, 2H), 6.95 - 6.90 (m, 1H), 4.68 - 4.55 (m, 1H), 3.86 (s, 2H), 1.32 (d, <i>J</i> = <i>6</i>.3 Hz, 6H). [M+H] = 387.25.

Example 43. 5-{[6-(Difluoromethoxy)-5-[3-(oxetan-3-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine.

0533<chemistry id="chem0135" num="0135"><img file="EP3345902A1_D0140.tif" /></chemistry>

0534¹HNMR (400 MHz, CD₃OD) δ 8.10 (s, 2H), 7.99 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.69 - 7.24 (m, 3H), 7.04 - 6.99 (m, 1H), 6.84 - 6.80 (m, 1H), 6.75 - 6.70 (m, 1H), 5.21 (m, 1H), 4.92 (t, <i>J</i> = <i>7</i>.0 Hz, 2H), 4.64 - 4.59 (m, 2H), 3.78 (s, 2H). [M+H] = 401.22.

Example 44.

N-

(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide.

0535<chemistry id="chem0136" num="0136"><img file="EP3345902A1_D0141.tif" /></chemistry><ul id="ul0022" list-style="none" compact="compact"><li>Step 1. To a solution of 5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine (Example 25, 50.0 mg, 0.15 mmol), in DCM (10 mL), was added and DIPEA (40 mg, 0.31 mmol). The solution was cooled to 0 °C and acetyl chloride (230 µL, (0.23 mmol) was added dropwise. The reaction mixture was allowed warm up to room temperature overnight, then concentrated to afford the corresponding imide (bis-acylated adduct), which was used crude in the next step.</li><li>Step 2. <i>N</i>-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide. A solution of the crude product from step 1 in added ammonia (7N in methanol) was stirred at room temperature for 1h. Purification (FCC, SiO₂, 0-100 % EtOAc/hexanes) afforded the title compound (11.4 mg, 21%) as an off white solid. ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 10.44 (s, 1H), 8.59 (s, 2H), 8.14 (d, <i>J</i> = <i>2</i>.7 Hz, 1H), 7.74 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.61 - 7.54 (m, 1H), 7.51 - 7.38 (m, 3H), 3.90 (s, 2H), 3.85 (s, 3H), 2.12 (s, 3H). [M+H] = 369.20.</li></ul>

Example 45. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methanesulfonylphenyl)methyl]pyridine.

0536<chemistry id="chem0137" num="0137"><img file="EP3345902A1_D0142.tif" /></chemistry>

0537¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 1H), 7.89 (d, <i>J</i> = <i>8</i>.2 Hz, 2H), 7.78 - 7.37 (m, 8H), 4.16 (s, 2H), 3.08 (s, 3H). [M+H] = 424.16.

Example 46. 5-{[6-(Difluoromethoxy)-5-(2-methoxypyridin-4-yl)pyridin-3-yl]methyl}pyrimidin-2-amine.

0538<chemistry id="chem0138" num="0138"><img file="EP3345902A1_D0143.tif" /></chemistry>

0539¹H NMR (400 MHz, CD₃OD) δ 8.27 - 8.16 (m, 4H), 7.85 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.63 (t, <i>J</i> = <i>1</i>.0 Hz, 1H), 7.16 - 6.96 (m, 2H), 3.96 (s, 3H), 3.89 (s, 2H). [M+H] = 360.23.

Example 47. 5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl} methyl)pyrimidin-2-amine.

0540<chemistry id="chem0139" num="0139"><img file="EP3345902A1_D0144.tif" /></chemistry>

0541¹H NMR (400 MHz, CD₃OD) δ 8.23 - 8.20 (m, 1H), 8.18 (s, 2H), 8.11 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.71 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.56 (s, 1H), 7.41 - 7.36 (m, 1H), 7.20 - 7.16 (m, 1H), 3.96 (s, 3H), 3.84 (s, 2H). [M+H] = 360.23.

Example 48. 2-[5-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-yl]propan-2-ol.

0542<chemistry id="chem0140" num="0140"><img file="EP3345902A1_D0145.tif" /></chemistry>

0543¹H NMR (400 MHz, CD₃OD) δ 8.69 (s, 2H), 8.09 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.63 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.46 - 7.35 (m, 2H), 7.31 (t, <i>J</i> = <i>1.</i>8 Hz, 1H), 7.12 (td, <i>J</i> = <i>1</i>.0, 7.4 Hz, 1H), 7.03 - 6.64 (m, 1H), 4.04 (s, 2H), 3.94 (s, 3H), 1.20 (s, 6H). [M+H] = 402.26.

Example 49. 3-(3-Chlorophenyl)-2-methoxy-5- {[6-(trifluoromethyl)pyridin-3-yl]methyl}pyridine.

0544<chemistry id="chem0141" num="0141"><img file="EP3345902A1_D0146.tif" /></chemistry>

0545¹H NMR (400 MHz, CD₃OD) δ 8.66 (d, <i>J</i> = <i>2</i>.0 Hz, 1H), 8.08 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.93 - 7.89 (m, 1H), 7.75 (d, <i>J</i> = <i>8</i>.6 Hz, 1H), 7.62 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.55 (t, <i>J</i> = <i>1</i>.6 Hz, 1H), 7.45 - 7.32 (m, 3H), 4.13 (s, 2H), 3.94 (s, 3H). [M+H] = 379.15.

Example 50. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5- {[6-(propan-2-yloxy)pyridin-3-yl]methyl}pyridine.

0546<chemistry id="chem0142" num="0142"><img file="EP3345902A1_D0147.tif" /></chemistry>

0547¹H NMR (400 MHz, CDCl₃) δ 8.03 (dd, <i>J</i> = <i>2</i>.15, 10.37 Hz, 2H), 7.31-7.72 (m, 7H), 6.64 (d, <i>J</i> = <i>8</i>.61 Hz, 1H), 5.27 (m, 1H), 3.90 (s, 2H), 1.34 (d, <i>J</i> = <i>6</i>.26 Hz, 6H). [M+H] = 405.22.

Example 51. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-propoxypyridin-3-yl)methyl]pyridine.

0548<chemistry id="chem0143" num="0143"><img file="EP3345902A1_D0148.tif" /></chemistry>

0549¹H NMR (400 MHz, CDCl₃) δ 8.06-8.00 (m, 2H), 7.71-7.31 (m, 7H), 6.70 (d, <i>J</i> = <i>9</i>.00 Hz, 1H), 4.23 (t, <i>J</i> = <i>6</i>.85 Hz, 2H), 3.91 (s, 2H), 1.80 (q, <i>J</i> = <i>6</i>.65 Hz, 2H), 1.02 (t, <i>J</i> = <i>7</i>.43 Hz, 3H).

Example 52. 5- {[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1-methyl-1,2-dihydropyridin-2-one.

0550<chemistry id="chem0144" num="0144"><img file="EP3345902A1_D0149.tif" /></chemistry>

0551¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, <i>J</i> = <i>2</i>.0 Hz, 1H), 7.60 - 7.51 (m, 3H), 7.47 - 7.30 (m, 4H), 6.51 (d, <i>J</i> = <i>9</i>.4 Hz, 1H), 3.93 (s, 3H), 3.76 (s, 2H), 3.55 (s, 3H). [M+H] = 341.19.

Example 53. 3-(3-Chlorophenyl)-2-methoxy-5-(pyridin-4-ylmethyl)pyridine .

0552<chemistry id="chem0145" num="0145"><img file="EP3345902A1_D0150.tif" /></chemistry>

0553¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.44 (d, <i>J</i> = 4.70 Hz, 1H), 8.12 (s, 1H), 7.71 (s, 1H), 7.61 - 7.56 (m, 2H), 7.55 - 7.31 (m, 3H), 7.29 (d, <i>J</i> = 4.70 Hz, 2H), 3.96 (s, 2H), 3.85 (s, 3H). [M+H] = 311.13.

Example 54. 5- {[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxylic acid.

0554<chemistry id="chem0146" num="0146"><img file="EP3345902A1_D0151.tif" /></chemistry>

0555Example 54 was prepared in a manner analogous to Example 21, with the appropriate starting materials and reagent substitutions. ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.61 (br s, 1H), 8.19 (br s, 1H), 8.12 - 7.94 (m, 1H), 7.93 - 7.75 (m, 2H), 7.72 - 7.57 (m, 3H), 7.56 - 7.39 (m, 3H), 4.10 (br s, 2H). [M+H] = 391.25.

Example 55. 3-(3-Chlorophenyl)-2-methoxy-5-[(2-methoxypyrimidin-5-yl)methyl]pyrazine.

0556<chemistry id="chem0147" num="0147"><img file="EP3345902A1_D0152.tif" /></chemistry>

0557¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.58 (s, 2H), 8.23 (s, 1H), 8.03 - 7.86 (m, 2H), 7.50 (d, <i>J =</i> 4.30 Hz, 2H), 4.09 (s, 2H), 3.96 (s, 3H), 3.85 (s, 3H). [M+H] = 343.01.

Example 56. 5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-

N

-methylpyrimidin-2-amine.

0558<chemistry id="chem0148" num="0148"><img file="EP3345902A1_D0153.tif" /></chemistry>

0559¹H NMR (400 MHz, CD₃OD) δ 8.48 (br s, 1H), 8.13 (s, 2H), 8.07 - 7.90 (m, 2H), 7.42 (d, <i>J</i> = 5.09 Hz, 2H), 4.11 - 3.94 (m, 5H), 2.96 (s, 3H). [M+H] = 342.05.

Example 57. 5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-

N

-cyclopropylpyrimidin-2-amine.

0560<chemistry id="chem0149" num="0149"><img file="EP3345902A1_D0154.tif" /></chemistry>

0561¹H NMR (400 MHz, CD₃OD) δ 8.12 - 8.18 (m, 1H), 7.93 - 8.05 (m, 2H), 7.59 - 7.70 (m, 1H), 7.50 - 7.55 (m, 1H), 7.41 (d, <i>J</i> = 5.09 Hz, 2H), 4.09 (s, 2H), 4.03 (s, 3H), 2.68 (m, 1H), 0.84 - 0.97 (m, 2H), 0.61 - 0.71 (m, 2H). [M+H] = 368.06.

Example 58. 3-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1

H

-pyrazol-4-yl)methyl]pyrazine.

0562<chemistry id="chem0150" num="0150"><img file="EP3345902A1_D0155.tif" /></chemistry>

0563¹H NMR (400 MHz, CD₃OD) δ 8.10-7.92 (m, 3H), 7.55 (br s, 1H), 7.45 - 7.39 (m, 3H), 4.01 (s, 3H), 3.98 (s, 2H), 3.83 (s, 3H). [M+H] = 315.01.

Example 59. (4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanamine.

0564<chemistry id="chem0151" num="0151"><img file="EP3345902A1_D0156.tif" /></chemistry>

0565¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, <i>J</i> = 1.96Hz, 2H), 7.47 (s, 2H), 7.44 - 7.14 (m, 6H), 3.94 (s, 2H), 3.91 (s, 3H). [M+H] = 339.10.

Example 60. 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine.

0566<chemistry id="chem0152" num="0152"><img file="EP3345902A1_D0157.tif" /></chemistry>

0567¹H NMR (400 MHz, CD₃OD) δ 8.02 (d, <i>J</i> = 1.96 Hz, 1H), 7.81 - 7.74 (m, 1H), 7.58 - 7.48 (m, 2H), 7.45 - 7.25 (m, 3H), 6.50 (d, <i>J</i> = 5.48 Hz, 1H), 6.43 (s, 1H), 3.93 (s, 3H), 3.85 (s, 2H). [M+H] = 326.01.

Example 61. 3-(3-Chlorophenyl)-5-[(2,6-dimethylpyridin-4-yl)methyl]-2-methoxypyridine.

0568<chemistry id="chem0153" num="0153"><img file="EP3345902A1_D0158.tif" /></chemistry>

0569¹H NMR (400 MHz, CD₃OD) δ 8.02 (d, <i>J</i> = 2.35 Hz, 1H), 7.59 - 7.48 (m, 2H), 7.47 - 7.25 (m, 3H), 6.97 (s, 2H), 3.98 - 3.86 (m, 5H), 2.43 (s, 6H). [M+H] = 339.05.

Example 62. 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carbonitrile.

0570<chemistry id="chem0154" num="0154"><img file="EP3345902A1_D0159.tif" /></chemistry>

0571¹H NMR (400 MHz, CD₃OD) δ 8.57 (d, <i>J</i> = 5.09 Hz, 1H), 8.07 (d, <i>J</i> = 2.35Hz, 1H), 7.79 (s, 1H), 7.60 (d, <i>J</i> = 2.35Hz, 1H), 7.54 (d, <i>J</i> = 1.96Hz, 2H), 7.48 - 7.26 (m, 3H), 4.08 (s, 2H), 3.93 (s, 3H). [M+H] = 336.14.

Example 63. 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide.

0572<chemistry id="chem0155" num="0155"><img file="EP3345902A1_D0160.tif" /></chemistry>

0573The title compound was made in a manner analogous to Example 23, from 4-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carbonitrile (Example 62), reaction run at rt. ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.49 (d, <i>J</i> = 5.09 Hz, 1H), 8.15 (d, <i>J</i> = 1.96Hz, 1H), 8.05 (br s, 1H), 7.92 (s, 1H), 7.74 (d, <i>J</i> = 1.96Hz, 1H), 7.58 (d, <i>J</i> = 1.57 Hz, 2H), 7.54 - 7.33 (m, 4H), 4.05 (s, 2H), 3.85 (s, 3H). [M+H] = 354.15.

Example 64. 3-(3-Chlorophenyl)-2-methoxy-5-(pyridin-3-ylmethyl)pyridine.

0574<chemistry id="chem0156" num="0156"><img file="EP3345902A1_D0161.tif" /></chemistry>

0575¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.55 (d, <i>J</i> = 2.0 Hz, 1H), 8.39 (dd, <i>J</i> = 1.2, 4.7 Hz, 1H), 8.13 (d, <i>J</i> = 2.0 Hz, 1H), 7.72 (d, <i>J</i> = 2.3 Hz, 1H), 7.70 - 7.66 (m, 1H), 7.58 (d, <i>J</i> = 1.6 Hz, 1H), 7.52 - 7.37 (m, 3H), 7.29 (dd, <i>J</i> = 4.7, 7.8 Hz, 1H), 3.96 (s, 2H), 3.85 (s, 3H). [M+H] = 318.09.

Example 65. 3-(3-Chlorophenyl)-2-methoxy-5-(1,3-thiazol-5-ylmethyl)pyridine.

0576<chemistry id="chem0157" num="0157"><img file="EP3345902A1_D0162.tif" /></chemistry>

0577¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.93 (s, 1H), 8.07 - 8.15 (m, 1H), 7.75 (s, 1H), 7.71 (d, <i>J =</i> 2.35 Hz, 1H), 7.56 - 7.62 (m, 1H), 7.37 - 7.52 (m, 3H), 4.21 (s, 2H), 3.86 (s, 3H). [M+H] = 318.15.

Example 66. 3-(3-Chlorophenyl)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]-2-methoxypyridine.

0578<chemistry id="chem0158" num="0158"><img file="EP3345902A1_D0163.tif" /></chemistry>

0579¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.06 (s, 1H), 7.63 (s, 1H), 7.57 (s, 1H), 7.50-7.40 (m, 3H), 4.03 (s, 2H), 3.85 (s, 3H), 2.48 (s, 3H), 2.28 (s, 3H). [M+H] = 345.17.

Example 67. 3-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxy-5-methylpyridin-3-yl)methyl]pyridine.

0580<chemistry id="chem0159" num="0159"><img file="EP3345902A1_D0164.tif" /></chemistry>

0581¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.09 (d, <i>J</i> = 2.3 Hz, 1H), 7.99 (d, <i>J</i> = 2.3 Hz, 1H), 7.94 (d, <i>J</i> = 2.0 Hz, 1H), 7.69 - 7.62 (m, 1H), 7.59 - 7.52 (m, 1H), 7.51 - 7.36 (m, 3H), 3.87 - 3.84 (m, 6H), 3.82 (s, 2H), 3.81 (s, 3H). [M+H] = 356.09.

Example 68. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-5-ylmethyl)pyridine.

0582<chemistry id="chem0160" num="0160"><img file="EP3345902A1_D0165.tif" /></chemistry>

0583¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.94 (s, 1H), 8.22 (d, <i>J</i> = 2.0 Hz, 1H), 7.94 (d, <i>J</i> = 2.3 Hz, 1H), 7.77 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.53 - 7.45 (m, 3H), 4.29 (s, 2H). [M+H] = 354.12.

Example 69. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]pyridine.

0584<chemistry id="chem0161" num="0161"><img file="EP3345902A1_D0166.tif" /></chemistry>

0585¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.14 (d, <i>J</i> = 2.0 Hz, 1H), 7.88 - 7.83 (m, 1H), 7.68 (s, 1H), 7.62 - 7.57 (m, 1H), 7.55 - 7.45 (m, 3H), 4.11 (s, 2H), 2.51 (s, 3H), 2.29 (s, 3H). [M+H] = 381.15.

Example 70. 5- {[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-3-carboxamide.

0586<chemistry id="chem0162" num="0162"><img file="EP3345902A1_D0167.tif" /></chemistry>

0587¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.86 (d, <i>J</i> = 2.0 Hz, 1H), 8.70 (d, <i>J</i> = 2.0 Hz, 1H), 8.26 (d, <i>J</i> = 2.0 Hz, 1H), 8.10 (s, 2H), 7.98 (d, <i>J</i> = 2.3 Hz, 1H), 7.60 (s, 1H), 7.55 (br s, 1H), 7.52 - 7.43 (m, 4H), 4.09 (s, 2H). [M+H] = 391.05.

Example 71. (5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-3-yl)methanamine.

0588<chemistry id="chem0163" num="0163"><img file="EP3345902A1_D0168.tif" /></chemistry><ul id="ul0023" list-style="none" compact="compact"><li>Step 1. <i>tert</i>-Butyl ((5-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)pyridin-3-yl)methyl)carbamate. The title compound was prepared in a manner analogous to Example 1, with the appropriate starting material substitutions.</li><li>Step 2. (5- {[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-3-yl)methanamine. Purified compound from Step 1, was treated with a solution of 20% TFA in DCM and stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue partitioned between EtOAc and sat. aq. NaHCO₃. The organic layers were washed with brine, dried (Na₂SO₄), filtered and concentrated under reduced pressure to afford the title compound. ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.61 - 8.47 (m, 1H), 8.31 (m, 2H), 8.22 (br s, 1H), 7.97 - 7.80 (m, 2H), 7.72 - 7.57 (m, 2H), 7.50 (br s, 2H), 4.12 - 4.03 (m, 2H), 4.00 (s, 2H), 3.15 (d, <i>J</i> = 4.7 Hz, 2H). [M+H] = 377.25.</li></ul>

Example 72. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-methylpyridin-3-yl)methyl]pyridine.

0589<chemistry id="chem0164" num="0164"><img file="EP3345902A1_D0169.tif" /></chemistry>

0590¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.42 (s, 1H), 8.20 (d, <i>J</i> = 2.0 Hz, 1H), 7.91 (d, <i>J</i> = 2.0 Hz, 1H), 7.85 (s, 1H), 7.89 - 7.83 (m, 1H), 7.69 - 7.65 (m, 1H), 7.67 (s, 1H), 7.61 - 7.54 (m, 3H), 3.97 (s, 2H), 2.39 (s, 3H). [M+H] = 361.06.

Example 73. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(2-methyl-1,3-thiazol-5-yl)methyl]pyridine.

0591<chemistry id="chem0165" num="0165"><img file="EP3345902A1_D0170.tif" /></chemistry>

0592¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.20 (s, 1H), 7.94 - 7.84 (m, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.53 - 7.42 (m, 4H), 4.19 (s, 2H), 2.55 (s, 3H). [M+H] = 368.02.

Example 74. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-2-ylmethyl)pyridine.

0593<chemistry id="chem0166" num="0166"><img file="EP3345902A1_D0171.tif" /></chemistry>

0594¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.27 (s, 1H), 8.01 (s, 1H), 7.74 - 7.64 (m, 1H), 7.63 - 7.56 (m, 2H), 7.55 - 7.41 (m, 4H), 4.43 (s, 2H). [M+H] = 354.05.

Example 75. 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methylpyrimidine.

0595<chemistry id="chem0167" num="0167"><img file="EP3345902A1_D0172.tif" /></chemistry>

0596¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.55 (s, 2H), 8.13 (d, <i>J</i> = 2.3 Hz, 1H), 7.72 (d, <i>J</i> = 2.3 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.53 - 7.34 (m, 3H), 4.02 (s, 2H), 3.80 (s, 3H), 3.85 (s, 3H). [M+H] = 327.15.

Example 76. 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methoxypyrimidine.

0597<chemistry id="chem0168" num="0168"><img file="EP3345902A1_D0173.tif" /></chemistry>

0598¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.55 (s, 2H), 8.13 (d, <i>J</i> = 2.3 Hz, 1H), 7.72 (d, <i>J</i> = 2.3 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.53 - 7.34 (m, 3H), 4.02 (s, 2H), 3.80 (s, 3H), 3.85 (s, 3H). [M+H] = 342.15.

Example 77. 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-

N

-(propan-2-yl)pyrimidin-2-amine.

0599<chemistry id="chem0169" num="0169"><img file="EP3345902A1_D0174.tif" /></chemistry>

0600¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.30 (s, 2H), 8.11 (d, <i>J</i> = 2.3 Hz, 1H), 7.70 (d, <i>J</i> = 2.3 Hz, 1H), 7.58 (t, <i>J</i> = 1.8 Hz, 1H), 7.53 - 7.36 (m, 3H), 7.35 (br s, 1H), 4.03 - 3.89 (m, 1H), 3.85 (s, 3H), 3.75 (s, 2H), 1.11 (d, <i>J</i> = 6.3 Hz, 6H). [M+H] = 370.05.

Example 78. 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine.

0601<chemistry id="chem0170" num="0170"><img file="EP3345902A1_D0175.tif" /></chemistry>

0602¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 9.02 (s, 1H), 8.77 (s, 2H), 8.16 (d, <i>J</i> = 2.3 Hz, 1H), 7.76 (d, <i>J</i> = 2.3 Hz, 1H), 7.65 - 7.36 (m, 4H), 3.98 (s, 2H), 3.30 (s, 3H). [M+H] = 313.01.

Example 79. 3-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyridine.

0603<chemistry id="chem0171" num="0171"><img file="EP3345902A1_D0176.tif" /></chemistry>

0604¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.05 (d, <i>J</i> = 2.0 Hz, 1H), 7.61 (d, <i>J</i> = 2.3 Hz, 1H), 7.57 (s, 1H), 7.52 - 7.38 (m, 4H), 7.28 (s, 1H), 3.84 (s, 3H), 3.75 (s, 2H), 3.65 (s, 3H). [M+H] = 315.02.

Example 80. 3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-4-ylmethyl)pyridine.

0605<chemistry id="chem0172" num="0172"><img file="EP3345902A1_D0177.tif" /></chemistry><ul id="ul0024" list-style="none" compact="compact"><li>Step 1. <i>tert</i>-Butyl 4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-1-carboxylate. The title compound was prepared in a manner analogous to Example 1, with the appropriate starting material substitutions.</li><li>Step 2. Purified compound from step 1, was treated with a solution of 20% TFA in DCM and stirred at rt for 4 h. The solvent was removed under reduced pressure and the residue partitioned between EtOAc and sat. NaHCO₃. The organic layers were washed with brine, dried (Na₂SO₄), filtered and concentrated under reduced pressure to afford the title compound. ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.05 (d, <i>J</i> = 2.0 Hz, 1H), 7.62 (d, <i>J</i> = 2.0 Hz, 1H), 7.58 - 7.54 (m, 3H), 7.50 - 7.36 (m, 4H), 3.84 (s, 3H), 3.72 (s, 2H). [M+H] = 301.02.</li></ul>

Example 81. 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-

N

-methylpyrimidin-2-amine.

0606<chemistry id="chem0173" num="0173"><img file="EP3345902A1_D0178.tif" /></chemistry>

0607¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.34 (s, 2H), 8.11 (d, <i>J</i> = 2.0 Hz, 1H), 7.84 (br s, 1H), 7.70 (d, <i>J</i> = 2.0 Hz, 1H), 7.58 (t, <i>J</i> = 1.8 Hz, 1H), 7.53 - 7.36 (m, 3H), 3.83 (s 3H), 3.80-3.75 (m, 3H), 3.73 (s, 2H). [M+H] = 342.05.

Example 82. 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-

N

-cyclopropylpyrimidin-2-amine.

0608<chemistry id="chem0174" num="0174"><img file="EP3345902A1_D0179.tif" /></chemistry>

0609¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.34 (s, 2H), 8.11 (d, <i>J</i> = 2.0 Hz, 1H), 7.84 (br s, 1H), 7.70 (d, <i>J</i> = 2.0 Hz, 1H), 7.58 (t, <i>J</i> = 1.8 Hz, 1H), 7.53 - 7.36 (m, 3H), 3.80 (s, 3H), 3.78 (s, 2H), 2.68 - 2.56 (m, 1H), 0.71 - 0.61 (m, 2H), 0.53 - 0.38 (m, 2H). [M+H] = 368.02.

Example 83. 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-

N

,

N

-dimethylpyrimidin-2-amine.

0610<chemistry id="chem0175" num="0175"><img file="EP3345902A1_D0180.tif" /></chemistry>

0611¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.38 (s, 2H), 8.16 (d, <i>J</i> = 2.0 Hz, 1H), 7.72 (d, <i>J</i> = 2.0 Hz, 1H), 7.56 (t, <i>J</i> = 1.8 Hz, 1H), 7.50 - 7.36 (m, 3H), 3.86 (s 3H), 3.73 (s, 2H), 3.01 (s, 6H). [M+H] = 355.18.

Example 84. 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-

N

-(2,2,2-trifluoroethyl)pyrimidin-2-amine.

0612<chemistry id="chem0176" num="0176"><img file="EP3345902A1_D0181.tif" /></chemistry>

0613¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.38 (s, 2H), 8.16 (d, <i>J</i> = 2.0 Hz, 1H), 7.84 (br s, 1H), 7.72 (d, <i>J</i> = 2.0 Hz, 1H), 7.56 (t, <i>J</i> = 1.8 Hz, 1H), 7.50 - 7.36 (m, 3H), 4.10-4.01 (m, 2H), 3.86 (s 3H), 3.73 (s, 2H). [M+H] = 409.14.

Example 85. Methyl 4-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzoate.

0614<chemistry id="chem0177" num="0177"><img file="EP3345902A1_D0182.tif" /></chemistry>

0615[M+H] = 369.16

Example 86. 4-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzonitrile.

0616<chemistry id="chem0178" num="0178"><img file="EP3345902A1_D0183.tif" /></chemistry>

0617[M+H] = 336.6.

Example 87. 5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidin-2-amine.

0618<chemistry id="chem0179" num="0179"><img file="EP3345902A1_D0184.tif" /></chemistry>

0619¹H NMR (400 MHz, CD₃OD) δ 8.29 (s, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 7.98 (t, <i>J</i> = 3.72 Hz, 1H), 7.69 - 7.52 (m, 1H), 7.41 (d, <i>J</i> = <i>5</i>.09 Hz, 2H), 4.03 (s, 3H), 3.98 (s, 2H). [M+H] = 328.21.

Example 88. 3-(3-Chlorophenyl)-5-[(4-fluorophenyl)methyl]-2-methoxypyridine.

0620<chemistry id="chem0180" num="0180"><img file="EP3345902A1_D0185.tif" /></chemistry>

0621¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.51 (t, <i>J</i> = <i>2</i>.5 Hz, 2H), 7.42 - 7.21 (m, 5H), 7.01 (t, <i>J</i> = <i>8</i>.8 Hz, 2H), 3.95 (s, 2H), 3.92 (s, 3H). [M+H] = 328.26.

Example 89. 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidin-2-amine.

0622<chemistry id="chem0181" num="0181"><img file="EP3345902A1_D0186.tif" /></chemistry>

0623¹H NMR (400 MHz, CD₃OD) δ 8.11 (s, 2H), 8.01 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.70 - 7.63 (m, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 7.38 - 7.28 (m, 3H), 3.78 (s, 2H). [M+H] = 363.30.

Example 90. 5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyridine-2-carboxamide.

0624<chemistry id="chem0182" num="0182"><img file="EP3345902A1_D0187.tif" /></chemistry><ul id="ul0025" list-style="none" compact="compact"><li>Step 1. Methyl 5-((6-(3-chlorophenyl)-5-methoxypyrazin-2-yl)methyl)picolinate. The title compound was prepared in a manner analogous to Example 1 from (6-(methoxycarbonyl)pyridin-3-yl)boronic acid and Intermediate 3. [M+H] = 370.10.</li><li>Step 2. 5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyridine-2-carboxamide. A solution of 5-((6-(3-chlorophenyl)-5-methoxypyrazin-2-yl)methyl)picolinate (from Step 1) and ammonia (7N in methanol) was heated at 60 °C for 8 h, then concentrated under reduced pressure. Trituration with diethyl ether obtained the title compound (12 mg, 70%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.66 (br s, 1H), 8.14 (s, 1H), 8.07 (d, <i>J</i> = 7.83 Hz, 1H), 8.02 (s, 1H), 7.69 - 7.60 (m, 1H), 7.59 - 7.50 (m, 1H), 7.41 (d, <i>J</i> = 4.70 Hz, 2H), 4.27 (s, 2H), 4.00 - 4.09 (m, 3H). [M+H] = 355.10.</li></ul>

Example 91. 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-

N-

cyclopropylpyrimidin-2-amine.

0625<chemistry id="chem0183" num="0183"><img file="EP3345902A1_D0188.tif" /></chemistry>

0626¹H NMR (400 MHz, CD₃OD) δ 8.25 (br s, 2H), 8.11 (br s, 1H), 7.75 (br s, 1H), 7.48 - 7.68 (m, 2H), 7.35 - 7.46 (m, 3H), 3.90 (br s, 2H), 2.63 (br s, 1H), 0.76 (d, <i>J</i> = 6.26 Hz, 2H), 0.51 (br s, 2H). [M+H] = 403.12.

Example 92. 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-2-methoxypyrimidine.

0627<chemistry id="chem0184" num="0184"><img file="EP3345902A1_D0189.tif" /></chemistry>

0628¹H NMR (400 MHz, CD₃OD) δ 8.49 (br s, 2H), 8.13 (br s, 1H), 7.78 (d, <i>J</i> = 2.74 Hz, 1H), 7.63 - 7.49 (m, 2H), 7.47- 7.31 (m, 3H), 4.07 - 3.81 (m, 5H). [M+H] = 376.20.

Example 93. 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-

N-

methylpyrimidin-2-amine.

0629<chemistry id="chem0185" num="0185"><img file="EP3345902A1_D0190.tif" /></chemistry>

0630¹H NMR (400 MHz, CD₃OD) δ 8.20 (br s, 2H), 8.10 (br s, 1H), 7.74 (br s, 2H), 7.68 - 7.49 (m, 1H), 7.46- 7.27 (m, 3H), 3.87 (br s, 2H), 2.89 (br s, 3H). [M+H] = 377.10.

Example 94. 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-

N-

(2,2,2-trifluoroethyl)pyrimidin-2-amine.

0631<chemistry id="chem0186" num="0186"><img file="EP3345902A1_D0191.tif" /></chemistry>

0632¹H NMR (400 MHz, CD₃OD) δ 8.27 (br s, 2H), 8.10 (br s, 1H), 7.80 - 7.68 (m, 1H), 7.61 - 7.49(m, 1H), 7.47 - 7.31 (m, 4H), 4.19 - 4.02 (m, 2H), 3.90 (br s, 2H). [M+H] = 445.10.

Example 95. 3-(3-Chlorophenyl)-2-methoxy-5-(1,2-oxazol-4-ylmethyl)pyrazine.

0633<chemistry id="chem0187" num="0187"><img file="EP3345902A1_D0192.tif" /></chemistry>

0634¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 8.09 (s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 8.02 - 7.95 (m, 1H), 7.47 - 7.38 (m, 2H), 4.20 - 3.90 (m, 5H). [M+H] = 302.10.

Example 96. 3-(3-Chlorophenyl)-2-methoxy-5-(1,2-oxazol-4-ylmethyl)pyridine.

0635<chemistry id="chem0188" num="0188"><img file="EP3345902A1_D0193.tif" /></chemistry>

0636¹H NMR (400 MHz, CD₃OD) δ 8.52 (s, 1H), 8.34 (s, 1H), 8.04 (s, 1H), 7.60 - 7.53 (m, 2H), 7.46 - 7.27 (m, 3H), 3.93 (s, 3H), 3.85 (s, 2H). [M+H] = 301.10.

Example 97. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,2-oxazol-4-ylmethyl)pyridine.

0637<chemistry id="chem0189" num="0189"><img file="EP3345902A1_D0194.tif" /></chemistry>

0638¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 8.36 (s, 1H), 8.12 (d, <i>J</i> = 1.96 Hz, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 7.55 (s, 1H), 7.48 - 7.31 (m, 3H), 3.91 (s, 2H). [M+H] = 337.10.

Example 98. 3-(3-Chlorophenyl)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]-2-methoxypyrazine.

0639<chemistry id="chem0190" num="0190"><img file="EP3345902A1_D0195.tif" /></chemistry>

0640¹H NMR (400 MHz, CD₃OD) δ 8.07 - 7.88 (m, 2H), 7.46 - 7.30 (m, 3H), 4.03 (s, 3H), 3.89 (br s, 2H), 2.40 (br s, 3H), 2.21 (s, 3H). [M+H] = 330.79.

Example 99. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]pyridine.

0641<chemistry id="chem0191" num="0191"><img file="EP3345902A1_D0196.tif" /></chemistry>

0642¹H NMR (400 MHz, CD₃OD) δ 8.01 (br s, 1H), 7.64 (br s, 1H), 7.58 (br s, 1H), 7.53 (br s, 1H), 7.47 - 7.31 (m, 3H), 3.81 (br s, 2H), 2.36 (br s, 3H), 2.12 (br s, 3H). [M+H] = 365.20.

Example 100. Methyl 2-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetate.

0643<chemistry id="chem0192" num="0192"><img file="EP3345902A1_D0197.tif" /></chemistry>

0644¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, <i>J</i> = 2.35 Hz, 1H), 8.02 (d, <i>J</i> = 2.35 Hz, 1H), 7.76 (s, 1H), 7.71 - 7.66 (m, 1H), 7.56 - 7.59 (m, 1H), 7.55 (s, 1H), 7.57 - 7.46 (m, 1H), 7.45 - 7.36 (m, 4H), 4.01 (s, 2H), 3.67 (s, 3H), 3.61 (s, 2H). [M+H] = 418.29.

Example 101. Ethyl 1-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxylate.

0645<chemistry id="chem0193" num="0193"><img file="EP3345902A1_D0198.tif" /></chemistry>

0646¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, <i>J</i> = 2.35 Hz, 1H), 7.76 (s, 1H), 7.68 (d, <i>J</i> = 2.35 Hz, 1H), 7.59- 7.52 (m, 1H), 7.52 - 7.47 (m, 2H), 7.45 - 7.36 (m, 4H), 7.31 - 7.27 (m, 1H), 4.10-4.05 (m, 4H), 4.03 (m, 1H), 4.00 (s, 2H), 1.55 - 1.49 (m, 2H), 1.14 - 1.19 (m, 3H). [M+H] = 445.10.

Example 102. 3-(3-Chlorophenyl)-5-{[6-(cyclopropylmethoxy)pyridin-3-yl]methyl}-2-(difluoromethoxy)pyridine.

0647<chemistry id="chem0194" num="0194"><img file="EP3345902A1_D0199.tif" /></chemistry>

0648¹H NMR (400 MHz, CD₃OD) δ 8.08-8.05 (m, 1H), 8.01-7.90 (m, 1H), 7.71 (d, <i>J</i> = 2.35Hz, 1H), 7.58 (s, 1H), 7.50 - 7.45 (m, 1H), 7.43 - 7.36 (m, 4H), 6.75-6.73 (m, 1H), 4.05 (d, <i>J</i> = 7.04 Hz, 2H), 3.96 (s, 2H), 1.32 - 1.17 (m, 1H), 0.52 - 0.63 (m, 2H), 0.25 - 0.36 (m, 2H). [M+H] = 417.33.

Example 103. 5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carbonitrile.

0649<chemistry id="chem0195" num="0195"><img file="EP3345902A1_D0200.tif" /></chemistry>

0650¹H NMR (400MHz, CD₃OD) δ 8.73 (d, <i>J</i> = 1.6 Hz, 1H), 8.13 (s, 1H), 8.01 - 7.90 (m, 2H), 7.86 (t, <i>J</i> = 1.8 Hz, 1H), 7.80 (dd, <i>J</i> = 0.8, 7.8 Hz, 1H), 7.46 (t, <i>J</i> = 8.0 Hz, 1H), 7.19 (dd, <i>J</i> = 2.0, 8.2 Hz, 1H), 7.05 - 6.59 (m, 1H), 4.48 (q, <i>J</i> = 7.3 Hz, 2H), 4.27 (s, 2H), 1.43 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 383.26.

Example 104. 5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidin-2-amine.

0651<chemistry id="chem0196" num="0196"><img file="EP3345902A1_D0201.tif" /></chemistry>

0652¹H NMR (400MHz, CD₃OD) δ 8.52 (s, 2H), 8.13 (s, 1H), 7.95 (qd, <i>J</i> = 0.9, 7.9 Hz, 1H), 7.89 - 7.85 (m, 1H), 7.47 (t, <i>J</i> = 8.2 Hz, 1H), 7.20 (dd, <i>J</i> = 3.3, 8.0 Hz, 1H), 7.05 - 6.62 (m, 1H), 4.49 (q, <i>J</i> = 7.2 Hz, 2H), 4.07 (s, 2H), 1.43 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 374.14.

Example 105. 5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidin-2-amine.

0653<chemistry id="chem0197" num="0197"><img file="EP3345902A1_D0202.tif" /></chemistry>

0654¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.23 - 8.17 (m, 2H), 8.15 (s, 1H), 8.05 - 8.02 (m, 1H), 7.99 (ddd, <i>J</i> = 1.6, 3.6, 5.4 Hz, 1H), 7.52 - 7.47 (m, 2H), 6.44 (s, 2H), 4.41 (q, <i>J</i> = 7.0 Hz, 2H), 3.90 (s, 2H), 1.35 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 342.15.

Example 106. 5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidin-2-amine.

0655<chemistry id="chem0198" num="0198"><img file="EP3345902A1_D0203.tif" /></chemistry>

0656¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.23 - 8.14 (m, 3H), 7.88 (d, <i>J</i> = 8.2 Hz, 1H), 7.77 (s, 1H), 7.52 (t, <i>J</i> = 8.0 Hz, 1H), 7.29 - 7.21 (m, 1H), 7.09 - 5.70 (m, 3H), 3.95 (s, 3H), 3.90 (s, 2H). [M+H] = 360.21.

Example 107. 5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile.

0657<chemistry id="chem0199" num="0199"><img file="EP3345902A1_D0204.tif" /></chemistry>

0658¹H NMR (400MHz, CD₃OD) δ 8.94 (s, 2H), 8.19 (s, 1H), 7.90 (td, <i>J</i> = 1.4, 7.8 Hz, 1H), 7.79 (t, <i>J</i> = 2.2 Hz, 1H), 7.46 (t, <i>J</i> = 8.0 Hz, 1H), 7.19 (dd, <i>J</i> = 2.3, 8.2 Hz, 1H), 7.03- 6.62 (m, 1H), 4.28 (s, 2H), 4.04 (s, 3H). M+H] = 370.19.

Example 108. 5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile.

0659<chemistry id="chem0200" num="0200"><img file="EP3345902A1_D0205.tif" /></chemistry>

0660¹H NMR (400MHz, CD₃OD) δ 8.93 (s, 2H), 8.17 (s, 1H), 8.06 - 8.02 (m, 1H), 7.97 (ddd, <i>J</i> = 1.6, 3.7, 5.3 Hz, 1H), 7.43 - 7.38 (m, 2H), 4.49 (q, <i>J</i> = 7.0 Hz, 2H), 4.27 (s, 2H), 1.43 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 352.26.

Example 109. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(pyridin-2-ylmethyl)pyridine.

0661<chemistry id="chem0201" num="0201"><img file="EP3345902A1_D0206.tif" /></chemistry><ul id="ul0026" list-style="none" compact="compact"><li>Step 1. ((5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)zinc(II) bromide. To a suspension of zinc (42.77 mg, 0.65 mmol) in THF (1 mL) was added 1,2-dibromoethane (2.48 µl, 0.03 mmol). The resulting mixture was heated at 70°C for 10 minutes before being cooled to room temperature. Once cooled, trimethylsilylchloride (2.92 µL, 0.02 mmol) was added and the solution was stirred at room temperature for an additional 30 min. To the activated zinc solution was added 5-(bromomethyl)-3-(3-chlorophenyl)-2-(difluoromethoxy)pyridine (Intermediate 12, 200 mg, 0.57 mmol) and the resulting mixture was heated at 70°C for 8 h. The reaction mixture was cooled to room temperature and decanted from the solids to afford a ∼0.5 M solution of the title compound.</li><li>Step 2. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(pyridin-2-ylmethyl)pyridine. To a solution of 2-bromopyridine (29.89 µL, 0.31 mmol) and Pd(PPh₃)₄ (9.88 mg, 0.01 mmol) in THF (3.00 mL) was added ((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)zinc(II) bromide (500.00 µL, 0.57 mol/L, 0.29 mmol, from step 1). The resulting solution was heated at 70 °C for 5 h. The solvent was removed, and the crude material was purified on the Shimadzu HPLC using the 5-95% gradient with TFA to obtain the title compound TFA salt as an oil (21 mg, 16 %). ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.72-8.78 (m, 1H), 8.46 (dt, <i>J</i> = 1.57, 8.02 Hz, 1H), 8.23 (d, <i>J</i> = 2.35 Hz, 1H), 7.84-7.93 (m, 3H), 7.39-7.83(m, 5H), 4.50 (s, 2H). [M+H] = 347.08.</li></ul>

0662Examples 110-111 were prepared in a manner analogous to Example 109, with the appropriate starting materials and reagent substitutions.

Example 110. 2-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrazine.

0663<chemistry id="chem0202" num="0202"><img file="EP3345902A1_D0207.tif" /></chemistry>

0664¹H NMR (400 MHz, CD₃OD) δ 8.65 (d, <i>J</i> = <i>1</i>.57 Hz, 1H), 8.55 (dd, <i>J</i> = <i>1</i>.57, 2.74 Hz, 1H), 8.47 (d, <i>J</i> = <i>2</i>.74 Hz, 1H), 8.18 (d, <i>J</i> = <i>2</i>.35 Hz, 1H), 7.86 (d, <i>J</i> = <i>2</i>.35 Hz, 1H), 7.79-7.36 (m, 5H), 4.25 (s, 2H). [M+H] = 348.06.

Example 111. 6-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridazin-3-amine.

0665<chemistry id="chem0203" num="0203"><img file="EP3345902A1_D0208.tif" /></chemistry>

0666¹H NMR (400 MHz, CD₃OD) δ 8.18 (d, <i>J</i> = <i>2</i>.35 Hz, 1H), 7.84 (d, <i>J</i> = <i>2</i>.35 Hz, 1H), 7.79 (d, <i>J</i> = <i>2</i>.35 Hz, 1H), 7.39-7.78 (m, 6H), 4.19 (s, 2H). [M+H] = 363.16.

Example 112. 3-(3-Chlorophenyl)-2-methoxy-6-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine.

