RU2802185C2 - Substituted pyridine and pyrazine compounds as pde4 inhibitors - Google Patents

Abstract

FIELD: pharmaceuticals and medicine.

SUBSTANCE: group of inventions is aimed at treating diseases mediated by inhibition of PDE4 enzymes. A pharmaceutical composition for the treatment of a disease, disorder or medical condition mediated by the PDE4 enzyme or PDE4 enzymatic activity, containing an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where: the values of the radicals are as indicated in paragraph 1 of the formula is disclosed. Also the methods of treating a disease, disorder, or medical condition mediated by PDE4 enzymatic activity, as well as mediated by PDE4 enzyme, comprising administering to a subject in need of such treatment, an effective amount of the present composition, and in addition, the use of the above composition in a method for treating a neurological disorder and use of the composition in a method of treating a peripheral disorder are disclosed.

EFFECT: group of inventions provides effective treatment of neurological and peripheral disorders mediated by inhibition of PDE4 enzymes.

19 cl, 3 tbl, 406 ex

Description

INCLUSION BY REFERENCE OF ALL PRIORITY APPLICATIONS

Any and all priority claims in the Application Information Sheet, or any amendment thereto, are incorporated herein by reference under 37 CFR Section 1.57. For example, the present application claims priority from U.S. Provisional Application No. 61/786,288, filed March 14, 2013, the entire contents of which are incorporated herein by reference.

FIELD OF TECHNOLOGY

The present invention relates to certain substituted pyridine and pyrazine compounds as inhibitors of PDE4 enzymes; derivatives of these compounds; compositions of said compounds; ways to get them; and their application in a variety of ways, including detection and imaging technologies; improvement of neuronal plasticity; treatment of neurological disorders, including psychiatric, neurodegenerative, cerebrovascular, cognitive and movement disorders; providing neuroprotection; improving the effectiveness of cognitive training and motor learning; facilitation of neurorecovery and neurorehabilitation; and treatment of peripheral disorders including inflammatory and renal disorders.

BACKGROUND OF THE INVENTION

Mammalian phosphodiesterases (PDEs) are a group of closely related enzymes classified into 11 families (PDE1-11) based on substrate specificity, inhibitor sensitivity and more recently sequence homology. The 11 families are encoded by 21 genes, so some families have multiple members. All mammalian PDEs share a common conserved catalytic domain located at the COOH-terminus of the protein. With GAF-containing PDEs, one or more GAFs may provide contact points for dimerization. In addition, one of the GAFs in each of these proteins mediates cGMP allosteric binding (PDE2, PDE5, PDE6, PDE11), cAMP allosteric binding (PDE10), and regulation of catalytic site functions (PDE2, PDE5, PDE6). Other families of PDEs have unique complements of different subdomains (UCR, NHR, PAS, membrane association) that contribute to the regulation of activity. PDEs 1, 2, 3, and 4 are expressed in many tissues, while others are more limited. In most cells, PDE3 and PDE4 provide the bulk of cAMP hydrolyzing activity (Francis, Physiological Reviews , 2011, 91, 651-690).

The PDE4 family includes four isoforms (PDE4A, B, C, and D) with over 20 splice variants, making it one of the largest PDE subfamilies (Bender and Beavo, 2006). PDE4 enzymes hydrolyze cAMP with an apparent substrate specificity constant Km of 1-5 μM for cAMP. The PDE4 enzyme is described to be regulated by two upper control region (UCR) domains. Depending on differential RNA splicing, PDE4 variants can be classified into two main subgroups: long and short forms (Conti et al., J Biol Chem ., 2003, 278, 5493-5496). Nine splice variants have been described. PDE4D1, 4D2 and 4D6 are shorter forms without UCR. PDE4D3, 4D4, 4D5, 4D7, 4D8 and 4D9 are longer forms that contain both the UCR and the N-terminal domains required for their subcellular localization (Bender and Beavo, 2006). PDE4D3 long form activity is increased by PKA phosphorylation at Ser54 at the N-terminal UCR1 (Alvarez et al ., Mol Pharmacol., 1995, 48, 616-622; Sette et al ., J BiolChem., 1996, 271, 16526-16534 ). Conversely, Erk2 phosphorylation at Ser597 at the C-terminus of PDE4D3 causes a decrease in catalytic activity. One or more PDE4D isoforms are expressed in most of the tissues studied, including the cerebral cortex, hippocampus, cerebellum, heart, liver, kidney, lung, and testes (Richter et al ., Biochem. J., 2005, 388, 803-811). The localization and regulation of PDE4D isoforms presumably provides a robust and local regulation of cAMP levels, possibly limiting signal propagation to specific subcellular regions.

Numerous studies highlight the role of PDE in general and PDE4 in particular in modulating intracellular signaling pathways that regulate many physiological processes, including those underlying neuronal plasticity, cognition, and memory. In particular, PDEs play an important role in intracellular signaling pathways involving the second messengers cAMP and cGMP. These cyclic nucleotides act as ubiquitous intracellular signaling molecules in all mammalian cells. PDE enzymes hydrolyze cAMP and cGMP, breaking the phosphodiester bonds to form the corresponding monophosphates (Bender and Beavo, Pharmacol. Rev., 2006, 58(3), 488-520). PDE activity is modulated along with adenylyl cyclase (AC) and guanylyl cyclase (GC) activities through direct effectors and feedback pathways, thereby maintaining cAMP and cGMP levels within optimal ranges for signal responsiveness. The ability of extracellular signals to modulate the intracellular concentration of cyclic nucleotides makes it possible for cells to respond to external stimuli on the other side of the cell membrane boundary.

Cyclic nucleotide signaling cascades are adapted to respond to a variety of transducer systems, including G protein-coupled receptors (GPCRs) and voltage-gated and ligand-gated ion channels. Cyclic nucleotides signal within the cell through various tertiary elements. The best described of these are cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG). The binding of a cyclic nucleotide to each enzyme allows the phosphorylation of subsequent enzymes and proteins that act as effectors or additional elements in the signaling cascade. For memory formation, cAMP activation of PKA, which phosphorylates the cAMP-response element of the activating protein (CREB), is especially important. pCREB is an activated transcription factor that binds to specific DNA loci and initiates the transcription of numerous genes involved in neuronal plasticity. In vitro and in vivo studies have shown an association between changes in cyclic nucleotide concentration and biochemical and physiological processes associated with cognitive function (Kelly and Brandon, Progress in Brain Research , 2009, 179, 67-73; Schmidt, Current Topics in Medicinal Chemistry, 2010 , 10, 222 - 230). The intensity of the signal and the levels of corresponding activity in the synapse are reasonable variables that can lead to the potentiation of transmission in a particular synapse. Among these processes, long-term potentiation (LTP) is best described, which is known to be modulated by cAMP and cGMP signaling cascades.

Attention to the role of PDE4 in memory is based on the discovery of a Drosophila dunce PDE4-like learning mutant (dnc gene), a cyclic nucleotide phosphodiesterase of the PDE4 subtype (Yun and Davis, Nucleic Acids Research , 1989, 17(20), 8313-8326). dnc mutant flies have defective recall and/or short-term memory when tested in several different situations for negative olfactory associative learning (Dudai et al., Proc Natl Acad Sci., 1976,73(5), 1684-1688; Dudai Y., Proc Natl Acad Sci., 1983, 80(17), 5445-5448; Tully and Quinn, Journal of Comparative Physiology , 1985, 157(2), 263-77) or positive reinforcement (Tempel et al., Proc Natl Acad Sci ., 1983, 80(5), 1482-1486). In the mammalian context, PDE4D knockout animals show a decrease in immobility in the tail hanging and forced swimming trial models with antidepressants (Zhang et al., Neuropsychopharmacology , 2002, 27(4), 587-595), an increase in in vitro LTP in hippocampal slices of CA1 (Rutten et al., Eur. J. Neurosci., 2008, 28(3), 625-632) and improved recall in the radial maze, object recognition, and Morris water maze tests (Li et al., J. Neurosci ., 2011, 31, 172-183).

These observations highlight the interest in PDE inhibition, including PDE4 inhibition, as a therapeutic target for multiple disorders and for cognitive enhancement. For example, by increasing cAMP levels, such inhibitors may be useful in the treatment of cognitive decline in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, as well as in the general improvement of cognitive function in normal, diseased, and aging subjects. Various small molecule inhibitors of the PDE4 enzyme have been described, such as aza-bridged bicycles (DeCODE Genetics; Intl. Pat. Appl. Publ. WO 2010/059836, May 27, 2010); N -substituted anilines (Memory Pharmaceuticals Corporation; International Patent Application Publication WO 2010/003084, January 7, 2010); biaryls (DeCODE Genetics; International Patent Application Publication WO 2009/067600, May 28, 2009, WO 2009/067621, May 28, 2009); benzothiasoles and benzoxazoles (DeCODE Genetics; US Patent Application Publication US 2009/0130076, May 21, 2009); catechins (DeCODE Genetics; US patent application publication US 2009/0131530, May 21, 2009), pteridines (Boehringer Ingelheim International GmbH; US patent 7674788, November 29, 2007); heteroaryl pyrazoles (Memory Pharmaceuticals Corporation; International Patent Application Publication WO 2007/123953, November 1, 2007); naphthyridines (Glaxo Group Limited; International Patent Application Publication WO 2006/053784, May 26, 2006); piperazinyldihydrothienopyrimidines (Boehringer Ingelheim International GmbH; European Patent 1874781, June 24, 2009); nicotinamide derivatives (Pfizer; US Patent Application Publication US 2005/0020587, January 27, 2005); heteroarylmethylphenylamines (Memory Pharmaceuticals Corporation; US Pat. No. 7,087,625, August 8, 2006); naphthyridines (Novartis AG; EP 1443925 Dec 26, 2007; US Pat 7468370 Dec 23, 2008).

However, PDE4 inhibitors are commonly associated with numerous side effects, most notably nausea, which tend to limit their usefulness and tolerability (eg Giembycz, Curr. Opin. Pharm. 2005, 5, 238-244). Therefore, there is a need to develop improved PDE4 inhibitors that have greater efficacy, higher specificity, and an improved side effect profile. The present invention addresses these and other needs in the art by providing a description of substituted pyridine and pyrazine compounds as effective and well tolerated PDE4 inhibitors.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a chemical compound of Formula (I):

,

Where

R ¹ , R ² , R ³ , R ⁴ , Y and Z have any meaning described herein.

In one aspect, the chemical compound 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).

Chemical compounds of Formula (I) are suitable for a wide range of methods described herein. Isotopically labeled compounds and prodrugs can be used in metabolism and reaction kinetics studies, detection and imaging technologies, and radioactive therapies. Chemical embodiments of the present invention can be used, in particular, to inhibit PDE4; in particular for the treatment of a disorder mediated by PDE4; to improve neuronal plasticity; for the treatment of neurological disorders, including neurodegenerative disorders, cognitive disorders and cognitive impairment associated with CNS disorders; to provide neuroprotection; and for the treatment of peripheral disorders including inflammatory and renal disorders. The chemical embodiments of the present invention are also suitable as the most effective agents for improving the effectiveness of cognitive training and motor learning, in stroke rehabilitation, for facilitating neurorecovery and neurorehabilitation, and for enhancing the effectiveness of non-human animal learning techniques. The present invention further relates to general and specific embodiments as defined, respectively, by the independent and dependent claims appended hereto, which are incorporated herein by reference.

DETAILED DESCRIPTION

The present invention will be better understood with reference to the following description, including examples. Unless otherwise indicated, all technical and scientific terms used in this document have the same meaning as generally understood by those skilled in the art. Although any methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, the following is a description of suitable methods and materials. In addition, the materials, methods and examples are illustrative only and are not limiting.

For the sake of brevity, all publications, including patent applications, patents and other references mentioned in this document are incorporated herein by reference in their entirety. However, the citation of any of these publications should not be construed as recognition of their prior art for the present invention.

Abbreviations

This description contains many abbreviations, the meaning of which is presented in the following table:

Reduction Meaning ACN Acetonitrile AcOH Acetic acid AIBN 2,2'-Azobis(2-methylpropionitrile) BOC tert -Butyl dicarbonate n-BuLi n -Butyllithium DXM dichloromethane Deoxo- ^Fluor® Bis(2-methoxyethyl)aminosulfur trifluoride Dess- ^Martin® reagent 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3(1H)-one DIPEA, foundation of Hünig N,N -Ethyldiisopropylamine or N,N-diisopropylethylamine DMA N,N -dimethylacetamide DMF N,N -Dimethylformamide DMSO Dimethyl sulfoxide dppf 1,1'-Bis(diphenylphosphino)ferrocene EtOAc or EA ethyl acetate EtOH ethanol HOAc or AcOH Acetic acid HPLC High Performance Liquid Chromatography LAH lithium aluminum hydride LCMS, LC/MS Liquid chromatography-mass spectrometry MeOH methanol NBS n-Bromosuccinimide PdCl ₂ (dppf)-DCM adduct Adduct of [1'1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride with dichloromethane Pd(PPh ₃ ) ₄ Tetrakis[triphenylphosphine]palladium (0) TBAF Tetrabutylammonium fluoride TEA, Et _3N Triethylamine TFK Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography ^XtalFluor® (Diethylamino) difluorosulfonium tetrafluoroborate

TERMS AND DEFINITIONS

Use of subheadings such as "General Information", "Chemistry" Compositions", "Compositions", etc. in this section, as well as in other sections of this application is intended only for convenience of reference, and not for limitation.

general information

As used herein, the term "about" or "approximately" means within the allowable range for a particular value as determined by a person skilled in the art, and may depend, in particular, on the method of measurement or determination of the value, for example, limitations of the measuring system or technologies. 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, in relation to biological systems or processes, the term "about" can mean within an order of magnitude, within 5 times, or within 2 times on either side of the value. Unless otherwise noted, the numerical values presented herein are approximate, meaning that the term "about" or "approximately" that is not explicitly stated can be assumed.

To provide a more concise description, some quantitative expressions presented in this document do not carry the "about" clause. It should be understood that whether the term "about" is used or not, each quantity presented herein refers to an actual given value, and also refers to an approximation of that value that is reasonable to assume based on general knowledge in the art. , including equivalents and approximations due to experimental and/or measurement conditions for a given value. If the yield is given as a percentage, then the reported yield refers to the mass of the substance for which the yield is given, relative to the maximum amount of the same substance that can be obtained under specific stoichiometric conditions. Concentrations expressed as a percentage refer to mass ratios unless otherwise indicated.

As used herein, terms in the singular are to be understood as meaning both the singular and the plural, unless otherwise expressly indicated. Therefore, terms in the singular (and, where appropriate, their grammatical variants) refer to one or more.

A group of objects connected by the union "and" should not be understood as the need for the presence of all and each object in the specified group, but should be understood as "and / or", unless otherwise explicitly indicated. Likewise, a group of objects linked by "or" should not be understood as requiring mutual exclusion within the group, and should also be understood as "and/or" unless explicitly stated otherwise. In addition, while the objects, elements, or components of the present invention may be described or claimed in the singular, the plural is also within its scope unless limited to the singular is expressly indicated.

The terms "including" and "comprising" are used herein in an open, non-limiting sense. Other terms and expressions used in this document, as well as variations thereof, unless expressly stated otherwise, should be construed as non-limiting as opposed to limiting. For example: the term "example" is used to provide illustrative instances of the subject matter in question, rather than an exhaustive or restrictive list; adjectives such as "usual", "traditional", "standard", "principled", "known" and terms with the same meaning, should not be construed as limiting the described object to a given period of time or to an object currently available, a should be understood to include conventional, conventional, standard or principle technologies that may be available or known at the present time or at any time in the future. Similarly, where this document refers to technologies known to those skilled in the art, said technologies encompass technologies currently understood or known to those skilled in the art or at any time in the future.

The presence of expanding words and expressions such as "one or more", "at least", "but not limited to", or similar expressions in some cases should not be understood as suggesting or requiring a narrower case in those cases in which the specified expansion expressions are missing. Upon reading this document, those skilled in the art will appreciate that the illustrated embodiments and numerous alternatives thereof may be implemented without limitation to the illustrated examples.

Chemistry

The term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be a straight or branched 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 can also be represented structurally by the symbol " ”), ethyl (Et), n -propyl, isopropyl, butyl, isobutyl, sec -butyl, t- butyl (tBu), pentyl, isopentyl, t- pentyl, hexyl, isohexyl and groups which, in light of standard knowledge in this the areas of technology and guidance provided herein are considered equivalent to any of the above examples. Alkyl groups may be optionally substituted with one or more substituents including, but not limited to, hydroxyl, alkoxy, cyano, thioalkoxy, amino, and aminoalkyl.

The term "haloalkyl" refers to an alkyl moiety, which may be a linear or branched alkyl group having 1 to 12 carbon atoms substituted with halogen groups. Examples of haloalkyl groups include, but are not limited to, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F, -CH ₂ CH ₂ Cl or - _{CH2CF2CF3 . _}

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

The term "cycloalkyl" refers to a saturated or partially saturated carbocycle, such as a monocyclic, fused polycyclic, bridged monocyclic, bridged polycyclic, spirocyclic or spiro polycyclic carbocycle, having 3 to 12 ring atoms per carbocycle. If the term "cycloalkyl" has a particular characteristic, such as monocyclic, fused polycyclic, bridged polycyclic, spirocyclic, and spiropolycyclic, then such term "cycloalkyl" refers only to that carbocycle that has the specified characteristic. Illustrative examples of cycloalkyl groups include the following structures, in the form of suitably linked moieties:

Those skilled in the art will appreciate that the cycloalkyl group structures listed or illustrated above are not exhaustive, and that additional structures may also be selected within the scope of the terms described.

The term "halogen" represents a chlorine, fluorine, bromine or iodine atom. The term "halo" is a chlorine, fluorine, bromine or iodine radical.

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

The term "heteroaryl" refers to a monocyclic, fused bicyclic or fused polycyclic aromatic heterocycle (a ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen and sulfur) having 3 to 12 ring atoms per one heterocycle. Illustrative examples of heteroaryl groups include the following structures, in the form of suitably linked moieties:

The term "substituted" means that the specified group or fragment has one or more substituents. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that said group is unsubstituted or substituted with one or more substituents. When using the term "substituted" to describe a structural system, substitution can take place at any position in the system allowed by the valency. If the specified fragment or group is not explicitly indicated as being optionally substituted or substituted by a specific substituent, it should be understood that such a fragment or group is considered unsubstituted.

Formulas

Any formula presented herein is intended to refer to compounds having the structures depicted by this structural formula, as well as some variations or forms. In particular, compounds of any formula provided herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of compounds of the general formula, as well as their mixtures, are considered to be included in the specified formula. Thus, any formula provided herein is intended to refer to the racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. In addition, some structures may exist as geometric isomers (ie, cis and trans isomers), tautomers, or atropisomers.

Symbols And used to indicate the same spatial arrangement in the depicted chemical structures. Likewise, symbols And used to indicate the same spatial arrangement in the depicted chemical structures.

Connections

As used herein, "compound" refers to any of: (a) the actual specified form of such compound; and (b) any form of such compound in the medium in which the compound is located when the name is formed. For example, reference herein to a compound such as R-COOH encompasses reference to any of, for example, R-COOH(s), R-COOH(sol) and R-COO-(sol). In this example, R-COOH(s) refers to a solid compound, such as in a tablet or some other solid pharmaceutical composition or formulation; 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 an aqueous medium, whether such dissociated form is formed from R-COOH, from its salt, or from some other structure that forms R-COO- upon dissociation in the environment in question.

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

In one aspect, the chemical compound 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).

In another example, a phrase such as "exposure of a compound to a compound of the formula R-COOH" refers to the effect of said compound on the form or forms of the R-COOH compound that exists or that exist in the environment in which such exposure occurs. In another example, a phrase such as "reaction of a compound with a compound of the formula R-COOH" refers to the interaction of (a) said compound in the chemically relevant form or forms of said compound that exists or that exist in the medium in which said interaction occurs, with (b) the chemically relevant form or forms of the R-COOH compound that exists or that exist in the environment in which said interaction takes place. In this regard, if such a compound is, for example, in an aqueous environment, it should be understood that the R-COOH compound is in the same environment and, therefore, said compound is exposed to particles such as R-COOH(aq) and/or R-COO-(aq), where the index "(aq)" is indicated for "aquatic" conditions, in accordance with the standard value in the field of chemistry and biochemistry. In these nomenclature examples, the carboxyl functional group is selected; however, such selection is not intended to be limiting, but merely illustrative. It should be understood that similar examples can be provided for other functional groups, including, but not limited to, hydroxyl, basic nitrogen-containing groups such as amines, and any other groups that react or transform in a known manner in a medium containing the indicated compound. These interactions and transformations include, but are not limited to, dissociation, association, tautomerism, solvolysis, including hydrolysis, solvation, including hydration, protonation and deprotonation. This document does not present additional relevant examples, since such interactions and transformations in this environment are known to all specialists in this field of technology.

In another example, a "zwitterionic" compound is included herein, which refers to a compound that forms a zwitterion, even though it is not explicitly referred to in its zwitterionic form. Terms such as zwitterion, zwitterions and their synonyms, zwitterionic compound(s), are standard IUPAC recommended names that are well known and are part of the standard set of defined scientific terms. In this regard, the term "zwitterion" has been assigned a unique identifier CHEBI:27369 in the Dictionary of Chemical Entities of Biological Interest (ChEBI). As generally well known, a zwitterion or zwitterionic compound is a generally neutral compound having formal unit charges of opposite signs. Sometimes such compounds are also referred to as "internal salts". In a number of sources, such compounds are called "dipolar ions", although in other sources the latter term is considered incorrect. As a specific example, aminoethanoic acid (amino acid glycine) has the formula H ₂ NCH ₂ COOH and in a number of environments (in this case in a neutral environment) exists in the form of the +H ₃ NCH ₂ COO- zwitterion. Zwitterions, zwitterionic compounds, internal salts and dipolar ions in the known and well-established meanings of the listed terms are within the scope of the present invention, which in any case will be understood by those skilled in the art. Since it is not necessary to name every single embodiment of the present invention, which can be determined by a person skilled in the art, structures of zwitterionic compounds related to the compounds according to the present invention are not explicitly given in this document. However, all such structures form part of the embodiments of the present invention. No additional relevant examples are provided herein, since such interactions and transformations in a given environment that lead to the various forms of the compounds in question are known to all those skilled in the art.

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

In discussing any formula herein, selecting a particular fragment from a list of possible particles for a particular variable does not imply fixing the same choice of those particles for that variable elsewhere. In other words, if a certain variable is present more than once, then the choice for it of options from the specified list in one place does not depend on the choice of options for the same variable elsewhere in the formula, unless otherwise specified.

As a first example for substituent terminology, if substituent S ¹ _example is one of S ₁ and S ₂ , and substituent S ² _example is one of S ₃ and S ₄ , then these designations refer to embodiments of the present invention according to the following sets: S ¹ _example is S ₁ and S ² _example is S ₃ ; S ¹ _example is S ₁ and S ² _example is S ₄ ; S ¹ _example is S ₂ and S ² _example is S ₃ ; S ¹ _example is S ₂ and S ² _example is S ₄ ; as well as the equivalents of each of the listed sets. Accordingly, for brevity, but not limitation, the abbreviated terminology used herein is "S ¹ _example is one of S ₁ and S ₂ ", and "S ² _example is one of S ₃ and S ₄ ". The above first example of substituent terminology, which is presented in general terms, illustrates the various substituent designations described herein. The above substituent condition applies, where applicable, to groups such as R ¹ , R ² , R ³ , R ⁴ 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 , R ⁿ and U, Y, Z, HAL, HET, as well as any other common substituent symbols used in this document.

In addition, if more than one option is given for any element or substituent, then the embodiments of the present invention include various independent combinations from the list of possible options, as well as their equivalents. As a second example of substituent terminology, if it is described herein that the substituent S _example is one of S ₁ , S ₂ and S ₃ , then this list includes embodiments of the present invention for which S _example is S ₁ ; S _example is S ₂ ; S _example is S ₃ ; S _example is one of S ₁ and S ₂ ; S _example is one of S ₁ and S ₃ ; S _example is one of S ₂ and S ₃ ; S _example is one of S ₁ , S ₂ and S ₃ ; and S _example is the equivalent of each of the listed options. Accordingly, for brevity, but not limitation, abbreviated terminology is used herein: "S _example is one of S ₁ , S ₂ and S ₃ ". The above second example of substituent terminology, which is presented in general terms, illustrates the various substituent designations described herein. The above substituent condition applies, where applicable, to groups such as R ¹ , R ² , R ³ , R ⁴ 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 , R ⁿ and U, Y, Z, HAL, HET, as well as any other common substituent symbols used in this document.

The nomenclature "C _ij ", where j > i, used herein to denote a class of substituents, refers to embodiments of the present invention for which each and all possible numbers of carbon atoms, from i to j, including i and j, are individually implemented. For example, the term C _1-3 independently refers to embodiments that have one carbon atom (C ₁ ), to embodiments that have two carbon atoms (C ₂ ), and to embodiments that have three carbon atoms (C ₃ ).

The term C _nm alkyl means a linear or branched aliphatic chain with a total number N of carbon atoms in the chain that satisfies the condition n≤ N≤ m, where > n.

Any reference in this application to a divalent substituent includes various options for attaching said substituent when there is more than one such possibility. For example, reference to a divalent substituent -A-B-, where A ≠ B, herein refers to such a divalent substituent in which A is attached to the first substituted fragment and B is attached to the second substituted fragment, and also refers to such a divalent substituent in which A is attached to the second fragment, and B is attached to the first substituted fragment.

In accordance with the above designation considerations for substituent nomenclature, it is to be understood that herein, explicit reference to a set of possibilities means, in the chemical sense and unless otherwise indicated, independent reference to embodiments of that set, as well as reference to each and every possible embodiment. subsets of an explicitly specified set of possible choices.

The term "prodrug" means a precursor of said compound which, after administration to a subject, forms a compound in vivo by a chemical or physiological process, such as solvolysis or enzymatic cleavage, or under physiological conditions (for example, by exposing the prodrug to physiological pH, it is converted to a compound of Formula (I )).

A "pharmaceutically acceptable prodrug" is a prodrug that is preferably non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject. Exemplary methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

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

Compositions

The term "composition" as in "pharmaceutical composition" includes a product containing the active ingredient(s) and the inert ingredient(s) (pharmaceutically acceptable excipients) that constitute the carrier, as well as any product that is directly or indirectly formed from the combination, complexation, or aggregation of any two or more ingredients, or from dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Accordingly, pharmaceutical compositions according to the present invention include any composition obtained by mixing a compound of Formula (I) and a pharmaceutically acceptable excipient.

The term "pharmaceutically acceptable" as used in relation to compositions of the present invention refers to molecular entities and other ingredients of said compositions that are physiologically tolerable and do not generally cause adverse reactions when administered to an animal (eg, human). The term "pharmaceutically acceptable" may also mean approved by a federal or state regulatory authority, or listed in the USP or other conventional pharmacopoeias for administration to animals (eg, mammals) and more preferably humans.

A "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 diluent to facilitate administration of an agent, and which is compatible with it. 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 Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins (2005).

A "pharmaceutically acceptable salt" means a free acid or base salt of a compound represented by Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See GS 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; Berge et al., Pharmaceutical Salts, J. Pharm. sci. 1977, 66 , 1-19; Stahl and Wermuth (eds), Pharmaceutical Salts; Properties, Selection, and Use: 2nd revised edition, Wiley-VCS, Zurich, Switzerland (2011). Exemplary pharmaceutically acceptable salts are salts that are pharmacologically effective and suitable for contact with patient tissues without undue toxicity, irritation, or allergic reaction. The compound of Formula (I) may have a sufficiently acidic group, a sufficiently basic group, or both types of functional groups and, accordingly, can react with a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable base addition salts, as well as inorganic and organic acids to form pharmaceutically acceptable salts.

The term "carrier" refers to the adjuvant, medium or excipients with which the specified compound is administered. In preferred embodiments of the present invention, the carrier is a solid carrier. Suitable pharmaceutical carriers include those described in Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins (2005).

The term "dosage form" as used herein is the form in which a dose is administered to a subject or patient. The drug is usually administered as part of a formulation that contains auxiliary agents. The dosage form has unique physical and pharmaceutical characteristics. Dosage forms, for example, can be solid, liquid or gaseous. "Dosage forms" may include, for example, capsule, tablet, caplet, gelcap, syrup, liquid composition, powder, concentrated powder, concentrated powder mixed with liquid, chewable form, edible form, soluble form, effervescent form , granular form or oral liquid solution. In a particular embodiment, the dosage form is a solid dosage form and, more specifically, contains a tablet or capsule.

As used herein, the term "inert" refers to any inactive ingredient of the described composition. The definition of "inactive ingredient" as used herein is in accordance with the definition of the U.S. Food and Drug Administration in 21 CFR section 201.3(b)(8) and is any component of a drug product other than the active ingredient. ingredient.

Methods and uses

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

As used herein, the term "cognitive disorder" is used interchangeably with "cognitive dysfunction" or "cognitive impairment", which cover the same therapeutic indications.

The terms "treat" and "treatment" include therapeutic methods directed at a disease state in a subject and include: (i) preventing the onset of the disease state, in particular if the subject is predisposed to the disease state but not yet diagnosed; (ii) suppressing the disease state, for example, stopping its development (progression) or delaying its onset; and (iii) alleviating the disease state, eg, reversing the disease state until the desired endpoint is reached. Treatment also includes alleviating a symptom of a disease (eg, reducing pain, discomfort, or deficiency), which alleviation may directly affect the disease (eg, affect the cause, transmission, or manifestation of the disease) or not directly affect the disease.

As used herein, the term "effective amount" is used interchangeably with "therapeutically effective amount" and means an amount or dose of a compound or composition effective to treat the particular disease, condition, or disorder described herein and, therefore, "treatment" includes providing the desired preventive, inhibitory, alleviating or attenuating effect. In the methods of treatment of the present invention, an "effective amount" of at least one compound of the present invention is administered to a subject (eg, a mammal). An "effective amount" also means an amount or dose of a compound or composition effective to modulate the activity of a PDE4 or related signaling pathway, such as the CREB cascade, and thereby provide the desired modulatory effect. An "effective amount" varies depending on the particular compound, the disease, the type of treatment desired, and the severity of the disease, as well as age, weight, and the like.

The term "animal" is used interchangeably with "subject" and may be a vertebrate, in particular a mammal and more specifically a human, and includes a laboratory animal in the context of clinical trials or screening or activity analysis. Thus, those skilled in the art will recognize that the compositions and methods of the present invention are particularly suitable for administration to any vertebrate animal, especially a mammal, and more particularly a human.

As used herein, a "control animal" or "normal animal" is an animal that is of the same species or otherwise comparable (e.g., same age, sex) to an animal subjected to conditions sufficient to initiate transcription-dependent memory formation. in the specified animal.

"Enhancement" or "enhancement" means the ability to potentiate, increase, intensify or increase or improve a biochemical or physiological action or effect, as compared to normal. For example, improving long-term memory formation refers to the ability to potentiate or improve long-term memory formation in an animal, as compared to normal long-term memory formation in said animal or control animals. As a result, the acquisition of long-term memory is faster or better preserved. Improvement in cognitive task performance refers to the ability to potentiate or improve the performance of a particular cognitive task by an animal, as compared to the normal performance of that cognitive task by said animal or control animals.

As used herein, the term "learning protocol" or "training" refers to either "cognitive training" or "motor learning". The expression "in combination" means that the compound or composition according to the present invention improves the function of the CREB cascade during cognitive training or motor learning.

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

CONNECTIONS

The present invention provides certain substituted pyridine and pyrazine derivatives which are suitable, for example, as inhibitors of PDE4 enzyme activity. They differ from the trisubstituted pyridines described in the following publications: US Pat. International Patent Application Publication WO 2003050098, (Maxia Pharmaceuticals, June 19, 2003, CAS No. 544475-13-0, 544475-12-9) and Japanese Patent 4321737 (International Patent Publication WO 9931062, Shionogi & Co., 24 June, 1999, CAS No. 228096-03-5, 228096-04-6).

Numerous embodiments of the present invention relate to a chemical compound of Formula (I):

Where:

Z is CH or N;

i) where if Z is CH, then;

R ¹ is selected from the group consisting of: -H, -C _1-3 alkyl and -C _1-3 haloalkyl;

Y represents -C(R ^a ) ₂ -, where each R ^a is independently selected from the group consisting of: -H, -F, -CH ₃ , -OH and -N(R ^b ) ₂ ;

R ² is selected from the group consisting of:

A) phenyl, unsubstituted or substituted with one or two R ^c , where each R ^c is independently selected from the group consisting of: halo, -CN, -CO ₂ R ^b , -CONH ₂ , -SO ₂ CH _{3 ,} -C(R ^b ) ₂ OH, -CH ₂ NH ₂ , -CH ₂ CONH ₂ , -CH ₂ CO ₂ C ₁ - ₃ alkyl, -NHCONH ₂ , -NHCONH-oxetane, -CONH-oxetane,

B) a six-membered monocyclic heteroaromatic ring containing one or two nitrogen atoms, unsubstituted or substituted with one or two substituents, each independently selected from the group consisting of: halo, -C _1-3 alkyl, -C _1-3 haloalkyl, - CN, -OH, -C(R ^b ) ₂ OH, -CH ₂ NH ₂ , -C(R ^b ) ₂ CN, -C(R ^b ) ₂ CONH ₂ , -OCH ₂ CONH ₂ , -OC _1-3 alkyl, -OCH ₂ C(R ^b ) ₂ OH, -OCH ₂ cyclopropyl, -OC _1-3 haloalkyl, -CO ₂ H, -CON(R ^b ) ₂ , -N(R ^b ) ₂ , -NHCH ₂ CF ₃ , -NHCH(CH ₃ ) ₂ , -NHCH ₂ CH ₂ N(CH ₃ ) ₂ , -NHCH ₂ CH ₂ OH, -NHcyclopropyl, -NHCOCH ₃ , morpholinyl, pyrrolidin-3-ol and azetidin-3-ol;

C) a five-membered monocyclic heteroaromatic ring containing two, three or four nitrogen atoms, unsubstituted or substituted with one or two substituents, each independently selected from the group consisting of halogen, -C _1-3 alkyl, -C _1-3 haloalkyl, -C(R ^b ) ₂ OH, -N(R ^b ) ₂ , -NO ₂ , -CN, -CH ₂ CN, -OC _1-3 alkyl, -CH ₂ OCH _3, -CH ₂ CH ₂ OH, - CH ₂ NH ₂ , -CH ₂ CONH ₂ , -CO ₂ C _1-3 alkyl, -CO ₂ H, -CONH ₂ , -NHCOCH ₃ and cyclopropyl; And

D) a five- or six-membered ring selected from: 1,2-dihydropyridin-2-one, thiazole or 1,2-oxazole, unsubstituted or substituted with one or two substituents, each independently selected from the group consisting of -CH ₃ and -NH ₂ ;

R ³ is phenyl or pyridine substituted with one or two substituents each independently selected from the group consisting of: halo, -C _1-3 alkyl, -OC _1-3 alkyl, -O-cyclopropyl, -O-oxetane, -C ₁ - ₃ haloalkyl, -OC ₁ - ₃ haloalkyl, -CN, -CH ₂ OH, -SO ₂ CH ₃ or -N(CH ₃ ) ₂ ;

R ⁴ is selected from the group consisting of -C _1-3 alkyl and -C _1-3 haloalkyl; And

each R ^b is independently selected from -H or -CH ₃ ;

ii) where if Z is N then:

R ¹ is -H;

Y is -CH ₂ -;

R ² selected from the group consisting of:

A) phenyl substituted with one or two R ^d , where each R ^d is independently selected from the group consisting of: -CN, -CONH ₂ and -CO ₂ C _1-3 alkyl;

B) a six-membered monocyclic heteroaromatic ring containing one or two nitrogen atoms, unsubstituted or substituted with a substituent selected from the group consisting of: -CN, -OC _1-3 alkyl, -CONH ₂ , -NHCH ₂ CH ₂ OH, -N( R ^b ) ₂ and -NH-cyclopropyl;

C) a five-membered monocyclic heteroaromatic ring containing two or three nitrogen atoms, unsubstituted or substituted with one or two substituents, 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

D) 1,2-oxazole optionally substituted with one or two R ^b ;

R ³ is phenyl substituted with one or two substituents each independently selected from the group consisting of: -Cl, -OC _1-3 alkyl, or -OC _{1-3 haloalkyl} ;

R ⁴ is -C _1-3 alkyl; And

each R ^b is independently selected from -H or -CH ₃ .

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

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

Some embodiments are represented by compounds of Formula (I) wherein Z is CH and R ¹ is -H, -CH ₃ or -CF ₃ .

In some embodiments, R ¹ is -H.

In some embodiments of compounds of Formula (I), Y is -CH ₂ -, -CH(F)-, -CH(OH)-, -C(OH)(CH ₃ )-, or -CH(CH ₃ )-, and Z is CH.

In some of these embodiments, Y is -CH ₂ - and Z is N.

In some embodiments of the compounds of Formula (I), R ² is ; and R ^c is halogen, -CN, -CO ₂ H, -(CH ₂ ) _0-1 CONH ₂ , -SO ₂ CH _{3 ,} -C(R ^b ) ₂ OH, -CH ₂ NH ₂ , -CH ₂ CO ₂ C _1-6 alkyl, -NHCONH ₂ , -NHCONH-oxetane, -CONH-oxetane,

In some of these embodiments, R ² is ; and R ^c is -F, -(CH ₂ ) _0-1 CONH ₂ , -CH ₂ NH ₂ , -C(CH ₃ ) ₂ OH, -SO ₂ CH ₃ , or -NHCONH ₂ .

In some embodiments of compounds of Formula (I), Z is N and R ² is 4-cyanophenyl, 4-phenylamide, or 4-phenylcarboxylic acid methyl ester.

Some embodiments are represented by compounds of Formula (I) wherein R ² is pyridine, unsubstituted or substituted with one or two substituents, each independently selected from: -F, -C _1-6 alkyl, -C _1-3 haloalkyl, - OC _1-6 alkyl, -OCH ₂ cyclopropyl, -CN, -N(R ^b ) ₂ , -CH ₂ NH ₂ , -CO ₂ H, -CON(R ^b ) ₂ or -C(R ^b ) ₂ OH.

In some of these embodiments, R ² is ; and R ^d is -C _1-6 alkyl, -CF ₃ , -CN, -N(R ^b ) _{2 ,} -CO ₂ H, -CON(R ^b ) ₂ , -OC _1-3 alkyl, -CH ₂ NH ₂ , -C(R ^b ) ₂ OH, -OCH ₂ cyclopropyl or -OCH(CH ₃ ) ₂ .

In some of these embodiments, R ² is ; and R ^d is -CH ₃ , -CF ₃ , -NH ₂ , -NHCH _{3 ,} -N(CH ₃ ) _{2 ,} -CONH ₂ , -CONHCH ₃ , -CON(CH ₃ ) ₂ , -OC _1-3 alkyl, -CH ₂ OH, -C(CH ₃ ) ₂ OH or -OCH ₂ cyclopropyl.

In some of these embodiments, Z is N and R ² is ; R ^d1 is -CN or -CONH ₂ .

