Oxadiazole selective histone deacetylase 6 inhibitors

Abstract

Formula (I) compounds are selective inhibitors of histone deacetylase 6 (HDAC6) for treating, for example, peripheral neuropathy, graft rejection, GVHD, myositis, diseases associated with lymphocyte dysfunction, multiple myeloma, non-Hodgkin's lymphoma, autoimmune diseases, inflammatory diseases, cancer and neurodegenerative diseases. Preferred compounds are, for example, 2-(4-((5-(benzo[b]thiophene-3-yl)-1H-tetrazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole derivatives and related compounds.

Description

Technical Field

[0001] The present invention relates to novel selective oxadiazole inhibitors of histone deacetylase 6 (HDAC6) with a pentaheterocyclic scaffold and pharmaceutical compositions thereof.

[0002] Therefore, these compounds are useful in treating diseases associated with HDAC6 activity, such as peripheral neuropathy, transplant rejection, GVHD, myositis, diseases associated with abnormal lymphocyte function, multiple myeloma, non-Hodgkin lymphoma, autoimmune diseases, inflammatory diseases, cancer, and neurodegenerative pathology. Background Art

[0003] The genetic material of eukaryotic cells is organized into chromatin, a complex and dynamic structure composed of DNA and proteins. The major protein components of chromatin are histones, basic proteins that interact with DNA to form the basic structural unit of chromatin (nucleosomes), the first level of chromosome compaction within the cell nucleus. The interaction between basic histone residues and acidic DNA residues is crucial for determining nucleosome compaction and the accessibility of the associated DNA to the molecular complexes that regulate replication and transcription. This interaction is primarily influenced by the degree of histone acetylation. Deacetylation of histone N-terminal lysine residues protonates the positively charged amine groups, which interact with the negative charges contained in DNA. This interaction occurs in a more compact state of chromatin and is involved in silencing gene expression. Conversely, acetylation of the same residues prevents ionic bond formation, resulting in a less compact form of chromatin that allows for greater DNA exposure and interaction with the macromolecular complexes that activate gene transcription.

[0004] The degree of histone acetylation is regulated by the balance of activity of two classes of enzymes: histone acetyl-transferases (HATs) and histone deacetylases (HDACs). Alterations in this delicate balance can lead to a loss of cellular homeostasis and are common in various human diseases, including cancer, neurological disorders, inflammation, and autoimmune diseases.

[0005] Histone deacetylases are classified as such because they reversibly catalyze the deacetylation of the amino group of the N-terminal lysine residues of histones. Subsequently, a large number of substrates for these enzymes have been discovered because their activity is also due to non-histone proteins that are substrates for HAT enzymes containing N-acetyl-lysine, such as transcription factors, DNA repair enzymes and other nuclear and cytoplasmic proteins.

[0006] The human HDAC class consists of 18 enzymes divided into two groups: zinc-dependent HDACs and NAD-dependent HDACs (also known as sirtuins (class III)). Zinc-dependent HDACs are further divided into four categories: 1) Class I, including HDAC1, 2, 3, and 8, ubiquitous isozymes located primarily in the nucleus; 2) Class IIa, including HDAC4, 5, 7, and 9, isozymes located in both the nucleus and cytoplasm; 3) Class IIb, including HDAC6 and HDAC10, located primarily in the cytoplasm; and 4) Class IV, including only HDAC11. Unlike class I HDACs, classes IIa and IIb have tissue-specific expression.

[0007] These enzymes participate in numerous cellular functions by regulating gene expression and acting on histones and transcription factors. In addition, by acting on many other protein substrates, these enzymes, as well as phosphatases, participate in many other processes, such as signal transduction and cytoskeletal rearrangement.

[0008] In recent decades, HDACs have become an extensively studied therapeutic target. Several HDAC inhibitors have been synthesized, some of which are currently in advanced clinical trials, and four of them have been approved for different types of cancer: vorinostat and romidepsin for cutaneous T-cell lymphoma (CTLC), belinostat for pericytic T-cell lymphoma (PTLC), and panobinostat for multiple myeloma. These inhibitors interact with different HDAC isoforms.

[0009] Regardless of their clinical efficacy, the use of pan-inhibitors is limited by their toxicity and side effects observed in preclinical models and, most importantly, clinical trials, due to their non-selectivity for a single isoform. Therefore, there is a need to develop HDAC inhibitors with better pharmacological profiles and therapeutic windows (efficacy / toxicity ratio).

[0010] As such, scientific attention has focused on the synthesis and development of selective inhibitors of individual HDAC isoforms, with the goal of developing molecules with improved pharmacological capabilities.

[0011] Therefore, the use of HDAC inhibitors may be an important therapeutic or diagnostic tool for pathologies caused by gene expression, such as inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukemia (APL), organ transplant rejection, autoimmune diseases, protozoal infections, cancer, etc. In addition, alterations in HDAC activity are also associated with chemotherapy-induced peripheral neuropathy (CIPN) and Charcot-Marie-Tooth disease (CMT), the most common hereditary peripheral neuropathy. Selective inhibitors of the HDAC family or specific isoforms, particularly HDAC6, may be particularly useful in treating disorders associated with proliferative disorders and protein accumulation, immune system disorders, and neurological and neurodegenerative diseases such as stroke, Huntington's disease, Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, CIPN, and CMT.

[0012] In particular, for HDAC6, different substrates have been identified, such as α-tubulin, Hsp90 (heat shock protein 90), cortactin, and β-catenin. The regulation of acetylation of these proteins by HDAC6 has been associated with several important processes, such as immune response (Kozikowski, J. Med. Chem. (2012), 55, 639-651; Mol. Cell. Biol. (2011), 31 (10), 2066-2078), regulation of microtubule dynamics including cell migration and cell-cell interactions (Aldana-Masangkay et al., J. Biomed. Biotechnol. (2011), 2011, 875824), axonal transport and axon regeneration (Rossaert and Van Den Bosch, Brain Research, 2020, 1733, 146692).

[0013] In addition, HDAC6 participates in the catabolic process of degrading proteins through a complex called aggresome: HDAC6 can bind to polyubiquitinated proteins and dynein, thereby activating a transport of denatured proteins along microtubules to the aggresome (Kawaguchi et al., Cell (2003) 115(6), 727-738).

[0014] Alterations in this HDAC6 cytoprotective activity have been associated with various neurodegenerative disorders, such as Parkinson's disease (Outerio et al., Science (2007), 317(5837), 516-519) and Huntington's disease (Dompierre et al., J. Neurosci. (2007), 27(13), 3571-3583), in which accumulation of degraded proteins is a common pathological feature.

[0015] The involvement of HDAC6 in microtubule dynamics and elimination of misfolded proteins has been associated with axonal transport defects, commonly observed in genetically derived and chemotherapy-induced peripheral neuropathies (Krukowski et al., Pain, 2017, 158(6), 1126-1137).

[0016] In addition, HDAC6 is involved in regulating many oncogenic proteins, particularly in hematological tumors, such as various types of leukemia (Fiskus et al., Blood (2008), 112 (7), 2896-2905) and multiple myeloma (Hideshima et al., Proc. Natl. Acad. Sci. USA (2005), 102 (24), 8567-8572). HDAC6 regulation of α-tubulin acetylation may be involved in metastasis, in which cell motility plays an important role (Sakamoto et al., J. Biomed. Biotechnol. (2011), 2011, 875-824).

[0017] Over the past decade, several selective HDAC6 inhibitors have been synthesized and studied. Some of these are still in active preclinical development, and two of them, ricolinostat and citarinostat, are currently in clinical studies.

[0018] Most selective HDAC6 inhibitors belong to the hydroxamate family. The hydroxamate group has the important function of binding Zn++ ions at the enzyme's active site. However, some degree of toxicity and genotoxicity has been associated with this moiety, likely due to its nonspecific metal binding ability and its tendency to release hydroxylamine (Kozikowski, ChemMedChem. 2016 Jan;11(1):15-21).

[0019] Therefore, the discovery of a new class of selective HDAC6 inhibitors could be useful in treating all of the above-mentioned disorders and diseases, especially when the treatment is long-term. Summary of the Invention

[0020] Several international patent applications (WO2020158762, WO2019027054, WO2017018803, WO2017065473, and WO2017023133) have disclosed 2-(difluoromethyl)-1,3,4-oxadiazole as an intrinsic HDAC6-selective zinc-binding group (ZBG). Surprisingly, for the class of inhibitors described in WO2018189340, replacing the hydroxamic acid moiety with a difluoromethyloxadiazole moiety was not sufficient to achieve good HDAC6 inhibition.

[0021] WO2020212479 discloses oxadiazole compounds suitable as HDAC6 inhibitors, their preparation methods, and their medical uses in treating HDAC6-related diseases or disorders.

[0022] The present inventors have synthesized a large number of compounds in order to identify the correct five-membered heterocyclic skeleton and the right combination of substitutions to ensure potency against HDAC6 as well as selectivity over other isoforms and metabolic stability.

[0023] In fact, relative to hydroxamate analogs, some subclasses, such as 1,2,4-triazoles and 1,5-disubstituted tetrazoles, require very careful exploration to achieve the desired potency.

[0024] The present invention discloses a novel oxadiazole series of metabolically stable, potent and selective non-hydroxamate HDAC6 inhibitors with a five-membered heterocyclic skeleton.

[0025] [definition]

[0026] Unless otherwise defined, all technical terms, symbols and other scientific terms used herein are intended to have the meanings commonly understood by those of ordinary skill in the art to which this disclosure belongs. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ease of reference; therefore, the inclusion of such definitions herein should not be construed as indicating a substantial difference from what is generally understood in the art.

[0027] The term "halogen" as used herein refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0028] The term "C1-C4 alkyl" herein refers to a branched or straight chain hydrocarbon containing 1 to 4 carbon atoms. Examples of C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; preferably, methyl, ethyl, n-propyl, and isopropyl.

[0029] The term "aryl" herein refers to mono- and poly-carbocyclic aromatic ring systems (i), wherein the individual carbocyclic rings in the polycarbocyclic system may be fused or linked to each other by single bonds. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, and biphenyl.

[0030] The term "aryloxy" refers herein to an O-aryl group, wherein "aryl" is as defined above.

[0031] The term "alkoxy" refers herein to an O-alkyl group, wherein "alkyl" is as defined above.

[0032] The term "thioalkoxy" herein refers to an S-alkyl group, wherein "alkyl" is as defined above. Preferred thioalkoxy groups are thioethoxy (-SEt) or thiomethoxy (-SMe), and even more preferably they are thiomethoxy. In a different embodiment, thioalkoxy refers to an alkyl group in which one of the non-terminal hydrocarbon units of the alkyl chain is replaced by a sulfur atom. The term "halogenated" herein refers to a halogen substitution, that is, any of the above-mentioned alkyl, alkoxy, and thioalkoxy groups may be completely or partially substituted with a halogen atom. Preferably, the halogen atom is F or Cl, more preferably it is F. A particularly preferred halogenated substituent is trifluoromethyl (-CF3).

[0033] The term "cycloalkyl" herein refers to a saturated or unsaturated hydrocarbon ring, preferably having 4 to 10 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0034] The term "arylalkyl" refers herein to an aryl group, as defined herein, attached to an alkyl group, as defined herein. An example of an arylalkyl group is benzyl.

[0035] The term "heterocycle" herein refers to a 4-, 5-, 6-, 7-, or 8-membered monocyclic ring that is saturated or unsaturated and consists of carbon atoms and one or more heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heterocycle may be attached to any heteroatom or carbon atom, provided that the attachment results in a stable structure. The term also includes any bicyclic ring system in which any of the above heterocycles is fused to an aryl group or another heterocycle. When the heterocycle is an aromatic heterocycle, it may be defined as a "heteroaromatic ring."

[0036] The term "unsaturated ring" herein refers to a partially or fully unsaturated ring. For example, an unsaturated C6 monocyclic ring refers to cyclohexene, cyclohexadiene, and benzene.

[0037] The term "substituted" herein refers to mono- or poly-substitution with defined (or undefined) substituents, provided that the mono- or poly-substitution is chemically permissible.

[0038] The term "physiologically acceptable excipient" herein refers to a substance that does not have any pharmacological effect by itself and does not produce adverse reactions when administered to a mammal (preferably a human). Physiologically acceptable excipients are well known in the art and are disclosed in, for example, the sixth edition of the Handbook of Pharmaceutical Excipients, 2009, which is incorporated herein by reference.

[0039] The term "pharmaceutically acceptable salts or derivatives thereof" herein refers to those salts or derivatives that have the biological effects and properties of the salified or derived compound and do not produce adverse reactions when administered to a mammal (preferably a human). Pharmaceutically acceptable salts may be inorganic or organic salts; examples of pharmaceutically acceptable salts include, but are not limited to, carbonates, hydrochlorides, hydrobromides, sulfates, bisulfates, citrates, maleates, fumarates, trifluoroacetates, 2-naphthalenesulfonates, and p-toluenesulfonates. Further information on pharmaceutically acceptable salts can be found in Handbook of pharmaceutical salts, P. Stahl, C. Wermuth, WILEY-VCH, 127-133, 2008, incorporated herein by reference. Pharmaceutically acceptable derivatives include esters, ethers, and N-oxides.

[0040] The terms "comprising," "having," "including," and "containing" should be construed as open-ended terms (meaning "including but not limited to") and should be considered support for terms such as "consisting essentially of," "consisting essentially of," "consisting of," or "consisting of."

[0041] The terms "consisting essentially of" and "essentially composed of" should be understood as semi-closed terms, meaning that other ingredients that affect the novel characteristics of the present invention are not included (thus, optional excipients may be included).

[0042] The terms “consisting of” and “composed of” are to be understood as closed terms.

[0043] The term "isomer" refers to stereoisomers (or spatial isomers), ie, diastereomers and enantiomers.

[0044] The term "prodrug" refers to a pharmacologically inactive derivative that undergoes metabolic transformation in vivo to obtain the active compound encompassed by the general formula of the present invention. Many different prodrugs are known in the art (Prodrug approach: an effective solution to overcome side-effects, Patil SJ, Shirote PJ, International Journal of Medical and Pharmaceutical Sciences, 2011, 1-13; Carbamate Prodrug Concept for Hydroxamate HDAC Inhibitors, Jung, Manfred et al., ChemMedChem, 2011, 1193-1198). DETAILED DESCRIPTION

[0045] The inventors of this case have experimentally discovered that this class of novel compounds characterized by the presence of 2-(difluoromethyl)-1,3,4-oxadiazole and a five-membered heterocyclic core exhibits high and selective inhibitory activity against the HDAC6 enzyme. The five-membered heterocyclic core includes 1,2,3-triazole, 1,2,4-triazole, 2,5-disubstituted tetrazole, 1,5-disubstituted tetrazole, imidazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole, 1,4-disubstituted pyrazole, and isoxazole. The five-membered heterocyclic core excludes 1,3-disubstituted pyrazole and has an aryl-CHF2-oxadiazole substituent on the carbon atom and a -LR on the nitrogen atom. 2 Substituents of 1,2,3-triazoles (referring to Formula I, where B=C and M=N) require very careful exploration to obtain good efficacy.