0667<chemistry id="chem0204" num="0204"><img file="EP3345902A1_D0209.tif" /></chemistry>

0668To a solution of 3-(chloromethyl)-5-(3-chlorophenyl)-6-methoxy-2-methylpyridine (Intermediate 8, 87 mg, 0.31 mmol), in acetone (12 mL), was added 1H-1,2,4-triazole (32 mg, 0.46 mmol), and Cs₂CO₃ (150 mg, 0.63 mmol). The reaction mixture stirred at room temperature for 2 h, then filtered and concentrated under reduced pressure. Purification (FCC, SiO₂, 0 - 100%, EtOAc/hexanes) afforded the title compound (82.4 mg, 84 %). ¹H NMR (400 MHz, CDCl₃) δ 8.03 (s, 1H), 7.98 (s, 1H), 7.52 (s, 1H), 7.45 - 7.37 (m, 2H), 7.37 - 7.29 (m, 2H), 5.34 (s, 2H), 3.98 (s, 3H), 2.52 (s, 3H). [M+H] = 315.22.

0669Examples 113, 115, 117, 123, 125-126 were prepared in a manner analogous to Example 13, with the appropriate starting materials and reagent substitutions.

Example 113. 4-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzamide.

0670<chemistry id="chem0205" num="0205"><img file="EP3345902A1_D0210.tif" /></chemistry>

0671¹H NMR (400 MHz, CD₃OD) δ 8.02 - 8.08 (m, 2H), 7.98 (td, <i>J</i> = 4.30, 1.57 Hz, 1H), 7.81 (d, <i>J</i> = 8.22 Hz, 2H), 7.47 - 7.37 (m, 4H), 4.21 (s, 2H), 4.02 (s, 3H). [M+H] = 354.20.

Example 114. 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxamide.

0672<chemistry id="chem0206" num="0206"><img file="EP3345902A1_D0211.tif" /></chemistry>

0673The title compound was prepared in a manner analogous to Example 90, with the appropriate starting material substitutions. ¹H NMR (400 MHz, CD₃OD) δ 8.49 (d, <i>J</i> = 2.0 Hz, 1H), 8.05 (d, <i>J</i> = 2.3 Hz, 1H), 7.95 (d, <i>J</i> = 8.2 Hz, 1H), 7.75 (dd, <i>J</i> = 2.0, 8.2 Hz, 1H), 7.71 - 7.27 (m, 6H), 4.07 (s, 2H). [M+H] = 390.16.

Example 115. 5-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidine-2-carboxamide.

0674<chemistry id="chem0207" num="0207"><img file="EP3345902A1_D0212.tif" /></chemistry>

0675¹H NMR (400 MHz, CD₃OD) δ 8.85 (s, 2H), 8.14 (d, <i>J</i> = <i>2</i>.35 Hz, 1H), 7.81 (d, <i>J</i> = <i>2</i>.35 Hz, 1H), 7.38 - 7.30 (m, 1H), 7.59 (s, 1H), 7.10 - 7.03 (m, 2H) 6.95 (dd, <i>J</i> = <i>8</i>.22, 1.57 Hz, 1H) 3.81 (s, 3H) 4.17 (s, 2H). [M+H] = 387.32.

Example 116. 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide.

0676<chemistry id="chem0208" num="0208"><img file="EP3345902A1_D0213.tif" /></chemistry>

0677The title compound was prepared in a manner analogous to Example 90, with the appropriate starting material substitutions. ¹H NMR (400 MHz, CD₃OD) δ 8.56 (d, <i>J</i> = 1.6 Hz, 1H), 8.09 - 8.00 (m, 2H), 7.82 (dd, <i>J</i> = 2.0, 8.2 Hz, 1H), 7.59 (d, <i>J</i> = 2.3 Hz, 1H), 7.53 (s, 1H), 7.45 - 7.30 (m, 3H), 4.09 (s, 2H), 3.93 (s, 3H). [M+H] = 354.20.

Example 117. 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carboxamide.

0678<chemistry id="chem0209" num="0209"><img file="EP3345902A1_D0214.tif" /></chemistry>

0679¹H NMR (400 MHz, CD₃OD) δ 8.85 (s, 2H), 8.18 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.84 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.80 - 7.37 (m, 5H), 4.18 (s, 2H). [M+H] = 391.16.

Example 118. 5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide.

0680<chemistry id="chem0210" num="0210"><img file="EP3345902A1_D0215.tif" /></chemistry>

0681¹H NMR (400 MHz, CD₃OD) δ 8.83 (s, 2H), 8.11 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.65 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.45 - 7.26 (m, 3H), 7.10 - 7.02 (m, 1H), 4.12 (s, 2H), 3.94 (s, 3H). [M+H] = 339.18.

Example 119. 5-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide.

0682<chemistry id="chem0211" num="0211"><img file="EP3345902A1_D0216.tif" /></chemistry>

0683¹H NMR (400 MHz, CD₃OD) δ 8.84 (s, 2H), 8.09 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.66 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.46 - 7.35 (m, 3H), 7.17 - 7.08 (m, 1H), 7.03 - 6.61 (m, 1H), 4.40 (q, <i>J</i> = <i>7</i>.0 Hz, 2H), 4.12 (s, 2H), 1.35 (t, <i>J</i> = <i>7</i>.0 Hz, 3H). [M+H] = 401.27.

Example 120. 5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl} methyl)pyrimidine-2-carboxamide.

0684<chemistry id="chem0212" num="0212"><img file="EP3345902A1_D0217.tif" /></chemistry>

0685¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.91 (s, 2H), 8.33 - 8.27 (m, 2H), 8.12 (br s, 1H), 7.95 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.93 - 7.55 (m, 2H), 7.50 (dd, <i>J</i> = <i>1.</i>6, 5.5 Hz, 1H), 7.32 - 7.29 (m, 1H), 4.09 (s, 2H), 3.91 (s, 3H). [M+H] = 388.24.

Example 121. 5-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide.

0686<chemistry id="chem0213" num="0213"><img file="EP3345902A1_D0218.tif" /></chemistry>

0687¹H NMR (400 MHz, CD₃OD) δ 8.84 (s, 2H), 8.11 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.66 (d, <i>J</i> = <i>2</i>.3 Hz, 1H), 7.46 - 7.35 (m, 2H), 7.32 (t, <i>J</i> = <i>1</i>.8 Hz, 1H), 7.14 - 7.10 (m, 1H), 6.83 (t, <i>J</i> = <i>1</i>.0 Hz, 1H), 4.13 (s, 2H), 3.95 (s, 3H). [M+H] = 387.25.

Example 122. 5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl} methyl)pyrimidine-2-carboxamide.

0688<chemistry id="chem0214" num="0214"><img file="EP3345902A1_D0219.tif" /></chemistry>

0689¹H NMR (400 MHz, CD₃OD) δ 8.84 (s, 2H), 8.23 - 8.15 (m, 2H), 7.79 (s, 1H), 7.75 - 7.36 (m, 2H), 7.22 - 7.20 (m, 1H), 4.44 (q, <i>J</i> = <i>7</i>.0 Hz, 2H), 4.13 (s, 2H), 1.37 (t, <i>J</i> = <i>7</i>.0 Hz, 3H). [M+H] = 402.26.

Example 123. 5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide.

0690<chemistry id="chem0215" num="0215"><img file="EP3345902A1_D0220.tif" /></chemistry>

0691¹H NMR (400 MHz, CD₃OD) δ 8.94 (s, 2H), 8.20 (s, 1H), 8.02 (s, 1H), 7.99 - 7.91 (m, 1H), 7.41 (d, <i>J</i> = 5.09 Hz, 2H), 4.28 (s, 2H), 4.04 (s, 3H). [M+H] = 356.20.

Example 124. 5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carboxamide.

0692<chemistry id="chem0216" num="0216"><img file="EP3345902A1_D0221.tif" /></chemistry>

0693The title compound was prepared in a manner analogous to Example 90, with the appropriate starting material substitutions. ¹H NMR (400MHz, CD₃OD) δ 8.66 - 8.63 (m, 1H), 8.11 (s, 1H), 8.04 (dd, <i>J</i> = 0.8, 7.8 Hz, 1H), 7.98 - 7.85 (m, 3H), 7.46 (t, <i>J</i> = 8.2 Hz, 1H), 7.19 (dd, <i>J</i> = 2.0, 8.2 Hz, 1H), 7.04 - 6.61 (m, 1H), 4.48 (q, <i>J</i> = 7.0 Hz, 2H), 4.25 (s, 2H), 1.43 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 401.25.

Example 125. 5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide.

0694<chemistry id="chem0217" num="0217"><img file="EP3345902A1_D0222.tif" /></chemistry>

0695¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.92 (s, 2H), 8.29 (s, 1H), 8.12 (br s, 1H), 7.88 - 7.82 (m, 1H), 7.74 (t, <i>J</i> = 2.0 Hz, 1H), 7.71 (br s, 1H), 7.52 (t, <i>J</i> = 8.0 Hz, 1H), 7.45 - 7.03 (m, 2H), 4.26 (s, 2H), 3.96 (s, 3H). [M+H] = 388.15.

Example 126. 5- {[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide.

0696<chemistry id="chem0218" num="0218"><img file="EP3345902A1_D0223.tif" /></chemistry>

0697¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.92 (s, 2H), 8.27 (s, 1H), 8.13 (br s, 1H), 8.04 - 7.99 (m, 1H), 7.99 - 7.91 (m, 1H), 7.71 (br s, 1H), 7.52 - 7.45 (m, 2H), 4.48 - 4.37 (m, 2H), 4.25 (s, 2H), 1.40 - 1.28 (m, 3H). [M+H] = 370.05.

Example 127. Methyl 1-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate.

0698<chemistry id="chem0219" num="0219"><img file="EP3345902A1_D0224.tif" /></chemistry>

0699To a solution of 5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyrazine (Intermediate 3, 200.00 mg, 0.64 mmol), in acetone (3.19 mL), was added methyl 1H-1,2,4-triazole-3-carboxylate (121.60 mg, 0.96 mmol) and K₂CO₃ (264.44 mg, 1.91 mmol). The reaction was stirred at rt for 2 h. The LC/MS showed two peaks with [M+H] values consistent with the two major regioproducts. The mixture was diluted with DCM (5 mL), dried (Na₂SO₄) and concentrated under reduced pressure. Purification (FCC, SiO₂, 20 - 100% EtOAc/hexanes) afforded the title compound (100 mg, 44%). ¹H NMR (400MHz, CD₃OD) δ 8.79 (s, 1H), 8.26 (s, 1H), 8.01 (td, <i>J</i> = 1.1, 2.1 Hz, 1H), 7.99 - 7.90 (m, 1H), 7.45 - 7.36 (m, 2H), 5.64 (s, 2H), 4.07 (s, 3H), 3.92 (s, 3H). [M+H] = 360.24.

0700Examples 128-149, 151-197 were prepared in a manner analogous to Example 4 or Example 127 with the appropriate starting materials and reagent substitutions.

Example 128. 3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-(difluoromethoxy)pyridine.

0701<chemistry id="chem0220" num="0220"><img file="EP3345902A1_D0225.tif" /></chemistry>

0702¹H NMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.71 - 7.63 (m, 1H), 7.50 (d, <i>J</i> = 19.17 Hz, 1H), 7.39 (s, 2H), 7.26 (s, 2H), 5.26 (s, 2H), 3.70 (s, 1H), 2.04 (s, 1H), 1.55 (s, 1H), 0.95 (d, <i>J</i> = <i>6</i>.65 Hz, 3H). [M+H] = 377.22.

Example 129. 3-(3-Fluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine.

0703<chemistry id="chem0221" num="0221"><img file="EP3345902A1_D0226.tif" /></chemistry>

0704¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 8.19 (d, <i>J</i> = 2.7 Hz, 1H), 8.00 (s, 1H), 7.75 (d, <i>J</i> = 2.3 Hz, 1H), 7.45 - 7.38 (m, 1H), 7.34 - 7.26 (m, 2H), 7.12 - 7.05 (m, 1H), 5.44 (s, 2H), 3.95 (s, 3H). [M+H] = 285.26.

Example 130. 3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyrazine.

0705<chemistry id="chem0222" num="0222"><img file="EP3345902A1_D0227.tif" /></chemistry>

0706¹H NMR (400 MHz, CD₃OD) δ 8.68 (s, 1H), 8.20 (s, 1H), 8.01 (s, 2H), 7.98 - 7.92 (m, 1H), 7.44 - 7.39 (m, 2H), 5.58 (s, 2H), 4.06 (s, 3H). [M+H] = 302.31.

Example 131. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine.

0707<chemistry id="chem0223" num="0223"><img file="EP3345902A1_D0228.tif" /></chemistry>

0708¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 8.25 (d, <i>J</i> = 2.3 Hz, 1H), 8.02 (s, 1H), 7.92 (d, <i>J =</i> 2.3 Hz, 1H), 7.83 - 7.61 (m, 1H), 7.56 (s, 1H), 7.50 - 7.39 (m, 3H), 5.51 (s, 2H). [M+H] = 337.15.

Example 132. 3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyrazine.

0709<chemistry id="chem0224" num="0224"><img file="EP3345902A1_D0229.tif" /></chemistry> as a mixtture

0710¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 2H), 8.18 (d, <i>J</i> = 6.65 Hz, 2H), 7.90 - 8.05 (m, 4H), 7.85 (s, 2H), 7.37 - 7.47 (m, 4H), 5.50 (d, <i>J</i> = 10.17 Hz, 4H), 4.07 (s, 6H), 2.27 - 2.69 (m, 6H). [M+H] = 316.22.

Example 133. 3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyrazine.

0711<chemistry id="chem0225" num="0225"><img file="EP3345902A1_D0230.tif" /></chemistry> as a mixture

0712¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 8.16 (s, 2H), 8.01 (d, <i>J</i> = 1.2 Hz, 4H), 7.78 (s, 1H), 7.44 - 7.39 (m, 4H), 5.62 (s, 2H), 5.45 (s, 2H), 4.06 (m, 6H), 2.43 - 2.33 (m, 1H), 2.04 - 1.94 (m, 1H), 1.20 - 0.84 (m, 8H). [M+H] = 342.33.

Example 134. 3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine.

0713<chemistry id="chem0226" num="0226"><img file="EP3345902A1_D0231.tif" /></chemistry>

0714¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, <i>J</i> = 2.3 Hz, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.55 (d, <i>J</i> = 2.3 Hz, 1H), 7.51 (d, <i>J</i> = 0.8 Hz, 1H), 7.43 - 7.32 (m, 3H), 5.33 (s, 2H), 3.98 (s, 3H). [M+H] = 301.19.

Example 135. 3-(3-Chlorophenyl)-2-(propan-2-yloxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine.

0715<chemistry id="chem0227" num="0227"><img file="EP3345902A1_D0232.tif" /></chemistry>

0716¹H NMR (400 MHz, CD₃OD) δ 8.63 - 8.57 (m, 1H), 8.16 (d, <i>J</i> = 2.3 Hz, 1H), 8.00 (s, 1H), 7.73 (d, <i>J</i> = 2.3 Hz, 1H), 7.56 (s, 1H), 7.49 - 7.31 (m, 3H), 5.44 - 5.40 (m, 3H), 1.31 (d, <i>J</i> = 6.3 Hz, 6H). [M+H] = 329.26.

Example 136. 3-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]benzonitrile.

0717<chemistry id="chem0228" num="0228"><img file="EP3345902A1_D0233.tif" /></chemistry>

0718¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.67 (s, 1H), 8.25 (d, <i>J</i> = 2.3 Hz, 1H), 7.99 (m, 2H), 7.91 - 7.83 (m, 3H), 7.69 - 7.62 (m, 1H), 5.43 (s, 2H), 3.90 (s, 3H). [M+H] = 292.26.

Example 137. 2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine.

0719<chemistry id="chem0229" num="0229"><img file="EP3345902A1_D0234.tif" /></chemistry>

0720¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 8.21 (d, <i>J</i> = 2.3 Hz, 1H), 8.00 (s, 1H), 7.77 (d, <i>J</i> = 2.3 Hz, 1H), 7.54 - 7.45 (m, 3H), 7.27 (d, <i>J</i> = 6.3 Hz, 1H), 5.45 (s, 2H), 3.96 (s, 3H). [M+H] = 351.29.

Example 138. 3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-4H-1,2,4-triazol-4-yl)methyl]pyridine.

0721<chemistry id="chem0230" num="0230"><img file="EP3345902A1_D0235.tif" /></chemistry>

0722¹H NMR (400 MHz, CD₃OD) δ 8.52 (s, 1H), 8.13 (d, <i>J</i> = 2.3 Hz, 1H), 7.66 (d, <i>J</i> = 2.3 Hz, 1H), 7.55 (s, 1H), 7.47 - 7.33 (m, 3H), 5.27 (s, 2H), 3.96 (s, 3H), 2.45 (s, 3H). [M+H] = 315.10.

Example 139. 3-(3,5-Difluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine.

0723<chemistry id="chem0231" num="0231"><img file="EP3345902A1_D0236.tif" /></chemistry>

0724¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 8.22 (d, <i>J</i> = 2.3 Hz, 1H), 8.00 (s, 1H), 7.80 (d, <i>J</i> = 2.3 Hz, 1H), 7.18 (dd, <i>J</i> = 2.0, 8.6 Hz, 2H), 7.00 - 6.89 (m, 1H), 5.44 (s, 2H), 3.97 (s, 3H). [M+H] = 303.09.

Example 140. Methyl 1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-5-carboxylate.

0725<chemistry id="chem0232" num="0232"><img file="EP3345902A1_D0237.tif" /></chemistry>

0726¹H NMR (400 MHz, CDCl₃) δ 8.31 - 8.23 (m, 1H), 8.00 (s, 1H), 7.70 - 7.63 (m, 1H), 7.52 - 7.45 (m, 1H), 7.41 - 7.29 (m, 3H), 5.79 (s, 2H), 4.05 - 3.92 (m, 6H). [M+H] = 359.33.

Example 141. Methyl 1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3 -carboxylate.

0727<chemistry id="chem0233" num="0233"><img file="EP3345902A1_D0238.tif" /></chemistry>

0728¹H NMR (400 MHz, CDCl₃) δ 8.21 - 8.18 (m, 1H), 8.18 - 8.15 (m, 1H), 7.56 (s, 1H), 7.50 (d, <i>J</i> = 1.2 Hz, 1H), 7.38 - 7.33 (m, 3H), 5.41 (s, 2H), 3.99 (m, 6H). [M+H] = 359.35.

Example 142. 3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine.

0729<chemistry id="chem0234" num="0234"><img file="EP3345902A1_D0239.tif" /></chemistry>

0730As a mixture ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, <i>J</i> = 2.0 Hz, 1H), 8.09 (d, <i>J</i> = 2.3 Hz, 1H), 7.99 (s, 1H), 7.82 (s, 1H), 7.56 - 7.49 (m, 4H), 7.42 - 7.32 (m, 6H), 5.26 (m, 4H), 3.98 (m, 6H), 2.49 (s, 3H), 2.40 (s, 3H). [M+H] = 315.22.

Example 143. 3-[3-(Difluoromethyl)phenyl]-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine.

0731<chemistry id="chem0235" num="0235"><img file="EP3345902A1_D0240.tif" /></chemistry>

0732¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.65 (s, 1H), 8.21 (d, <i>J</i> = 2.3 Hz, 1H), 7.95 (s, 1H), 7.79 (d, <i>J</i> = 2.3 Hz, 1H), 7.73 - 7.62 (m, 2H), 7.62 - 7.51 (m, 2H), 7.23 - 6.90 (m, 1H), 5.42 (s, 2H), 3.86 (s, 3H). [M+H] = 317.21.

Example 144. 3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyridine.

0733<chemistry id="chem0236" num="0236"><img file="EP3345902A1_D0241.tif" /></chemistry>

0734¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, <i>J</i> = 2.3 Hz, 1H), 7.76 (d, <i>J</i> = 2.0 Hz, 1H), 7.61 (d, <i>J =</i> 2.3 Hz, 1H), 7.52 (d, <i>J</i> = 1.2 Hz, 2H), 7.45 - 7.31 (m, 3H), 6.33 (s, 1H), 5.35 (s, 2H), 3.94 (s, 3H). [M+H] = 300.15.

Example 145. 3-(3-Chlorophenyl)-2-methoxy-5- {[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine.

0735<chemistry id="chem0237" num="0237"><img file="EP3345902A1_D0242.tif" /></chemistry>

0736¹H NMR (400 MHz, CD₃OD) δ 8.72 (s, 1H), 8.24 (d, <i>J</i> = 2.0 Hz, 1H), 7.79 (d, <i>J</i> = 2.3 Hz, 1H), 7.56 (s, 1H), 7.49 - 7.31 (m, 3H), 5.50 (s, 2H), 3.96 (s, 3H). [M+H] = 369.17.

Example 146. 3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridine.

0737<chemistry id="chem0238" num="0238"><img file="EP3345902A1_D0243.tif" /></chemistry>

0738As a mixture ¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 2H), 8.18 - 8.12 (m, 2H), 7.81 - 7.32 (m, 10H), 5.50 (s, 2H), 5.32 (s, 2H), 3.97 - 3.93 (m, 6H), 2.29 - 2.19 (m, 1H), 2.04 - 1.98 (m, 1H), 1.17 - 0.83 (m, 8H). [M+H] = 341.23.

Example 147. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine.

0739<chemistry id="chem0239" num="0239"><img file="EP3345902A1_D0244.tif" /></chemistry>

0740As a mixture ¹H NMR (400 MHz, CD₃OD) δ 8.58 - 7.32 (m, 14H), 5.43 (d, <i>J</i> = 13.3 Hz, 4H), 2.58 - 2.29 (m, 6H). [M+H] = 351.17.

Example 148. 3-(3-Chlorophenyl)-2-methoxy-5-{[4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}pyridine.

0741<chemistry id="chem0240" num="0240"><img file="EP3345902A1_D0245.tif" /></chemistry>

0742¹H NMR (400 MHz, CD₃OD) δ 8.48 (br s, 1H), 8.24 (br s, 1H), 8.02 (m, 2H), 7.88 - 7.62 (m, 4H), 5.58 (m, 2H), 4.25 (s, 3H). [M+H] = 368.10

Example 149. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[1-(1H-1,2,4-triazol-1-yl)ethyl]pyridine.

0743<chemistry id="chem0241" num="0241"><img file="EP3345902A1_D0246.tif" /></chemistry><ul id="ul0027" list-style="none" compact="compact"><li>Step 1. 1-(5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)ethanol. A solution of 5-(3-chlorophenyl)-6-(difluoromethoxy)nicotinaldehyde (Example 36 product from Step 2., 287 mg, 1.0 mmol) in DCM (5 mL) was cooled to 0 °C and methylmagnesium bromide (1.5 mL of a 1M solution in toluene, 1.5 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 30 minutes. A saturated aqueous solution of ammonium chloride was added and the mixture was extracted into DCM. The combined extracts were dried (Na₂SO₄), filtered and solvent removed under reduced pressure. Purification (FCC, SiO₂, 0 - 60%, EtOAc/hexanes) gave 1-(5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)ethanol (231 mg, 70%). [M+H] = 300.1.</li><li>Step 2. A solution of 1-(5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)ethanol (231 mg, 0.76 mmol) and DIPEA (196 mg, 1.52 mmol) in THF (5 mL) was cooled to 0 °C and methansulfonyl chloride (108 mg, 0.92 mmol) was added. The mixture was warmed to room temperature and stirred for 1 hour. The LCMS confirmed the disappearance of the starting material. All solvents were removed in vacuo and the crude material purified (FCC, SiO₂, 0 - 60%, EtOAc/hexanes) to give the desired intermediate mesylate (205 mg, 70%) which was not characterized, and used directly in the next step.</li><li>Step 3. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[1-(1H-1,2,4-triazol-1-yl)ethyl]pyridine. The mesylate from the previous step (90 mg, 0.23 mmol) was reacted in a manner analogous to Example 127, with the appropriated starting material substitutions. Purification (FCC, SiO₂, 50 - 100%, EtOAc/hexanes) gave the title compound (56 mg, 69%). ¹H NMR (400 MHz, CD₃OD) δ 8.64 (s, 1H), 8.24 (d, <i>J</i> = 2.3 Hz, 1H), 8.02 (s, 1H), 7.91 (d, <i>J</i> = 2.3 Hz, 1H), 7.82 - 7.59 (m, 1H), 7.54 (s, 1H), 7.48 - 7.40 (m, 3H), 5.86 (d, <i>J</i> = 7.0 Hz, 1H), 1.96 (d, <i>J</i> = 7.0 Hz, 3H). [M+H] = 351.19.</li></ul>

Example 150. 3-(3-Fluorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine.

0744<chemistry id="chem0242" num="0242"><img file="EP3345902A1_D0247.tif" /></chemistry>

0745As a mixture ¹H NMR (400 MHz, CD₃OD) δ 8.45 (s, 1H), 8.17 (d, <i>J</i> = 2.3 Hz, 1H), 8.11 (d, <i>J</i> = 2.3 Hz, 1H), 7.85 (s, 1H), 7.73 (d, <i>J</i> = 2.3 Hz, 1H), 7.67 (d, <i>J</i> = 2.3 Hz, 1H), 7.45 - 7.25 (m, 6H), 7.11 - 7.04 (m, 2H), 5.38 (s, 2H), 5.34 (s, 2H), 3.95 (m, 6H), 2.51 (s, 3H), 2.32 (s, 3H). [M+H] = 299.16.

Example 151. 3-(3-Chlorophenyl)-2-ethoxy-5- {[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine.

0746<chemistry id="chem0243" num="0243"><img file="EP3345902A1_D0248.tif" /></chemistry>

0747¹H NMR (400 MHz, CD₃OD) δ 8.71 (s, 1H), 8.21 (d, <i>J</i> = 2.3 Hz, 1H), 7.79 (d, <i>J</i> = 2.3 Hz, 1H), 7.58 (s, 1H), 7.49 - 7.32 (m, 3H), 5.49 (s, 2H), 4.42 (d, <i>J</i> = 7.0 Hz, 2H), 1.34(t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 383.18.

Example 152. 3-(3-Chlorophenyl)-2-ethoxy-5- {[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine.

0748<chemistry id="chem0244" num="0244"><img file="EP3345902A1_D0249.tif" /></chemistry>

0749¹H NMR (400 MHz, CD₃OD) δ 8.14 - 8.11 (m, 2H), 7.71 (d, <i>J</i> = 2.3 Hz, 1H), 7.55 (s, 1H), 7.46 - 7.33 (m, 3H), 5.59 (s, 2H), 4.41 (d, <i>J</i> = 7.0 Hz, 2H), 1.34 (t, <i>J</i> = 7.2 Hz, 3H). [M+H] = 383.18.

Example 153. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methyl-1H-imidazol-1-yl)methyl]pyridine.

0750<chemistry id="chem0245" num="0245"><img file="EP3345902A1_D0250.tif" /></chemistry>

0751¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.25 (d, <i>J</i> = 2.3 Hz, 1H), 7.99 (d, <i>J</i> = 2.3 Hz, 1H), 7.67 - 7.43 (m, 6H), 6.93 (s, 1H), 5.14 (s, 2H), 2.02 (s, 3H). [M+H] = 350.18.

Example 154. 3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine.

0752<chemistry id="chem0246" num="0246"><img file="EP3345902A1_D0251.tif" /></chemistry>

0753As a mixture ¹H NMR (400 MHz, CD₃OD) δ 8.44 (s, 1H), 8.19 - 8.09 (m, 2H), 7.74 - 7.65 (m, 3H), 7.47 - 7.29 (m, 6H), 7.17 - 7.10 (m, 2H), 7.04 - 6.64 (m, 2H), 5.40 - 5.37 (m, 2H), 5.34 (s, 2H), 3.94 (m, 6H), 2.51 (s, 3H), 2.32 (s, 3H). [M+H] = 347.23.

Example 155. 1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carbonitrile.

0754<chemistry id="chem0247" num="0247"><img file="EP3345902A1_D0252.tif" /></chemistry>

0755¹H NMR (400 MHz, CD₃OD) δ 8.76 (s, 1H), 8.29 (d, <i>J</i> = 2.3 Hz, 1H), 7.97 (d, <i>J</i> = 2.3 Hz, 1H), 7.82 - 7.40 (m, 5H), 5.58 (s, 2H). [M+H] = 362.01.

Example 156. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyllpyridine.

0756<chemistry id="chem0248" num="0248"><img file="EP3345902A1_D0253.tif" /></chemistry>

0757¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 8.25 (d, <i>J</i> = 2.3 Hz, 1H), 7.91 (d, <i>J</i> = 2.3 Hz, 1H), 7.80 - 7.40 (m, 5H), 5.48 (s, 2H), 4.46 (s, 2H), 3.36 (s, 3H). [M+H] = 381.17.

Example 157. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyllpyridine.

0758<chemistry id="chem0249" num="0249"><img file="EP3345902A1_D0254.tif" /></chemistry>

0759¹H NMR (400 MHz, CD₃OD) δ 8.23 (d, <i>J</i> = 2.3 Hz, 1H), 7.94 (s, 1H), 7.90 (d, <i>J</i> = 2.3 Hz, 1H), 7.80 - 7.40 (m, 5H), 5.51 (s, 2H), 4.71 (s, 2H), 3.37 (s, 3H). [M+H] = 381.17.

Example 158. 3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyllpyridine.

0760<chemistry id="chem0250" num="0250"><img file="EP3345902A1_D0255.tif" /></chemistry>

0761¹H NMR (400 MHz, CD₃OD) δ 8.71 (s, 1H), 8.24 (d, <i>J</i> = 2.3 Hz, 1H), 7.79 (d, <i>J</i> = 2.3 Hz, 1H), 7.47 - 7.36 (m, 2H), 7.33 (d, <i>J</i> = 2.0 Hz, 1H), 7.17 - 7.11 (m, 1H), 7.03 - 6.64 (m, 1H), 5.50 (s, 2H), 3.96 (s, 3H). [M+H] = 401.19.

Example 159. 3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyllpyridine.

0762<chemistry id="chem0251" num="0251"><img file="EP3345902A1_D0256.tif" /></chemistry>

0763¹H NMR (400 MHz, CD₃OD) δ 8.15 (d, <i>J</i> = 2.3 Hz, 1H), 8.12 (s, 1H), 7.72 (d, <i>J</i> = 2.3 Hz, 1H), 7.43 (d, <i>J</i> = 8.2 Hz, 1H), 7.37 (s, 1H), 7.30 (s, 1H), 7.16 - 7.11 (m, 1H), 7.03 - 6.65 (m, 1H), 5.60 (s, 2H), 3.95 (s, 3H). [M+H] = 401.19.

Example 160. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,3,4-tetrazol-1-ylmethyl)pyridine.

0764<chemistry id="chem0252" num="0252"><img file="EP3345902A1_D0257.tif" /></chemistry>

0765¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 8.23 (d, <i>J</i> = 2.3 Hz, 1H), 7.73 (d, <i>J</i> = 2.3 Hz, 1H), 7.39 (s, 5H), 5.64 (s, 2H). [M+H] = 338.15.

Example 161 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(2H-1,2,3,4-tetrazol-2-ylmethyl)pyridine.

0766<chemistry id="chem0253" num="0253"><img file="EP3345902A1_D0258.tif" /></chemistry>

0767¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1H), 8.30 (d, <i>J</i> = 2.3 Hz, 1H), 7.82 (d, <i>J</i> = 2.7 Hz, 1H), 7.73 - 7.34 (m, 5H), 5.85 (s, 2H). [M+H] = 338.15.

Example 162. 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine.

0768<chemistry id="chem0254" num="0254"><img file="EP3345902A1_D0259.tif" /></chemistry>

0769¹H NMR (400 MHz, CD₃OD) δ 8.72 (s, 1H), 8.21 (d, <i>J</i> = 2.38 Hz, 1H), 7.81 (d, <i>J</i> = 2.38 Hz, 1H), 7.48 - 7.35 (m, 3H), 7.18 - 7.06 (m, 1H), 7.06 - 6.60 (m, 1H), 5.50 (s, 2H), 4.42 (q, <i>J</i> = 7.07 Hz, 2H), 1.35 (t, <i>J</i> = 7.09 Hz, 3H). [M+H] = 415.21.

Example 163. 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine.

0770<chemistry id="chem0255" num="0255"><img file="EP3345902A1_D0260.tif" /></chemistry>

0771¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 2H), 7.74 (d, <i>J</i> = 2.51 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.40 - 7.34 (m, 2H), 7.14 (dd, <i>J</i> = 7.40,1.76 Hz, 1H), 7.05 - 6.63 (m, 1H) 5.60 (s, 2H), 4.41 (q, <i>J</i> = 7.03 Hz, 2H), 1.35 (t, <i>J</i> = 7.09 Hz, 3H). [M+H] = 415.21.

Example 164. 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine.

0772<chemistry id="chem0256" num="0256"><img file="EP3345902A1_D0261.tif" /></chemistry>

0773¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 8.17 (d, <i>J</i> = 2.3 Hz, 1H), 7.76 (d, <i>J</i> = 2.3 Hz, 1H), 7.49 - 7.35 (m, 3H), 7.13 (td, <i>J</i> = 2.0, 7.8 Hz, 1H), 7.04 - 6.63 (m, 1H), 5.41 (s, 2H), 4.47 (s, 2H), 4.41 (q, <i>J</i> = 7.0 Hz, 2H), 3.37 (s, 3H), 1.35 (t, <i>J</i> = 7.2 Hz, 3H). [M+H] = 391.28.

Example 165. 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine.

0774<chemistry id="chem0257" num="0257"><img file="EP3345902A1_D0262.tif" /></chemistry>

0775¹H NMR (400 MHz, CD₃OD) δ 8.15 (d, <i>J</i> = 2.3 Hz, 1H), 7.93 (s, 1H), 7.75 (d, <i>J</i> = 2.3 Hz, 1H), 7.49 - 7.33 (m, 3H), 7.12 (tdd, <i>J</i> = 1.0, 2.1, 7.7 Hz, 1H), 7.04 - 6.60 (m, 1H), 5.44 (s, 2H), 4.70 (s, 2H), 4.40 (q, <i>J</i> = 7.0 Hz, 2H), 3.38 (s, 3H), 1.34 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 391.25.

Example 166. 5-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-methoxypyridine.

0776<chemistry id="chem0258" num="0258"><img file="EP3345902A1_D0263.tif" /></chemistry>

0777¹H NMR (400 MHz, CD₃OD) δ 8.11 (d, <i>J</i> = 2.7 Hz, 1H), 7.84 (s, 1H), 7.67 (d, <i>J</i> = 2.3 Hz, 1H), 7.49 - 7.30 (m, 4H), 7.15 - 7.10 (m, 1H), 7.03 - 6.64 (m, 1H), 5.30 (s, 2H), 3.94 (s, 3H). [M+H] = 366.16.

Example 167. 1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide.

0778<chemistry id="chem0259" num="0259"><img file="EP3345902A1_D0264.tif" /></chemistry>

0779¹H NMR (400 MHz, CD₃OD) δ 8.14 (d, <i>J</i> = 2.3 Hz, 1H), 7.78 (d, <i>J</i> = 2.3 Hz, 1H), 7.70 (d, <i>J</i> = 2.3 Hz, 1H), 7.57 (s, 1H), 7.48 - 7.43 (m, 1H), 7.41 - 7.32 (m, 2H), 6.76 (d, <i>J</i> = 2.3 Hz, 1H), 5.39 (s, 2H), 4.41 (q, <i>J</i> = 7.0 Hz, 2H), 1.34 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 357.29.

Example 168. Ethyl 1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylate.

0780<chemistry id="chem0260" num="0260"><img file="EP3345902A1_D0265.tif" /></chemistry>

0781¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.48 (s, 1H), 8.20 (d, <i>J</i> = 2.35 Hz, 1H), 7.87 - 7.76 (m, 2H), 7.57 (s, 1H), 7.56 - 7.32 (m, 3H), 5.35 (s, 2H), 4.18 (q, <i>J</i> = 7.04 Hz, 2H), 3.87 (s, 3H), 1.23 (t, <i>J</i> = 7.04 Hz, 3H). [M+H] = 372.13.

Example 169. 1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carbonitrile.

0782<chemistry id="chem0261" num="0261"><img file="EP3345902A1_D0266.tif" /></chemistry>

0783¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.67 (s, 1H), 8.20 (d, <i>J</i> = 1.96 Hz, 1H), 8.05 (s, 1H), 7.81 (d, <i>J</i> = 1.96 Hz, 1H), 7.61 - 7.31 (m, 4H), 5.39 (s, 2H), 3.87 (s, 3H). [M+H] = 328.08.

Example 170. 2-Methoxy-3-(pyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine.

0784<chemistry id="chem0262" num="0262"><img file="EP3345902A1_D0267.tif" /></chemistry>

0785¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.83 (d, <i>J</i> = 3.91 Hz, 2H), 8.67 (s, 1H), 8.35 (s, 1H), 8.00 (dd, <i>J</i> = 13.30, 7.83 Hz, 4H), 5.45 (s, 2H), 3.93 (s, 3H). [M+H] = 298.15.

Example 171.

N

-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)acetamide.

0786<chemistry id="chem0263" num="0263"><img file="EP3345902A1_D0268.tif" /></chemistry>

0787The title compound was isolated as a bi-product from Example 236. ¹H NMR (400 MHz, CD₃OD) δ 8.04 (d, <i>J</i> = 1.57 Hz, 1H), 7.95 (s, 1H), 7.57 (d, <i>J</i> = 1.57 Hz, 1H), 7.47 (s, 1H), 7.44 (s, 1H), 7.34 - 7.29 (m, 3H), 5.22 (s, 2H), 3.88 (s, 3H), 2.01 (s, 3H). [M+H] = 357.32.

Example 172. 3-(3-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyridine.

0788<chemistry id="chem0264" num="0264"><img file="EP3345902A1_D0269.tif" /></chemistry>

0789¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.21 (d, <i>J</i> = 2.3 Hz, 1H), 7.84 - 7.77 (m, 2H), 7.58 (d, <i>J</i> = 0.8 Hz, 1H), 7.53 - 7.39 (m, 3H), 7.26 (s, 1H), 6.87 (s, 1H), 5.17 (s, 2H), 3.93 - 3.78 (m, 3H). [M+H] = 301.12.

Example 173. 2-(Difluoromethoxy)-3-(3-fluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine.

0790<chemistry id="chem0265" num="0265"><img file="EP3345902A1_D0270.tif" /></chemistry>

0791¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.73 - 8.62 (m, 1H), 8.32 - 8.20 (m, 1H), 8.06 - 7.96 (m, 1H), 7.93 - 7.85 (m, 1H), 7.75 - 7.66 (m, 1H), 7.60 - 7.49 (m, 1H), 7.44 - 7.33 (m, 1H), 7.28 (dt, <i>J =</i> 2.3, 8.6 Hz, 1H), 5.49 (s, 1H), 5.44 (s, 2H). [M+H] = 321.14.

Example 174. 2-(Difluoromethoxy)-3-(3-methoxyphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine.

0792<chemistry id="chem0266" num="0266"><img file="EP3345902A1_D0271.tif" /></chemistry>

0793¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.71 - 8.62 (m, 1H), 8.03 - 7.92 (m, 1H), 7.91 - 7.87 (m, 1H), 7.73 - 7.68 (m, 1H), 7.55 - 7.51 (m, 1H), 7.43 - 7.37 (m, 1H), 7.10 - 7.05 (m, 1H), 7.03 - 6.96 (m, 1H), 5.75 (s, 1H), 5.49 (s, 1H), 5.44 (s, 1H), 3.78 (s, 3H). [M+H] = 333.24.

Example 175. 2-(Difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine.

0794<chemistry id="chem0267" num="0267"><img file="EP3345902A1_D0272.tif" /></chemistry>

0795¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.67 (d, <i>J</i> = 9.8 Hz, 1H), 8.33 - 8.19 (m, 2H), 8.04 (d, <i>J</i> = 2.3 Hz, 1H), 7.98 (d, <i>J</i> = 3.1 Hz, 1H), 7.88 (d, <i>J</i> = 0.8 Hz, 1H), 7.70 (s, 1H), 7.67 - 7.39 (m, 2H), 5.50 (s, 1H), 5.44 (s, 1H). [M+H] = 386.14.

Example 176. 1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1,2-dihydropyridin-2-one.

0796<chemistry id="chem0268" num="0268"><img file="EP3345902A1_D0273.tif" /></chemistry>

0797¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, <i>J</i> = 1.96 Hz, 1H), 7.65 (d, <i>J</i> = 1.96 Hz, 1H), 7.52 (s, 1H), 7.42 - 7.32 (m, 1H), 7.36 - 7.29 (m, 4H), 6.61 (d, <i>J</i> = 9.00 Hz, 1H), 6.18 (t, <i>J</i> = 6.46 Hz, 1H), 5.12 (s, 2H),3.96 (s, 3H). [M+H] = 327.17.

Example 177. 5-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-(3-chlorophenyl)-2-methoxypyridine.

0798<chemistry id="chem0269" num="0269"><img file="EP3345902A1_D0274.tif" /></chemistry>

0799¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.20 (s, 1H), 8.10 (s, 1H), 7.80 (s, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.50 - 7.40 (m, 3H), 5.24 (s, 2H), 3.86 (s, 3H). [M+H] = 334.07.

Example 178. 3-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyridine.

0800<chemistry id="chem0270" num="0270"><img file="EP3345902A1_D0275.tif" /></chemistry>

0801¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.15 (s, 1H), 7.67 (s, 1H), 7.61-7.58 (m, 1H), 7.54 - 7.36 (m, 4H), 7.10 (s, 1H), 5.14 (s, 2H), 3.85 (s, 3H), 3.60 (s, 3H). [M+H] = 314.10.

Example 179. 3-(3-Chlorophenyl)-2-methoxy-5-[(4-mtro-1H-pyrazol-1-yl)methyl]pyridine.

0802<chemistry id="chem0271" num="0271"><img file="EP3345902A1_D0276.tif" /></chemistry>

0803¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 9.05 (s, 1H), 8.06 (s, 1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.52 - 7.38 (m, 4H), 5.54 (s, 2H), 3.85 (s, 3H). [M+H] = 345.09.

Example 180. 3-(3-Chlorophenyl)-2-methoxy-5-[(4-nitro-1H-pyrazol-1-yl)methyl]pyrazine.

0804<chemistry id="chem0272" num="0272"><img file="EP3345902A1_D0277.tif" /></chemistry>

0805¹H NMR (400 MHz, CD₃OD) δ 8.76 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 8.01 -7.91 (m, 1H), 7.45 - 7.35 (m, 2H), 5.52 (s, 2H), 4.06 (s, 3H). [M+H] = 346.70.

Example 181. 3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyrazine.

0806<chemistry id="chem0273" num="0273"><img file="EP3345902A1_D0278.tif" /></chemistry>

0807¹H NMR (400 MHz, CD₃OD) δ 8.76 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 8.01 -7.91 (m, 2H), 7.45 - 7.35 (m, 2H), 5.52 (s, 2H), 4.06 (s, 3H). [M+H] = 301.11.

Example 182. 3-(3-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyrazine.

0808<chemistry id="chem0274" num="0274"><img file="EP3345902A1_D0279.tif" /></chemistry>

0809¹H NMR (400 MHz, CD₃OD) δ 9.13 (br s, 1H), 8.33 (s, 1H), 8.05 - 7.89 (m, 2H), 7.73 (br s, 1H), 7.57 (br s, 1H), 7.48 - 7.35 (m, 2H), 5.60 (s, 2H), 4.09 (s, 3H). [M+H] = 303.11.

Example 183. 3-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyrazine.

0810<chemistry id="chem0275" num="0275"><img file="EP3345902A1_D0280.tif" /></chemistry>

0811¹H NMR (400 MHz, CD₃OD) δ 8.07 - 7.96 (m, 2H), 7.94 (s, 1H), 7.58 (br s, 1H), 7.42 (d, <i>J</i> = 3.91Hz, 2H), 7.34 (s, 1H), 5.39 (s, 2H), 4.04 (s, 3H), 2.09 (s, 3H). [M+H] = 315.10.