Some embodiments are represented by compounds of Formula (I) wherein R ² is selected from the group consisting of pyrazine, pyridazine, and pyrimidine; wherein the pyrazine is optionally unsubstituted or substituted with -C _1-3 alkyl, -OC _1-3 alkyl, -N(R ^b ) ₂ or -NHCH ₂ CH ₂ OH; pyridazine is optionally unsubstituted or substituted with —C _1-3 alkyl; and the pyrimidine is optionally substituted with a substituent selected from the group consisting of: -H, halo, -C _1-3 alkyl, -CN, -OH, -OC _1-3 alkyl, -OC _1-3 haloalkyl, -CO ₂ H, -CON(R ^b ) ₂ , -C(R ^b ) ₂ CONH ₂ , -C(R ^b ) ₂ OH, -C(R ^b ) ₂ CN, -CH ₂ CH ₂ N(CH ₃ ) ₂ , -OCH ₂ C(R ^b ) ₂ OH, -OCH ₂ CONH ₂ , -N(R ^b ) ₂ , -NHCH ₂ CF ₃ , -NHCH(CH ₃ ) ₂ , -NHCH ₂ CH ₂ OH, -NHcyclopropyl, -NHCOCH ₃ , morpholinyl, pyrrolidin-3-ol and azetidin-3-ol.

In some of these embodiments, R ² is , unsubstituted or substituted with one or two R ^e , where each R ^e independently represents -H, -Cl, -C _1-3 alkyl, -CN, -OCH ₃ , -OC _1-3 haloalkyl, -CO ₂ H, - CONH ₂ , -C(R ^b ) ₂ CONH _2, -C(R ^b ) ₂ OH, -C(R ^b ) ₂ CN, -CH ₂ CH ₂ N(CH ₃ ) ₂ , -OCH ₂ C(R ^b ) ₂ OH _, -OCH ₂ CONH ₂ , -N(R ^b ) ₂ , -NHCH ₂ CF ₃ , -NHCH(CH ₃ ) ₂ , -NHCH ₂ CH ₂ OH, -NHcyclopropyl, -NHCOCH ₃ , morpholinyl, pyrrolidine- 3-ol and azetidin-3-ol.

In some of these embodiments, Z is N and R ² is , unsubstituted or substituted by a group ^Re1 where R ^e1 represents -CN, -OCH ₃ , -CONH ₂ , -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₂ OH or -NHcyclopropyl.

In some of these embodiments, R ² is , and R ^e is -H, halogen, -CH ₃ , -CN, -OH, -OCH ₃ , -OCHF ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CF ₃ , -NHcyclopropyl, -C(CH ₃ ) ₂ OH, -CONH ₂ , -CONHCH ₃ or -CON(CH ₃ ) ₂ .

Some embodiments are compounds of Formula (I) wherein R ² is imidazole, pyrazole, triazole, and tetrazole, unsubstituted or substituted with one or two substituents, each independently selected from the group consisting of: -Cl, -CH ₃ , - CHF ₂ , -CF ₃ , -CH ₂ OH, -CH ₂ CN, -CH ₂ CONH ₂ , -CH ₂ CH ₂ OH, -NH ₂ , -NO ₂ , -CN, -CO ₂ C ₁ - ₃ alkyl, -CO ₂ H, -CONH ₂ or -NHCOCH ₃ .

In some of these embodiments, R ² is , and R ^f is -H, -Cl, -CH ₃ , -NO ₂ , -NH ₂ , -NHCOCH ₃ , -CH ₂ OH, -CN, -CONH ₂ , -CO ₂ H or -CO ₂ CH _{2 CH3} .

In some of these embodiments, R ² is , and R ^f represents -H, -NH ₂ or -CH ₂ OH.

In some of these embodiments, R ² is , where R ^g represents -H, -CH ₃ , -CH ₂ OH, -CONH ₂ or -NH ₂ .

Some embodiments are represented by compounds of Formula (I) wherein R ² is 1H-tetrazole, 2H-tetrazole, 1,2-oxazole, 1,3-thiazole, each independently unsubstituted or substituted with -CH ₃ , -CH ₂ OH, -CH ₂ CH ₂ OH or -NH ₂ .

Some embodiments are represented by compounds of Formula (I) wherein R ² is 1,2,3-triazole and 1,2,4-triazole, each independently unsubstituted or substituted with -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -CN, -CH ₂ CN, -CH ₂ CONH ₂ , -C(R ^b )OH, -CH ₂ OCH ₃ , N(R ^b ) _2, -NO ₂ , -CO ₂ CH ₃ , -CONH ₂ , cyclopropyl or -CH ₂ NH ₂ .

In some of these embodiments, R ² is , and R ^h is -H, -CH ₃ , -CF ₃ , -CH ₂ F, -CHF ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH ₂ OCH ₃ , -NO ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CN, -CH ₂ CN, -CH ₂ CONH ₂ , -CONH ₂ , -CO ₂ CH ₃ or -cyclopropyl.

In some of these embodiments, R ² is , and R ^j is -H, -CH ₃ , -CF ₃ , -OCH ₃ , -CH ₂ (OH), -C(CH ₃ ) ₂ OH, -CH ₂ OCH ₃ , -CO ₂ CH ₃ , or - _NO2 .

In some of these embodiments, R ² is , and R ^k is -H, -CH ₃ , -CF ₃ , -CH ₂ F, -CHF ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH ₂ OCH ₃ , -NO ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CN, -CONH ₂ , -CO ₂ CH ₃ , or -cyclopropyl.

Some embodiments are represented by compounds of Formula (I) wherein R ³ is , and R ^m is -Cl, -F, -CH ₃ , -CHF ₂ , -CN, -OCH ₃ , -CH ₂ OH, -OCH ₂ CH ₃ , -OCF ₃ , -OCHF ₂ , -N(CH ₃ ) ₂ , -SO ₂ CH ₃ , -OCH(CH ₃ ) ₂ ,

In some of these embodiments, R ³ is 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.

Some embodiments are represented by compounds of formula (I) wherein R ³ is , and R ⁿ is H, -Cl, -CH ₃ , -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -OCHF ₂ , -OCF ₃ or -CN.

Some embodiments are represented by compounds of Formula (I) wherein R ⁴ is -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , or -CHF ₂ .

Additional embodiments are 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).

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

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

Isotopically labeled compounds

The present invention also includes isotopically labeled compounds that are identical to those of Formula I, except 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 normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of carbon, chlorine, fluorine, hydrogen, iodine, nitrogen, oxygen, phosphorus, sulfur, and technetium, including ¹¹ C, ¹³ C, ¹⁴ C, ³⁶ Cl, ¹⁸ F , ^2H , ^3H , ^123I , ^125I , ^13N , ^15N , ^15O , ^17O , ^18O , ^31P , ^32P , ^35S and ^99m Tc.

Compounds of the present invention (and derivatives of said compounds such as pharmaceutically acceptable salts and prodrugs) which contain the aforementioned isotopes or other isotopes of other atoms are within the scope of the present invention. The isotopically labeled compounds of the present invention are useful in drug and substrate tissue distribution assays, as well as in targeted substitution assays. For example, isotopically labeled compounds are particularly suitable for SPECT (single photon emission computed tomography) and PET (positron emission tomography) described later in this document.

Derivatives

The present invention also provides derivatives of the chemical compound of Formula (I), which include, but are not limited to, any salts, solvates, conformers, or crystalline forms/polymorphs.

salt

Accordingly, in one embodiment, the present invention includes pharmaceutically acceptable salts of the compounds represented by Formula (I), as well as methods of using these salts.

Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, borates, nitrates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates , heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexine-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates , xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, besylates, mesylates and mandelates.

If the compound of Formula (I) contains a basic nitrogen atom, then the desired pharmaceutically acceptable salt can be obtained by any suitable method known in the art, for example, by treating 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 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, pyranosidilic acid such as glucuronic acid or galacturonic acid, alpha hydroxy acid such as mandelic acid , citric acid or tartaric acid, amino acid such as aspartic acid, glutaric acid or glutamic acid, aromatic acid such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid, sulfonic acid such as lauryl sulfonic acid, p-toluenesulfonic acid acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixtures of acids, such as those described in the examples provided herein, and any other acids and mixtures thereof that are considered equivalents or acceptable substitutes in light of the current state of the art.

If the compound of Formula (I) is an acid such as a carboxylic acid or a sulfonic acid, then the desired pharmaceutically acceptable salt can be obtained by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary) , alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases, such as those described in the examples provided herein, and any other bases and mixtures thereof that are considered equivalent or acceptable substitutes in light of the standard state of knowledge 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

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

More specifically, solvates include those obtained by reacting or complexing the compounds of the present invention with one or more solvents, either in solution or in solid or crystalline form. Said solvent molecules are those commonly used in the pharmaceutical field which are known to be harmless to the recipient, such as 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 t -butyl ether, ethyl acetate, methyl acetate, ( S )-propylene glycol, ( R )-propylene glycol, 1,4-butyndiol, etc. P. Hydrates include compounds obtained by the incorporation of one or more water molecules.

Conformers and crystalline forms/polymorphs

In other embodiments, the present invention provides conformers and crystalline forms of a compound of Formula (I) and the use of said derivatives in the methods of the present invention. A conformer is a structure that is a conformational isomer. Conformational isomerism is a phenomenon that occurs when molecules with the same structural formula have different atomic conformations (conformers) around a rotating bond.

A polymorph is a composition having the same chemical formula but a different solid state or crystalline structure. In some embodiments of the present invention, the compounds of Formula (I) are obtained in crystalline form. In addition, certain crystalline forms of compounds of Formula (I) or pharmaceutically acceptable salts of compounds of Formula (I) can be obtained as co-crystals. In other embodiments, the 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

The present invention also relates to prodrugs of the compounds of Formula (I) and to the use of said pharmaceutically acceptable prodrugs in the methods of the present invention, in particular in therapeutic methods. Exemplary prodrugs include compounds having an amino acid residue or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues covalently linked by an amide or ester bond to the free amino, hydroxy, or carboxyl group of a compound of Formula (I). Examples of amino acid residues include the twelve naturally occurring amino acids, usually denoted by three letter symbols, as well as 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. .

Additional types of prodrugs can be obtained, for example, by derivatizing the free carboxyl groups of the structures of Formula (I) as amides or alkyl esters. Examples of amides include amides derived from ammonia, primary C _1-6 alkylamines and secondary di(C _1-6 alkyl)amines. Secondary amines include 5- or 6-membered heterocycloalkyl or heteroaryl ring moieties. Examples of amides include amides derived from ammonia, primary C _1-3 alkylamines and di(C _1-2 alkyl)amines. Examples of esters according to the present invention include C _1-6 alkyl, C _1-6 cycloalkyl, phenyl and phenyl(C _1-6 alkyl) esters. Preferred esters include methyl esters. Prodrugs can also be prepared by derivatization of free hydroxy groups using groups including hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, following the methods described in Fleisher et al., Adv. Drug Delivery Rev. 1996, 19 , 115-130.

Carbamate derivatives of hydroxy and amino groups can also give prodrugs. Prodrugs can also give carbonate derivatives, sulfonate esters and sulfate esters of hydroxyl groups. Derivatization of hydroxy groups, such as (acyloxy)methyl and (acyloxy)ethyl ethers, where the acyl group may be an alkyl ester optionally substituted with one or more ether, amine, or carboxyl functional groups, or where the acyl group is an amino acid ester, as described above, is also suitable for obtaining prodrugs. Prodrugs of this type can be prepared as described in Robinson et al., J. Med. Chem . 1996, 39 , 10-18. Free amines can also be derivatized to amides, sulfonamides or phosphonamides. All of these prodrug moieties may contain groups including ether, amine, and carboxyl functional groups.

Prodrugs can be defined using standard techniques known or available in the art (e.g., Bundgard (Ed.), 1985, Design of prodrugs, Elsevier; Krogsgaard-Larsen et al., (Ed.), 1991, Design and Application of Prodrugs, Harwood Academic Publishers).

Metabolites

The present invention also relates to the metabolite of the compound of Formula (I) described above and its salts. The present invention further relates to the use of said metabolites and their salts in the methods of the present invention, including therapeutic methods.

The metabolites of a compound can be determined using standard techniques known or available in the art. For example, isolated metabolites can be produced enzymatically or synthetically (e.g., Bertolini et al., J. Med. Chem . 1997, 40 , 2011-2016; Shan et al., J. Pharm. Sci . 1997, 86 , 765-767 ; Bagshawe, Drug Dev. Res. 1995, 34 , 220-230; and Bodor, Adv Drug Res. 1984, 13 , 224-231).

COMPOSITIONS

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

Compositions and introduction

There are many standard reference books that describe methods for preparing various formulations suitable for administering the compounds of the present invention. Examples of possible compositions and formulations are described, for example, in Handbook of Pharmaceutical Excipients, US Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors), current edition published by Marcel Dekker, Inc. and also in Remington, Pharmaceutical Sciences (Osol, ed.), 1980, 1553-1593.

Any suitable route of administration may be used to provide an animal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ophthalmic, inhalation, nasal, and the like can be used. method of administration. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.

Suitable carriers, diluents, and adjuvants are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The specific carrier, diluent or excipient used will depend on the method and purpose for which the compound of the present invention is being used. Solvents are typically selected from solvents recognized as safe by those skilled in the art (GRAS) for administration to an animal. Typically, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (eg PEG400, PEG300), etc., as well as mixtures thereof. The formulations may also contain one or more buffers, stabilizing agents, surfactants, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, coating agents, lubricants, processing aids, coloring agents, sweeteners, flavors, flavors, and other known additives. to obtain an externally pleasing form of a drug (ie, a compound of the present invention or a pharmaceutical composition thereof) or to facilitate the manufacture of a pharmaceutical product (ie, a drug).

The compositions can be obtained by conventional dissolution and mixing procedures. For example, the bulk material (i.e., a compound of the present invention or a stabilized form of a compound (eg, a complex with a cyclodextrin derivative or other known complexing 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 easily controlled and appropriate doses of the drug.

The pharmaceutical composition (or composition) for use may be packaged in different ways, depending on the method used to administer the drug. As a rule, a commercial product contains a container having a pharmaceutical composition located therein in a suitable 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 contain a tamper evident system to prevent accidental access to the contents of the package. In addition, the container has a label located on it, which describes the contents of the container. The label may also contain appropriate warnings.

The compounds of the present invention may be administered systemically, for example orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be included in a hard or soft gelatin capsule, may be compressed into tablets, or may be administered directly to the patient's food. For oral therapeutic administration, the active compound may be mixed with one or more excipients and used in the form of tablets for swallowing, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, cachets, and the like. Said compositions and formulations must contain at least 0.1% active compound. Of course, the percentage in the compositions and formulations may vary and may typically range from about 2% to about 60% by weight of a given unit dosage form. The amount of active compound in said therapeutically useful compositions is such that an effective dose level is obtained.

Tablets, lozenges, pills, capsules, etc. may also contain the following agents: binders such as gum tragacanth, gum arabic, corn starch or gelatin; excipients such as dicalcium phosphate; a leavening 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, wintergen oil or cherry flavoring. If the unit dosage form is a capsule, it may contain, in addition to materials of the types listed above, a liquid carrier such as vegetable oil or polyethylene glycol. Various other materials may be present as coatings or to modify the physical form of the unit dosage form. For example, 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 propyl parabens as preservatives, a coloring agent, and a flavoring such as cherry or orange flavor. Of course, any material used in the preparation of any unit dosage form must be pharmaceutically acceptable and substantially non-toxic in the amounts used. In addition, the active compound can be placed in sustained release formulations and devices.

The 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 non-toxic surfactant. Dispersions can also be obtained in glycerol, liquid polyethylene glycols, triacetin and mixtures thereof, as well as in oils. Under normal conditions of storage and use, these formulations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical dosage forms suitable for injection or infusion may contain sterile aqueous solutions or dispersions, or sterile powders containing the active ingredient, which are formulated to immediately prepare sterile solutions or dispersions for injection or infusion, optionally encapsulated in liposomes. In all cases, the finished dosage form must be sterile, liquid and stable under the conditions of manufacture and storage. The liquid carrier or medium may be a solvent or liquid dispersion medium containing, for example, water, ethanol, a polyhydric alcohol (eg, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, non-toxic glyceryl ethers, and suitable mixtures thereof. The necessary fluidity can be maintained, for example, by the formation of liposomes, by maintaining the required particle size in the case of dispersions, or by the use of surfactants. The action of microorganisms can be prevented by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases it is preferable to include isotonicity agents, for example sugars, buffers or sodium chloride. Prolonged absorption of injectable compositions can be accomplished through the use of absorption delaying agents in the compositions, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are usually prepared by incorporating the active compound in the required amount in a suitable solvent with various other ingredients listed above, as appropriate, followed by filtered sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the usual methods of preparation are vacuum drying and freeze drying, resulting in a powder of the active ingredient and the additional required ingredient contained in pre-sterile filtered solutions.

For topical use, the compounds of the present invention may be applied in pure form, i. if they are liquid. However, it is generally necessary to apply them to the skin in the form of compositions or formulations, in combination with a dermatologically acceptable carrier, which may be solid or liquid.

Suitable solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like. Suitable liquid carriers include water, alcohols or glycols, or water-alcohol/glycol mixtures, in which the compounds of the present invention can be dissolved or dispersed at an effective concentration, optionally with non-toxic surfactants. Adjuvants such as flavors and additional antimicrobial agents may be added to optimize properties for a given application. The resulting liquid compositions can be applied from absorbent pads used to impregnate bandages and other dressings, or sprayed onto the injured area using a pump or aerosol type sprayer.

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

Doses

Suitable doses of the compounds of Formula (I) can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods are known in the art for extrapolating effective doses in mice and other animals to human doses. Suitable doses of compounds of formula I can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for extrapolating effective doses in mice and other animals to human doses are known in the art (eg, US Pat. No. 4,938,949). Suitable doses of PDE4 inhibitors are known in the art (eg US Pat. No. 7,829,713; US Pat. No. 8,338,405).

Optimal dosages to be administered in the therapeutic methods of the present invention can be determined by those skilled in the art and depend on a variety of factors including the particular composition used, the efficacy of the formulation, the route and time of administration, and the severity of the disease or condition. Additional factors may include characteristics of the subject being treated, such as age, weight, sex, and diet.

However, as a rule, a suitable dose is from about 0.01 to about 100 mg/kg, more specifically from about 0.1 to about 100 mg/kg, for example, from 10 to about 75 mg/kg of body weight per day, from 3 to about 50 mg per kilogram of body weight of the recipient per day, from 0.5 to 90 mg/kg/day, or from 1 to 60 mg/kg/day (or any value or range within the indicated values). The compound is usually administered in unit dosage form; for example, containing from about 1 to 1000 mg, in particular from about 10 to 750 mg, and more specifically from about 50 to 500 mg of the active ingredient per unit dosage form.

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

The required dose may conveniently be presented as a single dose or divided doses administered at appropriate intervals, such as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, for example, into several spaced administrations used in accordance with the compositions and methods of the present invention.

Effective amounts or doses of the active agents of the present invention may be determined by standard methods such as modeling, dose escalation studies, or clinical trials, as well as conventional factors such as route or route of drug administration or delivery, agent pharmacokinetics, severity, and course. the disease, disorder or condition, the subject's previous or current therapy, the subject's medical condition and drug response, and the judgment of the attending physician. Said compositions and formulations must contain at least 0.1% active compound. Of course, the percentage in the compositions and formulations may vary and may typically range from 2% to about 60% by weight of a given unit dosage form. The amount of active compound in said therapeutically useful composition is such that an effective dose level is obtained. An exemplary dosage is from about 0.001 to about 200 mg of active agent per kg of the subject's body weight per day, preferably from about 0.05 to 100 mg/kg/day, or from about 1 to 35 mg/kg/day, or from about 0. 1 to 10 mg/kg/day in single or fractional dosage units (eg BID, TID, QID). For a 70 kg human, an exemplary suitable dosage range is 1 to 200 mg/day, or about 5 to 50 mg/day.

Methods and uses

Applications of isotopically labeled compounds

In 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 ¹⁴ C), reaction kinetics studies (eg, with ² H or ³ H); (ii) detection or imaging technologies [such as positron emission tomography (PET) or single photon emission computed tomography (SPECT)], including drug or substrate tissue distribution assays; or (iii) in the radioactive treatment of patients.

Isotopically labeled compounds and prodrugs of the present invention can generally be prepared according to the methods described in the Schemes or in the examples and preparations described below by replacing the unlabeled reagent with a readily available isotopically labeled reagent. A compound labeled ¹⁸ F or ¹¹ C may be particularly preferred for PET studies, and a compound labeled I ¹²³ may be particularly preferred for SPECT. Additional substitution with heavier isotopes such as deuterium (ie ² H) may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced doses required.

Therapeutic methods

general information

In some 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, alone or in combination (collectively, "active agents") of the present invention, which are useful for PDE4 inhibition. in the methods of the present invention. Said methods of inhibiting PDE4 include administering to an animal an effective amount of at least one chemical compound 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 the present invention provide PDE4 inhibition. The present invention further includes the use of these compounds and their compositions in the methods described herein. In one aspect of these methods described herein, the animal is healthy. In another aspect of these methods, the animal is suffering from a disorder. In another aspect of all of these methods, the animal is an aged animal. In preferred embodiments, the animal in these methods is a human.

In one aspect, these chemicals are suitable 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 compound of Formula (I) or a composition thereof.

The chemical compounds of the present invention may be administered as monotherapy or as part of combination therapy. In one aspect, one or more compounds (or their salts, prodrugs, or metabolites) of the present invention may be co-administered or used in combination with one or more adjunctive therapies known in the art.

The compounds of the present invention may also be used as adjuvant therapy, for example with other PDE inhibitors.

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

In some embodiments, the present invention includes the use of a chemical compound of Formula (I) in the manufacture of a medicament for the treatment of a disease, condition, or disorder by inhibition of PDE4. The present invention further provides a method of administering a therapeutically effective amount of a drug according to the present invention to a patient in need of such treatment for the treatment of said disorder.

In one aspect, the compounds of the present invention are useful in increasing neuronal plasticity, a natural property of the brain that can be improved in healthy animals and can be impaired in many CNS disorders. For example, by inhibiting PDE4, a compound of the present invention may increase levels of cAMP that modulates cyclic nucleotide signaling cascades.

More specifically, the ability of extracellular signals to modulate the intracellular concentration of cyclic nucleotides allows cells to respond to external stimuli on the other side of the cell membrane boundary. Cyclic nucleotide signaling cascades are adapted to respond to a variety of transducer systems, including G protein-coupled receptors (GPCRs) and voltage-gated and ligand-gated ion channels. Cyclic nucleotides signal within the cell through various tertiary elements. The best described of these are cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG). The binding of a cyclic nucleotide to each enzyme allows the phosphorylation of subsequent enzymes and proteins that act as effectors or additional elements in the signaling cascade. The cAMP-dependent activation of PKA, which phosphorylates CREB, is especially important for memory formation. pCREB is an activated transcription factor that binds to specific DNA loci and initiates the transcription of numerous genes involved in neuronal plasticity (e.g., Tully et al., Nat. Rev. Drug. Discov. 2003, 2 , 267-277; and Alberini, Physiol. Rev. 2009, 89 , 121-145).

Consistent with these observations, in vitro and in vivo studies have correlated changes in cyclic nucleotide concentration with biochemical and physiological processes associated with cognitive function (Kelly and Brandon, Progress in Brain Research , 2009, 179, 67-73; Schmidt, Current Topics in Medicinal Chemistry, 2010 , 10, 222 - 230). In addition, signal intensity and levels of related activity at a synapse are reasonable variables that can lead to potentiation of transmission at a particular synapse. Among these processes, long-term potentiation (LTP) is best described, which is known to be modulated by cAMP and cGMP signaling cascades.

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

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

Chemical compounds and compositions according to the present invention are also suitable as neuroprotective agents, described in more detail in this document. 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 compound or composition of the present invention.

Chemical compounds and compositions according to the present invention are also suitable as agents for neurorehabilitation and neurorecovery, described in more detail herein. Accordingly, the present invention provides a method for neurorehabilitation or neurorecovery, comprising administering to an animal in need thereof an effective amount of at least one chemical compound or composition according to the present invention.

In addition, these compounds can be administered in combination with training protocols for the treatment of cognitive or motor impairment associated with CNS disorders, as described in more detail herein. In addition, these compounds can be used to improve the performance of training protocols in non-human animals, in particular healthy non-human animals, as described herein.

Neurological disorders

In 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.

A neurological disorder (or pathological condition or disease) is any disorder of the body's nervous system. Neurological disorders can be classified according to the primary lesion, the main type of dysfunction, or the main type of cause. The most common division is between disorders of the central nervous system (CNS) and disorders of the peripheral nervous system (PNS).

Neurological disorders include structural, biochemical, or electrical abnormalities in the brain, spinal cord, or other nerves, pathologies that can lead to a variety of symptoms. Examples of such symptoms include paralysis, muscle weakness, poor coordination, sensory loss, seizures, disorientation, pain, altered levels of consciousness, and cognitive impairment, including memory impairment. There are many known neurological disorders, some of which are relatively common, but many are rare. They can be assessed through neurological examination, studied and treated within the highly specialized fields of neurology and clinical neuropsychology.

Neurological disorders and their complications (direct consequences) affect approximately one billion people worldwide, according to estimates by the World Health Organization in 2006. Intervention for neurological disorders may include, in addition to drugs, preventive measures, lifestyle changes, physiotherapy or other therapies, neurorehabilitation, pain management, and surgery.

Neurological 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; disorders associated with the use of chemical compounds; dissociative disorders; eating disorders; sleep disorders; developmental disorders; neurodegenerative disorders, including movement disorders; traumatic disorders; pain disorders; and cognitive disorders, a category that includes memory disorders such as AAMI and MCI, as well as cognitive impairments (particularly memory impairment) associated with CNS disorders.

Psychiatric disorders

In one embodiment, the present invention provides a method for 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

In 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 dysthymic disorder, major depressive disorder (recurrent and single episodes), mania, bipolar disorders (I and II), and cyclothymic disorder. Years of research has highlighted the role of PDE4 in mood disorders, including depressive disorders, bipolar disorders, and chemical induced mood disorders, as described in the literature.

A specific embodiment of the present invention is a method of treating a chemical use disorder, comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound or pharmaceutical composition described herein. The suitability of PDE4 inhibitors in the treatment of mood disorders caused by the use of chemical compounds is described in the literature.

Psychotic disorders

In some embodiments, the psychiatric disorder is a psychotic disorder. Accordingly, the present invention provides a method of treating a psychotic disorder, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein. In a particular aspect, the psychotic disorder is one or more of the following: schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder; induced psychotic disorder; psychotic disorders caused by the use of chemical compounds, such as psychosis caused by the use of alcohol, amphetamine, marijuana, cocaine, hallucinogens, volatile drugs, opioids or phencyclidine; and personality disorders during stress (including paranoid personality disorder, schizoid personality disorder, and borderline personality disorder).

A specific embodiment of the present 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 has been described in the literature.

A specific embodiment of the present 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, has been described in the literature.

Anxiety disorders

In some embodiments, the psychiatric disorder is an anxiety (or neurotic) disorder. Accordingly, the present invention provides a method for 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 specifically, 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 described in the literature.

Personality disorders

In 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: Cluster A (selective or eccentric) personality disorders, such as paranoid or schizoid personality disorder; Cluster B personality disorders (theatrical, emotional, or unstable) such as antisocial, borderline, or narcissistic personality disorder; and cluster C (anxiety or fearful) personality disorders such as avoidant, dependent, or obsessive-compulsive personality disorder.

Disorders associated with the use of chemical compounds

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

More specifically, a substance use disorder includes one or more of the following: an alcohol use disorder such as overdose, addiction, and withdrawal; amphetamine use disorder such as overdose, addiction and withdrawal; cocaine use disorder such as overdose, dependence and withdrawal; hallucinogen use disorder such as overdose, addiction and withdrawal; inhalant drug use disorder such as addiction and withdrawal; nicotine use disorder such as dependence and withdrawal; an opioid use disorder such as overdose, dependence and withdrawal; phencyclidine use disorder such as overdose and dependence; and disorders associated with the use of sedatives, hypnotics, or anxiolytics such as overdose, dependence, and withdrawal.

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

Dissociative disorders

In some embodiments, the neurological disorder is a dissociative disorder. Accordingly, a particular embodiment of the present 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 specifically, a dissociative disorder includes one or more of the following: depersonalization disorder, dissociative amnesia, and dissociative identity disorder.

Eating Disorders

In some embodiments, the neurological disorder is an eating disorder. Accordingly, a specific embodiment of the present 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 specifically, the eating disorder is anorexia nervosa or bulimia nervosa. The suitability of PDE4 inhibitors in the treatment of eating disorders has been described in the literature.

Sleep disorders

In some embodiments, the neurological disorder is a sleep disorder. Accordingly, a particular embodiment of the present 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 specifically, the sleep disorder includes a primary sleep disorder such as primary hypersomnia, primary insomnia, and narcolepsy; parasomnia, such as a nightmare disorder or a sleep disorder associated with fear; and other sleep disorders. The suitability of PDE4 inhibitors in the treatment of sleep disorders has been described in the literature.

In other embodiments, the sleep disorder is restless leg syndrome. Restless legs syndrome (RLS) is a disorder of part of the nervous system that affects the legs and causes them to move. People with restless legs syndrome suffer from discomfort in the legs (and sometimes in the arms or other parts of the body) and an overwhelming need to move the legs to relieve these sensations. Such sensations are usually intensified during rest, especially when lying or sitting. These sensations can lead to sleep deprivation and stress. Because restless leg syndrome usually interferes with sleep, it is also 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

In some embodiments, the neurological disorder is a developmental disorder. Accordingly, a particular embodiment of the present 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.

More specifically, the developmental disorder is one or more of the following: mental retardation, including mild, moderate, and severe; a learning disability, such as a disability that impairs the ability to read, do math, or write; a motor skill disorder such as dyspraxia; communication disorder; pervasive developmental disorder such as autistic disorder, Rett syndrome, childhood disintegrative disorder and Asperger's syndrome; a disorder of lack of concentration or aggressive behavior, such as attention deficit hyperactivity disorder; a tic disorder such as Tourette's syndrome, a chronic motor disorder, or a vocal tic disorder.

A specific embodiment of the present 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 present invention provides a method of treating 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 suitability of PDE4 inhibitors in the treatment of attention deficit hyperactivity disorder has been described in the literature.

Neurodegenerative disorders

In specific embodiments, the present invention provides a method for treating a neurodegenerative 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, neurodegenerative disorders include Alzheimer's disease, amyotrophic lateral sclerosis, corticobasal degeneration, chronic traumatic encephalopathy, and multiple head injury disorder.

Alzheimer's disease

In a specific embodiment, the present 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 diagnosing Alzheimer's disease is provided in the Diagnostic and Statistical Manual of Mental Disorders (fourth edition, revised (2000), also known as DSM-IV-TR). First, several cognitive impairments must be present, one of which must be memory impairment. Second, one or more of the following must be present: afrasia (deterioration of speech abilities); apraxia (difficulty in the implementation of motor actions, even while maintaining the ability to move, perceive and understand questions); or agnosia (deterioration in the ability to recognize or identify objects, even though perceptual ability is preserved).

Amyotrophic lateral sclerosis

In another specific embodiment, the present 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.

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

Early symptoms of ALS often include an increase in muscle weakness, especially affecting the arms and legs, speech, swallowing, or breathing. The progressive degeneration of motor neurons in ALS eventually leads to their death. When motor neurons die, the ability of the brain to initiate and control muscle movement is lost. As voluntary muscle movement progressively deteriorates, patients in the advanced stages of this disease may become completely paralyzed.

Movement disorders

In other embodiments, the present invention provides a method for 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, essential tremor, Lewy body disease, hypokinetic disease, multiple sclerosis, various types of peripheral neuropathy, dystonia, basal ganglia disorder, hypokinesia (including akinesia), and dyskinesia. In addition, Tourette syndrome and other tic disorders may be included as categories of movement disorders. The suitability of PDE4 inhibitors in the treatment of movement disorders has been described in the literature.

In a related embodiment, the present invention provides a method for 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 pathological conditions and disorders and is the main feature of Huntington's disease, a progressive neurological disorder.

Huntington's disease

In a particular embodiment, the present invention provides a method for 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.

Huntington's disease (HD or Huntington's chorea) is a hereditary disorder in which nerve cells in certain parts of the brain become exhausted or degenerate. It is caused by a genetic defect on chromosome 4 that results in more CAG repeats than normal. The CAG element is normally repeated 10 to 28 times, but in patients with Huntington's disease it is repeated 36 to 120 times.

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

Symptoms of Huntington's disease include behavioral changes, abnormal and unusual movements, and worsening dementia. Behavioral changes may include behavioral disturbances, hallucinations, irritability, mood swings, restlessness or nervousness, paranoia, and psychosis. Abnormal and unusual movements include facial movements such as grimaces; turning the head to change the position of the eyes; quick, sudden, sometimes sharply twitching movements of the arms, legs, face and other parts of the body; slow, uncontrolled movements and unsteady gait. Worsening dementia includes disorientation or confusion; loss of mind; memory loss; personality changes; and speech changes (eg, Dumas et al., Front Biosci (Schol Ed) 2013, 5 , 1-18). The utility of PDE4 inhibitors in the treatment of Huntington's disease is known in the art.

Parkinson's disease

In a specific embodiment, the present invention provides a method for 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.

In another embodiment, the present invention provides a method for treating myoclonus, Gilles de la Tourette 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 suitability of PDE4 inhibitors in the treatment of myoclonus, Tourette's syndrome, dystonia and tics has been described in the literature.

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

Diseases of Lewy bodies

In one embodiment, the present invention provides a method of treating 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 are spherical inclusions that displace other components of the cell. The two morphological types are the classic Lewy bodies (brainstem) and Lewy bodies of the cerebral cortex. Classical Lewy bodies are an eosinophilic cytoplasmic inclusion consisting of a dense nucleus surrounded by a halo of 10 nm thick fibrils emanating from the center, the main structural component of which is alpha-synuclein. In contrast, cortical Lewy bodies are less defined and do not have a halo. However, they are also composed of alpha synuclein fibrils. Cortical Lewy bodies are the hallmark of dementia with Lewy bodies (DLB), but can sometimes be seen in swollen neurons characteristic of Pick's disease and corticobasal degeneration, as well as in patients with other taupathies.

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

Multiple sclerosis

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

MS is caused by damage to the myelin sheath, the protective covering that surrounds nerve cells. When this neural covering is disrupted, nerve signals slow down or stop. Because nerves in any part of the brain or spinal cord can be damaged, people with multiple sclerosis can have symptoms in different parts of the body. Symptoms vary due to the different location and severity of each attack. Episodes may last for days, weeks or months. These episodes alternate with periods of relief or absence of symptoms (remissions).

Muscular symptoms associated with MS include loss of balance; muscle spasms; numbness, tingling or abnormal sensitivity in any area; trouble moving your arms or legs; difficulty walking; problems of coordination and execution of small movements; tremor in one or more arms or legs; and weakness in one or more arms or legs.

Disorders of the basal nuclei of the brain

In specific embodiments, the present invention provides a method for treating a basal ganglia disorder. Basal ganglia disorders refer to a group of physical dysfunctions that occur when a group of nuclei in the brain known as the basal ganglia fail to properly suppress unwanted movements or properly direct the upper motor neuron circuit to initiate motor function (Leisman and Mello, Rev. Neurosci 2013, 24 , 9-25).

Increased performance of the basal ganglia suppresses thalamocortical projection neurons. Proper activation and deactivation of these neurons is an essential component for proper movement. If anything causes too high performance of the basal ganglia, then the thalamocortical projection neurons become too inhibited, and the subject cannot initiate voluntary movement. These disorders are known as hypokinetic disorders. However, a disorder leading to a pathologically low performance of the basal ganglia results in an almost complete absence of suppression of thalamocortical projection neurons. This situation leads to an inability to suppress unwanted movements. Such disorders are known as hyperkinetic disorders (Wichmann and DeLong, Curr. Opin. Neurobiol 1996, 6 , 751-758).

Hypokinesia

In specific embodiments of the present invention, a method for treating hypokinesia is provided. Hypokinesia refers to a decrease in torso movements, and these may be associated with diseases of the basal ganglia (such as Parkinson's disease), mental health disorders, and prolonged inactivity due to illness, among other diseases.

More generally, hypokinesia describes a range 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 the result of extremely reduced activity of dopaminergic cells in the direct pathway and is common in severe cases of Parkinson's disease; (ii) bradykinesia, which is characterized by slow movement and is associated with Parkinson's disease and other disorders of the basal ganglia. In contrast to the slowing of initiation (akinesia), bradykinesia describes the slowing down of the execution of a movement. It is one of the 3 main symptoms of parkinsonism which are bradykinesia, tremor and stiffness. Bradykinesia is also the cause of what is commonly referred to as "stone face" (an emotionless face) in patients with Parkinson's disease; (iii) stiffness, which is characterized by the inability to move the muscles in any desired direction; and (iv) stiffness, which is characterized by an increase in muscle tone, causing resistance to movement of the joints under external influence; and (v) postural instability, which is the loss of the ability to maintain upright posture.

Dyskinesia

In specific embodiments of the present invention, a method for treating dyskinesia is provided. Dyskinesia is a movement disorder that consists of adverse effects including decreased voluntary movements and the presence of involuntary movements similar to tics or chorea.

Dyskinesia can present from mild hand tremors to uncontrolled movement, most commonly in the upper body, but can also be seen in the lower extremities. Discoordination within the body, especially in the respiratory muscles, can also occur and often goes unnoticed. Dyskinesia is a symptom of several medical disorders distinguished by underlying cause and usually corresponding to one of three types: acute dyskinesia, chronic (or tardive) dyskinesia, and non-motor dyskinesia.

More specifically, dyskinesia may include one or more of the following: paroxysmal dyskinesias, such as primary and secondary paroxysmal dyskinesia; paroxysmal kinesigenic dyskinesias (PKD); paroxysmal non-kinesigenic dyskinesias (PNKD); paroxysmal exercise-induced (stress-induced) dyskinesias (PED); and paroxysmal hypnogenic dyskinesias (PHD).

Traumatic disorders

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

In specific embodiments, traumatic disorders include brain injury; traumatic brain injury (closed and penetrating); head injury; tumors, especially cerebral tumors affecting the thalamus, or trauma to the temporal lobe of the brain; cerebrovascular disorders (diseases affecting the blood vessels in the brain) such as stroke, ischemia, hypoxia, and viral infection (eg, encephalitis); excitotoxicity; and convulsions.

Pathological conditions within the scope of the present invention that are amenable to neuroprotection include: stroke; traumatic brain injury (TB); dementia; Alzheimer's disease; Parkinson's disease; Huntington's disease; cerebral paralysis; postpolio syndrome; Guillain-Barré syndrome and multiple sclerosis; and other age-related syndromes, genetic conditions, and progressive CNS diseases that impair 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

In specific embodiments, the present invention provides methods for 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 has been described in the literature.

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

cognitive disorders

In specific embodiments of the invention, the neurological disorder is a cognitive disorder. Accordingly, the present invention provides a method for 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 has been described in the literature (eg, US Pat. No. US 7,829,713; US Pat. No. US 8,338,405).

Cognitive impairment can significantly impair social and professional functioning, adversely affecting the autonomy and quality of life of the affected individual. An estimated four to five million Americans (approximately 2% of Americans of all ages and 15% of Americans over 65) suffer from some form or degree of cognitive impairment (Abrams et al., Merck Manual of Geriatrics , 1995, Whitehouse Station, New Jersey ), Medical Services).