[0046] Regarding this point, only in R 2 Compounds with H-donor groups in the substituents showed HDAC6 IC values ​​below 700 nM. 50 .

[0047] In the above framework, 1,2,3-triazole and 2,5-disubstituted tetrazoles showed good efficacy regardless of the nature of X, X', Y, and Y' of formula (I); however, 1,2,4-triazole and 1,5-disubstituted tetrazoles achieved high inhibition only when the Markush structure of formula (I) was restricted as follows:

[0048] ●For the 1,2,4-triazole skeleton, Y and Y' must be CH, X and X' must independently be CF or CH, Z must be -S-, and R1 must be -CH3;

[0049] For a 1,5-disubstituted tetrazole skeleton, Y and Y' must be CH, and X and X' can independently be CH or N, but not CF.

[0050] The compounds of the present invention show very low cytotoxicity, which makes them suitable for long-term use.

[0051] According to a first aspect, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts, isomers and prodrugs thereof,

[0052]

[0053] in:

[0054] X and X' are independently selected from CH, N, CF or CCl;

[0055] Y and Y' are independently selected from CH, N or CF;

[0056] A=C, N, O, S;

[0057] B=C、N;

[0058] D=C, N, O;

[0059] E=C, N, O;

[0060] M=C,N;

[0061] Z=-CD2-, -CF2-, -CHR 3 -, -NH-, -S-;

[0062] R 3＝ H, C1-C4 alkyl or can be selected from the following substructures:

[0063]

[0064] L = absent, C1-C4 alkyl, -CHPh-, -CH2NHCH2-, or can be selected from the following substructures:

[0065]

[0066] R 4 =H, C1-C4 alkyl;

[0067] R 1 = not present, -H, C1-C4 alkyl, -LR 2 When R 1 =-LR 2 When , the substitution on M does not exist;

[0068] R 2 Selected from:

[0069]

[0070]

[0071]

[0072]

[0073]

[0074] R 5 and R 6 Independently selected from: -H, -D, -OH, -O-C1-C4 alkyl, C1-C4 alkyl, -halogen, -CF3, -NR'R", -NHR 7 、-COOH、-COR 8 , -NO2, -CN, -Ph, -SO2NMe2, -CH2NH2, or can be selected from the following substructures:

[0075]

[0076]

[0077] R 7 =-CH2Ph ​​or can be selected from the following substructures:

[0078]

[0079]

[0080] R 8 =-NR'R", C1-C4 alkyl or can be selected from the following substructures:

[0081]

[0082] wherein R' and R" are independently -H or C1-C4 alkyl;

[0083] The conditions are:

[0084] - When A, D and E = N, B and M = C (ie, when the central heterocycle is 1,2,4-triazole), then Y and Y' = CH; X and X' are independently selected from CH or CF; Z = -S-; R1 = Me;

[0085] - When A = C and B, D, E and M = N (ie, when the central heterocycle is a 1,5-disubstituted tetrazole), then Y and Y' = CH; X and X' are independently selected from CH or N; R1 = -LR2.

[0086] Preferably, when A, D and E = N, B and M = C and when A = C and B, D, E and M = N (ie, when the central heterocycle is a 1,2,4-triazole or a 1,5-disubstituted tetrazole), then R 2 Select from the following substructures:

[0087]

[0088] in:

[0089] R 5 =-NH2 or selected from the following substructures:

[0090]

[0091] The following compounds of formula (I) are preferred:

[0092] -6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzo[d]thiazol-2-amine (Compound 1);

[0093] -N-(5-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)-2-hydroxyphenyl)morpholine-4-carboxamide (Compound 2);

[0094] -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzo[d]thiazol-2-amine (Compound 3);

[0095] -6-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)isoindolin-1-one (Compound 4);

[0096] -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 5);

[0097] -N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 6);

[0098] -5-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)benzo[d]oxazol-2-amine (Compound 7);

[0099] -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-2-amine (Compound 8);

[0100] -2-(6-((4-(2-chloro-1H-benzo[d]imidazol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 9);

[0101] -N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine (Compound 10);

[0102] -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-1-methyl-1H-benzo[d]imidazol-2-amine (Compound 11);

[0103] -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-imidazol-4-yl)pyridin-2-amine (Compound 12);

[0104] -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)pyridin-2-amine (Compound 13);

[0105] -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzo[d]thiazol-2-amine (Compound 14);

[0106] -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 15);

[0107] -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 16);

[0108] -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2-amine (Compound 17);

[0109] -6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-ethyl-1H-benzo[d]imidazol-2-amine (Compound 18);

[0110] -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)spiro[indoline-3,4′-piperidin]-2-one (Compound 19);

[0111] -N-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-imidazol-4-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine (Compound 20);

[0112] -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,3-difluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 21);

[0113] -N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-imidazol-4-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine (Compound 22);

[0114] -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2-amine (Compound 23);

[0115] -N-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine (Compound 24);

[0116] -N-(5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2-hydroxyphenyl)morpholine-4-carboxamide (Compound 25);

[0117] -5'-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)spiro[cyclopentane-1,3'-indolin]-2'-one (Compound 26);

[0118] -7'-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)-1',4'-dihydro-3'H-spiro[cyclopentane-1,2'-quinoxaline]-3'-one (Compound 27);

[0119] -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)spiro[indoline-3,3′-pyrrolidino]-2-one (Compound 28);

[0120] -3-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)benzamide (Compound 29);

[0121] -6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-2-amine (Compound 30);

[0122] -3-(5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2-hydroxyphenyl)-1,1-dimethylurea (Compound 31);

[0123] -(R)-5-(1-(1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 32);

[0124] -(4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)phenyl)methanamine (Compound 33);

[0125] -6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-methylquinolin-2-amine (Compound 34);

[0126] -2-amino-4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenol (Compound 35);

[0127] -7'-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1',4'-dihydro-3'H-spiro[piperidin-4,2'-quinoxaline]-3'-one (Compound 36);

[0128] -N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)acetamide (Compound 37);

[0129] -5-(3-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)phenyl)thiazol-2-amine (Compound 38);

[0130] -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,5-difluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 39);

[0131] -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-2H-tetrazol-5-yl)isoindolin-1-one (Compound 40);

[0132] -6'-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1',4'-dihydro-3'H-spiro[piperidin-4,2'-quinoxaline]-3'-one (Compound 41);

[0133] -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 42);

[0134] -(4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)methanamine (Compound 43);

[0135] -(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)methanamine (Compound 44);

[0136] -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)pyridin-2-amine (Compound 45);

[0137] -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)spiro[indoline-3,4′-piperidin]-2-one (Compound 46);

[0138] -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 47);

[0139] -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 48);

[0140] -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)spiro[indoline-3,3′-pyrrolidino]-2-one (Compound 49);

[0141] -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-2H-tetrazol-5-yl)benzamide (Compound 50);

[0142] -N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-4-methylpiperazine-1-carboxamide (Compound 51);

[0143] -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 52);

[0144] -2-(difluoromethyl)-5-(6-((4-(2-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (Compound 53);

[0145] -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)benzamide (Compound 54);

[0146] -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)isoindolin-1-one (Compound 55);

[0147] -4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenol (Compound 56);

[0148] -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)isoindolin-1-one (Compound 57);

[0149] -2-(difluoromethyl)-5-(4-((5-(3-(4-methylpiperazin-1-yl)phenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 58);

[0150] -5-(1-(1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 59);

[0151] -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-N-ethyl-1H-benzo[d]imidazol-2-amine (Compound 60);

[0152] -5'-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)spiro[cyclopentane-1,3'-indolin]-2'-one (Compound 61);

[0153] -N-(3-(4-(6-aminopyridin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)propyl)methanesulfonamide (Compound 62);

[0154] -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-4-methylpiperazine-1-carboxamide (Compound 63);

[0155] -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)pyridin-2-amine (Compound 64);

[0156] -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2-methylpyridin-3-amine (Compound 65);

[0157] -N-(3-(1-(1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 66);

[0158] -2-(3,5-difluoro-4-((4-(imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 67);

[0159] -N-(5-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-2H-tetrazol-5-yl)pyridin-2-yl)-2,2-difluoroacetamide (Compound 68);

[0160] -(3-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)phenyl)(morpholinyl)methanone (Compound 69);

[0161] -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)acetamide (Compound 70);

[0162] -N-(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)morpholine-4-carboxamide (Compound 71);

[0163] -2-amino-5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)benzamide (Compound 72);

[0164] -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-3-amine (Compound 73);

[0165] -2-(difluoromethyl)-5-(6-((4-(imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (Compound 74);

[0166] -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)benzamide (Compound 75);

[0167] -2-amino-5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)nicotinamide (Compound 76);

[0168] -5-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-2H-tetrazol-5-yl)pyridin-2-amine (Compound 77);

[0169] -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 78);

[0170] -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)pyrimidin-2-amine (Compound 79);

[0171] -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-N-(1-methylpiperidin-4-yl)benzamide (Compound 80);

[0172] -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-N,N-dimethylbenzamide (Compound 81);

[0173] -2-(4-((5-(5-bromopyridin-3-yl)-2H-tetrazol-2-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 82);

[0174] -7-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (Compound 83);

[0175] -7-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)quinazolin-4-amine (Compound 84);

[0176] -2-(difluoromethyl)-5-(6-((4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (Compound 85);

[0177] -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-1-methylazetidine-3-carboxamide (Compound 86);

[0178] -2-(difluoromethyl)-5-(4-((5-(4-(piperidin-1-ylmethyl)phenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 87);

[0179] -N-(5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)-2,2-difluoroacetamide (Compound 88);

[0180] -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-2H-tetrazol-5-yl)benzamide (Compound 89);

[0181] -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)pyridin-3-amine (Compound 90);

[0182] -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-N-ethylbenzamide (Compound 91);

[0183] -1-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-3,3-dimethylazetidin-2-one (Compound 92);

[0184] -(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-2H-tetrazol-5-yl)phenyl)(morpholinyl)methanone (Compound 93);

[0185] -2-(4-(6-aminopyridin-3-yl)-1H-1,2,3-triazol-1-yl)-2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethan-1-ol (Compound 94);

[0186] -N-(5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)-2-hydroxyphenyl)morpholine-4-carboxamide (Compound 95);

[0187] -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-N-(furan-2-ylmethyl)benzamide (Compound 96);

[0188] -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-2H-tetrazol-5-yl)isoindolin-1-one (Compound 97);

[0189] -N-(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)phenyl)morpholine-4-carboxamide (Compound 98);

[0190] -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-N-ethylpyridin-2-amine (Compound 99);

[0191] -(4-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1,2,4-oxadiazol-5-yl)phenyl)methanamine (Compound 100);

[0192] -(5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)methanamine (Compound 101);

[0193] -N-(5-(5-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)-2,2-difluoroacetamide (Compound 102);

[0194] -2-(difluoromethyl)-5-(4-((5-(4-(piperazin-1-yl)phenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 103);

[0195] -N-(3-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 104);

[0196] -2-(3,5-difluoro-4-((4-(2-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 105);

[0197] -(R)-5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 106);

[0198] -6-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-2H-tetrazol-5-yl)isoindolin-1-one (Compound 107);

[0199] -2-(difluoromethyl)-5-(4-((5-(3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 108);

[0200] -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)isoindolin-1-one (Compound 109);

[0201] -7'-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-1',4'-dihydro-3'H-spiro[cyclopentane-1,2'-quinoxaline]-3'-one (Compound 110);

[0202] -2-(difluoromethyl)-5-(4-((5-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)phenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 111);

[0203] -(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)phenyl)(morpholinyl)methanone (Compound 112);

[0204] -2-(difluoromethyl)-5-(4-((5-(quinolin-2-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 113);

[0205] -3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)-N-ethylaniline (Compound 114);

[0206] -2-(difluoromethyl)-5-(6-((4-(2-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (Compound 115);

[0207] -4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)benzamide (Compound 116);

[0208] -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 117);

[0209] -2-(difluoromethyl)-5-(4-((5-(isoquinolin-4-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 118);

[0210] -N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 119);

[0211] -(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)(morpholinyl)methanone (Compound 120);

[0212] -4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline (Compound 121);

[0213] -2-(3,5-difluoro-4-((4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 122);

[0214] -6'-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)spiro[cyclopentane-1,3'-indolin]-2'-one (Compound 123);

[0215] -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(pyrrolidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 124);

[0216] -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 125);

[0217] -N-(5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-imidazol-4-yl)pyridin-2-yl)-2,2-difluoroacetamide (Compound 126);

[0218] -2-(difluoromethyl)-5-(4-((5-(isoquinolin-7-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 127);

[0219] -2-(difluoromethyl)-5-(4-((5-(3,4-dimethoxyphenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 128);

[0220] -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)aniline (Compound 129);

[0221] -4-(5-(3-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)phenyl)thiazol-2-yl)morpholine (Compound 130);

[0222] -2-(difluoromethyl)-5-(4-((4-(2-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 131);

[0223] -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzo[d]thiazol-2-amine (Compound 132);

[0224] -N-(5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2-methylpyridin-3-yl)acetamide (Compound 133);

[0225] -5-(1-(2-chloro-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 134);

[0226] -5-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine (Compound 135);

[0227] -2-(4-((4-(2-chloro-1H-benzo[d]imidazol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 136);

[0228] -(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-2H-tetrazol-5-yl)phenyl)(morpholinyl)methanone (Compound 137);

[0229] -5-((4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzyl)amino)-2-methoxynicotinamide (Compound 138);

[0230] -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)acetamide (Compound 139);

[0231] -1-(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)ethan-1-one (Compound 140);

[0232] -5-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1,2,4-oxadiazol-5-yl)pyridin-2-amine (Compound 141);

[0233] -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-N-methylquinolin-2-amine (Compound 142);

[0234] -(R)-5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)butyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 143);

[0235] -2-amino-N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)acetamide (Compound 144);

[0236] -N-(3-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1,2,4-oxadiazol-5-yl)phenyl)morpholine-4-carboxamide (Compound 145);

[0237] -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-4-methylpiperazine-1-carboxamide (Compound 146);

[0238] -2-(difluoromethyl)-5-(4-((5-(1-(pyridin-2-yl)cyclopropyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 147);