Example 184. 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyrazine.

0812<chemistry id="chem0276" num="0276"><img file="EP3345902A1_D0281.tif" /></chemistry> as a mixture

0813¹H NMR (400MHz, CD₃OD) δ 8.53 (s, 1H), 8.15 (s, 1H), 8.14 (s, 1H), 7.96 - 7.90 (m, 2H), 7.86 (t, <i>J</i> = 2.0 Hz, 1H), 7.85 - 7.82 (m, 2H), 7.46 (dt, <i>J</i> = 1.6, 8.0 Hz, 2H), 7.21 (s, 1H), 7.19 (s, 1H), 7.04 - 6.64 (m, 2H), 5.50 (s, 2H), 5.47 (s, 2H), 4.57 - 4.45 (m, 4H), 2.63 (s, 3H), 2.32 (s, 3H), 1.44 (t, <i>J</i> = 7.0 Hz, 6H). [M+H] = 362.15.

Example 185. 5-[(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-ethoxypyrazine.

0814<chemistry id="chem0277" num="0277"><img file="EP3345902A1_D0282.tif" /></chemistry> as a mixture

0815¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 1H), 8.14 (s, 2H), 7.99 - 7.92 (m, 2H), 7.89 - 7.85 (m, 2H), 7.78 (s, 2H), 7.48 - 7.44 (m, 2H), 7.21 - 7.18 (m, 1H), 7.04 - 6.62 (m, 2H), 5.61 (s, 2H), 5.45 (s, 2H), 4.58 - 4.46 (m, 4H), 2.41 - 2.30 (m, 1H), 1.99 (tt, <i>J</i> = 5.2, 8.3 Hz, 1H), 1.45 (dt, <i>J</i> = 1.6, 7.0 Hz, 6H), 1.17 - 1.09 (m, 2H), 1.07 - 1.01 (m, 2H), 0.98 - 0.90 (m, 2H), 0.90 - 0.85 (m, 2H). [M+H] = 388.15.

Example 186. 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine.

0816<chemistry id="chem0278" num="0278"><img file="EP3345902A1_D0283.tif" /></chemistry>

0817¹H NMR (400MHz, CD₃OD) δ 8.80 (s, 1H), 8.23 (s, 1H), 7.93 - 7.90 (m, 1H), 7.86 (t, <i>J</i> = 2.0 Hz, 1H), 7.46 (t, <i>J</i> = 8.0 Hz, 1H), 7.20 (dd, <i>J</i> = 2.0, 8.2 Hz, 1H), 7.03 - 6.62 (m, 1H), 5.64 (s, 2H), 4.52 (q, <i>J</i> = 7.0 Hz, 2H), 1.45 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 416.12.

Example 187. 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine.

0818<chemistry id="chem0279" num="0279"><img file="EP3345902A1_D0284.tif" /></chemistry>

0819¹H NMR (400MHz, CD₃OD) δ 8.19 (s, 1H), 8.12 (s, 1H), 7.95 - 7.87 (m, 1H), 7.83 (t, <i>J</i> = 2.0 Hz, 1H), 7.44 (t, <i>J</i> = 8.0 Hz, 1H), 7.19 (dd, <i>J</i> = 2.2, 8.0 Hz, 1H), 7.02 - 6.59 (m, 1H), 5.74 (s, 2H), 4.52 (q, <i>J</i> = 7.3 Hz, 2H), 1.45 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 416.12.

Example 188. 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine.

0820<chemistry id="chem0280" num="0280"><img file="EP3345902A1_D0285.tif" /></chemistry>

0821¹H NMR (400MHz, CD₃OD) δ 8.63 (s, 1H), 8.18 (s, 1H), 7.96 - 7.91 (m, 1H), 7.85 (t, <i>J</i> = 2.2 Hz, 1H), 7.45 (t, <i>J</i> = 8.2 Hz, 1H), 7.20 (dd, <i>J</i> = 2.0, 8.2 Hz, 1H), 7.05 - 6.62 (m, 1H), 5.54 (s, 2H), 4.51 (q, <i>J</i> = 7.0 Hz, 2H), 4.46 (s, 3H), 4.30 (s, 2H), 1.44 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 392.26.

Example 189. 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine.

0822<chemistry id="chem0281" num="0281"><img file="EP3345902A1_D0286.tif" /></chemistry>

0823¹H NMR (400MHz, CD₃OD) δ 8.14 (s, 1H), 7.95 - 7.91 (m, 2H), 7.84 (d, <i>J</i> = 2.0 Hz, 1H), 7.46 (t, <i>J</i> = 8.0 Hz, 1H), 7.20 (dd, <i>J</i> = 2.2, 8.0 Hz, 1H), 7.03 - 6.63 (m, 1H), 5.60 (s, 2H), 4.79 (s, 2H), 4.51 (q, <i>J</i> = 7.0 Hz, 2H), 3.38 (s, 3H), 1.44 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 392.15.

Example 190. Methyl 1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate.

0824<chemistry id="chem0282" num="0282"><img file="EP3345902A1_D0287.tif" /></chemistry>

0825¹H NMR (400MHz, CD₃OD) δ 8.78 (s, 1H), 8.23 (s, 1H), 7.92 (td, <i>J</i> = 1.4, 7.8 Hz, 1H), 7.84 (t, <i>J</i> = 2.0 Hz, 1H), 7.45 (t, <i>J</i> = 8.0 Hz, 1H), 7.19 (dd, <i>J</i> = 2.3, 8.2 Hz, 1H), 7.03 - 6.63 (m, 1H), 5.63 (s, 2H), 4.51 (q, <i>J</i> = 7.0 Hz, 2H), 3.91 (s, 3H), 1.44 (t, <i>J</i> = 7.2 Hz, 3H). [M+H] = 406.15.

Example 191. Methyl 1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin2-yl)methyl)-1H-1,2,4-triazole-5-carboxylate.

0826<chemistry id="chem0283" num="0283"><img file="EP3345902A1_D0288.tif" /></chemistry>

0827¹H NMR (400MHz, CD₃OD) δ 8.63 (s, 1H), 8.18 (s, 1H), 7.95 - 7.92 (m, 1H), 7.87 - 7.85 (m, 1H), 7.45 (t, <i>J</i> = 8.2 Hz, 1H), 7.20 (dd, <i>J</i> = 2.0, 8.2 Hz, 1H), 7.03 - 6.64 (m, 1H), 5.54 (s, 2H), 4.51 (q, <i>J</i> = 7.0 Hz, 2H), 3.35 (s, 3H), 1.44 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 406.26.

Example 192. 3-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine.

0828<chemistry id="chem0284" num="0284"><img file="EP3345902A1_D0289.tif" /></chemistry>

0829¹H NMR (400MHz, CD₃OD) δ 8.82 (s, 1H), 8.28 (s, 1H), 7.92 (td, <i>J</i> = 1.4, 7.8 Hz, 1H), 7.86 (t, <i>J</i> = 2.0 Hz, 1H), 7.46 (t, <i>J</i> = 8.0 Hz, 1H), 7.20 (dd, <i>J</i> = 2.7, 8.2 Hz, 1H), 7.03 - 6.62 (m, 1H), 5.67 (s, 2H), 4.53 (q, <i>J</i> = 7.0 Hz, 2H), 1.45 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 393.15.

Example 193. 3-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((5-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine.

0830<chemistry id="chem0285" num="0285"><img file="EP3345902A1_D0290.tif" /></chemistry>

0831¹H NMR (400MHz, CD₃OD) δ 8.23 (s, 1H), 8.10 (s, 1H), 7.80 (td, <i>J</i> = 1.4, 7.8 Hz, 1H), 7.73 (t, <i>J</i> = 2.3 Hz, 1H), 7.43 (t, <i>J</i> = 8.0 Hz, 1H), 7.18 (dd, <i>J</i> = 2.0, 8.2 Hz, 1H), 7.02 - 6.61 (m, 1H), 6.01 (s, 2H), 4.51 (q, <i>J</i> = 7.0 Hz, 2H), 1.44 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 393.21.

Example 194. Methyl 1-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-5-carboxylate.

0832<chemistry id="chem0286" num="0286"><img file="EP3345902A1_D0291.tif" /></chemistry>

0833¹H NMR (400MHz, CD₃OD) δ 8.19 (s, 1H), 8.09 (s, 1H), 7.94 (td, <i>J</i> = 1.1, 2.1 Hz, 1H), 7.93 - 7.86 (m, 1H), 7.43 - 7.34 (m, 2H), 5.99 (s, 2H), 4.08 - 4.04 (m, 3H), 3.99 - 3.95 (m, 3H). [M+H] = 360.18.

Example 195. Methyl 1-({6-[3-(difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,4-triazole-3-carboxylate.

0834<chemistry id="chem0287" num="0287"><img file="EP3345902A1_D0292.tif" /></chemistry>

0835¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.88 (s, 1H), 8.35 (s, 1H), 7.83 (td, <i>J</i> = 1.4, 7.8 Hz, 1H), 7.72 - 7.68 (m, 1H), 7.52 (t, <i>J</i> = 8.0 Hz, 1H), 7.43 - 7.04 (m, 2H), 5.66 (s, 2H), 3.99 (s, 3H), 3.29 (s, 3H). [M+H] = 392.16.

Example 196. Methyl 1-{[6-(3-chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate.

0836<chemistry id="chem0288" num="0288"><img file="EP3345902A1_D0293.tif" /></chemistry>

0837¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.89 (s, 1H), 8.32 (s, 1H), 7.99 - 7.96 (m, 1H), 7.96 - 7.90 (m, 1H), 7.52 - 7.46 (m, 2H), 5.64 (s, 2H), 4.45 (q, <i>J</i> = 7.0 Hz, 2H), 3.83 - 3.77 (m, 3H), 1.39 - 1.34 (m, 3H). [M+H] = 374.18.

Example 197. 1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazole-4-carboxamide.

0838<chemistry id="chem0289" num="0289"><img file="EP3345902A1_D0294.tif" /></chemistry><ul id="ul0028" list-style="none" compact="compact"><li>Step 1. Methyl 1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-imidazole-4-carboxylate was prepared in a manner analogous to Example 127.</li><li>Step 2. 1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazole-4-carboxamide. To a solution of methyl 1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-imidazole-4-carboxylate in 7 N ammonia in MeOH (4 mL) was added NaCN (5 mg). Reaction mixture was heated 24 h at 130 °C. LC-MS confirms the disappearance of starting material. The reaction mixture was concentrated under reduced pressure. Purification (FCC, SiO₂, 0 - 1%, EtOAc/MeOH) gave the title compound. ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.18 (d, <i>J</i> = 2.3 Hz, 1H), 8.04 (s, 1H), 7.92 (d, <i>J</i> = 2.3 Hz, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.57 - 7.55 (m, 1H), 7.53 - 7.43 (m, 3H), 5.58 (s, 2H), 3.55 (s, 1H), 3.15 (d, <i>J</i> = 5.1 Hz, 1H). [M+H] = 379.15.</li></ul>

Example 198. (1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol.

0839<chemistry id="chem0290" num="0290"><img file="EP3345902A1_D0295.tif" /></chemistry>

0840To a solution of methyl 1-((6-(3-chlorophenyl)-5-methoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate (Example 127, 77.00 mg, 0.21 mmol), in THF (1 mL) was added LiBH₄ (4.66 mg, 0.21 mmol). The mixture was stirred at room temperature for 3 hr. The mixture was diluted with water and extracted into DCM. The combined extracts were dried (Na₂SO₄) and concentrated under reduced pressure. Purification (FCC, SiO₂, 0-5% DCM/MeOH) afforded the title compound (50 mg, 70 %). ¹H NMR (400MHz, CD₃OD) δ 8.61 (s, 1H), 8.21 (s, 1H), 8.02 (td, <i>J</i> = 1.1, 2.1 Hz, 1H), 8.00 - 7.92 (m, 1H), 7.45 - 7.38 (m, 2H), 5.53 (s, 2H), 4.59 (s, 2H), 4.06 (s, 3H). [M+H] = 332.15.

0841Examples 199-211 were prepared in a manner analogous to Example 198, with the appropriate starting materials and reagent substitutions.

Example 199. (1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol.

0842<chemistry id="chem0291" num="0291"><img file="EP3345902A1_D0296.tif" /></chemistry>

0843¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 8.26 (d, <i>J</i> = 2.3 Hz, 1H), 7.93 (d, <i>J</i> = 2.7 Hz, 1H), 7.82 - 7.38 (m, 5H), 5.46 (s, 2H), 4.59 (s, 2H). [M+H] = 367.18.

Example 200. [1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol.

0844<chemistry id="chem0292" num="0292"><img file="EP3345902A1_D0297.tif" /></chemistry>

0845¹H NMR (400 MHz, CD₃OD) δ 8.52 (s, 1H), 8.17 (d, <i>J</i> = 2.3 Hz, 1H), 7.76 (d, <i>J</i> = 2.3 Hz, 1H), 7.49 - 7.34 (m, 3H), 7.13 (td, <i>J</i> = 2.0, 7.8 Hz, 1H), 7.02 - 6.65 (m, 1H), 5.39 (s, 2H), 4.59 (s, 2H), 4.40 (q, <i>J</i> = 7.2 Hz, 2H), 1.34 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 377.25.

Example 201. [1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol.

0846<chemistry id="chem0293" num="0293"><img file="EP3345902A1_D0298.tif" /></chemistry>

0847¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 8.20 (d, <i>J</i> = 2.7 Hz, 1H), 7.76 (d, <i>J</i> = 2.3 Hz, 1H), 7.48 - 7.35 (m, 2H), 7.32 (t, <i>J</i> = 1.8 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.03 - 6.65 (m, 1H), 5.49 (s, 1H), 4.59 (s, 2H), 3.95 (s, 3H). [M+H] = 363.23.

Example 202. (1-((5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol.

0848<chemistry id="chem0294" num="0294"><img file="EP3345902A1_D0299.tif" /></chemistry>

0849¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 8.18 (d, <i>J</i> = 2.7 Hz, 1H), 7.75 (d, <i>J</i> = 2.7 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.49 - 7.45 (m, 1H), 7.42 - 7.33 (m, 2H), 5.39 (s, 2H), 4.59 (s, 2H), 4.42 (q, <i>J=</i> 7.0 Hz, 2H), 1.34 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 345.22.

Example 203. (1-{[6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol.

0850<chemistry id="chem0295" num="0295"><img file="EP3345902A1_D0300.tif" /></chemistry>

0851¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 8.22 (d, <i>J</i> = 2.3 Hz, 1H), 7.89 (d, <i>J</i> = 2.3 Hz, 1H), 7.61 (t, <i>J</i> = 1.0 Hz, 1H), 7.38 - 7.31 (m, 1H), 7.10 - 7.03 (m, 2H), 6.95 (ddd, <i>J</i> = 1.0, 2.4, 8.3 Hz, 1H), 5.46 (s, 2H), 4.59 (s, 2H), 4.07 (q, <i>J</i> = 7.0 Hz, 2H), 1.40 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 377.25.

Example 204. [1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol.

0852<chemistry id="chem0296" num="0296"><img file="EP3345902A1_D0301.tif" /></chemistry>

0853¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 8.28 (d, <i>J</i> = 2.3 Hz, 1H), 8.24 - 8.21 (m, 1H), 7.89 (d, <i>J</i> = 2.3 Hz, 1H), 7.76 - 7.37 (m, 2H), 7.20 - 7.17 (m, 1H), 5.41 (s, 2H), 4.59 (s, 2H), 3.98 (s, 3H). [M+H] = 364.22.

Example 205. [1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol.

0854<chemistry id="chem0297" num="0297"><img file="EP3345902A1_D0302.tif" /></chemistry>

0855¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 1H), 8.26 (d, <i>J</i> = 2.3 Hz, 1H), 8.24 (dd, <i>J</i> = 0.8, 5.5 Hz, 1H), 7.89 (d, <i>J</i> = 2.3 Hz, 1H), 7.77 - 7.56 (m, 1H), 7.44 - 7.41 (m, 1H), 7.23 - 7.20 (m, 1H), 5.41 (s, 2H), 4.59 (s, 2H), 4.45 (q, <i>J</i> = 7.0 Hz, 2H), 1.37 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 378.20.

Example 206. (1-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol.

0856<chemistry id="chem0298" num="0298"><img file="EP3345902A1_D0303.tif" /></chemistry>

0857¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 8.35 - 8.28 (m, 2H), 8.05 (d, <i>J</i> = 2.3 Hz, 1H), 7.83 - 7.41 (m, 2H), 7.41 - 7.39 (m, 1H), 7.19 - 7.17 (m, 1H), 5.49 (s, 2H), 4.59 (s, 2H). [M+H] = 400.21.

Example 207. [1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol.

0858<chemistry id="chem0299" num="0299"><img file="EP3345902A1_D0304.tif" /></chemistry>

0859¹H NMR (400MHz, CD₃OD) δ 8.60 (s, 1H), 8.18 (s, 1H), 7.93 (td, <i>J</i> = 1.4, 7.8 Hz, 1H), 7.86 (t, <i>J</i> = 2.0 Hz, 1H), 7.46 (t, <i>J</i> = 8.0 Hz, 1H), 7.20 (dd, <i>J</i> = 2.0, 8.2 Hz, 1H), 7.04 - 6.64 (m, 1H), 5.52 (s, 2H), 4.59 (s, 2H), 4.51 (q, <i>J</i> = 7.3 Hz, 2H), 1.44 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 378.25.

Example 208. [1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-5-yl]methanol.

0860<chemistry id="chem0300" num="0300"><img file="EP3345902A1_D0305.tif" /></chemistry>

0861¹H NMR (400MHz, CD₃OD) δ 8.14 (s, 1H), 7.90 (s, 1H), 7.93 - 7.89 (m, 1H), 7.83 (t, <i>J</i> = 2.0 Hz, 1H), 7.46 (t, <i>J</i> = 8.0 Hz, 1H), 7.19 (dd, <i>J</i> = 2.7, 7.8 Hz, 1H), 7.05 - 6.62 (m, 1H), 5.65 (s, 2H), 4.91 (s, 2H), 4.50 (q, <i>J</i> = 7.0 Hz, 2H), 1.44 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 378.15.

Example 209. (1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-5-yl)methanol.

0862<chemistry id="chem0301" num="0301"><img file="EP3345902A1_D0306.tif" /></chemistry>

0863¹H NMR (400MHz, CD₃OD) δ 8.16 (s, 1H), 8.02 - 7.99 (m, 1H), 7.94 (ddd, <i>J</i> = 1.8, 3.5, 5.3 Hz, 1H), 7.92 - 7.89 (m, 1H), 7.44 - 7.39 (m, 2H), 5.66 (s, 2H), 4.90 (s, 2H), 4.06 (s, 3H). [M+H] = 332.18.

Example 210. [1-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol.

0864<chemistry id="chem0302" num="0302"><img file="EP3345902A1_D0307.tif" /></chemistry>

0865¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.59 (s, 1H), 8.27 (s, 1H), 7.88 - 7.83 (m, 1H), 7.76 - 7.71 (m, 1H), 7.53 (t, <i>J</i> = 8.0 Hz, 1H), 7.45 - 7.06 (m, 2H), 5.50 (s, 2H), 5.16 (t, <i>J</i> = 6.1 Hz, 1H), 4.36 (d, <i>J</i> = 6.3 Hz, 2H), 3.98 (s, 3H). [M+H] = 364.14.

Example 211. (1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol.

0866<chemistry id="chem0303" num="0303"><img file="EP3345902A1_D0308.tif" /></chemistry>

0867¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.60 (s, 1H), 8.24 (s, 1H), 8.02 - 7.99 (m, 1H), 7.99 - 7.93 (m, 1H), 7.54 - 7.48 (m, 2H), 5.49 (s, 2H), 5.16 (t, <i>J</i> = 6.1 Hz, 1H), 4.45 (q, <i>J</i> = 7.0 Hz, 2H), 4.36 (d, <i>J</i> = 5.9 Hz, 2H), 1.36 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 346.25.

Example 212. 3-(3-Chlorophenyl)-2-methoxy-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine.

0868<chemistry id="chem0304" num="0304"><img file="EP3345902A1_D0309.tif" /></chemistry><ul id="ul0029" list-style="none" compact="compact"><li>Step 1. 3-(3-Chlorophenyl)-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine. The title compound was prepared in a manner analogous to Example 127 with the appropriate starting material substitutions.</li><li>Step 2. 3-(3-Chlorophenyl)-2-methoxy-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine. To a solution of 3-(3-chlorophenyl)-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine (135 mg, 0.39 mmol), in MeOH (3 mL) was added NaOCH₃ (63 mg, 1.17 mmol). The mixture was stirred at 60 °C for 16 h. The LC/MS showed approximately 70% conversion. All solvents removed under reduced pressure, the residue dissolved in DCM (50 mL) and water (50 mL), the layers shaken and separated and the aqueous layer extracted into DCM (3 x 50 mL). The combined extracts were dried (MgSO₄), filtered and solvent removed under reduced pressure. Purification (FCC, SiO₂, 0-100% EtOAc/DCM) afforded the title compound (72 mg, 56%). ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.33 (s, 1H), 8.19 (d, <i>J</i> = 2.0 Hz, 1H), 7.79 (d, <i>J</i> = 2.3 Hz, 1H), 7.58 (s, 1H), 7.52 - 7.38 (m, 3H), 5.23 (s, 2H), 3.87 (s, 3H), 3.79 (s, 3H). [M+H] = 331.21.</li></ul>

0869Examples 213-215 were prepared in a manner analogous to Example 212, with the appropriate starting materials and reagent substitutions.

Example 213. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine.

0870<chemistry id="chem0305" num="0305"><img file="EP3345902A1_D0310.tif" /></chemistry>

0871¹H NMR (400 MHz, CD₃OD) δ 8.27 (s, 1H), 8.24 (d, <i>J</i> = 2.3 Hz, 1H), 7.91 (d, <i>J</i> = 2.3 Hz, 1H), 7.82 - 7.61 (m, 1H), 7.57 (s, 1H), 7.49 - 7.40 (m, 3H), 5.32 (s, 2H), 3.92 (s, 3H). [M+H] = 367.16.

Example 214. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(5-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine.

0872<chemistry id="chem0306" num="0306"><img file="EP3345902A1_D0311.tif" /></chemistry>

0873¹H NMR(400 MHz, CD₃OD) δ 8.17 (d, <i>J</i> = 2.0 Hz, 1H), 7.84 (d, <i>J</i> = 2.3 Hz, 1H), 7.61 - 7.39 (m, 6H), 5.21 (s, 2H), 4.12 (s, 3H). [M+H] = 367.16.

Example 215. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-ethoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine.

0874<chemistry id="chem0307" num="0307"><img file="EP3345902A1_D0312.tif" /></chemistry>

0875¹H NMR (400 MHz, CD₃OD) δ 8.28 - 8.21 (m, 2H), 7.91 (d, <i>J</i> = 2.3 Hz, 1H), 7.84 - 7.60 (m, 1H), 7.56 (s, 1H), 7.49 - 7.40 (m, 3H), 5.31 (s, 2H), 4.26 (q, <i>J</i> = 7.0 Hz, 2H), 1.35 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 380.18.

Example 216. 1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine.

0876<chemistry id="chem0308" num="0308"><img file="EP3345902A1_D0313.tif" /></chemistry><ul id="ul0030" list-style="none" compact="compact"><li>Step 1. 3-(3-(Difluoromethoxy)phenyl)-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine. The title compound was prepared in a manner analogous to Example 127 with the appropriate starting material substitutions.</li><li>Step 2. 1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine. To a solution of 3-(3-(difluoromethoxy)phenyl)-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine (331.00 mg, 0.88 mmol) in HOAc (6 mL), and water (2 mL) was added zinc (573.57 mg, 8.77 mmol). The mixture was stirred at 50 °C for 1 hr. The solvent was removed under reduced pressure to afford a white solid. The crude solid was dissolved in DCM (50 mL), sonicated and filtered (repeated twice). The combined DCM extracts were washed with sat. aq. NaHCO₃ and the layers separated. The organic layers were combined, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The resulting solid was triturated with hexanes to give the title compound (287 mg, 94%). ¹H NMR (400 MHz, CD₃OD) δ 8.15 (d, <i>J</i> = 2.7 Hz, 1H), 8.13 (s, 1H), 7.71 (d, <i>J</i> = 2.3 Hz, 1H), 7.47 - 7.36 (m, 2H), 7.33 (t, <i>J</i> = 7.8 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.04 - 6.65 (m, 1H), 5.19 (s, 2H), 3.95 (s, 3H). [M+H] = 348.22.</li></ul>

0877Examples 217-218, 223-236 were prepared in a manner analogous to Example 216, with the appropriate starting materials and reagent substitutions.

Example 217. 1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine.

0878<chemistry id="chem0309" num="0309"><img file="EP3345902A1_D0314.tif" /></chemistry>

0879¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.17 (d, <i>J</i> = 2.3 Hz, 1H), 8.09 (s, 1H), 7.76 (d, <i>J</i> = 2.3 Hz, 1H), 7.58 (d, <i>J</i> = <i>1</i>.6 Hz, 1H), 7.51 - 7.42 (m, 3H), 5.26 (s, 2H), 5.11 (s, 2H), 3.88 (s, 3H). [M+H] = 316.21.

Example 218. 1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine.

0880<chemistry id="chem0310" num="0310"><img file="EP3345902A1_D0315.tif" /></chemistry>

0881¹H NMR (400 MHz, CD₃OD) δ 8.11 (d, <i>J</i> = 2.3 Hz, 1H), 8.06 (s, 1H), 7.78 (d, <i>J</i> = 2.3 Hz, 1H), 7.73 - 7.50 (m, 1H), 7.47 (s, 1H), 7.41 - 7.30 (m, 3H), 5.15 (s, 2H). [M+H] = 352.17.

Example 219. 1-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine.

0882<chemistry id="chem0311" num="0311"><img file="EP3345902A1_D0316.tif" /></chemistry><ul id="ul0031" list-style="none" compact="compact"><li>Step 1. 3-Bromo-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine. Title compound was prepared in a manner analogous to Intermediate 5 with the appropriate starting materials and reagent substitutions. [M+H] = 314.24/316.25.</li><li>Step 2. 1-((5-Bromo-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-amine. To a solution of 3-bromo-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine (60 mg, 0.191 mmol) in AcOH (3 mL), and water (1 mL) was added zinc (124 mg, 1.91 mmol). The mixture was stirred at 50 °C for 1 hr. The solvent was removed under reduced pressure to afford a white solid. The crude solid was dissolved in DCM (50 mL), sonicated and filtered (repeated twice). The combined DCM extracts were washed with sat. aq. NaHCO₃ and the layers separated. The organic layers were combined, dried (Na₂SO₄), filtered and concentrated under reduced pressure. The title compound was taken on to the next step without further purification.</li><li>Step 3. 1-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine. 1-((5-bromo-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-amine and (3-fluorophenyl) boronic (42 mg, 0.3 mmol) dissolved in mixture of water (2 mL), and ACN (4 mL) were added Pd(dppf)Cl₂ (8 mg, 0.01 mmol) followed by Na₂CO₃ (53 mg, 0.5 mmol). The mixture was irradiated under microwaves for 15 minutes at 100 °C. The reaction mixture was diluted with water and extracted with DCM (3 X5 mL). The combined organic phase was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Purification (FCC, SiO₂, 0-10% DCM/MeOH) afforded the title compound (49.7 mg, 89%). ¹H NMR (400 MHz, CD₃OD) δ 8.13 (br s, 1H), 7.71 (br s, 1H), 7.63 - 7.23 (m, 4H), 7.08 (br s, 1H), 5.19 (m, 2H), 3.95 (s, 3H). [M+H] = 300.27.</li></ul>

0883Examples 220-222 were prepared in a manner analogous to Example 220, with the appropriate starting material and reagent substitutions.

Example 220. 1-{[6-Methoxy-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine.

0884<chemistry id="chem0312" num="0312"><img file="EP3345902A1_D0317.tif" /></chemistry>

0885¹H NMR (400 MHz, CD₃OD) δ 8.12 (s, 2H), 7.67 (d, <i>J</i> = 2.3 Hz, 1H), 7.31 (dd, <i>J</i> = 8.2 Hz, 1H), 7.10 - 7.04 (m, 2H), 6.91 (dd, <i>J</i> = 1.6, 8.2 Hz, 1H), 5.18 (s, 2H), 3.94 (s, 3H), 3.82 (s, 3H). [M+H] = 312.28.

Example 221. 1-{[6-Methoxy-5-(3-methylphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine.

0886<chemistry id="chem0313" num="0313"><img file="EP3345902A1_D0318.tif" /></chemistry>

0887¹H NMR (400 MHz, CD₃OD) δ 8.12 (m, 2H), 7.64 - 7.29 (m, 4H), 7.16 (br s, 1H), 5.17 (br s, 2H), 3.94 (s, 3H), 2.37 (s, 3H). [M+H] = 296.29.

Example 222. 3- {5-[(3-Amino-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridin-3-yl}benzonitrile.

0888<chemistry id="chem0314" num="0314"><img file="EP3345902A1_D0319.tif" /></chemistry>

0889¹H NMR (400 MHz, CD₃OD) δ 8.19 (br s, 1H), 8.13 (br s, 1H), 7.92 - 7.68 (m, 4H), 7.61 (d, <i>J</i> = 7.8 Hz, 1H), 5.19 (br s, 2H), 3.96 (s, 3H). [M+H] = 307.26.

Example 223. 1-{[5-(3-Ethoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine.

0890<chemistry id="chem0315" num="0315"><img file="EP3345902A1_D0320.tif" /></chemistry>

0891¹H NMR (400 MHz, CD₃OD) δ 8.13 - 8.09 (m, 2H), 7.66 (d, <i>J</i> = 2.3 Hz, 1H), 7.31 - 7.25 (m, 1H), 7.07 - 7.03 (m, 2H), 6.91 - 6.87 (m, 1H), 5.17 (s, 2H), 4.05 (d, <i>J</i> = 7.0 Hz, 2H), 3.93 (s, 3H), 1.39 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 326.26.

Example 224. 1-{[5-(3-Cyclopropoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine.

0892<chemistry id="chem0316" num="0316"><img file="EP3345902A1_D0321.tif" /></chemistry>

0893¹H NMR (400 MHz, CD₃OD) δ 8.16 - 8.09 (m, 2H), 7.66 (d, <i>J</i> = 2.38 Hz, 1H), 7.36 -7.16 (m, 2H), 7.11 - 7.02 (m, 2H), 5.18 (s, 2H), 3.94 (s, 3H), 3.80 (tt, <i>J</i> = 6.01, 2.96 Hz, 1H), 0.82 - 0.67 (m, 4H). [M+H] = 338.27.

Example 225. 1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine.

0894<chemistry id="chem0317" num="0317"><img file="EP3345902A1_D0322.tif" /></chemistry>

0895¹H NMR (400 MHz, CD₃OD) δ 8.18 - 8.07 (m, 2H), 7.71 (d, <i>J</i> = 2.3 Hz, 1H), 7.50 - 7.34 (m, 3H), 7.17 - 7.09 (m, 1H), 7.06 - 6.62 (m, 1H), 5.18 (s, 2H), 4.41 (q, <i>J</i> = 7.0 Hz, 2H), 1.35 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 362.24.

Example 226. 1- {[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine.

0896<chemistry id="chem0318" num="0318"><img file="EP3345902A1_D0323.tif" /></chemistry>

0897¹H NMR (400 MHz, CD₃OD) δ 8.22 - 8.11 (m, 2H), 7.84 (d, <i>J</i> = 2.3 Hz, 1H), 7.80 - 7.39 (m, 1H), 7.35 (t, <i>J</i> = 8.0 Hz, 1H), 7.10 - 7.05 (m, 2H), 6.97 (dd, <i>J</i> = 2.5, 8.4 Hz, 1H), 5.24 (s, 2H), 3.82 (s, 3H). [M+H] = 348.22.

Example 227. 1-{[5-(5-Chloropyridin-3-yl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine.

0898<chemistry id="chem0319" num="0319"><img file="EP3345902A1_D0324.tif" /></chemistry>

0899¹H NMR (400 MHz, CD₃OD) δ 9.28 (s, 1H), 8.78 (d, <i>J</i> = 1.76 Hz, 1H), 8.66 (d, <i>J</i> = 2.13 Hz, 1H), 8.38 (d, <i>J</i> = 2.26 Hz, 1H), 8.31 (t, <i>J</i> = 2.01 Hz, 1H), 8.01 (d, <i>J</i> = 2.26 Hz, 1H), 5.38 (s, 2H), 4.02 (s, 3H). [M+H] = 317.21.

Example 228. 1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine.

0900<chemistry id="chem0320" num="0320"><img file="EP3345902A1_D0325.tif" /></chemistry>

0901¹H NMR (400 MHz, CD₃OD) δ 8.25 - 8.19 (m, 2H), 8.13 (s, 1H), 7.84 (d, <i>J</i> = 2.3 Hz, 1H), 7.76 - 7.55 (m, 1H), 7.44 - 7.36 (m, 1H), 7.18 (d, <i>J</i> = 0.8 Hz, 1H), 5.19 (s, 2H), 3.98 (s, 3H). [M+H] = 349.25.

Example 229. 1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine.

0902<chemistry id="chem0321" num="0321"><img file="EP3345902A1_D0326.tif" /></chemistry>

0903¹H NMR (400 MHz, CD₃OD) δ 8.24 (dd, <i>J</i> = 0.8, 5.1 Hz, 1H), 8.21 (d, <i>J</i> = 2.3 Hz, 1H), 8.14 (s, 1H), 7.85 (d, <i>J</i> = 2.7 Hz, 1H), 7.77 - 7.57 (m, 1H), 7.43 (dd, <i>J</i> = 1.6, 5.5 Hz, 1H), 7.22 (dd, <i>J =</i> 0.8, 1.6 Hz, 1H), 5.20 (s, 2H), 4.47 (q, <i>J</i> = 7.0 Hz, 2H), 1.37 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 363.19.

Example 230. 1-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine.

0904<chemistry id="chem0322" num="0322"><img file="EP3345902A1_D0327.tif" /></chemistry>

0905¹H NMR (400 MHz, CD₃OD) δ 8.32 - 8.27 (m, 2H), 8.16 (s, 1H), 7.99 (d, <i>J</i> = 2.3 Hz, 1H), 7.84 - 7.38 (m, 3H), 7.19 - 7.16 (m, 1H), 5.27 (s, 2H). [M+H] = 385.20.

Example 231. 1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-3-amine.

0906<chemistry id="chem0323" num="0323"><img file="EP3345902A1_D0328.tif" /></chemistry>

0907¹H NMR (400 MHz, CD₃OD) δ 8.04 (d, <i>J</i> = 2.3 Hz, 1H), 7.58 (d, <i>J</i> = 2.3 Hz, 1H), 7.46 - 7.30 (m, 4H), 7.14 - 7.09 (m, 1H), 7.02 - 6.64 (m, 1H), 5.64 (d, <i>J</i> = 2.3 Hz, 1H), 5.10 (s, 2H), 3.93 (s, 3H). [M+H] = 347.37.

Example 232. 1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-5-amine.

0908<chemistry id="chem0324" num="0324"><img file="EP3345902A1_D0329.tif" /></chemistry>

0909¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, <i>J</i> = 2.3 Hz, 1H), 7.55 (d, <i>J</i> = 2.7 Hz, 1H), 7.44 - 7.33 (m, 2H), 7.30 (t, <i>J</i> = 2.0 Hz, 1H), 7.22 (d, <i>J</i> = 2.0 Hz, 1H), 7.13 - 7.09 (m, 1H), 7.02 - 6.63 (m, 1H), 5.50 (d, <i>J</i> = 2.3 Hz, 1H), 5.16 (s, 2H), 3.92 (s, 3H). [M+H] = 347.37.

Example 233. 4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-amine.

0910<chemistry id="chem0325" num="0325"><img file="EP3345902A1_D0330.tif" /></chemistry>

0911¹H NMR (400 MHz, CD₃OD) δ 8.05 (d, <i>J</i> = 2.7 Hz, 1H), 7.62 (d, <i>J</i> = 2.3 Hz, 1H), 7.59 - 7.56 (m, 2H), 7.48 - 7.44 (m, 1H), 7.41 - 7.32 (m, 2H), 5.06 (s, 2H), 4.40 (q, <i>J</i> = 7.0 Hz, 2H), 1.38 - 1.30 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 363.30.

Example 234. 4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-amine.

0912<chemistry id="chem0326" num="0326"><img file="EP3345902A1_D0331.tif" /></chemistry>

0913¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, <i>J</i> = 2.3 Hz, 1H), 7.60 - 7.55 (m, 2H), 7.47 - 7.43 (m, 1H), 7.41 - 7.32 (m, 2H), 7.25 (s, 1H), 5.16 (s, 2H), 4.39 (q, <i>J</i> = 7.4 Hz, 2H), 1.34 (t, <i>J</i> = 7.0 Hz, 4H). [M+H] = 363.30.

Example 235. 1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-pyrazol-4-amine.

0914<chemistry id="chem0327" num="0327"><img file="EP3345902A1_D0332.tif" /></chemistry>

0915The title compound was prepared in a manner analogous to Example 216, two products were formed. ¹H NMR (400 MHz, CD₃OD) δ 8.14 (s, 1H), 8.07 (s, 1H), 8.03 (s, 1H), 7.98 (d, <i>J</i> = 4.30 Hz, 1H), 7.61 (s, 1H), 7.47 - 7.39 (m, 2H), 5.49 (s, 2H), 4.06 (s, 3H). [M+H] = 316.10.

Example 236. 1-((6-(3-(Difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazol-3-amine.

0916<chemistry id="chem0328" num="0328"><img file="EP3345902A1_D0333.tif" /></chemistry>

0917¹H NMR (400MHz, CD₃OD) δ 8.64 - 8.50 (m, 1H), 8.18 (s, 1H), 7.93 (td, <i>J</i> = 1.4, 7.8 Hz, 1H), 7.86 (t, <i>J</i> = 2.0 Hz, 1H), 7.46 (t, <i>J</i> = 8.0 Hz, 1H), 7.20 (dd, <i>J</i> = 2.0, 8.2 Hz, 1H), 7.05 - 6.60 (m, 1H), 5.52 (s, 2H), 4.51 (q, <i>J</i> = 7.3 Hz, 2H), 1.44 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 363.14.

Example 237. 1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methyl 1H-1,2,4-triazol-3-amine.

0918<chemistry id="chem0329" num="0329"><img file="EP3345902A1_D0334.tif" /></chemistry>

0919To a solution of 1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-amine (Example 218, 120 mg, 0.34 mmol) in DCM (2 mL), was added formaldehyde (26 µL of 37 wt% solution, 0.35 mmol), NaBH(OAc)₃ (145 mg, 0.68 mmol) and a few drops of HOAc. The mixture was stirred at room temperature for 16 h. Purification by reverse-phase PREP-HPLC gave the title compound (25 mg, 20%). ¹H NMR (400 MHz, CD₃OD) δ 8.19 - 8.11 (m, 1H), 7.82 (d, <i>J</i> = 2.0 Hz, 1H), 7.71 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 7.41 - 7.28 (m, 3H), 5.21 (s, 2H), 2.72 (s, 3H). [M+H] = 366.21.

Example 238. 1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-

N

,

N

-dimethyl-1H-1,2,4-triazol-3-amine.

0920<chemistry id="chem0330" num="0330"><img file="EP3345902A1_D0335.tif" /></chemistry>

0921Prepared as a product of the reaction from procedure as Example 237. Purification by reverse-phase PREP-HPLC gave the title compound (41 mg, 32%). ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 8.25 (d, <i>J</i> = 2.0 Hz, 1H), 7.93 (d, <i>J</i> = 2.3 Hz, 1H), 7.84 - 7.61 (m, 1H), 7.57 (s, 1H), 7.50 - 7.39 (m, 3H), 5.32 (s, 2H), 2.96 (s, 6H). [M+H] = 380.24.

Example 239. (1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanamine.

0922<chemistry id="chem0331" num="0331"><img file="EP3345902A1_D0336.tif" /></chemistry>

0923To a cooled solution, -78 °C, of 1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carbonitrile (Example 155, 345 mg, 0.95 mmol) in DCM (5 mL) was slowly added DIBAL (135.64 mg, 0.95 mmol). The mixture was stirred at -78 °C for 1 h. The reaction was quenched with wet Na₂SO₄ and stirred at room temperature for 30 min. The white aluminum precipitate was filtered and the filtrate concentrated under reduced pressure. Purification (FCC, SiO₂, 40 -100% EtOAc/DCM, followed by 0-10% MeOH/DCM) afforded the title compound (37 mg, 10%). ¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 1H), 8.25 (d, <i>J</i> = 2.3 Hz, 1H), 7.92 (d, <i>J</i> = 2.3 Hz, 1H), 7.81 - 7.40 (m, 5H), 5.45 (s, 2H), 3.85 - 3.82 (m, 2H). [M+H] = 366.20.

Example 240. 1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carboxamide.

0924<chemistry id="chem0332" num="0332"><img file="EP3345902A1_D0337.tif" /></chemistry>

0925To a solution of methyl 1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate (Example 141, 103 mg, 0.28 mmol) in MeOH (2 mL) was added ammonia in methanol (2 mL of 7N solution, 14 mmol). The mixture was heated using microwave irradiation at 130 °C for 20 min. The LC/MS showed incomplete conversion. To the reaction mixture was added more ammonia in methanol (2 mL, 14 mmol) and irradiated in a microwave at 120 °C for an additional 20 min. The solvent was removed under reduced pressure. Purification (FCC, SiO₂, 0-5% MeOH/DCM) afforded the title compound (77 mg, 77%). ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.74 (s, 1 H), 8.25 (d, <i>J=</i> 2.3 Hz, 1 H), 7.85 (d, <i>J=</i> 2.3 Hz, 1 H), 7.78 - 7.70 (m, 1 H), 7.62 - 7.40 (m, 5 H), 5.45 (s, 2 H), 3.87 (s, 3 H). [M+H] = 354.18.

0926Examples 241-244 were prepared in a manner analogous to Example 90, with the appropriate starting materials and reagent substitutions.

Example 241. 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-

N

-(oxetan-3-yl)benzamide.

0927<chemistry id="chem0333" num="0333"><img file="EP3345902A1_D0338.tif" /></chemistry>

0928¹H NMR (400 MHz, CD₃OD) δ 7.94 (d, <i>J</i> = 2.3 Hz, 1H), 7.71 (d, <i>J</i> = 8.2 Hz, 2H), 7.47 - 7.39 (m, 2H), 7.34 - 7.19 (m, 5H), 5.07 - 4.97 (m, 1H), 4.81 (d, <i>J</i> = 7.4 Hz, 2H), 4.60 (t, <i>J</i> = 6.5 Hz, 2H), 3.94 (s, 2H), 3.83 (s, 3H). [M+H] = 409.24.

Example 242. 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-

N-

methylpyridine-2-carboxamide.

0929<chemistry id="chem0334" num="0334"><img file="EP3345902A1_D0339.tif" /></chemistry>

0930¹H NMR (400 MHz, CD₃OD) δ 8.57 (d, <i>J</i> = 1.6 Hz, 1H), 8.14 (d, <i>J</i> = 2.0 Hz, 1H), 8.01 (d, <i>J</i> = 7.8 Hz, 1H), 7.83 (dd, <i>J</i> = 2.0, 8.2 Hz, 1H), 7.78 (d, <i>J</i> = 2.3 Hz, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.47 - 7.38 (m, 3H), 4.15 (s, 2H), 2.94 (s, 3H). [M+H] = 404.17.