Cognitive disorders reflect problems in the cognition process, i.e. the general processes by which knowledge is acquired, stored and used. Accordingly, cognitive disorders may include disturbances in functions such as concentration, perception, attention, information processing, learning, memory, or speech. Cognitive disorders can also include psychomotor learning disabilities, which include physical skills such as movement and coordination; fine motor skills, such as using precision tools or appliances; and gross motor skills such as dancing, playing musical instruments, or performing sports exercises.

Cognitive impairment also includes impairments to executive functions, which include the abilities that underlie the planning and execution of goal-directed activities. Such abilities include flexibility, ie. the ability to quickly switch to the required mental mode; expectation and prediction based on pattern recognition; substantiation and solution of the problem; leading the discussion; short-term memory, i.e. the ability to retain and process information received from inside or outside in real time; emotional self-control, including the ability to recognize and manage your emotions for a good result; planning, such as the ability to divide complex activities into manageable elements and rank them in the correct order; and self-restraint, i.e. the ability to withstand distractions and internal urges.

Cognitive disorders also include cognitive impairments (deficiencies or dysfunctions) that are associated (caused) with CNS disorders. In one aspect, the cognitive impairment may be a direct result of a CNS disorder. For example, speech and phrasing disorders may be the direct result of a stroke or head injury that damages areas of the brain that regulate speech and phrasing, as in the case of afrasia.

In another aspect, the cognitive impairment is associated with a complex disorder, pathological condition, or disease of the CNS. For example, cognitive impairment may include deficits in executive control that accompanies autism or mental retardation; memory deficits associated with schizophrenia or Parkinson's disease; or cognitive deficits associated with multiple sclerosis. In the case of multiple sclerosis (MS), for example, approximately half of MS patients experience problems with cognitive function, such as slow thinking, reduced concentration, or memory impairment. Such problems usually occur in the late stage of MS, although in some cases they can occur much earlier, if not at the very beginning of the disease.

Cognitive impairment may be due to numerous, non-exclusive categories of CNS disorders, including the following (and those described herein):

(1) dementias such as dementias associated with Alzheimer's disease, Parkinson's disease; Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, AIDS dementia and other neurodegenerative disorders; and cognitive impairment associated with progressive diseases affecting the nervous system, such as multiple sclerosis.

(2) psychiatric disorders, which 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 post-traumatic stress disorder.

(3) age-related syndromes, genetic conditions, and progressive CNS diseases that impair cognitive function, such as autism spectrum disorders; Fetal Alcohol Syndrome Spectrum Disorders (FASD); Rubinstein-Taybi syndrome; Down syndrome and other forms of mental retardation; as well as multiple sclerosis.

(4) cognitive impairment due to trauma, i.e. deterioration in memory, speech, or motor skills due to brain injury; traumatic brain injury (closed and penetrating); head injury; tumors, especially cerebral tumors affecting the thalamus, or trauma to the temporal lobe of the brain; cerebrovascular disorders (diseases affecting the blood vessels in the brain) such as stroke, ischemia, hypoxia, and viral infection (eg, encephalitis); excitotoxicity; and convulsions. These traumatic impairments also include cognitive impairment due to external agents such as alcohol use, long-term medication, and neurotoxins such as lead, mercury, carbon monoxide, and some insecticides (eg, Duncan et al., Drug Discover. Ther. 2012 , 6 , 112-122).

(5) age-related cognitive impairment, including age-related memory impairment (AAMI; also referred to as senile memory impairment (AMI)) and disorders affecting patients in the early stages of cognitive decline, such as mild cognitive impairment (MCI); And

(6) an inability to learn, speak or write, such as perceptual defects, dyslexia, and attention deficit disorders.

Accordingly, the present invention provides a method for treating a cognitive impairment associated with a CNS disorder selected from one or more disorders from the group consisting of: dementias, including dementias associated with neurodegenerative disorders; psychiatric disorders; age-related syndromes, genetic conditions and progressive CNS diseases and genetic conditions; traumatic impairment of cognitive function, age-related impairment of cognitive function; and learning, speech, or reading disorders.

dementia

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

Dementias are neurodegenerative diseases characterized by impaired learning and cognition, and are usually accompanied by behavioral symptoms, psychological symptoms, and motor symptoms. More specifically, the symptoms of dementia may include problems in many areas of mental function, including emotional behavior or personality traits, impaired speech, memory, perception, thinking, and judgment.

Dementias include, but are not limited to, Alzheimer's disease dementia (early or late onset), Parkinson's disease dementia, Pick's disease dementia, Creutzfeldt-Jakob disease dementia, HIV disease dementia, dementia against the background of a head injury; dementia due to vascular disease (“vascular dementia”), dementia with Lewy bodies, frontotemporal dementia, Pick's disease and corticobasal degeneration.

In one embodiment, the dementia is due to Alzheimer's disease. Accordingly, the present invention provides a method of treating dementia associated with 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 suitability of PDE4 inhibitors in the treatment of Alzheimer's disease has been described in the literature. Accordingly, the present invention provides a method of treating dementia associated with 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.

In another embodiment, the dementia is due to Parkinson's disease. Accordingly, the present invention provides a method of treating dementia associated with 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. There is evidence that dementia occurs in approximately 20%-60% of individuals with Parkinson's disease and is more likely to occur in older individuals or in individuals with more severe or advanced disease. Dementia associated with Parkinson's disease is characterized by cognitive and motor slowdown; executive functioning problems, such as task scheduling, organizational projects, or performing tasks in the correct sequence; and poor memory retrieval. The deterioration in cognitive performance in individuals with Parkinson's disease is often aggravated by depression. The suitability of PDE4 inhibitors in the treatment of Parkinson's disease has been described in the literature.

There is evidence that dementia occurs in approximately 20%-60% of individuals with Parkinson's disease and is more likely to occur in older individuals or in individuals with more severe or advanced disease. Dementia associated with Parkinson's disease is characterized by cognitive and motor slowdown, executive dysfunction, and impaired memory retrieval. The deterioration in cognitive performance in individuals with Parkinson's disease is often aggravated by depression. Reviewed in Davie, Br. Med. bull . 2008, 86 , 109-127. The motor symptoms of Parkinson's disease are due to the death of dopamine-generating cells in the substantia nigra, an area of the midbrain; the cause of cell death is unknown. At an early stage of the disease, the most noticeable symptoms are associated with movement. Four motor symptoms are considered the main ones in PD: trembling (tremor), stiffness, slowing down of movement and postural instability, i.e. walking and gait problems (eg, Jankovic, J. Neurol. Neurosurg. Psychiatr . 2008, 79 , 368-376). Cognitive and behavioral problems may occur later, with dementia usually occurring late in the disease. Other symptoms include sensory, emotional problems, and sleep disturbances. PD is most common in the elderly, and most cases occur over the age of 50.

In another aspect, the cognitive impairment is associated with a complex syndrome, pathological condition, or disease of the CNS. For example, cognitive impairment may include deficits in executive control that accompanies autism or mental retardation; memory deficits associated with schizophrenia or Parkinson's disease; or cognitive deficits associated with multiple sclerosis. In the case of multiple sclerosis (MS), for example, approximately half of MS patients experience problems with cognitive function, such as slow thinking, reduced concentration, or memory impairment. Such problems usually occur in the late stage of MS, although in some cases they can occur much earlier, if not at the very beginning of the disease.

In one aspect, the cognitive impairment may be a direct result of a CNS disorder. For example, speech and phrasing disorders may be the direct result of a stroke or head injury that damages areas of the brain that regulate speech and phrasing, as in the case of afrasia.

Psychiatric disorders

In a specific embodiment, the present invention provides a method for treating a cognitive impairment 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 mood 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 post-traumatic stress disorder.

Age-related syndromes, genetic disorders and progressive diseases

In a specific embodiment, the present invention provides a method for treating a cognitive impairment associated with age-related syndrome, a genetic disorder, or a 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 impairment is associated with an autism spectrum disorder; fetal alcohol spectrum disorder (FASD); Rubinstein-Taybi syndrome; Down syndrome and other forms of mental retardation; as well as multiple sclerosis.

Traumatic disorders

In a specific embodiment, the present invention provides a method for treating trauma-related cognitive impairment. Such trauma-related cognitive impairments include, but are not limited to, disorders associated with cerebrovascular disease, including stroke and ischemia; brain injury, including subdural hematoma and brain tumor; traumatic brain injury (TBI) and head trauma.

These trauma-related impairments also include cognitive impairments due to external agents such as alcohol use, long-term medication, and neurotoxins such as lead, mercury, carbon monoxide, and certain insecticides.

Stroke

In some embodiments, the chemical compounds and compositions of the present invention are suitable for the treatment of stroke, and in more specific embodiments, for the treatment of motor or cognitive impairment in stroke rehabilitation. Stroke treatment is a time continuum that includes immediate (acute) treatment and subsequent rehabilitative therapy.

Acute treatment targets the initial injury directly, such as that initiated by ischemic or hemorrhagic stroke; this usually involves the use of agents to dissolve clots and restore blood flow to reduce tissue damage and stabilize the patient. The effectiveness of acute treatment is usually limited to a short time interval of only a few hours after the onset of a stroke.

Once the patient is medically stabilized, rehabilitation becomes the therapeutic goal. Rehabilitation (also called "stroke rehabilitation" or "stroke recovery") addresses the cognitive and motor deficits that are present after the initial stroke, with the goal of maximizing the recovery and recovery of neurological function to compensate for permanent tissue necrosis. (e.g. 1995 Clinical Guideline by the Department of Health and Human Services on Post-Stroke Rehabilitation.)

Rehabilitation after a stroke is usually an extensive program agreed upon by a team of medical professionals. For example, a physical therapist may focus on maintaining and restoring movement and strength in an injured limb, maximizing walking mobility, improving manual dexterity, and rehabilitating other motor and sensorimotor functions. A mental health professional may be involved in the treatment of cognitive loss. Rehabilitation care can take place in a variety of settings, such as a rehabilitation clinic, chronic care facility, outpatient clinic, or home.

Neurological functions that are affected by stroke (and may be targeted for rehabilitation) include deterioration in cognitive and motor function. Cognitive impairment, for example, may manifest as impaired understanding of speech or writing (afrasia); knowledge of the correct words, but the difficulty of their clear pronunciation (dysarthria); as well as impairment of other cognitive functions such as attention, judgment, planning, execution and learning, and memory. Mobility impairments, for example, may present with weakness (hemiparesis) or paralysis (hemiplegia) on one side of the body, which may affect the entire half of the body or only an arm or leg; problems with balance or coordination; impaired gross motor skills such as gait and walking speed; violation of fine motor skills or manual dexterity; and dysfunction of the upper and lower extremities.

Accordingly, the present invention provides the use of a PDE4 inhibitor in the treatment of stroke, including methods of stroke rehabilitation. In some embodiments, the chemical compounds of the present invention are useful in stroke rehabilitation for the treatment of stroke-related disorders (or "post-stroke disorders") resulting from impaired neurological function. In some embodiments, the present invention provides methods of stroke rehabilitation comprising: (a) administering to a subject in need thereof a PDE4 inhibitor while the subject is recovering from a stroke; (b) providing training to the subject under conditions sufficient to improve the performance of neurological function, the deterioration of which is due to the specified stroke; and (c) repeating steps (a) and (b) one or more times, wherein the need for sufficient training to improve said performance is less than if training alone was used.

In one aspect, the PDE4 inhibitor is a chemical compound according to the present invention. In some embodiments, the disorder is a motor disorder. In other embodiments, the impairment is a cognitive impairment, in particular a memory impairment, and more specifically a long-term memory impairment. In other embodiments, said impairment may include cognitive and motor impairment. In another aspect, the training includes a set of tasks aimed at improving neurological function. In a specific aspect, the reduction in the need for training is a reduction in the number of training sessions.

In a further embodiment, one or more training steps are performed at a discrete interval. In one aspect, each stage of the training is provided daily. In other aspects, the interval between one or more stages of training may be less than one day or more than one day, such as once a week, twice a week, three times a week, or more.

In a further embodiment, said introduction in step (a) is performed in conjunction with said training in step (b). In one aspect, the subject is a human. In another aspect, the subject is subjected to neural stem cell surgery. In other aspects, said compound is administered before or during each training session.

Age-related cognitive impairment

AAMI

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

AAMI is a decline in various cognitive abilities, in particular memory abilities, associated with normal aging. For example, subjects with AAMI show impairment in the ability to process new memory of events and facts, as well as impairment in short-term memory (Hedden and Gabrieli, Nat. Rev. Neurosci . 2004, 5 , 87-96). In addition, subjects with AAMI, compared with age-matched controls, performed worse on tests of executive function related to frontal lobe function. These and other studies suggest an important role for frontal lobe dysfunction in memory loss in the elderly. (More generally, studies comparing the effects of aging on episodic memory, meaning memory, short-term memory, and triggering have found that episodic memory is particularly impaired with normal aging; but some types of short-term memory may also be impaired (Nilsson, Acta Neurol. Scand Suppl . 2003, 179 , 7-13.)

In general, a diagnosis of AAMI identifies subjects with subjectively and objectively observable memory impairment without sufficient cognitive impairment to warrant a diagnosis of dementia. According to the criteria established by the NIH Research Group (Crook et al. , Devel. Neuropsychol. 1986, 2 , 261-276), a diagnosis of AAMI includes the following in a subject 50 years of age or older:

(i) the presence of subjective memory impairment, for example, complaints of memory loss, reflected in daily problems such as difficulty remembering the names of individuals the subject meets, loss of objects, difficulty remembering a list of things to buy or a list of tasks to perform;

(ii) objective evidence of memory loss (eg, a score that is at least one standard deviation below the mean of younger people on a standard memory test);

(iii) evidence of adequate intellectual function (e.g., a score of at least 32) on the vocabulary subtest of the Wechsler Adult Intelligence Scale, and

(iv) absence of dementia (or other memory-impairing diseases such as stroke), for example, on the Global Cognitive Impairment Scale for Dementia, individuals with AAMI have very little cognitive impairment (level 2) (Reisberg et al ., Am J. Psych 1982, 139 , 1136-1139).

Individuals with AAMI have been shown to have a three times higher risk of developing dementia than individuals not meeting AAMI criteria (Goldman and Morris, Alzheimer Dis. Assoc. Disord. 2002, 15 :72-79).

MCI

In a specific embodiment, the present invention provides a method for 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.

MCI can be diagnosed if an individual's memory has been impaired below what is considered normal for that age group. In other words, MCI is a condition in which people experience memory problems more often than the average person their age. However, these symptoms do not interfere with their daily activities and are not as severe as the symptoms of Alzheimer's disease. Symptoms often include losing things, forgetting events or settings, and trouble thinking about information.

According to a recent study, MCI is referred to as a transitional state between the cognitive changes of normal aging and Alzheimer's disease (AD). Many people who experience mild cognitive impairment are at high risk of developing Alzheimer's disease. Indeed, research data suggest that: Approximately 12% of people aged 65 years or older diagnosed with MCI develop Alzheimer's disease within one year; and approximately 40% develop Alzheimer's disease within three years. This is a much higher rate than the general population, where only about 1% of people aged 65 years or older develop Alzheimer's each year.

Therefore, people with MCI are considered to have an increased risk of developing Alzheimer's disease. However, these symptoms do not prevent them from doing their daily activities and are not as severe as the symptoms of Alzheimer's disease. Symptoms often include losing things, forgetting events or settings, and trouble thinking through information (eg, Arnáiz and Almkvist, Acta Neurol. Scand. Suppl . 2003, 179 , 34-41). However, in some patients, MCI never progresses to AD.

Learning Disabilities and Related Disabilities

In a particular embodiment, the present invention provides a method for treating a learning disability, speech 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

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

Like neuroplasticity, neuroprotection reflects an endogenous neurobiological process that is key to protecting the nervous system. More specifically, neuroprotection refers to the ability to halt or slow neuronal loss, thereby preventing or slowing the progression of disease and secondary damage. In a specific aspect, neuroprotection is directed at neuronal damage caused by oxidative stress and excitotoxicity, which are closely related to CNS disorders, despite the difference in symptoms or damage.

The utility of PDE4 inhibitors in the treatment of neuronal injury has been described in the literature. In addition to neurodegenerative diseases, neuronal damage can also result from other injuries such as cerebrovascular disease, including stroke and ischemia; brain injury, including subdural hematoma and brain tumor; and traumatic brain injury.

Strengthening Cognitive Training and Motor Learning

In some embodiments, a compound or composition of the present invention is used as an adjunct agent in methods for enhancing the effectiveness of cognitive training or motor learning (collectively "learning"). Such enhancement methods are known generically as "reinforced learning", including "reinforced cognitive training" or "reinforced motor learning".

Training usually requires several sessions to achieve the desired beneficial effects, for example, for the rehabilitation of a motor or speech disorder after a stroke. This can be costly and time consuming, impairing subject compliance and limiting the realization of practical benefits gained over time. The performance of these training methods can be improved by introducing certain agents (known as enhancers) in parallel with the training method (eg, U.S. 7868015; U.S. 7947731; US 2008-0188525). Reinforcement learning includes a specific learning technique for a specific brain function, such as the function underlying declarative memory, fine motor skills characteristics, locomotion, language acquisition, executive function, etc., and the general administration of drugs that enhance the CREB cascade. A training technique (cognitive training or motor learning) induces neuronal activity in certain areas of the brain and improves the performance of a particular brain function (cognitive or motor). In other words, the use of reinforcing agents ensures that the effect of cognitive training is achieved with fewer repetitions, i.e. with fewer training sessions.

In some embodiments, the present invention provides methods for treating a cognitive disorder, and more specifically, methods for improving cognitive impairment associated with a central nervous system (CNS) disorder or condition in an animal, comprising treating the animal with an enhancer that enhances the function of the CREB cascade, in parallel with cognitive training, while the enhancing agent is a compound or composition according to the present invention. For example, exemplary compounds of the present invention have been shown to activate CREB in cellular assays.

In one aspect, said method comprises: (a) providing cognitive training to a subject in need of treatment for a cognitive impairment, under conditions sufficient to provide improvement in said animal's cognitive function performance associated with said cognitive impairment; (b) administering a compound or composition of the present invention to an animal in parallel with said cognitive training; repeating steps (a) and (b) one or more times; and (d) reducing the number of training sessions sufficient to provide performance improvement compared to the same performance improvement due to cognitive training alone.

In another aspect, said method includes: (a) providing cognitive training to a subject in need of treatment for a cognitive impairment, under conditions sufficient to provide improvement in performance of said animal's cognitive function that is impaired by said cognitive impairment; (b) administering a compound or composition of the present invention to an animal in parallel with said cognitive training; repeating steps (a) and (b) one or more times; and (d) providing a long-term improvement in the performance of said function as compared to an improvement in the performance of said function due to cognitive training alone.

In one aspect, a compound or composition of the present invention may be used as an enhancing agent in conjunction with any psychotherapeutic approach designed to modulate cognitive function in the brain, thereby enhancing the effectiveness of said therapy by reducing the number of sessions required to achieve a beneficial effect.

In another aspect, the cognitive impairment that can be treated by these methods is or includes memory impairment and, more specifically, long-term memory impairment. Long-term memory (LTM) usually involves two main biological properties. First, the formation of long-term memory requires the synthesis of new proteins. Second, it affects cAMP-responsive transcription and is mediated by transcription factors of the cAMP-response activating protein (CREB) family. The compounds of the present invention can act as CREB enhancing agents and are therefore suitable for improving memory formation in animals, and more particularly transcription-dependent memory. Indeed, exemplary compounds of the present invention activate CREB in cellular assays.

In some embodiments, the present invention provides methods for treating a movement disorder, and more specifically, methods for improving a movement disorder associated with a central nervous system (CNS) disorder or condition in an animal, comprising treating the animal with an enhancer that enhances the function of the CREB cascade, in parallel with motor learning. Also provided herein are methods for providing sustained improvement in a motor impairment 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.

In one aspect, said method includes: (a) providing motor learning to a subject in need of treatment for a motor disorder, under conditions sufficient to provide improvement in said animal's motor function performance associated with said cognitive impairment; (b) administering a compound or composition of the present invention to an animal in parallel with said motor learning; repeating steps (a) and (b) one or more times; and (d) reducing the number of training sessions sufficient to provide an improvement in performance compared to the same improvement in performance due to motor learning alone.

In another aspect, said method includes: (a) providing motor learning to a subject in need of treatment for a motor disorder, under conditions sufficient to provide improvement in performance of said animal's motor function, the deterioration of which is associated with said cognitive impairment; (b) administering a compound or composition of the present invention to an animal in parallel with said motor learning; repeating steps (a) and (b) one or more times; and (d) providing a long-term improvement in the performance of said function as compared to an improvement in the performance of said function due to motor learning alone.

In other embodiments, the present invention provides methods for enhancing a particular aspect of cognitive performance in an otherwise healthy animal (particularly a human or other mammal or vertebrate), comprising (a) administering to the animal an enhancing agent of the present invention; and (b) training the animal under conditions sufficient to ensure that the animal performs better on a particular cognitive task. In other embodiments, the present invention provides methods for enhancing cognitive or motor performance, as well as methods for repeatedly stimulating neuronal activity or a neuronal activity pathway, such as the pathway underlying a particular neuronal circuit(s).

Enhancers

Enhancers, including the compounds and compositions described herein, may enhance the function of the CREB cascade. By enhancing the function of the CREB cascade in parallel with training, such enhanced training can provide a reduction in the number of training sessions needed to improve cognitive or motor performance compared to the improvement seen with training alone (e.g., U.S. 2007-0203154, U.S. 2011-0160248 , U.S. 2010-0317648 and US Patent No. 8222243).

The enhancer may be administered before, during, or after one or more training sessions. In a particular embodiment, the enhancement agent is administered prior to and during each training session. Treatment with an enhancer in parallel with each training session is also referred to as "enhancing treatment".

Teaching Methods

Teaching techniques are commonly used for individuals undergoing rehabilitation who have some form or degree of cognitive or motor dysfunction. For example, teaching methods are commonly used in stroke rehabilitation and age-related memory loss rehabilitation. Since multiple training sessions are often needed before individuals achieve improvement or enhancement in a particular aspect of a cognitive (or motor) characteristic (ability or function), training techniques are often very costly and time consuming. Reinforced learning methods are more efficient and therefore more cost effective.

For example, a human brain injury often leads to motor and cognitive impairment. Although the benefits of resuscitation and patient management lead to improved patient outcomes after traumatic brain injury (TBI), there are currently no known treatments to prevent neuronal cell death and dysfunction after TBI. Although numerous agents have been approved as neuroprotective agents in preclinical models of TBI, most of them are not effective in humans.

Once the patient is stabilized after TBI, the standard of care dictates extensive motor or cognitive rehabilitation. During rehabilitation, the patient often restores lost skills, which ultimately leads to an improvement in the functional outcome of treatment. It would be desirable to develop pharmaceutical therapies to enhance motor or cognitive rehabilitation after TBI and thereby improve the functional outcome of the treatment.

Cognitive training and motor learning techniques and underlying principles are well known in the art (e.g., Allen et al., Parkinsons Dis. 2012, 1-15; Jaeggi et al., Proc. Natl. Acad. Sci. USA 2011, 108 , 10081-10086; Chein et al., Psychon Bull Rev. 2010, 17 , 193-199; Klingberg, Trends Cogn. Sci. 2010, 14 , 317-324; Owen et al., Nature 2010, 465 , 775 -778; Tsao et al., J. Pain 2010, 11 , 1120-1128; Lustig et al., Neuropsychol. Rev. 2009, 19 , 504-522; Park and Reuter-Lorenz, Ann. Rev. Psych . 2009, 60 , 173-196; Oujamaa et al., Ann. Phys. Rehabil. Med . 2009, 52, 269-293; Frazzitta et al., Movement Disorders 2009, 8 , 1139-1143; Jaeggi et al., Proc. Natl Acad. Sci. USA 2008, 105 , 6829-6833; Volpe et al., Neurorehabil. Neural Repair 2008, 22 , 305-310; Fischer et al., Top. Stroke Rehab . 2007, 14 , 1-12; Jonsdottir et al., Neurorehabil Neural Repair 2007, 21 , 191-194; Stewart et al., J. Neurol. Sci. 2006, 244 , 89-95; Krakauer, Curr. Opin. Neurol. 2006, 19 , 84-90 ; Belleville et al., Dement. Geriatr. Cogn. Discord . 2006, 22 , 486-499; Klingberg et al., J. Am. Acad. child. Adolesc. Psychiatry 2005, 44 , 177-186; Dean et al., Arch. Phys. Med. Rehabil. 2000 , 81 , 409-417; Whitall et al., Stroke 2000, 31 , 2390-2395; Hummelsheim and Eickhof, Scand. J. Rehabil. Med. 1999, 31 , 250-256; Merzenich et al., Science 1996, 271 , 77-81; Merzenich et al., Cold Spring Harb. Symp. quant. Biol. 1996, 61 , 1-8; Rider and Abdulahad, Percept. Mot. Skills 1991, 73 , 219-224; Wek and Husak, Percept. Mot. Skills, 1989, 68 , 107-113.

Cognitive training techniques target numerous cognitive dimensions, including memory, concentration, perception, learning, planning, sequencing, and judgment. Motor learning techniques can target multiple motor domains, such as hand and foot rehabilitation after a stroke or head injury. The subject may be offered one or more techniques (or modules) that form the basis of the training program.

In some embodiments, these techniques may be used to treat or rehabilitate cognitive or motor impairments in suffering subjects. These techniques may be restorative or therapeutic, designed to restore previous skills and functions, or they may be oriented towards delaying or slowing cognitive or motor deterioration due to neurological disease. Other protocols may be compensatory, providing a way to adapt to cognitive or motor impairment by enhancing the function of related or unaffected areas of the brain. In other embodiments, these methods may be used to improve certain skills or cognitive or motor functions in otherwise healthy individuals. For example, a cognitive training program should include modules focused on delaying or preventing the cognitive impairment that typically accompanies aging; such a program is designed to maintain or improve cognitive health.

Typically, a training methodology (or module) contains a set of individual exercises that may be specific to a particular process or skill: Process-specific training focuses on improving a specific domain, such as attention, memory, speech, executive function, or motor function. Here, the task of learning is to achieve an overall improvement that extends from trained activities to untrained activities associated with the same cognitive or motor function or domain. For example, an auditory cognitive training technique can be used to treat a student with impaired auditory attention. At the end of the training, the student should demonstrate a general improvement in auditory attention, which is manifested by an improved ability to perceive and concentrate on verbal information received in the classroom, and, therefore, remembering the need to write down and do homework. Similarly, a cognitive training technique may be aimed at improving executive function in an autistic subject, preventing the subject from following instructions to complete an activity, such as cooking, cleaning a room, or getting ready for school the next morning. Cognitive training allows the subject to focus and concentrate and, as a result, complete the sequence of tasks required for such activities.

Skill-based training is designed to improve the performance of a particular action or ability. Here the goal of training is to achieve an overall improvement in a skill or ability. For example, a teaching methodology may focus on learning a new language, playing a musical instrument, improving memory, or teaching fine motor skills. Various exercises of this technique are focused on the key components that underlie this skill. For example, modules for improving memory may include tasks aimed at recognizing and using a fact, as well as acquiring and understanding the rules of explicitly given knowledge.

Some rehabilitation programs are based on a single strategy (such as computer-assisted cognitive training) that targets either a single cognitive function or multiple functions at the same time. For example, the CogState test method includes a customizable range of computerized cognitive tasks that measure baseline and change in the cognitive domains underlying attention, memory, executive function, and language and socio-emotional cognition (e.g., Yoshida et al.,PloS ON, 2011,6, e20469; Fredericksonet al.,Neuroepidemiology 2010, 34, 65-75). Other rehabilitation programs may use integrated or interdisciplinary approaches. Cognitive training and motor learning programs may include computer games, handheld gaming devices, interactive exercises, and may have feedback or adaptive models.

Neurorehabilitation and neurorecovery

In other embodiments, the present invention further relates to the use of the compounds and compositions of the present invention for neurorecovery and neurorehabilitation, endogenous neurobiological processes that are key to the recovery of cognitive and motor impairments of the nervous system (e.g., Harkema et al., Arch. Phys. Med. Rehabil 2012, 93 , 1588-1597; Muresanu et al., J. Cell. Mol. Med. 2012, 16 , 2861-2871).

Neurorehabilitation or neurorecovery refers, in general, to a cumulative process that is focused on helping a patient recover from a neurological disorder or helping an individual live a more normal, active, and independent life. For example, a person's quality of life can be significantly impaired by damage to the brain or spinal cord, or as a result of a medical condition that impairs mobility, cognition, or other physical or psychological processes that are affected by changes in the nervous system. The goal of neurorehabilitation is to combat such changes and improve the quality of life through various therapies.

Pathological conditions within the scope of the present invention that can be treated through neurorehabilitation and neurorecovery include: stroke; traumatic brain injury (TB); dementia; Alzheimer's disease; Parkinson's disease; Huntington's disease; cerebral paralysis; postpolio syndrome; Guillain-Barré syndrome and multiple sclerosis; and other age-related syndromes, genetic conditions, and progressive CNS diseases that impair cognitive function, such as autism spectrum disorders, fetal alcohol spectrum disorders (FASD), Rubinstein-Taybi syndrome, Down syndrome, and other forms of mental retardation.

Focusing on all aspects of an individual's well-being, neurorehabilitation or neurorehabilitation provides a range of therapies, from psychological to occupational, training or re-education of patients in walking skills, the process of communication and other aspects that a person encounters on a daily basis. Neurorehabilitation or neurorecovery also focuses on the nutritional, physiological and creative areas of patient recovery.

In one embodiment, the present invention provides a method for enhancing neurorehabilitation or neurorecovery after a cognitive impairment, comprising (a) providing cognitive training to a subject in need of treatment for a cognitive impairment, under conditions sufficient to provide an improvement in the characteristics of the cognitive function of the specified animal, the deterioration of which is associated with the specified cognitive impairment; (b) administering a compound or composition of the present invention to an animal in parallel with said cognitive training; repeating steps (a) and (b) one or more times; and (d) providing a long-term improvement in the performance of said function as compared to an improvement in the performance of said function due to cognitive training alone.

In another embodiment, the present invention provides a method for enhancing neurorehabilitation or neurorecovery after a motor disorder, comprising: (a) providing motor learning to a subject in need of treatment for a motor disorder, under conditions sufficient to provide improvement in the performance of said animal's motor function, the deterioration of which is associated with said cognitive impairment; (b) administering a compound or composition of the present invention to an animal in parallel with said motor learning; repeating steps (a) and (b) one or more times; and (d) reducing the number of training sessions sufficient to provide an improvement in performance compared to the same improvement in performance due to motor learning alone.

Non-Human Animal Training Techniques

In addition to their use in humans, the compounds and compositions of the present invention have an additional use in non-human animals, namely to enhance (increase) the effectiveness of learning methods aimed at various cognitive and motor functions.

Conditions in which non-human animals would have a beneficial effect include enhanced (improved) training procedures for specific purposes (e.g. hunting dogs, guide dogs, police dogs, etc., or animals used in the film industry) .

Reinforced learning techniques may also be useful in animals that have been exposed to stressful or traumatic conditions and need training to treat the resulting cognitive impairment. Such a need may arise, for example, after the animal is captured or transported, placed in a new environment (as in a change of residence or owner), or if the animal has developed similar disorders and is anxious or aggressive, or exhibits stereotypical behavior, obsessive -compulsive behavior or anxiety. Stressed animals also include animals used in races (such as dogs, horses, camels) or other sports, stage animals (such as circus and stage, television or film animals), and horses that are undergoing training or other very disciplined programs.

The compounds of the present invention may also enhance the effectiveness of rehabilitation techniques following physical injury to a non-human animal, such as amputation of a limb. For example, administering an enhancer of the present invention in parallel with a training technique may increase the effectiveness of a rehabilitation program by reducing the number of training sessions required to achieve improvement in motor function.

In specific embodiments, the compounds and compositions of the present invention are used in methods for training service animals. The combination of the enhancers of the present invention with the training methods provides for improved training of non-human service animals in public and private segments. Service animals are typically animals. However, other non-human animals may also be trained to perform service tasks, such as assisting the blind or people with disabilities. For example, miniature horses can be trained to accompany the blind, pull wheelchairs, or support patients with Parkinson's disease. As another example, capuchins can be trained to help people with disabilities perform manual tasks such as grasping objects, pressing buttons and switches, and turning the pages of a book.

In specific embodiments, enhanced learning with the compounds and compositions of the present invention can be used to reduce the number of training sessions required to teach an animal skills required for community service, such as law enforcement. For example, in dogs, such skills include, but are not limited to: (i) maintaining public order, such as chasing, capturing or detaining suspects; (ii) search and rescue, for example, found suspects, missing persons or items; and (iii) detection of contraband, such as detection of illegal substances such as drugs, drugs, explosives, weapons, and even human remains. Therefore, these methods can be used for police dogs, bomb sniffer dogs, drug sniffer dogs, search and rescue dogs, and the like.

In other embodiments, enhanced learning (with the compounds and compositions of the present invention) can be used to reduce the number of training sessions required to teach an animal skills required by individuals, such as security and medical care. For example, in dogs, such skills may include, but are not limited to, the following: (i) private guarding, such as guarding property or protecting an individual; (ii) assistance for physical disabilities, such as eyes for a person with a visual impairment, ears for a person with a hearing impairment, hands and feet for a person with a physical disability; (iii) medical assistance, such as finding cancer or notifying a caregiver of an epileptic seizure in a subject; (iv) psychiatric care, such as calming the phobic person in stressful situations or drawing the autistic subject's attention to distracting repetitive movements such as hand clapping; and (v) pest control, such as determining the source of a bedbug or termite attack.

In some embodiments, the training methodology may be directed towards a single skill or task, such as detecting a single drug. In other implementations, the training methodology may focus on a complex set of skills, such as the skills underlying search and rescue. Therefore, for a complex set of skills, learning involves more than one task.

In another aspect, if training is carried out within a sufficiently wide range of tasks, a generalized "rehabilitation" effect is expected, resulting in an overall improvement in the function of one or more cognitive domains. This leads to improved performance by animals of related tasks (affecting the same cognitive domains), which are not in themselves included in the teaching methodology.

Accordingly, the present invention provides a method for reducing the time required to teach an animal one or more skills, said reduction comprising: a) administering to the animal an enhancing agent of the present invention; b) providing a training methodology to said dog under conditions that enhance performance of one or more tasks, wherein said training methodology includes multiple training sessions; and c) reducing the number of training sessions needed to improve the performance of said one or more tasks compared to the number of said training sessions needed to provide said improvement in performance using the training methodology alone.

The training technique can be provided to the animal under conditions that improve the performance of one task; a complex set of tasks; or a wide range of tasks, resulting in an overall improvement in the function of one or more cognitive domains. Tasks may be related to a skill required for community service, such as maintaining public order, search and rescue, and detecting contraband. Tasks can also be associated with a skill required for private service, such as private security, manual labor assistance, medical care, mental health care, and pest control.

Peripheral disorders

PDE4 enzymes are located in many peripheral tissues. For example, one or more PDE4D isoforms are expressed in most tissues studied, including the cerebral cortex, hippocampus, cerebellum, heart, liver, kidney, lung, and testes (Richter et al ., Biochem. J., 2005, 388, 803-811) . The localization and regulation of PDE4D isoforms presumably provides a robust and local regulation of cAMP levels, possibly limiting signal propagation to specific subcellular regions.

In one embodiment, the present invention provides a method of treating a psychiatric disorder associated with PDE4, comprising administering to an animal in need of such treatment an effective amount of a compound or pharmaceutical composition described herein.

The peripheral disorder may include, but is not limited to, PDE4-related disorders such as inflammatory bowel disease (Banner and Trevethick, 2004, Trends Pharmacol. Sci. 25, 430-436); rheumatoid arthritis (Kobayashi et al., 2007, Mediators Inflamm . 2007, 58901); chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis, pulmonary arterial hypertension (DeFranceschi et al., 2008, FASEB J ., 22, 1849-1860); renal diseases (Conti et al., 2003, J. Biol. Chem ., 278, 5493); allergic skin diseases and psoriasis (Baumer et al., 2007, Inflamm. Allergy Drug Targets , 6, 17-26).

EXAMPLES

The present invention is further illustrated by the following non-limiting examples. These examples are to be understood as illustrative only and should not be considered as limiting the scope of the present invention as defined by the appended claims.

PREPARATION EXAMPLES

Illustrative compounds suitable for the methods of the present invention are described below with reference to illustrative synthetic schemes intended to describe general methods for their synthesis, as well as to specific examples below.

Synthesis schemes

Those skilled in the art will appreciate that, in order to prepare the various compounds described herein, the starting materials may be selected to produce the final substituents required in the reaction scheme, with or without protection, as appropriate, to obtain the desired product. . Alternatively, instead of the ultimately required substituent, it may be necessary or desirable to use a suitable group that can be used in the reaction scheme and, if necessary, substituted by the desired substituent. Unless otherwise indicated, all variables are as described above with reference to Formula (I). The reactions can be carried out at -78° C. to the boiling point of the solvent. The reaction mixtures can be heated using conventional heating or heating in a microwave reactor. The reactions may also be carried out in sealed vessels at temperatures above the normal boiling point of the solvent.

SCHEME A

According to Scheme A, commercially available or synthetically available 3-bromo-5-methylpyridin-2-ol (II) is difluoromethylated with 2,2-difluoro-2-(fluorosulfonyl)acetic acid or silyl ester of 2-fluorosulfonyldifluoroacetate, preferably 2, 2-difluoro-2-(fluorosulfonyl)acetic acid in an aprotic solvent such as ACN in the presence of a base such as Na ₂ CO ₃ , NaH and the like, preferably Na ₂ CO ₃ , at temperatures ranging from room temperature to boiling point of the solvent, preferably at room temperature, to give a compound of formula (VI) wherein Z is CH and R ₄ is CHF ₂ (Chen et al., J. Flourine Chem. , 1989, 44, 433-440) .

In accordance with Scheme A, the compound of formula (VI), where Z represents CH, U represents -CH ₃ , R ⁴ represents -C _1-3 alkyl or -C _1-3 haloalkyl, is obtained from commercially available or synthetically available compounds of formula (III), where U represents-CH ₃ . 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 an alcohol used to form the alkoxide at a temperature ranging from room temperature to temperature refluxing the solvent for 4 to 48 hours gives the bromopyridyl ether of formula (VI). Alternatively, a compound of formula (VI) wherein R ⁴ is -C _1-3 alkyl or -C _1-3 haloalkyl can be prepared by reacting 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 boiling point of the solvent.

In accordance with Scheme A, the compound of formula (VI), where Z represents CH, U represents -CH ₂ OH, R ⁴ represents -C _1-3 alkyl or -C _1-3 haloalkyl, is obtained in two stages from the available commercially or synthetically available compounds of formula (III), where U represents -CO ₂ H or -CO ₂ C _1-3 alkyl. For example, 5-bromo-6-chloronicotinic acid is reacted with a suitably substituted alcohol in the presence of a base such as NaH, Cs ₂ CO ₃ and the like, with or without a solvent such as DMA, 1,4-dioxane , THF and the like, at temperatures ranging from room temperature to the boiling point of the solvent, using conventional or microwave heating for 30 minutes to 8 hours, to obtain a compound of formula (VI), where R ⁴ represents -C _1-3 alkyl or -C _1-3 haloalkyl. In an alternative process, a compound of formula (VI) wherein U is -CO ₂ C _1-3 alkyl and R ⁴ is -C _1-3 alkyl or -C _1-3 haloalkyl is prepared from a compound of formula (III) wherein U is -CO ₂ H, the acid is activated with a suitable activating agent and then reacted 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 form an acid chloride. Subsequent reaction with the alkoxide in a suitable solvent, such as the alcohol used to prepare the alkoxide, results in a compound of formula (VI) wherein U is -CO ₂ C _1-3 alkyl and R ⁴ is -C _1-3 alkyl or -C _1-3 haloalkyl. In the subsequent reaction, a compound of formula (VI) wherein U is -CO ₂ C _1-3 alkyl and R ⁴ is -C _1-3 alkyl or -C _1-3 haloalkyl is reduced with a reducing agent such as NaBH ₄ . LiBH ₄ or a mixture thereof, in a solvent such as THF and the like, at temperatures ranging from 0°C to room temperature to obtain a compound of formula (VI), where U represents -CH ₂ OH.