[0239] -2-(difluoromethyl)-5-(4-((5-(6-(piperazin-1-yl)pyridin-3-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 148);

[0240] -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-1-methylazetidine-3-carboxamide (Compound 149);

[0241] -2-(difluoromethyl)-5-(4-((5-(2-nitrophenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 150);

[0242] -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-imidazol-4-yl)pyridin-2-amine (Compound 151);

[0243] -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)benzo[d]oxazol-2-amine (Compound 152);

[0244] -2-(difluoromethyl)-5-(4-((5-(isoquinolin-5-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 153);

[0245] -5-((4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)benzyl)amino)-2-methoxynicotinamide (Compound 154);

[0246] -(5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)methanamine (Compound 155);

[0247] -N-(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)benzamide (Compound 156);

[0248] -7'-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-1',4'-dihydro-3'H-spiro[cyclohexane-1,2'-quinoxaline]-3'-one (Compound 157);

[0249] -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)-3,3,3-trifluoropropyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 158);

[0250] -(R)-2-(difluoromethyl)-5-(4-((5-(6-(3-methylpiperazin-1-yl)pyridin-3-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 159);

[0251] -2-amino-4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)phenylmorpholine-4-carboxylate (Compound 160);

[0252] -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)spiro[indoline-3,4′-piperidin]-2-one (Compound 161);

[0253] -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-imide (Compound 162);

[0254] -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-4-fluoro-N,N-dimethylbenzenesulfonamide (Compound 163);

[0255] -4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-N1-methylbenzene-1,2-diamine (Compound 164);

[0256] -N-(3-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorophenyl)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 165);

[0257] -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2-amine (Compound 166);

[0258] -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)isoindolin-1-one (Compound 167);

[0259] -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Compound 168);

[0260] -2-(difluoromethyl)-5-(4-((4-(4-((4-(ethylsulfonyl)piperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3,5-difluorophenyl)-1,3,4-oxadiazole (Compound 169);

[0261] -1-(5-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-3-methylurea (Compound 170);

[0262] -(S)-5-(1-(1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 171);

[0263] tert-Butyl-(2-((3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-oxoethyl)carbamate (Compound 172);

[0264] -7-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 173);

[0265] -4-(6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-2-yl)morpholine (Compound 174);

[0266] -1-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)thiourea (Compound 175);

[0267] -N-(5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2-(methylamino)phenyl)morpholine-4-carboxamide (Compound 176);

[0268] -tert-Butyl 5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-2-oxospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (Compound 177);

[0269] -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (Compound 178);

[0270] -N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)benzyl)-N-methyl-1-(pyridin-4-yl)methanamine (Compound 179);

[0271] -3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-N-ethylaniline (Compound 180);

[0272] -2-(difluoromethyl)-5-(4-((5-(2-fluorophenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 181);

[0273] -(S)-2-(difluoromethyl)-5-(4-((5-(6-(3-methylpiperazin-1-yl)pyridin-3-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 182);

[0274] -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-N-(furan-2-ylmethyl)acetamide (Compound 183);

[0275] -N-(3-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)propyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 184);

[0276] -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorophenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 185);

[0277] -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorophenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 186);

[0278] -2-(difluoromethyl)-5-(2-((5-(thiophen-2-yl)-2H-tetrazol-2-yl)methyl)pyrimidin-5-yl)-1,3,4-oxadiazole (Compound 187);

[0279] -2-(4-((5-(3-(1H-pyrazol-1-yl)phenyl)-2H-tetrazol-2-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 188);

[0280] -N-(3-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorophenyl)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 189);

[0281] -2-(difluoromethyl)-5-(4-((4-(2-(pyrrolidin-1-yl)-1H-benzo[d]imidazol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 190);

[0282] -(4-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,2,4-oxadiazol-5-yl)phenyl)methanamine (Compound 191);

[0283] -3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline (Compound 192);

[0284] -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)butyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 193);

[0285] -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)propyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 194);

[0286] -6'-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-1',4'-dihydro-3'H-spiro[cyclopentane-1,2'-quinoxaline]-3'-one (Compound 195);

[0287] -4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)-2-(morpholine-4-carboxamido)phenylmorpholine-4-carboxylate (Compound 196);

[0288] -3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-imidazol-4-yl)aniline (Compound 197);

[0289] -5-(1-((6-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 198);

[0290] -N-(5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)pyridin-3-yl)morpholine-4-carboxamide (Compound 199);

[0291] -5-(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)thiazol-2-amine (Compound 200);

[0292] -N-(4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)benzyl)-N-methyl-1-(pyridin-4-yl)methanamine (Compound 201);

[0293] -5-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)isoxazol-3-yl)pyridin-2-amine (Compound 202);

[0294] -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2,3-dihydro-1H-inden-1-one (Compound 203);

[0295] -2-(difluoromethyl)-5-(4-((5-(4-methoxyphenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 204);

[0296] -N-(3-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)butyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 205);

[0297] -N-(4-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1,2,4-oxadiazol-5-yl)benzyl)-2,2-difluoro-N-methylacetamide (Compound 206);

[0298] -2-(4-((5-(Benzo[b]thiophen-3-yl)-2H-tetrazol-2-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 207);

[0299] -4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2,3-dihydro-1H-inden-1-one (Compound 208);

[0300] -6'-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-1',4'-dihydro-3'H-spiro[cyclohexane-1,2'-quinoxaline]-3'-one (Compound 209);

[0301] -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (Compound 210);

[0302] -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-pyrazol-4-yl)pyridin-2-amine (Compound 211);

[0303] -2-(difluoromethyl)-5-(4-((5-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 212);

[0304] -2-(difluoromethyl)-5-(4-((5-(4-(4-methylpiperazin-1-yl)phenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 213);

[0305] -2-(3,5-difluoro-4-((4-(4-((3-(trifluoromethyl)azetidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 214);

[0306] -N-(4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)benzyl)-N-methyl-1-(pyridin-4-yl)methanamine (Compound 215);

[0307] -tert-Butyl 5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate (Compound 216);

[0308] -2-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-1,1,3,3-tetramethylguanidine (Compound 217);

[0309] -5-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine (Compound 218);

[0310] -2-(difluoromethyl)-5-(4-((5-(2-(pyridin-4-yl)propan-2-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 219);

[0311] -2-(difluoromethyl)-5-(4-((5-(furan-2-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 220);

[0312] -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)-2-phenylethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 221);

[0313] -2-(4-((4-(1H-indazol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 222);

[0314] -3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-imidazol-4-yl)benzamide (Compound 223);

[0315] -2-(difluoromethyl)-5-(4-((5-(3-fluoro-4-(piperazin-1-yl)phenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 224);

[0316] -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)benzo[d]oxazol-2(3H)-one (Compound 225);

[0317] -3-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,2,4-oxadiazol-3-yl)benzamide (Compound 226);

[0318] -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-pyrazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 227);

[0319] -N-(3-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,2,4-oxadiazol-5-yl)phenyl)morpholine-4-carboxamide (Compound 228);

[0320] -7-(2-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-2H-tetrazol-5-yl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 229);

[0321] -(4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)(morpholinyl)methanone (Compound 230);

[0322] -5-(1-(2-(4-chlorophenyl)-1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 231);

[0323] -4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-N-(1-methylpiperidin-4-yl)benzamide (Compound 232);

[0324] -2-(difluoromethyl)-5-(4-((4-(2-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 233);

[0325] -2-(difluoromethyl)-5-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 234);

[0326] -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 235);

[0327] -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)-2-phenoxyethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 236);

[0328] -8-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)-4-methyl-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepine -2-ketone (Compound 237);

[0329] -2-(difluoromethyl)-5-(4-((5-phenyl-1,3,4-thiadiazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 238);

[0330] -N-(cyclopropylmethyl)-1-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)benzoyl)piperidine-3-carboxamide (Compound 239);

[0331] tert-Butyl 3-(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (Compound 240);

[0332] -2-(difluoromethyl)-5-(4-((4-(6-fluoro-2-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 241);

[0333] -5-(1-(2-cyclobutyl-1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 242);

[0334] -5-(5-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)difluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine (Compound 243);

[0335] -N-(3-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 244);

[0336] -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-3,3-dimethylisoindolin-1-one (Compound 245);

[0337] -2-(4-((5-([1,1′-biphenyl]-3-yl)-2H-tetrazol-2-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 246);

[0338] -5-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,2,4-oxadiazol-5-yl)pyridin-2-amine (Compound 247);

[0339] -2-(difluoromethyl)-5-(4-((4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 248);

[0340] -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-N,N-dimethylbenzo[d]oxazol-2-amine (Compound 249);

[0341] -(S)-5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)butyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 250);

[0342] -2-(difluoromethyl)-5-(4-((5-(pyridin-2-ylmethyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 251);

[0343] -5-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-2H-tetrazol-5-yl)-1-methyl-1H-benzo[d]imidazol-2-amine (Compound 252)

[0344] -4-(5-(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)thiazol-2-yl)morpholine (Compound 253);

[0345] -N-(4-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1,2,4-oxadiazol-5-yl)benzyl)-N-methyl-1-(pyridin-4-yl)methanamine (Compound 254);

[0346] -(S)-5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 255);

[0347] -2-(difluoromethyl)-5-(4-((5-(1-phenylcyclopropyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 256);

[0348] -1-(4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)piperidin-1-yl)ethan-1-one (Compound 257);

[0349] -N-(5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2-(phenylthio)phenyl)morpholine-4-carboxamide (Compound 258);

[0350] -N-(4-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,2,4-oxadiazol-5-yl)benzyl)-2,2-difluoro-N-methylacetamide (Compound 259);

[0351] -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)benzoic acid (Compound 260);

[0352] -2-(difluoromethyl)-5-(4-((5-(thiophen-2-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 261);

[0353] -3-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,2,4-oxadiazol-5-yl)benzamide (Compound 262);

[0354] -2-(4-((5-(2,4-dichlorophenyl)-2H-tetrazol-2-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 263);

[0355] -N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-imidazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 264);

[0356] -tert-Butyl 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate Enantiomer A (Compound 265);

[0357] -tert-Butyl 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate Enantiomer B (Compound 266);

[0358] -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-imidazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 267);

[0359] -tert-Butyl 7'-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-3'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoxaline]-1-carboxylate (Compound 268);

[0360] -N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-pyrazol-4-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine (Compound 269);

[0361] -N-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine (Compound 270);

[0362] -7'-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1',4'-dihydro-3'H-spiro[piperidin-4,2'-quinoxaline]-3'-one (Compound 271);

[0363] tert-Butyl 2-(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (Compound 272);

[0364] -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)spiro[indoline-3,3'-pyrrolidino]-2-one enantiomer A (Compound 273);

[0365] -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)spiro[indoline-3,3'-pyrrolidino]-2-one enantiomer B (Compound 274);

[0366] -3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzoic acid (Compound 275);

[0367] -2-(difluoromethyl)-5-(6-((5-(3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)-2H-tetrazol-2-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (Compound 276);

[0368] -6'-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1',4'-dihydro-3'H-spiro[piperidin-4,2'-quinoxaline]-3'-one (Compound 277);

[0369] -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)quinazolin-2-amine (Compound 278);

[0370] -tert-Butyl 6'-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-3'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoxaline]-1-carboxylate (Compound 279);

[0371] -2-(difluoromethyl)-5-(4-((4-(imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 280);

[0372] -4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylaniline (Compound 281);

[0373] -N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzyl)-N-methyl-1-(pyridin-4-yl)methanamine (Compound 282);

[0374] -1-((1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-1-ethyl-3-(2-methoxypyridin-3-yl)urea (Compound 283);

[0375] -5-(5-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorophenyl)thio)-4-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (Compound 284);

[0376] -5-(5-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)thio)-4-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (Compound 285);

[0377] -5-((4-(4-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-1-yl)benzyl)amino)-2-methoxynicotinamide (Compound 286);

[0378] -2-(difluoromethyl)-5-(4-((5-(pyrimidin-2-yl)-1H-tetrazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 287);

[0379] -2-(4-((5-(Benzo[b]thiophen-3-yl)-1H-tetrazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 288);

[0380] -2-(4-((5-(3-(1H-pyrazol-1-yl)phenyl)-1H-tetrazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 289);

[0381] -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 290);

[0382] -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-1H-tetrazol-5-yl)-1-methyl-1H-benzo[d]imidazol-2-amine (Compound 291);

[0383] -6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-imidazol-4-yl)isoindolin-1-one (Compound 292);

[0384] -N-(3-(4-(6-aminopyridin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)propyl)methanesulfonamide (Compound 293);

[0385] -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-imidazol-4-yl)isoindolin-1-one (Compound 294);

[0386] -N-(3-(4-(6-aminopyridin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)propyl)-2,2-difluoroacetamide (Compound 295);

[0387] -4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline (Compound 296);

[0388] -3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline (Compound 297);

[0389] -6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-1H-tetrazol-5-yl)isoindolin-1-one (Compound 298);

[0390] -2-(difluoromethyl)-5-(2-((5-(thiophen-2-yl)-1H-tetrazol-1-yl)methyl)pyrimidin-5-yl)-1,3,4-oxadiazole (Compound 299);

[0391] -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-imidazol-4-yl)benzo[d]thiazol-2-amine (Compound 300);

[0392] -5-(1-(1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-(pyrrolidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 301).