Example 243. 1-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxamide.

0931<chemistry id="chem0335" num="0335"><img file="EP3345902A1_D0340.tif" /></chemistry>

0932¹H NMR (400 MHz, CD₃OD) δ 8.10 (d, <i>J</i> = 2.35Hz, 1H), 7.76 (s, 1H), 7.73 (d, <i>J</i> = 2.35 Hz, 1H), 7.58 (s, 1H), 7.53 - 7.49 (m, 1H), 7.46 - 7.30 (m, 4H), 7.30 - 7.21 (m, 2H), 4.04 (s, 2H), 1.47 (q, <i>J</i> = 3.65Hz, 1H), 1.09 - 1.00 (m, 2H) 0.90-0.80 (m, 2H). [M+H] = 429.10.

Example 244. 2-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetamide.

0933<chemistry id="chem0336" num="0336"><img file="EP3345902A1_D0341.tif" /></chemistry>

0934¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, <i>J</i> = 2.35 Hz, 1H), 7.76 (s, 1H), 7.67 (d, <i>J</i> = 2.35Hz, 1H), 7.57 (s, 1H), 7.50 (m, 1H), 7.34 - 7.44 (m, 2H), 7.17 - 7.28 (m, 4H), 4.01 (s, 2H), 3.47 (s, 2H). [M+H] = 403.29.

Example 245. 2-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)propan-2-ol.

0935<chemistry id="chem0337" num="0337"><img file="EP3345902A1_D0342.tif" /></chemistry>

0936To a solution of 1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate (Example 141, 104 mg, 0.28 mmol) in DCM (2 mL) was added methylmagnesium bromide in diethyl ether (0.28 mL of 3M solution, 0.84 mmol). The mixture was stirred at rt for 20 min. The mixture was carefully quenched with wet Na₂SO₄, diluted with DCM, filtered and concentrated under reduced pressure. Purification (FCC, SiO₂, 50-100% EtOAc/hexanes) afforded the title compound (67 mg, 67%). ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, <i>J</i> = 2.0 Hz, 1 H), 8.00 (s, 1 H), 7.59 - 7.48 (m, 2 H), 7.42 - 7.31 (m, 3 H), 5.28 (s, 2 H), 3.98 (s, 3 H), 3.70 (s, 1 H), 1.62 (s, 6 H). [M+H] = 359.09.

0937Examples 246-249 were prepared in a manner analogous to Example 245, with the appropriate starting materials and reagent substitutions.

Example 246. 2-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-5-yl)propan-2-ol.

0938<chemistry id="chem0338" num="0338"><img file="EP3345902A1_D0343.tif" /></chemistry>

0939¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, <i>J</i> = 2.0 Hz, 1H), 7.79 (s, 1H), 7.64 (d, <i>J</i> = 2.0 Hz, 1H), 7.51 (s, 1H), 7.41 - 7.29 (m, 3H), 5.63 (s, 2H), 3.96 (s, 3H), 2.11 (s, 1H), 1.70 (s, 6H). [M+H] = 359.09.

Example 247. 2-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)propan-2-ol.

0940<chemistry id="chem0339" num="0339"><img file="EP3345902A1_D0344.tif" /></chemistry>

0941¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, <i>J</i> = 2.0 Hz, 1H), 7.49 (d, <i>J</i> = 1.6 Hz, 2H), 7.45 - 7.27 (m, 5H), 7.19 (d, <i>J=</i> 8.2 Hz, 2H), 3.94 (s, 2H), 3.65 (s, 3H), 1.50 (s, 6H). [M+H] = 368.23.

Example 248. 2-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol.

0942<chemistry id="chem0340" num="0340"><img file="EP3345902A1_D0345.tif" /></chemistry>

0943¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 8.04 (d, <i>J</i> = 2.0 Hz, 1H), 7.70 - 7.58 (m, 2H), 7.57 - 7.48 (m, 2H), 7.43 - 7.28 (m, 3H), 3.99 (s, 2H), 3.92 (s, 3H), 1.51 (s, 6H). [M+H] = 369.23.

Example 249. 2-(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol.

0944<chemistry id="chem0341" num="0341"><img file="EP3345902A1_D0346.tif" /></chemistry>

0945¹H NMR (400 MHz, CD₃OD) δ 8.41 (d, <i>J</i> = 2.0 Hz, 1H), 8.12 (d, <i>J</i> = 2.3 Hz, 1H), 7.78 - 7.57 (m, 4H), 7.52 (d, <i>J</i> = 1.6 Hz, 1H), 7.46 - 7.36 (m, 3H), 4.07 (s, 2H), 1.51 (s, 6H). [M+H] = 405.22.

Example 250. 3-[3-(Difluoromethoxy)phenyl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine.

0946<chemistry id="chem0342" num="0342"><img file="EP3345902A1_D0347.tif" /></chemistry>

0947To a solution of (1-((5-(3-(difluoromethoxy)phenyl)-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol (Example 201, 40.0 mg, 0.11 mmol) in DCM (3 mL) was added Deoxo-Fluor® (36.64 mg, 0.17 mmol). The mixture was stirred at room temperature for 2 h. The material was adsorbed on silica and purified (FCC, SiO₂, 20- 100% EtOAc/hexanes) to afford the title compound (11 mg, 27%). ¹H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H), 8.21 (d, <i>J=</i> 2.3 Hz, 1H), 7.77 (d, <i>J</i> = 2.3 Hz, 1H), 7.49 - 7.36 (m, 2H), 7.33 (t, <i>J</i> = 2.2 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.04 - 6.65 (m, 1H), 5.44 (s, 2H), 5.41 - 5.28 (m, 2H), 3.96 (s, 3H). [M+H] = 365.21.

0948Examples 251-255 were prepared in a manner analogous to Example 250, with the appropriate starting materials and reagent substitutions.

Example 251. 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]methyllpyridine.

0949<chemistry id="chem0343" num="0343"><img file="EP3345902A1_D0348.tif" /></chemistry>

0950¹H NMR (400 MHz, CD₃OD) δ 8.23 - 8.18 (m, 2H), 7.76 (d, <i>J</i> = 2.3 Hz, 1H), 7.48 - 7.36 (m, 3H), 7.17 - 7.11 (m, 1H), 7.03 - 6.65 (m, 1H), 5.64 (s, 2H), 5.42 (d, <i>J</i> = 48 Hz, 2H), 4.42 (q, <i>J</i> = 7.0 Hz, 2H), 1.35 (t, <i>J</i> = 7.2 Hz, 3H). [M+H] = 379.23.

Example 252. 2-(Difluoromethoxy)-3-(3-ethoxyphenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine.

0951<chemistry id="chem0344" num="0344"><img file="EP3345902A1_D0349.tif" /></chemistry>

0952¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 8.23 (d, <i>J</i> = 2.3 Hz, 1H), 7.90 (d, <i>J</i> = 2.3 Hz, 1H), 7.81 - 7.42 (m, 1H), 7.38 - 7.31 (m, 1H), 7.10 - 7.03 (m, 2H), 6.96 (ddd, <i>J</i> = 1.0, 2.5, 8.2 Hz, 1H), 5.53 - 5.27 (m, 4H), 4.16 - 4.00 (q, <i>J</i> = 7.0 Hz, 2H), 1.47 - 1.35 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 379.27.

Example 253. 3-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine.

0953<chemistry id="chem0345" num="0345"><img file="EP3345902A1_D0350.tif" /></chemistry>

0954¹H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H), 8.29 (d, <i>J</i> = 2.3 Hz, 1H), 8.26 - 8.21 (m, 1H), 7.90 (d, <i>J</i> = 2.3 Hz, 1H), 7.76 - 7.39 (m, 2H), 7.19 (dd, <i>J</i> = 0.8, 1.6 Hz, 1H), 5.48 - 5.27 (m, 4H), 4.00 (s, 3H). [M+H] = 366.23.

Example 254. 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine.

0955<chemistry id="chem0346" num="0346"><img file="EP3345902A1_D0351.tif" /></chemistry>

0956¹H NMR (400MHz, CD₃OD) δ 8.77 - 8.66 (m, 1H), 8.24 (s, 1H), 8.03 - 7.92 (m, 1H), 7.87 (d, <i>J</i> = 10.6 Hz, 1H), 7.57 - 7.41 (m, 1H), 7.25 (dd, <i>J</i> = 2.7, 8.2 Hz, 1H), 7.17 - 6.71 (m, 1H), 5.61 (s, 2H), 5.58 - 5.54 (m, 1H), 5.45 - 5.29 (m, 1H), 4.61 - 4.47 (m, 2H), 1.52 - 1.43 (m, 3H). [M+H] = 380.13.

Example 255. 3-(3-Chlorophenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyrazine.

0957<chemistry id="chem0347" num="0347"><img file="EP3345902A1_D0352.tif" /></chemistry>

0958¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.76 (s, 1H), 8.31 (s, 1H), 8.00 - 7.86 (m, 2H), 7.58 - 7.45 (m, 2H), 5.58 (s, 2H), 5.38 (s, 1H), 5.26 (s, 1H), 3.99 (s, 3H). [M+H] = 334.16.

Example 256. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine.

0959<chemistry id="chem0348" num="0348"><img file="EP3345902A1_D0353.tif" /></chemistry><ul id="ul0032" list-style="none" compact="compact"><li>Step 1. Methyl 1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate. The title compound was prepared in a manner analogous to Example 127 with the appropriate starting material substitutions.</li><li>Step 2. 1-((5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carbaldehyde. To a cooled solution, -78 °C, of methyl 1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate (146 mg, 0.37 mmol) in DCM (5 mL) was added DIBAL (52.6 mg, 0.37 mmol) slowly. The mixture was stirred at -78 °C for 1 h. The reaction was quenched with wet Na₂SO₄ and stirred at room temperature for 30 min. The white aluminum salt precipitate obtained was filtered and (the filtrate) concentrated under reduced pressure. The crude product was purified (FCC, SiO₂, 40 -100 % EtOAc/DCM followed by 0-5% MeOH/DCM) to afford the title compound (69 mg, 51%).</li><li>Step 3. 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5- {[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine. To a solution of ((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carbaldehyde (69 mg, 0.19 mmol) in DCM (5 mL) was added Deoxo-Fluor® (104.6 mg, 0.47 mmol). The mixture was stirred at room temperature for 16 h. The LC/MS suggested the presence of the title compound. The material was adsorbed on silica and purified (FCC, SiO₂, 10-100% EtOAc/hexanes) to afford the title compound (13 mg, 18%). ¹H NMR (400 MHz, CD₃OD) δ 8.69 (s, 1H), 8.28 (d, <i>J</i> = 2.3 Hz, 1H), 7.95 (d, <i>J</i> = 2.3 Hz, 1H), 7.81 - 7.39 (m, 5H), 6.94 - 6.65 (m, 1H), 5.54 (s, 2H). [M+H] = 387.17.</li></ul>

0960Examples 257-258 were prepared in a manner analogous to Example 256, with the appropriate starting materials and reagent substitutions.

Example 257. 3-[3-(Difluoromethoxy)phenyl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-ethoxypyridine.

0961<chemistry id="chem0349" num="0349"><img file="EP3345902A1_D0354.tif" /></chemistry>

0962¹H NMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.20 (d, <i>J</i> = 2.3 Hz, 1H), 7.79 (d, <i>J</i> = 2.3 Hz, 1H), 7.51 - 7.35 (m, 3H), 7.18 - 7.10 (m, 1H), 7.04 - 6.63 (m, 2H), 5.47 (s, 2H), 4.42 (q, <i>J</i> = 7.0 Hz, 2H), 1.35 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 397.24.

Example 258. 3-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine.

0963<chemistry id="chem0350" num="0350"><img file="EP3345902A1_D0355.tif" /></chemistry>

0964¹H NMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.30 (d, <i>J</i> = 2.3 Hz, 1H), 8.23 (d, <i>J</i> = 5.1 Hz, 1H), 7.92 (d, <i>J</i> = 2.3 Hz, 1H), 7.77 - 7.55 (m, 1H), 7.41 - 7.39 (m, 1H), 7.21 - 7.17 (m, 1H), 6.95 - 6.63 (m, 1H), 5.49 (s, 2H), 3.99 (s, 3H). [M+H] = 384.21.

Example 259. 3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,3-triazol-1-ylmethyl)pyridine.

0965<chemistry id="chem0351" num="0351"><img file="EP3345902A1_D0356.tif" /></chemistry><ul id="ul0033" list-style="none" compact="compact"><li>Step 1. 5-(Azidomethyl)-3-(3-chlorophenyl)-2-methoxypyridine. To a solution of 5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyridine (Intermediate 2, 160 mg, 0.51 mmol) in DMF (5 mL) was added NaN₃ (0.05 g, 0.77 mmol) and K₂CO₃ (0.14 g, 1.02 mmol). The mixture was stirred at room temperature for 16 h. The mixture was diluted with brine and extracted into diethyl ether. All solvents were removed under reduced pressure to afford the title compound, which was used in the next step without further purification.</li><li>Step 2. 3-(3-Chlorophenyl)-2-methoxy-5-((4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine. To a solution of 5-(azidomethyl)-3-(3-chlorophenyl)-2-methoxypyridine (directly used from previous reaction) and ethynyltrimethylsilane (75.1 mg, 0.77 mmol) in THF (3 mL), water (1 mL), was added copper (I) iodide (19.4 mg, 0.10 mmol) and DIPEA (132 mg, 1.02 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted in to DCM. The organic layers were combined, dried (Na₂SO₄), filtered and concentrated under reduced pressure. Purification (FCC, SiO₂, 0-50% EtOAc/hexanes) afforded the title compound (92 mg, 48%). [M+H] = 373.2.</li><li>Step 3. 3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,3-triazol-1-ylmethyl)pyridine. To a solution of 3-(3-chlorophenyl)-2-methoxy-5-((4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine (92.0 mg, 0.25 mmol) in THF (3 mL) was added TBAF (129 mg, 0.49 mmol). The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted in to DCM. The DCM extracts were combined, dried (Na₂SO₄), filtered and concentrated under reduced pressure. Purification (FCC, SiO₂, 0-80% EtOAc/DCM) afforded the title compound (44 mg, 59%). ¹H NMR (400 MHz, CD₃OD) δ 8.10 (br s, 1H), 7.95 (s, 1H), 7.65 - 7.59 (m, 2H), 7.42 (br s, 1H), 7.35 - 7.21 (m, 3H), 5.54 (s, 2H), 3.85 (s, 3H). [M+H] = 301.17.</li></ul>

0966Examples 260-265 were prepared in a manner analogous to Example 259, with the appropriate starting materials and reagent substitutions.

Example 260. [1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol.

0967<chemistry id="chem0352" num="0352"><img file="EP3345902A1_D0357.tif" /></chemistry>

0968¹H NMR (400 MHz, CD₃OD) δ 8.19 (d, <i>J</i> = 2.7 Hz, 1H), 7.98 (s, 1H), 7.74 (d, <i>J</i> = 2.3 Hz, 1H), 7.47 - 7.35 (m, 3H), 7.14 (dd, <i>J</i> = 1.2, 2.0Hz, 1H), 7.03 - 6.64 (m, 1H), 5.60 (s, 2H), 4.73 - 4.60 (m, 2H), 4.41 (d, <i>J</i> = 7.0 Hz, 2H), 1.34 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 377.25.

Example 261. (1-((6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol.

0969<chemistry id="chem0353" num="0353"><img file="EP3345902A1_D0358.tif" /></chemistry>

0970¹H NMR (400 MHz, CD₃OD) δ 8.23 (d, <i>J</i> = 2.3 Hz, 1H), 8.00 (s, 1H), 7.86 (d, <i>J</i> = 2.3 Hz, 1H), 7.61 (t, <i>J</i> = 1.0 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.05 (ddd, <i>J</i> = 1.2, 2.5, 3.7 Hz, 2H), 6.95 (ddd, <i>J</i> = 1.0, 2.4, 8.3 Hz, 1H), 5.67 (s, 2H), 4.66 (s, 2H), 4.07 (q, <i>J</i> = 6.8 Hz, 2H), 1.40 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 377.25.

Example 262. [1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol.

0971<chemistry id="chem0354" num="0354"><img file="EP3345902A1_D0359.tif" /></chemistry>

0972¹H NMR (400MHz, CD₃OD) δ 8.19 (s, 1H), 8.05 (s, 1H), 7.98 - 7.93 (m, 1H), 7.88 (t, <i>J</i> = 2.0 Hz, 1H), 7.47 (t, <i>J</i> = 8.0 Hz, 1H), 7.21 (dd, <i>J</i> = 3.5, 8.2 Hz, 1H), 7.05 - 6.65 (m, 1H), 5.73 (s, 2H), 4.67 (s, 2H), 4.51 (q, <i>J</i> = 7.0 Hz, 2H), 1.44 (t, <i>J</i> = 7.2 Hz, 3H). [M+H] = 378.24.

Example 263. (1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methanol.

0973<chemistry id="chem0355" num="0355"><img file="EP3345902A1_D0360.tif" /></chemistry>

0974¹H NMR (400MHz, CD₃OD) δ 8.22 (s, 1H), 8.06 - 8.02 (m, 2H), 7.99 (ddd, <i>J</i> = 1.6, 3.6, 5.4 Hz, 1H), 7.44 - 7.40 (m, 2H), 5.74 (s, 2H), 4.67 (s, 2H), 4.06 (s, 3H). [M+H] = 332.15.

Example 264. [1-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol.

0975<chemistry id="chem0356" num="0356"><img file="EP3345902A1_D0361.tif" /></chemistry>

0976¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.31 - 8.29 (m, 1H), 8.05 (s, 1H), 7.88 - 7.84 (m, 1H), 7.76 - 7.72 (m, 1H), 7.53 (t, <i>J</i> = 8.0 Hz, 1H), 7.45 - 7.05 (m, 2H), 5.72 (s, 2H), 5.16 - 5.05 (m, 1H), 4.49 (d, <i>J</i> = 5.1 Hz, 2H), 3.98 (s, 3H). [M+H] = 364.24.

Example 265. (1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methanol.

0977<chemistry id="chem0357" num="0357"><img file="EP3345902A1_D0362.tif" /></chemistry>

0978¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.28 (s, 1H), 8.05 (s, 1H), 8.03 - 8.00 (m, 1H), 7.99 - 7.94 (m, 1H), 7.53 - 7.49 (m, 2H), 5.71 (s, 2H), 5.16 - 5.08 (m, 1H), 4.50 - 4.41 (m, 4H), 1.39 - 1.32 (m, 3H). [M+H] = 346.18.

Example 266. 3-[3-(Difluoromethoxy)phenyl]-5-{[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}-2-ethoxypyridine.

0979<chemistry id="chem0358" num="0358"><img file="EP3345902A1_D0363.tif" /></chemistry><ul id="ul0034" list-style="none" compact="compact"><li>Step 1. 1-((5-(3-(Difluoromethoxy)phenyl)-6-ethoxypyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde. To a solution of [1-({5-[3-(difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol (Example 260, 115 mg, 0.31 mmol), in DCM (5 mL) was added Dess-Martin Reagent® (1.22 mL, 0.30 mol/L, 0.37 mmol). The reaction mixture was allowed to stir at room temperature for 3 hr. The reaction was quenched with wet Na₂SO₄. The reaction mixture was extracted into DCM, filtered and solvent removed under reduced pressure. Purification (FCC, SiO₂, 10 -100% EtOAc/hexanes) afforded the title compound (90 mg, 79%).</li><li>Step 2. 3-[3-(Difluoromethoxy)phenyl]-5-{[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}-2-ethoxypyridine. To a solution of 1-((5-(3-(difluoromethoxy)phenyl)-6-ethoxypyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (90 mg, 0.24 mmol) in DCM (5 mL) was added Deoxo-Fluor® (133 mg, 0.60 mmol). The mixture was stirred at room temperature for 4 h. The material was adsorbed on silica. Purification (FCC, SiO₂, 0 -80% EtOAc/hexanes) afforded the title compound (53 mg, 56%). ¹H NMR (400 MHz, CD₃OD) δ 8.36 (t, <i>J</i> = 1.4 Hz, 1H), 8.20 (d, <i>J</i> = 2.3 Hz, 1H), 7.77 (d, <i>J</i> = 2.7 Hz, 1H), 7.47 - 7.36 (m, 3H), 7.16 - 7.10 (m, 1H), 7.07 - 6.63 (m, 2H), 5.66 (s, 2H), 4.41 (q, <i>J</i> = 7.0 Hz, 2H), 1.34 (t, <i>J</i> = 7.2 Hz, 3H). [M+H] = 397.24.</li></ul>

Example 267. 1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylic acid.

0980<chemistry id="chem0359" num="0359"><img file="EP3345902A1_D0364.tif" /></chemistry>

0981To a solution of ethyl 1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carboxylate (Example 168, 25.00 mg, 0.07 mmol) in THF (2 mL), MeOH (2 mL) was added aq. LiOH (1.00 mL, 1.00 mol/L, 1.00 mmol). The mixture was stirred at room temperature for 2 h. The solvents were removed under reduced pressure and the crude residue dissolved in water. The aqueous reaction mixture was acidified with 1 N HCl (5 mL), and extracted into ethyl acetate. The combined organic layers were dried (Na₂SO₄), filtered and concentrated under reduced pressure to afford the title compound (20 mg, 87%). ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 12.30 (br s, 1H), 8.39 (br s, 1H), 8.19 (br s, 1H), 7.80 (br s, 2H), 7.68 - 7.26 (m, 4H), 5.34 (br s, 2H), 3.87 (br s, 3H). [M+H] = 344.31.

Example 268. 1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxamide.

0982<chemistry id="chem0360" num="0360"><img file="EP3345902A1_D0365.tif" /></chemistry>

0983A solution of 1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carbonitrile (Example 170, 25.00 mg, 0.08 mmol) in MeOH (1.54 mL) was heated to 50 °C, until the starting material dissolved. Aq. NaOH (0.23 mL, 1.00 mol/L, 0.23 mmol) and H₂O₂ (0.23 mL, 1.00 mol/L, 0.23 mmol) were added and the reaction stirred at 50 °C for 2h. Water was added (5 mL), and the mixture was filtered and washed with water (3 x 5 mL) to afford the title compound as a solid (25.0 mg, 95%). ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.20 (d, <i>J</i> = 13.69 Hz, 2H), 7.80 (d, <i>J</i> = 14.48 Hz, 2H), 7.65 - 7.37 (m, 5H), 6.95 (br s, 1H), 5.32 (br s, 2H), 3.87 (br s, 3H). [M+H] = 343.33.

Example 269. [1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-4-yl]methanol.

0984<chemistry id="chem0361" num="0361"><img file="EP3345902A1_D0366.tif" /></chemistry><ul id="ul0035" list-style="none" compact="compact"><li>Step 1. 1-((5-(3-(Difluoromethoxy)phenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carbaldehyde. The title compound was prepared in a manner analogous to Example 127, with the appropriate starting material substitutions.</li><li>Step 2. [1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-4-yl]methanol. To a solution of 1-((5-(3-(difluoromethoxy)phenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carbaldehyde (99 mg, 0.27 mmol) in MeOH (5 mL) was added NaBH₄ (14.3 mg, 0.38 mmol). The mixture was stirred at room temperature for 10 min. The mixture was quenched with water (0.5 mL), diluted with DCM (10 mL), dried (Na₂SO₄), filtered and concentrated under reduced pressure. Purification (FCC, SiO₂, 20 -100% EtOAc/hexanes) afforded the title compound (100 mg, 100%). ¹H NMR (400 MHz, CD₃OD) δ 8.10 (d, <i>J</i> = 2.3 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.63 (d, <i>J</i> = 2.3 Hz, 1H), 7.50 (s, 1H), 7.45 - 7.34 (m, 2H), 7.30 (t, <i>J</i> = 2.3 Hz, 1H), 7.13 (s, 1H), 7.03 - 6.64 (m, 1H), 5.31 (s, 2H), 4.49 (s, 2H), 3.94 (s, 3H). [M+H] = 362.21.</li></ul>

0985Examples 270-275 were prepared in a manner analogous to Example 269, with the appropriate starting materials and reagent substitutions.

Example 270. (1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-5-yl)methanol.

0986<chemistry id="chem0362" num="0362"><img file="EP3345902A1_D0367.tif" /></chemistry>

0987¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.08 - 8.30 (m, 1H), 7.92 (d, <i>J</i> = 2.35 Hz, 1H), 7.77 (s, 1H), 7.57 - 7.62 (m, 1H), 7.43 - 7.54 (m, 3H), 6.81 (s,1H), 5.27 (s, 2H), 5.16 (t, <i>J</i> = 5.28 Hz, 1H), 4.41 (d, <i>J</i> = 5.09 Hz, 2H), 3.49 - 3.59 (m, 2H). [M+H] = 366.20.

Example 271. (1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-4-yl)methanol.

0988<chemistry id="chem0363" num="0363"><img file="EP3345902A1_D0368.tif" /></chemistry>

0989¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.19 - 8.40 (m, 1H), 8.05 (d, <i>J</i> = 2.35 Hz, 1H), 7.83 - 7.46 (m, 6H), 7.13 (s, 1H), 5.20 (s, 2H), 4.28 (s, 2H), 3.55 (s, 1H). [M+H] = 366.20.

Example 272. [1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-3-yl]methanol.

0990<chemistry id="chem0364" num="0364"><img file="EP3345902A1_D0369.tif" /></chemistry>

0991¹H (400 MHz, CD₃OD) δ 8.04 (d, <i>J</i> = 2.3 Hz, 1H), 7.61 (d, <i>J</i> = 2.3 Hz, 1H), 7.47 - 7.27 (m, 4H), 7.13 - 7.08 (m, 1H), 7.03 - 6.63 (m, 1H), 6.29 (d, <i>J</i> = 2.0 Hz, 1H), 5.40 (s, 2H), 4.65 (s, 2H), 3.92 (s, 3H). [M+H] = 362.17.

Example 273. (1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)methanol.

0992<chemistry id="chem0365" num="0365"><img file="EP3345902A1_D0370.tif" /></chemistry>

0993¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, <i>J</i> = 2.3 Hz, 1H), 7.72 (s, 1H), 7.63 (d, <i>J</i> = 2.3 Hz, 1H), 7.55 (t, <i>J</i> = 1.6 Hz, 1H), 7.50 (s, 1H), 7.46 - 7.42 (m, 1H), 7.40 - 7.31 (m, 2H), 5.30 (s, 2H), 4.49 (s, 2H), 4.39 (q, <i>J</i> = 7.0 Hz, 2H), 1.33 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 344.33.

Example 274. (4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-yl)methanol.

0994<chemistry id="chem0366" num="0366"><img file="EP3345902A1_D0371.tif" /></chemistry>

0995¹H NMR (400 MHz, CD₃OD) δ 8.10 (d, <i>J</i> = 2.3 Hz, 1H), 7.80 (s, 1H), 7.68 (d, <i>J</i> = 2.3 Hz, 1H), 7.56 (s, 1H), 7.47 - 7.43 (m, 1H), 7.40 - 7.31 (m, 2H), 5.25 (s, 2H), 4.53 (s, 2H), 4.39 (q, <i>J</i> = 7.0 Hz, 2H), 1.33 (t, <i>J</i> = 7.0 Hz, 3H). [M+H] = 378.27.

Example 275. (4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-yl)methanol.

0996<chemistry id="chem0367" num="0367"><img file="EP3345902A1_D0372.tif" /></chemistry>

0997¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, <i>J</i> = 2.3 Hz, 1H), 7.68 (d, <i>J</i> = 2.3 Hz, 1H), 7.56 (s, 1H), 7.47 (s, 1H), 7.46 - 7.42 (m, 1H), 7.40 - 7.31 (m, 2H), 5.40 (s, 2H), 4.67 (s, 2H), 4.40 (q, <i>J</i> = 7.0 Hz, 2H), 1.33 (t, <i>J</i> = 7.0 Hz, 4H). [M+H] = 378.27.

Example 276. 4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}benzoic acid.

0998<chemistry id="chem0368" num="0368"><img file="EP3345902A1_D0373.tif" /></chemistry>

0999The title compound was prepared in a manner analogous to Example 21, with the appropriated starting material and reagent substitutions. ¹H NMR (400 MHz, CD₃OD) δ 8.01 (d, <i>J</i> = 2.3 Hz, 1H), 7.87 (d, <i>J</i> = 8.2 Hz, 2H), 7.63 (d, <i>J</i> = 2.3 Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.35 - 7.24 (m, 5H), 4.01 (s, 2H). [M+H] = 390.09.

Example 277. (1-((6-Ethoxy-5-(2-fluorophenyl)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol.

1000<chemistry id="chem0369" num="0369"><img file="EP3345902A1_D0374.tif" /></chemistry>

1001The title compound was prepared in a manner analogous to Intermediate 21, from (1-((5-bromo-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol (Intermediate 19) and (2-fluorophenyl)boronic acid, substituting Pd(dppf)Cl₂ · DCM for Pd(dppf)Cl₂. ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.57 (s, 1H), 8.23 (d, <i>J</i> = 2.26 Hz, 1H), 7.69 (d, <i>J</i> = 2.26 Hz, 1H), 7.34 - 7.49 (m, 2H), 7.22 - 7.31 (m, 2H), 5.36 (s, 2H), 5.18 (t, <i>J</i> = 6.02 Hz, 1H), 4.38 (d, <i>J</i> = 6.02 Hz, 2H), 4.33 (q, <i>J</i> = 7.03 Hz, 2H), 1.22 (t, <i>J</i> = 7.03 Hz, 3H); [M+H] = 329.4.

Example 278. 5-((5-(3,4-Difluorophenyl)-6-propoxypyridin-3-yl)methyl)pyrimidin-2-amine.

1002<chemistry id="chem0370" num="0370"><img file="EP3345902A1_D0375.tif" /></chemistry>

1003The title compound was prepared in a manner analogous to Intermediate 21 from 5-(chloromethyl)-3-(3,4-difluorophenyl)-2-propoxypyridine (Intermediate 22) and 2-aminopyrimidine-5-boronic acid, substituting Pd(PPh₃)₄ for Pd(dppf)Cl₂. ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.18 (s, 2H), 8.07 (d, <i>J</i> = 2.35 Hz, 1H), 7.69 (d, <i>J</i> = 2.35 Hz, 1H), 7.62 - 7.68 (m, 1H), 7.45 - 7.53 (m, 1H), 7.39- 7.44 (m, 1H), 6.45 (s, 2H), 4.24 (t, <i>J</i> = 6.46 Hz, 2H), 3.72 (s, 2H), 1.68 (q, <i>J</i> = 6.65 Hz, 2H), 0.92 (t, <i>J</i> = 7.43 Hz, 3H); [M+H] = 357.4.

Example 279. 5-((5-(3-Chloro-4-fluorophenyl)-6-ethoxypyridin-3-yl)methyl)pyrimidin-2-amine.

1004<chemistry id="chem0371" num="0371"><img file="EP3345902A1_D0376.tif" /></chemistry>

1005The title compound was prepared in a manner analogous to Intermediate 24, from 5-((5-bromo-6-ethoxypyridin-3-yl)methyl)pyrimidin-2-amine (Intermediate 52) and (3-chloro-4-fluorophenyl)boronic acid, substituting aq. NaHCO₃ for Na₂CO₃. ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.33 (s, 2H), 8.08 (d, <i>J</i> = 2.3 Hz, 1H), 7.77 (dd, <i>J</i> = 2.2, 7.2 Hz, 1H), 7.71 (d, <i>J</i> = 2.3 Hz, 1H), 7.58 (ddd, <i>J</i> = 2.2, 4.9, 8.6 Hz, 1H), 7.49 - 7.42 (m, 1H), 4.33 (q, <i>J</i> = 7.0 Hz, 2H), 3.76 (s, 2H), 1.26 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 359.25.

Example 280. 2-(4-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)acetamide.

1006<chemistry id="chem0372" num="0372"><img file="EP3345902A1_D0377.tif" /></chemistry><ul id="ul0036" list-style="none" compact="compact"><li>Step 1. 2-(4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)acetic acid. To a solution of 2-(4-((5-(3,4-difluorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)acetate (Intermediate 50, 100.00 mg, 0.25 mmol) in THF (1.26 mL) and MeOH (1.3 mL) was added IN solution of LiOH (0.63 mL, 0.25 mmol). The reaction mixture stirred at room temperature for 30 min. EtOAc (10 mL) was added to the reaction mixture followed by sat. aq. NaHCO₃ (10 mL). The aqueous layer was extracted and acidified with conc. HCl. The acidified aq. layer was extracted with EtOAc (10 mL), and the combined organic layers were collected, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The title compound was used crude in the next step without further purification.</li><li>Step 2. 2-(4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)acetyl chloride. To a solution of 2-(4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)acetic acid in DCM (2.0 mL) was added oxalyl chloride (0.25 mL, 0.50 mmol). The reaction mixture was stirred at room temperature for 30 min, and the solvent was removed under reduced pressure. The crude title compound was used in the next step without further purification.</li><li>Step 3. 2-(4-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)acetamide. A solution of 2-(4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)acetyl chloride in 4N ammonia in dioxane (0.75 mL, 0.75 mmol) was stirred at room temperature for 30 min. The reaction mixture was concentrated and the precipitate was filtered and washed with water to obtain the title compound (60 mg, 64%) as a white solid. ¹H NMR (400MHz, CD₃OD) δ 8.10 (d, <i>J</i> = 2.3 Hz, 1H), 7.66 (d, <i>J</i> = 2.3 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.51 - 7.33 (m, 4H), 7.25 - 7.11(m, 4H), 6.81 (br s, 1H), 3.90 (s, 2H), 3.85 (s, 3H), 3.30 (s, 2H); [M+H] = 367.40.</li></ul>

Example 281. 2-(5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide.

1007<chemistry id="chem0373" num="0373"><img file="EP3345902A1_D0378.tif" /></chemistry>

1008H₂SO₄ (1 mL) was added to 2-(5-((5-(4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)acetonitrile (Intermediate 53, 100 mg, 0.30 mmol) and the reaction stirred at room temperature for 1 h. The reaction mixture was cooled in an ice bath, ice was added to the reaction mixture, followed by water (100 mL), and stirred for 30 min. Solids were filtered, and the pH of the aq. layer adjusted to neutral with aq. NaHCO₃. The aq. layer was extracted with DCM, the combined organic layers were dried (Na₂SO₄), filtered and concentrated onto silica gel. Purification (FCC, SiO₂, 10%MeOH/90% EtOAc) afforded the title compound (60 mg, 57%). ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.69 (s, 2H), 8.13 (d, <i>J</i> = 2.3 Hz, 1H), 7.70 (d, <i>J</i> = 2.3 Hz, 1H), 7.61 - 7.49 (m, 4H), 7.29 -7.18 (m, 4H), 3.94 (s, 2H), 3.83 (s, 5H), 3.66 (s, 2H); [M+H] = 353.25.

Example 282. 5-{[5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide.

1009<chemistry id="chem0374" num="0374"><img file="EP3345902A1_D0379.tif" /></chemistry>

1010The title compound was prepared in a manner analogous to Example 13 from 5-((5-(3-chloro-4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine-2-carbonitrile. ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ8.88 (s, 2H), 8.18 (d, <i>J</i> = 2.3 Hz, 1H), 8.10 (br s, 1H), 7.79 (d, <i>J</i> = 2.3 Hz, 1H), 7.75 (dd, <i>J</i> = 2.2, 7.2 Hz, 1H), 7.71 (br s, 1H), 7.58 - 7.52 (m, 1H), 7.49 - 7.39 (m, 1H), 4.05 (s, 2H), 3.85 (s, 3H); [M+H] = 373.10.

Example 283. 2-[(5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-ol.

1011<chemistry id="chem0375" num="0375"><img file="EP3345902A1_D0380.tif" /></chemistry>

1012The title compound was prepared in manner analogous to Example 3, employing 2-Chloro-5-((5-(4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine (Intermediate 51). ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ8.20 (s, 2H), 8.06 (d, <i>J</i> = 2.3 Hz, 1H), 7.61 (d, <i>J</i> = 2.3 Hz, 1H), 7.58 - 7.51 (m, 2H), 7.28 - 7.19 (m, 2H), 6.86 (t, <i>J</i> = 5.9 Hz, 1H), 4.65 - 4.57 (m, 1H), 3.83 (s, 3H), 3.71 (s, 2H), 3.45 (q, <i>J</i> = 6.1 Hz, 2H), 3.27 (q, <i>J</i> = 6.5 Hz, 2H); [M+H] = 355.25.

Example 284. 2-(5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)-2-methylpropanenitrile.

1013<chemistry id="chem0376" num="0376"><img file="EP3345902A1_D0381.tif" /></chemistry>

1014To a cooled 0 °C mixture of 2-(5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrmidin-2-yl)acetonitrile (100.00 mg, 0.29 mmol), DMSO (2.85 mL), water (0.40 mL) and NaOH (45.6 mg, 1.14 mmol) was added MeI (0.070 mL, 1.14mmol) dropwise. The resultant mixture was stirred at rt for 40 min. before being poured into water (10 mL). The precipitate was filtered and washed with water to obtain the title compound (85 mg, 78%) as a white solid. ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.85 - 8.81 (m, 2H), 8.17 (d, <i>J</i> = 2.3 Hz, 1H), 7.80 (d, <i>J</i> = 2.3 Hz, 1H), 7.61 - 7.59 (m, 1H), 7.53 - 7.48 (m, 1H), 7.47 - 7.38 (m, 2H), 3.99 (s, 2H), 3.85 (s, 3H), 1.68 (s, 7H); [M+H] = 379.40.

Example 285. 2-(1-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)acetonitrile.

1015<chemistry id="chem0377" num="0377"><img file="EP3345902A1_D0382.tif" /></chemistry><ul id="ul0037" list-style="none" compact="compact"><li>Step 1. 5-((3-(Chloromethyl)-1H-1,2,4-triazol-1-yl)methyl)-3-(3-chlorophenyl)-2-(difluoromethoxy)pyridine. To a solution of (1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol (Example 199, 200 mg, 0.55 mmol) in DCM (15 mL) was added thionylchloride (97.32 mg, 0.82 mmol). The mixture was stirred at rt for 1 hr. The solvent was removed under reduced pressure to afford a white solid which was used without further purification in the following step.</li><li>Step 2. 2-(1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)acetonitrile. To a solution of 5-((3-(chloromethyl)-1H-1,2,4-triazol-1-yl)methyl)-3-(3-chlorophenyl)-2-(difluoromethoxy)pyridine (201 mg, 0.52 mmol) in DMF (1 mL) was added Cs₂CO₃ (510 mg, 1.572 mmol) followed by KCN (50.97 mg, 0.78 mmol). The mixture was stirred at rt for 3 h. The reaction mixture was diluted with water and extracted into EtOAc. The combined organic fractions were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Purification (FCC, SiO₂, 30 - 90%, EtOAc/hexanes) afforded the title compound (165 mg, 84%). ¹H NMR (400MHz, CD₃OD) δ 8.58 (s, 1H), 8.26 (s, 1H), 7.94 (d, <i>J</i> = 2.3 Hz, 1H), 7.81 - 7.61 (m, 1H), 7.58 - 7.55 (m, 1H), 7.48 - 7.41 (m, 3H), 5.47 - 5.46 (m, 2H), 4.01 - 3.97 (m, 2H); [M+H] = 376.</li></ul>

Example 286. 3-(3-Chlorophenyl)-5((5-ethoxypyridin-2-yl)methyl)-2-methoxy pyridine.

1016<chemistry id="chem0378" num="0378"><img file="EP3345902A1_D0383.tif" /></chemistry>

1017The title compound was prepared in a manner analogous to Intermediate 55 employing 3-(3-chlorophenyl)-2-methoxy-5-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)pyridine (Intermediate 31) and 2-bromo-5-ethoxypyridine. ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, <i>J</i> = 2.35 Hz, 1H), 8.07 (d, <i>J</i> = 1.96 Hz, 1H), 7.52 (s, 1H), 7.49 (d, <i>J</i> = 1.96 Hz, 1H), 7.38-7.43 (m, 1H), 7.29-7.36 (m, 2H), 7.10-7.16 (m, 1H), 7.04-7.09 (m, 1H), 4.02-4.11 (m, 4H), 3.96 (s, 3H), 1.42 (t, <i>J</i> = 7.04 Hz, 3H); [M+H] = 355.3.

Example 287. 5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-amine.

1018<chemistry id="chem0379" num="0379"><img file="EP3345902A1_D0384.tif" /></chemistry>

1019<i>tert</i>-Butyl (5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-yl)carbamate (Intermediate 55) was dissolved in DCM (5 mL)/TFA (1 mL) and stirred at rt for 4 hrs. The reaction mixture was concentrated under reduced pressure. After evaporating the solvent, the material was dissolved in EtOAc, washed with sat. aq. NaHCO₃. The organics were dried (Na₂SO₄), filtered, and concentrated under reduced pressure to provide the title compound as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, <i>J</i> = 2.35 Hz, 1H), 7.89 (s, 2H), 7.60 (d, <i>J</i> = 2.35 Hz, 1H), 7.53 (t, <i>J</i> = 1.96 Hz, 1H), 7.40-7.44 (m, 1H), 7.37 (t, <i>J</i> = 7.43 Hz, 1H), 7.30-7.34 (m, 1H), 3.95 (s, 2H), 3.92 (s, 3H); [M+H] = 327.3.

Example 288. 5-((5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-amine.

1020<chemistry id="chem0380" num="0380"><img file="EP3345902A1_D0385.tif" /></chemistry>

1021The title compound was prepared in a manner analogous to Example 291. ¹H NMR (400 MHz, CD₃OD) δ 8.07 (d, <i>J</i> = 2.35 Hz, 1H), 8.05 (s, 1H), 7.80 (s, 1H), 7.57 (dd, <i>J</i> = 2.35, 7.04 Hz, 1H), 7.46 (d, <i>J</i> = 2.35 Hz, 1H), 7.39 (ddd, <i>J</i> = 2.35, 4.70, 8.61 Hz, 1H), 7.17 (t, <i>J</i> = 8.61 Hz, 1H), 3.98 (s, 2H), 3.96 (s, 3H); [M+H] = 345.32.

Example 289. 2-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-5-ethoxypyrazine.

1022<chemistry id="chem0381" num="0381"><img file="EP3345902A1_D0386.tif" /></chemistry>

1023To a solution of 5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-amine (Example 287, 39 mg, 0.12 mmol) in EtOH (3 mL) was added <i>tert</i>-butyl nitrite (48 µL, 0.36 mmol) followed by 4 N HCl in dioxane (6 µL, 4.00 mol/L, 0.02 mmol). The resulting solution was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between DCM/sat NaHCO₃. The organic layer dried (Na₂SO₄), filtered, and concentrated under reduced pressure to afford a yellow oil. Purification (prep TLC, SiO₂, hexanes/EtOAc (8:2)) provided the title compound as a colorless oil (19.7 mg, 47%). ¹H NMR (400 MHz, CD₃OD) δ 8.15 (d, <i>J</i> = 1.17 Hz, 1H), 8.09 (d, <i>J</i> = 2.35 Hz, 1H), 7.97 (d, <i>J</i> = 1.57 Hz, 1H), 7.52 (t, <i>J</i> = 1.76 Hz, 1H), 7.50 (d, <i>J</i> = 2.35 Hz, 1H), 7.39-7.43 (m, 1H), 7.30-7.35 (m, 2H), 4.35 (q, <i>J</i> = 7.04 Hz, 2H), 4.04 (s, 2H), 3.96 (s, 3H), 1.40 (t, <i>J</i> = 7.24 Hz, 3H); [M+H] = 356.31.

Example 290. 2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-yl)amino) ethanol.