According to Scheme A, a compound of formula (VI) wherein Z is CH, U is -CH ₂ Cl and R ⁴ is -C _1-3 alkyl or -C _1-3 haloalkyl is prepared from a compound of formula ( VI), where Z is CH, U is -CH ₂ OH, and R ⁴ is -C _1-3 alkyl or -C _1-3 haloalkyl. 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 room temperature with obtaining 3-bromo-5-(chloromethyl)-2-ethoxypyridine.

A compound of formula (VI) wherein Z is CH, U is -CH(=O) and R ⁴ is -C _1-3 alkyl or -C _1-3 haloalkyl, e.g. 5-bromo-6-methoxynicotinaldehyde , is prepared from 6-methoxynicotinaldehyde a using bromination reaction conditions known to those skilled in the art. For example, 6-methoxynicotinaldehyde is reacted with Br ₂ , NaOAc in a solvent such as HOAc at temperatures ranging from room temperature to 90° C. to give 5-bromo-6-methoxynicotinaldehyde a.

According to Scheme A, commercially available or synthetically available 5-methylpyrazin-2-amine (IV) wherein R ¹ is H, U is CH ₃ , and Z is N is brominated under conditions known to those skilled in the art. field of technology, for example, by reaction with a suitable halogenating agent such as NBS, Br ₂ and the like, in a suitable solvent such as DCM, 1,4-dioxane, THF, CHCl ₃ , preferably DCM, at temperatures ranging from 0°C to room temperature for 8 to 16 hours to obtain 3-bromo-5-methylpyrazine-2-amine. The subsequent reaction of 3-bromo-5-methylpyrazin-2-amine (V) with an oxidizing agent such as, but not limited to, tert -butyl nitrite, in the presence of an anhydrous acid source, such as HCl in 1,4-dioxane, in alcohol solvent such as MeOH, EtOH and the like, at temperatures ranging from 0°C to 60°C for 8 to 16 hours leads to compounds of formula (VI), where Z is N, U is -CH ₃ and R ₄ is -C _1-3 alkyl.

In accordance with Scheme A, commercially available or synthetically available 6-amino-2-methylnicotinonitrile (IV), where R ¹ represents -CH ₃ , U represents -CN, and Z represents CH, is obtained in two stages (bromination and diazotization/alcohol addition) according to the methods previously described to give compounds of formula (VI) wherein R ¹ is -CH ₃ , U is -CN, and Z is CH.

SCHEME B

In accordance with Scheme B, 2-(difluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)pyridine (IX) is obtained in 2 stages 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 boiling point of the solvent in within 6 to 12 hours (also described in WO 2010/056195, May 20, 2010) results in 4-bromo-2-(difluoromethoxy)pyridine (VIII). The boronate ester is obtained by methods known to those skilled in the art, for example, 2-difluoromethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (IX) obtained from 4-bromo-2-(difluoromethoxy)pyridine (VIII) by reacting with KOAc, K ₃ PO ₄ etc., a catalyst such as Pd(dppf)Cl ₂ , Pd(PPh ₃ ) ₄ etc. n., bis(pinacolato)diboron and the like, in a solvent such as 1,4-dioxane, 1,2-dimethoxyethane, DMF, DMSO and the like, at temperatures from 60 to 150°C for 6-24 hours.

SCHEME C

As shown in Scheme C, a compound of formula (VI) wherein U is -CH₃, -CN, -CH₂OH, -CH(=O) or -NH₂, Z is CH or N; R¹ is H or -CH₃, and R⁴ represents -C_1-3alkyl or -C_1-3haloalkyl; reacted under Suzuki reaction conditions known to those skilled in the art with commercially available or synthetically available aromatic or heteroaromatic boronic acids or esters, or with synthetically available 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 so on. and a palladium catalyst such as Pd(dppf)₂, Pd(PPh₃)₄ and the like using conventional or microwave heating at temperatures in the range of 80 to 120° C. to obtain a compound of formula (X). A compound of formula (X) wherein R³ is aryl or heteroaryl optionally substituted with -OH, under standard alkylation conditions known to those skilled in the art, treated with commercially available or synthetically available alkyl groups with suitable leaving groups such as halides, e.g. -Cl, -Br or -I, or sulfonates such as methanesulfonyl,P-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 boiling point of the solvent for 8 to 24 hours to obtain aryl or a heteroaryl-O-alkyl compound of formula (X).

Halogenation of a compound of formula (X) wherein U is -CH ₃ or -CH ₂ OH, Z is CH or N; R ¹ is H or -CH ₃ , R ₃ is aryl or heteroaryl, and R ⁴ is -C _1-3 alkyl or -C _1-3 haloalkyl, under free radical halogenation conditions. For example, a compound of formula (X) wherein U is -CH ₃ is reacted with NBS, a radical initiator such as AIBN or benzoyl peroxide, in a solvent such as CCl ₄ at temperatures ranging from 60° C. to reflux solvent for 4 to 24 hours to give a compound of formula (XI) wherein HAL is -Br. In an alternative method, a compound of formula (X) where U is -CH ₂ OH is reacted with a chlorinating agent such as thionyl chloride using the methods described previously to give a compound of formula (X) where HAL is -Cl.

A nitrile compound of formula (X) wherein U is -CN, Z is CH; R ¹ is -CH ₃ , R ₃ is aryl or heteroaryl, and R ⁴ is -CH ₃ 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 a low temperature, preferably -78° C., for 1 to 3 hours. The subsequent reduction of the aldehyde moiety to the corresponding alcohol is carried out with a reducing agent such as sodium or lithium borohydride, etc., in a solvent such as MeOH, THF, etc., at temperatures from 0° C. to room temperature ^. Activation of the alcohol with methanesulfonyl chloride in a suitable solvent such as DCM in the presence of an alkylamine base such as Hunig's base, TEA, etc. results in a compound of formula (XI) wherein U is -CN, Z is CH ; R ¹ is -CH ₃ , R ⁴ is -CH ₃ and HAL is -Cl.

In accordance with Scheme C, 5-bromo-6-methoxypyridine-3-amine, where U represents -NH ₂ Z represents CH; R ¹ is H, R ⁴ is -CH ₃ is reacted under standard Suzuki reaction conditions as described previously to give compounds of formula (X) wherein U is -NH ₂ , Z is CH; R ¹ is H, R ³ is aryl or heteroaryl, and R ⁴ is -CH ₃ . Alternatively, a compound of formula (X) may be prepared from commercially available or synthetically available, suitably substituted pyridinamines, such as 5-bromo-6-ethoxypyridine-3-amine, as described in the processes above, wherein U is -NH ₂ , Z is CH; R ¹ is H, R ³ is aryl or heteroaryl, and R ⁴ is -C _1-3 alkyl.

SCHEME D

In accordance with Scheme D, a compound of formula (XII) under Sandmeyer conditions known to those skilled in the art is reacted with an oxidizing agent, such as, but not limited to, t -butyl nitrite, in the presence of a halogenating agent, for example, copper bromide ( II) in a suitable solvent such as ACN and the like at a suitable temperature, preferably 60° C., to give a compound of formula (XIII). Lithiation of a compound of formula (XIII) with a suitable metal base such as n -BuLi or the like in an aprotic solvent such as THF, Et ₂ O or the like at low temperature, preferably -78°C, for 30-60 minutes followed by addition of the appropriate aryl or heteroarylcarbonyl compound, followed by further stirring at temperatures ranging from -78° C. to ambient temperature, results in a compound of Formula (I) where Y is CHOH, Z is CH , R ² and R ³ are monocyclic aromatic or heteroaromatic rings, and R ⁴ is -CH ₃ .

A fluorine compound of Formula (I) wherein Y is -C(R ^a ) ₂ - and R ^a is -H or -F is prepared by reacting an alcohol of Formula (I) where Y is CH(OH) using fluorination conditions such as, but not limited to, interaction with Deoxo-Fluor®, XtalFluor®, etc., in a solvent such as DCM, etc., at room temperature for 1 to 24 hours.

A compound of Formula (I) wherein 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, triflatic acid and the like, in a solvent such as DCM and the like, at room temperature for up to 24 hours.

The amine compound of Formula (I) where Y is -CHNH ₂ -, -CHNH(CH ₃ )- or -CHN (CH ₃ ) ₂ - is prepared in two steps by reacting an alcohol of Formula (I) where Y is - CH(OH), with a chlorinating agent such as thionyl chloride, oxalyl chloride, etc., with or without the addition of a catalytic amount of DMF, in a solvent such as DCM, etc., at temperatures from 0°C to room temperature to form a chlorine-containing intermediate which is then reacted with a suitable amine such as, but not limited to, ammonia, methylamine, and the like, with or without the addition of a catalytic amount of sodium iodide, in a solvent such as ACN at a temperature in the range from room temperature to 80°C.

SCHEME E

As described in Scheme E, a compound of Formula (I) can be prepared from a compound of formula (IX) by a reaction such as, but not limited to, Suzuki or Negishi coupling reactions, as well as by substitution reactions with nitrogen-containing heteroaryls. The compound of formula (IX), using standard Suzuki coupling conditions known to those skilled in the art and described earlier herein, is reacted with commercially available aromatic or heteroaromatic boronic acids, boronic esters, trifluoroborates, or synthetically available heteroaromatic boronic esters such as compound (IV), to obtain a compound of Formula (I). In an alternative method, a compound of formula (IX) wherein HAL is -Cl is reacted with dipinacoldibor, a suitable base such as K ₂ CO ₃ , a palladium catalyst such as Pd(PPh ₃ ) ₄ , etc., in a solvent such as dioxane to give the corresponding boronate ester. Subsequent reaction of the boronate ester with a suitable halogen-substituted heteroaryl compound using the Suzuki reaction conditions described previously results in a compound of Formula (I).

The compound of formula (IX) is reacted using standard Negishi coupling conditions known to those skilled in the art. Example of Negishi reaction conditions: Combination of commercially available halogenated aromatic or heteroaromatic intermediates with pre-synthesized zincate obtained by reacting compounds of formula (IX) with zinc pre-treated with activators such as trimethylsilyl chloride and 1,2-dibromoethane in a suitable solvent such as as THF, 1,4-dioxane and the like, at a temperature ranging from room temperature to boiling point, preferably at boiling point, for 12 to 24 hours. Mixing the zincate intermediate with commercially available halogenated aromatic or heteroaromatic compounds in the presence of a palladium catalyst such as Pd(PPh ₃ ) ₄ or the like in a suitable solvent such as THF, 1,4-dioxane or the like. , at temperatures in the range from 50°C to the boiling point of the solvent, within 12 to 48 hours leads to the receipt of the compounds of Formula (I), where R ² represents a six-membered heteroaryl ring containing one or two nitrogen atoms.

Mixing a compound of formula (IX) with a suitable heterocycle (HET) with an acidic proton, such as, but not limited to, 1H-1,2,4-triazole or imidazole, in an aprotic solvent, such as DMF, acetone, CAN, etc. p., with a suitable base such as Cs ₂ CO ₃ , K ₂ CO ₃ and the like, at temperatures from room temperature to 60°C for 2 to 24 hours results in a compound of Formula (I), where R ² is a five-membered heteroaryl ring containing two to three nitrogen atoms.

A compound of Formula (I) wherein Y is -CH ₂ and R ² is an optionally substituted 1,2,3-triazole is prepared by click chemistry (eg, azide-alkyne addition on a copper catalyst) under the conditions known to those skilled in the art, for example by treating the compound of formula (IX) with sodium azide in a suitable solvent such as DMF, acetone, DMSO, etc., and a base such as K ₂ CO ₃ , etc., at temperatures ranging from room temperature to 100°C, to obtain an intermediate azido compound, which is then mixed with a commercially available or synthetically available alkyne, such as, but not limited to, ethynyltrimethylsilane, and the like, in a solvent such as DMSO , 1,4-dioxane, THF, ACN, tert -butanol and water or a mixture thereof, in the presence of a catalyst such as copper (II) iodide, copper (II) bromide, copper (I) sulfate, etc., and a base such as DIPEA and the like at temperatures ranging from room temperature to 100° C. for 2 to 12 hours to give a compound of Formula (I) wherein R ² is an optionally substituted 1,2,3 -triazole.

The compound of Formula (I) wherein R ² is an amide (-CONH ₂ ) is prepared from the corresponding nitriles (-CN) or esters (-CO ₂ C _1-3 alkyl) using methods known to those skilled in the art. For example, an amide of Formula (I) is prepared by reacting a nitrile compound of Formula (I) with a base such as NaOH or KOH, preferably NaOH, and a peroxide such as H ₂ O ₂ in a solvent such as MeOH and the like, at temperatures in the range from 0 to 50°C for 8 to 24 hours. Optionally, the carboxylic acid compound of Formula (I) is prepared by treating the nitrile compound of Formula (I) as described above at 50° C. for 2 to 4 hours. The ester compound of Formula (I) is converted into an amide of Formula (I) by treatment with a suitable amine such as ammonia, methylamine or the like in a solvent such as MeOH, 1,4-dioxane and the like at temperatures of range from room temperature to the boiling point of the solvent.

A compound of Formula (I) wherein R ² is substituted with a primary (-(CH ₂ ) _1-2 OH) or tertiary (-C(CH ₃ ) ₂ OH) alcohol is prepared from the 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 NaBH ₄ or NaBH ₃ CN or the like in a solvent such as MeOH, THF, DMF or the like at temperatures ranging from 0° C. to room temperature temperature for 0.2 to 2 hours results in a primary alcohol compound of Formula (I) wherein R ² is substituted with a -CH ₂ OH group. The compound of Formula (I) wherein R ² is substituted with an ester moiety is reduced with a reducing agent such as NaBH ₄ , LiBH ₄ , LAH, DIBAL, etc. with or without the addition of KF in a solvent such as MeOH, THF, Et ₂ O and the like, at temperatures in the range from 0°C to room temperature for 2 to 24 hours to obtain a primary alcohol compound of Formula (I), where R ² is substituted by a group-CH ₂ OH.

The compound of Formula (I) wherein R ² is substituted with -CH ₂ OH or -CHO is fluorinated using fluorination conditions such as, but not limited to, reaction with Deoxo-Fluor®, XtalFluor®, etc., in a solvent , such as DCM and the like, at room temperature for 2 to 24 hours to obtain a fluoroalkyl compound of Formula (I) wherein R ² is substituted with a -CH ₂ F or -CHF ₂ group.

The compound of Formula (I) wherein R ² is substituted with an ester moiety is reacted under Grignard conditions known to those skilled in the art with a Grignard reagent such as, but not limited to, methylmagnesium bromide, in a solvent such as THF, Et ₂ O and the like, at a temperature in the range from 0°C to room temperature for 0.3 to 2 hours to obtain a compound of Formula (I), where R ² is substituted with a tertiary alcohol (-C(CH ₃ ) ₂ OH) .

The compound of Formula (I) wherein R ² is substituted with -CN is reduced with a reducing agent such as DIBAL and the like in a solvent such as Et ₂ O, THF and the like at low temperatures, preferably -78 °C, for 1 to 4 hours to obtain a primary amine compound of Formula (I), where R ² is replaced by a primary amine (-CH ₂ NH ₂ ).

The compound of Formula (I) wherein R ² is substituted with a -CN group is reacted with acetyl chloride in an alcoholic solvent such as MeOH, EtOH, etc. at a low temperature, preferably 0° C., for 30 minutes to 2 hours to obtain a compound of Formula (I) wherein R ² is substituted with CO ₂ C _1-3 alkyl.

The compound of Formula (I) wherein R ² is substituted by a -CH ₂ CN group is reacted under alkylation conditions known to those skilled in the art to give a compound of Formula (I) wherein R ² is substituted by a -C(CH ₃ ) ₂ CN group . For example, reaction with an alkylating agent such as MeI, a base such as NaOH, in a solvent such as DMSO, water or a mixture thereof, at low temperatures such as 0° C. for 30 minutes to 2 hours.

The compound of Formula (I) wherein R ² is substituted with an ester moiety is reacted under standard hydrolysis conditions known to those skilled in the art with a base such as, but not limited to, KOH, LiOH, NaOH, and the like, to solvent such as THF, 1,4-dioxane, MeOH, H ₂ O or a mixture thereof, at temperatures in the range from room temperature to the boiling point of the solvent for 1 to 4 hours to obtain a compound of Formula (I), where R ² is substituted carboxylic acid (-CO ₂ H).

The compound of Formula (I) where R ² is substituted with an amide (-CONH ₂ ) is prepared in two steps from a compound of Formula (I) where R ² is substituted with a carboxylic acid (-CO ₂ H). Halogenation to the acid chloride using known methods, followed by reaction with an ammonia source such as ammonia in dioxane, results in a compound of Formula (I) wherein R ² is substituted with an amide (-CONH ₂ ).

The compound of Formula (I) wherein R ² is an optionally substituted pyrimidine or pyrazine substituted with -Cl or -Br is reacted with alkyl or heteroalkyl oxygen or nitrogen nucleophiles such as N1,N1 -dimethylethane-1,2-diamine, 2 -aminoethanol, morpholine and the like, in a solvent such as ACN, THF, EtOH, DMF, toluene and the like, in the presence of a base such as DIPEA, TEA, NaH, K ₂ CO ₃ and the like ., at a temperature in the range from 50 to 180°C, using conventional or microwave heating for 1 to 4 hours, to obtain a compound of Formula (I), where R ² represents an optionally substituted pyrimidine or pyrazine.

A compound of Formula (I) wherein R ² is substituted with a -NO ₂ group 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 temperatures up to 50°C for 1 to 4 hours to obtain a primary amine compound of Formula (I), where R ² is replaced by a primary amine (-NH ₂ ).

The compound of Formula (I) wherein R ² is substituted with a primary amine (-NH ₂ ) is reacted with tert- butyl nitrite, in a solvent such as DMF, water, or a mixture thereof, at temperatures ranging from 0° C. to 60° C. in for 8 to 16 hours to give a compound of Formula (I) wherein R ² is substituted with -OH.

The compound of Formula (I) wherein R ² is substituted with (-NHR ^b ) or (-N(R ^b ) ₂ ) is prepared from the corresponding amine compounds of Formula (I) using methods known to those skilled in the art, such as, but not limited to, reductive amination reaction. For example, a compound of Formula (I) wherein R ² is substituted with (-NH ₂ ) 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 , NaBH ₃ CN and the like, at temperatures from 0 to 50°C for 1 to 4 hours to obtain an alkylamine compound of Formula (I ), where R ^b represents -CH ₃ .

The compound of Formula (I) wherein R ² is substituted with (-NHCOCH ₃ ) is prepared from the corresponding amine compound of Formula (I) using methods known to those skilled in the art such as, but not limited to, treatment with an acyl chloride or anhydride. For example, a compound of Formula (I) wherein R ² is substituted with (-NH ₂ ) 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, in the presence of a base such as TEA, DIPEA, and the like, at temperatures ranging from 0°C to room temperature for up to 24 hours to obtain an acyl-substituted amine compound of Formula (I), where R ² is (-NHCOCH ₃ ).

The compound of Formula (I) wherein R ² is substituted with (-NHCONH ₂ ) is prepared from the corresponding amine compound of Formula (I) using methods known to those skilled in the art such as, but not limited to, treatment with potassium cyanate, etc. .p., 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 hours to obtain a substituted urea compound of Formula (I), where R ² is (-NHCONH ₂ ). Optionally, the compound of Formula (I) wherein R ² is substituted with (-NHCONH-oxetane) is prepared from the corresponding carboxylic acid compounds of Formula (I) using a Curtius rearrangement using methods known to those skilled in the art. For example, a compound of Formula (I) wherein R ² is substituted with (-CO ₂ H) is 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 a suitable solvent such as toluene, 1,4-dioxane, and the like at the reflux temperature of the solvent for up to 1 hour. The acyl azide intermediate is then reacted with a suitable amine in the presence of a base such as TEA, DIPEA, etc. to give a compound of Formula (I) wherein R ² is substituted with (-NHCONH-oxetane).

The compound of Formula (I) wherein R ² is substituted with -NO ₂ is reacted with a commercially available or synthetically available metal alkoxide, e.g., 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 a temperature in the range from room temperature to the boiling point of the solvent for 24 hours to obtain a compound of Formula (I), where R ² is substituted with a group (-OC _1-3 alkyl).

The compound of Formula (I) wherein R ² 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 8 to 24 hours.

A compound of Formula (I) wherein R ² is substituted with a -CHO group is prepared from the corresponding alcohols or esters described previously by 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 a suitable solvent such as DCM or THF, etc., at room temperature for 3 to 8 hours leads to 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 a suitable solvent such as THF, Et ₂ O and the like at a low temperature, preferably -78° C. for 1 to 4 hours.

Removal of tert -butyl carbamate (BOC) or para-methoxybenzyl (PMB) in a compound of Formula (I) wherein R ² is optionally substituted with (-NH-BOC), (-HET-N-BOC), (-NH-PMB), carried out according to methods known to those skilled in the art, for example with HCl, TFA or p -toluenesulfonic acid in a solvent such as CH ₃ OH, dioxane or CH ₂ CI ₂ . In a preferred embodiment, a compound of the indicated formula is treated with TFA in DCM or HCl to give a compound of Formula (I) wherein R ² is optionally substituted with (-NH ₂ ) or (-HET-NH ₂ ).

SCHEME F

In accordance with Scheme F, the compound of formula (VI), where U represents-CH ₃ ; R ¹ is H, R ⁴ is -C _1-3 alkyl or -C _1-3 haloalkyl, halogenated according to previously described methods to give the corresponding alkyl bromide 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 previously described methods, results in the compound of formula (XII), where HET is an optionally substituted five-membered heteroaryl ring.

In accordance with Scheme F, the compound of formula (XII), where HET is an optionally substituted five-membered heteroaryl ring, is obtained from a compound of formula (VI), where U is -CH ₂ Cl, R ¹ is H, R ⁴ is - C _1-3 alkyl or -C _1-3 haloalkyl, using previously described methods. For example, the reaction of (5-bromo-6-ethoxypyridin-3-yl)methanol with an optionally substituted five-membered heteroaryl ring, a base such as K ₂ CO _{3 ,} Cs ₂ CO ₃ , etc., with or without the addition of NaI, in a solvent such as DCM, CHCl ₃ , CAN, and the like, at temperatures ranging from room temperature to the boiling point of the solvent, results in a compound of formula (XII).

A compound of formula (XII) wherein HET is a five-membered heteroaryl ring optionally substituted with -CO ₂ C _1-3 alkyl or a C(=O)H moiety is reduced according to methods known to those skilled in the art or previously described, with obtaining a compound of formula (XII) wherein HET is substituted with a -CH ₂ OH group. 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 LiBH ₄ , NaBH ₄ and etc., in a solvent such as THF, MeOH, etc., at temperatures in the range from 0°C to room temperature for 1 to 5 hours to obtain a compound of formula (XII), where HET is substituted with a group - _CH2OH .

The compound of formula (XII) wherein HET is a five-membered heteroaryl ring optionally substituted with -NO ₂ is reduced according to methods known to those skilled in the art or previously described to give a compound of formula (XII) wherein HET is substituted with - _NH2 .

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

Optionally, a compound of Formula (I) wherein R ³ is substituted with pyrazole is prepared from the corresponding compounds of formula (XII) using methods known to those skilled in the art, such as, but not limited to, Buchwald coupling conditions. For example, a compound of formula (XII) is reacted with an 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, in the presence of a suitable a base such as sodium tert -butoxide, sodium methoxide, a palladium catalyst such as, but not limited to, Pd ₂ (dba) ₃ , Pd(OAc) ₂ and the like, and a phosphine ligand such as (2- dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, tri( tert -butyl)phosphine and the like, at temperatures ranging from room temperature to the boiling point of the solvent for 4 to 48 hours to obtain a compound of Formula ( I), where the inserted R ³ is an optionally substituted pyrazole.

The compounds of Formula (I) may be converted to their respective salts according to 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 Et ₂ O, DCM, THF or MeOH to give the corresponding salt forms.

Compounds prepared according to the schemes described above may be obtained as a single enantiomer, diastereomer or regioisomer, by enantio-, diastereo- or regiospecific synthesis, or by resolution. If the compounds according to the present invention have at least one chiral center, they can accordingly exist as enantiomers. Where compounds have two or more chiral centers, they may additionally exist as diastereomers. It should be understood that all such isomers and mixtures thereof are within the scope of the present invention. Compounds prepared according to the schemes above may alternatively be prepared as racemic (1:1) or non-racemic (not 1:1) mixtures or mixtures of diastereomers or regioisomers. When preparing racemic and non-racemic mixtures of enantiomers, individual enantiomers can be isolated using standard separation methods known to those skilled in the art, such as chiral chromatography, recrystallization, formation of diastereomeric salts, derivatization to diastereomeric adducts, biotransformation, or enzymatic transformation. In the preparation of regioisomeric or diastereomeric mixtures, the individual isomers may be separated by standard methods such as chromatography or crystallization.

The following examples are presented to further illustrate the present invention and various preferred embodiments.

EXAMPLES

Chemical structure:

The following experimental and analytical procedures were used in the preparation of the compounds described in the examples below and the corresponding analytical data, unless otherwise indicated.

Unless otherwise indicated, the reaction mixtures were stirred with a magnetic stirrer at room temperature (rt) under a nitrogen atmosphere. If the solutions were "dried", they were usually dried over a drying agent such as Na ₂ SO ₄ or MgSO ₄ . If the mixtures, solutions and extracts were "concentrated", they were usually concentrated on a rotary evaporator under reduced pressure.

Reactions under microwave conditions were performed on a CEM Discover-SP instrument with Activent microwave equipment, model number 909150, or Biotage Initiator, model number 355302.

Normal phase flash column chromatography (FCC) was performed on silica gel (SiO ₂ ) using packaged or prepackaged cartridges eluting with the indicated solvents.

LC/MS was recorded on a Waters 2695 separation unit with a DAD 2487 Dual Wavelength Absorption Detector, Micromass ZQ equipped with an ESI sensor, or ultra high performance LC (UHPLC) with photodiode array (PDA) eλ and SQ detectors.

Nuclear magnetic resonance (NMR) spectra were recorded on a Varian 400 MHz or Bruker 400 MHz NMR analyzer. Samples were analyzed in deuterated chloroform (CDCl₃), methanol-d ₄ (CD₃OD) or in dimethylsulfoxide-d ₆ (DMSO-d ₆ ). For samples in CDCl₃the signal of tetramethylsilane (TMS) was used as an internal standard with a related chemical shift of the TMS resonance of 0.00 ppm for the spectra¹H NMR. For CD₃OD when assigning chemical shifts used the residual central resonance peak at 3.31 for¹H, and for DMSOd ₆ when assigning chemical shifts, the residual central resonance peak at 2.50 ppm was used for¹H. Data recording format¹H NMR: downfield chemical shift in ppm from tetramethylsilane reference signal (multiplicity, coupling constantJ in Hz, integration).

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

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

Step 1. 3-Bromo-5-methylpyrazine-2-amine. To a solution of 5-methylpyrazine-2-amine (5.00 g, 0.05 mol) in DCM (230 ml) cooled to 0°C was added 1-bromopyrrolidine-2,5-dione (8.97 g, 0 .05 mol). The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction was quenched with 1 N. sodium thiosulfate solution (50 ml), the layers were separated and the organic phase was extracted with water (2×50 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent removed under reduced pressure. Purification (flash column chromatography (FCC0 SiO ₂ , 0-50%, EtOAc/hexanes) gave the title compound as a yellow solid (8.61 g, 65%). [M+H] = 188.9 /190.11.

Stage 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 tert- butyl nitrite (7.65 ml, 63.82 mmol), then 4 n. HCl solution in 1,4-dioxane (1.91 ml, 7.66 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 8 hours. The mixture was concentrated under reduced pressure. The residue was diluted with an aqueous solution of NaHCO ₃ and was extracted into DCM. The combined organic layers were dried and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 0-20%, EtOAc/hexanes) gave the title compound as a white solid (2.5 g, 54%). [M+H] = 217.06/219.05.

Step 3 3-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-methylpyrazine. 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(PPh ₃ ) ₄ (958.25 mg, 0.83 mmol), Na ₂ CO ₃ (21.63 ml, 1.15 mol/l, 24.88 mmol) in EtOH (22 ml) and toluene (118 ml) were heated under nitrogen at 88°C for 1 hour. The reaction mixture was extracted with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 0-50%, EtOAc/hexanes) gave 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 benzoyl peroxide (0.26 g, 1.07 mmol). The mixture was heated at 88°C for 8 hours. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 0-5%, EtOAc/hexanes) gave the title compound with ~10% of starting material (1.5 g, 59%). [M+H] = 459.13/361.13.

Intermediates 2-3 were prepared analogously to Intermediate 1, Steps 3-4 with appropriate changes in starting materials.

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

M+H] = 312.05/314.04

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

[M+H] = 313.17/315.19

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

3-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 Na ₂ CO ₃ (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 (Na ₂ SO ₄ ) and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 0-10%, EtOAc/hexanes) gave 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.

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 hours. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 10-90%, EtOAc/hexanes) gave the title compound (400 mg, 60%). [M+H] = 317.88.

Step 2 5-((1H-1,2,4-Triazol-1-yl)methyl)-3-bromo-2-(difluoromethoxy)pyridine. 1H-1,2,4-triazole ( 202 mg, 2.9 mmol) and K ₂ CO ₃ (650 mg, 4.7 mmol). The reaction mixture was stirred at room temperature for 2 hours, then filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 30-70%, EtOAc/hexanes) gave the title compound (431 mg, 90%). [M+H] = 304.91/306.91.

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

To 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 parts. The mixture was stirred under nitrogen at 100° C. for 2 days. The reaction mixture was cooled to room temperature, diluted with water and extracted with DCM. The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 20%, EtOAc/hexanes) gave the title compound (3.00 g, 72%). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 7.94 (dd, J = 0.8, 2.3 Hz, 1H), 7.89 - 7.82 (m, 1H), 4.31 ( k, J = 7.0 Hz, 2H), 2.18 (t, J = 0.8 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H).

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

Step 1 5-(3-Chlorophenyl)-6-methoxypyridine-3-amine. A 10 ml microwave test tube was charged with 5-bromo-6-methoxypyridine-3-amine (2.00 g, 10 mmol), (3-chlorophenyl)boronic acid (1.87 g, 12 mmol), Pd (dppf)Cl ₂ ·DCM (365 mg, 0.45 mmol), ACN (6 ml) and saturated aqueous NaHCO ₃ (3 ml). The tube was closed, purged with nitrogen and heated at 110° C. for 15 minutes. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 0-50%, EtOAc/hexanes) gave the title compound (1.95 g, 84%) which was used directly in the next step.

Stage 2. 5-Bromo-3-(3-chlorophenyl)-2-methoxypyridine. A solution of 5-(3-chlorophenyl)-6-methoxypyridine-3-amine (1.95 g, 8.39 mmol), copper (II) bromide (3.72 g, 16.7 mmol), tert- butyl nitrite (1 .7 g, 16.7 mmol) in ACN (50 ml) under nitrogen was heated at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. Purification (FCC, SiO ₂ , 0-10%, EtOAc/hexanes) gave the title compound as an orange solid (1.53 g, 61%). [M+H] = 298.20/300.21.

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

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 hour. The reaction mixture was concentrated under reduced pressure. Purification (FCC, SiO ₂ , 1:1 EtOAc/DCM) gave the title compound as a tan solid (4.5 g, 56%). [M+H] = 211.95/213.96.

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 4N HCl in 1,4-dioxane), tert- butyl nitrite (6.56 g, 63 .7 mmol) and methanol (50 ml) were heated at 60°C for 12 hours. The solvent was removed under reduced pressure. Purification (FCC, SiO ₂ , 0-25%, EtOAc/hexanes) gave the title compound (2.5 g, 51%). [M+H] = 226.96/228.96.

Step 3 5-(3-Chlorophenyl)-6-methoxy-2-methylnicotinonitrile. A 20 ml microwave test tube 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(dppf)Cl ₂ ·DCM (191 mg, 0.26 mmol), ACN (10 ml) and saturated aqueous NaHCO ₃ (3 ml). The tube was closed, purged with nitrogen and heated at 100° C. under microwave radiation for 10 minutes. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 0-50%, EtOAc/hexanes) gave the title compound as an off-white solid (995 mg, 74%). [M+H] = 259.06.

Stage 4. 5-(3-Chlorophenyl)-6-methoxy-2-methylnicotinaldehyde. DIBAL (1 M in hexanes, 4.8 ml, 4.8 mmol) in 3 minutes. The reaction mixture was stirred at -78°C for 1 hour. The reaction was carefully quenched by adding saturated sodium fluoride solution (1 ml). After stirring for 30 minutes, the suspension was filtered and the filtrate was concentrated under reduced pressure. Purification (FCC, SiO ₂ , 0-50%, EtOAc/hexanes) gave the title compound (358 mg, 72%). [M+H] = 262.05.

Step 5: (5-(3-Chlorophenyl)-6-methoxy-2-methylpyridin-3-yl)methanol To a solution of 5-(3-chlorophenyl)-6-methoxy-2-methylnicotinaldehyde a (350 mg, 1.34 mmol) in methanol (3 ml) was added NaBH ₄ (52 mg, 1.3 mmol). The reaction mixture was stirred at room temperature for 20 minutes, then concentrated under reduced pressure. Purification (FCC, SiO ₂ , 0-50%, EtOAc/hexanes) gave the title compound (322 mg, 91%). [M+H] = 264.06.

Step 6 3-(Chloromethyl)-5-(3-chlorophenyl)-6-methoxy-2-methylpyridine. To a scintillation tube 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 hour. The reaction mixture was extracted with water (3x). The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 0-30%, EtOAc/hexanes) gave the title compound (87 mg, 24%). [M+H] = 282.03

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

Step 1. 4-Bromo-2-(difluoromethoxy)pyridine. To a stirred 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 hours. The resulting mixture was filtered and the filtrate was extracted with hexanes (6×20 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated at room temperature to give the title compound as a liquid (2.60 g, 42% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.19-8.20 (s, 1H), 7.48 (s, 1H), 7.52 (s, 1H), 7.54 -7, 88 (m, 1H).

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 attached to a reflux condenser and a vacuum/nitrogen feeder and degassed/filled with nitrogen (3X). The catalyst, Pd(dppf)Cl ₂ (2.35 g, 3.2 mmol) was added and the reaction mixture was refluxed for 8 hours. The resulting mixture was filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 1:1 petroleum ether/hexanes) gave the title compound (6.10 g, 70%) as a liquid. ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.31-8.32 (d, J = 4.8 Hz, 1H), 7.52-7.89 (m, 1H), 7.42- 7.44 (d, J = 4.8 Hz, 1H), 7.156 (s, 1H), 1.32 (s, 12H).

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

Step 1 3-(2-(Difluoromethoxy)-5-methylpyridin-3-yl)phenol. A 20 ml microwave tube 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(dppf)Cl ₂ (330 mg, 0.40 mmol), Na ₂ CO ₃ (2.12 g, 19.96 mmol), water (4.0 ml) and ACN (12 ml ). The tube was closed, purged with nitrogen and heated under microwave radiation at 100° C. for 15 minutes. The reaction mixture was diluted with water and extracted with DCM (3X). The combined organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 0-40% EtOAc/hexanes) gave the title compound (1.81 g, 91%) as a colorless waxy substance. [M+H] = 252.12.

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 K ₂ CO ₃ (553 mg, 4.00 mmol). The reaction mixture was stirred at 60°C for 8 hours. LC-MS data indicated about 50% conversion. The temperature was raised to 90°C and the reaction mixture was stirred for another 4 hours. Saturated aqueous NaCl solution was added and the mixture was extracted with DCM (3X). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 10-30% EtOAc/hexanes) gave the title compound (310 mg, 50%) as a colorless solid. [M+H] = 308.11

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-bromopyrrolidin-2, 5-dione (180 mg, 1.0 mmol) and benzoyl peroxide (37 mg, 0.15 mmol). The reaction mixture was stirred at 80°C for 8 hours. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 10-30%, EtOAc/hexanes) gave the title compound (140 mg, 36%). [M+H] = 387.21.

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

The title compound was prepared analogously 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.

The title compound was prepared analogously to Intermediate 10 using Intermediate 4 and 3-chlorophenylboronic 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.

The title compound was prepared analogously to Intermediate 5 with appropriate changes in starting materials. [M+H] = 269.21/271.23.

Intermediate 14 Ethyl 5-bromo-6-ethoxynicotinate.

Step 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 chloride (42.29 ml, 84.58 mmol) and a few drops of DMF. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give the crude title compound (9.0 g, 83%). The crude material was used without further purification. [M+H] = 253.2/255.2/257.2.

Stage 2. Ethyl 5-bromo-6-ethoxynicotinate. To a suspension 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 at room temperature for 75 minutes. The product crystallized after adding 2 volumes of water in an ice bath. The solid was filtered off, washed with hexanes and water to give the title compound (4.5 g, 84%). ¹ H NMR (400 MHz, DMSO- d 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, J = 6.9, 18.7 Hz, 6H); [M+H] = 274.3/276.3.

Intermediate 15 Methyl 5-bromo-6-methoxynicotinate.

To a suspension 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 at room temperature for 2 hours. The product crystallized. The suspension was cooled to 0° C. and water (80 ml) was added and stirred for 30 minutes, then filtered. The filter cake was washed with water and dried to give the title compound (9.05 g, 92%). [M+H] = 246.2.

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

A 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), keeping the temperature below 25°C. After completion of the addition, the mixture was stirred at room temperature for 45 minutes. The reaction mixture was cooled to 0°C, then quenched with aqueous NaOH solution (5.78 ml, 11.56 mmol) and stirred at room temperature for 1 hour. The mixture was diluted with MTBE and water, then extracted into MTBE. The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 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.

A 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). After completion of the addition, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM (250 ml) and brought to basic pH with saturated aqueous NaHCO ₃ . The crude product was extracted into DCM (3×250 ml) and the combined organic extracts were washed with water (100 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 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.

A solution of 3-bromo-5-(chloromethyl)-2-ethoxypyridine (13.60 g, 54.29 mmol), CHCl ₃ (250 ml), 18-crown-6 (12.20 g, 46.14 mmol), K ₂ CO ₃ (15.01 g, 108.57 mmol) and methyl 1H-1,2,4-triazole-3-carboxylate (10.70 g, 84.18 mmol) were stirred at 35°C for 17 hours. ^Celite® was added to the reaction mixture and the mixture was concentrated in vacuo to give crude material condensed onto ^Celite® . Purification (FCC, SiO ₂ , 10-100% EtOAc/hexanes) gave 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.