[0393] The following compounds of formula (I) are also preferred:

[0394] -N-[2-[4-(6-aminopyridin-3-yl)triazol-1-yl]-2-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]ethyl]methanesulfonamide Compound 302

[0395] -5-[1-[1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]-4-piperidin-1-ylbutyl]triazol-4-yl]pyridin-2-amine compound 303

[0396] -5-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoropyridin-2-yl]methyl]triazol-4-yl]pyridin-2-amine compound 304

[0397] -3-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]imidazol-4-yl]benzamide Compound 305

[0398] -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]imidazol-4-yl]-1,3-benzothiazol-2-amine compound 306

[0399] -6-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]imidazol-4-yl]-1,3-benzothiazol-2-amine Compound 307

[0400] -5-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]imidazol-4-yl]-1,3-benzoxazol-2-amine Compound 308

[0401] -5-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]imidazol-4-yl]-1,3-benzoxazol-2-amine compound 309

[0402] -N-[(3S)-3-[4-(6-aminopyridin-3-yl)triazol-1-yl]-3-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]propyl]methanesulfonamide Compound 310

[0403] -N-[(3R)-3-[4-(6-aminopyridin-3-yl)triazol-1-yl]-3-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]propyl]methanesulfonamide Compound 311

[0404] -5-[1-[(1R)-1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]-2-pyrrolidin-1-ylethyl]triazol-4-yl]pyridin-2-amine Compound 312

[0405] -5-[1-[(1S)-1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]-2-pyrrolidin-1-ylethyl]triazol-4-yl]pyridin-2-amine Compound 313

[0406] -(2R)-2-[4-(6-aminopyridin-3-yl)triazol-1-yl]-2-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]ethanol Compound 314

[0407] -4-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-1-yl]aniline compound 315

[0408] -N-[4-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-1-yl]phenyl]-4,5-dihydro-1H-imidazol-2-amine Compound 316

[0409] -7-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]triazol-4-yl]quinazolin-4-amine Compound 317

[0410] -6-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]pyrazol-4-yl]-2,3-dihydroisoindole-1-one Compound 318

[0411] -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]pyrazol-4-yl]-2,3-dihydroisoindole-1-one compound 319

[0412] -5-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]pyrazol-4-yl]-1-methylbenzimidazol-2-amine compound 320

[0413] -5-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]pyrazol-4-yl]-1-methylbenzimidazol-2-amine compound 321

[0414] -5-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]imidazol-4-yl]-1,3-benzothiazol-2-amine compound 322

[0415] -5-[1-[1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]-3-pyrrolidin-1-ylpropyl]triazol-4-yl]pyridin-2-amine Compound 323

[0416] -5-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]triazol-4-yl]-3,3-dimethyl-1H-indol-2-one Compound 324

[0417] -5-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]triazol-4-yl]-1,3-dihydroindolin-2-one compound 325

[0418] -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]pyrazol-4-yl]-1,3-benzothiazol-2-amine compound 326

[0419] -6-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]pyrazol-4-yl]-1,3-benzothiazol-2-amine Compound 327

[0420] -5-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]imidazol-4-yl]-1-methylbenzimidazol-2-amine Compound 328

[0421] -5-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]imidazol-4-yl]-1-methylbenzimidazol-2-amine compound 329

[0422] -4-[5-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-1,3-oxazol-2-yl]aniline compound 330

[0423] -5-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]pyrazol-4-yl]-1H-benzimidazol-2-amine Compound 331

[0424] -5-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]pyrazol-4-yl]-1H-benzimidazol-2-amine compound 332

[0425] -3-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]pyrazol-4-yl]benzamide Compound 333

[0426] -3-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]pyrazol-4-yl]benzamide Compound 334

[0427] -4-[4-(6-aminopyridin-3-yl)triazol-1-yl]-4-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]butan-1-ol Compound 335

[0428] -N-[3-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoropyridin-2-yl]methyl]triazol-4-yl]phenyl]morpholine-4-carboxamide Compound 336

[0429] -N-[3-[1-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]phenyl]morpholine-4-carboxamide Compound 337

[0430] -N-[3-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]phenyl]morpholine-4-carboxamide Compound 338

[0431] -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine compound 339

[0432] -6-[1-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine compound 340

[0433] -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 341

[0434] -6-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoropyridin-2-yl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 342

[0435] -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine compound 343

[0436] -5-[1-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine compound 344

[0437] -5-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine compound 345

[0438] -5-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine compound 346

[0439] -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 347

[0440] -5-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]-1-methylbenzimidazol-2-amine compound 348

[0441] -5-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoropyridin-2-yl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine compound 349

[0442] -5-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine compound 350

[0443] -6-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine compound 351

[0444] -N-[3-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]phenyl]morpholine-4-carboxamide Compound 352

[0445] -2-(difluoromethyl)-5-[5-fluoro-6-[[5-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl]tetrazol-2-yl]methyl]pyridin-3-yl]-1,3,4-oxadiazole compound 353

[0446] -2-(difluoromethyl)-5-[3-fluoro-4-[[5-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl]tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole Compound 354

[0447] -2-(difluoromethyl)-5-[2,3-difluoro-4-[[5-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl]tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole Compound 355

[0448] -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]pyridin-2-amine compound 356

[0449] -N-[4-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]imidazol-4-yl]phenyl]-4,5-dihydro-1H-imidazol-2-amine Compound 357

[0450] -N-[4-[1-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]imidazol-4-yl]phenyl]-4,5-dihydro-1H-imidazol-2-amine Compound 358

[0451] -N-[4-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]imidazol-4-yl]phenyl]-4,5-dihydro-1H-imidazol-2-amine Compound 359

[0452] -N-[4-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]imidazol-4-yl]phenyl]-4,5-dihydro-1H-imidazol-2-amine Compound 360

[0453] -N-[4-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]imidazol-4-yl]phenyl]-4,5-dihydro-1H-imidazol-2-amine Compound 361

[0454] -5-[1-[dideuterio-[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]triazol-4-yl]pyridin-2-amine compound 362

[0455] -N-[3-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]triazol-4-yl]phenyl]morpholine-4-carboxamide Compound 363

[0456] -2-(difluoromethyl)-5-[2-fluoro-4-[[5-[3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)phenyl]tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole Compound 364

[0457] -2-[3-chloro-4-[[5-[3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)phenyl]tetrazol-2-yl]methyl]phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole Compound 365

[0458] -6-[5-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-1,2-oxazol-3-yl]-1,3-benzothiazol-2-amine compound 366

[0459] -2-(difluoromethyl)-5-[2,5-difluoro-4-[[5-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl]tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole Compound 367

[0460] -N-[4-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]imidazol-4-yl]phenyl]-4,5-dihydro-1H-imidazol-2-amine Compound 368

[0461] -N-[3-[1-[dideuterio-[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]triazol-4-yl]phenyl]morpholine-4-carboxamide Compound 369

[0462] -5-[2-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoropyridin-2-yl]methyl]tetrazol-5-yl]-1-methylbenzimidazol-2-amine compound 370

[0463] -5-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]tetrazol-5-yl]-1-methylbenzimidazol-2-amine compound 371

[0464] -5-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]-1-methylbenzimidazol-2-amine compound 372

[0465] -5-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]-1-methylbenzimidazol-2-amine compound 373

[0466] -5-[2-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]-1-methylbenzimidazol-2-amine compound 374

[0467] -4-[5-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-1,2,4-oxadiazol-3-yl]aniline compound 375

[0468] -6-[1-[dideuterio-[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine compound 376

[0469] -6-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-1-yl]-1,3-benzothiazol-2-amine Compound 377

[0470] -5-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine Compound 378

[0471] -N-[4-[5-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-1,2,4-oxadiazol-3-yl]phenyl]-4,5-dihydro-1H-imidazol-2-amine Compound 379

[0472] -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]triazol-4-yl]pyridin-2-amine Compound 381

[0473] -6-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine compound 382

[0474] -N-(4-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-1,2,4-oxadiazol-3-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine Compound 383

[0475] -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,3-difluorobenzyl)-1H-1,2,3-triazol-4-yl)thieno[2,3-d]pyrimidin-4-amine Compound 384

[0476] -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]pyridin-2-amine compound 385

[0477] -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)thieno[2,3-d]pyrimidin-4-amine Compound 386

[0478] -7-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]quinazolin-4-amine Compound 387

[0479] -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)-N-methylquinolin-2-amine Compound 388

[0480] -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]-N-methylquinazolin-2-amine Compound 389

[0481] -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]-N-methylquinazolin-2-amine Compound 390

[0482] -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]-N-methylquinazolin-2-amine Compound 391

[0483] -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]-N-methylquinazolin-2-amine Compound 392

[0484] -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]-N-methylquinazolin-2-amine Compound 393

[0485] -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]-N-ethylquinazolin-2-amine Compound 394

[0486] -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-N-ethylquinazolin-2-amine Compound 395

[0487] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]isoquinolin-1-amine Compound 396

[0488] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]isoquinolin-1-amine Compound 397

[0489] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]quinolin-3-amine Compound 398

[0490] -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylquinolin-2-amine Compound 399

[0491] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]quinolin-3-amine compound 400

[0492] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]-N-methylquinolin-2-amine Compound 401

[0493] -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]-N,N-dimethylquinazolin-2-amine Compound 402

[0494] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]-N-methylquinolin-2-amine compound 403

[0495] -6-(1-(2-chloro-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)isoquinolin-3-amine Compound 404

[0496] -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]isoquinolin-3-amine Compound 405

[0497] -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]isoquinolin-3-amine Compound 406

[0498] -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,3-difluorobenzyl)-2H-tetrazol-5-yl)-N-methylquinolin-2-amine Compound 407

[0499] -4-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-1,2,4-oxadiazol-3-yl)aniline compound 408

[0500] -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,5-difluorobenzyl)-2H-tetrazol-5-yl)-N-ethylquinolin-2-amine Compound 409

[0501] -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-2H-tetrazol-5-yl)-N-ethylquinolin-2-amine Compound 410

[0502] -5-(4-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-1-yl)pyridin-2-amine Compound 413

[0503] -5-[4-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}methyl)-1H-1,2,3-triazol-1-yl]-1-methyl-1H-1,3-benzodiazol-2-amine Compound 414

[0504] -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]thieno[2,3-d]pyrimidin-4-amine Compound 415

[0505] -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]thieno[2,3-d]pyrimidin-4-amine Compound 416

[0506] -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]thieno[2,3-d]pyrimidin-4-amine Compound 417

[0507] -7-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)quinazolin-4-amine Compound 418

[0508] -4-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1,2,4-oxadiazol-3-yl)aniline compound 419

[0509] -N-(4-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1,2,4-oxadiazol-3-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine Compound 420

[0510] -6-(2-(2-chloro-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)isoquinolin-1-amine Compound 422

[0511] -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,5-difluorobenzyl)-2H-tetrazol-5-yl)quinazolin-2-amine Compound 423

[0512] -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-2H-tetrazol-5-yl)quinazolin-2-amine Compound 424

[0513] -6-(2-(2-chloro-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)quinazolin-2-amine Compound 425

[0514] -2-(3-chloro-4-((5-(isoquinolin-6-yl)-2H-tetrazol-2-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole Compound 426

[0515] -2-(difluoromethyl)-5-(3-fluoro-4-((5-(isoquinolin-6-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole Compound 427

[0516] -2-(2,5-difluoro-4-((5-(isoquinolin-6-yl)-2H-tetrazol-2-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole Compound 428

[0517] -6-(2-(2-chloro-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)quinolin-3-amine Compound 429

[0518] -2-(3-chloro-4-((5-(isoquinolin-1-yl)-2H-tetrazol-2-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole compound 430

[0519] -2-(difluoromethyl)-5-(3-fluoro-4-((5-(isoquinolin-1-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole Compound 431

[0520] -2-(2,5-difluoro-4-((5-(isoquinolin-1-yl)-2H-tetrazol-2-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole Compound 432

[0521] -7-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,5-difluorobenzyl)-1H-1,2,3-triazol-4-yl)quinazolin-4-amine Compound 433

[0522] -7-(1-(2-chloro-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)quinazolin-4-amine Compound 434

[0523] -2-(Difluoromethyl)-5-[3-fluoro-4-[[5-(1-pyrazin-2-ylcyclopropyl)tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole compound 435

[0524] -2-(Difluoromethyl)-5-[2-fluoro-4-[[5-(1-pyrazin-2-ylcyclopropyl)tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole compound 436

[0525] -2-(Difluoromethyl)-5-[2,3-difluoro-4-[[5-(1-pyrazin-2-ylcyclopropyl)tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole Compound 437

[0526] -2-(Difluoromethyl)-5-[2,5-difluoro-4-[[5-(1-pyrazin-2-ylcyclopropyl)tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole Compound 438

[0527] -2-(Difluoromethyl)-5-[3,5-difluoro-4-[[5-(1-pyrazin-2-ylcyclopropyl)tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole compound 439

[0528] -2-[3-chloro-4-[[5-(1-pyrazin-2-ylcyclopropyl)tetrazol-2-yl]methyl]phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole compound 440

[0529] -6-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-3-amine Compound 441

[0530] -6-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-3-amine Compound 442

[0531] -6-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-3-amine Compound 443

[0532] -6-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-3-amine Compound 444

[0533] -6-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-3-amine compound 445

[0534] -6-[2-[2-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-3-amine Compound 446

[0535] -2-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-4-amine Compound 447

[0536] -2-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-4-amine Compound 448

[0537] -2-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-4-amine Compound 449

[0538] -2-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-4-amine compound 450

[0539] -2-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-4-amine Compound 451

[0540] -2-[2-[2-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-4-amine compound 452

[0541] -2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]pyrimidin-5-amine compound 453

[0542] -2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]pyrimidin-5-amine compound 454

[0543] -2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]tetrazol-5-yl]pyrimidin-5-amine compound 455

[0544] -2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]pyrimidin-5-amine compound 456

[0545] -2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]tetrazol-5-yl]pyrimidin-5-amine compound 457

[0546] -2-[2-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]pyrimidin-5-amine compound 458

[0547] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]tetrazol-5-yl]isoquinolin-1-amine Compound 459

[0548] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]tetrazol-5-yl]isoquinolin-1-amine compound 460

[0549] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]tetrazol-5-yl]quinolin-3-amine Compound 461

[0550] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]tetrazol-5-yl]quinolin-3-amine Compound 462

[0551] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]quinazolin-2-amine compound 463

[0552] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]tetrazol-5-yl]quinazolin-2-amine compound 464

[0553] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]tetrazol-5-yl]quinazolin-2-amine compound 465

[0554] -2-(difluoromethyl)-5-[2-fluoro-4-[(5-isoquinolin-6-yl tetrazol-2-yl)methyl]phenyl]-1,3,4-oxadiazole compound 466

[0555] -2-[2,3-difluoro-4-[(5-isoquinolin-6-yl tetrazol-2-yl)methyl]phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole compound 467

[0556] -2-[3,5-difluoro-4-[(5-isoquinolin-6-yl tetrazol-2-yl)methyl]phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole compound 468

[0557] -2-(difluoromethyl)-5-[2-fluoro-4-[(5-isoquinolin-1-yltetrazol-2-yl)methyl]phenyl]-1,3,4-oxadiazole compound 469

[0558] -2-[2,3-difluoro-4-[(5-isoquinolin-1-yl tetrazol-2-yl)methyl]phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole compound 470

[0559] -2-[3,5-difluoro-4-[(5-isoquinolin-1-yl tetrazol-2-yl)methyl]phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole compound 471

[0560] -6-[2-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]-N-methylquinolin-2-amine Compound 472

[0561] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]-N-ethylquinolin-2-amine Compound 473

[0562] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]tetrazol-5-yl]-N-ethylquinolin-2-amine Compound 474

[0563] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]tetrazol-5-yl]-N-ethylquinolin-2-amine compound 475

[0564] -6-[2-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]-N-ethylquinolin-2-amine Compound 476

[0565] -6-[1-[(1R)-1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]ethyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 477