1024<chemistry id="chem0382" num="0382"><img file="EP3345902A1_D0387.tif" /></chemistry>

1025A solution consisting of 2-bromo-5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazine (Intermediate 57, 37.5 mg, 0.10 mmol) and 2-aminoethanol (23 µL, 0.38 mmol) in dioxane (2 mL) and <i>n</i>-butanol (1 mL) was heated at 175 °C overnight. The solvent was removed under reduced pressure and the crude residue purified by preparative HPLC using a 15-85% gradient with formate as the additive. Addition of concentrated NH₄OH followed by evaporation of the solvent gave the desired compound as a white solid (19 mg, 47%). ¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, <i>J</i> = 2.35 Hz, 1H), 7.92 (d, <i>J</i> = 1.17 Hz, 1H), 7.88 (d, <i>J</i> = 1.17 Hz, 1H), 7.60 (d, <i>J</i> = 2.35 Hz, 1H), 7.53 (t, <i>J</i> = 1.76 Hz, 1H), 7.41-7.45 (m, 1H), 7.35-7.40 (m, 1H), 7.31-7.35 (m, 1H), 3.94 (s, 2H), 3.92 (s, 3H), 3.69 (t, <i>J</i> = 5.67 Hz, 2H), 3.45 (t, <i>J</i> = 5.67 Hz, 2H); [M+H] = 371.32.

Example 291. 3-(3-Chlorophenyl)-2-methoxy-5-((5-methyl-1

H

-tetrazol-1-yl)methylpyridine.

1026<chemistry id="chem0383" num="0383"><img file="EP3345902A1_D0388.tif" /></chemistry>

1027The title compound was prepared in a manner analogous to Intermediate 32 employing 5-(chloromethyl)-3-(3-chlorophenyl)-2-methoxypyridine (Intermediate 30) and 5-methyl-2H-tetrazole. ¹H NMR (400 MHz, CD₃OD) δ 8.26 (d, <i>J</i> = 2.35 Hz, 1H), 7.65 (d, <i>J</i> = 2.74 Hz, 1H), 7.52 (q, <i>J</i> = 1.57 Hz, 1H), 7.32-7.42 (m, 3H), 5.69 (s, 2H), 3.98 (s, 3H), 2.53 (s, 3H); [M+H] = 316.36.

Example 292. 4-(5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)pyrimidin-2-yl)morpholine.

1028<chemistry id="chem0384" num="0384"><img file="EP3345902A1_D0389.tif" /></chemistry>

1029A mixture of 2-chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine (Example 2, 73 mg, 0.21 mmol), DIEA (184 µL, 1.06 mmol) and morpholine (73.17 µL, 0.85 mmol) in dioxane (2 mL) was heated at 110 °C for 24 h. The dioxane was removed under reduced pressure and the residue taken up in MeOH (2 mL) before being purified. Purification (Preparative HPLC, 15-85% gradient with formic acid in the mobile phase) provided the title compound as a white solid (48 mg, 57%). ¹H NMR (400 MHz, CD₃OD) d 8.27 (s, 2H), 8.03 (d, <i>J</i> = 2.35 Hz, 1H), 7.55 (d, <i>J</i> = 2.35 Hz, 1H), 7.52-7.54 (m, 1H), 7.40-7.44 (m, 1H), 7.35-7.40 (m, 1H), 7.31-7.35 (m, 1H), 3.93 (s, 3H), 3.83 (s, 2H), 3.72 (s, 8H); [M+H] = 397.42.

Example 293. 5-((6-(3,4-difluorophenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidin-2-amine.

1030<chemistry id="chem0385" num="0385"><img file="EP3345902A1_D0390.tif" /></chemistry>

1031A mixture of 5-(bromomethyl)-3-(3,4-difluorophenyl)-2-ethoxypyrazine (Intermediate 46, 91 mg, 0.28 mmol), Pd(PPh₃)₄ (26 mg, 0.02 mmol), K₂CO₃ (115 mg, 0.83 mmol) and 2-aminopyrimidine-5-boronic acid (58 mg, 0.41 mmol) in dioxane (2 mL) and water (500.00 µL) was heated employing microwave irradiation at 130 °C for 30 min. Purification (preparative HPLC, 15-85% gradient with formic acid as the additive) afforded the title compound as a white solid (29 mg, 31%). ¹H NMR (400 MHz, CD₃OD) d 8.29 (s, 2H), 8.06 (s, 1H), 7.95-8.06 (m, 2H), 7.32 (td, <i>J</i> = 8.56, 10.27 Hz, 1H), 4.49 (q, <i>J</i> = 7.04 Hz, 2H), 3.97 (s, 2H), 1.44 (t, <i>J</i> = 7.04 Hz, 3H); [M+H] = 344.41.

Example 294. 2-((5-((6-(3,4-difluorophenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidin-2-yl)amino)ethanol.

1032<chemistry id="chem0386" num="0386"><img file="EP3345902A1_D0391.tif" /></chemistry>

1033A mixture consisting of 2-chloro-5-((6-(3,4-difluorophenyl)-5-ethoxypyrazin-2-yl)methyl) pyrimidine (Intermediate 48, 59.10 mg, 0.16 mmol) in 2-aminoethanol (1 mL) was heated at 100 °C for 2 h. The mixture was poured into H₂0 (10 mL) and let sit at rt overnight. The reaction mixture was filtered, and the collected solid was purified (preparative HPLC, 15-85% gradient with formic acid as additive). Treatment with concentrated NH₄OH and evaporation gave the desired compound as a white solid (37 mg, 58%). ¹H NMR (400 MHz, CD₃OD) d 8.51 (s, 1H), 8.30 (s, 2H), 8.06-8.07 (m, 1H), 7.95-8.05 (m, 2H), 7.33 (td, <i>J</i> = 8.61, 10.56 Hz, 1H), 4.50 (q, <i>J</i> = 7.04 Hz, 2H), 3.97 (s, 2H), 3.65-3.72 (m, 2H), 3.44-3.52 (m, 2H), 1.44 (t, <i>J</i> = 7.04 Hz, 3H); [M+H] = 388.46.

Example 295. 2-(1-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-tetrazol-5-yl)ethanol.

1034<chemistry id="chem0387" num="0387"><img file="EP3345902A1_D0392.tif" /></chemistry>

1035To a solution of ethyl 2-(2-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-tetrazol-5-yl)acetate (Intermediate 33, 49.30 mg, 0.13 mmol) in THF (5 mL) at 0 °C was added LAH (69 µL, 2.40 mol/L, 0.17 mmol). The resulting solution was allowed to warm to rt over 3 h then carefully quenched by adding dropwise a solution of KF (37 mg, 0.64 mmol) dissolved in water (1 mL). The reaction mix was stirred for 15 min then filtered thru a bed of Celite®. The Celite® was washed throughly with EtOAc, and the EtOAC washes were concentrated under reduced pressure. Purification (preparative HPLC, 15-85% gradient with formic acid as additive) afforded the title compound as a colorless oil (1 mg, 3%). ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, <i>J</i> = 2.35 Hz, 1H), 7.55 (d, <i>J</i> = 2.35 Hz, 1H), 7.49-7.52 (m, 1H), 7.36 (d, <i>J</i> = 1.17 Hz, 3H), 5.54 (s, 2H), 4.12 (t, <i>J</i> = 5.09 Hz, 2H), 3.99 (s, 3H), 3.01-3.09 (m, 2H).

Example 296. 2-Ethoxy-3-(4-fluorophenyl)-5-((5-methyl-1H-tetrazol-1-yl)methyl)pyridine.

1036<chemistry id="chem0388" num="0388"><img file="EP3345902A1_D0393.tif" /></chemistry>

1037The title compound was prepared in a manner analogous to Intermediate 21, employing 3-bromo-2-ethoxy-5-((5-methyl-1H-tetrazol-1-yl)methyl)pyridine (Intermediate 32) and (4-fluorophenyl)boronic acid, in dioxane/water. ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, <i>J</i> = 2.35 Hz, 1H), 7.44-7.53 (m, 3H), 7.06-7.14 (m, 2H), 5.46 (s, 2H), 4.43 (q, <i>J</i> = 7.04 Hz, 2H), 2.56 (s, 3H), 1.37 (t, <i>J</i> = 7.04 Hz, 3H); [M+H] = 314.43.

Example 297. 2'-(Difluoromethoxy)-5-((4-(difluoromethyl)-2-methyl-1H-imidazol-1-yl)methyl)-2-methoxy-3,4'-bipyridine.

1038<chemistry id="chem0389" num="0389"><img file="EP3345902A1_D0394.tif" /></chemistry><ul id="ul0038" list-style="none" compact="compact"><li>Step 1. 1-((2'-(difluoromethoxy)-2-methoxy-[3,4'-bipyridin]-5-yl)methyl)-2-methyl-1H-imidazole-4-carbaldehyde. A solution of 5-(chloromethyl)-2'-(difluoromethoxy)-2-methoxy-3,4'-bipyridine (Intermediate 42, 300 mg, 1.0 mmol), 2-methyl-1H-imidazole-4-carbaldehyde (109.8 mg, 1.0 mmol), Cs₂CO₃ (487.6 mg, 1.5 mmol) and acetone (5 mL) were stirred at rt for 3 h. The reaction mixture was diluted with DCM, filtered, and the organics were removed under reduced pressure. Purification (FCC, SiO₂, 10%MeOH/DCM/EtOAc) provided the title compound as a mixture of two regioisomers (60 mg, 16%).</li><li>Step 2. 5-((2'-(Difluoromethoxy)-2-methoxy-[3,4'-bipyridin]-5-yl)methyl)-3-fluoropyridin-2-amine. The title compound was prepared in a manner analogous to Example 256 Step 3. ¹H NMR (400MHz, CD₃OD) δ 8.25 - 8.21 (m, 1H), 8.12 (d, <i>J</i> = 2.3 Hz, 1H), 7.75 - 7.72 (m, 1H), 7.58 - 7.35 (m, 3H), 7.18 (d, <i>J</i> = 0.8 Hz, 1H), 6.62 (s, 1H), 5.21 (s, 2H), 3.98 (s, 3H), 2.40 (s, 3H); [M+H] = 397.</li></ul>

Example 298. 2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)acetamide.

1039<chemistry id="chem0390" num="0390"><img file="EP3345902A1_D0395.tif" /></chemistry><ul id="ul0039" list-style="none" compact="compact"><li>Step 1. Methyl 2-((5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)acetate. To a solution of methyl glycolate (106.47 mg, 1.18 mmol) in toluene (5 mL) was added 60% NaH in mineral oil (35 mg, 0.89 mmol). The solution was stirred under nitrogen at 0 °C for 30 min. then [2-chloro-5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine] (Example 2, 204.60 mg, 0.59 mmol) was added. The reaction mixture was stirred at 60 °C for 18 h. Additional NaH (20 mg, 0.51 mmol) was added, and the reaction mixture was heated an additional 8 h. The reaction mix was cooled in an ice water bath and 1M NH₄Cl was added. The crude reaction mixture was extracted with EtOAc. The combined organic phase was treated with brine, dried (Na₂SO₄), filtered and concentrated to afford (224.5 mg, 95%) of the title compound as an oil. [M+H] = 400.39.</li><li>Step 2. 2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)acetamide. The title compound was prepared in a manner analogous to Example 240. ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.55 (s, 2H), 8.13 (d, <i>J</i> = 2.35 Hz, 1H), 7.74 (d, <i>J</i> = 2.35 Hz, 1H), 7.59 (t, <i>J</i> = 1.57 Hz, 1H), 7.35 - 7.53 (m, 4H), 7.12 (br s, 1H), 4.65 (s, 2H), 3.89 (s, 2H), 3.55 (s, 1H), 3.30 (s, 3 H); [M+H] = 385.38.</li></ul>

Example 299. (5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)methanol.

1040<chemistry id="chem0391" num="0391"><img file="EP3345902A1_D0396.tif" /></chemistry>

1041To a cooled, 0 °C, solution of methyl 5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine-2-carboxylate (Intermediate 44, 277 mg, 0.75 mmol) in MeOH (4 mL), was added NaBH₄ (28 mg, 0.75 mmol). The reaction mixture was stirred at 0 °C for an additional 8 h then neutralized to pH 7 with 1M aq. citric acid and extracted with EtOAc. The combined organics were dried (Na₂SO₄), filtered and concentrated under reduced pressure. Purification (FCC, SiO₂, hexanes/ (10% MeOH in EtOAc) 0-100%) afforded (64 mg, 25%) of the title compound as a light yellow semi-solid. ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.74 (s, 2H), 8.16 (d, <i>J</i> = 2.35 Hz, 1H), 7.75 (d, <i>J</i> = 2.35 Hz, 1H), 7.54 - 7.64 (m, 1H), 7.33 - 7.54 (m, 3H), 5.12 - 5.23 (m, 1H), 4.54 (d, <i>J</i> = 6.26 Hz, 2H), 3.96 (s, 2H), 3.85 (s, 3 H); [M+H] = 342.40.

Example 300. (1-((5-(3-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol.

1042<chemistry id="chem0392" num="0392"><img file="EP3345902A1_D0397.tif" /></chemistry><ul id="ul0040" list-style="none" compact="compact"><li>Step 1. Methyl 1-((5-(3-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate. The title compound was prepared in a manner analogous to Example 127 from 5-(chloromethyl)-3-(3-chlorophenyl)-2-(2,2,2-trifluoroethoxy)pyridine. [M+H] = 427.35.</li><li>Step 2. (1-((5-(3-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol. To a cooled, 0 °C, solution of methyl 1-((5-(3-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate (172.30 mg, 0.40 mmol) in THF (5 mL), under nitrogen was added DIBAL (0.81 mL, 1.00 mol/L, 0.81 mmol) over 1 min. The ice bath was removed, and the reaction mixture was stirred at rt for 3.5 h. The reaction mixture was concentrated then re-dissolved in DCM (5 mL), and IN NaOH aq. (0.5 mL) was added. The solution was stirred for an additional 8 h at rt. The layers were separated and the aq. phase was extracted with DCM. The combined organic phase was dried (Na₂SO₄), filtered and concentrated under reduced pressure. (FCC, SiO₂, 0-10% DCM/MeOH) afforded the title compound (25 mg, 16%) as a white powder. ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.57 (s, 1 H), 8.22 (d, <i>J</i> = 2.3 Hz, 1H) 7.95 (d, <i>J</i> = 2.3 Hz, 1H), 7.55 - 7.41 (m, 1H), 5.39 (s, 1H), 5.03 (q, <i>J</i> = 9.0 Hz, 1H), 4.36 (d, <i>J</i> = 6.3 Hz, 1H), 3.30 (s, 2H), 2.48 (td, <i>J</i> = 1.9, 3.6 Hz, 4H); [M+H] = 399.35.</li></ul>

Example 301. 5-((2'-(Difluoromethoxy)-2-methoxy-[3,4'-bipyridin]-5-yl)methyl)-3-fluoropyridin-2-amine.

1043<chemistry id="chem0393" num="0393"><img file="EP3345902A1_D0398.tif" /></chemistry><ul id="ul0041" list-style="none" compact="compact"><li>Step 1. 5-((2'-(Difluoromethoxy)-2-methoxy-[3,4'-bipyridin]-5-yl)methyl)-3-fluoro-<i>N</i>-(4-methoxybenzyl)pyridin-2-amine. The title compound was prepared in a manner analogous to Example 3 using Intermediate 58. [M+H] = 497.52.</li><li>Step 2. 5-((2'-(Difluoromethoxy)-2-methoxy-[3,4'-bipyridin]-5-yl)methyl)-3-fluoropyridin-2-amine. A solution of 5-((2'-(difluoromethoxy)-2-methoxy-[3,4'-bipyridin]-5-yl)methyl)-3-fluoro-<i>N</i>-(4-methoxybenzyl)pyridin-2-amine (90.7 mg, 0.18 mmol) in TFA (5 mL) was heated 50 °C for 8 h. The reaction mixture was concentrated and re-dissolved in EtOAc then washed with NaHCO₃. The organics were separated, dried (Na₂SO₄), filtered and concentrated under reduced pressure. Purification (FCC, SiO₂, 0-100 % EtOAc/hexanes) afforded (6.14 mg, 9%) of the title compound as a tan solid. ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.30 (d, <i>J</i> = 5.4 Hz, 1H), 8.18 (d, <i>J</i> = 2.2 Hz, 1H), 7.84 (d, <i>J</i> = 2.2 Hz, 1H), 7.78 - 7.55 (m, 2H), 7.49 (dd, <i>J</i> = 1.3, 5.3 Hz, 1H), 7.30 (s, 2H), 6.02 (s, 2H), 3.89 (s, 3H), 3.80 (s, 2H); [M+H] = 377.20.</li></ul>

Example 302. 5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-ol.

1044<chemistry id="chem0394" num="0394"><img file="EP3345902A1_D0399.tif" /></chemistry>

1045To a cooled, 0 °C, solution of 5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-amine (Example 25, 104 mg, 0.32 mmol), in DMF (5 mL) and water (5 mL) was added <i>tert-</i>butyl nitrite (150 µL, 1.27 mmol). The reaction mixture was allowed to warm up to rt and stirred for an additional 7 h. The rxn mixture was diluted with water and extracted with EtOAc. The combined organic phase was treated with brine, dried (Na₂SO₄), filtered and concentrated under reduced pressure. Purification (FCC, SiO₂, 0-15% MeOH/DCM) afforded the title compound as a white solid (80.48 mg, 77%). ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 11.80 (s, 1H), 8.19 (br s, 1H), 8.11 (d, <i>J</i> = 2.35 Hz, 1H), 7.71 (d, <i>J</i> = 2.35 Hz, 1H), 7.59 (t, <i>J</i> = 1.57 Hz, 1H), 7.32 - 7.56 (m, 3H), 3.69 (s, 3H), 3.55 (s, 2H); [M+H] = 326.26.

Example 303. 2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)ethanol.

1046<chemistry id="chem0395" num="0395"><img file="EP3345902A1_D0400.tif" /></chemistry>

1047To a cooled, 0 °C, solution of ethylene glycol (4.0 mL) was added NaH (10.40 mg, 0.43 mmol). The solution was stirred under nitrogen at 0 °C for 30 min. then 2-chloro-5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine (Example 2, 100.00 mg, 0.29 mmol) was added. The reaction mixture was allowed to warm to rt and stirred for an additional 8 h. The rxn mixture was diluted with water to obtain a ppt, which was washed with diethyl ether and dried (Na₂SO₄), filtered, and concentrated under reduced pressure to afford (41 mg, 37%) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.54 (s, 2H), 8.13 (d, <i>J</i> = 2.35 Hz, 1H), 7.72 (d, <i>J</i> = 2.35 Hz, 1H), 7.54 - 7.65 (m, 1H), 7.35 - 7.54 (m, 3H), 4.83 (t, <i>J</i> = 5.48 Hz, 1H), 4.18 - 4.30 (m, 2H), 3.79 - 3.93 (m, 4H), 3.60 - 3.74 (m, 2H); [M+H] = 372.38

Example 304. 5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-2-(difluoromethoxy)pyrimidine.

1048<chemistry id="chem0396" num="0396"><img file="EP3345902A1_D0401.tif" /></chemistry>

1049To a solution of 5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-ol (Example 306, 248.20 mg, 0.76 mmol) in ACN (5 mL) was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (87.26 µL, 0.83 mmol) and Na₂CO₃ (160.52 mg, 1.51 mmol). The suspension was stirred at rt for 48 h. The reaction mixture was filtered, diluted with EtOAc and washed with water. The organic phase was treated with brine, dried (Na₂SO₄), filtered and concentrated. Purification (FCC, SiO₂, 0-30% EtOAc/hexanes) afforded the title compound as a colorless oil (17 mg, 6 %). ¹H NMR (400 MHz, CDCl₃) δ 8.45 (s, 2H), 8.04 (d, <i>J</i> = 2.35 Hz, 1H), 7.49 (t, <i>J</i> = 36 Hz, 1H), 7.29 - 7.22 (m, 5H), 3.96 (s, 3H), 3.93 (s, 2H); [M+H] = 378.35.

1050Examples 305 - 306 were prepared in a manner analogous to Example 1, with the appropriate starting material and reagent substitutions.

Example 305. 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-3-methylpyridazine.

1051<chemistry id="chem0397" num="0397"><img file="EP3345902A1_D0402.tif" /></chemistry>

1052¹H NMR (400MHz, CD₃OD) δ 8.97 (d, <i>J</i> = 2.0 Hz, 1H), 8.10 (d, <i>J</i> = 2.7 Hz, 1H), 7.63 (d, <i>J</i> = 2.3 Hz, 1H), 7.55 (s, 1H), 7.49 - 7.31 (m, 4H), 4.07 - 4.03 (m, 2H), 3.95 (s, 3H), 2.65 - 2.61 (m, 3H); [M+H] = 326.

Example 306. 3-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-fluoropyridin-3-yl)methyl]pyridine.

1053<chemistry id="chem0398" num="0398"><img file="EP3345902A1_D0403.tif" /></chemistry>

1054¹H NMR (400MHz, CD₃OD) δ 8.39 - 8.35 (m, 1H), 8.34 - 8.31 (m, 1H), 8.23 - 8.19 (m, 1H), 8.12 (s, 1H), 7.77 - 7.73 (m, 1H), 7.57 - 7.19 (m, 4H), 4.47 - 4.38 (m, 2H), 4.11 - 4.05 (m, 2H), 1.36 (s, 3H); [M+H] = 376.

1055Examples 307 - 314 were prepared in a manner analogous to Example 127, with the appropriate starting material and reagent substitutions.

Eample 307. 1-{[5-(2-Cyanopyridin-4-yl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide.

1056<chemistry id="chem0399" num="0399"><img file="EP3345902A1_D0404.tif" /></chemistry>

1057¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.75 - 8.85 (m, 1H), 8.22 - 8.34 (m, 2H), 8.02 (d, <i>J</i> = 2.35 Hz, 1H), 7.86 - 7.99 (m, 2H), 7.42 (br s, 1H), 7.18 (br s, 1H), 6.62 (d, <i>J</i> = 2.35 Hz, 1H), 5.38 (s, 2H), 3.91 (s, 3H); [M+H] = 335.37.

Example 308. 1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide.

1058<chemistry id="chem0400" num="0400"><img file="EP3345902A1_D0405.tif" /></chemistry>

1059¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.19 (d, <i>J</i> = 2.3 Hz, 1H), 7.92 (d, <i>J</i> = 2.3 Hz, 1H), 7.78 (d, <i>J</i> = 2.3 Hz, 1H), 7.59 - 7.56 (m, 1H), 7.50 - 7.40 (m, 4H), 7.22 - 7.16 (m, 1H), 6.61 (d, <i>J</i> = 2.3 Hz, 1H), 5.39 - 5.34 (m, 2H), 3.87 (s, 3H); [M+H] = 343.

Example 309. 1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazole-3-carboxamide.

1060<chemistry id="chem0401" num="0401"><img file="EP3345902A1_D0406.tif" /></chemistry>

1061¹H NMR (400MHz, CD₃OD) δ 8.26 - 8.20 (m, 2H), 7.88 - 7.77 (m, 2H), 7.75 - 7.55 (m, 1H), 7.41 - 7.36 (m, 1H), 7.18 (dd, <i>J</i> = 0.8, 1.6 Hz, 1H), 6.76 (s, 1H), 5.41 (s, 2H), 3.98 (s, 3H); [M+H] = 376.

Example 310. 1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-imidazole-4-carboxamide.

1062<chemistry id="chem0402" num="0402"><img file="EP3345902A1_D0407.tif" /></chemistry>

1063¹H NMR (400MHz, CDCl₃) δ 8.07 (d, <i>J</i> = 2.3 Hz, 1H), 7.57 (d, <i>J</i> = 1.6 Hz, 1H), 7.52 - 7.48 (m, 2H), 7.41 (d, <i>J</i> = 2.3 Hz, 1H), 7.40 - 7.29 (m, 3H), 7.03 - 6.87 (m, 1H), 5.71 - 5.58 (m, 1H), 5.09 (s, 2H), 4.43 (d, <i>J</i> = 7.0 Hz, 2H), 1.37 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 357.

Example 311. 1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-imidazole-4-carboxamide.

1064<chemistry id="chem0403" num="0403"><img file="EP3345902A1_D0408.tif" /></chemistry>

1065¹H NMR (400MHz, CD₃OD) δ 8.27 - 8.21 (m, 2H), 7.86 - 7.81 (m, 2H), 7.75 - 7.56 (m, 2H), 7.43 - 7.40 (m, 1H), 5.33 - 5.25 (m, 2H), 4.50 - 4.41 (m, 2H), 1.41 - 1.33 (m, 3H); [M+H] = 390.

Example 312. 1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-imidazole-4-carboxamide.

1066<chemistry id="chem0404" num="0404"><img file="EP3345902A1_D0409.tif" /></chemistry>

1067¹H NMR (400MHz, CD₃OD) δ 8.18 (s, 1H), 8.10 - 8.06 (m, 1H), 8.04 - 7.98 (m, 1H), 7.89 - 7.85 (m, 1H), 7.80 (s, 1H), 7.43 (s, 2H), 5.39 (s, 2H), 4.58 - 4.47 (m, 2H), 1.44 (s, 3H); [M+H] = 358.

Example 313. 1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-pyrazole-3-carboxamide.

1068<chemistry id="chem0405" num="0405"><img file="EP3345902A1_D0410.tif" /></chemistry>

1069¹H NMR (400MHz, CD₃OD) δ 8.07 (m, 2H), 8.02 - 7.97 (m, 1H), 7.87 - 7.84 (m, 1H), 7.43 - 7.40 (m, 2H), 6.81 - 6.77 (m, 1H), 5.52 (s, 2H), 4.49 (q, <i>J</i> = 7.0 Hz, 2H), 1.43 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 358.

Example 314. 1-{[6-(3,4-Difluorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-imidazole-4-carboxamide.

1070<chemistry id="chem0406" num="0406"><img file="EP3345902A1_D0411.tif" /></chemistry>

1071¹H NMR (400MHz, CD₃OD) δ 8.17 (s, 1H), 8.04 (s, 2H), 7.90 - 7.78 (m, 2H), 7.33 (td, <i>J</i> = 8.6, 10.3 Hz, 1H), 5.38 (s, 2H), 4.58 - 4.49 (m, 2H), 1.45 (s, 3H); [M+H] = 360.

1072Examples 315 - 316 were prepared in a manner analogous to Example 198, with the appropriate starting material and reagent substitutions.

Example 315. [1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-2-methyl-1H-imidazol-4-yl]methanol.

1073<chemistry id="chem0407" num="0407"><img file="EP3345902A1_D0412.tif" /></chemistry>

1074¹H NMR (400MHz, CD₃OD) δ 8.25 - 8.21 (m, 1H), 8.11 (d, <i>J</i> = 2.3 Hz, 1H), 7.76 - 7.55 (m, 2H), 7.38 (dd, <i>J</i> = 1.4, 5.3 Hz, 1H), 7.17 (dd, <i>J</i> = 0.8, 1.6 Hz, 1H), 7.02 (s, 1H), 5.21 - 5.13 (m, 2H), 4.47 - 4.42 (m, 2H), 3.98 (s, 3H), 2.36 (s, 3H); [M+H] = 377.

Example 316. [1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-5-methyl-1H-pyrazol-3-yl]methanol.

1075<chemistry id="chem0408" num="0408"><img file="EP3345902A1_D0413.tif" /></chemistry>

1076¹H NMR (400MHz, CD₃OD) δ 8.23 - 8.20 (m, 1H), 8.05 - 8.02 (m, 1H), 7.56 (s, 2H), 7.38 - 7.35 (m, 1H), 7.18 - 7.14 (m, 1H), 6.20 - 6.11 (m, 1H), 5.28 (s, 2H), 4.51 (s, 2H), 3.96 (s, 3H), 2.30 (d, <i>J</i> = 0.8 Hz, 3H); [M+H] = 377.

Example 317. 1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-5-methyl-1H-pyrazol-3-amine.

1077<chemistry id="chem0409" num="0409"><img file="EP3345902A1_D0414.tif" /></chemistry>

1078The title compound was prepared in a manner analogous to Example 219, with the appropriate starting material and reagent substitutions. ¹H NMR (400MHz, CD₃OD) δ 7.90 (d, <i>J</i> = 2.3 Hz, 1H), 7.54 (t, <i>J</i> = 2.0 Hz, 1H), 7.48 (d, <i>J</i> = 2.3 Hz, 1H), 7.45 - 7.41 (m, 1H), 7.40 - 7.31 (m, 2H), 5.49 (d, <i>J</i> = 0.8 Hz, 1H), 5.07 (s, 2H), 4.38 (d, <i>J</i> = 7.0 Hz, 2H), 2.21 (s, 3H), 1.33 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 343.

Example 318. 1-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)oxy]-2-methylpropan-2-ol.

1079<chemistry id="chem0410" num="0410"><img file="EP3345902A1_D0415.tif" /></chemistry>

1080The title compound was prepared in a manner analogous to Example 245, with the appropriate starting material and reagent substitutions. ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.53 (s, 2H), 8.13 (d, <i>J</i> = 2.35 Hz, 1H), 7.72 (d, <i>J</i> = 2.35 Hz, 1H), 7.36 - 7.65 (m, 4H), 4.62 (s, 1H), 4.01 (s, 2H), 3.85 (s, 3H), 3.55 (s, 2H), 1.15 (s, 6H); [M+H] = 400.43.

1081Examples 319 - 326 were prepared in a manner analogous to Example 269, with the appropriate starting material and reagent substitutions.

Example 319. (1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-5-yl)methanol.

1082<chemistry id="chem0411" num="0411"><img file="EP3345902A1_D0416.tif" /></chemistry>

1083¹H NMR (400MHz, CD₃OD) δ 7.87 (d, <i>J</i> = 2.3 Hz, 1H), 7.56 - 7.30 (m, 5H), 6.85 (s, 1H), 5.27 (s, 2H), 4.53 (s, 2H), 4.39 (d, <i>J</i> = 7.0 Hz, 2H), 2.31 (s, 3H), 1.33 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 358.

Example 320. (1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-3-methyl-1H-pyrazol-5-yl)methanol.

1084<chemistry id="chem0412" num="0412"><img file="EP3345902A1_D0417.tif" /></chemistry>

1085¹H NMR (400MHz, CD₃OD) δ 8.00 (d, <i>J</i> = 2.3 Hz, 1H), 7.60 (d, <i>J</i> = 2.3 Hz, 1H), 7.55 (s, 1H), 7.46 - 7.30 (m, 3H), 6.10 - 6.05 (m, 1H), 5.29 (s, 2H), 4.59 (s, 2H), 4.38 (d, <i>J</i> = 7.0 Hz, 2H), 2.20 (s, 3H), 1.33 (s, 3H); [M+H] = 358.

Example 321. (1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol.

1086<chemistry id="chem0413" num="0413"><img file="EP3345902A1_D0418.tif" /></chemistry>

1087¹H NMR (400MHz, CD₃OD) δ 8.10 - 8.06 (m, 1H), 7.80 - 7.42 (m, 6H), 7.06 - 7.02 (m, 1H), 5.24 - 5.21 (m, 2H), 4.48 - 4.44 (m, 2H), 2.36 (s, 3H); [M+H] = 380.

Example 322. (1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol .

1088<chemistry id="chem0414" num="0414"><img file="EP3345902A1_D0419.tif" /></chemistry>

1089¹H NMR (400MHz, CDCl₃) δ 7.99 - 7.96 (m, 1H), 7.88 (ddd, <i>J</i> = 1.6, 3.6, 5.4 Hz, 1H), 7.75 (s, 1H), 7.31 (d, <i>J</i> = 1.2 Hz, 2H), 6.84 - 6.79 (m, 1H), 5.03 (s, 2H), 4.49 - 4.38 (m, 2H), 3.94 (s, 3H), 2.36 (s, 3H); [M+H] = 345.

Example 323. (1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-5-methyl-1H-pyrazol-3-yl)methanol.

1090<chemistry id="chem0415" num="0415"><img file="EP3345902A1_D0420.tif" /></chemistry>

1091¹H NMR (400MHz, CD₃OD) δ 8.10 - 8.06 (m, 1H), 8.05 - 7.97 (m, 1H), 7.90 (s, 1H), 7.45 - 7.40 (m, 2H), 6.19 - 6.13 (m, 1H), 5.37 (s, 2H), 4.55 - 4.44 (m, 4H), 2.42 (d, <i>J</i> = 0.8 Hz, 3H), 1.43 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 359.

Example 324. (1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol.

1092<chemistry id="chem0416" num="0416"><img file="EP3345902A1_D0421.tif" /></chemistry>

1093¹H NMR (400MHz, CD₃OD) δ 8.05 (m, 3H), 7.45 - 7.40 (m, 2H), 7.08 - 7.02 (m, 1H), 5.24 (s, 2H), 4.56 - 4.47 (m, 2H), 4.46 - 4.43 (m, 2H), 2.45 (s, 3H), 1.44 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 359.38.

Example 325. (1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-5-methyl-1H-pyrazol-3-yl)methanol.

1094<chemistry id="chem0417" num="0417"><img file="EP3345902A1_D0422.tif" /></chemistry>

1095¹H NMR (400MHz, CD₃OD) δ 7.94 (d, <i>J</i> = 2.3 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.45 - 7.31 (m, 3H), 6.13 (s, 1H), 5.27 (s, 2H), 4.51 (s, 2H), 4.39 (d, <i>J</i> = 7.0 Hz, 2H), 2.30 (d, <i>J</i> = 0.8 Hz, 3H), 1.33 (s, 3H); [M+H] = 358.

Example 326. (1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol.

1096<chemistry id="chem0418" num="0418"><img file="EP3345902A1_D0423.tif" /></chemistry>

1097¹H NMR (400MHz, CD₃OD) δ 8.01 (d, <i>J</i> = 2.3 Hz, 1H), 7.57 - 7.53 (m, 2H), 7.46 - 7.32 (m, 3H), 7.01 (s, 1H), 5.16 - 5.11 (m, 2H), 4.44 (d, <i>J</i> = 0.8 Hz, 4H), 2.36 (s, 3H), 1.34 (s, 4H); [M+H] = 358.

1098Examples 327 - 346 were prepared in a manner analogous to Example 277, with the appropriate starting material and reagent substitutions.

Example 327. (1-{[6-Ethoxy-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol.

1099<chemistry id="chem0419" num="0419"><img file="EP3345902A1_D0424.tif" /></chemistry>

1100¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.62 (s, 1H), 8.15 (d, <i>J</i> = 2.3 Hz, 1H), 7.76 (d, <i>J</i> = 2.3 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.13 - 7.05 (m, 2H), 6.94 - 6.88 (m, 1H), 5.41 - 5.38 (m, 1H), 5.35 (s, 2H), 4.39 - 4.21 (m, 4H), 3.76 (s, 3H), 1.27 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 341.37.

Example 328. (1-{[5-(4-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol.

1101<chemistry id="chem0420" num="0420"><img file="EP3345902A1_D0425.tif" /></chemistry>

1102¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.60 (s, 1H), 8.17 (d, <i>J</i> = 2.3 Hz, 1H), 7.76 (d, <i>J</i> = 2.3 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.52 - 7.45 (m, 2H), 5.34 (s, 2H), 4.41 - 4.24 (m, 5H), 1.26 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 345.12.

Example 329. (1-{[5-(5-Chloropyridin-3-yl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol.

1103<chemistry id="chem0421" num="0421"><img file="EP3345902A1_D0426.tif" /></chemistry>

1104¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.72 (d, <i>J</i> = 2.0 Hz, 1H), 8.61 (s, 1H), 8.24 (d, <i>J</i> = 2.3 Hz, 1H), 8.14 - 8.11 (m, 1H), 8.02 (d, <i>J</i> = 2.3 Hz, 1H), 7.94 (d, <i>J</i> = 2.3 Hz, 1H), 5.36 (s, 2H), 4.43 - 4.26 (m, 7H), 1.29 - 1.24 (m, 3H); [M+H] = 346.25.

Example 330. (1-{[5-(3,4-Dichlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol.

1105<chemistry id="chem0422" num="0422"><img file="EP3345902A1_D0427.tif" /></chemistry>

1106¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.54 (s, 1H), 8.19 (d, <i>J</i> = 2.3 Hz, 1H), 7.85 (d, <i>J</i> = 2.3 Hz, 1H), 7.82 (d, <i>J</i> = 2.0 Hz, 1H), 7.69 (d, <i>J</i> = 8.6 Hz, 1H), 7.59 - 7.53 (m, 2H), 5.34 (s, 2H), 5.15 (t, <i>J</i> = 6.1 Hz, 1H), 4.41 - 4.30 (m, 4H), 1.27 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 379.25.

Example 331. (1-{[6-Ethoxy-5-(4-fluoro-3-methylphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol.

1107<chemistry id="chem0423" num="0423"><img file="EP3345902A1_D0428.tif" /></chemistry>

1108¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.62 (s, 1H), 8.14 (d, <i>J</i> = 2.3 Hz, 1H), 7.73 (d, <i>J</i> = 2.3 Hz, 1H), 7.46 - 7.32 (m, 2H), 7.18 (dd, <i>J</i> = 8.4, 9.6 Hz, 1H), 5.34 (s, 2H), 4.43 - 4.22 (m, 4H), 2.26 (d, <i>J</i> = 2.0 Hz, 3H), 1.26 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 343.25.

Example 332. [1-({6-Ethoxy-5-[3-(trifluoromethyl)phenyl]pyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol.

1109<chemistry id="chem0424" num="0424"><img file="EP3345902A1_D0429.tif" /></chemistry>

1110¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.58 (s, 1H), 8.21 (d, <i>J</i> = 2.3 Hz, 1H), 7.94 - 7.83 (m, 3H), 7.75 - 7.61 (m, 2H), 5.36 (s, 2H), 4.44 - 4.27 (m, 6H), 1.26 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 379.20.

Example 333. [1-({6-Ethoxy-5-[3-(trifluoromethoxy)phenyl]pyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol .

1111<chemistry id="chem0425" num="0425"><img file="EP3345902A1_D0430.tif" /></chemistry>

1112¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.59 (s, 1H), 8.19 (d, <i>J</i> = 2.3 Hz, 1H), 7.84 (d, <i>J</i> = 2.3 Hz, 1H), 7.63 - 7.51 (m, 3H), 7.40 - 7.29 (m, 1H), 5.35 (s, 2H), 4.44 - 4.18 (m, 6H), 1.27 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 395.25.

Example 334. (1-{[6-Ethoxy-5-(3-ethoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol.

1113<chemistry id="chem0426" num="0426"><img file="EP3345902A1_D0431.tif" /></chemistry>

1114¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.61 (s, 1H), 8.14 (d, <i>J</i> = 2.3 Hz, 1H), 7.75 (d, <i>J</i> = 2.3 Hz, 1H), 7.36 - 7.28 (m, 1H), 7.12 - 7.02 (m, 2H), 6.90 (ddd, <i>J</i> = 1.2, 2.3, 8.2 Hz, 1H), 5.34 (s, 2H), 4.40 - 4.29 (m, 4H), 4.04 (q, <i>J</i> = 7.0 Hz, 2H), 1.32 (t, <i>J</i> = 6.8 Hz, 3H), 1.27 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 355.25.

Example 335. [1-({5-[3-(Dimethylammo)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methano l.

1115<chemistry id="chem0427" num="0427"><img file="EP3345902A1_D0432.tif" /></chemistry>

1116¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.63 (s, 1H), 8.14 (d, <i>J</i> = 2.3 Hz, 1H), 7.74 (d, <i>J</i> = 2.3 Hz, 1H), 7.34 - 7.23 (m, 1H), 7.09 (br s, 1H), 7.00 - 6.85(m, 2H), 5.35 (s, 2H), 4.37 (s, 2H), 4.33 (q, <i>J</i> = 7.0 Hz, 2H), 2.96 (s, 7H), 1.27 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 354.25.

Example 336. (1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol.

1117<chemistry id="chem0428" num="0428"><img file="EP3345902A1_D0433.tif" /></chemistry>

1118¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.55 (s, 1H), 8.21 (d, <i>J</i> = 2.3 Hz, 1H), 7.81 (d, <i>J</i> = 2.3 Hz, 1H), 7.59 - 7.56 (m, 1H), 7.51 - 7.39 (m, 3H), 5.35 (s, 2H), 5.15 (t, <i>J</i> = 6.1 Hz, 1H), 4.36 (d, <i>J</i> = 5.9 Hz, 2H), 3.87 (s, 3H); [M+H] = 331.77.

Example 337. (1-{[5-(3-Chloro-4-fluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol.

1119<chemistry id="chem0429" num="0429"><img file="EP3345902A1_D0434.tif" /></chemistry>

1120¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.54 (s, 1H), 8.18 (d, <i>J</i> = 2.3 Hz, 1H), 7.82 (d, <i>J</i> = 2.3 Hz, 1H), 7.77 (dd, <i>J</i> = 2.2, 7.2 Hz, 1H), 7.60 - 7.54 (m, 1H), 7.51 - 7.44 (m, 1H), 5.33 (s, 2H), 5.15 (t, <i>J</i> = 6.1 Hz, 1H), 4.39 - 4.30 (m, 5H), 1.32 - 1.21 (m, 4H); [M+H] = 363.25.

Example 338. (1-{[5-(3,5-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol.

1121<chemistry id="chem0430" num="0430"><img file="EP3345902A1_D0435.tif" /></chemistry>

1122¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.56 (s, 1H), 8.22 (d, <i>J</i> = 2.26 Hz, 1H), 7.89 (d, <i>J</i> = 2.26 Hz, 1H), 7.33 (dd, <i>J</i> = 8.97, 2.20 Hz, 2H), 7.26 (d, <i>J</i> = 2.26 Hz, 1H), 5.35 (s, 2H), 5.18 (t, <i>J</i> = 6.02 Hz, 1H), 4.32 - 4.45 (m, 4H), 1.30 (t, <i>J</i> = 7.03 Hz, 3H); [M+H] = 347.3.

Example 339. [1-({6-Ethoxy-5-[2-(trifluoromethyl)pyridin-4-yl]pyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol.

1123<chemistry id="chem0431" num="0431"><img file="EP3345902A1_D0436.tif" /></chemistry>

1124¹H NMR (400 MHz, CD₃OD) δ 8.74 (d, <i>J</i> = 5.48 Hz, 1H), 8.54 (s, 1H), 8.30 (d, <i>J</i> = 2.35 Hz, 1H), 8.10 (d, <i>J</i> = 1.17 Hz, 1H), 7.98 (d, <i>J</i> = 2.35 Hz, 1H), 7.88 (dd, <i>J</i> = 5.09, 1.57 Hz, 1H), 5.43 (s, 2H), 4.59 (s, 2H), 4.47 (q, <i>J</i> = 7.04 Hz, 2H), 1.37 (t, <i>J</i> = 7.04 Hz, 3H); [M+H] = 380.3.

Example 340. (1-{[5-(3,4-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol.

1125<chemistry id="chem0432" num="0432"><img file="EP3345902A1_D0437.tif" /></chemistry>

1126¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.56 (s, 1H), 8.19 (d, <i>J</i> = 2.38 Hz, 1H), 7.82 (d, <i>J</i> = 2.26 Hz, 1H), 7.61 - 7.69 (m, 1H), 7.39 - 7.56 (m, 2H), 5.35 (s, 2H), 5.18 (t, <i>J</i> = 6.02 Hz, 1H), 4.31 - 4.42 (m, 4H), 1.29 (t, <i>J</i> = 7.03 Hz, 3H); [M+H] = 347.3.

Example 341. (1-{[6-Ethoxy-5-(3-fluorophenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol.