(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, LiBH ₄ (787.00 mg, 36.13 mmol) was added and the mixture was heated to 25°C for 3 hours. Water (10 ml), 1N was added to the reaction mixture. NaOH solution (10 ml) and Celite ^® and concentrated the mixture under vacuum to obtain the crude material, condensed on Celite ^® . Purification (FCC, SiO ₂ , 0-15% MeOH/DCM) gave the title compound (9.36 g, 87%) as a white solid. [M+H] = 313.3/315.3.

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

Stage 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 Cs ₂ CO ₃ (5.51 g, 16.92 mmol ) was irradiated in a microwave reactor at 120°C for 1 hour. The mixture was additionally irradiated for another 8 hours at 120°C. The mixture was diluted with DCM (100 ml) and water (100 ml). The aqueous layer was acidified with 1 N. aqueous HCl solution and extracted into DCM (3×100 ml). The combined organic extracts were washed with saturated aqueous NaCl (100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound (2.04 g, 93%) as an off-white solid. The crude material was used without further purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.30 (s, 1H), 8.59 - 8.76 (m, 1H), 8.35 (d, J = 1.96 Hz, 1H) , 4.28 - 4.45 (m, 2H), 1.61 - 1.86 (m, 2H), 0.99 (t, J = 7.43 Hz, 3H); [M+H] = 260.3/262.3.

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) and the mixture was stirred at 0° C. for 2 hours. The mixture was filtered, washed (solid) with additional THF (20 ml), cooled to 0°C, NaBH ₄ (0.47 g, 12.38 mmol) was added and the mixture was stirred at 0°C for 90 minutes. LiBH ₄ (0.18 g, 8.05 mmol) was added and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with DCM (100 ml) and water (100 ml), the layers were separated and the aqueous layer was extracted with DCM (3×80 ml). The extracts were dried (Na ₂ SO ₄ ), filtered, ^Celite® added and solvent removed to give crude alcohol condensed on ^Celite® . Purification (FCC, SiO ₂ , 5-40% EtOAc/hexanes) gave the title compound (966 mg, 63%). [M+H] = 246.3/248.3.

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

Nitrogen gas was bubbled through a solution of (5-bromo-6-propoxypyridin-3-yl)methanol (Intermediate 20, 483 mg, 1.96 mmol), (3,4-difluorophenyl)boronic acid (464.8 mg, 2. 94 mmol), K ₂ CO ₃ (813.7 mg, 5.89 mmol) in water (2.9 ml), Pd(dppf)Cl ₂ (215.4 mg, 0.29 mmol) was added and the mixture was irradiated at stirring in a microwave reactor at 120°C for 20 minutes. ^Celite® was added to the reaction mixture and the mixture was concentrated in vacuo to give crude material condensed onto ^Celite® . Purification (FCC, SiO ₂ , 5-100% EtOAc/hexanes) gave the title compound (547 mg, 100%). [M+H] = 280.4.

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

The title compound was prepared analogously to Intermediate 17, replacing (5-(3,4-difluorophenyl)-6-propoxypyridin-3-yl)methanol (Intermediate 21) (5-bromo-6-ethoxypyridin-3-yl)methanol . [M+H] = 298.4.

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

To a solution of methyl 5-bromo-6-methoxynicotinate (8.00 g, 32.51 mmol) in THF (162.56 ml) was added LiBH ₄ (1.06 g, 48.77 mmol). MeOH (40.64 ml) was slowly added to the reaction mixture with vigorous stirring. The reaction mixture was allowed to stir at room temperature for 2 hours. To the reaction mixture was added 2 N. NaOH solution and stirred the mixture at room temperature for 1 hour. The crude mixture was added to EtOAc and H ₂ O, the organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ ) gave the title compound (6.00 g, 84%). [M+H] = 218.2.

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

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), Na ₂ CO ₃ (29.31 ml, 1.15 mol/l, 33.71 mmol) and Pd(dppf)Cl ₂ (822.15 mg, 1.12 mmol) in ACN (74.91 ml) were heated in microwave reactor at 120°C for 20 minutes. The aqueous layer was removed and the organic layer was dried (Na ₂ SO ₄ ). Na ₂ SO ₄ washed with EtOAc (3×15 ml). Purification (FCC, SiO ₂ , 10% MeOH/90% EtOAc) gave the title compound (2.0 g, 76%). [M+H] = 234.50.

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

The title compound was prepared analogously to Intermediate 17 using Intermediate 23. [M+H]=235.9/237.9.

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

The title compound was prepared analogously to Intermediate 17. [M+H] = 286.25.

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

To a mixture of 6-methoxynicotinaldehyde a (24 g, 0.175 mol) and NaOAc (28.7 g, 0.35 mol) in HOAc (180 ml) was added Br ₂ (42 g, 0.263 mol) over 20 minutes. The mixture was stirred and heated to 90°C for 5 hours. The mixture was cooled to room temperature and poured into ice water. The resulting mixture was neutralized to pH 9 with saturated aqueous NaOH (10 ml) and extracted with EtOAc (2×100 ml). The organic layer was washed with brine (100 ml), filtered, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound (7 g, 22%). The title compound was used crude in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.93 (s, 1H), 8.57 (s, 1H), 8.31 (s, 1H), 4.12 (s, 3H).

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

The title compound was prepared analogously to Intermediate 1, Step 3 using 5-bromo-6-methoxynicotinaldehyde and 3-chlorophenylboronic acid in THF/water at 75° C. under N ₂ overnight. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.03 (s, 1 H), 8.65 (d, J = 2.4 Hz, 1 H), 8.09 (d, J = 2.4 Hz , 1 H), 7.57, (d, J = 0.88 Hz, 1 H), 7.42-7.46 (m, 1 H), 7.36-7.41 (m, 2 H) , 4.09 (s, 3H).

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

To a solution of 5-(3-chlorophenyl)-6-methoxynicotinaldehyde (18 g, 0.072 mol) in EtOH (150 ml) was added NaBH ₄ (5.5 g, 0.144 mol) at 0°C. The reaction mixture was stirred at room temperature under N ₂ for 2 hours. HCl (1 M, 5 ml) was added dropwise to the mixture followed by water (100 ml) at 0°C. The mixture was extracted with EtOAc (2×100 ml). The organic layers were combined, washed with brine (100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound (16.2 g, 90%) as a yellow solid, which was used in the next step without further purification.

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

The title compound was prepared analogously to Intermediate 17 using (5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methanol. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.17 (d, J =2.0 Hz, 1H), 7.66 (d, J =2.0 Hz, 1H), 7.55-7.66 (d, J =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-dioxaborolan-2-yl)methyl)pyridine.

The title compound was prepared analogously to Intermediate 9 using 5-(chloromethyl)-3-(3-chlorophenyl)-2-methoxypyridine using K ₂ CO ₃ and Pd(PPh ₃ ) ₄ (114 mg, 0.10 mmol) instead of potassium acetate and Pd(dppf)Cl ₂ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J = 2.35 Hz, 1H), 7.55 (t, J = 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.

A solution of 3-bromo-5-(chloromethyl)-2-ethoxypyridine (2.84 g, 11.34 mmol), NaI (169.93 mg, 1.13 mmol), K ₂ CO ₃ (3.13 g, 22 .67 mmol) and 5-methyl-2H-tetrazole (1.91 g, 22.67 mmol) in ACN (50 ml) were stirred at room temperature for 72 hours. The reaction mixture was filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , hexanes/EtOAc, 0-100%) gave the title compound as an oil (1.83 g, 54%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (d, J = 2.35 Hz, 1H), 7.74 (d, J = 2.35 Hz, 1H), 5.40 (s, 2H ), 4.44 (k, J = 7.04 Hz, 2H), 2.54 (s, 3H), 1.43 (t, J = 7.04 Hz, 3H).

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

The title compound was prepared analogously to Intermediate 32 with appropriate changes in starting materials. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J = 2.35 Hz, 1H), 7.55 (d, J = 2.35 Hz, 1H), 7.50-7.52 (m, 1H), 7.34-7.38 (m, 3H), 5.59 (s, 2H), 4.20 (k, J = 7.30 Hz, 2H), 4.00 (s, 3H), 3.97 (s, 2H), 1.27 (t, J = 7.24 Hz, 3H).

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

Isolated from the reaction mixture of Intermediate 32. White solid (1.32 g, 39%) ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J = 2.35 Hz, 1H), 7.87 (d, J = 1.96 Hz, 1H), 5.61 (s, 2H), 4.44 (q, J = 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.

Step 1 1-((5-Bromo-6-methoxypyridin-3-yl)methyl)-2-methyl-1H-imidazole-4-carbaldehyde. To 3-bromo-5-(chloromethyl)-2-methoxypyridine (Intermediate 25, 630 mg, 2.66 mmol) in acetone (10 ml) was added Cs ₂ CO ₃ (1.32 g, 4.0 mmol) and NaI (39.93 mg, 0.27 mmol). The reaction mixture was allowed to stir for 3 hours. The mixture was diluted with DCM and filtered. The filtrate was dried (Na ₂ SO ₄ ), filtered and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 20-100%, EtOAc/hexanes) gave the title compound, which was used directly in the next step.

Step 2: (1-((5-Bromo-6-methoxypyridin-3-yl)methyl)-2-methyl-1H-imidazol-4-yl)methanol. NaBH ₄ ( 42.33 mg, 1.22 mmol). The reaction mixture was allowed to stir at room temperature for 0.5 hour. The mixture was diluted with water and extracted into DCM. The organic fractions were dried (Na ₂ SO ₄ ), filtered and the solvent was removed under reduced pressure. Purification (FCC, SiO ₂ , 50-100%, EtOAc/hexanes) gave the title compound.

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

Step 1 3-Bromo-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine. The title compound was prepared analogously to Intermediate 5 with appropriate changes in starting materials.

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) zinc (2.07 g, 31.8 mmol) was added. The mixture was stirred at 50°C for 1 hour. The solvent was removed under reduced pressure to give a white solid. The crude solid was dissolved in DCM (50 ml), sonicated and filtered (repeated twice). The combined DCM extracts were washed with saturated aqueous NaHCO ₃ and the layers were separated. The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting solid was triturated with hexanes to give the title compound.

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

Step 1 2'-Chloro-2-methoxy-[3,4'-bipyridine]-5-carbaldehyde. The title compound was prepared analogously to Intermediate 8 Step 3 using 5-bromo-6-methoxynicotinaldehyde (Intermediate 27) and (2-chloropyridin-4-yl)boronic acid. [M+H] = 249.25.

Step 2 5-Formyl-2-methoxy-[3,4'-bipyridine]-2'-carbonitrile. To a 10 ml microwave tube was added 2'-chloro-2-methoxy-[3,4'-bipyridine]-5-carbaldehyde (684 mg, 2.75 mmol), dicyanozinc (226 mg, 1.93 mmol), Pd(PPh ₃ ) ₄ (318 mg, 0.28 mmol) and DMF (15 ml). The tube was closed, purged with nitrogen, then heated at 150° C. for 15 minutes. The reaction mixture was diluted with EtOAc and extracted with water. The remaining organic phase was treated with brine, dried (NaSO ₄ ), filtered and concentrated. Purification (FCC, SiO ₂ , 0-75% EtOAc/hexanes) gave the title compound (602.00 mg, 91%). [M+H] = 240.28.

Step 3 5-(Hydroxymethyl)-2-methoxy-[3,4'-bipyridine]-2'-carbonitrile. To a 100 ml round bottom flask containing 5-formyl-2-methoxy-[3,4'-bipyridine]-2'-carbonitrile (602 mg, 2.52 mmol) MeOH (25 ml) was added followed by NaBH ₄ ( 95 mg, 2.52 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The reaction was quenched with HCl (1 ml) then concentrated. The residue was diluted with saturated aqueous NaHCO ₃ and EtOAc. The layers were separated and the organic phase was extracted with EtOAc. The combined organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (219 mg, 36%) as a white solid. The crude material was used without further purification. [M+H] = 242.30.

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 room temperature for 2.5 hours then concentrated to give the title compound as a yellow solid (0.2225 g, 94%). [M+H] = 260.27.

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

Step 1: (2'-Chloro-2-methoxy-[3,4'-bipyridin]-5-yl)methanol. The title compound was prepared analogously to Intermediate 8, Step 3 using (5-bromo-6-methoxypyridin-3-yl)methanol (Intermediate 23) and (2-chloropyridin-4-yl)boronic acid. [M+H] = 251.30.

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% wt./mass. a solution of NaOEt in EtOH (22 ml) was heated at 75°C for 8 hours under nitrogen. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with 1 M citric acid solution (2X), dried (Na ₂ SO ₄ ), filtered and concentrated. Purification (FCC, SiO ₂ , 0-75% EtOAc/hexanes) gave the title compound as an amber oil (0.499 g, 52%). [M+H] = 261.39.

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 for ice bath for 5 minutes. Thionyl chloride (0.35 ml, 4.8 mmol) was added dropwise over 1 minute. A white precipitate immediately formed. The reaction mixture was stirred for 1 hour at room temperature, then quenched with saturated aqueous NaHCO ₃ . The layers were separated and the aqueous phase was extracted with DCM. The combined organic phase was dried (NaSO ₄ ), filtered and concentrated to give the title compound (543 mg, 101%) as an amber oil. [M+H] = 278.38.

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

The title compound was prepared analogously to Intermediate 38 using (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.

The title compound was prepared analogously to Intermediate 38 using (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.

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 bath under nitrogen for 5 minutes, then potassium tert- butoxide (12.58 mL, 1.00 mol/L, 12.58 mmol) was added dropwise over 5 minutes. The reaction mixture was stirred for 16 hours, then diluted with NaHCO ₃ and EtOAc. The layers were separated and the organic phase was washed with water and brine. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 0-15% EtOAc/hexanes) gave the title compound (2.355 g, 63%) as a white solid. [M+H] = 314.22/317.22.

Step 2: (5-Bromo-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol. DIBAL (15.00 ml , 1.00 mol/l, 15.00 mmol) in 2 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 8 hours. The reaction mixture was concentrated, then diluted with DCM and stirred for 48 hours with 1 M NaOH (25 ml). The layers were separated and the aqueous phase was extracted with DCM. The combined organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (2.778 g, 130%) as a colorless oil. [M+H] = 286.23/288.23.

Step 3: (5-(3-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol. 3-Chlorophenylboronic acid ( 902.02 mg, 5.77 mmol), Pd(dppf)Cl ₂ .DCM (42.82 mg, 0.05 mmol) and 2 M Na ₂ CO ₃ aqueous solution (10.0 mL). The reaction mixture was purged with nitrogen and heated under microwave radiation for 30 minutes at 100°C. The layers were separated and the aqueous phase was extracted with EtOAc. Purification (FCC, SiO ₂ , 0-50% EtOAc/hexanes) gave 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 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) cooled to 0°C ) thionyl chloride (0.63 mL, 8.6 mmol) was added dropwise over 1 minute. A white precipitate immediately formed. After stirring for 1 hour at room temperature, additional thionyl chloride (300 μl) was added and the reaction mixture was stirred for another 8 hours. The reaction was quenched with saturated aqueous NaHCO ₃ , the layers were separated and the aqueous phase was extracted with DCM. The combined organic phase was dried (NaSO ₄ ), filtered and concentrated to give the title compound (0.9143 g, 79%) as an amber oil. [M+H] = 336.24.

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

The title compound was prepared analogously to Intermediate 38, Step 1 and Step 3 using 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.

The title compound was prepared analogously to Intermediate 38. [M+H] = 315.05.

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

Step 1 5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine-2-carbonitrile. The title compound was prepared analogously to Intermediate 7, Step 1 using 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 using Pd(PPh ₃ ) ₄ instead of Pd(dppf)Cl ₂ ·DCM. [M+H] = 337.34.

Step 2 Methyl 5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine-2-carboxylate. Acetyl chloride (2.0 ml) was added dropwise to a solution of wet MeOH cooled to 0° C. over 5 minutes. The reaction mixture was stirred for an additional 35 minutes 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 mixture was heated to 50°C for 2.5 hours. The reaction mixture was concentrated, diluted with EtOAc, neutralized with saturated aqueous NaHCO ₃ . The layers were separated, the organic phase was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound (277.5 mg, 91%) as a colorless oily substance which contained some of the corresponding carboxylic acid. The title compound was used in the next step without purification. [M+H] = 370.37.

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

Prepared similarly to Intermediate 44 using Intermediate 39. [M+H] = 448.39.

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

The title compound was prepared analogously to Intermediate 1.

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

The title compound was prepared analogously to Intermediate 17 using (5-(4-fluorophenyl)-6-methoxypyridin-3-yl)methanol.

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

The title compound was prepared analogously to Intermediate 1, Step 3 using 5-(bromomethyl)-3-(3,4-difluorophenyl)-2-ethoxypyrazine (Intermediate 46) and (2-chloropyrimidin-5-yl)boronic acid using an aqueous solution of NaHCO ₃ instead of Na ₂ CO ₃ . ¹ H NMR (400 MHz, CDCl ₃ ) 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 (k, J = 7.04 Hz, 2H), 4.10 (s, 2H), 1.47 (t, J = 7.04 Hz, 3H). [M+H] = 363.4.

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

The title compound was prepared analogously to Intermediate 24 using 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.

The title compound was prepared analogously to Intermediate 24 using 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.

The title compound was prepared analogously to Intermediate 24 using 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.

The title compound was prepared analogously 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.

The title compound was prepared analogously 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.

The title compound was prepared analogously to Intermediate 10, Step 1 using Intermediate 30 and 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2- yl)acetonitrile without using water as a co-solvent.

Intermediate 55 tert- Butyl-(5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-yl)carbamate.

3-(3-chlorophenyl)-2-methoxy-5-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)pyridine solution (Intermediate 31, 127.7 mg, 0.36 mmol), tert- butyl-(5-bromopyrazin-2-yl) carbamate (126.53 mg, 0.46 mmol), K ₂ CO ₃ (98 mg, 0.70 mmol) and Pd( PPh ₃ ) 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.

The title compound was prepared analogously to Intermediate 21 using 3-(3-chloro-4-fluorophenyl)-5-(chloromethyl)-2-methoxypyridine (Intermediate 26) and t- 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.

The title compound was prepared analogously to Intermediate 55 using 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. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.62 (d, J = 1.57 Hz, 1H), 8.29 (d, J = 0.78 Hz, 1H), 8.10 (d, J = 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.

The title compound was prepared analogously to Intermediate 1 using Intermediate 39 using microwave heating replacing sodium carbonate with sodium bicarbonate.

Examples:

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

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(PPh ₃ ) ₄ (56.63 mg, 0.05 mmol) and NaHCO ₃ aqueous solution (1.38 ml, 1.15 mol/l, 1.59 mmol). The tube was closed, purged with nitrogen and heated to 125°C in a microwave reactor for 15 minutes. Water was removed from the reaction mixture with a pipette, and the crude reaction mixture was filtered through CELITE ^® and washed with EtOAc (3×5 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 0-30%, EtOAc/hexanes) gave the title compound as a white solid (100 mg, 53%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.94 (s, 2H), 8.17 (s, 1H), 7.95-7.90 (m, 1H), 7.85 (t, J = 1.8 Hz, 1H), 7.46 (t, J = 8.2 Hz, 1H), 7.19 (dd, J = 2.3, 7.8 Hz, 1H), 7.04 - 6 .61 (m, 1H), 4.49 (k, J = 7.0 Hz, 2H), 4.30 - 4.25 (m, 2H), 1.44 (t, J = 7.0 Hz, 3H). [M+H] = 384.15.

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

To 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 NaHCO ₃ (417 mg, 1.282 mmol) and PdCI ₂ (dppf)-DCM (23 mg, 0.032 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 12 minutes. Water was removed from the reaction mixture with a pipette and the crude reaction mixture was filtered through CELITE® and washed with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated on silica. Purification (FCC, SiO ₂ , 30-70% EtOAc/hexanes) gave the title compound (61 mg, 55%). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.34 (s, 2H), 8.11 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 2.0 Hz , 1H), 7.58 (t, J = 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.

To 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 N1,N1 -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 (3X). The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 0-15% MeOH/DCM) gave the title compound (15.6 mg, 28%). ¹ H NMR (400 MHz, DMSO -d 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-methoxypyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

5-((1H-1,2,4-triazol-1-yl)methyl)-3-bromo-2-(difluoromethoxy)pyridine solution (Intermediate 13, 50 mg, 0.16 mmol), (6-methoxypyridine -2-yl)boronic acid (46 mg, 0.30 mmol), in EtOH (2.45 ml), benzene (7.00 ml) was mixed with Pd(PPh ₃ ) ₄ (27 mg, 0.02 mmol) and 4 M aqueous solution of Na ₂ CO ₃ (3 ml) in a microwave test tube. The tube was closed, purged with nitrogen and heated in a microwave reactor to 120°C for 12 minutes. Water was removed from the reaction mixture with a pipette, and the crude reaction mixture was filtered through CELITE® and washed with EtOAc (3×5 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 30-70% EtOAc/hexanes) gave the title compound (11.9 mg, 25%). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 7.88 (s, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.41 (d, J = 2.3 Hz , 1H), 7.24 (s, 1H), 6.91 - 6.84 (m, 2H), 5.93 (d, J = 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 similarly to the methods described in Examples 1 or 2 with appropriate changes in starting materials and reagents.

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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.65 (s, 1H), 8.18 - 8.15 (m, 1H), 7.95 (s, 1H), 7.70 (d, J = 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-triazol-1-ylmethyl)pyridine

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.93 (s, 1H), 8.77 (s, 2H), 8.57 (s, 1H), 8.35 (d, J = 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.77 - 8.63 (m, 2H), 8.37 (d, J = 2.3 Hz, 1H), 8.04 (d, J = 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-triazol-1-ylmethyl)pyridin-3-yl]phenyl}methanol

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.65 (s, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.95 (s, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.45 - 7.26 (m, 4H), 5.41 (s, 2H), 5.22 (t, J = 5.7 Hz, 1H) , 4.51 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.61 (s, 1H), 8.24 (d, J = 1.96 Hz, 1H), 8.12 (s, 1H), 8.00 ( s, 1H), 7.94 (d, J = 7.83 Hz, 1H), 7.89 (d, J = 7.83 Hz, 1H), 7.83 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.60 (s, 1H), 8.44 (d, J = 5.1 Hz, 1H), 8.26 (d, J = 2.3 Hz, 1H), 8.01 (d, J = 2.3 Hz, 1H), 7.98 (s, 1H), 7.70 (s, 1H), 7.22 (d, J = 5.1 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.50 (s, 1H), 8.32-8.27 (m, 1H), 8.22 (d, J = 2.3 Hz, 1H), 7.89 (s, 1H), 7.68 - 7.62 (m, 1H), 7.56 (d, J = 2.7 Hz, 1H), 7.26 (dd, J = 5.1 , 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

As a mixture of compounds, ¹ H NMR (400 MHz, DMSO -d 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, J = 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.

To 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 an aqueous solution of NaOH (0.78 ml, 0.78 mmol), then H ₂ O ₂ (0.78 ml, 0.79 mmol). The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated and the precipitate was filtered off and washed with water to give the title compound as a white solid (70 mg, 67%). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.93 (s, 2H), 8.27 (s, 1H), 8.12 (br s, 1H), 7.91-7.84 (m , 1H), 7.81 (t, J = 1.8 Hz, 1H), 7.72 (br s, 1H), 7.52 (s, 1H), 7.44 - 7.02 (m, 2H ), 4.42 (k, J = 7.0 Hz, 2H), 4.25 (s, 2H), 1.35 (t, J = 7.0 Hz, 3H). [M+H] = 402.26.

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

n BuLi (4.8 ml, 5.5 mmol) in 2 minutes. The reaction mixture was stirred at -78°C for 40 minutes. A solution of 4-fluorobenzaldehyde (744 mg, 6 mmol) in THF (2 ml) was added and the reaction mixture was stirred for another 30 minutes at -78°C. The reaction was quenched with saturated Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 0-25% EtOAc/hexanes) gave the title compound as a colorless solid (1.65 g, 96%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.11 (d, J = 2.3 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.51 (s, 1H), 7.47 - 7.29 (m, 5H), 7.07 (t, J = 8.6 Hz, 2H), 5.84 (s, 1H), 3.93 (s, 3H). [M+H] = 344.18.

Examples 15-16 were prepared analogously to Example 14 with appropriate changes in starting materials and reagents.

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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.16 (d, J = 2.7 Hz, 1H), 7.68 (d, J = 2.7 Hz, 1H), 7.53 - 7, 43 (m, 3H), 7.42 - 7.28 (m, 3H), 7.04 (t, J = 8.8 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (d, J = 2.7 Hz, 1H), 8.16 (d, J = 2.3 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-methoxypyridin-3-yl](4-fluorophenyl)methyl}(methyl)amine

Step 1 5-(Chloro(4-fluorophenyl)methyl)-3-(3-chlorophenyl)-2-methoxypyridine. To a solution of [5-(3-chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol (Example 14, 1.43 g, 4.17 mmol) in DCM (10 ml) cooled to 0°C thionyl chloride (744 mg, 6.25 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. Purification (FCC, SiO ₂ , 0-10% EtOAc/hexanes) gave the title compound, which was used directly in the next step.

Step 2 {[5-(3-chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}(methyl)amine K ₂ CO ₃ (53 mg, 0.39 mmol), NaI (5 mg, 0.03 mmol) and methylamine (0.5 ml, 0.97 mmol). The reaction mixture was closed and heated at 45°C for 12 hours. The reaction mixture was concentrated. Purification (FCC, SiO ₂ , 0-10% MeOH/DCM) gave the title compound (23 mg, 33%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.20 (d, J = 2.3 Hz, 1H), 7.71 (s, 1H), 7.50 - 7.42 (m, 3H), 7.40 - 7.27 (m, 3H), 7.18 (t, J = 8.8 Hz, 2H), 5.54 - 5.49 (m, 1H), 3.90 (s, 3H) , 2.63 (s, 3H). [M ⁺ ; loss of NHMe]= 326.14.

Examples 18-19 were prepared analogously to Example 17 with appropriate changes in starting materials and reagents.

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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.17 (d, J = 2.3 Hz, 1H), 7.72 (d, J = 2.7 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 NH ₂ ] = 326.14.

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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.28 (d, J = 2.3 Hz, 1H), 7.86 (s, 1H), 7.57 (dd, J = 5.1.8 .6 Hz, 2H), 7.50 (t, J = 1.6 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

Deoxo- ^Fluor® (79 mg, 0.36 mmol). The solution was stirred at room temperature for 1 hour, then concentrated under reduced pressure. Purification (FCC, SiO ₂ , 0-10% EtOAc/hexanes) gave the title compound (21 mg, 34%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.13 (s, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.52 (s, 1H), 7.47 - 7.31 (m, 5H), 7.15 (t, J = 8.8 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.

Stage 1. Methyl 4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)benzoate was obtained analogously to Example 2 with appropriate replacement of starting materials. Purification (FCC, SiO ₂ , 0-50% EtOAc/hexanes) gave the title compound. [M+H] = 368.11

Step 2 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-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 2N. aqueous solution of NaOH (2.0 ml). The reaction mixture was stirred at room temperature for 2 hours. The 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 filtrate was concentrated under reduced pressure to give the title compound (74 mg, 85%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.03 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 7.8 Hz, 2H), 7.60 (d, J = 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.

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

Example 22 was prepared analogously to Example 1 with appropriate changes in starting materials and reagents. [M+H] = 338.10

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

A solution of 5-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidin-2-carbonitrile (Example 22, 30 mg, 0.0845 mmol) in MeOH (1.54 ml) was heated to 50°C until dissolution of the starting material. Added 1 n. an aqueous solution of NaOH (0.23 ml, 0.23 mmol), then H ₂ O ₂ (0.23 ml, 1.00 mol/l, 0.23 mmol) and the solution was heated at 50°C for another 2 hours. Water (5 ml) was added and the reaction mixture was filtered and washed with water (3×5 ml). A mixture of products was observed: 5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxylic acid (title compound) and 5-{[5-(3-chlorophenyl) -6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide (Example 24, 4 mg, 13%). The acid contained was filtered off and the aqueous layer was acidified with concentrated HCl (3 drops) and extracted with DCM (3×20 ml). The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the title compound (23 mg, 74%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.86 (br s, 2H), 8.11 (d, J = 1.96 Hz, 1H), 7.66 (d, J = 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.

The title compound was prepared analogously to Example 13. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.83 (s, 2H), 8.11 (d, J = 2.0 Hz, 1H), 7.65 ( e, J = 2.3 Hz, 1H), 7.54 (s, 1H), 7.47 - 7.29 (m, 3H), 4.12 (s, 2H), 3.94 (s, 3H ). [M+H] = 355.21.

Examples 25, 27-30, 32-35, 37-43, 45-89, 91-108 were prepared similarly to the methods described in Examples 1 or 2 with appropriate changes in starting materials and reagents.

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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.18 (s, 2H), 8.02 (d, J = 2.3 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

Step 1. 3-(3-Chlorophenyl)-2-methoxy-5-(4-nitrobenzyl)pyridine. The title compound was prepared analogously to Example 1 from Intermediate 2 and 4-nitrophenylboronic acid as a tan solid. [M+H] = 355.07.

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 hour, then hot filtered through a 1 cm pad of ^Celite® and used directly in the next step.

Step 3. (4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)urea. KCNO (73 mg, 0.9 mmol) was added to the 4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)aniline solution from Step 2. The mixture was sonicated for 20 minutes to give a tarry precipitate. The reaction mixture was diluted with water, neutralized with an aqueous solution of Na ₂ CO ₃ to pH 7, then was extracted with EtOAc (3×5 ml). The combined organic layers were concentrated under reduced pressure to give a solid which was triturated with DCM to give the title compound (55 mg, 34%) as a white solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.41 (s, 1H), 8.06 (d, J = 2.3 Hz, 1H), 7.64 - 7.53 (m, 2H) , 7.49 - 7.37 (m, 3H), 7.28 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 5.75 ( s, 2H), 3.85 - 3.81 (m, 5H). [M+H] = 368.27.

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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.02 (d, J = 2.0 Hz, 1H), 7.81 (d, J = 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

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

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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.19 (s, 2H), 8.07 (d, J = 2.35 Hz, 1H), 7.71 (d, J = 1.96 Hz, 1H), 7.57 (s, 1H), 7.30 - 7.38 (m, 1H), 7.02 - 7.10 (m, 2H), 6.95 (dd, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 7.99 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 2.0 Hz, 2H), 7.43 - 7.29 (m, 4H), 6.55 (d, J = 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

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 data 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 hours. LCMS data confirmed the presence of the product. All solvents were removed under reduced pressure. Purification (FCC, SiO ₂ , 0-5%, MeOH/DCM) gave the title compound (50 mg, 46%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.99 (d, J = 2.3 Hz, 1H), 7.49 (d, J = 2.3 Hz, 2H), 7.41 - 7, 24 (m, 5H), 7.14 (d, J = 8.6 Hz, 2H), 4.87 (br s, 3H), 4.55 (s, 2H), 3.91 (s, 3H) , 3.90 (s, 2H). [M+H] = 424.20.

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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.10 (dd, J = 2.0, 6.3 Hz, 2H), 7.67 (d, J = 2.3 Hz, 1H), 7 .61 - 7.54 (m, 2H), 7.50 - 7.36 (m, 3H), 6.72 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.06 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 2.0 , 9.4 Hz, 1H), 7, 73 - 7.64 (m, 2H), 7.51 - 7.30 (m, 5H), 6.89 (d, J = 9.4 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.00 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 1.6 Hz, 2H), 7.43 - 7.29 (m, 4H), 6.63 (d, J = 9.0 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.85 (s, 2H), 8.18 (s, 1H), 7.85 (d, J = 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

Step 1 3-(3-Chlorophenyl)-5-(dibromomethyl)-2-(difluoromethoxy)pyridine was prepared analogously to Intermediate 1, Step 4 with appropriate changes in starting materials. [M+H] = 426.1, 428.1, 430.1.

Stage 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 Na ₂ CO mmol) in water (4 ml) and the mixture was stirred at 70°C for 16 hours. LCMS data confirmed complete conversion. All solvents were removed under reduced pressure. The residue was dissolved in DCM, washed with water, dried (Na ₂ SO ₄ ), filtered and the solvent was removed under reduced pressure. Purification (FCC, SiO ₂ , 0-20%, EtOAc/hexanes) gave 5-(3-chlorophenyl)-6-(difluoromethoxy)nicotinaldehyde (355 mg, 76%). [M+H] = 284.1.

Step 3 t- Butyl-(5-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)(hydroxy)methyl)thiazol-2-yl)carbamate. A solution of tert- butyl-(5-bromothiazol-2-yl)carbamate (100 mg, 0.36 mmol) in THF (2 ml) was cooled to -78° C. and n -butyllithium (0.51 ml 1, 4 M solution in hexanes, 0.72 mmol) and stirred the mixture 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 mixture, and the resulting mixture was stirred for 30 minutes at -78°C. LCMS data confirmed the product. Saturated aqueous ammonium chloride solution was added and the mixture was extracted into EtOAc. The combined extracts were dried (Na ₂ SO ₄ ), filtered and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 10-80%, EtOAc/hexanes) gave tert- butyl-(5-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)(hydroxy)methyl )thiazol-2-yl)carbamate (73 mg, 42%). [M( -tBu )+H] = 428.1.

Step 4 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1,3-thiazol-2-amine. To a solution of tert- 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 hours. LCMS data confirmed complete conversion. All solvents were removed under vacuum. The residue was dissolved in DCM and saturated aqueous NaHCO ₃ , shaken and the layers were separated, and the aqueous layer was extracted into DCM. The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 20-100%, EtOAc/hexanes) gave the title compound (34.4 mg, 62%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.02 (d, J = 2.3 Hz, 1H), 7.71 - 7.30 (m, 6H), 6.68 (s, 1H), 3.94 (s, 2H). [M+H] = 368.06.

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

¹ H NMR (400 MHz, CD ₃ OD) δ 7.94 (d, J = 2.3 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.17 (s, 2H), 8.02 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 2.3 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

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.71 (s, 2H), 8.06 (d, J = 2.3 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.18 (s, 2H), 7.99 (d, J = 2.3 Hz, 1H), 7.56 (d, J = 2.3 Hz, 2H), 7.47 - 7.30 (m, 3H), 4.38 (d, J = 7.0 Hz, 2H), 3.81 (s, 2H), 1.33 (t, J = 7 .0 Hz, 3H). [M+H] = 341.04.

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

¹ H NMR (400 MHz, CD ₃ OD) 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, J = 6.3 Hz, 6H). [M+H] = 355.21.

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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.19 (s, 2H), 8.06 (d, J = 2.3 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, J = 6.3 Hz, 6H). [M+H] = 387.25.

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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.10 (s, 2H), 7.99 (d, J=2.3 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, J = 7.0 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

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) DIPEA (40 mg, 0.31 mmol) was added. The solution was cooled to 0°C and acetyl chloride (230 μl, (0.23 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight, then concentrated to give the corresponding imide (bis-acylated adduct) which was used in the next stages without purification.

Step 2 N- (5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide. Ammonia (7N in methanol) was added to a solution of the crude product from Step 1 and stirred at room temperature for 1 hour. Purification (FCC, SiO ₂ , 0-100% EtOAc/hexanes) gave the title compound (11.4 mg, 21%) as an off-white solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 10.44 (s, 1H), 8.59 (s, 2H), 8.14 (d, J = 2.7 Hz, 1H), 7.74 (d, J = 2.3 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.

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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.13 (s, 1H), 7.89 (d, J = 8.2 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.27 - 8.16 (m, 4H), 7.85 (d, J = 2.3 Hz, 1H), 7.63 (t, J = 1 .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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.23 - 8.20 (m, 1H), 8.18 (s, 2H), 8.11 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 2.3 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.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.69 (s, 2H), 8.09 (d, J = 2.3 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.46 - 7.35 (m, 2H), 7.31 (t, J = 1.8 Hz, 1H), 7.12 (td, J = 1.0 , 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.66 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 2.3 Hz, 1H), 7.93 - 7, 89 (m, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.55 (t, J = 1.6 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (dd, J = 2.15, 10.37 Hz, 2H), 7.31-7.72 (m, 7H), 6.64 (d, J = 8.61 Hz, 1H), 5.27 (m, 1H), 3.90 (s, 2H), 1.34 (d, J = 6.26 Hz, 6H). [M+H] = 405.22.

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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06-8.00 (m, 2H), 7.71-7.31 (m, 7H), 6.70 (d, J = 9.00 Hz, 1H), 4.23 (t, J = 6.85 Hz, 2H), 3.91 (s, 2H), 1.80 (k, J = 6.65 Hz, 2H), 1.02 (t, J = 7.43 Hz, 3H).

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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.03 (d, J = 2.0 Hz, 1H), 7.60 - 7.51 (m, 3H), 7.47 - 7.30 (m , 4H), 6.51 (d, J = 9.4 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.44 (d, J = 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, J = 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 m.p.

Example 54 was prepared analogously to Example 21 with appropriate changes in starting materials and reagents. ¹ H NMR (400 MHz, DMSO -d 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.58 (s, 2H), 8.23 (s, 1H), 8.03-7.86 (m, 2H), 7.50 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.48 (br s, 1H), 8.13 (s, 2H), 8.07-7.90 (m, 2H), 7.42 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) 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, J = 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-1H-pyrazol-4-yl)methyl]pyrazine

¹ H NMR (400 MHz, CD ₃ OD) 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

¹ H NMR (400 MHz, CD ₃ OD) δ 7.99 (d, J = 1.96 Hz, 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.02 (d, J = 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, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.02 (d, J = 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 m.p.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.57 (d, J = 5.09 Hz, 1H), 8.07 (d, J = 2.35 Hz, 1H), 7.79 (s, 1H), 7.60 (d, J = 2.35 Hz, 1H), 7.54 (d, J = 1.96 Hz, 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

The title compound was prepared analogously to Example 23 from 4-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carbonitrile (Example 62) at room temperature. ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.49 (d, J = 5.09 Hz, 1H), 8.15 (d, J = 1.96 Hz, 1H), 8.05 (br s, 1H), 7.92 (s, 1H), 7.74 (d, J = 1.96 Hz, 1H), 7.58 (d, J = 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.55 (d, J = 2.0 Hz, 1H), 8.39 (dd, J = 1.2, 4.7 Hz, 1H), 8 .13 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.70 - 7.66 (m, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.52 - 7.37 (m, 3H), 7.29 (dd, J = 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.93 (s, 1H), 8.07 - 8.15 (m, 1H), 7.75 (s, 1H), 7.71 (d, J = 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

¹ H NMR (400 MHz, DMSO -d 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.09 (d, J = 2.3 Hz, 1H), 7.99 (d, J = 2.3 Hz, 1H), 7.94 (d , J = 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.94 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.14 (d, J = 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.86 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.26 (d , J = 2.0 Hz, 1H), 8.10 (s, 2H), 7.98 (d, J = 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

Step 1 tert- Butyl-((5-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)pyridin-3-yl)methyl)carbamate. The title compound was prepared analogously to Example 1 with appropriate changes in starting materials.

Step 2: (5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-3-yl)methanamine. The purified compound obtained in Step 1 was treated with 20% TFA in DCM and stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and saturated aqueous NaHCO ₃ . The organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound. ¹ H NMR (400 MHz, DMSO -d 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, J = 4.7 Hz, 2H). [M+H] = 377.25.

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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.42 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 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

¹ H NMR (400 MHz, DMSO -d 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

¹ H NMR (400 MHz, DMSO -d 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.55 (s, 2H), 8.13 (d, J = 2.3 Hz, 1H), 7.72 (d, J = 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.55 (s, 2H), 8.13 (d, J = 2.3 Hz, 1H), 7.72 (d, J = 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.30 (s, 2H), 8.11 (d, J = 2.3 Hz, 1H), 7.70 (d, J = 2.3 Hz , 1H), 7.58 (t, J = 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, J = 6.3 Hz, 6H). [M+H] = 370.05.