[0566] -6-[1-[(1R)-1-[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]ethyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 478

[0567] -6-[1-[(1R)-1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]ethyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 479

[0568] -6-[1-[(1R)-1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]ethyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 480

[0569] -6-[1-[(1R)-1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]ethyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 481

[0570] -6-[1-[(1R)-1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]ethyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 482

[0571] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]-N-methylquinazolin-2-amine Compound 483

[0572] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]-N-methylquinazolin-2-amine Compound 484

[0573] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]-N-methylquinazolin-2-amine Compound 485

[0574] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]-N,N-dimethylquinazolin-2-amine Compound 486

[0575] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]-N,N-dimethylquinazolin-2-amine Compound 487

[0576] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]-N,N-dimethylquinazolin-2-amine Compound 488

[0577] -6-[1-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]-N-methylquinazolin-2-amine Compound 489

[0578] -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]-N-ethylquinazolin-2-amine Compound 490

[0579] -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]triazol-4-yl]-N-ethylquinazolin-2-amine Compound 491

[0580] -6-[1-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]-N-ethylquinazolin-2-amine Compound 492

[0581] -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]triazol-4-yl]-N,N-dimethylquinazolin-2-amine Compound 494

[0582] -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]-N,N-dimethylquinazolin-2-amine Compound 495

[0583] -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]triazol-4-yl]-N,N-dimethylquinazolin-2-amine Compound 496

[0584] -6-[1-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]-N,N-dimethylquinazolin-2-amine Compound 497

[0585] -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]isoquinolin-3-amine Compound 498

[0586] -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]triazol-4-yl]isoquinolin-3-amine Compound 499

[0587] -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]triazol-4-yl]isoquinolin-3-amine compound 500

[0588] -6-[1-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]thieno[2,3-d]pyrimidin-4-amine compound 501

[0589] -7-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]quinazolin-4-amine compound 502

[0590] -7-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]triazol-4-yl]quinazolin-4-amine compound 503

[0591] -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,5-difluorobenzyl)-2H-tetrazol-5-yl)-N-methylquinolin-2-amine Compound 504

[0592] -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]triazol-4-yl]pyridin-2-amine compound 505

[0593] -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]triazol-4-yl]pyridin-2-amine compound 506

[0594] -6-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine compound 507

[0595] -6-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine compound 508

[0596] -6-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine compound 509

[0597] -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine compound 510

[0598] -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine compound 511

[0599] -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine compound 512

[0600] -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine compound 513

[0601] -6-[5-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-1,2,4-oxadiazol-3-yl]-1,3-benzothiazol-2-amine compound 514

[0602] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]isoquinolin-1-amine compound 515

[0603] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]quinolin-3-amine compound 516

[0604] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]-N-methylquinolin-2-amine Compound 517

[0605] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]isoquinolin-3-amine Compound 518

[0606] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]isoquinolin-3-amine compound 519

[0607] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]isoquinolin-3-amine compound 520

[0608] -7-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]quinazolin-4-amine Compound 521

[0609] -7-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]quinazolin-4-amine compound 522

[0610] -7-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]quinazolin-4-amine compound 523

[0611] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]thieno[2,3-d]pyrimidin-4-amine compound 524

[0612] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]thieno[2,3-d]pyrimidin-4-amine compound 525

[0613] -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]thieno[2,3-d]pyrimidin-4-amine Compound 526.

[0614] Another class of preferred compounds comprises compounds of formula (I) and pharmaceutically acceptable salts, isomers and prodrugs thereof, wherein the five-membered heterocyclic nucleus ABDEM is selected from 1,2,3-triazole, 2,5-disubstituted tetrazole, 1,4-disubstituted pyrazole, imidazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole and isoxazole. Preferably, the five-membered heterocyclic nucleus ABDEM is selected from 1,2,3-triazole (wherein B=C and M=N), 2,5-disubstituted tetrazole, 1,4-disubstituted pyrazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole and isoxazole. More preferably, the five-membered heterocyclic nucleus ABDEM is selected from 1,2,3-triazole (wherein B═C and M═N), 1,3,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, and isoxazole. Another preferred class of compounds comprises compounds of formula (I) and pharmaceutically acceptable salts, isomers, and prodrugs thereof, wherein at least one of X, X′, Y, and Y′ is CF, or at least one of X and X′ is CCl.

[0615] Another class of preferred compounds comprises compounds of formula (I) and pharmaceutically acceptable salts, isomers and prodrugs thereof, wherein Z = -CD2-, -CF2-, -CHR 3 -, -NH-, -S-;

[0616] where R 3 Select from the following substructures:

[0617]

[0618] More preferably, Z=-CD2-, -CF2, -CHR 3 -、-S-,

[0619] where R 3 Select from the following substructures:

[0620]

[0621] Another class of preferred compounds comprises compounds of formula (I) and pharmaceutically acceptable salts, isomers and prodrugs thereof,

[0622] in:

[0623] R 2 Selected from:

[0624]

[0625]

[0626] where R 5 and R 6 At least one of: -OH, -NR'R", -NHR 7 、-SO2NMe2、CH2NH2、-COR 8 , or selected from the following substructures:

[0627]

[0628] R 7 Select from the following substructures:

[0629]

[0630] R 8 =-NR'R" or selected from the following substructures:

[0631]

[0632] wherein R' and R" are independently -H or C1-C4 alkyl.

[0633] In this preferred embodiment, R 2 The substituent is a polar group, preferably an H-donor group.

[0634] In contrast, WO2020 / 212479 discloses R 2 The substituent is preferably a relatively non-polar group. The relatively non-polar group is preferably a phenyl group, or a phenyl group substituted with an alkyl group, an alkoxy group, a thioalkoxy group or a halogenated derivative thereof, or a halogen, and most preferably a phenyl group substituted with a halogen.

[0635] In another embodiment, when B═N, Z═CHR 3 , where R 3 When L is absent and each of X, X', Y, and Y' is CH or one or two of X, X', Y, and Y' are N, then R 2 Not selected from phenyl or pyridyl, unsubstituted or substituted by one or more alkyl, alkoxy, thioalkoxy or halogenated derivatives thereof, or halogen, unsubstituted thienyl or furyl.

[0636] In another specific embodiment, the following compounds are excluded:

[0637] 2-(Difluoromethyl)-5-(4-((5-phenyl-1H-tetrazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole;

[0638] 2-(difluoromethyl)-5-(6-((4-phenyl-1H-imidazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0639] 2-(Difluoromethyl)-5-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole;

[0640] 2-(4-((4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0641] 2-(difluoromethyl)-5-(4-((4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole;

[0642] 2-(Difluoromethyl)-5-(4-((4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole;

[0643] 2-(Difluoromethyl)-5-(4-((4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole;

[0644] 2-(Difluoromethyl)-5-(4-((4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole;

[0645] 2-(Difluoromethyl)-5-(4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)ethyl)phenyl)-1,3,4-oxadiazole;

[0646] 2-(Difluoromethyl)-5-(4-((5-methyl-4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole;

[0647] 2-(Difluoromethyl)-5-(6-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0648] 2-(Difluoromethyl)-5-(5-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)-1,3,4-oxadiazole;

[0649] 2-(6-((4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0650] 2-(6-((4-(2-chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0651] 2-(6-((4-(3-chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0652] 2-(6-((4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0653] 2-(6-((4-(3,5-dichlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0654] 2-(difluoromethyl)-5-(6-((4-(2-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0655] 2-(Difluoromethyl)-5-(6-((4-(2,6-difluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0656] 2-(6-((4-(3-chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,34-oxadiazole; and

[0657] 2-(Difluoromethyl)-5-(6-((4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole.

[0658] Another class of preferred compounds comprises compounds of formula (I) and pharmaceutically acceptable salts, isomers and prodrugs thereof, wherein:

[0659] X and X' are independently selected from CH, N or CF;

[0660] Y and Y' are independently selected from CH, N or CF;

[0661] A=C, N, S;

[0662] B=C、N;

[0663] D=C、N;

[0664] E=C, N, O;

[0665] M=C;

[0666] Z=CH2、CHR 3 ;

[0667] R 3 =Me or can be selected from the following substructures:

[0668]

[0669] L does not exist;

[0670] R 2 Selected from:

[0671]

[0672]

[0673]

[0674] R 5 and R 6 Independently selected from: -OH, -OMe, -Br, NH2, -NHR 7 、-COR 8 , -COCH3, -CH3, -CH2NH2, or can be selected from the following substructures:

[0675]

[0676] R 7 =Me, Et or can be selected from the following substructures:

[0677]

[0678] R 8 =-NH2, -NHEt, -NMe2 or can be selected from the following substructures:

[0679]

[0680] The following compounds of formula (I) are particularly preferred: compounds (1) to (67), (69), (71), (72), (252), (264), (265), (269), (270), (273), (274), (276), (292), (293), (306), (307), (339), (340), (345) to (348), (350), (351), (356), (359), (362), (376), (382), (477) to (482).

[0681] The compounds of the invention may contain one or more chiral centers (asymmetric carbon atoms) and may therefore exist in enantiomeric and / or diastereomeric forms.

[0682] All possible optical isomers, alone or in mixtures with one another, fall within the scope of the present invention.

[0683] The compounds according to the present invention may be used alone or in combination with other drugs, such as proteasome inhibitors, immunochemical inhibitors, steroids, bromodomain inhibitors and other epigenetic drugs, traditional chemotherapeutic agents (such as but not limited to cisplatin, paclitaxel), proteasome inhibitors (such as but not limited to bortezomib), kinase inhibitors (such as but not limited to the JAK family), CTLA4, PD1 or PDL1 checkpoint inhibitors (such as nivolumab, pemprolizumab, pidilizumab or BMS-936559 (anti-PD1), atezolizumab or avelumab (anti-PDL1), ipilimumab or tremelimumab (anti-CTLA4)).

[0684] The compounds of the present invention, alone or in combination, are preferably used to treat HDAC6-mediated diseases.

[0685] The compounds of the present invention, alone or in combination, are preferably used to treat peripheral neuropathy, including both those caused by genetic factors (such as, but not limited to, Chamadin-Double disease), drug-induced peripheral neuropathy (chemotherapy or antibiotics, such as metronidazole and fluoroquinolones), and those due to systemic diseases (such as diabetes or leprosy), or generally for the treatment of peripheral neuropathy associated with severe axonal transport defects. The compounds of the present invention may also be used to treat chemotherapy-related cognitive impairment (CRCI).

[0686] The compounds of the present invention, alone or in combination, are preferably used to treat transplant rejection, GVHD, myositis, diseases associated with abnormal lymphocyte function, multiple myeloma, non-Hodgkin's lymphoma, peripheral neuropathy, autoimmune diseases, inflammatory diseases, cancer and neurodegenerative diseases, eye diseases (e.g., uveitis).

[0687] Therefore, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isomer, and pharmacologically acceptable prodrug thereof, and at least one pharmaceutically acceptable excipient.

[0688] Such compositions may be liquid, suitable for enteral or parenteral administration; or solid, for example in the form of capsules, tablets, pills, powders or granules for oral administration; or in a form suitable for skin application, such as a cream or ointment; or for delivery by inhalation.

[0689] The pharmaceutical composition of the present invention can be prepared by using known methods.

[0690] General synthetic route

[0691] The compounds described in the present invention can be prepared by using methods known to those skilled in the art.

[0692] All starting materials, reagents, acids, bases, solvents and catalysts used in the synthesis of the described compounds are commercially available.

[0693] The reaction progress was monitored by TLC, HPLC, UPLC or HPLC-MS analysis.

[0694] In most cases, the 2-(difluoromethyl)-1,3,4-oxadiazole moiety is synthesized by treating the corresponding hydrazide with an excess of difluoroacetic anhydride (see Scheme 1). This reagent has the dual function of an acylating agent and a dehydrating agent (Lee, Jaekwang; Han, Younghue; Kim, Yuntae; Min, Jaeki; Bae, Miseon; Kim, Dohoon; Jin, Seokmin; Kyung, Jangbeen; 2017; "1,3,4-Oxadiazole sulfonamide derivatives as histonedeacetylase 6 inhibitors and their pharmaceutical composition and preparation"; WO2017018805). In some cases, the 2-(difluoromethyl)-1,3,4-oxadiazole moiety is prepared starting from the corresponding tetrazole, which is converted to 2-(difluoromethyl)-1,3,4-oxadiazole in the presence of difluoroacetic anhydride (Vereshchagin et al. Rus. J. Org. Chem. 2007, 43(11), 1710-1714).

[0695]

[0696] Scheme 1: Synthesis of the 2-(difluoromethyl)-1,3,4-oxadiazole moiety.

[0697] Appropriate common intermediates (depending on the central heterocyclic skeleton) are synthesized to allow the preparation of various compounds with different "cap terms" by assembling the central heterocyclic ring. In a few cases, the 2-(difluoromethyl)-1,3,4-oxadiazole moiety is synthesized in the last step.

[0698] Regarding compounds containing 1,2,3-triazole, the common intermediate is 2-(4-(azidomethyl)aryl)-5-(difluoromethyl)-1,3,4-oxadiazole, which undergoes Cu(I)-catalyzed azide / alkyne cycloaddition with appropriate derivatized alkynes in water / DMSO using copper(II) sulfate and sodium L-ascorbate(+) as a catalytic system (see Scheme 3) (in plate: T. Suzuki et al. J. Med. Chem. 2012, 55(22), 9562-9575; batch: T.U. Connell et al. J. Label Compd. Radiopharm. 2014, 57, 262-269.). These intermediate azidomethyl derivatives are prepared from the corresponding methyl 4-methylbenzoate, which is first converted to difluoromethyl-1,3,4-oxadiazole via hydrazide as described above. These are then brominated by treatment with N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) or benzoyl peroxide as catalysts. The azido moiety is introduced by nucleophilic substitution of the bromide obtained by treatment with sodium azide (Scheme 2). For fluorinated and chlorinated aryl derivatives, the 2-(difluoromethyl)-1,3,4-oxadiazole moiety is constructed after the introduction of the azido group (Scheme 2).

[0699]

[0700] Scheme 2: Synthesis of the common intermediate 2-(4-(azidomethyl)aryl)-5-(difluoromethyl)-1,3,4-oxadiazole for the synthesis of compounds bearing a 1,2,3-triazole core.

[0701] In the case of the pyridazine derivative, the 2-(difluoromethyl)-1,3,4-oxadiazole moiety is synthesized in the last step.

[0702]

[0703] Scheme 3: Synthesis of compounds with 1,2,3-triazole as the central skeleton.