1127<chemistry id="chem0433" num="0433"><img file="EP3345902A1_D0438.tif" /></chemistry>

1128¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.57 (s, 1H), 8.20 (d, <i>J</i> = 2.26 Hz, 1H), 7.83 (d, <i>J</i> = 2.38 Hz, 1H), 7.45 - 7.53 (m, 1H), 7.37 - 7.44 (m, 2H), 7.17 - 7.25 (m, 1H), 5.36 (s, 2H), 5.18 (t, <i>J</i> = 6.02 Hz, 1H), 4.30 - 4.45 (m, 4H), 1.29 (t, <i>J</i> = 7.03 Hz, 3H); [M+H] = 329.4.

Example 342. (1-{[6-Ethoxy-5-(4-fluorophenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol.

1129<chemistry id="chem0434" num="0434"><img file="EP3345902A1_D0439.tif" /></chemistry>

1130¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.57 (s, 1H), 8.17 (d, <i>J</i> = 2.26 Hz, 1H), 7.76 (d, <i>J</i> = 2.26 Hz, 1H), 7.53 - 7.66 (m, 2H), 7.22 - 7.32 (m, 2H), 5.35 (s, 2H), 5.18 (t, <i>J</i> = 6.02 Hz, 1H), 4.30 - 4.43 (m, 4H), 1.28 (t, <i>J</i> = 7.03 Hz, 3H); [M+H] = 329.4.

Example 343. (1-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol.

1131<chemistry id="chem0435" num="0435"><img file="EP3345902A1_D0440.tif" /></chemistry>

1132¹H NMR (400MHz, CD₃OD) δ 8.03 - 8.00 (m, 1H), 7.57 - 7.53 (m, 1H), 7.25 - 7.20 (m, 1H), 7.14 - 6.99 (m, 3H), 5.18 - 5.13 (m, 2H), 4.48 - 4.43 (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 2.37 (s, 3H); [M+H] = 358.

Example 344. (1-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol.

1133<chemistry id="chem0436" num="0436"><img file="EP3345902A1_D0441.tif" /></chemistry>

1134¹H NMR (400MHz, CD₃OD) δ 8.03 - 7.99 (m, 1H), 7.55 - 7.48 (m, 3H), 7.12 (t, <i>J</i> = 8.8 Hz, 2H), 7.01 (s, 1H), 5.13 (s, 2H), 4.44 (d, <i>J</i> = 0.8 Hz, 2H), 3.93 (s, 3H), 2.35 (s, 3H); [M+H] = 328.

Example 345. (1-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol.

1135<chemistry id="chem0437" num="0437"><img file="EP3345902A1_D0442.tif" /></chemistry>

1136¹H NMR (400MHz, CD₃OD) δ 8.04 (d, <i>J</i> = 2.3 Hz, 1H), 7.56 (d, <i>J</i> = 2.3 Hz, 1H), 7.51 - 7.44 (m, 1H), 7.30 (dd, <i>J</i> = 1.6, 6.7 Hz, 2H), 7.02 (s, 1H), 5.16 - 5.12 (m, 2H), 4.44 (s, 2H), 3.95 (s, 3H), 2.36 (s, 3H); [M+H] = 346.

Example 346. (1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol.

1137<chemistry id="chem0438" num="0438"><img file="EP3345902A1_D0443.tif" /></chemistry>

1138¹H NMR (400MHz, CD₃OD) δ 8.03 (d, <i>J</i> = 2.3 Hz, 1H), 7.57 - 7.51 (m, 2H), 7.44 - 7.32 (m, 3H), 7.01 (s, 1H), 5.14 (s, 2H), 4.45 (d, <i>J</i> = 0.8 Hz, 2H), 3.94 (s, 3H), 2.36 (s, 3H); [M+H] = 344.

1139Examples 347 - 349 were prepared in a manner analogous to Intermediate 21, with the appropriate starting material and reagent substitutions.

Example 347. 4-{5-[(2-Ammopyrimidin-5-yl)methyl]-2-methoxypyridin-3-yl}pyridine-2-carbonitrile.

1140<chemistry id="chem0439" num="0439"><img file="EP3345902A1_D0444.tif" /></chemistry>

1141¹H NMR (400 MHz, DMSO-d 6) δ 8.69 - 8.83 (m, 1H), 8.26 (dd, <i>J</i> = 1.57, 0.78 Hz, 1H), 8.08 - 8.24 (m, 3H), 7.92 - 8.03 (m, 1H), 7.90 (d, <i>J</i> = 2.35 Hz, 1H), 6.44 (s, 2H), 3.89 (s, 3H), 3.73 (s, 2H); [M+H] = 319.37.

Example 348. 2-(5-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetonitrile.

1142<chemistry id="chem0440" num="0440"><img file="EP3345902A1_D0445.tif" /></chemistry>

1143¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.74 - 8.86 (m, 2H), 8.17 (d, <i>J</i> = 2.35 Hz, 1H), 7.80 - 7.91 (m, 1H), 7.65 (t, <i>J</i> = 1.57 Hz, 1H), 7.30 - 7.60 (m, 3H), 6.13 - 6.54 (m, 1H), 4.49 - 4.71 (m, 2H), 4.34 (s, 1H), 4.01 (s, 2H), 3.22 - 3.32 (m, 1H); [M+H] = 401.38.

Example 349. 5-{[5-(2-Ethoxypyridin-4-yl)-6-methoxypydin-3-yl]methyl}pyrimidin-2-amine.

1144<chemistry id="chem0441" num="0441"><img file="EP3345902A1_D0446.tif" /></chemistry>

1145¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.25 - 8.07 (m, 4H), 7.75 (d, <i>J</i> = 2.3 Hz, 1H), 7.13 (dd, <i>J</i> = 1.6, 5.5 Hz, 1H), 6.88 (s, 1H), 6.44 (br. s, 2H), 4.31 (q, <i>J</i> = 7.0 Hz, 2H), 3.86 (s, 3H), 3.71 (s, 2H), 1.31 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 338.21.

1146Examples 350 - 362 were prepared in a manner analogous to Intermediate 24, with the appropriate starting material and reagent substitutions.

Example 350. 5-{[6-Ethoxy-5-(4-fluorophenyl)pyridin-3-yl]methyl}pyrimidin-2-amine.

1147<chemistry id="chem0442" num="0442"><img file="EP3345902A1_D0447.tif" /></chemistry>

1148¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.35 (s, 2H), 8.06 (d, <i>J</i> = 2.3 Hz, 1H), 7.64 (d, <i>J</i> = 2.3 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.28 - 7.19 (m, 2H), 4.31 (q, <i>J</i> = 7.0 Hz, 2H), 3.77 (s, 2H), 1.25 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 325.25.

Example 351. 5-{[5-(4-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine.

1149<chemistry id="chem0443" num="0443"><img file="EP3345902A1_D0448.tif" /></chemistry>

1150¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.36 (s, 2H), 8.07 (d, <i>J</i> = 2.3 Hz, 1H), 7.66 (d, <i>J</i> = 2.3 Hz, 1H), 7.60 - 7.54 (m, 3H), 7.51 - 7.43 (m, 3H), 4.31 (q, <i>J</i> = 7.0 Hz, 2H), 3.77 (s, 2H), 1.25 (t, <i>J</i> = 7.0 Hz, 4H); [M+H] = 341.25.

Example 352. 5- {[6-Ethoxy-5-(4-fluoro-3-methylphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine.

1151<chemistry id="chem0444" num="0444"><img file="EP3345902A1_D0449.tif" /></chemistry>

1152¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.33 (s, 2H), 8.04 (d, <i>J</i> = 2.3 Hz, 1H), 7.62 (d, <i>J</i> = 2.3 Hz, 1H), 7.47 - 7.34 (m, 3H), 7.20 - 7.12 (m, 2H), 4.31 (q, <i>J</i> = 7.0 Hz, 2H), 3.75 (s, 2H), 2.25 (d, <i>J</i> = 2.0 Hz, 3H), 1.29 - 1.20 (m, 3H); [M+H] = 339.25.

Example 353. 5-{[5-(3,4-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine.

1153<chemistry id="chem0445" num="0445"><img file="EP3345902A1_D0450.tif" /></chemistry>

1154¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.34 (s, 2H), 8.08 (d, <i>J</i> = 2.3 Hz, 1H), 7.70 (d, <i>J</i> = 2.3 Hz, 1H), 7.64 (ddd, <i>J</i> = 2.3, 8.0, 12.3 Hz, 1H), 7.52 - 7.38 (m, 2H), 4.33 (q, <i>J</i> = 7.0 Hz, 2H), 3.77 (s, 2H), 1.27 (t, <i>J</i> = 7.0 Hz, 3H); [M+H] = 343.25.

Example 354. 5-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine.

1155<chemistry id="chem0446" num="0446"><img file="EP3345902A1_D0451.tif" /></chemistry>

1156¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.37 (s, 2H), 8.08 (d, <i>J</i> = 2.3 Hz, 1H), 7.67 (d, <i>J</i> = 2.3 Hz, 1H), 7.30 - 7.25 (m, 1H), 7.25 - 7.19 (m, 1H), 7.07 (ddd, <i>J</i> = 2.2, 4.4, 8.3 Hz, 1H), 3.84 (s, 6H), 3.79 (s, 2H); [M+H] = 341.25.

Example 355. 5-{[5-(3-Ethoxy-4-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine.

1157<chemistry id="chem0447" num="0447"><img file="EP3345902A1_D0452.tif" /></chemistry>

1158¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.36 - 8.30 (m, 2H), 8.09 - 8.04 (m, 1H), 7.65 (d, <i>J</i> = 2.3 Hz, 1H), 7.30 - 7.19 (m, 3H), 7.06 (ddd, <i>J</i> = 2.3, 4.5, 8.4 Hz, 1H), 4.11 (q, <i>J</i> = 7.0 Hz, 2H), 3.86 - 3.82 (m, 3H), 3.77 (s, 2H), 1.38 - 1.29 (m, 3H); [M+H] = 355.15.

Example 356. 3-{5-[(2-Aminopyrimidin-5-yl)methyl]-2-methoxypyridin-3-yl}benzonitrile.

1159<chemistry id="chem0448" num="0448"><img file="EP3345902A1_D0453.tif" /></chemistry>

1160¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.37 - 8.26 (m, 2H), 8.14 (d, <i>J</i> = 2.3 Hz, 1H), 7.99 (t, <i>J</i> = 1.8 Hz, 1H), 7.89 (td, <i>J</i> = 1.5, 7.6 Hz, 1H), 7.81 (td, <i>J</i> = 1.3, 8.0 Hz, 1H), 7.76 (d, <i>J</i> = 2.3 Hz, 1H), 7.62 (t, <i>J</i> = 7.8 Hz, 1H), 3.86 (s, 3H), 3.78 (s, 2H); [M+H] = 318.25.

Example 357. 5-{[5-(4-Fluoro-3-methylphenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine.

1161<chemistry id="chem0449" num="0449"><img file="EP3345902A1_D0454.tif" /></chemistry>

1162¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.34 (s, 2H), 8.07 (d, <i>J</i> = 2.3 Hz, 1H), 7.62 (d, <i>J</i> = 2.3 Hz, 1H), 7.44 - 7.31 (m, 3H), 7.16 (dd, <i>J</i> = 8.4, 9.6 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 2H), 2.25 (d, <i>J</i> = 1.6 Hz, 3H); [M+H] = 325.15.

Example 358. 2-(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetonitrile.

1163<chemistry id="chem0450" num="0450"><img file="EP3345902A1_D0455.tif" /></chemistry>

1164¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.81 - 8.76 (m, 2H), 8.16 (d, <i>J</i> = 2.3 Hz, 1H), 7.76 (d, <i>J</i> = 2.3 Hz, 1H), 7.63 (ddd, <i>J</i> = 2.2, 7.9, 12.2 Hz, 1H), 7.47 (td, <i>J</i> = 8.5, 10.9 Hz, 1H), 7.42 - 7.34 (m, 1H), 4.34 (s, 2H), 3.98 (s, 2H), 3.85 (s, 3H); [M+H] = 353.35.

Example 359. 5-{[5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine.

1165<chemistry id="chem0451" num="0451"><img file="EP3345902A1_D0456.tif" /></chemistry>

1166¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.35 (s, 2H), 8.11 (d, <i>J</i> = 2.3 Hz, 1H), 7.77 - 7.68 (m, 2H), 7.55 (ddd, <i>J</i> = 2.2, 4.9, 8.6 Hz, 1H), 7.51 - 7.43 (m, 1H), 3.85 (s, 3H), 3.78 (s, 2H); [M+H] = 345.25.

Example 360. 5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine.

1167<chemistry id="chem0452" num="0452"><img file="EP3345902A1_D0457.tif" /></chemistry>

1168¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.36 (s, 2H), 8.09 (d, <i>J</i> = 2.3 Hz, 1H), 7.64 (d, <i>J</i> = 2.3 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.28 - 7.19 (m, 2H), 3.85 - 3.83 (m, 3H), 3.78 (s, 2H); [M+H] = 311.36.

Example 361. 5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine.

1169<chemistry id="chem0453" num="0453"><img file="EP3345902A1_D0458.tif" /></chemistry>

1170¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.35 (s, 2H), 8.13 (d, <i>J</i> = 2.3 Hz, 1H), 7.73 (d, <i>J</i> = 2.3 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.45 - 7.39 (m, 1H), 3.86 (s, 3H), 3.78 (s, 2H); [M+H] = 345.21.

Example 362. 5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine.

1171<chemistry id="chem0454" num="0454"><img file="EP3345902A1_D0459.tif" /></chemistry>

1172¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.34 (s, 2H), 8.11 (d, <i>J</i> = 2.3 Hz, 1H), 7.70 (d, <i>J</i> = 2.3 Hz, 1H), 7.62 (ddd, <i>J</i> = 2.2, 7.9, 12.2 Hz, 1H), 7.47 (td, <i>J</i> = 8.5, 10.9 Hz, 1H), 7.42 - 7.34 (m, 2H), 3.85 (s, 3H), 3.77 (s, 2H); [M+H] = 329.39.

1173Examples 363 - 365 were prepared in a manner analogous to Example 280, with the appropriate starting material and reagent substitutions.

Example 363. 2-(4-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide.

1174<chemistry id="chem0455" num="0455"><img file="EP3345902A1_D0460.tif" /></chemistry>

1175¹H NMR (400MHz, CD₃OD) δ 8.09 (d, <i>J</i> = 2.0 Hz, 1H), 7.66 (d, <i>J</i> = 2.3 Hz, 1H), 7.62 (ddd, <i>J</i> = 2.2, 7.9, 12.2 Hz, 1H), 7.47 (td, <i>J</i> = 8.6, 11.0 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.23 - 7.13 (m, 5H), 6.82 (br s, 1H), 3.90 (s, 2H), 3.86 (s, 3H), 3.30 (s, 2H); [M+H] = 369.40.

Example 364. 2-(4-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide.

1176<chemistry id="chem0456" num="0456"><img file="EP3345902A1_D0461.tif" /></chemistry>

1177¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.05 (d, <i>J</i> = 2.0 Hz, 1H), 7.57 (d, <i>J</i> = 2.3 Hz, 1H), 7.56 - 7.49 (m, 2H), 7.38 (br s, 1H), 7.26 - 7.20 (m, 2H), 7.20 - 7.12 (m, 4H), 6.80 (br s, 1H), 3.88 (s, 2H), 3.82 (s, 3H), 3.29 (s, 2H); [M+H] = 351.25.

Example 365. 2-(4-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide.

1178<chemistry id="chem0457" num="0457"><img file="EP3345902A1_D0462.tif" /></chemistry>

1179¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.09 (d, <i>J</i> = 2.3 Hz, 1H), 7.68 (d, <i>J</i> = 2.3 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.42 - 7.34 (m, 2H), 7.22 - 7.11 (m, 4H), 6.80 (br s, 1H), 3.89 (s, 2H), 3.84 (s, 3H), 3.28 (s, 2H); [M+H] = 385.26.

1180Examples 366 - 372 were prepared in a manner analogous to Example 281, with the appropriate starting material and reagent substitutions.

Example 366. 2-(5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide.

1181<chemistry id="chem0458" num="0458"><img file="EP3345902A1_D0463.tif" /></chemistry>

1182¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.69 (s, 2H), 8.17 (d, <i>J</i> = 2.3 Hz, 1H), 7.80 (d, <i>J</i> = 2.3 Hz, 1H), 7.65 - 7.58 (m, 3H), 7.44 - 7.40 (m, 2H), 3.94 (s, 2H), 3.85 (s, 4H), 3.66 (s, 3H); [M+H] = 387.25.

Example 367. 2-(5- {[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)-2-methylpropanamide.

1183<chemistry id="chem0459" num="0459"><img file="EP3345902A1_D0464.tif" /></chemistry>

1184¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.71 (s, 2H), 8.15 (d, <i>J</i> = 2.3 Hz, 1H), 7.78 (d, <i>J</i> = 2.3 Hz, 1H), 7.61 - 7.57 (m, 1H), 7.52 - 7.48 (m, 1H), 7.47 - 7.38 (m, 2H), 6.82 (br s, 2H), 3.94 (s, 2H), 3.30 (s, 2H), 1.45 (s, 7H); [M+H] = 397.40.

Example 368. 2-(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide.

1185<chemistry id="chem0460" num="0460"><img file="EP3345902A1_D0465.tif" /></chemistry>

1186¹H NMR (400MHz, CD₃OD) δ 8.71 (s, 1H), 8.19 - 8.15 (m, 1H), 7.78 (d, <i>J</i> = 2.3 Hz, 1H), 7.69 - 7.60 (m, 1H), 7.51 - 7.44 (m, 2H), 7.43 - 7.35 (m, 2H), 6.97 (br s, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.67 (s, 2H); [M+H] = 371.40.

Example 369. 2-(5- {[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide.

1187<chemistry id="chem0461" num="0461"><img file="EP3345902A1_D0466.tif" /></chemistry>

1188¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.69 (s, 2H), 8.16 (d, <i>J</i> = 2.0 Hz, 1H), 7.76 (d, <i>J</i> = 2.0 Hz, 1H), 7.59 (s, 1H), 7.53 - 7.37 (m, 4H), 6.95 (br s, 1H), 3.94 (s, 2H), 3.84 (s, 3H), 3.65 (s, 2H); [M+H] = 369.35.

Example 370. 2-(5-{[5-(3-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetamide.

1189<chemistry id="chem0462" num="0462"><img file="EP3345902A1_D0467.tif" /></chemistry>

1190¹H NMR (400MHz, DMSO-<i>d</i>₆) δ = 8.71 (s, 2H), 8.20 (d, <i>J</i> = 2.3 Hz, 1H), 7.92 (d, <i>J</i> = 2.3 Hz, 1H), 7.68 - 7.59 (m, 1H), 7.57 - 7.38 (m, 4H), 6.96 (br s, 1H), 4.99 (q, <i>J</i> = 9.3 Hz, 2H), 3.98 (s, 2H), 3.66 (s, 2H); [M+H] = 437.39.

Example 371. 2-(5-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetamide.

1191<chemistry id="chem0463" num="0463"><img file="EP3345902A1_D0468.tif" /></chemistry>

1192¹H NMR (400MHz, DMSO-<i>d</i>₆) δ = 8.70 (s, 2H), 8.17 (d, <i>J</i> = 2.3 Hz, 1H), 7.87 (d, <i>J</i> = 2.3 Hz, 1H), 7.65 (t, <i>J</i> = 1.6 Hz, 1H), 7.60 - 7.51 (m, 1H), 7.51 - 7.35 (m, 3H), 6.96 (br s, 1H), 6.35 (t, <i>J</i> = 3.5 Hz, 1H), 4.58 (dt, <i>J</i> = 3.5, 15.1 Hz, 2H), 3.97 (s, 2H), 3.66 (s, 2H), 3.55 (s, 1H); [M+H] = 419.39.

Example 372. 2-(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)acetamide.

1193<chemistry id="chem0464" num="0464"><img file="EP3345902A1_D0469.tif" /></chemistry>

1194¹H NMR (400MHz, CD₃OD) δ 8.52 (s, 1H), 8.27 - 8.24 (m, 1H), 7.94 - 7.92 (m, 1H), 7.62 (s, 1H), 7.58 - 7.55 (m, 1H), 7.46 (s, 3H), 5.46 - 5.44 (m, 2H), 3.65 (s, 2H); [M+H] = 394.

1195Examples 373 - 374 were prepared in a manner analogous to Example 13, with the appropriate starting material and reagent substitutions.

Example 373. 5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide.

1196<chemistry id="chem0465" num="0465"><img file="EP3345902A1_D0470.tif" /></chemistry>

1197¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.88 (s, 2H), 8.18 (d, <i>J</i> = 2.3 Hz, 1H), 8.10 (br s, 1H), 7.78 (d, <i>J</i> = 2.3 Hz, 1H), 7.71 (br s, 1H), 7.63 (ddd, <i>J</i> = 2.2, 7.9, 12.2 Hz, 1H), 7.47 (td, <i>J</i> = 8.6, 10.7 Hz, 1H), 7.41 - 7.34 (m, 1H), 4.05 (s, 2H), 3.86 (s, 3H); [M+H] = 357.15.

Example 374. 5- {[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide.

1198<chemistry id="chem0466" num="0466"><img file="EP3345902A1_D0471.tif" /></chemistry>

1199¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.88 (s, 2H), 8.15 (d, J= 2.3 Hz, 1H), 8.10 (br s, 1H), 7.71 (d, <i>J</i> = 2.3 Hz, 2H), 7.60 - 7.52 (m, 2H), 7.28 - 7.19 (m, 2H), 4.05 (s, 2H), 3.84 (s, 3H); [M+H] = 339.15.

Example 375. 2-[(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-ol.

1200<chemistry id="chem0467" num="0467"><img file="EP3345902A1_D0472.tif" /></chemistry>

1201The title compound was prepared in a manner analogous to Example 3, with the appropriate starting material and reagent substitutions. ¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.20 (s, 2H), 8.08 (d, <i>J</i> = 2.3 Hz, 1H), 7.67 (d, <i>J</i> = 2.3 Hz, 1H), 7.62 (ddd, <i>J</i> = 2.2, 7.9, 12.2 Hz, 1H), 7.52 - 7.42 (m, 1H), 7.41 - 7.33 (m, 1H), 6.84 (t, <i>J</i> = 5.9 Hz, 1H), 4.63 - 4.56 (m, 1H), 3.85 (s, 3H), 3.72 (s, 2H), 3.45 (q, <i>J</i> = 6.1 Hz, 2H), 3.29 - 3.23 (m, 2H); [M+H] = 373.40.

1202Examples 376 - 378 were prepared in a manner analogous to Intermediate 55, with the appropriate starting material and reagent substitutions.

Example 376. (5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrazin-2-yl)methanol.

1203<chemistry id="chem0468" num="0468"><img file="EP3345902A1_D0473.tif" /></chemistry>

1204¹H NMR (400MHz, DMSO-<i>d</i>₆) δ 8.59 (d, <i>J</i> = 1.6 Hz, 2H), 8.17 - 8.13 (m, 1H), 7.78 - 7.72 (m, 1H), 7.61 - 7.57 (m, 1H), 7.52 - 7.40 (m, 3H), 5.57- 5.48 (m, 1H), 4.63 - 4.54 (m, 2H), 4.19 - 4.10 (m, 2H), 3.86 (s, 3H); [M+H] = 342.20.

Example 377. 2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-5-methylpyrazine.

1205<chemistry id="chem0469" num="0469"><img file="EP3345902A1_D0474.tif" /></chemistry>

1206¹H NMR (400 MHz, CD₃OD) δ 8.46 (d, <i>J</i> = 1.17 Hz, 1H), 8.43 (s, 1H), 8.08 (d, <i>J</i> = 2.35 Hz, 1H), 7.64 (d, <i>J</i> = 2.35 Hz, 1H), 7.52 (t, <i>J</i> = 1.57 Hz, 1H), 7.39-7.43 (m, 1H), 7.36 (t, <i>J</i> = 7.63 Hz, 1H), 7.32 (t, <i>J</i> = 1.96 Hz, 1H), 4.12 (s, 2H), 3.92 (s, 3H), 2.50 (s, 3H); [M+H] = 326.29.

Example 378. 6-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-3-carbonitrile.

1207<chemistry id="chem0470" num="0470"><img file="EP3345902A1_D0475.tif" /></chemistry>

1208¹H NMR (400 MHz, CDCl₃) δ 8.83 (dd, <i>J</i> = 0.78, 1.96 Hz, 1H), 8.09 (d, <i>J</i> = 2.35 Hz, 1H), 7.85-7.92 (m, 1H), 7.47-7.55 (m, 2H), 7.39-7.43 (m, 1H), 7.28-7.37 (m, 3H), 4.19 (s, 2H), 3.95-3.98 (m, 3H); [M+H] = 336.34.

Example 379. 5- {[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrazin-2-amine.

1209<chemistry id="chem0471" num="0471"><img file="EP3345902A1_D0476.tif" /></chemistry>

1210The title compound was prepared in a manner analogous to Example 287, employing <i>tert</i>-butyl (5-((5-(3-chloro-4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-yl)carbamate (Intermediate 56). ¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, <i>J</i> = 2.35 Hz, 1H), 7.95 (d, <i>J</i> = 1.56 Hz, 1H), 7.91 (d, <i>J</i> = 1.17 Hz, 1H), 7.49 (d, <i>J</i> = 2.35 Hz, 1H), 7.35-7.44 (m, 2H), 7.26 (dd, <i>J</i> = 0.78, 1.96 Hz, 1H), 4.54 (br s, 2H), 3.98 (s, 2H), 3.96 (s, 3H); [M+H] = 345.35.

1211Examples 380 - 388 were prepared in a manner analogous to Intermediate 32, with the appropriate starting material and reagent substitutions.

Example 380. 3-(3-Chlorophenyl)-2-methoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine.

1212<chemistry id="chem0472" num="0472"><img file="EP3345902A1_D0477.tif" /></chemistry>

1213¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, <i>J</i> = 2.35 Hz, 1H), 7.52 (d, <i>J</i> = 2.35 Hz, 1H), 7.47-7.50 (m, 1H), 7.31-7.38 (m, 3H), 5.47 (s, 2H), 3.97 (s, 3H), 2.55 (s, 3H); [M+H] = 313.36.

Example 381. (2-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol.

1214<chemistry id="chem0473" num="0473"><img file="EP3345902A1_D0478.tif" /></chemistry>

1215¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, <i>J</i> = 2.35 Hz, 1H), 7.65 (d, <i>J</i> = 2.35 Hz, 1H), 7.45-7.53 (m, 2H), 7.08-7.16 (m, 2H), 5.75 (s, 2H), 4.94 (s, 2H), 3.98 (s, 3H);.

Example 382. (1-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol.

1216<chemistry id="chem0474" num="0474"><img file="EP3345902A1_D0479.tif" /></chemistry>

1217¹H NMR (400 MHz, CD₃OD) δ 8.24 (d, <i>J</i> = 2.35 Hz, 1H), 7.78 (d, <i>J</i> = 2.35 Hz, 1H), 7.50-7.57 (m, 2H), 7.09-7.17 (m, 2H), 5.72 (s, 2H), 4.95 (s, 2H), 3.95 (s, 3H); [M+H] = 316.08.

Example 383. (2-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol.

1218<chemistry id="chem0475" num="0475"><img file="EP3345902A1_D0480.tif" /></chemistry>

1219¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, <i>J</i> = 2.35 Hz, 1H), 7.65 (d, <i>J</i> = 2.35 Hz, 1H), 7.35-7.44 (m, 1H), 7.16-7.25 (m, 2H), 5.75 (s, 2H), 4.94 (s, 2H), 3.99 (s, 3H); [M+H] = 334.42.

Example 384. (1-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol.

1220<chemistry id="chem0476" num="0476"><img file="EP3345902A1_D0481.tif" /></chemistry>

1221¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, <i>J</i> = 2.35 Hz, 1H), 7.65 (d, <i>J</i> = 2.35 Hz, 1H), 7.34-7.43 (m, 1H), 7.15-7.23 (m, 2H), 5.65 (s, 2H), 4.99 (s, 2H), 3.97 (s, 3H); [M+H] = 334.42.

Example 385. (2-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol.

1222<chemistry id="chem0477" num="0477"><img file="EP3345902A1_D0482.tif" /></chemistry>

1223¹H NMR (400 MHz, CDCl₃) δ 8.29 (d, <i>J</i> = 2.35 Hz, 1H), 7.67 (d, <i>J</i> = 2.35 Hz, 1H), 7.44 (t, <i>J</i> = 8.02 Hz, 1H), 7.37 (dd, <i>J</i> = 1.96, 10.17 Hz, 1H), 7.22-7.26 (m, 1H), 5.75 (s, 2H), 4.94 (s, 2H), 3.99 (s, 3H); [M+H] = 350.08.

Example 386. (1-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol.

1224<chemistry id="chem0478" num="0478"><img file="EP3345902A1_D0483.tif" /></chemistry>

1225¹H NMR (400 MHz, CD₃OD) δ 8.28 (d, <i>J</i> = 2.35 Hz, 1H), 7.85 (d, <i>J</i> = 2.35 Hz, 1H), 7.44-7.54 (m, 2H), 7.30-7.37 (m, 1H), 5.73 (s, 2H), 4.95 (s, 2H), 3.97 (s, 3H); [M+H] = 350.08.

Example 387. (1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol.

1226<chemistry id="chem0479" num="0479"><img file="EP3345902A1_D0484.tif" /></chemistry>

1227¹H NMR (400 MHz, CD₃OD) δ 8.25-8.28 (m, 1H), 7.80 (d, <i>J</i> = 2.35 Hz, 1H), 7.53 (t, <i>J</i> = 1.76 Hz, 1H), 7.40-7.44 (m, 1H), 7.32-7.40 (m, 2H), 5.72 (s, 2H), 4.95 (s, 2H), 3.95 (s, 3H); [M+H] = 332.03.

Example 388. (2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol.

1228<chemistry id="chem0480" num="0480"><img file="EP3345902A1_D0485.tif" /></chemistry>

1229¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, <i>J</i> = 2.35 Hz, 1H), 7.67 (d, <i>J</i> = 2.35 Hz, 1H), 7.52 (q, <i>J</i> = 1.57 Hz, 1H), 7.33-7.42 (m, 3H), 5.75 (s, 2H), 4.94 (s, 2H), 3.98 (s, 3H); [M+H] = 332.03.

1230Examples 389 - 391 were prepared in a manner analogous to Example 292, with the appropriate starting material and reagent substitutions.

Example 389. 1-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)pyrrolidin-3-ol.

1231<chemistry id="chem0481" num="0481"><img file="EP3345902A1_D0486.tif" /></chemistry>

1232¹H NMR (400 MHz, CD₃OD) δ 8.24 (s, 2H), 8.03 (d, <i>J</i> = 2.35 Hz, 1H), 7.55 (d, <i>J</i> = 2.35 Hz, 1H), 7.53 (t, <i>J</i> = 1.76 Hz, 1H), 7.40-7.44 (m, 1H), 7.37 (t, <i>J</i> = 7.63 Hz, 1H), 7.31-7.35 (m, 1H), 4.46-4.53 (m, 1H), 3.93 (s, 3H), 3.83 (s, 2H), 3.59-3.68 (m, 3H), 3.52-3.57 (m, 1H), 1.97-2.17 (m, 2H);.

Example 390. 1-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)azetidin-3-ol.

1233<chemistry id="chem0482" num="0482"><img file="EP3345902A1_D0487.tif" /></chemistry>

1234¹H NMR (400 MHz, CD₃OD) δ 8.25 (s, 2H), 8.03 (d, <i>J</i> = 2.35 Hz, 1H), 7.56 (d, <i>J</i> = 2.35 Hz, 1H), 7.53 (t, <i>J</i> = 1.57 Hz, 1H), 7.41-7.44 (m, 1H), 7.37 (t, <i>J</i> = 7.63 Hz, 1H), 7.31-7.35 (m, 1H), 4.61-4.69 (m, 1H), 4.27-4.36 (m, 2H), 3.93 (s, 3H), 3.86-3.90 (m, 2H), 3.84 (s, 2H); [M+H] = 383.4.

Example 391. 2-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-ol.

1235<chemistry id="chem0483" num="0483"><img file="EP3345902A1_D0488.tif" /></chemistry>

1236¹H NMR (400 MHz, CD₃OD) δ 8.20 (s, 2H), 8.03 (d, <i>J</i> = 2.35 Hz, 1H), 7.56 (d, <i>J</i> = 2.74 Hz, 1H), 7.53 (t, <i>J</i> = 1.57 Hz, 1H), 7.41-7.45 (m, 1H), 7.38 (t, <i>J</i> = 7.63 Hz, 1H), 7.31-7.35 (m, 1H), 3.93 (s, 3H), 3.82 (s, 2H), 3.65-3.72 (m, 2H), 3.43-3.51 (m, 2H); [M+H] = 371.39.

1237Examples 392 - 402 were prepared in a manner analogous to Intermediate 21, with the appropriate starting material and reagent substitutions.

Example 392. 2-Ethoxy-3-(4-fluorophenyl)-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine.

1238<chemistry id="chem0484" num="0484"><img file="EP3345902A1_D0489.tif" /></chemistry>

1239¹H NMR (400 MHz, CDCl₃) δ 8.21 (d, <i>J</i> = 1.96 Hz, 1H), 7.63 (d, <i>J</i> = 1.96 Hz, 1H), 7.47-7.56 (m, 2H), 7.06-7.15 (m, 2H), 5.68 (s, 2H), 4.43 (q, <i>J</i> = 7.04 Hz, 2H), 2.52 (s, 3H), 1.37 (t, <i>J</i> = 6.85 Hz, 3H); [M+H] = 314.42.

Example 393. 3-(3,4-Difluorophenyl)-2-ethoxy-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine.

1240<chemistry id="chem0485" num="0485"><img file="EP3345902A1_D0490.tif" /></chemistry>

1241¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, <i>J</i> = 2.35 Hz, 1H), 7.63 (d, <i>J</i> = 2.35 Hz, 1H), 7.42 (ddd, <i>J</i> = 2.15, 7.53, 11.44 Hz, 1H), 7.17-7.26 (m, 2H), 5.68 (s, 2H), 4.44 (q, <i>J</i> = 7.04 Hz, 2H), 2.53 (s, 3H), 1.38 (t, <i>J</i> = 7.04 Hz, 3H); [M+H] = 332.4.

Example 394. 3-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine.

1242<chemistry id="chem0486" num="0486"><img file="EP3345902A1_D0491.tif" /></chemistry>

1243¹H NMR (400 MHz, CDCl₃) δ 8.29 (d, <i>J</i> = 2.35 Hz, 1H), 8.20-8.24 (m, 1H), 7.71 (d, <i>J</i> = 2.35 Hz, 1H), 7.50 (t, <i>J</i> = 73.20 Hz, 1H), 7.27-7.29 (m, 1H), 7.11 (dd, <i>J</i> = 0.78, 1.57 Hz, 1H), 5.69 (s, 2H), 4.45 (q, <i>J</i> = 7.04 Hz, 2H), 2.52 (s, 3H), 1.38 (t, <i>J</i> = 7.04 Hz, 3H); [M+H] = 363.41.

Example 395. 3-(3,4-Difluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine.

1244<chemistry id="chem0487" num="0487"><img file="EP3345902A1_D0492.tif" /></chemistry>

1245¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, <i>J</i> = 2.35 Hz, 1H), 7.52 (d, <i>J</i> = 2.35 Hz, 1H), 7.34-7.45 (m, 1H), 7.15-7.23 (m, 2H), 5.46 (s, 2H), 4.43 (q, <i>J</i> = 7.04 Hz, 2H), 2.56 (s, 3H), 1.37 (t, <i>J</i> = 7.04 Hz, 3H); [M+H] = 332.4.

Example 396. 3-[2-(Diauoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine.

1246<chemistry id="chem0488" num="0488"><img file="EP3345902A1_D0493.tif" /></chemistry>

1247¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, <i>J</i> = 4.70 Hz, 1H), 8.19 (d, <i>J</i> = 2.35 Hz, 1H), 7.61 (d, <i>J</i> = 2.35 Hz, 1H), 7.50 (t, <i>J</i> = 73.60 Hz, 1H), 7.25 (dd, <i>J</i> = 1.37, 5.28 Hz, 1H), 7.09 (d, <i>J</i> = 0.78 Hz, 1H), 5.47 (s, 2H), 4.46 (q, <i>J</i> = 7.04 Hz, 2H), 2.57 (s, 3H), 1.39 (t, <i>J</i> = 7.24 Hz, 3H); [M+H] = 363.41.

Example 397. 3-(4-Chloro-3-fluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine.

1248<chemistry id="chem0489" num="0489"><img file="EP3345902A1_D0494.tif" /></chemistry>

1249¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, <i>J</i> = 2.74 Hz, 1H), 7.53 (d, <i>J</i> = 2.74 Hz, 1H), 7.41-7.46 (m, 1H), 7.37 (dd, <i>J</i> = 2.15, 10.37 Hz, 1H), 7.19-7.24 (m, 1H), 5.46 (s, 2H), 4.44 (q, <i>J</i> = 7.04 Hz, 2H), 2.56 (s, 3H), 1.35-1.42 (m, 3H); [M+H] = 348.36.

Example 398. 3-(3-Chloro-4-fluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine.

1250<chemistry id="chem0490" num="0490"><img file="EP3345902A1_D0495.tif" /></chemistry>

1251¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, <i>J</i> = 2.35 Hz, 1H), 7.57 (dd, <i>J</i> = 2.35, 7.04 Hz, 1H), 7.51 (d, <i>J</i> = 2.35 Hz, 1H), 7.37 (ddd, <i>J</i> = 2.15, 4.50, 8.61 Hz, 1H), 7.18 (t, <i>J</i> = 8.61 Hz, 1H), 5.46 (s, 2H), 4.43 (q, <i>J</i> = 7.04 Hz, 2H), 2.56 (s, 3H), 1.37 (t, <i>J</i> = 7.04 Hz, 3H); [M+H] = 348.36.

Example 399. 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazo1-1-yl)methyl]pyridine.

1252<chemistry id="chem0491" num="0491"><img file="EP3345902A1_D0496.tif" /></chemistry>

1253¹H NMR (400MHz, CDCl₃) δ 8.12 (d, <i>J</i> = 2.3 Hz, 1H), 7.55 (d, <i>J</i> = 2.3 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.37 (s, 1H), 7.34 - 7.30 (m, 1H), 7.13 (dd, <i>J</i> = 2.2, 8.0 Hz, 1H), 6.55 (t, <i>J</i> = 73.6 Hz, 1H), 5.47 (s, 2H), 4.43 (q, <i>J</i> = 7.0 Hz, 2H), 2.56 (s, 3H), 1.38 (t, <i>J</i> = 7.0 Hz, 3H);.

Example 400. 2-Ethoxy-3-(2-ethoxypyridin-4-yl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine.

1254<chemistry id="chem0492" num="0492"><img file="EP3345902A1_D0497.tif" /></chemistry>

1255¹H NMR (400MHz, CDCl₃) δ 8.18 (d, <i>J</i> = 5.1 Hz, 1H), 8.15 (s, 1H), 7.58 (br s, 1H), 7.03 (d, <i>J</i> = 5.1 Hz, 1H), 6.87 (s, 1H), 5.46 (s, 2H), 4.49 - 4.36 (m, 4H), 2.59 - 2.54 (m, 3H), 1.46 - 1.36 (m, 6H);.

Example 401. 2-Ethoxy-3-(3-ethoxyphenyl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine.

1256<chemistry id="chem0493" num="0493"><img file="EP3345902A1_D0498.tif" /></chemistry>

1257¹H NMR (400MHz, CDCl₃) δ 8.09 (d, <i>J</i> = 2.3 Hz, 1H), 7.53 (d, <i>J</i> = 2.3 Hz, 1H), 7.32 (t, <i>J</i> = 8.0 Hz, 1H), 7.08 - 7.04 (m, 2H), 6.93 - 6.89 (m, 1H), 5.46 (s, 2H), 4.43 (q, <i>J</i> = 7.0 Hz, 2H), 4.07 (q, <i>J</i> = 7.0 Hz, 2H), 2.55 (s, 3H), 1.44 (t, <i>J</i> = 6.8 Hz, 3H), 1.38 (t, <i>J</i> = 7.0 Hz, 3H);.

Example 402. 2-Ethoxy-3-(3-fluoro-5-methoxyphenyl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine.

1258<chemistry id="chem0494" num="0494"><img file="EP3345902A1_D0499.tif" /></chemistry>

1259¹H NMR (400MHz, CDCl₃) δ 8.11 (d, <i>J</i> = 2.3 Hz, 1H), 7.54 (d, <i>J</i> = 2.3 Hz, 1H), 6.88 - 6.80 (m, 2H), 6.63 (td, <i>J</i> = 2.3, 10.6 Hz, 1H), 5.46 (s, 2H), 4.44 (q, <i>J</i> = 7.0 Hz, 2H), 3.83 (s, 3H), 2.56 (s, 3H), 1.38 (t, <i>J</i> = 7.0 Hz, 3H);.

Example 403. 3-(3-Chlorophenyl)-5- {[4-(difluoromethyl)-2-methyl-1H-imidazol-1-yl]methyl}-2-ethoxypyrazine.

1260<chemistry id="chem0495" num="0495"><img file="EP3345902A1_D0500.tif" /></chemistry>

1261The title compound was prepared in a manner analogous to Example 297, with the appropriate starting material and reagent substitutions. ¹H NMR (400MHz, CD₃OD) δ 8.10 (s, 3H), 7.42 (d, <i>J</i> = 1.2 Hz, 3H), 6.77 - 6.48 (m, 1H), 5.31 (s, 2H), 4.51 (d, <i>J</i> = 7.0 Hz, 2H), 2.48 (s, 3H), 1.44 (s, 3H); [M+H] = 379.

1262Examples 404 - 405 were prepared in a manner analogous to Example 299, with the appropriate starting material and reagent substitutions.

Example 404. (5-{[6-(2,2-Difluoroethoxy)-5-(2-ethoxypyridin-4-yl)pyridin-3-yl]methyl}-3-fluoropyridin-2-yl)methanol.

1263<chemistry id="chem0496" num="0496"><img file="EP3345902A1_D0501.tif" /></chemistry>

1264¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.38 (t, <i>J</i> = 1.76 Hz, 1H), 8.12 - 8.26 (m, 2H), 7.92 (d, <i>J</i> = 2.35 Hz, 1H), 7.65 (dd, <i>J</i> = 10.76, 1.76 Hz, 1H), 7.17 (dd, <i>J</i> = 5.48, 1.57 Hz, 1H), 6.99 (dd, <i>J</i> = 1.57, 0.78 Hz, 1H), 5.19 (t, <i>J</i> = 5.87 Hz, 1H), 4.45 - 4.66 (m, 4H), 4.31 (q, <i>J</i> = 7.04 Hz, 2H), 4.01 (s, 2H), 1.31 (t, <i>J</i> = 7.04 Hz, 3H); [M+H] = 420.5.

Example 405. [5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-3-fluoropyridin-2-yl]methanol.

1265<chemistry id="chem0497" num="0497"><img file="EP3345902A1_D0502.tif" /></chemistry>

1266¹H NMR (400MHz, CD₃OD) δ 8.34 - 8.29 (m, 1H), 8.23 - 8.19 (m, 1H), 8.13 - 8.10 (m, 1H), 7.73 (d, <i>J</i> = 2.3 Hz, 1H), 7.56 (s, 1H), 7.53 - 7.48 (m, 1H), 7.43 - 7.39 (m, 1H), 7.21 - 7.18 (m, 1H), 4.75 - 4.68 (m, 2H), 4.46 - 4.38 (m, 2H), 4.08 - 4.03 (m, 2H), 1.39 - 1.32 (m, 3H); [M+H] = 406.

Example 406. (1-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol.