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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 9.02 (s, 1H), 8.77 (s, 2H), 8.16 (d, J = 2.3 Hz, 1H), 7.76 (d, J = 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.05 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 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

Step 1 tert -Butyl 4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-1-carboxylate. The title compound was prepared analogously to Example 1 with appropriate changes in starting materials.

Step 2 The purified compound from Step 1 was treated with 20% TFA in DCM and stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and saturated NaHCO ₃ solution. The organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound. ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.05 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 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.

Example 81 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl} -N -methylpyrimidin-2-amine

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.34 (s, 2H), 8.11 (d, J = 2.0 Hz, 1H), 7.84 (br s, 1H), 7, 70 (d, J = 2.0 Hz, 1H), 7.58 (t, J = 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.34 (s, 2H), 8.11 (d, J = 2.0 Hz, 1H), 7.84 (br s, 1H), 7, 70 (d, J = 2.0 Hz, 1H), 7.58 (t, J = 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.38 (s, 2H), 8.16 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 2.0 Hz , 1H), 7.56 (t, J = 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.38 (s, 2H), 8.16 (d, J = 2.0 Hz, 1H), 7.84 (br s, 1H), 7, 72 (d, J = 2.0 Hz, 1H), 7.56 (t, J = 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

[M+H] = 369.16

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

[M+H] = 336.6.

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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.29 (s, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 7.98 (t, J = 3.72 Hz, 1H), 7.69 - 7.52 (m, 1H), 7.41 (d, J = 5.09 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

¹ H NMR (400 MHz, CD ₃ OD) δ 7.99 (d, J = 2.3 Hz, 1H), 7.51 (t, J = 2.5 Hz, 2H), 7.42 - 7, 21 (m, 5H), 7.01 (t, J = 8.8 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.11 (s, 2H), 8.01 (d, J = 2.3 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

Step 1. Methyl 5-((6-(3-chlorophenyl)-5-methoxypyrazin-2-yl)methyl)picolinate. The title compound was prepared analogously to Example 1 from (6-(methoxycarbonyl)pyridin-3-yl)boronic acid and Intermediate 3. [M+H] = 370.10.

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 hours, then concentrated under reduced pressure. Trituration with diethyl ether gave the title compound (12 mg, 70%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.66 (br s, 1H), 8.14 (s, 1H), 8.07 (d, J = 7.83 Hz, 1H), 8.02 (s, 1H), 7.69 - 7.60 (m, 1H), 7.59 - 7.50 (m, 1H), 7.41 (d, J = 4.70 Hz, 2H), 4, 27 (s, 2H), 4.00-4.09 (m, 3H). [M+H] = 355.10.

Example 91 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl} -N -cyclopropylpyrimidin-2-amine

¹ H NMR (400 MHz, CD ₃ OD) 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 (w s, 2H), 2.63 (w s, 1H), 0.76 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.49 (br s, 2H), 8.13 (br s, 1H), 7.78 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) 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

¹ H NMR (400 MHz, CD ₃ OD) 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

¹ H NMR (400 MHz, CD ₃ OD) 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

¹ H NMR (400 MHz, CD ₃ OD) 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.55 (s, 1H), 8.36 (s, 1H), 8.12 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) 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

¹ H NMR (400 MHz, CD ₃ OD) 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.08 (d, J = 2.35 Hz, 1H), 8.02 (d, J = 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.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.08 (d, J = 2.35 Hz, 1H), 7.76 (s, 1H), 7.68 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.08-8.05 (m, 1H), 8.01-7.90 (m, 1H), 7.71 (d, J = 2.35 Hz , 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, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.73 (d, J = 1.6 Hz, 1H), 8.13 (s, 1H), 8.01 - 7.90 (m, 2H), 7.86 (t, J = 1.8 Hz, 1H), 7.80 (dd, J = 0.8, 7.8 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H ), 7.19 (dd, J = 2.0, 8.2 Hz, 1H), 7.05 - 6.59 (m, 1H), 4.48 (k, J = 7.3 Hz, 2H) , 4.27 (s, 2H), 1.43 (t, J = 7.0 Hz, 3H). [M+H] = 383.26.

Example 104 5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidin-2-amine

¹ H NMR (400 MHz, CD ₃ OD) δ 8.52 (s, 2H), 8.13 (s, 1H), 7.95 (qd, J = 0.9, 7.9 Hz, 1H), 7.89 - 7.85 (m, 1H), 7.47 (t, J = 8.2 Hz, 1H), 7.20 (dd, J = 3.3, 8.0 Hz, 1H), 7 .05 - 6.62 (m, 1H), 4.49 (k, J = 7.2 Hz, 2H), 4.07 (s, 2H), 1.43 (t, J = 7.0 Hz, 3H). [M+H] = 374.14.

Example 105 5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidin-2-amine

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.23-8.17 (m, 2H), 8.15 (s, 1H), 8.05-8.02 (m, 1H), 7, 99 (ddd, J = 1.6, 3.6, 5.4 Hz, 1H), 7.52 - 7.47 (m, 2H), 6.44 (s, 2H), 4.41 (k, J = 7.0 Hz, 2H), 3.90 (s, 2H), 1.35 (t, J = 7.0 Hz, 3H). [M+H] = 342.15.

Example 106 5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidin-2-amine

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.23 - 8.14 (m, 3H), 7.88 (d, J = 8.2 Hz, 1H), 7.77 (s, 1H) , 7.52 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.94 (s, 2H), 8.19 (s, 1H), 7.90 (td, J = 1.4, 7.8 Hz, 1H), 7.79 (t, J = 2.2 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.19 (dd, J = 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 m.p.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.93 (s, 2H), 8.17 (s, 1H), 8.06-8.02 (m, 1H), 7.97 (ddd, J = 1.6, 3.7, 5.3 Hz, 1H), 7.43 - 7.38 (m, 2H), 4.49 (k, J = 7.0 Hz, 2H), 4.27 ( s, 2H), 1.43 (t, J = 7.0 Hz, 3H). [M+H] = 352.26.

Example 109 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(pyridin-2-ylmethyl)pyridine

Stage 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, then cooled to room temperature. After cooling, trimethylsilyl chloride (2.92 µl, 0.02 mmol) was added and the solution was stirred at room temperature for another 30 minutes. 5-(Bromomethyl)-3-(3-chlorophenyl)-2-(difluoromethoxy)pyridine (Intermediate 12, 200 mg, 0.57 mmol) was added to the activated zinc solution and the resulting mixture was heated at 70°C for 8 hours . The reaction mixture was cooled to room temperature and decanted from the solid to give a ~0.5 M solution of the title compound.

Step 2 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(pyridin-2-ylmethyl)pyridine. ( ₍ 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 hours. The solvent was removed and the crude material was purified by Shimadzu HPLC using a 5-95% gradient with TFA to give the TFA salt of the title compound as an oil (21 mg, 16%). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.72-8.78 (m, 1H), 8.46 (dt, J = 1.57, 8.02 Hz, 1H), 8.23 ( e, J = 2.35 Hz, 1H), 7.84-7.93(m, 3H), 7.39-7.83(m, 5H), 4.50(s, 2H). [M+H] = 347.08.

Examples 110-111 were prepared analogously to Example 109 with appropriate changes in starting materials and reagents.

Example 110 2-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrazine

¹ H NMR (400 MHz, CD ₃ OD) δ 8.65 (d, J = 1.57 Hz, 1H), 8.55 (dd, J = 1.57 , 2.74 Hz, 1H), 8, 47 (d, J = 2.74 Hz, 1H), 8.18 (d, J = 2.35 Hz, 1H), 7.86 (d, J = 2.35 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.18 (d, J = 2.35 Hz, 1H), 7.84 (d, J = 2.35 Hz, 1H), 7.79 (d, J = 2.35 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

To 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 Cs ₂ CO ₃ (150 mg, 0.63 mmol). The reaction mixture was stirred at room temperature for 2 hours, then filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 0-100%, EtOAc/hexanes) gave the title compound (82.4 mg, 84%). ¹ H NMR (400 MHz, CDCl ₃ ) 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.

Examples 113, 115, 117, 123, 125-126 were prepared analogously to Example 13 with appropriate changes in starting materials and reagents.

Example 113 4-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzamide

¹ H NMR (400 MHz, CD ₃ OD) δ 8.02 - 8.08 (m, 2H), 7.98 (td, J = 4.30, 1.57 Hz, 1H), 7.81 (d , J = 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

The title compound was prepared analogously to Example 90 with appropriate changes in starting materials. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.49 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 2.3 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.75 (dd, J = 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 m.p.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.85 (s, 2H), 8.14 (d, J = 2.35 Hz, 1H), 7.81 (d, J = 2.35 Hz, 1H), 7.38 - 7.30 (m, 1H), 7.59 (s, 1H), 7.10 - 7.03 (m, 2H) 6.95 (dd, J = 8.22.1 .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

The title compound was prepared analogously to Example 90 with appropriate changes in starting materials. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.56 (d, J = 1.6 Hz, 1H), 8.09 - 8.00 (m, 2H), 7.82 (dd, J = 2 .0, 8.2 Hz, 1H), 7.59 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.85 (s, 2H), 8.18 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 2.3 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.83 (s, 2H), 8.11 (d, J = 2.3 Hz, 1H), 7.65 (d, J = 2.3 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.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.84 (s, 2H), 8.09 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.46 - 7.35 (m, 3H), 7.17 - 7.08 (m, 1H), 7.03 - 6.61 (m, 1H), 4.40 (k, J = 7.0 Hz, 2H), 4.12 (s, 2H), 1.35 (t, J = 7.0 Hz, 3H). [M+H] = 401.27.

Example 120 5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide.

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.91 (s, 2H), 8.33-8.27 (m, 2H), 8.12 (br s, 1H), 7.95 (d , J = 2.3 Hz, 1H), 7.93 - 7.55 (m, 2H), 7.50 (dd, J = 1.6 , 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.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.84 (s, 2H), 8.11 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.46 - 7.35 (m, 2H), 7.32 (t, J = 1.8 Hz, 1H), 7.14 - 7.10 (m, 1H), 6.83 (t , J = 1.0 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.

¹ H NMR (400 MHz, CD ₃ OD) 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 (k, J = 7.0 Hz, 2H), 4.13 (s, 2H), 1.37 (t, J = 7.0 Hz, 3H). [M+H] = 402.26.

Example 123 5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide m.p.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.94 (s, 2H), 8.20 (s, 1H), 8.02 (s, 1H), 7.99-7.91 (m, 1H ), 7.41 (d, J = 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

The title compound was prepared analogously to Example 90 with appropriate changes in starting materials. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.66 - 8.63 (m, 1H), 8.11 (s, 1H), 8.04 (dd, J = 0.8, 7.8 Hz , 1H), 7.98 - 7.85 (m, 3H), 7.46 (t, J = 8.2 Hz, 1H), 7.19 (dd, J = 2.0, 8.2 Hz, 1H), 7.04 - 6.61 (m, 1H), 4.48 (k, J = 7.0 Hz, 2H), 4.25 (s, 2H), 1.43 (t, J = 7 .0 Hz, 3H). [M+H] = 401.25.

Example 125 5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide.

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.92 (s, 2H), 8.29 (s, 1H), 8.12 (br s, 1H), 7.88 - 7.82 (m , 1H), 7.74 (t, J = 2.0 Hz, 1H), 7.71 (w s, 1H), 7.52 (t, J = 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 m.p.

¹ H NMR (400 MHz, DMSO -d 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.

Methyl-1H-1,2 ,4-triazole-3-carboxylate (121.60 mg, 0.96 mmol) and K ₂ CO ₃ (264.44 mg, 1.91 mmol). The reaction mixture was stirred at room temperature for 2 hours. LC/MS showed two peaks with [M+H] values consistent with the two major regioproducts. The mixture was diluted with DCM (5 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 20-100% EtOAc/hexanes) gave the title compound (100 mg, 44%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.79 (s, 1H), 8.26 (s, 1H), 8.01 (td, J = 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.

Examples 128-149, 151-197 were prepared analogously to Example 4 or Example 127 with appropriate changes in starting materials and reagents.

Example 128 3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-(difluoromethoxy)pyridine

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.71 - 7.63 (m, 1H), 7.50 (d, J = 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, J = 6.65 Hz, 3H). [M+H] = 377.22.

Example 129 3-(3-Fluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹ H NMR (400 MHz, CD ₃ OD) δ 8.60 (s, 1H), 8.19 (d, J = 2.7 Hz, 1H), 8.00 (s, 1H), 7.75 ( d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.63 (s, 1H), 8.25 (d, J = 2.3 Hz, 1H), 8.02 (s, 1H), 7.92 ( d, J = 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

in the form of a mixture.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.54 (s, 2H), 8.18 (d, J = 6.65 Hz, 2H), 7.90 - 8.05 (m, 4H), 7.85 (s, 2H), 7.37 - 7.47 (m, 4H), 5.50 (d, J = 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

in the form of a mixture.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.47 (s, 1H), 8.16 (s, 2H), 8.01 (d, J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J = 2.3 Hz, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.55 (d , J = 2.3 Hz, 1H), 7.51 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.63 - 8.57 (m, 1H), 8.16 (d, J = 2.3 Hz, 1H), 8.00 (s, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.56 (s, 1H), 7.49 - 7.31 (m, 3H), 5.44 - 5.40 (m, 3H) , 1.31 (d, J = 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.67 (s, 1H), 8.25 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.60 (s, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.00 (s, 1H), 7.77 ( d, J = 2.3 Hz, 1H), 7.54 - 7.45 (m, 3H), 7.27 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.52 (s, 1H), 8.13 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.60 (s, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.00 (s, 1H), 7.80 ( d, J = 2.3 Hz, 1H), 7.18 (dd, J = 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.

¹ H NMR (400 MHz, CDCl ₃ ) 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.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.21-8.18 (m, 1H), 8.18-8.15 (m, 1H), 7.56 (s, 1H), 7.50 ( e, J = 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

in the form of a mixture.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.15 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.65 (s, 1H), 8.21 (d, J = 2.3 Hz, 1H), 7.95 (s, 1H), 7.79 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.08 (d, J = 2.3 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.72 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 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

in the form of a mixture.

¹ H NMR (400 MHz, CD ₃ OD) 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

in the form of a mixture.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.58 - 7.32 (m, 14H), 5.43 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) 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

Step 1 1-(5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)ethanol. A solution of 5-(3-chlorophenyl)-6-(difluoromethoxy)nicotinaldehyde (Example 36, product of Step 2, 287 mg, 1.0 mmol) in DCM (5 ml) was cooled to 0°C and methylmagnesium bromide (1, 5 ml of a 1 M solution in toluene, 1.5 mmol). The mixture was warmed to room temperature and stirred for 30 minutes. Saturated aqueous ammonium chloride solution was added and the mixture was extracted into DCM. The combined extracts were dried (Na ₂ SO ₄ ), filtered and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 0-60%, EtOAc/hexanes) gave 1-(5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)ethanol (231 mg, 70%). [M+H] = 300.1.

Step 2. 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 methanesulfonyl chloride (108 mg, 0.92 mmol) was added. The mixture was warmed to room temperature and stirred for 1 hour. LCMS data confirmed the disappearance of starting material. All solvents were removed under vacuum and the crude material was purified (FCC, SiO ₂ , 0-60%, EtOAc/hexanes) to give the desired mesylate intermediate (205 mg, 70%), which was not characterized and was used directly in the next step.

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 subjected to the same reaction as in Example 127 with appropriate changes in starting materials. Purification (FCC, SiO ₂ , 50-100%, EtOAc/hexanes) gave the title compound (56 mg, 69%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.64 (s, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.02 (s, 1H), 7.91 ( d, J = 2.3 Hz, 1H), 7.82 - 7.59 (m, 1H), 7.54 (s, 1H), 7.48 - 7.40 (m, 3H), 5.86 (d, J = 7.0 Hz, 1H), 1.96 (d, J = 7.0 Hz, 3H). [M+H] = 351.19.

Example 150 3-(3-Fluorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine

in the form of a mixture.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (s, 1H), 8.17 (d, J = 2.3 Hz, 1H), 8.11 (d, J = 2.3 Hz, 1H), 7.85 (s, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.67 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.71 (s, 1H), 8.21 (d, J = 2.3 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.58 (s, 1H), 7.49 - 7.32 (m, 3H), 5.49 (s, 2H), 4.42 (d, J = 7.0 Hz, 2H), 1.34 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.14 - 8.11 (m, 2H), 7.71 (d, J = 2.3 Hz, 1H), 7.55 (s, 1H), 7.46 - 7.33 (m, 3H), 5.59 (s, 2H), 4.41 (d, J = 7.0 Hz, 2H), 1.34 (t, J = 7.2 Hz , 3H). [M+H] = 383.18.

Example 153 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methyl-1H-imidazol-1-yl)methyl]pyridine

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.25 (d, J = 2.3 Hz, 1H), 7.99 (d, J = 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

in the form of a mixture.

¹ H NMR (400 MHz, CD ₃ OD) 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 m.p.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.76 (s, 1H), 8.29 (d, J = 2.3 Hz, 1H), 7.97 (d, J = 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]methyl}pyridine

¹ H NMR (400 MHz, CD ₃ OD) δ 8.58 (s, 1H), 8.25 (d, J = 2.3 Hz, 1H), 7.91 (d, J = 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]methyl}pyridine

¹ H NMR (400 MHz, CD ₃ OD) δ 8.23 (d, J = 2.3 Hz, 1H), 7.94 (s, 1H), 7.90 (d, J = 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]methyl}pyridine

¹ H NMR (400 MHz, CD ₃ OD) δ 8.71 (s, 1H), 8.24 (d, J = 2.3 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.47 - 7.36 (m, 2H), 7.33 (d, J = 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]methyl}pyridine

¹ H NMR (400 MHz, CD ₃ OD) δ 8.15 (d, J = 2.3 Hz, 1H), 8.12 (s, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.43 (d, J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.65 (s, 1H), 8.23 (d, J = 2.3 Hz, 1H), 7.73 (d, J = 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.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.55 (s, 1H), 8.30 (d, J = 2.3 Hz, 1H), 7.82 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.72 (s, 1H), 8.21 (d, J = 2.38 Hz, 1H), 7.81 (d, J = 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 (k, J = 7.07 Hz, 2H), 1.35 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.13 (s, 2H), 7.74 (d, J= 2.51 Hz, 1H), 7.49-7.42 (m, 1H), 7.40 - 7.34 (m, 2H), 7.14 (dd, J = 7.40,1.76 Hz, 1H), 7.05 - 6.63 (m, 1H) 5.60 (s , 2H), 4.41 (k, J = 7.03 Hz, 2H), 1.35 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.56 (s, 1H), 8.17 (d, J = 2.3 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.49 - 7.35 (m, 3H), 7.13 (td, J = 2.0, 7.8 Hz, 1H), 7.04 - 6.63 (m, 1H), 5 .41 (s, 2H), 4.47 (s, 2H), 4.41 (k, J = 7.0 Hz, 2H), 3.37 (s, 3H), 1.35 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.15 (d, J = 2.3 Hz, 1H), 7.93 (s, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.49 - 7.33 (m, 3H), 7.12 (tdd, J = 1.0, 2.1, 7.7 Hz, 1H), 7.04 - 6.60 (m, 1H), 5.44 (s, 2H), 4.70 (s, 2H), 4.40 (c, J = 7.0 Hz, 2H), 3.38 (s, 3H), 1.34 ( t, J = 7.0 Hz, 3H). [M+H] = 391.25.

Example 166 5-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-methoxypyridine m.p.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.11 (d, J = 2.7 Hz, 1H), 7.84 (s, 1H), 7.67 (d, J = 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 m.p.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.14 (d, J = 2.3 Hz, 1H), 7.78 (d, J = 2.3 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.57 (s, 1H), 7.48 - 7.43 (m, 1H), 7.41 - 7.32 (m, 2H), 6.76 (d , J = 2.3 Hz, 1H), 5.39 (s, 2H), 4.41 (k, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H ). [M+H] = 357.29.

Example 168 Ethyl 1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylate

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.48 (s, 1H), 8.20 (d, J = 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, J = 7.04 Hz, 2H), 3, 87 (s, 3H), 1.23 (t, J = 7.04 Hz, 3H). [M+H] = 372.13.

Example 169 1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carbonitrile m.p.

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.67 (s, 1H), 8.20 (d, J = 1.96 Hz, 1H), 8.05 (s, 1H), 7.81 (d, J = 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.83 (d, J = 3.91 Hz, 2H), 8.67 (s, 1H), 8.35 (s, 1H), 8.00 (dd, J = 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 m.p.

The title compound was isolated as a by-product from Example 236. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.04 (d, J = 1.57 Hz, 1H), 7.95 (s, 1H), 7.57 (d, J = 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.21 (d, J = 2.3 Hz, 1H), 7.84 - 7.77 (m, 2H), 7.58 (d, J = 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

¹ H NMR (400 MHz, DMSO -d 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, J = 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

¹ H NMR (400 MHz, DMSO -d 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.67 (d, J = 9.8 Hz, 1H), 8.33 - 8.19 (m, 2H), 8.04 (d, J = 2.3 Hz, 1H), 7.98 (d, J = 3.1 Hz, 1H), 7.88 (d, J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J = 1.96 Hz, 1H), 7.65 (d, J = 1.96 Hz, 1H), 7.52 (s, 1H ), 7.42 - 7.32 (m, 1H), 7.36 - 7.29 (m, 4H), 6.61 (d, J = 9.00 Hz, 1H), 6.18 (t, J = 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 m.p.

¹ H NMR (400 MHz, DMSO -d 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

¹ H NMR (400 MHz, DMSO -d 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-nitro-1H-pyrazol-1-yl)methyl]pyridine

¹ H NMR (400 MHz, DMSO -d 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

¹ H NMR (400 MHz, CD ₃ OD) 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

¹ H NMR (400 MHz, CD ₃ OD) 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

¹ H NMR (400 MHz, CD ₃ OD) 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.07 - 7.96 (m, 2H), 7.94 (s, 1H), 7.58 (br s, 1H), 7.42 (d, J = 3.91 Hz, 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

in the form of a mixture.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.53 (s, 1H), 8.15 (s, 1H), 8.14 (s, 1H), 7.96-7.90 (m, 2H ), 7.86 (t, J = 2.0 Hz, 1H), 7.85 - 7.82 (m, 2H), 7.46 (dt, J = 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, J = 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 m.p.

in the form of a mixture.

¹ H NMR (400 MHz, CD ₃ OD) 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, J = 5.2, 8.3 Hz, 1H), 1.45 (dt, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.80 (s, 1H), 8.23 (s, 1H), 7.93-7.90 (m, 1H), 7.86 (t, J = 2.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.20 (dd, J = 2.0, 8.2 Hz, 1H), 7.03 - 6 .62 (m, 1H), 5.64 (s, 2H), 4.52 (k, J = 7.0 Hz, 2H), 1.45 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.19 (s, 1H), 8.12 (s, 1H), 7.95-7.87 (m, 1H), 7.83 (t, J = 2.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.19 (dd, J = 2.2, 8.0 Hz, 1H), 7.02 - 6 .59 (m, 1H), 5.74 (s, 2H), 4.52 (k, J = 7.3 Hz, 2H), 1.45 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.63 (s, 1H), 8.18 (s, 1H), 7.96-7.91 (m, 1H), 7.85 (t, J = 2.2 Hz, 1H), 7.45 (t, J = 8.2 Hz, 1H), 7.20 (dd, J = 2.0, 8.2 Hz, 1H), 7.05 - 6 .62 (m, 1H), 5.54 (s, 2H), 4.51 (k, J = 7.0 Hz, 2H), 4.46 (s, 3H), 4.30 (s, 2H) , 1.44 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.14 (s, 1H), 7.95 - 7.91 (m, 2H), 7.84 (d, J = 2.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.20 (dd, J = 2.2, 8.0 Hz, 1H), 7.03 - 6.63 (m, 1H), 5 .60 (s, 2H), 4.79 (s, 2H), 4.51 (k, J = 7.0 Hz, 2H), 3.38 (s, 3H), 1.44 (t, J = 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.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.78 (s, 1H), 8.23 (s, 1H), 7.92 (td, J = 1.4, 7.8 Hz, 1H), 7.84 (t, J = 2.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.19 (dd, J = 2.3, 8.2 Hz, 1H ), 7.03 - 6.63 (m, 1H), 5.63 (s, 2H), 4.51 (k, J = 7.0 Hz, 2H), 3.91 (s, 3H), 1 .44 (t, J = 7.2 Hz, 3H). [M+H] = 406.15.

Example 191 Methyl 1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-5-carboxylate.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.63 (s, 1H), 8.18 (s, 1H), 7.95-7.92 (m, 1H), 7.87-7.85 (m, 1H), 7.45 (t, J = 8.2 Hz, 1H), 7.20 (dd, J = 2.0, 8.2 Hz, 1H), 7.03 - 6.64 ( m, 1H), 5.54 (s, 2H), 4.51 (k, J = 7.0 Hz, 2H), 3.35 (s, 3H), 1.44 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.82 (s, 1H), 8.28 (s, 1H), 7.92 (td, J = 1.4, 7.8 Hz, 1H), 7.86 (t, J = 2.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.20 (dd, J = 2.7, 8.2 Hz, 1H ), 7.03 - 6.62 (m, 1H), 5.67 (s, 2H), 4.53 (k, J = 7.0 Hz, 2H), 1.45 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.23 (s, 1H), 8.10 (s, 1H), 7.80 (td, J = 1.4, 7.8 Hz, 1H), 7.73 (t, J = 2.3 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.18 (dd, J = 2.0, 8.2 Hz, 1H ), 7.02 - 6.61 (m, 1H), 6.01 (s, 2H), 4.51 (k, J = 7.0 Hz, 2H), 1.44 (t, J = 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.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.19 (s, 1H), 8.09 (s, 1H), 7.94 (td, J = 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.

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.88 (s, 1H), 8.35 (s, 1H), 7.83 (td, J = 1.4, 7.8 Hz, 1H) , 7.72 - 7.68 (m, 1H), 7.52 (t, J = 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.

¹ H NMR (400 MHz, DMSO -d 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 (k, J = 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

Step 1 Methyl 1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-imidazole-4-carboxylate was prepared analogously to Example 127.

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 7N. a solution of ammonia in MeOH (4 ml) was added NaCN (5 mg). The reaction mixture was heated for 24 hours at 130°C. LC-MS confirmed the disappearance of starting material. The reaction mixture was concentrated under reduced pressure. Purification (FCC, SiO ₂ , 0-1%, EtOAc/MeOH) gave the title compound. ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.18 (d, J = 2.3 Hz, 1H), 8.04 (s, 1H), 7.92 (d, J = 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, J = 5.1 Hz, 1H). [M+H] = 379.15.

Example 198 (1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

To 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 LiBH ₄ (4.66 mg, 0.21 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted into DCM. The combined extracts were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 0-5% DCM/MeOH) gave the title compound (50 mg, 70%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.61 (s, 1H), 8.21 (s, 1H), 8.02 (td, J = 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.

Examples 199-211 were prepared analogously to Example 198 with appropriate changes in starting materials and reagents.

Example 199 (1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹ H NMR (400 MHz, CD ₃ OD) δ 8.55 (s, 1H), 8.26 (d, J = 2.3 Hz, 1H), 7.93 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.52 (s, 1H), 8.17 (d, J = 2.3 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.49 - 7.34 (m, 3H), 7.13 (td, J = 2.0, 7.8 Hz, 1H), 7.02 - 6.65 (m, 1H), 5 .39 (s, 2H), 4.59 (s, 2H), 4.40 (k, J = 7.2 Hz, 2H), 1.34 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.53 (s, 1H), 8.20 (d, J = 2.7 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.48 - 7.35 (m, 2H), 7.32 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.53 (s, 1H), 8.18 (d, J = 2.7 Hz, 1H), 7.75 (d, J = 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 (k, J = 7.0 Hz, 2H), 1.34 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.56 (s, 1H), 8.22 (d, J = 2.3 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.61 (t, J = 1.0 Hz, 1H), 7.38 - 7.31 (m, 1H), 7.10 - 7.03 (m, 2H), 6.95 (ddd , J = 1.0, 2.4, 8.3 Hz, 1H), 5.46 (s, 2H), 4.59 (s, 2H), 4.07 (k, J = 7.0 Hz, 2H), 1.40 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.53 (s, 1H), 8.28 (d, J = 2.3 Hz, 1H), 8.24 - 8.21 (m, 1H), 7.89 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.54 (s, 1H), 8.26 (d, J = 2.3 Hz, 1H), 8.24 (dd, J = 0.8.5 .5 Hz, 1H), 7.89 (d, J = 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 (k, J = 7.0 Hz, 2H), 1.37 ( t, J = 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.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.56 (s, 1H), 8.35 - 8.28 (m, 2H), 8.05 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.60 (s, 1H), 8.18 (s, 1H), 7.93 (td, J = 1.4, 7.8 Hz, 1H), 7.86 (t, J = 2.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.20 (dd, J = 2.0, 8.2 Hz, 1H ), 7.04 - 6.64 (m, 1H), 5.52 (s, 2H), 4.59 (s, 2H), 4.51 (k, J = 7.3 Hz, 2H), 1 .44 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.14 (s, 1H), 7.90 (s, 1H), 7.93 - 7.89 (m, 1H), 7.83 (t, J = 2 .0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.19 (dd, J = 2.7, 7.8 Hz, 1H), 7.05 - 6.62 (m, 1H), 5.65 (s, 2H), 4.91 (s, 2H), 4.50 (k, J = 7.0 Hz, 2H), 1.44 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.16 (s, 1H), 8.02 - 7.99 (m, 1H), 7.94 (ddd, J = 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

¹ H NMR (400 MHz, DMSO -d 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, J = 8.0 Hz, 1H), 7.45 - 7.06 (m, 2H), 5.50 (s, 2H), 5.16 (t , J = 6.1 Hz, 1H), 4.36 (d, J = 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

¹ H NMR (400 MHz, DMSO -d 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, J = 6.1 Hz, 1H), 4.45 (k , J = 7.0 Hz, 2H), 4.36 (d, J = 5.9 Hz, 2H), 1.36 (t, J = 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

Step 1 3-(3-Chlorophenyl)-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine. The title compound was prepared analogously to Example 127 with appropriate changes in starting materials.

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) added NaOCH ₃ (63 mg, 1.17 mmol). The mixture was stirred at 60°C for 16 hours. LC/MS data showed approximately 70% conversion. All solvents were removed under reduced pressure, the residue was dissolved in DCM (50 ml) and water (50 ml), the layers were shaken and separated, and the aqueous layer was extracted into DCM (3×50 ml). The combined extracts were dried (MgSO ₄ ), filtered and the solvent removed under reduced pressure. Purification (FCC, SiO ₂ , 0-100% EtOAc/DCM) gave the title compound (72 mg, 56%). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.33 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 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.

Examples 213-215 were prepared analogously to Example 212 with appropriate changes in starting materials and reagents.

Example 213 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine

¹ H NMR (400 MHz, CD ₃ OD) δ 8.27 (s, 1H), 8.24 (d, J = 2.3 Hz, 1H), 7.91 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.17 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.28 - 8.21 (m, 2H), 7.91 (d, J = 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, J = 7.0 Hz, 2H) , 1.35 (t, J = 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

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 analogously to Example 127 with appropriate changes in starting materials.

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 hour. The solvent was removed under reduced pressure to give a white solid. The crude solid was dissolved in DCM (50 ml), sonicated and filtered (repeated twice). The combined DCM extracts were washed with saturated aqueous NaHCO ₃ and the layers were separated. The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The resulting solid was triturated with hexanes to give the title compound (287 mg, 94%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.15 (d, J = 2.7 Hz, 1H), 8.13 (s, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.47 - 7.36 (m, 2H), 7.33 (t, J = 1.8 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.

Examples 217-218, 223-236 were prepared analogously to Example 216 with appropriate changes in starting materials and reagents.

Example 217 1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.17 (d, J = 2.3 Hz, 1H), 8.09 (s, 1H), 7.76 (d, J = 2.3 Hz , 1H), 7.58 (d, J = 1.6 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.11 (d, J = 2.3 Hz, 1H), 8.06 (s, 1H), 7.78 (d, J = 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

Step 1 3-Bromo-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine. The title compound was prepared analogously to Intermediate 5 with appropriate changes in starting materials and reagents. [M+H] = 314.24/316.25.

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) added zinc (124 mg, 1.91 mmol). The mixture was stirred at 50°C for 1 hour. The solvent was removed under reduced pressure to give a white solid. The crude solid was dissolved in DCM (50 ml), sonicated and filtered (repeated twice). The combined DCM extracts were washed with saturated aqueous NaHCO ₃ and the layers were separated. The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The title compound was used in the next step without further purification.

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 acid (42 mg, 0.3 mmol) were dissolved in a mixture of water (2 ml) and ACN (4 ml) and added Pd(dppf)Cl ₂ (8 mg, 0.01 mmol), then Na ₂ CO ₃ (53 mg, 0.5 mmol). The mixture was irradiated in a microwave reactor for 15 minutes at 100°C. The reaction mixture was diluted with water and extracted with DCM (3 X 5 ml). The combined organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 0-10% DCM/MeOH) gave the title compound (49.7 mg, 89%). ¹ H NMR (400 MHz, CD ₃ OD) 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.

Examples 220-222 were prepared analogously to Example 220 with appropriate changes in starting materials and reagents.

Example 220 1-{[6-Methoxy-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹ H NMR (400 MHz, CD ₃ OD) δ 8.12 (s, 2H), 7.67 (d, J = 2.3 Hz, 1H), 7.31 (dd, J = 8.2 Hz, 1H), 7.10 - 7.04 (m, 2H), 6.91 (dd, J = 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

¹ H NMR (400 MHz, CD ₃ OD) 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.19 (b s, 1H), 8.13 (b s, 1H), 7.92-7.68 (m, 4H), 7.61 (d , J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.13 - 8.09 (m, 2H), 7.66 (d, J = 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, J = 7.0 Hz, 2H), 3.93 (s, 3H), 1.39 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.16 - 8.09 (m, 2H), 7.66 (d, J = 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, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.18 - 8.07 (m, 2H), 7.71 (d, J = 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, J = 7.0 Hz, 2H), 1.35 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.22 - 8.11 (m, 2H), 7.84 (d, J = 2.3 Hz, 1H), 7.80 - 7.39 (m , 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.10 - 7.05 (m, 2H), 6.97 (dd, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 9.28 (s, 1H), 8.78 (d, J = 1.76 Hz, 1H), 8.66 (d, J = 2.13 Hz, 1H), 8.38 (d, J = 2.26 Hz, 1H), 8.31 (t, J = 2.01 Hz, 1H), 8.01 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.25 - 8.19 (m, 2H), 8.13 (s, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.76 - 7.55 (m, 1H), 7.44 - 7.36 (m, 1H), 7.18 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.24 (dd, J = 0.8, 5.1 Hz, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8, 14 (s, 1H), 7.85 (d, J = 2.7 Hz, 1H), 7.77 - 7.57 (m, 1H), 7.43 (dd, J = 1.6, 5, 5 Hz, 1H), 7.22 (dd, J = 0.8, 1.6 Hz, 1H), 5.20 (s, 2H), 4.47 (k, J = 7.0 Hz, 2H) , 1.37 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.32-8.27 (m, 2H), 8.16 (s, 1H), 7.99 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.04 (d, J = 2.3 Hz, 1H), 7.58 (d, J = 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, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 7.99 (d, J = 2.3 Hz, 1H), 7.55 (d, J = 2.7 Hz, 1H), 7.44 - 7, 33 (m, 2H), 7.30 (t, J = 2.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.13 - 7.09 (m, 1H ), 7.02 - 6.63 (m, 1H), 5.50 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.05 (d, J = 2.7 Hz, 1H), 7.62 (d, J = 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 (k, J = 7.0 Hz, 2H), 1.38 - 1.30 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 7.99 (d, J = 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, J = 7.4 Hz, 2H) , 1.34 (t, J = 7.0 Hz, 4H). [M+H] = 363.30.

Example 235 1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-pyrazol-4-amine

The title compound was prepared analogously to Example 216 to give two products. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.14 (s, 1H), 8.07 (s, 1H), 8.03 (s, 1H), 7.98 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.64 - 8.50 (m, 1H), 8.18 (s, 1H), 7.93 (td, J = 1.4, 7.8 Hz , 1H), 7.86 (t, J = 2.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.20 (dd, J = 2.0, 8, 2 Hz, 1H), 7.05 - 6.60 (m, 1H), 5.52 (s, 2H), 4.51 (k, J = 7.3 Hz, 2H), 1.44 (t, J = 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.

To 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 a 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 hours. Purification by reverse phase preparative HPLC gave the title compound (25 mg, 20%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.19 - 8.11 (m, 1H), 7.82 (d, J = 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

Received as the reaction product of Example 237. Purification by reverse phase preparative HPLC gave the title compound (41 mg, 32%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.57 (s, 1H), 8.25 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 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

To a solution of 1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carbonitrile cooled to -78°C (Example 155 , 345 mg, 0.95 mmol) in DCM (5 ml) DIBAL (135.64 mg, 0.95 mmol) was added slowly. The mixture was stirred at -78°C for 1 hour. The reaction was quenched with wet Na ₂ SO ₄ and stirred at room temperature for 30 minutes. The white aluminum precipitate was filtered off and the filtrate was concentrated under reduced pressure. Purification (FCC, SiO ₂ , 40-100% EtOAc/DCM then 0-10% MeOH/DCM) gave the title compound (37 mg, 10%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.54 (s, 1H), 8.25 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 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 m.p.

To 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 radiation at 130°C for 20 minutes. LC/MS showed incomplete conversion. Additional ammonia in methanol (2 ml, 14 mmol) was added to the reaction mixture and irradiated in a microwave reactor at 120° C. for another 20 minutes. The solvent was removed under reduced pressure. Purification (FCC, SiO ₂ , 0-5% MeOH/DCM) gave the title compound (77 mg, 77%). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.74 (s, 1 H), 8.25 (d, J = 2.3 Hz, 1 H), 7.85 (d, J = 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 , 3H). [M+H] = 354.18.

Examples 241-244 were prepared analogously to Example 90 with appropriate changes in starting materials and reagents.

Example 241 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl} -N- (oxetan-3-yl)benzamide

¹ H NMR (400 MHz, CD ₃ OD) δ 7.94 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 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, J = 7.4 Hz, 2H), 4 .60 (t, J = 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.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.57 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.83 (dd, J = 2.0, 8.2 Hz, 1H), 7.78 (d, J = 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)cyclopropan-1-carboxamide

¹ H NMR (400 MHz, CD ₃ OD) δ 8.10 (d, J = 2.35 Hz, 1H), 7.76 (s, 1H), 7.73 (d, J = 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 (k, J = 3.65 Hz, 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.08 (d, J = 2.35 Hz, 1H), 7.76 (s, 1H), 7.67 (d, J = 2.35 Hz, 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

To 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 a 3 M solution, 0.84 mmol). The mixture was stirred at room temperature for 20 minutes. The mixture was carefully quenched with wet Na ₂ SO ₄ , diluted with DCM, filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 50-100% EtOAc/hexanes) gave the title compound (67 mg, 67%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.15 (d, J = 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, 6H). [M+H] = 359.09.