[0704] Most alkynes used to synthesize these 1,2,3-triazole-containing analogs are commercially available. Non-commercial building blocks are synthesized via Sonogashira coupling: appropriate halogen derivatives are reacted with ethynyl(trimethyl)silane using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) and copper(I) iodide as catalysts in the presence of triethylamine, followed by removal of the silicon protecting group with tetrabutylammonium fluoride (TBAF) (Scheme 3) (AG Sams et al. Bioorg. Med. Chem. Lett. 2011, 21(11), 3407-3410).

[0705] When Z = CHR, the same synthetic pathway is followed to form the 1,2,3-triazole core skeleton. The synthesis of suitable azides follows different strategies depending on the R group (Scheme 4). In some cases, the azide is installed by nucleophilic substitution of bromide or activated hydroxyl (mesylate) and treatment with sodium azide. In this last case, the alcohol precursor is obtained from an aldehyde undergoing a Grignard or Barbier reaction, or by reduction of a ketone with sodium borohydride. For R = ethylmethanesulfonamide, both the ketone and the nitrile are reduced using a catalytic amount of nickel(II) chloride with an excess of sodium borohydride, and the primary amine is trapped with Boc2O (S. Caddick et al. Tetrahedron 2003, 59, 5417–5423). Suitable ketones are commercially available or can be obtained using known methods; for example, by reacting a suitable carboxylic acid with (4-(methoxycarbonyl)phenyl)boronic acid (LJ Gooβen et al. Eur. J. Org. Chem. 2002, 3254-3267). When R is -CH2OH, the epoxy ring of the methyl 4-(oxiran-2-yl)benzoate derivative is directly opened with sodium azide to provide the corresponding azide. Finally, when R is -CH2CF3, the azide is prepared by treating methyl 4-vinylbenzoate with Togni's reagent, TMS-N3, and a catalytic amount of [Cu(CH3CN)4]PF6 (Wang, F., Qi, X., Liang, Z., Chen, P. and Liu, G. (2014), Copper-Catalyzed Intermolecular Trifluoromethylazidation of Alkenes: Convenient Access to CF3-Containing AlkylAzides. Angew. Chem. Int. Ed., 53: 1881-1886).

[0706]

[0707] Scheme 4: Different synthetic routes to substituted azide intermediates.

[0708] Compounds containing tetrazole, imidazole, and pyrazole as central backbones are synthesized via nucleophilic substitution: the common intermediate 2-(4-(bromomethyl)aryl)-5-(difluoromethyl)-1,3,4-oxadiazole is reacted with the appropriately substituted tetrazole, pyrazole, or imidazole in DMF using potassium carbonate as a base at room temperature overnight (see Scheme 5). The common intermediate bromomethyl derivative is synthesized as described for compounds containing a 1,2,3-triazole core (Scheme 2). In a few cases, the 2-(difluoromethyl)-1,3,4-oxadiazole moiety is synthesized in the final step. In other rare cases, the bromo intermediate is reacted with an iodopyrazole, and the R group is inserted in the final step via a Stille or Suzuki reaction. Other non-commercially available substituted imidazoles or pyrazoles are prepared by coupling N-THP-protected imino- or pyrazolyl-pinacol boronates with appropriate aryl halides under Suzuki conditions. Thereafter, the THP protection is removed under acidic conditions before the alkylation step. In a few cases, the imidazole ring is formed by reacting a suitable bromomethylketone with formamide (Cong et al. J. Chem. Res. 2014, 38(4), 208-210).

[0709]

[0710] Scheme 5: Synthesis of compounds with tetrazole, pyrazole or imidazole as central skeleton.

[0711] Most of the substituted tetrazoles used are commercially available. Non-commercial building blocks are synthesized from the corresponding nitriles by reaction with an excess of sodium azide in the presence of ammonium chloride.

[0712] Compounds with an isoxazole core were obtained via the Sonogashira reaction: 2-(difluoromethyl)-5-(4-iodoaryl)-1,3,4-oxadiazole was reacted with ethynyl(trimethyl)silane and triethylamine in the presence of CuI and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) as catalysts. The trimethylsilyl protection was removed in one pot by treatment with tetrabutylammonium fluoride (Scheme 6). The obtained product is subjected to Glazer coupling with an appropriate alkyne in the presence of copper(II) acetate (B. Nammalwar et al. WO2017083434 2017; Ding, Shi et al. Bioorg. Med. Chem. Lett. 2018, 28(2), 94-102) to provide a ring-opened intermediate, which is cyclized by treatment with hydroxylamine hydrochloride and triethylamine at 110°C (L. Wang et al. Org. Lett. 2012, 14(9), 2418-2421). In the case of compounds with oxazole as the core skeleton, 2-(difluoromethyl)-5-(4-iodoaryl)-1,3,4-oxadiazole is reacted with the corresponding propynylamide in the presence of bis(triphenylphosphine)palladium(II) dichloride and copper iodide. The oxazole ring is cyclized in the presence of diazabicycloundecene (DBU).

[0713]

[0714] Scheme 6: Synthesis of compounds with isoxazole and oxazole as core skeletons.

[0715] Compounds with a 1,2,4-oxadiazole core are synthesized by reacting a carboxylic acid with an appropriately substituted N'-hydroxybenzamidine in the presence of EDC and HOBT. These two moieties can be installed at the benzyl position on the ZBG side or on the cap, depending on the desired structural isomer (Scheme 7). N'-hydroxybenzamidines were previously obtained by treating the corresponding nitrile with hydroxylamine hydrochloride in the presence of sodium bicarbonate (SD Diwakar et al. J. Het. Chem. 2011, 48(4), 882-887; F. Yokokawa et al. J. Med. Chem. 2016, 59(8), 3935-3952). In most cases, the 2-(difluoromethyl)-1,3,4-oxadiazole moiety is synthesized in the last step of the synthesis starting from the corresponding methyl ester or from the corresponding nitrile. The nitrile is treated with sodium azide to produce the tetrazole, which is converted to 2-(difluoromethyl)-1,3,4-oxadiazole in the presence of difluoroacetic anhydride. When Z=CF2, the 2-(difluoromethyl)-1,3,4-oxadiazole moiety is formed on methyl 4-iodobenzoate in a first step. The resulting intermediate is treated with ethyl 2-bromo-2,2-difluoroacetate in the presence of copper powder to obtain the ethyl ester (M.-T. Hsieh et al. Adv. Synth. Cat. 2018, 360(8), 1605-1610), which is hydrolyzed with LiOH to the carboxylate common intermediate.

[0716]

[0717] Scheme 7: Synthesis of compounds with 1,2,4-oxadiazole ring as the central core.

[0718] The methyl ester intermediate obtained is in fact treated with hydrazine in order to obtain the corresponding hydrazide, which undergoes acylation and cyclization in the presence of difluoroacetic anhydride (Scheme 7).

[0719] Compounds bearing 1,3,4-oxadiazole and 1,3,4-thiadiazole cores are synthesized by coupling 2-(4-(methoxycarbonyl)phenyl)acetic acid or an appropriate aryl analog with a substituted benzoylhydrazide and treating the linear intermediate with a dehydrating agent to obtain the cyclic desired product. Burgess' reagent is used as a cyclizing agent to prepare 1,3,4-oxadiazole (Lv. Fengping et al. Bioorg. Med. Chem. Lett. 2016, 26(15), 3714-3718) and Lawesson's reagent is used to prepare 1,3,4-thiadiazole (Scheme 8) (B. Sybo et al. J. Mater. Chem. 2007, 17, 3406-3411; J. Slawinski et al. Eur J. Med. Chem. 2014, 82, 47-55). The obtained methyl ester was converted to the corresponding 2-(difluoromethyl)-1,3,4-oxadiazole by treatment first with hydrazine and then with difluoroacetic anhydride.

[0720]

[0721] Scheme 8: Synthesis of compounds with 1,3,4-oxadiazole or 1,3,4-thiadiazole ring as the central core.

[0722] The triazole-thiol core compound was obtained by reacting an optionally substituted 1,2,4-triazole-thiol with 2-(difluoromethyl)-5-(4-iodophenyl)-1,3,4-oxadiazole or 2-(difluoromethyl)-5-(3,4,5-trifluorophenyl)-1,3,4-oxadiazole in DMF in the presence of potassium carbonate with heating overnight. The reaction with 2-(difluoromethyl)-5-(4-iodophenyl)-1,3,4-oxadiazole was catalyzed by copper iodide and L-proline (Scheme 9) and heated at 80°C (Liang-Feng et al., Tetrahedron (2011), 67, 2878-2881). On the other hand, the reaction with 2-(difluoromethyl)-5-(3,4,5-trifluorophenyl)-1,3,4-oxadiazole proceeds even under mild conditions (70° C.) and without catalysis (Scheme 9) (Dudutiene et al., Bioorg. Med. Chem. (2013), 21(7), 2093-2106; WO03 / 062225).

[0723]

[0724] Scheme 9: Synthesis of compounds with a 1,2,4-triazole ring as the central core.

[0725] The 2-(difluoromethyl)-1,3,4-oxadiazole moiety was prepared from the corresponding hydrazide as described above. 4-Iodobenzohydrazide was synthesized starting from methyl 4-iodobenzoate in methanol at reflux in the presence of hydrazine monohydrate. 3,4,5-trifluorobenzohydrazide was obtained by treating 3,4,5-trifluorobenzoic acid with EDC, HOBt, and DIPEA in the presence of hydrazine monohydrate.

[0726]

[0727] Scheme 10: Non-commercial synthesis of 1,2,4-triazole-thiols.

[0728] Many starting 1,2,4-triazole-thiols are commercially available. In some cases, they are synthesized according to the pathway shown in Scheme 10. The ring-opening intermediate is prepared from the carboxylic acid by activation with T3P and condensation with N-methylhydrazinethiocarboxamide in DMF in the presence of DIPEA (US2007 / 0232808). Cyclization of the ring-opening intermediate is achieved by adding aqueous NaOH to the reaction mixture.

[0729] Compounds with a 1,2,3-triazole core structure with B═C and M═N were prepared via copper-catalyzed azide-alkyne cycloaddition under the described conditions. The alkynyl intermediates were prepared via a Grignard reaction from the common intermediate 2-(4-(bromomethyl)aryl)-5-(difluoromethyl)-1,3,4-oxadiazole in the presence of a catalytic amount of Pd(dppf)Cl2·DCM complex. In some cases, the 2-(difluoromethyl)-1,3,4-oxadiazole moiety was introduced via a hydrazide in the final step. When not commercially available, azides are prepared from the corresponding arylboronic acid by treatment with tetrabutylammonium fluoride and trimethylsilyl azide in the presence of copper chloride as a catalyst (Yu et al. Chem. Eur. J. 2010 16(27), 7969–7972); or from the appropriate aryl iodide by reaction with sodium azide in the presence of sodium ascorbate, copper iodide and N,N'-dimethylethane-1,2-diamine (Wang et al. Tetrahedron Lett. 2011, 52, 3295–3297).

[0730] The following examples are intended to further illustrate the present invention but are not intended to limit the present invention.

[0731] Example 1: Synthesis of 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate A)

[0732] Step A

[0733]

[0734] 6-nicotinate methyl ester (4g, 1 equivalent) is dissolved in MeOH (25mL), then under stirring, hydrazine monohydrate (5 equivalents) is added. The mixture is refluxed for 3 hours (h). By LC-MS (and TLC), it is observed that the methyl ester is completely converted into hydrazide. Under vacuum, the reaction mixture is concentrated and dried. The white solid (3.93g) obtained is used for subsequent steps without further purification.

[0735] Step B

[0736]

[0737] The hydrazide obtained in step A (3.93 g, 1 equivalent) was dissolved in dry DMF (30 mL) under argon. Difluoroacetic anhydride (3 equivalents) was slowly added, maintaining the temperature below 30°C (ice / NaCl bath). After the addition was complete, the temperature was allowed to reach room temperature (rt). The flask was sealed and the reaction mixture was stirred at room temperature overnight. Complete conversion was observed by LC-MS.

[0738] Saturated NaHCO3 aqueous solution (aq.) was added to the reaction mixture to quench the excess difluoroacetic anhydride. Water was then added and the product was extracted with ethyl acetate (3x). The organic layers were collected together, washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude yellow oil (5.43 g) obtained was used in the next step without further purification.

[0739] Step C

[0740]

[0741] 2-(Difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole (1 g, 4.7 mmol, 1 eq) was dissolved in 20 mL of degassed carbon tetrachloride. N-bromosuccinimide (NBS, 1.2 eq) and azobisisobutyronitrile (AIBN, 0.04 eq) were added to the reaction mixture, which was stirred at 80° C. overnight.

[0742] The solution was diluted with water, extracted with DCM, dried over MgSO4 and concentrated to dryness under reduced pressure.

[0743] Purification by flash column chromatography (hexanes / EtOAc 9:1) afforded the desired product (623 mg, 45% yield) as a purple solid.

[0744] The following compounds were prepared according to the same procedure:

[0745]

[0746]

[0747] Example 2: Synthesis of 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate F)

[0748]

[0749] A solution of 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate F, 82 mg, 0.285 mmol, 1 eq) and sodium azide (1 eq) in 0.5 mL of DMSO was stirred at room temperature for 1 hour. Conversion was confirmed by LC-MS (98%). The reaction mixture was filtered and used directly in the next step.

[0750] The following compounds were prepared according to the same procedure:

[0751]

[0752] Example 3: Synthesis of 2-(4-(azidomethyl)-2,3-difluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate H)

[0753] Step A

[0754]

[0755] Methyl 2,3-difluoro-4-methylbenzoate (2 g, 10.7 mmmol, 1 eq) and N-bromosuccinimide (NBS, 1.05 eq) were dissolved in 40 mL of degassed carbon tetrachloride. Benzoyl peroxide (0.05 eq) was then added to the reaction mixture, which was stirred at 70 ° C overnight. The mixture was allowed to reach room temperature, then diluted with DCM and washed successively with saturated aqueous NaHCO 3 solution, water, and brine. The organic layer was separated, dried over MgSO 4 , filtered, and concentrated under reduced pressure to provide a colorless oil, which was purified by flash column chromatography (hexane / EtOAc 95:5) to provide the product (1.72 g, 6.49 mmol, 60.4% yield) as a white solid.

[0756] Step B

[0757]

[0758] A solution of methyl 4-(bromomethyl)-2,3-difluorobenzoate (1.72 g, 6.49 mmol, 1 eq) and sodium azide (1.4 eq) in 20 mL of DMSO was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure to provide the product as a yellow oil (1.41 g, 6.21 mmol, 95% yield), which was used in the next step without further purification.