1267<chemistry id="chem0498" num="0498"><img file="EP3345902A1_D0503.tif" /></chemistry>

1268The title compound was prepared in a manner analogous to Intermediate 35, with the appropriate starting material and reagent substitutions. ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 8.09 (d, <i>J</i> = 2.35 Hz, 1H), 7.80 (d, <i>J</i> = 1.96 Hz, 1H), 7.64 (dt, <i>J</i> = 2.45, 0.93 Hz, 1H), 7.37 - 7.59 (m, 3H), 6.97 (s, 1H), 6.36 (t, <i>J</i> = 3.52 Hz, 1H), 5.08 (s, 2H), 4.52 - 4.74 (m, 3H), 4.22 (dd, <i>J</i> = 5.48, 0.78 Hz, 2H), 2.27 (s, 3H); [M+H] = 394.41.

Example 407. 1-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine.

1269<chemistry id="chem0499" num="0499"><img file="EP3345902A1_D0504.tif" /></chemistry>

1270The title compound was prepared in a manner analogous to Intermediate 10, employing Intermediate 36. ¹H NMR (400MHz, CD₃OD) δ 8.11 (s, 2H), 7.68 (d, <i>J</i> = 2.3 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.10 (d, <i>J</i> = 11.0 Hz, 2H), 5.20 - 5.16 (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H); [M+H] = 330.

PHARMACOLOGICAL EXAMPLES

1271The present disclosure will be further illustrated by the following pharmacological examples. These examples are understood to be exemplary only and are not intended to limit the scope of the invention disclosed herein.

Enzymatic Assay

1272An IMAP TR-FRET based PDE assay was developed using the PDE4D3 isoform. IMAP technology is based on high-affinity binding of phosphate by immobilized metal (MIII) coordination complexes on nanoparticles. The IMAP "binding reagent" recognizes phosphate groups on AMP or GMP generated from cAMP or cGMP in a PDE reaction. The cyclic nucleotides that carry a phosphodiester bond and not a free phosphate are not recognized by the binding reagent. The time resolved fluorescence resonance energy transfer (TR-FRET) is afforded by a Terbium (Tb)-Donor prebound to the nanoparticles. FRET can occur when fluorescent-labeled AMP or GMP product of a PDE reaction binds comes into close proximity of the Tb-Donor complex. Due to the long lifetime of Tb fluorescence, detection can be run in time-resolved mode to eliminate interference from auto fluorescent compounds.

1273The IMAP TR-FRET PDE4D3 FAM-cAMP assay was performed in 1536-well white plates 15 pg per well GST-tagged PDE4D3 was dispensed in 2.5 µL IMAP assay buffer consisting of 10 mM Tris pH 7.2, 10 mM MgCl₂, 1mM DTT, 0.1 % fatty acid free BSA and 0.01% Tween-20. 30 nL of compound was then added from 1 mM stock in DMSO using the Kalypsys 1536 10 nL pintool. Plates were incubated for 5 min at RT before dispensing 1.5 µL of 533 nM FAM-cAMP for a final concentration of 200 nM. Plates were incubated 30 min at RT after a brief centrifugation. The assay was terminated by adding 5 µL IMAP binding reagent Tb complex to each well, prepared according to manufacturer's recommendations. Plates were incubated an additional 90 minutes at RT and read on a Viewlux plate reader. Compounds were solvated at 10 mM in DMSO and tested in 11-point dose-response in the PDE4D3 assay.

Pharmacological Example 1

PDE4 Inhibition

1274Representative compounds of the invention were evaluated in the PDE4 enzymatic assay. Typically, the compounds of the invention show PDE4 inhibitory properties at a concentration of 0.1 to 10 µM, typically at 5-100%.

1275As depicted in the following Table, these inhibitory properties were mirrored by pEC₅₀ values ranging from less than 5 (10^-5 M or 10 µM) to greater than 7 (10^-7 M or 0.1 µM). <tables id="tabl0003" num="0003"><table frame="all"><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="20mm" /><colspec colnum="2" colname="col2" colwidth="146mm" /><thead><row><entry valign="top"><b>PD4d3 pEC₅₀</b></entry><entry valign="top"><b>Example Numbers</b></entry></row></thead><tbody><row><entry>> 7</entry><entry>1, 13, 25, 27, 28, 29, 30, 32, 33, 36, 38, 40, 46, 47, 48, 55, 56, 58, 65, 66, 68, 69, 71, 72, 73, 76, 78, 79, 80, 82, 84, 87, 89, 92, 93, 95, 100, 103, 104, 105, 106, 110, 119, 122, 123, 124, 125, 126, 131, 134, 142, 143, 144, 147, 150, 152, 154, 161, 164, 167, 172, 173, 182, 184, 200, 201, 202, 203, 204, 205, 216, 225, 228, 229, 231, 244, 250, 253, 257, 258, 259, 260, 261, 269, 271, 272, 278, 279, 280, 281, 287, 288, 290, 291, 293, 294, 296, 298, 299, 301, 303, 306, 309, 312, 325, 326, 327, 336, 337, 340, 348, 349, 350, 352, 353, 358, 359, 360, 362, 363, 364, 365, 368, 369, 371, 372, 375, 376, 377, 380, 391, 392, 393, 394, 395, 396, 398, 399, 404, 405, 406, Intermediate 49,</entry></row><row><entry>6-7</entry><entry>2, 5, 7, 12, 14, 20, 21, 24, 26, 34, 37, 41, 43, 44, 45, 49, 51, 53, 57, 59, 60, 64, 67, 74, 75, 81, 83, 85, 86, 88, 90, 91, 94, 96, 97, 102, 107, 108, 109, 111, 112, 113, 114, 115, 116, 117, 118, 120, 121, 128, 129, 130, 132, 136, 137, 139, 141, 145, 146, 149, 151, 153, 156, 158, 159, 160, 162, 163, 165, 166, 169, 170, 175, 177, 178, 179, 187, 188, 190, 199,</entry></row><row><entry /><entry>206, 207, 210, 211, 212, 213, 215, 217, 218, 219, 220, 221, 222, 223, 226, 230, 232, 233, 237, 238, 242, 243, 247, 248, 249, 251, 252, 256, 262, 263, 264, 265, 266, 268, 273, 274, 275, 282, 283, 285, 289, 297, 300, 304, 305, 308, 310, 311, 313, 314, 315, 316, 317, 319, 321, 322, 324, 328, 330, 331, 333, 334, 338, 341, 342, 344, 345, 346, 347, 351, 354, 355, 356, 357, 361, 366, 367, 370, 373, 374, 378, 379, 381, 383, 385, 388, 389, 390, 397, 400, 401, 402, 403, Intermediate 50,</entry></row><row><entry>5-6</entry><entry>3, 8, 15, 16, 17, 18, 19, 23, 31, 35, 39, 42, 50, 52, 54, 61, 62, 63, 70, 77, 98, 99, 101, 127, 133, 135, 138, 148, 155, 157, 168, 171, 176, 180, 181, 183, 185, 186, 189, 191, 192, 193, 194, 195, 196, 197, 198, 208, 209, 214, 224, 227, 234, 236, 239, 240, 241, 245, 254, 255, 270, 276, 284, 292, 295, 302, 307, 318, 323, 329, 332, 335, 339, 343, 382, 384, 386, 387, 407,</entry></row><row><entry>< 5</entry><entry>4, 6, 9, 10, 11, 22, 140, 174, 235, 246, 267, 277, 286, 320.</entry></row></tbody></tgroup></table></tables>

BIOLOGICAL EXAMPLES

1276The present disclosure will be further illustrated by the following biological examples. These examples are understood to be exemplary only and are not intended to limit the scope of the invention disclosed herein.

Behavioral Assays

1277Numerous behavioral assays are available to assess the ability of a candidate compound to enhance memory formation, including contextual conditioning (<i>e.g.</i>, fear conditioning), temporal conditioning (<i>e.g.</i>, trace conditioning), and object recognition. Other non-limiting examples of appropriate assays to assess memory include those that incorporate or relate to multiple training sessions, spaced training sessions, contextual fear training with single or multiple trials, trace fear conditioning with single or multiple trials, contextual memory generally, temporal memory, spatial memory, episodic memory, passive avoidance memory, active avoidance memory, food preference memory, conditioned taste avoidance, and social recognition memory.

1278The behavioral assays can also be used in accordance with the present invention, as will be understood by those of ordinary skill in the art. These assays can be directed towards the evaluation of, without limitation, hippocampus-, cortex, and/or amygdala-dependent memory formation or cognitive performance.

Biological Example 1

Effect of PDE4 Inhibitors on Contextual Memory Rationale

1279Contextual fear conditioning is a form of associative learning in which animals learn to recognize a training environment (conditioned stimulus, CS) that has been previously paired with an aversive stimulus such as foot shock (unconditioned stimulus, US). When exposed to the same context at a later time, conditioned animals show a variety of conditional fear responses, including freezing behavior. The percent of time during the test that the animal exhibits such freezing provides a quantitative measure of the contextual associative memory (<i>e.g.,</i><nplcit id="ncit0092" npl-type="s"><text>Fanselow, Behav. Neurosci. 1984, 98, 269-277</text></nplcit>; <nplcit id="ncit0093" npl-type="s"><text>Fanselow, Behav. Neurosci. 1984, 98, 79-95</text></nplcit>; and <nplcit id="ncit0094" npl-type="s"><text>Phillips and LeDoux, Behav. Neurosci. 1992, 106, 274-285</text></nplcit>).

1280Contextual conditioning has been extensively used to investigate the neural substrates mediating fear-motivated learning (<i>e.g.,</i><nplcit id="ncit0095" npl-type="s"><text>Phillips and LeDoux, Behav. Neurosci. 1992, 106, 274-285</text></nplcit>; <nplcit id="ncit0096" npl-type="s"><text>Kim et al., Behav. Neurosci. 1993, 107, 1093-1098</text></nplcit>; and <nplcit id="ncit0097" npl-type="s"><text>Bourtchouladze et al., Learn. Mem. 1998, 5, 365-374</text></nplcit>). Studies in mice and rats provided evidence for functional interaction between hippocampal and nonhippocampal systems during contextual conditioning training <i>(e.g.,</i><nplcit id="ncit0098" npl-type="s"><text>Maren et al., Behav. Brain Res. 1997, 88, 261-274</text></nplcit>;<nplcit id="ncit0099" npl-type="s"><text> Maren et al., Neurobiol. Learn. Mem. 1997, 67, 142-149</text></nplcit>; and<nplcit id="ncit0100" npl-type="s"><text> Frankland et al., Behav. Neurosci. 1998, 112, 863-874</text></nplcit>). Specifically, post-training lesions of the hippocampus (but not pre-training lesions) greatly reduced contextual fear, implying that: 1) the hippocampus is essential for contextual memory but not for contextual learning per se and 2) in the absence of the hippocampus during training, nonhippocampal systems can support contextual conditioning.

1281Contextual conditioning has been extensively used to study the impact of various mutations on hippocampus-dependent learning, as well as strain and genetic background differences in mice (<i>e.g.,</i><nplcit id="ncit0101" npl-type="s"><text>Bourtchouladze et al., Cell 1994, 79, 59-68</text></nplcit>; <nplcit id="ncit0102" npl-type="s"><text>Bourtchouladze et al., Learn Mem. 1998, 5, 365-374</text></nplcit>; <nplcit id="ncit0103" npl-type="s"><text>Kogan et al., Current Biology 1997, 7, 1-11</text></nplcit>; <nplcit id="ncit0104" npl-type="s"><text>Silva et al., Current Biology 1996, 6, 1509-1518</text></nplcit>; <nplcit id="ncit0105" npl-type="s"><text>Abel et al., Cell 1997, 88, 615-626</text></nplcit>; <nplcit id="ncit0106" npl-type="s"><text>Giese et al., Science 1998, 279, 870-873</text></nplcit>; <nplcit id="ncit0107" npl-type="s"><text>Logue et al., Neuroscience 1997, 80, 1075-1086</text></nplcit>; <nplcit id="ncit0108" npl-type="s"><text>Chen et al., Behav. Neurosci. 1996, 110, 1177-1180</text></nplcit>; and <nplcit id="ncit0109" npl-type="s"><text>Nguyen et al., Learn Mem. 2000, 7, 170-179</text></nplcit>).

1282Because robust learning can be triggered with a few minutes training session, contextual conditioning has been especially useful to study the biology of temporally distinct processes of short- and long-term memory (<i>e.g.,</i><nplcit id="ncit0110" npl-type="s"><text>Kim et al., Behav. Neurosci. 1993, 107, 1093-1098</text></nplcit>; <nplcit id="ncit0111" npl-type="s"><text>Bourtchouladze et al., Cell 1994, 79, 59-68</text></nplcit>; <nplcit id="ncit0112" npl-type="s"><text>Abel et al., Cell 1997, 88, 615-626</text></nplcit>; <nplcit id="ncit0113" npl-type="s"><text>Logue et al., Behav. Neurosci. 1997, 111, 104-113</text></nplcit>; <nplcit id="ncit0114" npl-type="s"><text>Bourtchouladze et al., Learn. Mem. 1998, 5, 365-374</text></nplcit>; and <nplcit id="ncit0115" npl-type="s"><text>Nguyen et al., Learn. Mem. 2000, 7, 170-179</text></nplcit>). As such, contextual conditioning provides an excellent model to evaluate the effects of novel drug compounds on hippocampal-dependent memory formation.

Procedures

1283Previous investigations have established that training with 1× or 2× CS-US pairings induces sub-maximal (weak) memory in wild-type mice (<i>e.g.</i>, <patcit id="pcit0033" dnum="US20090053140A"><text>U.S.2009/0053140</text></patcit>; <nplcit id="ncit0116" npl-type="s"><text>Tully et al., Nat. Rev. Drug Discov. 2003, 2, 267-77</text></nplcit>; and <nplcit id="ncit0117" npl-type="s"><text>Bourtchouladze et al. Learn. Mem. 1998, 5, 365-374</text></nplcit>). Accordingly, contextual conditioning in this study was performed as described by <nplcit id="ncit0118" npl-type="s"><text>Bourtchouladze et al., Cell 1994, 79, 59-68</text></nplcit>.

1284Young-adult (10-12 weeks old) C57BL/6 male mice and Sprague Dawley male rats were used. Mice and rats were group-housed in standard laboratory and maintained on a 12:12 light-dark cycle. The experiments were always conducted during the light phase of the cycle. With the exception of testing times, the mice had ad libidum access to food and water. To assess contextual memory, a modified contextual fear conditioning task originally developed for evaluation of memory in CREB knock-out mice was used (Bourtchouladze et al., 1994). Training sessions are comprised of a baseline period in the conditioning chamber (Med Associates, Inc.) followed by presentation of unconditioned stimuli (1-5 footshocks each at 0.2-1.0 mA for 2-sec) spaced at 60-sec intervals. Thirty seconds following the last shock, the animal is returned to the home cage. One to 7 days later, the animals are returned to the chamber and freezing behavior is scored. Freezing (complete immobility except respiration) is scored by Video Freeze software (Med Associates, Inc.) over an 8 minute test period. Treatment with cognition enhancers are expected to significantly increase freezing when compared with controls.

1285All experiments were designed and performed in a counterbalanced fashion. In each experiment, the experimenter was unaware (blind) to the treatment of the subjects during training and testing. Training and test sessions were recorded as digital video files. Data were analyzed by one-way ANOVA with appropriate post-hoc tests using GraphPad Prism software package.

Results

1286Exemplary compounds were found to enhance contextual memory in the fear conditioning assay. Significant enhancing effects are seen at several concentrations, including 0.01 mg/kg, 0.03 mg/kg, and 1.0 mg/kg.

Biological Example 2

Effect of PDE4 Inhibitors on Novel Object Recognition Rationale

1287Novel Object Recognition (NOR) is an assay of recognition learning and memory retrieval, and it takes advantage of the spontaneous preference of rodents to investigate a novel object compared with a familiar one. It is an ethologically relevant task, which in contrast to fear conditioning, does not result from negative reinforcement (foot shock)(<i>e</i>.<i>g</i>., <nplcit id="ncit0119" npl-type="s"><text>Ennaceur and Delacour, Behav. Brain Res. 1988, 31, 47-59</text></nplcit>).

1288The NOR test has been employed extensively to assess the potential cognitive-enhancing properties of novel compounds derived from high-throughput screening. Object recognition the task relies on the natural curiosity of rodents to explore novel objects in their environments more than familiar ones. Obviously, for an object to be "familiar," the animal must have attended to it before and remembered that experience. Hence, animals with better memory will attend and explore a new object more than an object familiar to them. During testing, the animal is presented with the training object and a second, novel one. Memory of the training object renders it familiar to the animal, and it then spends more time exploring the new novel object rather than the familiar one (<nplcit id="ncit0120" npl-type="s"><text>Bourtchouladze et. al., Proc. Natl. Acad. Sci. USA 2003, 100, 10518-10522</text></nplcit>).

1289Neuroimaging, pharmacological, and lesion studies have demonstrated that the hippocampus and adjacent perirhinal cortex are critical for object recognition memory in rodents, monkeys, and humans (<i>e.g.,</i><nplcit id="ncit0121" npl-type="s"><text>Mitchell, Behav. Brain Res. 1998, 97, 107-113</text></nplcit>;<nplcit id="ncit0122" npl-type="s"><text> Teng et al., J. Neurosci. 2000, 20, 3853-3863</text></nplcit>; <nplcit id="ncit0123" npl-type="s"><text>Mumby, Brain Res. 2001, 127, 159-181</text></nplcit>;<nplcit id="ncit0124" npl-type="s"><text> Eichenbaum et al., Annu. Rev. Neurosci. 2007, 30, 127-152</text></nplcit>;<nplcit id="ncit0125" npl-type="s"><text> Squire et al., Nat. Rev. Neurosci. 2007, 8, 872-883</text></nplcit>; and <nplcit id="ncit0126" npl-type="s"><text>Vann and Alabasser, Curr. Opin. Neurobiol. 2011, 21, 440-445</text></nplcit>). Hence, object recognition provides an excellent behavioral model to evaluate drug-compound effects on cognitive tasks associated with function of the hippocampus and cortex.

Procedures

1290Object recognition was tested in young adult mice and rats using the following protocol. Animals are briefly handled by the experimenter 2-5 days prior to training. Each compound was administered between 15 minutes and 24-hours prior to, or following, training. Habituation sessions (duration 1-20 min, over 1-3 days) were conducted to familiarize the animal to the arena. During training trials (duration of 1-20 min) the animals were allowed to explore two identical objects. A test trial (duration of 1-20 min) was then performed 1-96 hrs later.

1291For novel object recognition, one object is replaced with one that is novel. All combinations and locations of objects are used in a balanced manner to reduce potential biases attributable to preference for particular locations or objects. Training and test trials are recorded and scored by video-tracking software (<i>e.g.</i> Noldus Ethovision). An animal is scored as exploring an object when its head was oriented toward the object within a distance of 1 cm (rat)/2 cm (mouse) or when the nose is touching the object. Turning around, climbing, or sitting on an object was not considered as exploration. If the animal generates a long-term memory for the familiar object, it will spend significantly more time exploring the novel object compared to the familiar object during the retention test (Cognitive enhancers are therefore expected to facilitate this discrimination between the familiar and novel object).

1292A discrimination index was calculated as previously described (<nplcit id="ncit0127" npl-type="s"><text>Bourtchouladze et al., Proc. Natl. Acad. Sci. USA 2003, 100, 10518-10522</text></nplcit>). In each experiment, the experimenter was unaware (blind) to the treatment of the subjects during training and testing. Data were analyzed by one-way ANOVA with appropriate post-hoc tests using GraphPad Prism software package.

Results

1293Exemplary compounds of Formula (I) were found to significantly enhance 24 hour memory. Significant effects were seen at several concentrations, including 1.0 mg/kg and 3 mg/kg.

1294The specification, including the examples, is intended to be exemplary only, and it will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention as defined by the appended claims.

1295Furthermore, while certain details in the present disclosure are provided to convey a thorough understanding of the invention as defined by the appended claims, it will be apparent to those skilled in the art that certain embodiments may be practiced without these details. Moreover, in certain instances, well-known methods, procedures, or other specific details have not been described to avoid unnecessarily obscuring aspects of the invention defined by the appended claims.

<u>Further Embodiments of the Invention</u>

1296<b>Embodiment 1.</b> A chemical entity of Formula (I): <chemistry id="chem0500" num="0500"><img file="EP3345902A1_D0505.tif" /></chemistry> wherein: <ul id="ul0042" list-style="none" compact="compact"><li>Z is CH or N; <ol id="ol0005" compact="compact"><li>i) wherein when Z is CH, then; <ul id="ul0043" list-style="none" compact="compact"><li>R¹ is a member selected from the group consisting of: -H, -C_1-3alkyl and -C_1-3haloalkyl;</li><li>Y is -C(R^a)₂-, where each R^a is independently selected from the group consisting of: -H, -F,-CH₃, -OH and -N(R^b)₂;</li><li>R² is a member selected from the group consisting of: <ol id="ol0006" compact="compact"><li>A) phenyl unsubstituted or substituted with one or two R^c members, where each R^c is independently selected from the group consisting of: halo, -CN, -CO₂R^b, -CONH₂, -SO₂CH₃, -C(R^b)₂OH, -CH₂NH₂, -CH₂CONH₂, -CH₂CO₂C₁-₃alkyl, -NHCONH₂,-NHCONH-oxetane, -CONH-oxetane, <chemistry id="chem0501" num="0501"><img file="EP3345902A1_D0506.tif" /></chemistry></li><li>B) six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of: halo, -C_1-3alkyl, -C_1-3haloalkyl, -CN, -OH,_-C(R^b)₂OH, -CH₂NH₂, -C(R^b)₂CN, -C(R^b)₂CONH₂,-OCH₂CONH₂, -OC_1-3alkyl, -OCH₂C(R^b)₂OH, -OCH₂cyclopropyl, -OC_1-3haloalkyl, -CO₂H, -CON(R^b)₂, -N(R^b)₂, -NHCH₂CF₃, -NHCH(CH₃)₂,-NHCH₂CH₂N(CH₃)₂, -NHCH₂CH₂OH, -NHcyclopropyl, -NHCOCH₃, morpholinyl, pyrrolidin-3-ol, and azetidin-3-ol;</li><li>C) five-membered monocyclic heteroaromatic ring containing two, three, or four nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of halo, -C_1-3alkyl, -C_1-3haloalkyl, -C(R^b)₂OH, -N(R^b)₂, -NO₂, -CN, -CH₂CN, -OC_1-3alkyl, -CH₂OCH₃,-CH₂CH₂OH, -CH₂NH₂, -CH₂CONH₂, -CO₂C_1-3alkyl, -CO₂H, -CONH₂,-NHCOCH₃, and cyclopropyl; and</li><li>D) five or six-membered ring selected from: 1,2-dihydro-pyridin-2-one, thiazole or 1,2-oxazole unsubstituted or substituted with one or two members each independently selected from the group consisting of -CH₃, and -NH₂;</li></ol></li><li>R³ is phenyl or pyridine, each substituted with one or two members each independently selected from the group consisting of: -halo, -C_1-3alkyl, -OC_1-3alkyl,-Ocyclopropyl, -O-oxetane,-C_1-3haloalkyl, -OC_1-3haloalkyl, -CN,-CH₂OH, -SO₂CH₃, or -N(CH₃)₂;</li><li>R⁴ is a member selected from the group consisting of -C_1-3alkyl and -C_1-3haloalkyl; and</li><li>each R^b is independently selected from -H or -CH₃;</li></ul></li><li>ii) wherein when Z is N, then; <ul id="ul0044" list-style="none" compact="compact"><li>R¹ is -H;</li><li>Y is -CH₂-;</li><li>R² is a member selected from the group consisting of: <ol id="ol0007" compact="compact"><li>A) phenyl substituted with one or two R^d members, where each R^d is independently selected from the group consisting of: -CN, -CONH₂, and -CO₂C_1-3alkyl;</li><li>B) six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with a member selected from the group consisting of: -CN, -OC_1-3alkyl, -CONH₂, -NHCH₂CH₂OH, -N(R^b)₂, and -NH-cyclopropyl;</li><li>C) five-membered monocyclic heteroaromatic ring containing two or three nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of -C_1-3alkyl, -C_1-3haloalkyl,-CH₂OR^b, -N(R^b)₂, -NO₂, -CO₂CH₃, -CO₂N(R^b)₂, or cyclopropyl; and</li><li>D) 1,2-oxazole optionally substituted with one or two R^b members;</li></ol></li><li>R³ phenyl substituted with one or two members each independently selected from the group consisting of: -Cl, -OC_1-3alkyl, or -OC₁-₃haloalkyl;</li><li>R⁴ is -C_1-3alkyl; and</li><li>each R^b is independently selected from -H or -CH₃;</li><li>wherein the chemical entity is selected from the group consisting of compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I); and pharmaceutically active metabolites of compounds of Formula (I).</li></ul></li></ol></li></ul>

1297<b>Embodiment 2.</b> A chemical entity as in Embodiment 1, wherein Z is CH.

1298<b>Embodiment 3.</b> A chemical entity as in Embodiment 1, wherein Z is N.

1299<b>Embodiment 4.</b> A chemical entity as in Embodiment 2, wherein R¹ is selected from the group consisting of -H, -CH₃, and -CF₃.

1300<b>Embodiment 5.</b> A chemical entity as in Embodiment 3, wherein R¹ is -H.

1301<b>Embodiment 6.</b> A chemical entity as in Embodiment 2, wherein Y is selected from the group consisting of -CH₂-, -CH(F)-, -CH(OH)-, -C(OH)(CH₃)-, and -CH(CH₃)-.

1302<b>Embodiment 7.</b> A chemical entity as in Embodiment 3, wherein Y is -CH₂-.

1303<b>Embodiment 8.</b> A chemical entity as in Embodiment 1, wherein Z is CH and R² is <chemistry id="chem0502" num="0502"><img file="EP3345902A1_D0507.tif" /></chemistry> where R^c is a member selected from the group consisting of: -F, -CN, -CO₂H,-CONH₂, -SO₂CH₃, -C(CH₃)₂OH, -CH₂NH₂, -CH₂CONH₂, -CH₂CO₂CH₃, -CH₂CO₂CH₂CH₃,-NHCONH₂, -NHCONH-oxetane, -CONH-oxetane, <chemistry id="chem0503" num="0503"><img file="EP3345902A1_D0508.tif" /></chemistry>

1304<b>Embodiment 9.</b> A chemical entity as in Embodiment 2, wherein R² is <chemistry id="chem0504" num="0504"><img file="EP3345902A1_D0509.tif" /></chemistry> and R^c is selected from -F, -CONH₂, -CH₂CONH₂, -CH₂NH₂, -C(CH₃)₂OH, -SO₂CH₃, and-NHCONH₂.

1305<b>Embodiment 10.</b> A chemical entity as in Embodiment 3, wherein R² is 4-cyanophenyl, 4-phenylamide or 4-phenylcarboxylic acid methyl ester.

1306<b>Embodiment 11.</b> A chemical entity as in Embodiment 1, wherein Z is CH and R² is selected from the group consisting of pyridine, unsubstituted or substituted with one or two members each independently selected from the group consisting of -F, -C_1-3alkyl, -C_1-3haloalkyl, -OC_1-3alkyl, -OCH₂cyclopropyl, -CN, -N(R^b)₂, -CH₂NH₂, -CH₂OH, -CO₂H, -CON(R^b)₂, and-C(CH₃)₂OH.

1307<b>Embodiment 12.</b> A chemical entity as in Embodiment 1, wherein Z is CH and R² is <chemistry id="chem0505" num="0505"><img file="EP3345902A1_D0510.tif" /></chemistry> R^d is selected from the group consisting of: -CH₃, -CF₃, -CN, -N(R^b)₂, -CO₂H,-CON(R^b)₂, -OC_1-3alkyl, -CH₂NH₂, -CH₂OH, -C(CH₃)₂OH, -OCH₂cyclopropyl, and-OCH(CH₃)₂.

1308<b>Embodiment 13.</b> A chemical entity as in Embodiment 1, wherein Z is CH and R² is <chemistry id="chem0506" num="0506"><img file="EP3345902A1_D0511.tif" /></chemistry> unsubstituted or substituted with R^d; where R^d is -CH₃, -CF₃, -NH₂, -NHCH₃,-N(CH₃)₂, -CONH₂, -CONHCH₃, -CON(CH₃)₂, -OC_1-3alkyl, -CH₂OH, -C(CH₃)₂OH, or-OCH₂cyclopropyl.

1309<b>Embodiment 14.</b> A chemical entity as in Embodiment 3, wherein R² is <chemistry id="chem0507" num="0507"><img file="EP3345902A1_D0512.tif" /></chemistry> R^d1 is-CN or -CONH₂.

1310<b>Embodiment 15.</b> A chemical entity as in Embodiment 2, wherein R² is selected from the group consisting of pyrazine, pyridazine and pyrimidine; where pyrazine is optionally unsubstituted or substituted with -C_1-3alkyl, -OC_1-3alkyl, -N(R^b)₂, or -NHCH₂CH₂OH; pyridazine is optionally unsubstituted or substituted with -C_1-3alkyl; and pyrimidine is optionally substituted with a group consisting of: -H, -Cl, -C_1-3alkyl, -CN, -OH, -OC_1-3alkyl,-OC_1-3haloalkyl, -CO₂H, -CON(R^b)₂, -C(R^b)₂CONH₂, -C(R^b)₂OH, -C(R^b)₂CN,-CH₂CH₂N(CH₃)₂, -OCH₂C(R^b)₂OH, -OCH₂CONH₂, -N(R^b)₂, -NHCH₂CF₃, -NHCH(CH₃)₂,-NHCH₂CH₂OH, -NHcyclopropyl, -NHCOCH₃, morpholinyl, pyrrolidin-3-ol, and azetidin-3-ol.

1311<b>Embodiment 16.</b> A chemical entity as in Embodiment 2, wherein R² is <chemistry id="chem0508" num="0508"><img file="EP3345902A1_D0513.tif" /></chemistry> unsubstituted or substituted with one or two R^e members, where each R^e is independently -H, -Cl, -C_1-3alkyl, -CN, -OCH₃, -OC_1-3haloalkyl, -CO₂H, -CONH₂, -C(R^b)₂CONH₂, -C(R^b)₂OH,-C(R^b)₂CN, -CH₂CH₂N(CH₃)₂, -OCH₂C(R^b)₂OH, -OCH₂CONH₂, -N(R^b)₂, -NHCH₂CF₃,-NHCH(CH₃)₂, -NHCH₂CH₂OH, -NHcyclopropyl, -NHCOCH₃, morpholinyl, pyrrolidin-3-ol, and azetidin-3-ol.

1312<b>Embodiment 17.</b> A chemical entity as in Embodiment 3, wherein R² is <chemistry id="chem0509" num="0509"><img file="EP3345902A1_D0514.tif" /></chemistry> unsubstituted or substituted with R^e1, where R^e1 is -OCH₃, -CN, -CONH₂, -NH₂, -NHCH₃,-NHCH₂CH₂OH, -NHcyclopropyl.

1313<b>Embodiment 18.</b> A chemical entity as in Embodiment 2, wherein R² is <chemistry id="chem0510" num="0510"><img file="EP3345902A1_D0515.tif" /></chemistry> unsubstituted or substituted with R^e, where R^e is selected from: -H, -Cl, -CH₃, -CN, -OH,-OCH₃, -OCHF₂, -NH₂, -NHCH₃, -N(CH₃)₂, -NHCH₂CF₃, -NHcyclopropyl, -C(CH₃)₂OH,-CONH₂, -CONHCH₃, and -CON(CH₃)₂.

1314<b>Embodiment 19.</b> A chemical entity as in Embodiment 2, wherein R² is selected from the group consisting of imidazole, pyrazole, triazole, and tetrazole, where each is unsubstituted or substituted with one or two members each independently selected from the group consisting of: -Cl, -CH₃, -CHF₂, -CF₃, -CH₂OH, -CH₂CN, -CH₂CONH₂, -CH₂CH₂OH, -NH₂, -NO₂,-CN, -CO₂C₁-₃alkyl, -CO₂H, -CONH₂, and -NHCOCH₃.

1315<b>Embodiment 20.</b> A chemical entity as in Embodiment 2, wherein R² is <chemistry id="chem0511" num="0511"><img file="EP3345902A1_D0516.tif" /></chemistry> and R^f is a member selected from the group consisting of: -H, -Cl, -CH₃, -NO₂, -NH₂, -NHCOCH₃,-CH₂OH, -CN, -CONH₂, -CO₂H, and -CO₂CH₂CH₃.

1316<b>Embodiment 21.</b> A chemical entity as in Embodiment 1, wherein R² is <chemistry id="chem0512" num="0512"><img file="EP3345902A1_D0517.tif" /></chemistry> and R^f is a member selected from the group consisting of: -H, -NH₂, and -CH₂OH.

1317<b>Embodiment 22.</b> A chemical entity as in Embodiment 1, wherein R² is <chemistry id="chem0513" num="0513"><img file="EP3345902A1_D0518.tif" /></chemistry> where R^g is a member selected from the group consisting of: -H, -CH₃, -CH₂OH, -CONH₂, and -NH₂.

1318<b>Embodiment 23.</b> A chemical entity as in Embodiment 2, wherein R² is 1H-tetrazole, 2H-tetrazole, 1,2-oxazole, 1,3-thiazole, optionally unsubstituted or substituted with a member independently selected from the group consisting of: -CH₃, -CH₂OH, -CH₂CH₂OH, and-NH₂.

1319<b>Embodiment 24.</b> A chemical entity as in Embodiment 2, wherein R² is selected from the group consisting of 1,2,3-triazole and 1,2,4-triazole, each unsubstituted or substituted with a member independently selected from the group consisting of: -CH₃, -CH₂F, -CHF₂, -CF₃,-OCH₃, -OCH₂CH₃, -CN, -CH₂CN, -CH₂CONH₂, -C(R^b)OH, -CH₂OCH₃, N(R^b)₂, -NO₂,-CO₂CH₃, -CONH₂, cyclopropyl and -CH₂NH₂.

1320<b>Embodiment 25.</b> A chemical entity as in Embodiment 1, wherein R² is <chemistry id="chem0514" num="0514"><img file="EP3345902A1_D0519.tif" /></chemistry> and R^h is a member selected from the group consisting of: -H, -CH₃, -CF₃, -CH₂F, -CHF₂, -OCH₃,-OCH₂CH₃, -CH₂OH, -C(CH₃)₂OH, -CH₂OCH₃, -NO₂, -NH₂, -NHCH₃, -N(CH₃)₂, -CN,-CH₂CN, -CH₂CONH₂, -CONH₂, -CO₂CH₃, and -cyclopropyl.

1321<b>Embodiment 26.</b> A chemical entity as in Embodiment 2, wherein R² is <chemistry id="chem0515" num="0515"><img file="EP3345902A1_D0520.tif" /></chemistry> and R^j is a member selected from the group consisting of: -H, -CH₃, -CF₃, -OCH₃, -CH₂(OH),-C(CH₃)₂OH, -CH₂OCH₃, -CO₂CH₃, and -NO₂.

1322<b>Embodiment 27.</b> A chemical entity as in Embodiment 2, wherein R² is <chemistry id="chem0516" num="0516"><img file="EP3345902A1_D0521.tif" /></chemistry> and R^k is a member selected from the group consisting of: -H, -CH₃, -CF₃, -CH₂F, -CHF₂, -OCH₃,-OCH₂CH₃, -CH₂OH, -C(CH₃)₂OH, -CH₂OCH₃, -NO₂, -NH₂, -NHCH₃, -N(CH₃)₂, -CN,-CONH₂, -CO₂CH₃, and -cyclopropyl.

1323<b>Embodiment 28.</b> A chemical entity as in Embodiment 2, wherein R³ is a member selected from the group consisting of: <chemistry id="chem0517" num="0517"><img file="EP3345902A1_D0522.tif" /></chemistry> where R^m is -Cl, -F, -CH₃, -CHF₂, -CF₃, -CN,-OCH₃, -CH₂OH, -OCH₂CH₃, -OCF₃, -OCHF₂, -N(CH₃)₂, -SO₂CH₃, -OCH(CH₃)₂, <chemistry id="chem0518" num="0518"><img file="EP3345902A1_D0523.tif" /></chemistry>

1324<b>Embodiment 29.</b> A chemical entity as in Embodiment 2, wherein R³ is a member selected from the group consisting of: 3-chlorophenyl, 3-cyanophenyl, 3-fluorophenyl, 3-methylphenyl, 3-(trifluoromethyl)phenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3-(trifluoromethoxy)phenyl, 3-(difluoromethoxy)phenyl, 3-(difluoromethyl)phenyl, 3-(dimethylamino)phenyl, 4-fluorophenyl, 4-chlorophenyl, 5-chloropyridin-3-yl, 3,4-difluorophenyl, 3,5-difluorophenyl, (3-fluoro-5-methoxyphenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methoxyphenyl or 3-ethoxy-4-fluorophenyl.

1325<b>Embodiment 30.</b> A chemical entity as in Embodiment 2, wherein R³ is <chemistry id="chem0519" num="0519"><img file="EP3345902A1_D0524.tif" /></chemistry> substituted or unsubstituted with Rⁿ, where Rⁿ is a member selected from the group consisting of: -Cl, -CH₃, -CF₃, -OCH₃, -OCH₂CH₃, -OCHF₂, -OCF₃ and -CN.

1326<b>Embodiment 31.</b> A chemical entity as in Embodiment 2, wherein R⁴ is a member selected from the group consisting of -CH₃, -CH₂CH₃, -CH(CH₃)₂, and -CHF₂.