Examples 246-249 were prepared analogously to Example 245 with appropriate changes in starting materials and reagents.

Example 246 2-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-5-yl)propan-2-ol

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.15 (d, J = 2.0 Hz, 1H), 7.79 (s, 1H), 7.64 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 7.99 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 1.6 Hz, 2H), 7.45 - 7, 27 (m, 5H), 7.19 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.39 (s, 1H), 8.04 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.41 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.78 - 7, 57 (m, 4H), 7.52 (d, J = 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

To 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 hours. The material was absorbed onto silica and purified (FCC, SiO ₂ , 20-100% EtOAc/hexanes) to give the title compound (11 mg, 27%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.61 (s, 1H), 8.21 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.49 - 7.36 (m, 2H), 7.33 (t, J = 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.

Examples 251-255 were prepared analogously to Example 250 with appropriate changes in starting materials and reagents.

Example 251 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}pyridine

¹ H NMR (400 MHz, CD ₃ OD) δ 8.23 - 8.18 (m, 2H), 7.76 (d, J = 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, J = 48 Hz, 2H), 4.42 (k, J = 7.0 Hz, 2H), 1.35 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.63 (s, 1H), 8.23 (d, J = 2.3 Hz, 1H), 7.90 (d, J = 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, J = 1.0, 2.5, 8.2 Hz, 1H), 5.53 - 5.27 (m, 4H), 4.16 - 4.00 (k, J = 7.0 Hz, 2H), 1 .47 - 1.35 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.61 (s, 1H), 8.29 (d, J= 2.3 Hz, 1H), 8.26-8.21 (m, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.76 - 7.39 (m, 2H), 7.19 (dd, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.77-8.66 (m, 1H), 8.24 (s, 1H), 8.03-7.92 (m, 1H), 7.87 (d, J = 10.6 Hz, 1H), 7.57 - 7.41 (m, 1H), 7.25 (dd, J = 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

¹ H NMR (400 MHz, DMSO -d 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

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 analogously to Example 127 with appropriate changes in starting materials.

Step 2 1-((5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carbaldehyde. To a solution 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) DIBAL (52.6 mg, 0.37 mmol) was added slowly. The mixture was stirred at -78°C for 1 hour. The reaction was quenched with wet Na ₂ SO ₄ and stirred at room temperature for 30 minutes. The white precipitate of the aluminum salt was filtered off and concentrated (filtrate) under reduced pressure. The crude product was purified (FCC, SiO ₂ , 40-100% EtOAc/DCM then 0-5% MeOH/DCM) to give the title compound (69 mg, 51%).

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) added Deoxo-Fluor ^® (104.6 mg, 0.47 mmol). The mixture was stirred at room temperature for 16 hours. LC/MS data indicated the presence of the title compound. The material was adsorbed onto silica and purified (FCC, SiO ₂ , 10-100% EtOAc/hexanes) to give the title compound (13 mg, 18%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.69 (s, 1H), 8.28 (d, J = 2.3 Hz, 1H), 7.95 (d, J = 2.3 Hz, 1H), 7.81-7.39(m, 5H), 6.94-6.65(m, 1H), 5.54(s, 2H). [M+H] = 387.17.

Examples 257-258 were prepared analogously to Example 256 with appropriate changes in starting materials and reagents.

Example 257 3-[3-(Difluoromethoxy)phenyl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-ethoxypyridine

¹ H NMR (400 MHz, CD ₃ OD) δ 8.67 (s, 1H), 8.20 (d, J = 2.3 Hz, 1H), 7.79 (d, J = 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 (k, J = 7.0 Hz, 2H), 1.35 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.67 (s, 1H), 8.30 (d, J = 2.3 Hz, 1H), 8.23 (d, J = 5.1 Hz, 1H), 7.92 (d, J = 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

Step 1. 5-(Azidomethyl)-3-(3-chlorophenyl)-2-methoxypyridine. NaN ₃ (0.05 g, 0.77 mmol) and K ₂ CO ₃ (0.14 g, 1.02 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with brine and extracted into diethyl ether. All solvents were removed under reduced pressure to give the title compound, which was used in the next step without further purification.

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 (used directly from the previous reaction) and ethynyltrimethylsilane (75.1 mg, 0.77 mmol) in THF (3 ml), water (1 ml ) copper(I) iodide (19.4 mg, 0.10 mmol) and DIPEA (132 mg, 1.02 mmol) were added. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted into DCM. The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 0-50% EtOAc/hexanes) gave the title compound (92 mg, 48%). [M+H] = 373.2.

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 hours. The mixture was diluted with water and extracted into DCM. The DCM extracts were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 0-80% EtOAc/DCM) gave the title compound (44 mg, 59%). ¹ H NMR (400 MHz, CD ₃ OD) 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.

Examples 260-265 were prepared analogously to Example 259 with appropriate changes in starting materials and reagents.

Example 260 [1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol

¹ H NMR (400 MHz, CD ₃ OD) δ 8.19 (d, J = 2.7 Hz, 1H), 7.98 (s, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.47 - 7.35 (m, 3H), 7.14 (dd, J = 1.2, 2.0 Hz, 1H), 7.03 - 6.64 (m, 1H), 5 .60 (s, 2H), 4.73 - 4.60 (m, 2H), 4.41 (d, J = 7.0 Hz, 2H), 1.34 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.23 (d, J = 2.3 Hz, 1H), 8.00 (s, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.61 (t, J = 1.0 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.05 (ddd, J = 1.2, 2.5, 3, 7 Hz, 2H), 6.95 (ddd, J = 1.0, 2.4, 8.3 Hz, 1H), 5.67 (s, 2H), 4.66 (s, 2H), 4, 07 (k, J = 6.8 Hz, 2H), 1.40 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.19 (s, 1H), 8.05 (s, 1H), 7.98-7.93 (m, 1H), 7.88 (t, J = 2.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.21 (dd, J = 3.5, 8.2 Hz, 1H), 7.05 - 6 .65 (m, 1H), 5.73 (s, 2H), 4.67 (s, 2H), 4.51 (k, J = 7.0 Hz, 2H), 1.44 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.22 (s, 1H), 8.06 - 8.02 (m, 2H), 7.99 (ddd, J = 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

¹ H NMR (400 MHz, DMSO -d 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, J = 8.0 Hz, 1H), 7.45 - 7.05 (m, 2H), 5.72 (s, 2H), 5 .16 - 5.05 (m, 1H), 4.49 (d, J = 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

¹ H NMR (400 MHz, DMSO -d 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

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 hours. The reaction was quenched with wet Na ₂ SO ₄ . The reaction mixture was extracted into DCM, filtered and the solvent was removed under reduced pressure. Purification (FCC, SiO ₂ , 10-100% EtOAc/hexanes) gave the title compound (90 mg, 79%).

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 hours. The material was adsorbed onto silica. Purification (FCC, SiO ₂ , 0-80% EtOAc/hexanes) gave the title compound (53 mg, 56%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.36 (t, J = 1.4 Hz, 1H), 8.20 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 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 (k, J = 7.0 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H). [M+H] = 397.24.

Example 267 1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylic acid m.p.

To 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 an aqueous solution of LiOH (1.00 ml, 1.00 mol/l, 1.00 mmol). The mixture was stirred at room temperature for 2 hours. The solvents were removed under reduced pressure and the crude residue was dissolved in water. The aqueous reaction mixture was acidified with 1 N. HCl solution (5 ml) and extracted into ethyl acetate. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound (20 mg, 87%). ¹ H NMR (400 MHz, DMSO -d 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 m.p.

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 was dissolved. An aqueous solution of NaOH (0.23 ml, 1.00 mol/l, 0.23 mmol) and H ₂ O ₂ (0.23 ml, 1.00 mol/l, 0.23 mmol) was added and the reaction mixture was stirred at 50°C for 2 hours. Water (5 ml) was added and the mixture was filtered and washed with water (3 x 5 ml) to give the title compound as a solid (25.0 mg, 95%). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.20 (d, J = 13.69 Hz, 2H), 7.80 (d, J = 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

Step 1. 1-((5-(3-(Difluoromethoxy)phenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carbaldehyde. The title compound was prepared analogously to Example 127 with appropriate changes in starting materials.

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) added NaBH ₄ (14.3 mg, 0.38 mmol). The mixture was stirred at room temperature for 10 minutes. The mixture was quenched with water (0.5 ml), diluted with DCM (10 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 20-100% EtOAc/hexanes) gave the title compound (100 mg, 100%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.10 (d, J = 2.3 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.63 (d, J = 2 .3 Hz, 1H), 7.50 (s, 1H), 7.45 - 7.34 (m, 2H), 7.30 (t, J = 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.

Examples 270-275 were prepared analogously to Example 269 with appropriate changes in starting materials and reagents.

Example 270 (1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-5-yl)methanol

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.08 - 8.30 (m, 1H), 7.92 (d, J = 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 , J = 5.28 Hz, 1H), 4.41 (d, J = 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

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.19 - 8.40 (m, 1H), 8.05 (d, J = 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

¹ H (400 MHz, CD ₃ OD) δ 8.04 (d, J = 2.3 Hz, 1H), 7.61 (d, J = 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, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.08 (d, J = 2.3 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.55 (t, J = 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 (k, J = 7.0 Hz, 2H), 1.33 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.10 (d, J = 2.3 Hz, 1H), 7.80 (s, 1H), 7.68 (d, J = 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 (k, J = 7.0 Hz, 2H), 1.33 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.08 (d, J = 2.3 Hz, 1H), 7.68 (d, J = 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 (k, J = 7.0 Hz, 2H), 1.33 (t, J = 7.0 Hz, 4H). [M+H] = 378.27.

Example 276 4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}benzoic acid

The title compound was prepared analogously to Example 21 with appropriate changes in starting materials and reagents. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.01 (d, J = 2.3 Hz, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 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

The title compound was prepared analogously 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 using Pd(dppf)Cl ₂ ·DCM instead of Pd(dppf)Cl ₂ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.57 (s, 1H), 8.23 (d, J = 2.26 Hz, 1H), 7.69 (d, J = 2.26 Hz , 1H), 7.34 - 7.49 (m, 2H), 7.22 - 7.31 (m, 2H), 5.36 (s, 2H), 5.18 (t, J = 6.02 Hz, 1H), 4.38 (d, J = 6.02 Hz, 2H), 4.33 (k, J = 7.03 Hz, 2H), 1.22 (t, J = 7.03 Hz, 3H); [M+H] = 329.4.

Example 278 5-((5-(3,4-Difluorophenyl)-6-propoxypyridin-3-yl)methyl)pyrimidin-2-amine

The title compound was prepared analogously to Intermediate 21 from 5-(chloromethyl)-3-(3,4-difluorophenyl)-2-propoxypyridine (Intermediate 22) and 2-aminopyrimidine-5-boronic acid using Pd(PPh ₃ ) ₄ instead of Pd(dppf)Cl ₂ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.18 (s, 2H), 8.07 (d, J = 2.35 Hz, 1H), 7.69 (d, J = 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, J = 6.46 Hz, 2H), 3.72 (s, 2H), 1.68 (k, J = 6.65 Hz, 2H), 0.92 (t, J = 7.43 Hz, 3H); [M+H] = 357.4.

Example 279 5-((5-(3-Chloro-4-fluorophenyl)-6-ethoxypyridin-3-yl)methyl)pyrimidin-2-amine

The title compound was prepared analogously to Intermediate 24 from 5-((5-bromo-6-ethoxypyridin-3-yl)methyl)pyrimidin-2-amine (Intermediate 52) and (3-chloro-4-fluorophenyl)boronic acid using an aqueous solution of NaHCO ₃ instead of Na ₂ CO ₃ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.33 (s, 2H), 8.08 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 2.2, 7.2 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.58 (ddd, J = 2.2, 4.9, 8.6 Hz, 1H), 7, 49 - 7.42 (m, 1H), 4.33 (k, J = 7.0 Hz, 2H), 3.76 (s, 2H), 1.26 (t, J = 7.0 Hz, 3H ); [M+H] = 359.25.

Example 280 2-(4-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)acetamide

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 1N. LiOH solution (0.63 ml, 0.25 mmol). The reaction mixture was stirred at room temperature for 30 minutes. EtOAc (10 ml) was added to the reaction mixture followed by saturated aqueous NaHCO ₃ (10 ml). The aqueous layer was extracted and acidified with concentrated HCl. The acidified aqueous layer was extracted with EtOAc (10 ml) and the combined organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude title compound was used in the next step without further purification.

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 mmol). The reaction mixture was stirred at room temperature for 30 minutes and the solvent was removed under reduced pressure. The crude title compound was used in the next step without further purification.

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. a solution of ammonia in dioxane (0.75 ml, 0.75 mmol) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the precipitate was filtered off and washed with water to give the title compound (60 mg, 64%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.10 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 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.

Example 281 2-(5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide

H ₂ SO ₄ (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 stirred the reaction mixture at room temperature for 1 hour. The reaction mixture was cooled in an ice bath, ice was added to the reaction mixture, then water (100 ml) and stirred for 30 minutes. The solid was filtered off and the pH of the aqueous layer was adjusted to neutral with aqueous NaHCO ₃ solution. The aqueous layer was extracted with DCM, the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated on silica gel. Purification (FCC, SiO ₂ , 10% MeOH/90% EtOAc) gave the title compound (60 mg, 57%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.69 (s, 2H), 8.13 (d, J = 2.3 Hz, 1H), 7.70 (d, J = 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.

The title compound was prepared analogously to Example 13 from 5-((5-(3-chloro-4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine-2-carbonitrile. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.88 (s, 2H), 8.18 (d, J = 2.3 Hz, 1H), 8.10 (br s, 1H), 7, 79 (d, J = 2.3 Hz, 1H), 7.75 (dd, J = 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

The title compound was prepared analogously to Example 3 using 2-chloro-5-((5-(4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine (Intermediate 51). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.20 (s, 2H), 8.06 (d, J = 2.3 Hz, 1H), 7.61 (d, J = 2.3 Hz , 1H), 7.58 - 7.51 (m, 2H), 7.28 - 7.19 (m, 2H), 6.86 (t, J = 5.9 Hz, 1H), 4.65 - 4.57 (m, 1H), 3.83 (s, 3H), 3.71 (s, 2H), 3.45 (q, J = 6.1 Hz, 2H), 3.27 (q, J = 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

To a mixture of 2-(5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)acetonitrile (100.00 mg, 0.29 mmol) cooled to 0°C , DMSO (2.85 ml), water (0.40 ml) and NaOH (45.6 mg, 1.14 mmol) were added dropwise MeI (0.070 ml, 1.14 mmol). The resulting mixture was stirred at room temperature for 40 minutes, then poured into water (10 ml). The precipitate was filtered off and washed with water to give the title compound (85 mg, 78%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.85 - 8.81 (m, 2H), 8.17 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 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 m.p.

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 thionyl chloride (97.32 mg, 0.82 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to give a white solid which was used in the next step without further purification.

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 Cs ₂ CO ₃ (510 mg, 1.572 mmol) followed by KCN (50.97 mg, 0.78 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted into EtOAc. The organically combined fractions were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 30-90%, EtOAc/hexanes) gave the title compound (165 mg, 84%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.58 (s, 1H), 8.26 (s, 1H), 7.94 (d, J = 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.

Example 286 3-(3-Chlorophenyl)-5((5-ethoxypyridin-2-yl)methyl)-2-methoxypyridine

The title compound was prepared analogously to Intermediate 55 using 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. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (d, J = 2.35 Hz, 1H), 8.07 (d, J = 1.96 Hz, 1H), 7.52 (s, 1H ), 7.49 (d, J = 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, J= 7.04 Hz, 3H); [M+H] = 355.3.

Example 287 5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-amine

tert- 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 room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. After evaporation of the solvent, the material was dissolved in EtOAc, washed with saturated aqueous NaHCO ₃ . The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a yellow oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.03 (d, J = 2.35 Hz, 1H), 7.89 (s, 2H), 7.60 (d, J = 2.35 Hz, 1H), 7.53 (t, J = 1.96 Hz, 1H), 7.40-7.44 (m, 1H), 7.37 (t, J = 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

The title compound was prepared analogously to Example 291. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.07 (d, J = 2.35 Hz, 1H), 8.05 (s, 1H), 7.80 ( s, 1H), 7.57 (dd, J = 2.35, 7.04 Hz, 1H), 7.46 (d, J = 2.35 Hz, 1H), 7.39 (ddd, J = 2 .35, 4.70, 8.61 Hz, 1H), 7.17 (t, J = 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

tert- butyl nitrite (48 µl, 0.36 mmol), then 4 n. HCl solution in dioxane (6 μl, 4.00 mol/l, 0.02 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between DCM/saturated NaHCO ₃ solution. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give a yellow oil. Purification (preparative TLC, SiO ₂ , hexanes/EtOAc (8:2)) gave the title compound as a colorless oil (19.7 mg, 47%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.15 (d, J = 1.17 Hz, 1H), 8.09 (d, J = 2.35 Hz, 1H), 7.97 (d, J = 1.57 Hz, 1H), 7.52 (t, J = 1.76 Hz, 1H), 7.50 (d, J = 2.35 Hz, 1H), 7.39-7.43 ( m, 1H), 7.30-7.35 (m, 2H), 4.35 (k, J = 7.04 Hz, 2H), 4.04 (s, 2H), 3.96 (s, 3H ), 1.40 (t, J = 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

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 n- butanol (1 ml), heated at 175° C. overnight. The solvent was removed under reduced pressure and the crude residue was purified by preparative HPLC using a 15-85% gradient with the addition of formate. A concentrated NH ₄ OH solution was added, then the solvent was evaporated to give the desired compound as a white solid (19 mg, 47%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.03 (d, J = 2.35 Hz, 1H), 7.92 (d, J = 1.17 Hz, 1H), 7.88 (d, J = 1.17 Hz, 1H), 7.60 (d, J = 2.35 Hz, 1H), 7.53 (t, J = 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, J = 5.67 Hz, 2H), 3.45 (t, J = 5.67 Hz, 2H); [M+H] = 371.32.

Example 291 3-(3-Chlorophenyl)-2-methoxy-5-((5-methyl- 1H -tetrazol-1-yl)methylpyridine

The title compound was prepared analogously to Intermediate 32 using 5-(chloromethyl)-3-(3-chlorophenyl)-2-methoxypyridine (Intermediate 30) and 5-methyl-2H-tetrazole. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.26 (d, J = 2.35 Hz, 1H), 7.65 (d, J = 2.74 Hz, 1H), 7.52 (q, J = 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

2-Chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine mixture (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) were heated at 110°C for 24 hours. The dioxane was removed under reduced pressure and the residue taken up in MeOH (2 ml) then purified. Purification (preparative HPLC, gradient 15-85% with formic acid in mobile phase) gave the title compound as a white solid (48 mg, 57%). ¹ H NMR (400 MHz, CD ₃ OD) d 8.27 (s, 2H), 8.03 (d, J = 2.35 Hz, 1H), 7.55 (d, J = 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

5-(bromomethyl)-3-(3,4-difluorophenyl)-2-ethoxypyrazine mixture (Intermediate 46, 91 mg, 0.28 mmol), Pd(PPh ₃ ) ₄ (26 mg, 0.02 mmol), K ₂ CO ₃ (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) were heated using microwave radiation at 130°C for 30 minutes. Purification (preparative HPLC, gradient 15-85% with formic acid) gave the title compound as a white solid (29 mg, 31%). ¹ H NMR (400 MHz, CD ₃ OD) d 8.29 (s, 2H), 8.06 (s, 1H), 7.95-8.06 (m, 2H), 7.32 (td, J = 8.56, 10.27 Hz, 1H), 4.49 (k, J = 7.04 Hz, 2H), 3.97 (s, 2H), 1.44 (t, J = 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

A 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), heated at 100°C for 2 hours. The mixture was poured into H ₂ O (10 ml) and left to precipitate at room temperature overnight. The reaction mixture was filtered and the collected solid was purified (preparative HPLC gradient 15-85% with formic acid). Treated with concentrated NH ₄ OH solution and evaporated to give the desired compound as a white solid (37 mg, 58%). ¹ H NMR (400 MHz, CD ₃ OD) d 8.51 (s, 1H), 8.30 (s, 2H), 8.06-8.07 (m, 1H), 7.95-8.05 (m, 2H), 7.33 (td, J = 8.61, 10.56 Hz, 1H), 4.50 (k, J = 7.04 Hz, 2H), 3.97 (s, 2H) , 3.65-3.72 (m, 2H), 3.44-3.52 (m, 2H), 1.44 (t, J = 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

To 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 room temperature for 3 hours, then carefully quenched by adding dropwise a solution of KF (37 mg, 0.64 mmol) dissolved in water (1 ml). The reaction mixture was stirred for 15 minutes, then filtered through a pad of ^Celite® . ^Celite® was washed thoroughly with EtOAc and the EtOAc wash solutions were concentrated under reduced pressure. Purification (preparative HPLC, gradient 15-85% with formic acid) gave the title compound as a colorless oil (1 mg, 3%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J = 2.35 Hz, 1H), 7.55 (d, J = 2.35 Hz, 1H), 7.49-7.52 (m, 1H), 7.36 (d, J = 1.17 Hz, 3H), 5.54 (s, 2H), 4.12 (t, J = 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

The title compound was prepared analogously to Intermediate 21 using 3-bromo-2-ethoxy-5-((5-methyl-1H-tetrazol-1-yl)methyl)pyridine (Intermediate 32) and (4-fluorophenyl)boronic acid in dioxane/water. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (d, J = 2.35 Hz, 1H), 7.44-7.53 (m, 3H), 7.06-7.14 (m, 2H), 5.46 (s, 2H), 4.43 (k, J = 7.04 Hz, 2H), 2.56 (s, 3H), 1.37 (t, J = 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.

Step 1 1-((2'-(difluoromethoxy)-2-methoxy-[3,4'-bipyridin]-5-yl)methyl)-2-methyl-1H-imidazole-4-carbaldehyde. 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), Cs ₂ CO ₃ (487.6 mg, 1.5 mmol) and acetone (5 ml) were stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM, filtered and the organic solvents were removed under reduced pressure. Purification (FCC, SiO ₂ , 10% MeOH/DCM/EtOAc) gave the title compound as a mixture of two regioisomers (60 mg, 16%).

Step 2 5-((2'-(Difluoromethoxy)-2-methoxy-[3,4'-bipyridin]-5-yl)methyl)-3-fluoropyridin-2-amine. The title compound was prepared analogously to Example 256 Step 3. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.25-8.21 (m, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.75 - 7.72 (m, 1H), 7.58 - 7.35 (m, 3H), 7.18 (d, J = 0.8 Hz, 1H), 6.62 (s , 1H), 5.21 (s, 2H), 3.98 (s, 3H), 2.40 (s, 3H); [M+H] = 397.

Example 298 2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)acetamide.

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 minutes. Then [2-chloro-5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine] was added (Example 2, 204.60 mg, 0.59 mmol). The reaction mixture was stirred at 60°C for 18 hours. Added additional amount of NaH (20 mg, 0.51 mmol) and heated the reaction mixture for another 8 hours. The reaction mixture was cooled in an ice bath and 1 M NH ₄ Cl solution was added. The crude reaction mixture was extracted with EtOAc. The combined organic phase was treated with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (224.5 mg, 95%) as an oil. [M+H] = 400.39.

Step 2 2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)acetamide. The title compound was prepared analogously to Example 240. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.55 (s, 2H), 8.13 (d, J = 2.35 Hz, 1H), 7.74 (d, J = 2.35 Hz, 1H), 7.59 (t, J = 1.57 Hz, 1H), 7.35 - 7.53 (m, 4H), 7.12 (w s, 1H ), 4.65 (s, 2H), 3.89 (s, 2H), 3.55 (s, 1H), 3.30 (s, 3H); [M+H] = 385.38.

Example 299 (5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)methanol

To a solution of methyl 5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine-2-carboxylate (Intermediate 44, 277 mg, 0.75 mmol) cooled to 0°C in MeOH (4 ml) added NaBH₄ (28 mg, 0.75 mmol). The reaction mixture was stirred at 0°C for another 8 hours, then neutralized to pH 7 with 1 M aqueous citric acid solution and extracted with EtOAc. The combined organic layers were dried (Na₂SO₄), filtered and concentrated under reduced pressure. After purification (FCC, SiO₂, hexanes/(10% MeOH in EtOAc), 0-100%) gave the title compound (64 mg, 25%) as a light yellow semi-solid.¹H NMR (400 MHz, DMSO-d ₆) δ 8.74 (s, 2H), 8.16 (d,J=2.35 Hz, 1H), 7.75 (d,J=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,J=6.26 Hz, 2H), 3.96 (s, 2H), 3.85 (s, 3 H); [M+H] = 342.40.

Example 300 methanol.

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 analogously to Example 127 from 5-(chloromethyl)-3-(3-chlorophenyl)-2-(2,2,2-trifluoroethoxy)pyridine. [M+H] = 427.35.

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 solution of methyl 1-((5-(3-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole cooled to 0°C -3-carboxylate (172.30 mg, 0.40 mmol) in THF (5 mL) DIBAL (0.81 mL, 1.00 mol/L, 0.81 mmol) was added under nitrogen over 1 minute. The ice bath was removed and the reaction mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated, then redissolved in DCM (5 ml) and 1N hydrochloric acid was added. aqueous solution of NaOH (0.5 ml). The solution was stirred for another 8 hours at room temperature. The layers were separated and the aqueous phase was extracted with DCM. The combined organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 0-10% DCM/MeOH) gave the title compound (25 mg, 16%) as a white powder. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.57 (s, 1 H), 8.22 (d, J = 2.3 Hz, 1H) 7.95 (d, J = 2.3 Hz , 1H), 7.55 - 7.41 (m, 1H), 5.39 (s, 1H), 5.03 (q, J = 9.0 Hz, 1H), 4.36 (d, J = 6.3 Hz, 1H), 3.30 (s, 2H), 2.48 (td, J = 1.9, 3.6 Hz, 4H); [M+H] = 399.35.

Example 301 5-((2'-(Difluoromethoxy)-2-methoxy-[3,4'-bipyridin]-5-yl)methyl)-3-fluoropyridin-2-amine

Step 1. 5-((2'-(Difluoromethoxy)-2-methoxy-[3,4'-bipyridin]-5-yl)methyl)-3-fluoro- N- (4-methoxybenzyl)pyridine-2-amine . The title compound was prepared analogously to Example 3 using Intermediate 58. [M+H] = 497.52.

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- N- (4-methoxybenzyl)pyridine-2-amine (90 .7 mg, 0.18 mmol) in THFA (5 ml) was heated at 50° C. for 8 hours. The reaction mixture was concentrated and redissolved in EtOAc, then washed with NaHCO ₃ . The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 0-100% EtOAc/hexanes) gave the title compound as a tan solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.30 (d, J = 5.4 Hz, 1H), 8.18 (d, J = 2.2 Hz, 1H), 7.84 (d , J = 2.2 Hz, 1H), 7.78 - 7.55 (m, 2H), 7.49 (dd, J = 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.

Example 302 5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-ol.

To a 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 tert- butyl nitrite (150 μl, 1.27 mmol). The reaction mixture was left to warm to room temperature and stirred for another 7 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phase was treated with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , 0-15% MeOH/DCM) gave the title compound as a white solid (80.48 mg, 77%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.80 (s, 1H), 8.19 (br s, 1H), 8.11 (d, J = 2.35 Hz, 1H), 7, 71 (d, J = 2.35 Hz, 1H), 7.59 (t, J = 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

NaH (10.40 mg, 0.43 mmol) was added to an ethylene glycol solution (4.0 ml) cooled to 0°C. The solution was stirred under nitrogen at 0° C. for 30 minutes. 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 room temperature and stirred for another 8 hours. The reaction mixture was diluted with water to give a precipitate, which was washed with diethyl ether and dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound (41 mg, 37%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.54 (s, 2H), 8.13 (d, J = 2.35 Hz, 1H), 7.72 (d, J = 2.35 Hz , 1H), 7.54 - 7.65 (m, 1H), 7.35 - 7.54 (m, 3H), 4.83 (t, J = 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

To 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 Na ₂ CO ₃ (160.52 mg, 1.51 mmol). The suspension was stirred at room temperature for 48 hours. The reaction mixture was filtered, diluted with EtOAc and washed with water. The organic phase was treated with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. Purification (FCC, SiO ₂ , 0-30% EtOAc/hexanes) gave the title compound as a colorless oil (17 mg, 6%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (s, 2H), 8.04 (d, J = 2.35 Hz, 1H), 7.49 (t, J = 36 Hz, 1H), 7.29-7.22(m, 5H), 3.96(s, 3H), 3.93(s, 2H); [M+H] = 378.35.

Examples 305 - 306 were prepared analogously to Example 1 with appropriate changes in starting materials and reagents.

Example 305 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-3-methylpyridazine

¹ H NMR (400 MHz, CD ₃ OD) δ 8.97 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.63 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) 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.

Examples 307-314 were prepared analogously to Example 127 with appropriate changes in starting materials and reagents.

Example 307 1-{[5-(2-Cyanopyridin-4-yl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.75 - 8.85 (m, 1H), 8.22 - 8.34 (m, 2H), 8.02 (d, J = 2.35 Hz, 1H), 7.86 - 7.99 (m, 2H), 7.42 (w s, 1H), 7.18 (w s, 1H), 6.62 (d, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.19 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.78 (d , J = 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, J = 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.

¹ H NMR (400 MHz, CD ₃ OD) 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, J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.52 - 7.48 (m, 2H), 7.41 (d, J = 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, J = 7.0 Hz, 2H), 1.37 (t, J = 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.

¹ H NMR (400 MHz, CD ₃ OD) 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

¹ H NMR (400 MHz, CD ₃ OD) 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

¹ H NMR (400 MHz, CD ₃ OD) 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 (k, J = 7.0 Hz, 2H), 1, 43 (t, J = 7.0 Hz, 3H); [M+H] = 358.

Example 314 1-{[6-(3,4-Difluorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-imidazole-4-carboxamide

¹ H NMR (400 MHz, CD ₃ OD) δ 8.17 (s, 1H), 8.04 (s, 2H), 7.90-7.78 (m, 2H), 7.33 (td, J = 8.6, 10.3 Hz, 1H), 5.38 (s, 2H), 4.58 - 4.49 (m, 2H), 1.45 (s, 3H); [M+H] = 360.

Examples 315 - 316 were prepared analogously to Example 198 with appropriate changes in starting materials and reagents.

Example 315 [1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-2-methyl-1H-imidazol-4-yl]methanol

¹ H NMR (400 MHz, CD ₃ OD) δ 8.25 - 8.21 (m, 1H), 8.11 (d, J = 2.3 Hz, 1H), 7.76 - 7.55 (m , 2H), 7.38 (dd, J = 1.4, 5.3 Hz, 1H), 7.17 (dd, J = 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

¹ H NMR (400 MHz, CD ₃ OD) 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, J = 0.8 Hz, 3H); [M+H] = 377.

Example 317 1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-5-methyl-1H-pyrazol-3-amine

The title compound was prepared analogously to Example 219 with appropriate changes in starting materials and reagents. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.90 (d, J = 2.3 Hz, 1H), 7.54 (t, J = 2.0 Hz, 1H), 7.48 (d, J = 2.3 Hz, 1H), 7.45 - 7.41 (m, 1H), 7.40 - 7.31 (m, 2H), 5.49 (d, J = 0.8 Hz, 1H ), 5.07 (s, 2H), 4.38 (d, J = 7.0 Hz, 2H), 2.21 (s, 3H), 1.33 (t, J = 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.

The title compound was prepared analogously to Example 245 with appropriate changes in starting materials and reagents. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.53 (s, 2H), 8.13 (d, J = 2.35 Hz, 1H), 7.72 (d, J = 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.

Examples 319 - 326 were prepared analogously to Example 269 with appropriate changes in starting materials and reagents.

Example 319 (1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-5-yl)methanol

¹ H NMR (400 MHz, CD ₃ OD) δ 7.87 (d, J = 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, J = 7.0 Hz, 2H), 2.31 (s, 3H), 1.33 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.00 (d, J = 2.3 Hz, 1H), 7.60 (d, J = 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, J = 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

¹ H NMR (400 MHz, CD ₃ OD) 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 - 7.96 (m, 1H), 7.88 (ddd, J = 1.6, 3.6, 5.4 Hz, 1H), 7, 75 (s, 1H), 7.31 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) 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 , J = 0.8 Hz, 3H), 1.43 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) 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, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 7.94 (d, J = 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, J = 7.0 Hz, 2H), 2.30 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.01 (d, J = 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, J = 0.8 Hz, 4H), 2.36 (s, 3H) , 1.34 (s, 4H); [M+H] = 358.

Examples 327-346 were prepared analogously to Example 277 with appropriate changes in starting materials and reagents.

Example 327 (1-{[6-Ethoxy-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.62 (s, 1H), 8.15 (d, J = 2.3 Hz, 1H), 7.76 (d, J = 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, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.60 (s, 1H), 8.17 (d, J = 2.3 Hz, 1H), 7.76 (d, J = 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, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.72 (d, J = 2.0 Hz, 1H), 8.61 (s, 1H), 8.24 (d, J = 2.3 Hz , 1H), 8.14 - 8.11 (m, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.94 (d, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.54 (s, 1H), 8.19 (d, J = 2.3 Hz, 1H), 7.85 (d, J = 2.3 Hz , 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.59 - 7.53 (m, 2H), 5 .34 (s, 2H), 5.15 (t, J = 6.1 Hz, 1H), 4.41 - 4.30 (m, 4H), 1.27 (t, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.62 (s, 1H), 8.14 (d, J = 2.3 Hz, 1H), 7.73 (d, J = 2.3 Hz , 1H), 7.46 - 7.32 (m, 2H), 7.18 (dd, J = 8.4, 9.6 Hz, 1H), 5.34 (s, 2H), 4.43 - 4.22 (m, 4H), 2.26 (d, J = 2.0 Hz, 3H), 1.26 (t, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.58 (s, 1H), 8.21 (d, J= 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, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.59 (s, 1H), 8.19 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 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, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.61 (s, 1H), 8.14 (d, J = 2.3 Hz, 1H), 7.75 (d, J = 2.3 Hz , 1H), 7.36 - 7.28 (m, 1H), 7.12 - 7.02 (m, 2H), 6.90 (ddd, J = 1.2, 2.3, 8.2 Hz , 1H), 5.34 (s, 2H), 4.40 - 4.29 (m, 4H), 4.04 (k, J = 7.0 Hz, 2H), 1.32 (t, J = 6.8 Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H); [M+H] = 355.25.

Example 335 [1-({5-[3-(Dimethylamino)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.63 (s, 1H), 8.14 (d, J = 2.3 Hz, 1H), 7.74 (d, J = 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 (k, J = 7.0 Hz, 2H), 2.96 (s, 7H), 1.27 (t, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.55 (s, 1H), 8.21 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 2.3 Hz , 1H), 7.59 - 7.56 (m, 1H), 7.51 - 7.39 (m, 3H), 5.35 (s, 2H), 5.15 (t, J = 6.1 Hz, 1H), 4.36 (d, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.54 (s, 1H), 8.18 (d, J = 2.3 Hz, 1H), 7.82 (d, J = 2.3 Hz , 1H), 7.77 (dd, J = 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, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.56 (s, 1H), 8.22 (d, J = 2.26 Hz, 1H), 7.89 (d, J = 2.26 Hz , 1H), 7.33 (dd, J = 8.97, 2.20 Hz, 2H), 7.26 (d, J = 2.26 Hz, 1H), 5.35 (s, 2H), 5 .18 (t, J = 6.02 Hz, 1H), 4.32 - 4.45 (m, 4H), 1.30 (t, J = 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 .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.74 (d, J = 5.48 Hz, 1H), 8.54 (s, 1H), 8.30 (d, J = 2.35 Hz, 1H), 8.10 (d, J = 1.17 Hz, 1H), 7.98 (d, J = 2.35 Hz, 1H), 7.88 (dd, J = 5.09, 1.57 Hz, 1H), 5.43 (s, 2H), 4.59 (s, 2H), 4.47 (k, J = 7.04 Hz, 2H), 1.37 (t, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.56 (s, 1H), 8.19 (d, J = 2.38 Hz, 1H), 7.82 (d, J = 2.26 Hz , 1H), 7.61 - 7.69 (m, 1H), 7.39 - 7.56 (m, 2H), 5.35 (s, 2H), 5.18 (t, J = 6.02 Hz, 1H), 4.31 - 4.42 (m, 4H), 1.29 (t, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.57 (s, 1H), 8.20 (d, J = 2.26 Hz, 1H), 7.83 (d, J = 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, J = 6.02 Hz, 1H), 4.30 - 4.45 (m, 4H), 1.29 (t, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.57 (s, 1H), 8.17 (d, J = 2.26 Hz, 1H), 7.76 (d, J = 2.26 Hz , 1H), 7.53 - 7.66 (m, 2H), 7.22 - 7.32 (m, 2H), 5.35 (s, 2H), 5.18 (t, J = 6.02 Hz, 1H), 4.30 - 4.43 (m, 4H), 1.28 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.03 - 7.99 (m, 1H), 7.55 - 7.48 (m, 3H), 7.12 (t, J = 8.8 Hz , 2H), 7.01 (s, 1H), 5.13 (s, 2H), 4.44 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.04 (d, J = 2.3 Hz, 1H), 7.56 (d, J = 2.3 Hz, 1H), 7.51 - 7, 44 (m, 1H), 7.30 (dd, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.03 (d, J = 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, J = 0.8 Hz, 2H), 3.94 (s, 3H), 2.36 (s, 3H); [M+H] = 344.

Examples 347-349 were prepared analogously to Intermediate 21 with appropriate changes in starting materials and reagents.

Example 347 4-{5-[(2-Aminopyrimidin-5-yl)methyl]-2-methoxypyridin-3-yl}pyridine-2-carbonitrile

¹ H NMR (400 MHz, DMSO-d6) δ 8.69 - 8.83 (m, 1H), 8.26 (dd, J = 1.57, 0.78 Hz, 1H), 8.08 - 8 .24 (m, 3H), 7.92 - 8.03 (m, 1H), 7.90 (d, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.74 - 8.86 (m, 2H), 8.17 (d, J = 2.35 Hz, 1H), 7.80 - 7.91 ( m, 1H), 7.65 (t, J = 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-methoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.25 - 8.07 (m, 4H), 7.75 (d, J = 2.3 Hz, 1H), 7.13 (dd, J = 1.6, 5.5 Hz, 1H), 6.88 (s, 1H), 6.44 (br s, 2H), 4.31 (k, J = 7.0 Hz, 2H), 3.86 (s, 3H), 3.71 (s, 2H), 1.31 (t, J = 7.0 Hz, 3H); [M+H] = 338.21.

Examples 350-362 were prepared analogously to Intermediate 24 with appropriate changes in starting materials and reagents.

Example 350 5-{[6-Ethoxy-5-(4-fluorophenyl)pyridin-3-yl]methyl}pyrimidin-2-amine

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.35 (s, 2H), 8.06 (d, J = 2.3 Hz, 1H), 7.64 (d, J = 2.3 Hz , 1H), 7.61 - 7.54 (m, 2H), 7.28 - 7.19 (m, 2H), 4.31 (k, J = 7.0 Hz, 2H), 3.77 ( s, 2H), 1.25 (t, J = 7.0 Hz, 3H); [M+H] = 325.25.