[0759] Step C

[0760]

[0761] Methyl 4-(azidomethyl)-2,3-difluorobenzoate (1.38 g, 1 equivalent) was dissolved in MeOH (20 mL), and hydrazine monohydrate (4 equivalents) was added with stirring. The mixture was stirred at 65 ° C overnight. LC-MS (and TLC) showed that the methyl ester was completely converted to hydrazide. The reaction mixture was concentrated and the residue was triturated in water. The obtained white solid was filtered, washed with water and dried under vacuum (1.17 g, 84% yield). The product was used in the subsequent step without further purification.

[0762] Step D

[0763]

[0764] The hydrazide obtained in step C (584 mg, 1 equivalent) was dissolved in dry DMF (30 mL) under argon. Difluoroacetic anhydride (3 equivalents) was slowly added, maintaining the temperature below 30°C (ice / NaCl bath). After the addition was complete, the temperature was allowed to reach room temperature. The flask was sealed and the reaction mixture was stirred at room temperature overnight. Complete conversion was observed by LC-MS.

[0765] Saturated NaHCO3 aqueous solution was added to the reaction mixture to quench the excess difluoroacetic anhydride. Water was then added and the product was extracted with ethyl acetate (3x). The organic layers were collected together, washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4 and evaporated to dryness under reduced pressure. A sufficiently pure product (701 mg, 95% yield) was obtained as a solidified yellow oil and was used in the next step without further purification.

[0766] Starting from the corresponding bromides (Step B), the following building blocks were prepared following the same procedure:

[0767]

[0768]

[0769] Example 4: Synthesis of 2-(4-((5-(Benzo[b]thiophen-3-yl)-2H-tetrazol-2-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 207) and 2-(4-((5-(Benzo[b]thiophen-3-yl)-1H-tetrazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 288)

[0770] Step A

[0771]

[0772] A mixture of benzo[b]thiophene-3-carbonitrile (55 mg, 0.34 mmol, 1 eq), sodium azide (2 eq), and ammonium chloride (2 eq) in 1.5 mL of DMF was stirred at 110°C overnight. The reaction mixture was cooled to 0°C and diluted with water. Precipitation occurred. The solid was filtered and washed five times with water. The product was used in the next step without further purification.

[0773] Step B

[0774]

[0775] A mixture of 5-(1-benzothiophen-3-yl)-2H-tetrazole (65 mg, 0.321 mmol, 1 eq) and sodium hydride (1.1 eq) in 1 mL of DMF was stirred at room temperature for 1 hour. 2-[4-(bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate B, 111.5 mg, 1.2 eq) was added and the reaction mixture was stirred overnight. Complete conversion was observed by LC-MS. The reaction mixture was diluted with water. Precipitation occurred. The solid was recovered by filtration and submitted to prep-HPLC. 47.2 mg of 2-[4-[[5-(1-benzothiophen-3-yl)tetrazol-2-yl]methyl]phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (0.115 mmol, m / z 452.06 [M+ACN+H] + ) and 8 mg of 2-[4-[[5-(1-benzothiophen-3-yl)tetrazol-1-yl]methyl]phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (0.019 mmol, m / z 452.06 [M+ACN+H] + ).

[0776] The following compounds were synthesized according to the same procedure:

[0777]

[0778]

[0779]

[0780]

[0781] *[M+ACN+H] observed + .

[0782] Example 5: Synthesis of 5-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)benzo[d]oxazol-2-amine (Compound 7)

[0783] Step A

[0784]

[0785] 2-Amino-4-(2H-tetrazol-5-yl)phenol (150 mg, 0.85 mmol, 1 eq) and cyanogen bromide (89.7 mg, 0.85 mmol, 1 eq) were dissolved in DMF (5 mL) and the reaction mixture was stirred at 60 ° C overnight. Complete conversion to benzoxazole was observed by LC-MS. 2-[6-(bromomethyl)pyridin-3-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate A, 245.6 mg, 0.85 mmol, 1 eq) and potassium carbonate (234 mg, 1.69 mmol, 2 eq) were added and the reaction mixture was stirred at room temperature overnight. Complete conversion to the desired product was observed by LC-MS. The reaction mixture was diluted with water and the product was extracted with EtOAc. The organic phase was washed with aqueous sodium bicarbonate solution and brine, dried over Na2SO4, filtered and evaporated. The residual DMF was diluted with EtOAc. Precipitation occurred and the solid was filtered. After drying, the solid was suspended in MeOH and freeze-dried to afford the pure product (72.1 mg, 20.12% yield, m / z 412.34 [MH+]).

[0786] The following compounds were synthesized according to the same procedure:

[0787]

[0788] Example 6: Synthesis of 4-(5-(3-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)phenyl)thiazol-2-yl)morpholine (Compound 130)

[0789] Step A

[0790]

[0791] A solution of 3-(2-bromoacetyl)benzonitrile (500 mg, 1.23 mmol, 1 eq) and morpholine-4-carbothioamide (326.19 mg, 2.23 mmol, 1 eq) in ethanol (10 mL) was refluxed for 2 hours. The solvent was removed under reduced pressure. The product, 3-(2-morpholin-4-yl-1,3-thiazol-5-yl)benzonitrile, was obtained as a white solid and used without further purification.

[0792] Step B

[0793]

[0794] A mixture of 3-(2-morpholin-4-yl-1,3-thiazol-5-yl)benzonitrile (605.4 mg, 2.23 mmol, 1 eq), sodium azide (290.1 ​​mg, 4.46 mmol, 2 eq), and ammonium chloride (119.3 mg, 2.23 mmol, 1 eq) in DMF (10 mL) was stirred at 90°C overnight. Additional portions of sodium azide (1.0 eq) and ammonium chloride (1.0 eq) were added to achieve complete conversion. The reaction mixture was stirred at 90°C for 12 hours, then cooled to room temperature and concentrated by rotary evaporation. The reaction mixture was then diluted with water and cooled to 0°C. Acetic acid was added dropwise. Precipitation occurred, and the solid was collected by filtration, dried under vacuum, and used in the next step without further purification.

[0795] Step C

[0796]

[0797] 2-[6-(Bromomethyl)pyridin-3-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate A, 92.27 mg, 0.32 mmol, 1 eq) was added to a solution of 4-[5-[3-(2H-tetrazol-5-yl)phenyl]-1,3-thiazol-2-yl]morpholine (100 mg, 0.32 mmol, 1 eq) and potassium carbonate (87.93 mg, 0.64 mmol, 2 eq) in DMF (5 mL). The reaction mixture was stirred at room temperature overnight. Complete conversion was confirmed by LC-MS. The reaction mixture was diluted with water and precipitation occurred. The solid was filtered and purified by prep-HPLC to provide the pure product (87 mg, 0.16 mmol, 25.7% yield, m / z 523.94 [MH+]).

[0798] The following compounds were synthesized according to the same procedure:

[0799]

[0800] Example 7: Synthesis of 5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)benzo[d]oxazol-2-amine (Compound 152)

[0801] Step A

[0802]

[0803] A solution of 2-amino-4-(2H-tetrazol-5-yl)phenol (500 mg, 2.82 mmol, 1 eq), tert-butylchlorodimethylsilane (680.61 mg, 4.5 mmol, 1.6 eq) and imidazole (345.86 mg, 5.08 mmol, 1.8 eq) in DMF (4 mL) was stirred at room temperature overnight. Complete conversion was observed by LC-MS. The reaction mixture was diluted with water and precipitation occurred. The solid product (690 mg, 2.37 mmol, 83.9% yield) was filtered, washed with n-hexane, dried, and used in the next step without further purification.

[0804] Step B

[0805]

[0806] To a solution of 2-[tert-butyl(dimethyl)silyl]oxy-5-(2H-tetrazol-5-yl)aniline (120 mg, 0.41 mmol, 1 eq) and 2-[4-(bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate B, 130.9 mg, 0.45 mmol, 1.1 eq) in DMF (2 mL) was added potassium carbonate (114 mg, 0.824 mmol, 2 eq) and the reaction mixture was stirred at room temperature overnight. Complete conversion was confirmed by LC-MS. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude material was used in the next step without any purification.

[0807] Step C

[0808]

[0809] 2-Amino-4-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]phenol (96 mg, 0.197 mmol, 1 eq) and cyanogen bromide (22.98 mg, 0.217 mmol, 1.1 eq) were dissolved in EtOH (2 mL) and the reaction mixture was stirred at room temperature overnight. Complete conversion to benzoxazole was observed by LC-MS. The solvent was evaporated under reduced pressure and the crude product was purified by LC-MS to provide 14 mg of pure product (0.034 mmol, 17.4% yield, m / z 411.06 [MH+]).

[0810] Example 8: 5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)benzo[d]oxazol-2(3H)-one (Compound 225)

[0811] Step A

[0812]

[0813] A solution of 2-amino-4-(2H-tetrazol-5-yl)phenol (500 mg, 2.82 mmol, 1 eq), tert-butylchlorodimethylsilane (680.61 mg, 4.5 mmol, 1.6 eq) and imidazole (345.86 mg, 5.08 mmol, 1.8 eq) in DMF (4 mL) was stirred at room temperature overnight. Complete conversion was observed by LC-MS. The reaction mixture was diluted with water and precipitation occurred. The solid product (690 mg, 2.37 mmol, 83.9% yield) was filtered, washed with n-hexane, dried and used in the next step without any purification.

[0814] Step B

[0815]

[0816] Potassium carbonate (113.82 mg, 0.824 mmol, 2 eq) was added to a solution of 2-[tert-butyl(dimethyl)silyl]oxy-5-(2H-tetrazol-5-yl)aniline (120 mg, 0.41 mmol, 1 eq) and 2-[4-(bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate B, 130.9 mg, 0.45 mmol, 1.1 eq) in DMF (2 mL), and the resulting mixture was stirred at room temperature overnight. Complete conversion was confirmed by LC-MS. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude material was used in the next step without any purification.

[0817] Step C

[0818]

[0819] 1,1'-Carbonyldiimidazole (35.18 mg, 0.217 mmol, 1.1 equiv) was added to a solution of 2-amino-4-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]phenol (95 mg, 0.197 mmol, 1 equiv) in ACN (2 mL). The reaction mixture was stirred at 60°C. After one night, only 10% conversion was observed by LC-MS. An additional 2 equiv of CDI was added. After stirring at 100°C for 2 hours, triphosgene (29.26 mg, 0.099 mmol, 0.5 equiv) was added. The reaction mixture was stirred at 80°C for 1 hour. Complete conversion was observed. The solvent was evaporated under reduced pressure and the crude product was purified by prep-HPLC (13.9 mg, 0.034 mmol, 17.05% yield, m / z 409.7 [MH]).

[0820] Example 9: Synthesis of (3-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)phenyl)(morpholinyl)methanone (Compound 69)

[0821] Step A

[0822]

[0823] A mixture of 3-(1H-tetrazol-5-yl)benzoic acid (1.4 g, 7.4 mmol, 1 eq), HATU (4.2 g, 11 mmol, 1.5 eq), and DIPEA (3.2 mL, 18.4 mmol, 2.5 eq) in 12 mL of DMF was stirred at room temperature for 1 hour. Morpholine (705.5 mg, 8 mmol, 1.1 eq) was then added, and the resulting mixture was stirred at room temperature overnight. The DMF was removed under reduced pressure. The resulting slurry was purified by flash column chromatography (DCM / MeOH / NH3 8:2:0.2) to provide the product (1.12 g, 4.3 mmol, 58.6% yield) as a thick yellow oil.

[0824] Step B

[0825]

[0826] A mixture of morpholin-4-yl-[3-(2H-tetrazol-5-yl)phenyl]methanone (75 mg, 0.289 mmol, 1 eq) and sodium hydride (1.1 eq) in 1 mL of DMF was stirred at room temperature for 15 minutes (min). 2-[6-(bromomethyl)pyridin-3-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate A, 83.9 mg, 1 eq) was added and the reaction mixture was stirred overnight. Complete conversion was observed by LC-MS. The reaction mixture was diluted with water and precipitation occurred. The off-white solid was filtered, washed with water and dried. The crude product (~100 mg) obtained was purified by prep-HPLC using neutral conditions. The product was further purified by p-TLC (DCM / MeOH 97:3) to afford 12.5 mg (0.027 mmol, 9.22% yield) of pure product as a white solid (m / z 469.00 [MH+]).

[0827] The following compounds were synthesized according to the same procedure:

[0828]

[0829] Example 10: Synthesis of 3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)benzamide (Compound 75)

[0830] Step A

[0831]

[0832] A mixture of methyl 3-(1H-tetrazol-5-yl)benzoate (995 mg, 4.87 mmol, 1 equivalent) and sodium hydride (1.1 equivalents) in 6 mL of DMF was stirred at room temperature for 15 minutes. 2-[4-(bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate B, 1.4 g, 1 equivalent) was added and the reaction mixture was stirred at room temperature for 4 hours. Complete conversion was observed by LC-MS. The reaction mixture was diluted with water and precipitated. The white solid formed was filtered and washed with water. It was then dissolved in EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to provide a white solid (1.7 g), which was used in the next step without any further purification.

[0833] Step B

[0834]

[0835] Methyl 3-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]benzoate (1.7 g, 4.12 mmol, 1 equivalent) was dissolved in 30 mL of a 1:1 THF / water mixture and lithium hydroxide monohydrate was added. The reaction mixture was stirred at 50°C for 3 hours. Complete conversion was observed by LC-MS. The THF was removed under reduced pressure and more water was added. The aqueous solution was acidified with 1 M HCl and precipitation occurred. The white precipitate was filtered, washed with water, and dried. The product (1.3 g) was used in the next step without further purification.

[0836] Step C

[0837]

[0838] 3-[2-[[4-[[(2,2-difluoroacetyl)amino]carbamoyl]phenyl]methyl]tetrazol-5-yl]benzoic acid (1.34 g, 1 equivalent) was dissolved in dry DMF (10 mL) under argon. Difluoroacetic anhydride (3 equivalents) was slowly added, maintaining the temperature below 30°C (ice / NaCl bath). After the addition was complete, the temperature was allowed to reach room temperature. The flask was sealed and the reaction mixture was stirred at 70°C for 3 hours. Complete conversion was observed by LC-MS.

[0839] Water was added to the reaction mixture and precipitation occurred. The solid was filtered, washed with water and dried. The product was used in the next step without further purification.

[0840] Step D

[0841]

[0842] A mixture of 3-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]benzoic acid (100 mg, 0.25 mmol, 1 eq), HATU (2 eq) and DIPEA (3 eq) in 2.5 mL of DMF was stirred at room temperature for 30 minutes. A clear yellow solution was obtained. A solution of 25% aqueous ammonia (10 eq) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting brown oil was purified by prep-HPLC to provide the product as a white solid (15.1 mg, 0.036 mmol, 14.2% yield, m / z 397.95 [MH+]).