1327<b>Embodiment 32.</b> A chemical entity, selected from the group consisting of: <ul id="ul0045" list-style="none" compact="compact"><li>5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile;</li><li>2-Chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine;</li><li>{2-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethyl}dimethylamine;</li><li>2-Methoxy-3-(6-methoxypyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</li><li>2-Methoxy-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</li><li>2-Methoxy-3-(5-methylpyridin-3-yl)-5-(1H-1,2,4-triazo1-1-ylmethyl)pyridine;</li><li>2-Methoxy-3-(2-methylpyridin-4-yl)-5-(1H-1,2,4-triazo1-1-ylmethyl)pyridine;</li><li>{3-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]phenyl}methanol;</li><li>3-(3-Methanesulfonylphenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</li><li>2-Methoxy-3-(4-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</li><li>2-Methoxy-3-(6-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</li><li>2-(Difluoromethoxy)-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</li><li>5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide;</li><li>[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol;</li><li>1-[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]-1-(4-fluorophenyl)ethan-1-ol;</li><li>[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](5-fluoropyridin-2-yl)methanol;</li><li>{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}(methyl)amine;</li><li>[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanamine;</li><li>{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}dimethylamine;</li><li>3-(3-Chlorophenyl)-5-[fluoro(4-fluorophenyl)methyl]-2-methoxypyridine;</li><li>4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzoic acid;</li><li>5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile;</li><li>5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxylic acid;</li><li>5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide;</li><li>5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)urea;</li><li>4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzamide;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-pyrazol-4-ylmethyl)pyridine;</li><li>5-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine;</li><li>1-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)-3-(oxetan-3-yl)urea;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxypyridin-3-yl)methyl]pyridine;</li><li>5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-amine;</li><li>5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyridin-2-amine;</li><li>5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carbonitrile;</li><li>5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1,3-thiazol-2-amine;</li><li>(2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanol;</li><li>5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carbonitrile;</li><li>5-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>5-{[5-(3-Chlorophenyl)-6-(propan-2-yloxy)pyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>5-{[6-(Difluoromethoxy)-5-[3-(propan-2-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>5-{[6-(Difluoromethoxy)-5-[3-(oxetan-3-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>N-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methanesulfonylphenyl)methyl]pyridine;</li><li>5-{[6-(Difluoromethoxy)-5-(2-methoxypyridin-4-yl)pyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-amine;</li><li>2-[5-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-yl]propan-2-ol;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyridine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[6-(propan-2-yloxy)pyridin-3-yl]methyl}pyridine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-propoxypyridin-3-yl)methyl]pyridine;</li><li>5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1-methyl-1,2-dihydropyridin-2-one;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-(pyridin-4-ylmethyl)pyridine;</li><li>5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxylic acid;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-[(2-methoxypyrimidin-5-yl)methyl]pyrazine;</li><li>5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-methylpyrimidin-2-amine;</li><li>5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-cyclopropylpyrimidin-2-amine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyrazine;</li><li>(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanamine;</li><li>4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine;</li><li>3-(3-Chlorophenyl)-5-[(2,6-dimethylpyridin-4-yl)methyl]-2-methoxypyridine;</li><li>4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carbonitrile;</li><li>4-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-(pyridin-3-ylmethyl)pyridine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-(1,3-thiazol-5-ylmethyl)pyridine;</li><li>3-(3-Chlorophenyl)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]-2-methoxypyridine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxy-5-methylpyridin-3-yl)methyl]pyridine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-5-ylmethyl)pyridine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]pyridine;</li><li>5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-3-carboxamide;</li><li>(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-3-yl)methanamine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-methylpyridin-3-yl)methyl]pyridine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(2-methyl-1,3-thiazo1-5-yl)methyl]pyridine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-2-ylmethyl)pyridine;</li><li>5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methylpyrimidine;</li><li>5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methoxypyrimidine;</li><li>5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(propan-2-yl)pyrimidin-2-amine;</li><li>5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyridine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-4-ylmethyl)pyridine;</li><li>5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-methylpyrimidin-2-amine;</li><li>5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-cyclopropylpyrimidin-2-amine;</li><li>5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyrimidin-2-amine;</li><li>5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine;</li><li>Methyl 4-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzoate;</li><li>4-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzonitrile;</li><li>5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidin-2-amine;</li><li>3-(3-Chlorophenyl)-5-[(4-fluorophenyl)methyl] -2-methoxypyridine;</li><li>5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyridine-2-carboxamide;</li><li>5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-cyclopropylpyrimidin-2-amine;</li><li>5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-2-methoxypyrimidine;</li><li>5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methylpyrimidin-2-amine;</li><li>5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-(1,2-oxazol-4-ylmethyl)pyrazine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-(1,2-oxazol-4-ylmethyl)pyridine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,2-oxazol-4-ylmethyl)pyridine;</li><li>3-(3-Chlorophenyl)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]-2-methoxypyrazine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]pyridine;</li><li>Methyl 2-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetate;</li><li>Ethyl 1-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxylate;</li><li>3-(3-Chlorophenyl)-5-{[6-(cyclopropylmethoxy)pyridin-3-yl]methyl}-2-(difluoromethoxy)pyridine;</li><li>5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carbonitrile;</li><li>5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidin-2-amine;</li><li>5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidin-2-amine;</li><li>5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidin-2-amine;</li><li>5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile;</li><li>5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(pyridin-2-ylmethyl)pyridine;</li><li>2-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrazine;</li><li>6-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridazin-3-amine;</li><li>3-(3-Chlorophenyl)-2-methoxy-6-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</li><li>4-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzamide;</li><li>5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxamide;</li><li>5-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidine-2-carboxamide;</li><li>5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide;</li><li>5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carboxamide;</li><li>5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide;</li><li>5-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide;</li><li>5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide;</li><li>5-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide;</li><li>5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide;</li><li>5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide;</li><li>5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carboxamide;</li><li>5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide;</li><li>5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide;</li><li>Methyl 1-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate;</li><li>3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-(difluoromethoxy)pyridine;</li><li>3-(3-Fluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyrazine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyrazine;</li><li>3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyrazine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</li><li>3-(3-Chlorophenyl)-2-(propan-2-yloxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</li><li>3-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]benzonitrile;</li><li>2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-4H-1,2,4-triazol-4-yl)methyl]pyridine;</li><li>3-(3,5-Difluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</li><li>Methyl 1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-5-carboxylate;</li><li>Methyl 1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carboxylate;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine;</li><li>3-[3-(Difluoromethyl)phenyl]-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyridine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</li><li>3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-{[4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}pyridine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[1-(1H-1,2,4-triazol-1-yl)ethyl]pyridine;</li><li>3-(3-Fluorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine;</li><li>3-(3-Chlorophenyl)-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</li><li>3-(3-Chlorophenyl)-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methyl-1H-imidazol-1-yl)methyl]pyridine;</li><li>3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine;</li><li>1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carbonitrile;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</li><li>3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</li><li>3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,3,4-tetrazol-1-ylmethyl)pyridine; 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(2H-1,2,3,4-tetrazol-2-ylmethyl)pyridine;</li><li>3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</li><li>3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</li><li>3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</li><li>3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</li><li>5-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-methoxypyridine;</li><li>1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide;</li><li>Ethyl 1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylate;</li><li>1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carbonitrile;</li><li>2-Methoxy-3-(pyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</li><li>N-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)acetamide;</li><li>3-(3-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyridine;</li><li>2-(Difluoromethoxy)-3-(3-fluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</li><li>2-(Difluoromethoxy)-3-(3-methoxyphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;</li><li>2-(Difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine;</li><li>1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1,2-dihydropyridin-2-one;</li><li>5-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-(3-chlorophenyl)-2-methoxypyridine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyridine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-[(4-nitro-1H-pyrazol-1-yl)methyl]pyridine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-[(4-nitro-1H-pyrazol-1-yl)methyl]pyrazine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyrazine;</li><li>3-(3-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyrazine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyrazine;</li><li>3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyrazine;</li><li>5-[(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-ethoxypyrazine;</li><li>3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine;</li><li>3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine;</li><li>3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine;</li><li>3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine;</li><li>Methyl 1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate;</li><li>Methyl 1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-5-carboxylate;</li><li>3-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine;</li><li>3-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((5-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine;</li><li>Methyl 1-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-5-carboxylate;</li><li>Methyl 1-({6-[3-(difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,4-triazole-3 -carboxylate;</li><li>Methyl 1-{[6-(3-chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate;</li><li>1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazole-4-carboxamide;</li><li>(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</li><li>(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</li><li>[1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;</li><li>[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;</li><li>(1-((5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol;</li><li>(1-{[6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</li><li>[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;</li><li>[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;</li><li>(1-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</li><li>[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;</li><li>[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-5-yl]methanol;</li><li>(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-5-yl)methanol;</li><li>[1-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;</li><li>(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(5-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-ethoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine;</li><li>1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine;</li><li>1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</li><li>1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</li><li>1-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</li><li>1-{[6-Methoxy-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</li><li>1-{[6-Methoxy-5-(3-methylphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</li><li>3-{5-[(3-Amino-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridin-3-yl}benzonitrile;</li><li>1-{[5-(3-Ethoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</li><li>1-{[5-(3-Cyclopropoxyphenyl)-6-methoxypyndin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</li><li>1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine;</li><li>1-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</li><li>1-{[5-(5-Chloropyridin-3-yl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</li><li>1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine;</li><li>1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine;</li><li>1-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</li><li>1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-3-amine;</li><li>1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-5-amine;</li><li>4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-amine;</li><li>4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-amine;</li><li>1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-pyrazol-4-amine;</li><li>1-((6-(3-(Difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazol-3-amine;</li><li>1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methyl-1H-1,2,4-triazol-3-amine;</li><li>1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N,N-dimethyl-1H-1,2,4-triazol-3-amine;</li><li>(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanamine;</li><li>1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carboxamide;</li><li>4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(oxetan-3-yl)benzamide;</li><li>5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methylpyridine-2-carboxamide;</li><li>1-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxamide;</li><li>2-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetamide;</li><li>2-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)propan-2-ol;</li><li>2-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-5-yl)propan-2-ol;</li><li>2-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)propan-2-ol;</li><li>2-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol;</li><li>2-(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol;</li><li>3-[3-(Difluoromethoxy)phenyl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine;</li><li>3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}pyridine;</li><li>2-(Difluoromethoxy)-3-(3-ethoxyphenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</li><li>3-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine;</li><li>3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine;</li><li>3-(3-Chlorophenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyrazine;</li><li>3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;</li><li>3-[3-(Difluoromethoxy)phenyl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-ethoxypyridine;</li><li>3-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,3-triazol-1-ylmethyl)pyridine;</li><li>[1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol;</li><li>(1-((6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol;</li><li>[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol;</li><li>(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methanol;</li><li>[1-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol;</li><li>(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methanol;</li><li>3-[3-(Difluoromethoxy)phenyl]-5-{[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}-2-ethoxypyridine;</li><li>1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylic acid;</li><li>1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxamide;</li><li>[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-4-yl]methanol;</li><li>(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-5-yl)methanol;</li><li>(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-4-yl)methanol;</li><li>[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-3-yl]methanol;</li><li>(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)methanol;</li><li>(4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-yl)methanol;</li><li>(4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-yl)methanol;</li><li>4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}benzoic acid;</li><li>(1-((6-Ethoxy-5-(2-fluorophenyl)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol;</li><li>5-((5-(3,4-Difluorophenyl)-6-propoxypyridin-3-yl)methyl)pyrimidin-2-amine;</li><li>5-((5-(3-Chloro-4-fluorophenyl)-6-ethoxypyridin-3-yl)methyl)pyrimidin-2-amine;</li><li>2-(4-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)acetamide;</li><li>2-(5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide;</li><li>5-{[5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide;</li><li>2-[(5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-ol;</li><li>2-(5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)-2-methylpropanenitrile;</li><li>2-(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)acetonitrile;</li><li>3-(3-Chlorophenyl)-5-[(5-ethoxypyridin-2-yl)methyl]-2-methoxypyridine;</li><li>5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-amine;</li><li>5-((5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-amine;</li><li>2-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-5-ethoxypyrazine;</li><li>2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-yl)amino)ethanol;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-((5-methyl-1H-tetrazol-1-yl)methylpyridine;</li><li>4-(5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)pyrimidin-2-yl)morpholine;</li><li>5-((6-(3,4-difluorophenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidin-2-amine;</li><li>2-((5-((6-(3,4-difluorophenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidin-2-yl)amino)ethanol;</li><li>2-(1-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-tetrazol-5-yl)ethanol;</li><li>2-Ethoxy-3-(4-fluorophenyl)-5-((5-methyl-1H-tetrazol-1-yl)methyl)pyridine;</li><li>2'-(Difluoromethoxy)-5-((4-(difluoromethyl)-2-methyl-1H-imidazol-1-yl)methyl)-2-methoxy-3,4'-bipyridine;</li><li>2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)acetamide;</li><li>(5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)methanol;</li><li>(1-((5-(3-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol;</li><li>5-((2'-(Difluoromethoxy)-2-methoxy-[3,4'-bipyridin]-5-yl)methyl)-3-fluoropyridin-2-amine;</li><li>5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-ol;</li><li>2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)ethanol;</li><li>5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-2-(difluoromethoxy)pyrimidine;</li><li>5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-3-methylpyridazine;</li><li>3-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-fluoropyridin-3-yl)methyl]pyridine;</li><li>1-{[5-(2-Cyanopyridin-4-yl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide;</li><li>1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide;</li><li>1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazole-3-carboxamide;</li><li>1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-imidazole-4-carboxamide;</li><li>1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-imidazole-4-carboxamide;</li><li>1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-imidazole-4-carboxamide;</li><li>1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-pyrazole-3-carboxamide;</li><li>1-{[6-(3,4-Difluorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-imidazole-4-carboxamide;</li><li>[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-2-methyl-1H-imidazol-4-yl]methanol;</li><li>[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-5-methyl-1H-pyrazol-3-yl]methanol;</li><li>1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-5-methyl-1H-pyrazol-3-amine;</li><li>1-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)oxy]-2-methylpropan-2-ol;</li><li>(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-2-methyl-1H-imidazo1-5-yl)methanol;</li><li>(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-3-methyl-1H-pyrazol-5-yl)methanol;</li><li>(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</li><li>(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</li><li>(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-5-methyl-1H-pyrazol-3-yl)methanol;</li><li>(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</li><li>(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-5-methyl-1H-pyrazol-3-yl)methanol;</li><li>(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</li><li>(1-{[6-Ethoxy-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</li><li>(1-{[5-(4-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</li><li>(1-{[5-(5-Chloropyridin-3-yl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</li><li>(1-{[5-(3,4-Dichlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</li><li>(1-{[-(4-fluoro-3-methylphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</li><li>[1-({6-Ethoxy-5-[3-(trifluoromethyl)phenyl]pyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;</li><li>[1-({6-Ethoxy-5-[3-(trifluoromethoxy)phenyl]pyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;</li><li>(1-{[-(3-ethoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</li><li>[1-({5-[3-(Dimethylamino)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;</li><li>(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</li><li>(1-{[5-(3-Chloro-4-fluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</li><li>(1-{[5-(3,5-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</li><li>[1-({6-Ethoxy-5-[2-(trifluoromethyl)pyridin-4-yl]pyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;</li><li>(1-{[5-(3,4-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</li><li>(1-{[-(3-fluorophenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</li><li>(1-{[6-Ethoxy-5-(4-fluorophenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;</li><li>(1-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</li><li>(1-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</li><li>(1-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</li><li>(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</li><li>4-{5-[(2-Aminopyrimidin-5-yl)methyl]-2-methoxypyridin-3-yl}pyridine-2-carbonitrile;</li><li>2-(5-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetonitrile;</li><li>5-{[5-(2-Ethoxypyridin-4-yl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>5-{[6-Ethoxy-5-(4-fluorophenyl)pyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>5-{[5-(4-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>5-{[6-Ethoxy-5-(4-fluoro-3-methylphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>5-{[5-(3,4-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>5-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>5-{[5-(3-Ethoxy-4-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>3-{5-[(2-Aminopyrimidin-5-yl)methyl]-2-methoxypyridin-3-yl}benzonitrile;</li><li>5-{[5-(4-Fluoro-3-methylphenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>2-(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetonitrile;</li><li>5-{[5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;</li><li>2-(4-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide;</li><li>2-(4-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide;</li><li>2-(4-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide;</li><li>2-(5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide;</li><li>2-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)-2-methylpropanamide;</li><li>2-(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide;</li><li>2-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide;</li><li>2-(5-{[5-(3-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetamide;</li><li>2-(5-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetamide;</li><li>2-(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)acetamide;</li><li>5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide;</li><li>5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide;</li><li>2-[(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-ol;</li><li>(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrazin-2-yl)methanol;</li><li>2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-5-methylpyrazine;</li><li>6-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-3-carbonitrile;</li><li>5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrazin-2-amine;</li><li>3-(3-Chlorophenyl)-2-methoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</li><li>(2-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol;</li><li>(1-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol;</li><li>(2-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol;</li><li>(1-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol;</li><li>(2-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol;</li><li>(1-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol;</li><li>(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol;</li><li>(2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol;</li><li>1-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)pyrrolidin-3-ol;</li><li>1-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)azetidin-3-οl;</li><li>2-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-ol;</li><li>2-Ethoxy-3-(4-fluorophenyl)-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine;</li><li>3-(3,4-Difluorophenyl)-2-ethoxy-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine;</li><li>3-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine;</li><li>3-(3,4-Difluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</li><li>3-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</li><li>3-(4-Chloro-3-fluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</li><li>3-(3-Chloro-4-fluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</li><li>3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</li><li>2-Ethoxy-3-(2-ethoxypyridin-4-yl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</li><li>2-Ethoxy-3-(3-ethoxyphenyl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</li><li>2-Ethoxy-3-(3-fluoro-5-methoxyphenyl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine;</li><li>3-(3-Chlorophenyl)-5-{[4-(difluoromethyl)-2-methyl-1H-imidazol-1-yl]methyl}-2-ethoxypyrazine;</li><li>(5-{[6-(2,2-Difluoroethoxy)-5-(2-ethoxypyridin-4-yl)pyridin-3-yl]methyl}-3-fluoropyridin-2-yl)methanol;</li><li>[5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-3-fluoropyridin-2-yl]methanol;</li><li>(1-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;</li><li>1-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;</li><li>Ethyl 2-(4-{[5-(3,4-difluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetate;</li><li>Ethyl 2-(4-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetate; and</li><li>pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, or pharmaceutically active metabolites thereof.</li></ul>

1328<b>Embodiment 33.</b> A pharmaceutical composition comprising an effective amount of at least one chemical entity selected from the compounds of Formula (I): <chemistry id="chem0520" num="0520"><img file="EP3345902A1_D0525.tif" /></chemistry> wherein: <ul id="ul0046" list-style="none" compact="compact"><li>Z is CH or N; <ol id="ol0008" compact="compact"><li>i) wherein when Z is CH, then; <ul id="ul0047" list-style="none" compact="compact"><li>R¹ is a member selected from the group consisting of: -H, -C_1-3alkyl and -C_1-3haloalkyl;</li><li>Y is -C(R^a)₂-, where each R^a is independently selected from the group consisting of: -H, -F, - CH₃, -OH and -N(R^b)₂;</li><li>R² is a member selected from the group consisting of: <ol id="ol0009" compact="compact"><li>A) phenyl unsubstituted or substituted with one or two R^c members, where each R^c is independently selected from the group consisting of: halo, -CN, -CO₂R^b, -CONH₂, -SO₂CH₃, -C(R^b)₂OH, -CH₂NH₂, -CH₂CONH₂, -CH₂CO₂C_1-3alkyl, -NHCONH₂, - NHCONH-oxetane, -CONH-oxetane, <chemistry id="chem0521" num="0521"><img file="EP3345902A1_D0526.tif" /></chemistry></li><li>B) six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of: halo, -C_1-3alkyl, -C_1-3haloalkyl, -CN, -OH, -C(R^b)₂OH, -CH₂NH₂, -C(R^b)₂CN, -C(R^b)₂CONH₂, - OCH₂CONH₂, -OC_1-3alkyl, -OCH₂C(R^b)₂OH, -OCH₂cyclopropyl, -OC_1-3haloalkyl, -CO₂H, -CON(R^b)₂, -N(R^b)₂, -NHCH₂CF₃, -NHCH(CH₃)₂, - NHCH₂CH₂N(CH₃)₂, -NHCH₂CH₂OH, -NHcyclopropyl, -NHCOCH₃, morpholinyl, pyrrolidin-3-ol, and azetidin-3-ol;</li><li>C) five-membered monocyclic heteroaromatic ring containing two, three, or four nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of halo, -C_1-3alkyl, -C_1-3haloalkyl, -C(R^b)₂OH, -N(R^b)₂, -NO₂, -CN, -CH₂CN, -OC_1-3alkyl, -CH₂OCH₃, - CH₂CH₂OH, -CH₂NH₂, -CH₂CONH₂, -CO₂C_1-3alkyl, -CO₂H, -CONH₂, - NHCOCH₃, and cyclopropyl; and</li><li>D) five or six-membered ring selected from: 1,2-dihydro-pyridin-2-one, thiazole or 1,2-oxazole unsubstituted or substituted with one or two members each independently selected from the group consisting of -CH₃, and -NH₂;</li></ol></li><li>R³ is phenyl or pyridine, each substituted with one or two members each independently selected from the group consisting of: -halo, -C_1-3alkyl, -OC_1-3alkyl, - Ocyclopropyl, -C_1-3haloalkyl, -OC_1-3haloalkyl, -CN, -CH₂OH, -SO₂CH₃, or - N(CH₃)₂; R⁴ is a member selected from the group consisting of -C_1-3alkyl and -C_1-3haloalkyl; and</li><li>each R^b is independently selected from -H or -CH₃;</li></ul></li><li>ii) wherein when Z is N, then; <ul id="ul0048" list-style="none" compact="compact"><li>R¹ is -H;</li><li>Y is -CH₂-;</li><li>R² is a member selected from the group consisting of: <ol id="ol0010" compact="compact"><li>A) phenyl substituted with one or two R^d members, where each R^d is independently selected from the group consisting of: -CN, -CONH₂, and -CO₂C_1-3alkyl;</li><li>B) six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with a member selected from the group consisting of: -CN, -OC_1-3alkyl, -CONH₂, -NHCH₂CH₂OH, -N(R^b)₂, and -NHcyclopropyl;</li><li>C) five-membered monocyclic heteroaromatic ring containing two or three nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of -C_1-3alkyl, -C_1-3haloalkyl, - CH₂OR^b -N(R^b)₂, -NO₂, -CO₂CH₃, -CO₂N(R^b)₂, or cyclopropyl; and</li><li>D) 1,2-oxazole optionally substituted with one or two R^b members;</li></ol></li><li>R³ phenyl substituted with one or two members each indeoendently selected from the group consisting of: -Cl, -OC_1-3alkyl, or -OC_1-3haloalkyl;</li><li>R⁴ is -C_1-3alkyl; and</li><li>each R^b is independently selected from -H or -CH₃;</li><li>and pharmaceutically acceptable salt of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I); or pharmaceutically active metabolites of compounds of Formula (I).</li></ul></li></ol></li></ul>

1329<b>Embodiment 34.</b> A pharmaceutical composition comprising an effective amount of at least one chemical entity of Embodiment 1 or 32.

1330<b>Embodiment 35.</b> A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by PDE4 enzymatic activity, comprising administering to a subject in need of such treatment an effective amount of a chemical entity selected from compounds of Formula (I) <chemistry id="chem0522" num="0522"><img file="EP3345902A1_D0527.tif" /></chemistry> wherein: <ul id="ul0049" list-style="none" compact="compact"><li>Z is CH or N; <ol id="ol0011" compact="compact"><li>i) wherein when Z is CH, then; <ul id="ul0050" list-style="none" compact="compact"><li>R¹ is a member selected from the group consisting of: -H, -C_1-3alkyl and -C_1-3haloalkyl;</li><li>Y is -C(R^a)₂-, where each R^a is independently selected from the group consisting of: -H, -F, - CH₃, -OH and -N(R^b)₂;</li><li>R² is a member selected from the group consisting of: <ol id="ol0012" compact="compact"><li>A) phenyl unsubstituted or substituted with one or two R^c members, where each R^c is independently selected from the group consisting of: halo, -CN, -CO₂R^b, -CONH₂, -SO₂CH₃, -C(R^b)₂OH, -CH₂NH₂, -CH₂CONH₂, -CH₂CO₂C_1-3alkyl, -NHCONH₂, - NHCONH-oxetane, -CONH-oxetane, <chemistry id="chem0523" num="0523"><img file="EP3345902A1_D0528.tif" /></chemistry></li><li>B) six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of: halo, -C_1-3alkyl, -C_1-3haloalkyl, -CN, -OH, -C(R^b)₂OH, -CH₂NH₂, -C(R^b)₂CN, -C(R^b)₂CONH₂, - OCH₂CONH₂, -OC_1-3alkyl, -OCH₂C(R^b)₂OH, -OCH₂cyclopropyl, -OC_1-3haloalkyl, -CO₂H, -CON(R^b)₂, -N(R^b)₂, -NHCH₂CF₃, -NHCH(CH₃)₂, - NHCH₂CH₂N(CH₃)₂, -NHCH₂CH₂OH, -NHcyclopropyl, -NHCOCH₃, morpholinyl, pyrrolidin-3-ol, and azetidin-3-ol;</li><li>C) five-membered monocyclic heteroaromatic ring containing two, three, or four nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of halo, -C_1-3alkyl, -C_1-3haloalkyl, -C(R^b)₂OH, -N(R^b)₂, -NO₂, -CN, -CH₂CN, -OC_1-3alkyl, -CH₂OCH₃, - CH₂CH₂OH, -CH₂NH₂, -CH₂CONH₂, -CO₂C_1-3alkyl, -CO₂H, -CONH₂, - NHCOCH₃, and cyclopropyl; and</li><li>D) five or six-membered ring selected from: 1,2-dihydro-pyridin-2-one, thiazole or 1,2-oxazole unsubstituted or substituted with one or two members each independently selected from the group consisting of -CH₃, and -NH₂;</li></ol></li><li>R³ is a phenyl or pyridine, each substituted with one or two members each independently selected from the group consisting of: -halo, -C_1-3alkyl, -OC_1-3alkyl, - Ocyclopropyl, -O-oxetane, -C_1-3haloalkyl, -OC_1-3haloalkyl, -CN, -CH₂OH, - SO₂CH₃, or -N(CH₃)₂; R⁴ is a member selected from the group consisting of -C_1-3alkyl and -C_1-3haloalkyl; and</li><li>each R^b is independently selected from -H or -CH₃;</li></ul></li><li>ii) wherein when Z is N, then; <ul id="ul0051" list-style="none" compact="compact"><li>R¹ is -H;</li><li>Y is -CH₂-;</li><li>R² is a member selected from the group consisting of: <ol id="ol0013" compact="compact"><li>A) phenyl substituted with one or two R^d members, where each R^d is independently selected from the group consisting of: -CN, -CONH₂, and -CO₂C_1-3alkyl;</li><li>B) six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with a member selected from the group consisting of: -CN, -OC_1-3alkyl, -CONH₂, -NHCH₂CH₂OH, -N(R^b)₂, and -NHcyclopropyl;</li><li>C) five-membered monocyclic heteroaromatic ring containing two or three nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of -C_1-3alkyl, -C_1-3haloalkyl, - CH₂OR^b, -N(R^b)₂, -NO₂, -CO₂CH₃, -CO₂N(R^b)₂, or cyclopropyl; and</li><li>D) 1,2-oxazole optionally substituted with one or two R^b members;</li></ol></li><li>R³ phenyl substituted with one or two members each independently selected from the group consisting of: -Cl, -OC_1-3alkyl, or -OC_1-3haloalkyl;</li><li>R⁴ is -C_1-3alkyl; and</li><li>each R^b is independently selected from -H or -CH₃;</li><li>and pharmaceutically acceptable salt of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I); or pharmaceutically active metabolites of compounds of Formula (I).</li></ul></li></ol></li></ul>

1331<b>Embodiment 36.</b> The method of Embodiment 35, wherein Y is -CH₂- and Z is CH.

1332<b>Embodiment 37.</b> A method of treating a disease, disorder, or medical condition mediated by a PDE4 enzyme, comprising administering to an animal in need of such treatment an effective amount of a chemical entity of Embodiment 1 or Embodiment 32.

1333<b>Embodiment 38.</b> The method of Embodiment 35, 36, or 37, wherein the disorder is selected from one or more of the group selected from Alzheimer's Disease, Age Associated Memory Impairment (AAMI), Age Associated Cognitive Decline, vascular dementia, delirium, Parkinson's disease, Huntington's disease, Pick's disease, mental retardation, cerebrovascular disease, an affective disorder, psychotic disorders, neurotic disorders, attention deficit disorder, subdural hematoma, normal-pressure hydrocephalus, brain tumor, stroke, cognitive impairment due to sleep deprivation, intellectual and developmental disabilitie; multiple sclerosis; inflammatory bowel disease; rheumatoid arthritis; COPD, asthma, allergic rhinitis, pulmonary artery hypertension; renal diseases; allergic skin diseases and psoriasis.

1334<b>Embodiment 39.</b> A method for modulating PDE4 enzyme activity, comprising exposing a PDE4 enzyme to an effective amount of at least one chemical entity selected from compounds of Formula (I) <chemistry id="chem0524" num="0524"><img file="EP3345902A1_D0529.tif" /></chemistry> wherein: <ul id="ul0052" list-style="none" compact="compact"><li>Z is CH or N; <ol id="ol0014" compact="compact"><li>i) wherein when Z is CH, then; <ul id="ul0053" list-style="none" compact="compact"><li>R¹ is a member selected from the group consisting of: -H, -C_1-3alkyl and -C_1-3haloalkyl;</li><li>Y is -C(R^a)₂-, where each R^a is independently selected from the group consisting of: -H, -F, - CH₃, -OH and -N(R^b)₂;</li><li>R² is a member selected from the group consisting of: <ol id="ol0015" compact="compact"><li>A) phenyl unsubstituted or substituted with one or two R^c members, where each R^c is independently selected from the group consisting of: halo, -CN, -CO₂R^b, -CONH₂, -SO₂CH₃, -C(R^b)₂OH, -CH₂NH₂, -CH₂CONH₂, -CH₂CO₂C_1-3alkyl, -NHCONH₂, - NHCONH-oxetane, -CONH-oxetane, <chemistry id="chem0525" num="0525"><img file="EP3345902A1_D0530.tif" /></chemistry></li><li>B) six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of: halo, -C_1-3alkyl, -C_1-3haloalkyl, -CN, -OH, -C(R^b)₂OH, -CH₂NH₂, -C(R^b)₂CN, -C(R^b)₂CONH₂, - OCH₂CONH₂, -OC_1-3alkyl, -OCH₂C(R^b)₂OH, -OCH₂cyclopropyl, -OC_1-3haloalkyl, -CO₂H, -CON(R^b)₂, -N(R^b)₂, -NHCH₂CF₃, -NHCH(CH₃)₂, - NHCH₂CH₂N(CH₃)₂, -NHCH₂CH₂OH, -NHcyclopropyl, -NHCOCH₃, morpholinyl, pyrrolidin-3-ol, and azetidin-3-ol;</li><li>C) five-membered monocyclic heteroaromatic ring containing two, three, or four nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of halo, -C_1-3alkyl, -C_1-3haloalkyl, -C(R^b)₂OH, -N(R^b)₂, -NO₂, -CN, -CH₂CN, -OC_1-3alkyl, -CH₂OCH₃, - CH₂CH₂OH, -CH₂NH₂, -CH₂CONH₂, -CO₂C_1-3alkyl, -CO₂H, -CONH₂, - NHCOCH₃, and cyclopropyl; and</li><li>D) five or six-membered ring selected from: 1,2-dihydro-pyridin-2-one, thiazole or 1,2-oxazole unsubstituted or substituted with one or two members each independently selected from the group consisting of -CH₃, and -NH₂;</li></ol></li><li>R³ is phenyl or pyridine, each substituted with one or two members each independently selected from the group consisting of: -halo, -C_1-3alkyl, -OC_1-3alkyl, - Ocyclopropyl, -C_1-3haloalkyl, -OC_1-3haloalkyl, -CN, -CH₂OH, -SO₂CH₃, or - N(CH₃)₂; R⁴ is a member selected from the group consisting of -C_1-3alkyl and -C_1-3haloalkyl; and</li><li>each R^b is independently selected from -H or -CH₃;</li></ul></li><li>ii) wherein when Z is N, then; <ul id="ul0054" list-style="none" compact="compact"><li>R¹ is -H;</li><li>Y is -CH₂-;</li><li>R² is a member selected from the group consisting of: <ol id="ol0016" compact="compact"><li>A) phenyl substituted with one or two R^d members, where each R^d is independently selected from the group consisting of: -CN, -CONH₂, and -CO₂C_1-3alkyl;</li><li>B) six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with a member selected from the group consisting of: -CN, -OC_1-3alkyl, -CONH₂, -NHCH₂CH₂OH, -N(R^b)₂, and -NHcyclopropyl;</li><li>C) five-membered monocyclic heteroaromatic ring containing two or three nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of -C_1-3alkyl, -C_1-3haloalkyl, - CH₂OR^b, -N(R^b)₂, -NO₂, -CO₂CH₃, -CO₂N(R^b)₂, or cyclopropyl; and</li><li>D) 1,2-oxazole optionally substituted with one or two R^b members;</li></ol></li><li>R³ phenyl substituted with one or two members each independently selected from the group consisting of: -Cl, -OC_1-3alkyl, or -OC_1-3haloalkyl;</li><li>R⁴ is -C_1-3alkyl; and</li><li>each R^b is independently selected from -H or -CH₃;</li><li>and pharmaceutically acceptable salt of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I); or pharmaceutically active metabolites of compounds of Formula (I).</li></ul></li></ol></li></ul>

1335<b>Embodiment 40.</b> The method of Embodiment 39, wherein Y is -CH₂- and Z is CH.

1336<b>Embodiment 41.</b> A method for modulating PDE4 enzyme activity, comprising exposing a PDE4 enzyme to an effective amount of a chemical entity of Embodiment 1 or Embodiment 32.

1337<b>Embodiment 42.</b> The method of Embodiment 41, wherein said one or more PDE4 enzymes are in a human subject.

1338<b>Embodiment 43.</b> The method of Embodiment 42, wherein said human subject is suffering from or is diagnosed with a disease, disorder, or medical condition mediated by PDE4 enzymatic activity.

1339<b>Embodiment 44.</b> The method of Embodiment 43, wherein said disease, disorder, or medical condition is of the central nervous system selected from the group consisting of age-associated memory impairment, mild cognitive impairment, Alzheimer's disease, Parkinson's disease, and Pick's disease.

1340<b>Embodiment 45.</b> A method of treating a neurological disorder, comprising administering to a subject in need of such treatment an effective amount of a chemical entity of Embodiment 1 or Embodiment 32.

1341<b>Embodiment 46.</b> The method of Embodiment 45, wherein the disorder is selected from the group consisting of a central nervous system (CNS) disorder, psychiatric disorder, personality disorder, substance-related disorder, dissociative disorder, eating disorder, sleep disorder, developmental disorder, neurodegenerative disorder, trauma-related disorder, pain disorder, and a cognitive disorder.

1342<b>Embodiment 47.</b> The method of Embodiment 46, wherein the psychiatric disorder is selected from the group consisting of a mood disorder, psychotic disorder, and anxiety disorder.

1343<b>Embodiment 48.</b> The method of Embodiment 47, wherein the mood disorder is selected from the group consisting of a depressive disorder, including a dysthymic disorder, major depressive disorder, mania, bipolar disorders (I and II), and cyclothymic disorder.

1344<b>Embodiment 49.</b> The method of Embodiment 47, wherein the psychotic disorder is one or more selected from the group consisting of schizophrenia; schizophreniform disorder; schizoaffective disorder; a delusional disorder; a brief psychotic disorder; shared psychotic disorder; and a substance-induced psychotic disorder.

1345<b>Embodiment 50.</b> The method of Embodiment 47, wherein the anxiety disorder is selected from the group consisting of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, generalized anxiety disorder, post-traumatic stress disorder; and acute stress disorder.

1346<b>Embodiment 51.</b> The method of Embodiment 46, wherein the personality disorder is selected from the group consisting of a disorder of Cluster A (odd or eccentric), such as paranoid or schizoid personality disorder; a disorder of Cluster B (dramatic, emotional, or erratic), such as antisocial, borderline, or narcissistic personality disorder; and a disorder of Cluster C (anxious or fearful), such as avoidant, dependent, or obsessive-compulsive personality disorder.

1347<b>Embodiment 52.</b> The method of Embodiment 46, wherein the substance-related disorder is selected from the group consisting of an alcohol-related disorder, a cocaine-related disorder, a hallucinogen-related disorder, an inhalant-related disorder, a nicotine-related disorder, an opioid-related disorder, a phencyclidine (or phencyclidine-like) related disorder, and a sedative-, hypnotic-, or anxiolytic-related disorder.

1348<b>Embodiment 53.</b> A method of smoking cessation, comprising administering to an animal in need thereof of a chemical entity of Embodiment 1 or Embodiment 32.

1349<b>Embodiment 54.</b> The method of Embodiment 53, wherein the dissociative disorder is selected from the group consisting of depersonalization disorder, dissociative amnesia, and dissociative identity disorder.

1350<b>Embodiment 55.</b> The method of Embodiment 46, wherein the eating disorder is selected from the group consisting of anorexia nervosa and bulimia nervosa.

1351<b>Embodiment 56.</b> The method of Embodiment 46, wherein the sleep disorder is selected from the group consisting of a primary sleep disorder, parasomnia, and restless legs syndrome.

1352<b>Embodiment 57.</b> The method of Embodiment 46, wherein the developmental disorder is selected from the group consisting of mental retardation, a learning disorder, a motor skill disorder, a communication disorder, a pervasive developmental disorder, an attention-deficit or disruptive disorder, and a tic disorder.

1353<b>Embodiment 58.</b> The method of Embodiment 57, wherein the pervasive developmental disorder is an autistic disorder.

1354<b>Embodiment 59.</b> The method of Embodiment 57, wherein the attention-deficit or disruptive disorder is an attention-deficit hyperactivity disorder.

1355<b>Embodiment 60.</b> The method of Embodiment 46, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis (ALS).

1356<b>Embodiment 61.</b> The method of Embodiment 60, wherein the neurodegenerative disorder is Parkinson's disease.

1357<b>Embodiment 62.</b> The method of Embodiment 46, wherein the neurodegenerative disorder is selected from the group consisting of a dyskinesia, a basal ganglia disease, a hypokinetic disease, a movement disorder, and neuronal damage.

1358<b>Embodiment 63.</b> The method of Embodiment 62, wherein the neuronal damage is selected from the group consisting of brain edema and ocular damage.

1359<b>Embodiment 64.</b> The method of Embodiment 46, wherein the pain disorder is selected from the group consisting of acute pain, chronic pain, severe pain, intractable pain, neuropathic pain, and post-traumatic pain.

1360<b>Embodiment 65.</b> The method of Embodiment 46, wherein the cognitive disorder is selected from the group consisting of age-associated memory impairment (AAMI), mild cognitive impairment (MCI), delirium, and dementia.

1361<b>Embodiment 66.</b> A method of treating Alzheimer's disease or Parkinson's disease, comprising administering to an animal in need thereof an effective amount of a chemical entity of Embodiment 1 or Embodiment 32.

1362<b>Embodiment 67.</b> A method of treating a cognitive disorder, comprising administering to an animal in need thereof an effective amount of a compound, or derivative of Embodiment 1 or Embodiment 32.

1363<b>Embodiment 68.</b> The method of Embodiment 67, wherein the cognitive disorder is an age-associated cognitive disorder.

1364<b>Embodiment 69.</b> The method of Embodiment 68, wherein the age-associated cognitive disorder is age-associated memory impairment (AAMI or AMI).

1365<b>Embodiment 70.</b> The method of Embodiment 68, wherein the age-associated cognitive disorder is mild cognitive impairment (MCI).

1366<b>Embodiment 71.</b> A method of treating a cognitive deficit associated with Parkinson's disease, comprising administering to an animal in need thereof an effective amount of a chemical entity of Embodiment 1 or Embodiment 32.

1367<b>Embodiment 72.</b> A method of treating a cognitive disorder, comprising: <ol id="ol0017" compact="compact"><li>(a) providing cognitive training to a subject in need of treatment of a cognitive deficit under conditions sufficient to produce an improvement in performance by said animal of a cognitive function whose impairment is associated with said cognitive deficit;</li><li>(b) administering a chemical entity of Embodiment 1 or Embodiment 32 to the animal in conjunction with said cognitive training; and</li><li>(c) repeating steps (a) and (b) one or more times; whereby</li></ol> the number of training sessions sufficient to produce the improvement in performance are reduced relative to the same improvement in performance produced by cognitive training alone.

1368<b>Embodiment 73.</b> A method of treating a motor deficit, comprising: <ol id="ol0018" compact="compact"><li>(a) providing motor training to a subject in need of treatment of a motor deficit under conditions sufficient to produce an improvement in performance by said animal of a motor function whose impairment is associated with said motor deficit;</li><li>(b) administering a chemical entity of Embodiment 1 or Embodiment 32 to the animal in conjunction with said motor training; and</li><li>(c) repeating steps (a) and (b) one or more times; whereby</li></ol> the number of training sessions sufficient to produce the improvement in performance are reduced relative to the same improvement in performance produced by motor training alone.

1369<b>Embodiment 74.</b> The method of Embodiment 35-38, 42-73, wherein said subject is a human.

1370<b>Embodiment 75.</b> A method comprising: <ol id="ol0019" compact="compact"><li>a) administering a CREB augmenting agent to a non-human animal; b) providing to said animal a training protocol under conditions to improve performance by said animal of one or more tasks, wherein said training protocol comprises multiple training sessions; whereby the number of training sessions necessary to improve said performance relative to the number of said training sessions required to improve said performance in the absence of said CREB augmenting agent are reduced, wherein said CREB augmenting agent is a chemical entity of Embodiment 1 or Embodiment 32.</li></ol>

1371<b>Embodiment 76.</b> The method of Embodiment 75, wherein providing step b) is under conditions to improve performance of a single task.

1372<b>Embodiment 77.</b> The method of Embodiment 75, wherein said providing step b) is under conditions to improve performance of a complex set of tasks.

1373<b>Embodiment 78.</b> The method of Embodiment 75, wherein said providing step b) is under conditions that improve performance by said animal of related tasks that are not part of the training protocol.

1374<b>Embodiment 79.</b> The method of Embodiment 75, wherein said non-human animal is a horse.

1375<b>Embodiment 80.</b> The method of Embodiment 75, wherein said non-human animal is a dog.

1376<b>Embodiment 81.</b> The method of Embodiment 75, wherein said one or more tasks relate to a skill useful in law enforcement.

1377<b>Embodiment 82.</b> The method of Embodiment 81, wherein said skill includes one or more of the following: public order maintenance, search and rescue, and contraband detection.

1378<b>Embodiment 83.</b> The method of Embodiment 75, wherein said one or more tasks relate to a skill useful in private security.

1379<b>Embodiment 84.</b> The method of Embodiment 75, wherein said one or more tasks relate to a skill useful in service to the handicapped.

1380<b>Embodiment 85.</b> The method of Embodiment 75, wherein said one or more tasks relate to a skill useful in health care.

1381<b>Embodiment 86.</b> The method of Embodiment 75, wherein said one or more tasks relate to a skill useful in psychiatric assistance.

1382<b>Embodiment 87.</b> The method of Embodiment 75, wherein said one or more tasks relate to pest control.

1383<b>Embodiment 88.</b> The method of Embodiment 75, wherein said training protocol is provided under conditions to improve performance by said non-human animal of a wide scope of tasks, thereby resulting in a generalized improved function of one or more cognitive domains in said non-human animal.

1384<b>Embodiment 89.</b> A method of augmenting neurorehabilitation or neurorecovery from a cognitive impairment, comprising (a) providing cognitive training to a subject in need of treatment of a cognitive deficit under conditions sufficient to produce an improvement in performance by said animal of a cognitive function whose impairment is associated with said cognitive deficit; (b) administering a chemical entity of Embodiment 1 or Embodiment 32 to the subject in conjunction with said cognitive training; repeating steps (a) and (b) one or more times; and (d) producing a long-lasting improvement in performance of said function relative to the improvement in performance of said function produced by cognitive training alone.

1385<b>Embodiment 90.</b> A method of augmenting neurorehabilitation or neurorecovery from a motor impairment, comprising: (a) providing motor training to a subject in need of treatment of a motor deficit under conditions sufficient to produce an improvement in performance by said animal of a motor function whose impairment is associated with said cognitive deficit; and (b) administering a chemical entity of Embodiment 1 or Embodiment 32 to the subject in conjunction with said motor training; repeating steps (a) and (b) one or more times; thereby reducing the number of training sessions sufficient to produce the improvement in performance, relative to the same improvement in performance produced by motor training alone.

1386<b>Embodiment 91.</b> A method of providing neuroprotection, comprising administering to an animal in need thereof an effective amount of a chemical entity as in Embodiment 1 or Embodiment 32.

1387<b>Embodiment 92.</b> The method of any one of Embodiments 75-91 wherein the animal or subject is a human.

1388<b>Embodiment 93.</b> A method of using a chemical entity as in Embodiment 1 or Embodiment 32 in metabolic studies, detection or imaging techniques, or radioactive treatment.

1389<b>Embodiment 94.</b> A chemical entity as in Embodiment 1 or Embodiment 32, further comprising an isotopic label.

1390<b>Embodiment 95.</b> The a chemical entity as in Embodiment 94, wherein the isotopic label includes at least one atom selected from Hydrogen-2, Hydrogen-3, Carbon-11, Nitrogen-13, Fluorine-18, and Iodine-123.

1391<b>Embodiment 96.</b> A method of treating a disorder selected from the group consisting of inflammatory bowel disease; rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis, pulmonary artery hypertension; renal diseases; allergic skin diseases, and psoriasis, comprising administering to a subject in need thereof an effective amount of a chemical entity as in Embodiment 1 or Embodiment 32.

1392<b>Embodiment 97.</b> The method of Embodiment 96, wherein the disorder is inflammatory bowel disease.

1393<b>Embodiment 98.</b> The method of Embodiment 96, wherein the disorder is rheumatoid arthritis.

1394<b>Embodiment 99.</b> The method of Embodiment 96, wherein the disorder is COPD.

1395<b>Embodiment 100.</b> The method of Embodiment 96, wherein the disorder is asthma.

1396<b>Embodiment 101.</b> The method of Embodiment 96, wherein the disorder is allergic rhinitis.

1397<b>Embodiment 102.</b> The method of Embodiment 96, wherein the disorder is pulmonary artery hypertension.

1398<b>Embodiment 103.</b> The method of Embodiment 96, wherein the disorder is a renal disease.

1399<b>Embodiment 104.</b> The method of Embodiment 96, wherein the disorder is an allergic skin disease.

1400<b>Embodiment 105.</b> The method of Embodiment 96, wherein the disorder is psoriasis.

1401<b>Embodiment 106.</b> The method of any one of Embodiments 97-105, wherein the animal or subject is a human.

1402<b>Embodiment 108.</b> A chemical entity as in Embodiment 33 or Embodiment 34, wherein the chemical entity of Embodiment 1 or 32 is a compound of Formula (I).

1403<b>Embodiment 109.</b> A composition of Embodiment 33 or Embodiment 34 , wherein the chemical entity of Embodiment 1 or 32 is selected from compounds of Formula (I) and pharmaceutically acceptable salts of compounds of Formula (I).

1404<b>Embodiment 110.</b> The method of any one of Embodiments 36-107, wherein the chemical entity of Embodiment 1 or 32 is a compound of Formula (I).

1405<b>Embodiment 111.</b> The method of any one of Embodiments 36-107, wherein the chemical entity of Embodiment 1 or 32 is selected from compounds of Formula (I) and pharmaceutically acceptable salts of compounds of Formula (I).

1406<b>Embodiment 112.</b> The use of a chemical entity of Embodiments 1 or 32 in a method of treating stroke.

1407<b>Embodiment 113.</b> The use of Embodiment 1, wherein the method of treating stroke is post-stroke rehabilitation.

1408<b>Embodiment 114.</b> A method of post-stroke rehabilitation, comprising: <ol id="ol0020" compact="compact"><li>a. administering to a subject in need thereof a PDE4 inhibitor during recovery of the subject from stroke;</li><li>b. providing training to the subject under conditions sufficient to improve performance of a neurological function whose impairment is due to said stroke;</li><li>c. repeating steps (a) and (b) one or more times, whereby the amount of training sufficient to improve said performance is reduced relative to that produced by training alone.</li></ol>

1409<b>Embodiment 115.</b> The method of Embodiment 114, wherein said PDE4 inhibitor is a chemical entity of Embodiments 1 or 32.

1410<b>Embodiment 116.</b> The method of Embodiment 114, wherein the impairment of the neurological function is a motor deficit.

1411<b>Embodiment 117.</b> The method of Embodiment 114, wherein the impairment of the neurological function is a cognitive deficit.

1412<b>Embodiment 118.</b> The method of Embodiment 117, wherein the cognitive deficit is a deficit in memory formation.

1413<b>Embodiment 119.</b> The method of Embodiment 118, wherein the deficit in memory formation is a deficit in long-term memory formation.

1414<b>Embodiment 120.</b> The method of Embodiment 114, wherein the training comprises a battery of tasks directed to the neurological function.

1415<b>Embodiment 121.</b> The method of Embodiment 114, wherein said administering step (a) occurs in conjunction with said training step (b).

1416<b>Embodiment 122.</b> The method of Embodiment 114, wherein the one or more training steps are separated by a discrete interval.

1417<b>Embodiment 123.</b> The method of Embodiment 122, wherein each training step is provided daily.

1418<b>Embodiment 124.</b> The method of Embodiment 123, wherein the reduction in the amount of training is a reduction in the number of training sessions.