Example 351 5-{[5-(4-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.36 (s, 2H), 8.07 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 2.3 Hz , 1H), 7.60 - 7.54 (m, 3H), 7.51 - 7.43 (m, 3H), 4.31 (k, J = 7.0 Hz, 2H), 3.77 ( s, 2H), 1.25 (t, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.33 (s, 2H), 8.04 (d, J = 2.3 Hz, 1H), 7.62 (d, J = 2.3 Hz , 1H), 7.47 - 7.34 (m, 3H), 7.20 - 7.12 (m, 2H), 4.31 (k, J = 7.0 Hz, 2H), 3.75 ( s, 2H), 2.25 (d, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.34 (s, 2H), 8.08 (d, J = 2.3 Hz, 1H), 7.70 (d, J = 2.3 Hz , 1H), 7.64 (ddd, J = 2.3, 8.0, 12.3 Hz, 1H), 7.52 - 7.38 (m, 2H), 4.33 (k, J = 7 .0 Hz, 2H), 3.77 (s, 2H), 1.27 (t, J = 7.0 Hz, 3H); [M+H] = 343.25.

Example 354 5-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.37 (s, 2H), 8.08 (d, J = 2.3 Hz, 1H), 7.67 (d, J = 2.3 Hz , 1H), 7.30 - 7.25 (m, 1H), 7.25 - 7.19 (m, 1H), 7.07 (ddd, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.36 - 8.30 (m, 2H), 8.09 - 8.04 (m, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.30 - 7.19 (m, 3H), 7.06 (ddd, J = 2.3, 4.5, 8.4 Hz, 1H), 4.11 (k, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.37 - 8.26 (m, 2H), 8.14 (d, J = 2.3 Hz, 1H), 7.99 (t, J = 1.8 Hz, 1H), 7.89 (td, J = 1.5, 7.6 Hz, 1H), 7.81 (td, J = 1.3, 8.0 Hz, 1H), 7, 76 (d, J = 2.3 Hz, 1H), 7.62 (t, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.34 (s, 2H), 8.07 (d, J = 2.3 Hz, 1H), 7.62 (d, J = 2.3 Hz , 1H), 7.44 - 7.31 (m, 3H), 7.16 (dd, J = 8.4, 9.6 Hz, 1H), 3.83 (s, 3H), 3.77 ( s, 2H), 2.25 (d, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.81 - 8.76 (m, 2H), 8.16 (d, J = 2.3 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.63 (ddd, J = 2.2, 7.9, 12.2 Hz, 1H), 7.47 (td, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.35 (s, 2H), 8.11 (d, J= 2.3 Hz, 1H), 7.77-7.68 (m, 2H) , 7.55 (ddd, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.36 (s, 2H), 8.09 (d, J = 2.3 Hz, 1H), 7.64 (d, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.35 (s, 2H), 8.13 (d, J = 2.3 Hz, 1H), 7.73 (d, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.34 (s, 2H), 8.11 (d, J = 2.3 Hz, 1H), 7.70 (d, J = 2.3 Hz , 1H), 7.62 (ddd, J = 2.2, 7.9, 12.2 Hz, 1H), 7.47 (td, J = 8.5, 10.9 Hz, 1H), 7, 42 - 7.34 (m, 2H), 3.85 (s, 3H), 3.77 (s, 2H); [M+H] = 329.39.

Examples 363-365 were prepared analogously to Example 280 with appropriate changes in starting materials and reagents.

Example 363 2-(4-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide

¹ H NMR (400 MHz, CD ₃ OD) δ 8.09 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.62 (ddd, J = 2.2, 7.9, 12.2 Hz, 1H), 7.47 (td, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.05 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.56 - 7 .49 (m, 2H), 7.38 (w s, 1H), 7.26 - 7.20 (m, 2H), 7.20 - 7.12 (m, 4H), 6.80 (w 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.09 (d, J = 2.3 Hz, 1H), 7.68 (d, J = 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.

Examples 366 - 372 were prepared analogously to Example 281 with appropriate changes in starting materials and reagents.

Example 366 2-(5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.69 (s, 2H), 8.17 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.71 (s, 2H), 8.15 (d, J = 2.3 Hz, 1H), 7.78 (d, J = 2.3 Hz , 1H), 7.61 - 7.57 (m, 1H), 7.52 - 7.48 (m, 1H), 7.47 - 7.38 (m, 2H), 6.82 (w 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.71 (s, 1H), 8.19 - 8.15 (m, 1H), 7.78 (d, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.69 (s, 2H), 8.16 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 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.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.71 (s, 2H), 8.20 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.68 - 7.59 (m, 1H), 7.57 - 7.38 (m, 4H), 6.96 (w s, 1H), 4.99 (k, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.70 (s, 2H), 8.17 (d, J = 2.3 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.65 (t, J = 1.6 Hz, 1H), 7.60 - 7.51 (m, 1H), 7.51 - 7.35 (m, 3H), 6.96 (w s, 1H), 6.35 (t, J = 3.5 Hz, 1H), 4.58 (dt, J = 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.

¹ H NMR (400 MHz, CD ₃ OD) 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.

Examples 373 - 374 were prepared analogously to Example 13 with appropriate changes in starting materials and reagents.

Example 373 5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.88 (s, 2H), 8.18 (d, J = 2.3 Hz, 1H), 8.10 (br s, 1H), 7, 78 (d, J = 2.3 Hz, 1H), 7.71 (w s, 1H), 7.63 (ddd, J = 2.2, 7.9, 12.2 Hz, 1H), 7, 47 (td, J = 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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.88 (s, 2H), 8.15 (d, J = 2.3 Hz, 1H), 8.10 (br s, 1H), 7, 71 (d, J = 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

The title compound was prepared analogously to Example 3 with appropriate changes in starting materials and reagents. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.20 (s, 2H), 8.08 (d, J = 2.3 Hz, 1H), 7.67 (d, J = 2.3 Hz , 1H), 7.62 (ddd, J = 2.2, 7.9, 12.2 Hz, 1H), 7.52 - 7.42 (m, 1H), 7.41 - 7.33 (m , 1H), 6.84 (t, J = 5.9 Hz, 1H), 4.63 - 4.56 (m, 1H), 3.85 (s, 3H), 3.72 (s, 2H) , 3.45 (k, J = 6.1 Hz, 2H), 3.29 - 3.23 (m, 2H); [M+H] = 373.40.

Examples 376-378 were prepared analogously to Intermediate 55 with appropriate changes in starting materials and reagents.

Example 376 (5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrazin-2-yl)methanol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.59 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.46 (d, J = 1.17 Hz, 1H), 8.43 (s, 1H), 8.08 (d, J = 2.35 Hz, 1H), 7.64 (d, J = 2.35 Hz, 1H), 7.52 (t, J = 1.57 Hz, 1H), 7.39-7.43 (m, 1H), 7, 36 (t, J = 7.63 Hz, 1H), 7.32 (t, J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.83 (dd, J = 0.78, 1.96 Hz, 1H), 8.09 (d, J = 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

The title compound was prepared analogously to Example 287 using t- butyl-(5-((5-(3-chloro-4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-yl)carbamate (Intermediate compound 56). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (d, J = 2.35 Hz, 1H), 7.95 (d, J = 1.56 Hz, 1H), 7.91 (d, J = 1.17 Hz, 1H), 7.49 (d, J = 2.35 Hz, 1H), 7.35-7.44 (m, 2H), 7.26 (dd, J = 0.78, 1.96 Hz, 1H), 4.54 (br s, 2H), 3.98 (s, 2H), 3.96 (s, 3H); [M+H] = 345.35.

Examples 380-388 were prepared similarly to Intermediate 32 with appropriate changes in starting materials and reagents.

Example 380 3-(3-Chlorophenyl)-2-methoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, J = 2.35 Hz, 1H), 7.52 (d, J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.26 (d, J = 2.35 Hz, 1H), 7.65 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.24 (d, J = 2.35 Hz, 1H), 7.78 (d, J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (d, J = 2.35 Hz, 1H), 7.65 (d, J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (d, J = 2.35 Hz, 1H), 7.65 (d, J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (d, J = 2.35 Hz, 1H), 7.67 (d, J = 2.35 Hz, 1H), 7.44 (t, J = 8.02 Hz, 1H), 7.37 (dd, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.28 (d, J = 2.35 Hz, 1H), 7.85 (d, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.25-8.28 (m, 1H), 7.80 (d, J = 2.35 Hz, 1H), 7.53 (t, J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (d, J = 2.35 Hz, 1H), 7.67 (d, J = 2.35 Hz, 1H), 7.52 (q, J = 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.

Examples 389 - 391 were prepared analogously to Example 292 with appropriate changes in starting materials and reagents.

Example 389 1-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)pyrrolidin-3-ol

¹ H NMR (400 MHz, CD ₃ OD) δ 8.24 (s, 2H), 8.03 (d, J = 2.35 Hz, 1H), 7.55 (d, J = 2.35 Hz, 1H), 7.53 (t, J = 1.76 Hz, 1H), 7.40-7.44 (m, 1H), 7.37 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.25 (s, 2H), 8.03 (d, J = 2.35 Hz, 1H), 7.56 (d, J = 2.35 Hz, 1H), 7.53 (t, J = 1.57 Hz, 1H), 7.41-7.44 (m, 1H), 7.37 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.20 (s, 2H), 8.03 (d, J = 2.35 Hz, 1H), 7.56 (d, J = 2.74 Hz, 1H), 7.53 (t, J = 1.57 Hz, 1H), 7.41-7.45 (m, 1H), 7.38 (t, J = 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.

Examples 392-402 were prepared analogously to Intermediate 21 with appropriate changes in starting materials and reagents.

Example 392 2-Ethoxy-3-(4-fluorophenyl)-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.21 (d, J = 1.96 Hz, 1H), 7.63 (d, J = 1.96 Hz, 1H), 7.47-7.56 (m, 2H), 7.06-7.15 (m, 2H), 5.68 (s, 2H), 4.43 (q, J = 7.04 Hz, 2H), 2.52 (s, 3H), 1.37 (t, J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 (d, J = 2.35 Hz, 1H), 7.63 (d, J = 2.35 Hz, 1H), 7.42 (ddd, J = 2.15, 7.53, 11.44 Hz, 1H), 7.17-7.26 (m, 2H), 5.68 (s, 2H), 4.44 (k, J = 7.04 Hz, 2H), 2.53 (s, 3H), 1.38 (t, J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (d, J = 2.35 Hz, 1H), 8.20-8.24 (m, 1H), 7.71 (d, J = 2, 35 Hz, 1H), 7.50 (t, J = 73.20 Hz, 1H), 7.27-7.29 (m, 1H), 7.11 (dd, J = 0.78, 1.57 Hz, 1H), 5.69 (s, 2H), 4.45 (k, J = 7.04 Hz, 2H), 2.52 (s, 3H), 1.38 (t, J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (d, J = 2.35 Hz, 1H), 7.52 (d, J = 2.35 Hz, 1H), 7.34-7.45 (m, 1H), 7.15-7.23 (m, 2H), 5.46 (s, 2H), 4.43 (q, J = 7.04 Hz, 2H), 2.56 (s, 3H), 1.37 (t, J = 7.04 Hz, 3H); [M+H] = 332.4.

Example 396 3-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (d, J = 4.70 Hz, 1H), 8.19 (d, J = 2.35 Hz, 1H), 7.61 (d, J = 2.35 Hz, 1H), 7.50 (t, J = 73.60 Hz, 1H), 7.25 (dd, J = 1.37, 5.28 Hz, 1H), 7.09 (d , J = 0.78 Hz, 1H), 5.47 (s, 2H), 4.46 (k, J = 7.04 Hz, 2H), 2.57 (s, 3H), 1.39 (t , J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12 (d, J = 2.74 Hz, 1H), 7.53 (d, J = 2.74 Hz, 1H), 7.41-7.46 (m, 1H), 7.37 (dd, J = 2.15, 10.37 Hz, 1H), 7.19-7.24 (m, 1H), 5.46 (s, 2H), 4, 44 (q, J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (d, J = 2.35 Hz, 1H), 7.57 (dd, J = 2.35, 7.04 Hz, 1H), 7.51 (d, J = 2.35 Hz, 1H), 7.37 (ddd, J = 2.15, 4.50, 8.61 Hz, 1H), 7.18 (t, J = 8.61 Hz, 1H), 5.46 (s, 2H), 4.43 (k, J = 7.04 Hz, 2H), 2.56 (s, 3H), 1.37 (t, J = 7.04 Hz, 3H); [M+H] = 348.36.

Example 399 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12 (d, J = 2.3 Hz, 1H), 7.55 (d, J = 2.3 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.37 (s, 1H), 7.34 - 7.30 (m, 1H), 7.13 (dd, J = 2.2, 8.0 Hz, 1H), 6, 55 (t, J = 73.6 Hz, 1H), 5.47 (s, 2H), 4.43 (k, J = 7.0 Hz, 2H), 2.56 (s, 3H), 1, 38 (t, J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.18 (d, J = 5.1 Hz, 1H), 8.15 (s, 1H), 7.58 (br s, 1H), 7.03 ( d, J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (d, J = 2.3 Hz, 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.08 - 7.04 (m, 2H), 6.93 - 6.89 (m, 1H), 5.46 (s, 2H), 4.43 (k, J = 7.0 Hz, 2H), 4.07 (k, J = 7.0 Hz, 2H), 2.55 (s, 3H), 1.44 (t, J = 6.8 Hz, 3H) , 1.38 (t, J = 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (d, J = 2.3 Hz, 1H), 7.54 (d, J = 2.3 Hz, 1H), 6.88 - 6.80 (m, 2H), 6.63 (td, J = 2.3, 10.6 Hz, 1H), 5.46 (s, 2H), 4.44 (k, J = 7.0 Hz, 2H) , 3.83 (s, 3H), 2.56 (s, 3H), 1.38 (t, J = 7.0 Hz, 3H);

Example 403 3-(3-Chlorophenyl)-5-{[4-(difluoromethyl)-2-methyl-1H-imidazol-1-yl]methyl}-2-ethoxypyrazine

The title compound was prepared analogously to Example 297 with appropriate changes in starting materials and reagents. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.10 (s, 3H), 7.42 (d, J= 1.2 Hz, 3H), 6.77-6.48 (m, 1H), 5.31 (s, 2H), 4.51 (d, J = 7.0 Hz, 2H), 2.48 (s, 3H), 1.44 (s, 3H); [M+H] = 379.

Examples 404-405 were prepared analogously to Example 299 with appropriate changes in starting materials and reagents.

Example 404 (5-{[6-(2,2-Difluoroethoxy)-5-(2-ethoxypyridin-4-yl)pyridin-3-yl]methyl}-3-fluoropyridin-2-yl)methanol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.38 (t, J = 1.76 Hz, 1H), 8.12 - 8.26 (m, 2H), 7.92 (d, J = 2.35 Hz, 1H), 7.65 (dd, J = 10.76, 1.76 Hz, 1H), 7.17 (dd, J = 5.48, 1.57 Hz, 1H), 6, 99 (dd, J = 1.57, 0.78 Hz, 1H), 5.19 (t, J = 5.87 Hz, 1H), 4.45 - 4.66 (m, 4H), 4.31 (k, J = 7.04 Hz, 2H), 4.01 (s, 2H), 1.31 (t, J = 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

¹ H NMR (400 MHz, CD ₃ OD) δ 8.34-8.29 (m, 1H), 8.23-8.19 (m, 1H), 8.13-8.10 (m, 1H) , 7.73 (d, J = 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

The title compound was prepared analogously to Intermediate 35 with appropriate changes in starting materials and reagents. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.09 (d, J = 2.35 Hz, 1H), 7.80 (d, J = 1.96 Hz, 1H), 7.64 (dt , J = 2.45, 0.93 Hz, 1H), 7.37 - 7.59 (m, 3H), 6.97 (s, 1H), 6.36 (t, J = 3.52 Hz, 1H), 5.08 (s, 2H), 4.52 - 4.74 (m, 3H), 4.22 (dd, J = 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

The title compound was prepared analogously to Intermediate 10 using Intermediate 36. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.11 (s, 2H), 7.68 (d, J = 2.3 Hz, 1H ), 7.27 - 7.22 (m, 1H), 7.10 (d, J = 11.0 Hz, 2H), 5.20 - 5.16 (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H); [M+H] = 330.

PHARMACOLOGICAL EXAMPLES

The present invention is further illustrated by the following pharmacological examples. These examples are to be understood as illustrative only and are not intended to limit the scope of the invention described herein.

Enzymatic analysis

An IMAP TR-FRET based PDE assay was developed using the PDE4D3 isoform. The IMAP technology is based on the high affinity binding of phosphate by immobilized metal (MIII) coordination complexes on nanoparticles. The "linking reagent" IMAP recognizes phosphate groups on AMP or GMP formed from cAMP or cGMP in a PDE reaction. Cyclic nucleotides that have a phosphodiester bond and are not free phosphate are not recognized by the binding reagent. The possibility of time-resolved fluorescence resonance energy transfer (TR-FRET) is provided by donor terbium (Tb) pre-bound to nanoparticles. FRET occurs when an AMP or GMP fluorescently labeled PDE reaction product approaches the Tb donor complex. Due to the continuous Tb fluorescence, detection can be performed in time-resolved mode to avoid interference with autofluorescent compounds.

The IMAP TR-FRET PDE4D3 FAM-cAMP assay was performed in 1536-well white plates with 15 pg per well of GST-labeled PDE4D3 in 2.5 µl of IMAP assay buffer consisting of 10 mM Tris pH 7.2, 10 mM MgCl ₂ . 1 mM DTT, 0.1% free fatty acid free BSA, and 0.01% Tween-20. 30 nl of the compound was then added from a 1 mM stock solution in DMSO using 1536 10 nl Kalypsys pipettes. The plates were incubated for 5 minutes at room temperature, then 1.5 μl of a 533 nM FAM-cAMP solution was added to a final concentration of 200 nM. After rapid centrifugation, the plates were incubated for 30 minutes at room temperature. The assay was terminated by adding 5 µl of IMAP Tb Complex Binding Reagent, prepared according to the manufacturer's recommendations, to each well. The plates were incubated for an additional 90 minutes at room temperature and read on a Viewlux plate reader. Compounds were dissolved at 10 mM in DMSO and tested in an 11-point dose-dependent PDE4D3 assay.

Pharmacological Example 1

PDE4 inhibition

Exemplary compounds of the present invention were tested in a PDE4 enzymatic assay. Typically, the compounds of the present invention exhibit PDE4 inhibitory properties at a concentration of 0.1 to 10 μM, typically 5-100%.

As shown in the following table, these inhibitory properties are reflected by pEC ₅₀ values ranging from less than 5 (10 ^-5 M or 10 μM) to greater than 7 (10 ^-7 M or 0.1 μM).

_pEC50PD4d3 Example numbers > 7 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, 2 31, 244 250 253 257 258 259 260 261 269 271 272 278 279 280 281 287 288 290 291 293 294 296 298 299 3 01, 303, 306, 309, 312, 325, 326, 327, 336, 337, 340, 348, 349, 350, 352, 353, 358, 359, 360, 362, 363, 364, 365, 368, 369, 3 71, 372, 375, 376, 377, 380, 391, 392, 393, 394, 395, 396, 398, 399, 404, 405, 406, Intermediate 49, 6-7 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, 1 78, 179 187 188 190 199 206 207 210 211 212 213 215 217 218 219 220 221 222 223 226 230 232 233 237 2 38, 242, 243, 247, 248, 249, 251, 252, 256, 262, 263, 264, 265, 266, 268, 273, 274, 275, 282, 283, 285, 289, 297, 300, 304, 3 05, 308, 310, 311, 313, 314, 315, 316, 317, 319, 321, 322, 324, 328, 330, 331, 333, 334, 338, 341, 342, 344, 345, 346, 347, 3 51, 354 355 356 357 361 366 367 370 373 374 378 379 381 383 385 388 389 390 397 400 401 402 403 Intermediate 5 0, 5-6 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, 2 14, 224, 227, 234, 236, 239, 240, 241, 245, 254, 255, 270, 276, 284, 292, 295, 302, 307, 318, 323, 329, 332, 335, 339, 343, 3 82, 384, 386, 387, 407, < 5 4, 6, 9, 10, 11, 22, 140, 174, 235, 246, 267, 277, 286, 320.

BIOLOGICAL EXAMPLES

The present invention is further illustrated by the following biological examples. These examples are to be understood as illustrative only and are not intended to limit the scope of the invention described herein.

Behavioral analyzes

A variety of behavioral assays exist to assess the ability of a potential compound to improve memory formation, including contextual conditioning (eg, fear conditioning), temporal conditioning (eg, trace conditioning), and object recognition. Other non-limiting examples of suitable assays for assessing memory include assays that involve or are related to multiple training sessions, separate training sessions, contextual freezing learning with one or more experiments, trace conditioning of freezing with one or more experiments, contextual memory in general, temporal memory, spatial memory, episodic memory, passive avoidance memory, active avoidance memory, food preference memory, taste avoidance, and social recognition memory.

Behavioral assays may also be used in accordance with the present invention, as will be appreciated by those skilled in the art. These assays are aimed at assessing, without limitation, hippocampal, cortical and/or amygdala dependent memory formation or cognitive characteristics.

Biological example 1

Effects of PDE4 Inhibitors on Contextual Memory

Rationale

Contextual conditioning in connection with the experience of fear is a form of associative learning in which animals learn to recognize a learning condition (conditioned stimulus, CS) that was previously accompanied by a negative stimulus, such as an electric pain stimulation of the paws (unconditioned stimulus, US). Later, under the same conditions, the accustomed animals demonstrate various conditioned fearful reactions, including freezing. The percentage of time during the experiment that the animal exhibits this freezing provides a quantitative measure of contextual associative memory (e.g., Fanselow, Behav. Neurosci . 1984 , 98 , 269-277; Fanselow, Behav. Neurosci. 1984, 98 , 79-95 and Phillips and LeDoux, Behav Neurosci 1992, 106 , 274-285).

Contextual conditioning has been widely used to investigate the neural substrates mediating fear-motivated learning (e.g., Phillips and LeDoux, Behav. Neurosci . 1992, 106 , 274-285; Kim et al ., Behav. Neurosci . 1993, 107 , 1093-1098; and Bourtchouladze et al., Learn Mem 1998, 5 , 365-374). Studies in mice and rats have provided data on the functional interaction between the hippocampal and non-hippocampal systems in contextually conditioned learning (e.g., Maren et al ., Behav. Brain Res. 1997, 88 , 261-274; Maren et al ., Neurobiol. Learn. Mem 1997, 67 , 142-149 and Frankland et al , Behav Neurosci 1998, 112 , 863-874). In particular, damage to the hippocampus after learning (but not before learning) significantly reduces contextual fear, suggesting that: 1) the hippocampus is required for contextual memory but not for contextual learning per se, and 2) when learning in the absence of the hippocampus, contextual conditioning may support non-hippocampal systems.

Contextual conditioning has been widely used to study the effect of various mutations on hippocampal-dependent learning as well as species and genetic differences in mice (e.g., Bourtchouladze et al ., Cell 1994, 79 , 59-68; Bourtchouladze et al ., Learn Mem. 1998 , 5 , 365-374; Kogan et al ., Current Biology 1997, 7 , 1-11; Silva et al ., Current Biology 1996, 6 , 1509-1518; Abel et al ., Cell 1997, 88 , 615-626 ; Giese et al ., Science 1998, 279 , 870-873; Logue et al ., Neuroscience 1997, 80 , 1075-1086; Chen et al ., Behav. Neurosci. 1996, 110 , 1177-1180; and Nguyen et al. ., Learn Mem. 2000, 7 , 170-179).

Because robust learning can be initiated within minutes of a training session, contextual conditioning is particularly suited to the study of the biology of the time-different processes of short-term and long-term memory (e.g., Kim et al ., Behav. Neurosci. 1993, 107 , 1093-1098; Bourtchouladze et al ., Cell 1994, 79 , 59-68; Abel et al ., Cell 1997, 88 , 615-626; Logue et al., Behav. Neurosci 1997, 111 , 104-113; Bourtchouladze et al ., Learn Mem 1998, 5 , 365-374 and Nguyen et al., Learn Mem 2000, 7 , 170-179). Therefore, contextual conditioning provides an excellent model for evaluating the effect of novel drug compounds on hippocampal-dependent memory formation.

Ways

Previous studies have found that 1× or 2× CS-US training induces submaximal (poor) memory in wild-type mice (e.g., US2009/0053140; Tully et al. , Nat. Rev. Drug Discov . 2003, 2 , 267-77 and Bourtchouladze et al Learn Mem 1998, 5 , 365-374). Accordingly, contextual conditioning in this study was performed as described by Bourtchouladze et al. , Cell 1994, 79 , 59-68.

Young (10-12 weeks old) male C57BL/6 mice and male Sprague-Dawley rats were used. Mice and rats were housed in groups under standard laboratory conditions and maintained on a 12:12 light-dark cycle. The experiments were always performed during the light phase of the cycle. Except during testing, mice were given ad libidum access to food and water. Contextual memory was assessed using a modified contextual fear conditioning task originally developed to assess memory in CREB knockout mice (Bourtchouladze et al., 1994). Training sessions consisted of a base period in an acclimatization cage (Med Associates, Inc.) followed by the introduction of unconditioned stimuli (1-5 electric pain stimulations of the paws at 0.2-1.0 mA for 2 s) at intervals of 60 s. Thirty seconds after the last shock, the animals were returned to their cage. After 7 days, the animals were returned to the experimental chamber and freezing was assessed. Freezing (complete immobility except for breathing) was assessed using Video Freeze software (Med Associates, Inc.) during the 8 minute experiment. The introduction of cognitive enhancers presumably significantly increases freezing compared to control animals.

All experiments were designed and performed in a balanced manner. In each experiment, the experimenter was unaware (was "blind") about the treatment of subjects during training and testing. The training and testing sessions were recorded as digital video files. The data was analyzed by one-way ANOVA, post-analysis using GraphPad Prism software.

results

Exemplary compounds have been found to improve contextual memory in a fear conditioning assay. Significant reinforcing effects were observed 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

Novel Object Recognition (NOR) is an analysis of recognition learning and memory retrieval, and uses the rodent self-preference to explore a new object rather than a familiar one. This is an ethologically relevant task that, unlike fear conditioning, does not occur as a result of a negative stimulus (electric pain stimulation of the paws) (eg, Ennaceur and Delacour, Behav. Brain Res . 1988, 31 , 47-59).

The NOR assay is widely used to evaluate the potential cognitive-enhancing properties of novel compounds obtained after high-throughput screening. The object recognition task is based on the natural curiosity of rodents to explore new objects in their environment more than familiar things. It is obvious that the "familiar" object must have attracted the animal's attention earlier, and the animal remembers this experience. Therefore, animals with better memories will notice and explore a new item more than a familiar item. During the test, the animal is presented with the subject of training and the second, new subject. The memory of the learning subject ensures that the animal is familiar with the subject, and therefore the animal spends more time exploring a new subject rather than a familiar one (Bourtchouladze et. al ., Proc. Natl. Acad. Sci. USA 2003, 100 , 10518-10522) .

Neuroimaging, pharmacological, and injury studies demonstrate that the hippocampus and adjacent paranasal cortex are required for object recognition memory in rodents, monkeys, and humans (e.g., Mitchell, Behav. Brain Res. 1998, 97 , 107-113; Teng et al., J Neurosci 2000, 20 , 3853-3863; Mumby, Brain Res . 2001, 127 , 159-181; Eichenbaum et al., Annu. Rev. Neurosci 2007, 30 , 127-152; Squire et al., Nat. Rev Neurosci 2007 8 872-883 and Vann and Alabasser Curr Opin Neurobiol 2011 21 440-445) . Therefore, object recognition provides an excellent behavioral model for evaluating the effects of drugs on cognitive tasks related to hippocampal and cortical function.

Ways

Object recognition was tested on young mice and rats using the following procedure. Animals were briefly kept in the experimental cage for 2-5 days prior to training. Each compound was administered at a specific time, from 15 minutes to 24 hours, before or after training. To familiarize the animal with the place, habituation sessions were performed (lasting 1-20 minutes for 1-3 days). During training trials (lasting 1-20 minutes), animals were given the opportunity to examine two identical items. Then, after 1-96 hours, an experimental test (duration 1-20 minutes) was performed.

To recognize a new object, one of the objects was replaced with a new object. All combinations and positions of objects were used in a balanced manner to reduce possible bias due to preference for certain positions or objects. Educational and experimental trials were recorded and evaluated using video recording software (eg Noldus Ethovision). Animals were rated as investigating an object if its head was oriented towards the object at a distance of 1 cm (rat)/2 cm (mouse) or if its nose touched the object. Walking around, climbing, or sitting on an object was not considered research. If an animal develops a long-term memory of a familiar item, it spends significantly more time exploring the new item than the familiar item during a memory retention test (therefore, cognitive enhancers might presumably facilitate this separation between familiar and new item).

The separation factor was calculated as described previously (Bourtchouladze et al., Proc. Natl. Acad. Sci. USA 2003, 100, 10518-10522). In each experiment, the experimenter was unaware (was "blind") about the treatment of subjects during training and testing. The data was analyzed by one-way ANOVA, post-analysis using GraphPad Prism software.

results

The exemplary compounds of Formula (I) have been found to significantly enhance 24 hour memory. Significant effects were observed at several concentrations including 1.0 mg/kg and 3 mg/kg.

The present description, including examples, is for illustrative purposes only, and those skilled in the art will appreciate that various modifications and variations may be made in accordance with the present invention without departing from the scope or general idea of the present invention as defined by the appended claims.

In addition, although certain details are provided in the present description to facilitate a thorough understanding of the present invention as defined by the appended claims, those skilled in the art will appreciate that certain embodiments may be practiced without such details. In addition, in some cases, certain well-known methods, techniques, or other specific details have not been described in order to avoid unduly obscure aspects of the present invention as defined by the appended claims.

Claims (123)

1. Pharmaceutical composition for the treatment of a disease, disorder or medical condition mediated by the PDE4 enzyme or PDE4 enzymatic activity, containing an effective amount of a compound of Formula (I): , or a pharmaceutically acceptable salt thereof, Where Z is CH or N; i) where if Z is CH, then R ¹ is selected from the group consisting of: -H and -C _1-3 alkyl; Y is -C(R ^a ) ₂ - where each R ^a is independently selected from the group consisting of: -H, -F, -CH ₃ , -OH and -N(R ^b ) ₂ ; R ² is selected from the group consisting of: A) phenyl, unsubstituted or substituted with one R ^c substituent, where R ^c is selected from the group consisting of: halogen, -CN, -CO ₂ R ^b , -CONH ₂ , -SO ₂ CH _3, -C(R ^b ) ₂ OH, -CH ₂ NH ₂ , -CH ₂ CONH ₂ , -CH ₂ CO ₂ C ₁ - ₃ alkyl, -NHCONH ₂ , -NHCONH-oxetane, -CONH-oxetane, B) a six-membered monocyclic heteroaromatic ring containing one or two nitrogen atoms, unsubstituted or substituted with one or two substituents, each independently selected from the group consisting of: halo, -C _1-3 alkyl, -C _1-3 haloalkyl, - CN, -OH, -C(R ^b ) ₂ OH, -CH ₂ NH ₂ , -C(R ^b ) ₂ CN, -C(R ^b ) ₂ CONH ₂ , -OCH ₂ CONH ₂ , -OC _1-3 alkyl, -OCH ₂ C(R ^b ) ₂ OH, -OCH ₂ cyclopropyl, -OC _1-3 haloalkyl, -CO ₂ H, -CON(R ^b ) ₂ , -N(R ^b ) ₂ , -NHCH ₂ CF ₃ , -NHCH(CH ₃ ) ₂ , -NHCH ₂ CH ₂ N(CH ₃ ) ₂ , -NHCH ₂ CH ₂ OH, -NHcyclopropyl, -NHCOCH ₃ , morpholinyl, pyrrolidin-3-ol and azetidin-3-ol; C) a five-membered monocyclic heteroaromatic ring containing two, three or four nitrogen atoms, unsubstituted or substituted with one or two substituents, each independently selected from the group consisting of halogen, -C _1-3 alkyl, -C _1-3 haloalkyl, -C(R ^b ) ₂ OH, -N(R ^b ) ₂ , -NO ₂ , -CN, -CH ₂ CN, -OC _1-3 alkyl, -CH ₂ OCH _3, -CH ₂ CH ₂ OH, - CH ₂ NH ₂ , -CH ₂ CONH ₂ , -CO ₂ C _1-3 alkyl, -CO ₂ H, -CONH ₂ , -NHCOCH ₃ and cyclopropyl; And D) a five- or six-membered ring selected from: 1,2-dihydropyridin-2-one, thiazole or 1,2-oxazole, unsubstituted or substituted with one or two substituents, each independently selected from the group consisting of -CH ₃ and -NH ₂ ; R ³ is phenyl or pyridine each substituted with one or two substituents each independently selected from the group consisting of: halo, -C _1-3 alkyl, -OC _1-3 alkyl, -O cyclopropyl, -O -oxetane, -C _{1 -3} haloalkyl, -OC _{1 -3} haloalkyl, -CN, -CH ₂ OH, -SO ₂ CH ₃ and -N(CH ₃ ) ₂ ; R ⁴ is selected from the group consisting of -C _1-3 alkyl and -C _1-3 haloalkyl; And each R ^b is -H or -CH ₃ ; ii) where if Z is N then: R ¹ is -H; Y is -CH ₂ -; R ² is selected from the group consisting of: A) phenyl substituted with one R ^d substituent, where R ^d is selected from the group consisting of: -CN, -CONH ₂ and -CO ₂ C _1-3 alkyl; B) a six-membered monocyclic heteroaromatic ring containing one or two nitrogen atoms, unsubstituted or substituted with a substituent selected from the group consisting of: -CN, -OC _1-3 alkyl, -CONH ₂ , -NHCH ₂ CH ₂ OH, -N( R ^b ) ₂ and -NH-cyclopropyl; C) a five-membered monocyclic heteroaromatic ring containing two or three nitrogen atoms, unsubstituted or substituted with one or two substituents, 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 D) 1,2-oxazole optionally substituted with one or two R ^b substituents; R ³ is phenyl substituted with one substituent selected from the group consisting of: -Cl, -OC _1-3 alkyl or -OC ₁ - ₃ haloalkyl; R ⁴ is -C _1-3 alkyl; And each R ^b is independently selected from -H or -CH ₃ ; and a pharmaceutically acceptable excipient. 2 . The composition of claim 1, wherein the compound of Formula (I) is selected from the group consisting of: 5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile; 2-Chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine; {2-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethyl}dimethylamine; 2-Methoxy-3-(6-methoxypyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 2-Methoxy-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 2-Methoxy-3-(5-methylpyridin-3-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 2-Methoxy-3-(2-methylpyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; {3-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]phenyl}methanol; 3-(3-Methanesulfonylphenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 2-Methoxy-3-(4-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; And 2-Methoxy-3-(6-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine. 3 . The composition of claim 1, wherein the compound of Formula (I) is selected from the group consisting of: 2-(Difluoromethoxy)-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide; [5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol; 1-[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]-1-(4-fluorophenyl)ethan-1-ol; [5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](5-fluoropyridin-2-yl)methanol; {[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}(methyl)amine; [5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanamine; {[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}dimethylamine; 3-(3-Chlorophenyl)-5-[fluoro(4-fluorophenyl)methyl]-2-methoxypyridine; And 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzoic acid. 4 . The composition of claim 1, wherein the compound of Formula (I) is selected from the group consisting of: 5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile; 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxylic acid; 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide; 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; (4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)urea; 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzamide; 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-pyrazol-4-ylmethyl)pyridine; 5-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine; 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine; And 1-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)-3-(oxetan-3-yl)urea. 5 . The composition of claim 1, wherein the compound of Formula (I) is selected from the group consisting of: 3-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxypyridin-3-yl)methyl]pyridine; 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-amine; 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyridin-2-amine; 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carbonitrile; 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1,3-thiazol-2-amine; (2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanol; 5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; 5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carbonitrile; 5-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine; And 5-{[5-(3-Chlorophenyl)-6-(propan-2-yloxy)pyridin-3-yl]methyl}pyrimidin-2-amine. 6 . The composition of claim 1, wherein the compound of Formula (I) is selected from the group consisting of: 5-{[6-(Difluoromethoxy)-5-[3-(propan-2-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine; 5-{[6-(Difluoromethoxy)-5-[3-(oxetan-3-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine; N-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide; 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methanesulfonylphenyl)methyl]pyridine; 5-{[6-(Difluoromethoxy)-5-(2-methoxypyridin-4-yl)pyridin-3-yl]methyl}pyrimidin-2-amine; 5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-amine; 2-[5-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-yl]propan-2-ol; 3-(3-Chlorophenyl)-2-methoxy-5-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyridine; 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[6-(propan-2-yloxy)pyridin-3-yl]methyl}pyridine; And 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-propoxypyridin-3-yl)methyl]pyridine. 7 . The composition of claim 1, wherein the compound of Formula (I) is selected from the group consisting of: 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1-methyl-1,2-dihydropyridin-2-one; 3-(3-Chlorophenyl)-2-methoxy-5-(pyridin-4-ylmethyl)pyridine; 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxylic acid; 3-(3-Chlorophenyl)-2-methoxy-5-[(2-methoxypyrimidin-5-yl)methyl]pyrazine; 5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-methylpyrimidin-2-amine; 5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-cyclopropylpyrimidin-2-amine; 3-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyrazine; (4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanamine; 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine; 3-(3-Chlorophenyl)-5-[(2,6-dimethylpyridin-4-yl)methyl]-2-methoxypyridine; And 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carbonitrile. 8 . The composition of claim 1, wherein the compound of Formula (I) is selected from the group consisting of: 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzoic acid; 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzamide; (4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)urea; 1-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)-3-(oxetan-3-yl)urea; And (4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanamine. 9 . The composition of claim 1, wherein the compound of Formula (I) is selected from the group consisting of: 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; (4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)urea; 5-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine; 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide; And 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxylic acid. 10 . The composition of claim 1, wherein the compound of Formula (I) is: 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine. 11 . The composition of claim 1, wherein the compound of Formula (I) is: (4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)urea. 12 . The composition of claim 1, wherein the compound of Formula (I) is: 5-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine. 13 . The composition of claim 1, wherein the compound of Formula (I) is: 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide. 14 . The composition of claim 1, wherein the compound of Formula (I) is: 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxylic acid. 15 . The composition of claim 1, wherein the compound of Formula (I) is: (4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanamine. 16. A method of treating 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 composition according to any one of paragraphs. 1-15. 17 . A method of treating a disease, disorder, or medical condition mediated by the PDE4 enzyme, comprising administering to a subject in need of such treatment an effective amount of a composition according to any one of paragraphs. 1-15. 18.The use of a composition according to any one of paragraphs. 1-15 in a method of treating a neurological disorder selected from the group consisting of a central nervous system (CNS) disorder, a psychiatric disorder, a personality disorder, a substance use disorder, a dissociative disorder, an eating disorder, a sleep disorder, a developmental disorder, a neurodegenerative disorder, a traumatic disorder, pain disorder, and cognitive disorder, comprising administering to a subject in need of such treatment an effective amount of said composition. 19. The use of a composition according to any one of paragraphs. 1-15 in a method of treating a peripheral disorder, selected from the group consisting of inflammatory bowel disease; rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis, pulmonary arterial hypertension; kidney disease; allergic skin diseases and psoriasis, comprising administering to a subject in need of such treatment, an effective amount of a composition according to any one of paragraphs. 1-15.