[0843] The following compounds were synthesized according to the same procedure:

[0844]

[0845] Example 11: Synthesis of 2-(difluoromethyl)-5-(4-((5-(3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)phenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 111)

[0846] Step A

[0847]

[0848] Tetrakis(triphenylphosphine)palladium(0) (76.48 mg, 0.066 mmol, 0.08 eq) was added to a suspension of tert-butyl-3-bromo-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (250 mg, 0.827 mmol, 1 eq), (3-cyanophenyl)boronic acid (145.88 mg, 0.99 mmol, 1.2 eq) and cesium carbonate (808.7 mg, 2.48 mmol, 3 eq) in 9 mL of 1:2 water / dioxane. The reaction mixture was degassed and stirred at 80° C. for 2 hours. It was then diluted with EtOAc and stirred by The organic phase was washed with water (twice), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was used in the next step without any purification.

[0849] Step B

[0850]

[0851] Sodium azide (2.5 equivalents) and ammonium acetate (2.5 equivalents) were added to a solution of tert-butyl 3-(3-cyanophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate in DMSO (5 mL). The reaction mixture was stirred at 80°C for 48 hours and then diluted with water and ethyl acetate. The two phases were separated, and the aqueous phase was acidified with 1M HCl (pH = 4) and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was used in the next step without further purification.

[0852] Step C

[0853]

[0854] Potassium carbonate (78 mg, 0.562 mmol, 2 eq) was added to a solution of tert-butyl 3-[3-(2H-tetrazol-5-yl)phenyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (129 mg, 0.28 mmol, 1 eq) and 2-[4-(bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate B, 89 mg, 0.309 mmol, 1.1 eq) in 1 mL of DMF, and the resulting mixture was stirred at room temperature overnight. Complete conversion was confirmed by LC-MS. The reaction mixture was diluted with water, and precipitation occurred. The solid was filtered and used in the next step without further purification.

[0855] Step D

[0856]

[0857] Trifluoroacetic acid (0.119 mL, 15 eq) was added to a solution of tert-butyl 3-[3-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]phenyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (70 mg, 0.103 mmol, 1 eq) in dichloromethane (1 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by LC-MS. The reaction mixture was diluted with additional DCM and washed with NaHCO (3 times). The organic phase was dried over NaSO, filtered and dried under reduced pressure. The crude product was purified by prep-HPLC under neutral conditions to provide 4.1 mg (0.008 mmol, 8.2% yield) of pure product (m / z 475.97 [MH]).

[0858] The following compounds were synthesized according to the same procedure:

[0859]

[0860] Example 12: Synthesis of 2-(difluoromethyl)-5-(4-((5-(6-(piperazin-1-yl)pyridin-3-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 148)

[0861] Step A

[0862]

[0863] 6-Piperazin-1-ylpyridine-3-carbonitrile (600 mg, 3.18 mmol, 1 eq), sodium azide (455.9 mg, 7.01 mmol, 2.2 eq) and ammonium chloride (375.11 mg, 7.01 mmol, 2.2 eq) were suspended in DMSO (6 mL) and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature and di-tert-butyl dicarbonate (1391.4 mg, 6.37 mmol, 2 eq) was added. After stirring overnight, the reaction mixture was diluted with water and acidified with acetic acid (pH = 3). The product precipitated as a white solid, which was collected by filtration, washed with water and used in the next step without any further purification (980 mg, 2.8 mmol, 88% yield).

[0864] Step B

[0865]

[0866] Potassium carbonate (79.2 mg, 0.57 mmol, 2 eq) was added to a solution of tert-butyl 4-[5-(2H-tetrazol-5-yl)pyridin-2-yl]piperazine-1-carboxylate (100 mg, 0.29 mmol, 1 eq) and 2-[4-(bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate B, 83 mg, 0.29 mmol, 1 eq) in 2 mL of DMF. The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with water. The resulting precipitate was recovered by filtration, dried, and used in the next step without further purification.

[0867] Step C

[0868]

[0869] Tert-butyl 4-(5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)pyridin-2-yl)piperazine-1-carboxylate was suspended in DCM and TFA (10 equiv.) was added. The reaction mixture was stirred at room temperature for 2 hours. Complete conversion was observed by LC-MS. The reaction mixture was diluted with EtOAc and washed twice with a solution of sodium bicarbonate and brine. The organic phase was dried over Na2SO4, filtered and evaporated to provide the crude product, which was purified by prep-HPLC under neutral conditions. 24 mg (0.054 mmol, 19% yield) of pure product (m / z 440.05 [MH+]) were obtained.

[0870] The following compounds were synthesized according to the same procedure:

[0871]

[0872] *[M+ACN+H] observed + .

[0873] Example 13: Synthesis of N-(5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2-(methylamino)phenyl)morpholine-4-carboxamide (Compound 176) and 4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-N-1-methylbenzene-1,2-diamine (Compound 164)

[0874] Step A

[0875]

[0876] 5-(4-Fluoro-3-nitrophenyl)-2H-tetrazole (1 g, 4.78 mmol, 1 equivalent) was dissolved in DMF (10 mL). A 2M solution of methylamine in THF (10 equivalents) was added and the reaction mixture was stirred at room temperature overnight. Complete conversion was confirmed by LC-MS. The reaction mixture was evaporated under reduced pressure and the crude product was used in the next step without any further purification.

[0877] Step B

[0878]

[0879] Under inert gas, palladium (0.2 equivalent) supported on activated carbon was added to a solution of N-methyl-2-nitro-4-(2H-tetrazol-5-yl)aniline (1 g, 4,5 mmol, 1 equivalent) in MeOH (150 mL). The flask was then filled with H and the reaction mixture was stirred at room temperature overnight. Precipitation occurred. The solid (300 mg, 1.57 mmol, 34.7% yield) was filtered through sintered glass and used in the next step.

[0880] Step C

[0881]

[0882] 1-N-Methyl-4-(2H-tetrazol-5-yl)benzene-1,2-diamine (300 mg, 1.57 mmol, 1 eq) was suspended in DMF (3 mL). 2-[4-(bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate B, 300.92 mg, 1.04 1, 0.66 eq) and potassium carbonate (326.98 mg, 2.36 mmol, 1.5 eq) were added and the reaction mixture was stirred at room temperature overnight. Complete conversion was observed by LC-MS. The reaction mixture was diluted with water and the product was extracted with EtOAc. The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure to provide the crude product, which was purified by prep-HPLC. 60 mg of pure product (0.15 mmol, 9.5% yield) (Compound 164, m / z 399.01 [MH+]) was obtained. Also recovered were 16 mg of 4-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]-1-N-methylbenzene-1,2-diamine (0.04 mmol) (m / z 399.01 [MH+]).

[0883] Step D

[0884]

[0885] Morpholine-4-carbonyl chloride (12.4 mg, 0.083 mmol, 1.1 eq) was added to a solution of 4-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]-1-N-methylbenzene-1,2-diamine (30 mg, 0.075 mmol, 1 eq) in pyridine (2 mL). The reaction mixture was stirred at 40 ° C for 1 hour. Complete conversion was observed by LC-MS. The solvent was evaporated under reduced pressure and the crude material was purified by prep-HPLC. 16.6 mg (0.032 mmol, 42.9% yield) of pure product (Compound 176, m / z 512.05 [MH + ]) was obtained.

[0886] Example 14: Synthesis of 4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)-2-(morpholine-4-carboxamido)phenylmorpholine-4-carboxylate (Compound 196) and 2-amino-4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)phenylmorpholine-4-carboxylate (Compound 160)

[0887] Step A

[0888]

[0889] A solution of 2-amino-4-(2H-tetrazol-5-yl)phenol (500 mg, 2.82 mmol, 1 eq), tert-butylchlorodimethylsilane (680.61 mg, 4.5 mmol, 1.6 eq) and imidazole (345.86 mg, 5.08 mmol, 1.8 eq) in DMF (4 mL) was stirred at room temperature overnight. Complete conversion was observed by LC-MS. The reaction mixture was diluted with water and precipitation occurred. The solid product (690 mg, 2.37 mmol, 83.9% yield) was filtered, washed with n-hexane, dried and used in the next step without any purification.

[0890] Step B

[0891]

[0892] 2-[4-(Bromomethyl)-3,5-difluorophenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate C, 123 mg, 0.377 mmol, 1.1 equiv) was added to a solution of 2-[tert-butyl(dimethyl)silyl]oxy-5-(2H-tetrazol-5-yl)aniline (100 mg, 0.343 mmol, 1 equiv) and triethylamine (0.096 mL, 0.686 mmol, 2 equiv) in acetonitrile (3 mL). The resulting mixture was stirred at room temperature for 4 days. Complete conversion and partial deprotection of the hydroxyl group were observed by LC-MS. Tetrabutylammonium fluoride (54 mg, 0.206 mmol, 0.6 equiv) was added to the reaction mixture. Complete deprotection was observed. The solvent was evaporated under reduced pressure and the crude material was purified by prep-HPLC. 54 mg of product (0.103 mmol, 29.9% yield) was obtained.

[0893] Step C

[0894]

[0895] Morpholine-4-carbonyl chloride (23 mg, 0.154 mmol, 1.2 eq) was added dropwise to a solution of 2-amino-4-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]tetrazol-5-yl]phenol (54 mg, 0,128 mmol, 1 eq) in pyridine (2 mL). The reaction mixture was stirred at room temperature overnight. Complete conversion of the starting material was observed by LC-MS. The solvent was evaporated under reduced pressure and the crude product was purified by prep-HPLC. 6 mg of [4-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]tetrazol-5-yl]-2-(morpholine-4-carbonylamino)phenyl]-morpholine-4-carboxylate (compound 196, m / z 535.0 [MH+]) and 9.7 mg of [2-amino-4-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]tetrazol-5-yl]phenyl]-morpholine-4-carboxylate (compound 160, m / z 647.99 [MH+]) were obtained.

[0896] The following compounds were synthesized according to the same procedure:

[0897]

[0898] Example 15: Synthesis of N-(5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)pyridin-3-yl)morpholine-4-carboxamide (Compound 199)

[0899] Step A

[0900]

[0901] 3-Bromo-5-(2H-tetrazol-5-yl)pyridine (200 mg, 0.885 mmol, 1 eq) and potassium carbonate (244.59 mg, 1.77 mmol, 2 eq) were suspended in DMF (3 mL). After 15 minutes, 2-[4-(bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate B, 281.37 mg, 0.973 mmol, 1.1 eq) was added to the suspension and the reaction mixture was stirred at room temperature overnight. Complete conversion was observed by LC-MS. Water was added to the reaction mixture and precipitation occurred. The solid was filtered and purified by prep-HPLC to provide the pure product.

[0902] Step B

[0903]

[0904] Tris(dibenzylideneacetone)dipalladium(0) (23.73 mg, 0.026 mmol, 0.1 eq) and Xantphos (29.95 mg, 0.052 mmol, 0.2 eq) were added to a solution of 2-[4-[[5-(5-bromopyridin-3-yl)tetrazol-2-yl]methyl]phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (125 mg, 0.259 mmol, 1 eq), morpholine-4-carboxamide (67.44 mg, 0.518 mmol, 2 eq) and cesium carbonate (168.84 mg, 0.518 mmol, 2 eq) in degassed 1,4-dioxane (2 mL). The reaction mixture was degassed with Ar for 20 min and heated to 80° C. overnight. The reaction mixture was diluted with EtOAc and stirred for 2 hours. The product was filtered. The filtrate was washed twice with aqueous NaHCO₃ and brine, dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The crude product was purified by prep-HPLC under neutral conditions. The pure product (m / z 484.05 [MH⁺]) (2.3 mg, 0.004 mmol, 1.65% yield) was obtained.

[0905] Example 16: Synthesis of 7'-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)-1',4'-dihydro-3'H-spiro[cyclopentane-1,2'-quinoxaline]-3'-one (Compound 27)

[0906] Step A

[0907]

[0908] 1,8-Diazabicyclo[5.4.0]undec-7-ene (8.9 mL, 60.03 mmol, 1 eq) was added dropwise to a mixture of cyclopentanone (5 g, 60.03 mmol, 1 eq) and dry chloroform (9.7 mL, 120 mmol, 2 eq) under argon. The reaction mixture was stirred at room temperature for 48 hours, then diluted with dichloromethane (25 mL), washed with 1N HCl, water, and brine, dried over NaSO, and concentrated under reduced pressure. The residual dark liquid was used in the next step without further purification.

[0909] Step B

[0910]

[0911] To a solution of 3,4-diaminobenzonitrile (700 mg, 5.26 mmol, 1 eq), 1-(trichloromethyl)cyclopentan-1-ol (2.1 g, 10.5 mmol, 2 eq) and benzyltriethylammonium chloride (120.28 mg, 0.52 mmol, 0.1 eq) in DCM (40 mL) was added 50% aqueous sodium hydroxide solution (1.4 mL) dropwise at 0°C under Ar. The reaction mixture was stirred at 0°C for 1 hour and then at room temperature overnight. The reaction mixture was diluted with water until complete dissolution. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / EtOAc 85:15 to 1:1) to provide the desired product as a white solid (isomeric structure confirmed by NOESY).

[0912] Step C

[0913]

[0914] A mixture of 2-oxospiro[1,4-dihydroquinoxaline-3,1'-cyclopentane]-6-carbonitrile (240 mg, 1.06 mmol, 1 eq), sodium azide (137.3 mg, 2.11 mmol, 2 eq), and ammonium chloride (112.9 mg, 2.11 mmol, 2 eq) in DMF was stirred at 100°C overnight. Water (15 mL) was added to the reaction mixture, followed by ethyl acetate (15 mL). The layers were separated. Acetic acid (300 μL, 4 eq) was added to the aqueous phase, and precipitation occurred after a few minutes. The white solid was filtered, washed with water, and dried. The product was used in the next step without further purification.

[0915] Step D

[0916]

[0917] 6-(2H-tetrazol-5-yl)spiro[1,4-dihydroquinoxaline-3,1'-cyclopentane]-2-one (120 mg, 0.444 mmol, 1 eq) and potassium carbonate (67.5 mg, 0.488 mmol, 1.1 eq) were suspended in DMF (3 mL). After 15 minutes, 2-(4-(bromomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate B, 129 mg, 0.444 mmol, 1 eq) was added to the suspension and the reaction mixture was stirred at room temperature for 1 hour. Complete conversion was observed by LC-MS. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The organic phase was washed several times with aqueous sodium bicarbonate solution and brine. After concentration under reduced pressure, the residue (120 mg) was purified by prep-HPLC using neutral conditions. The pure product was isolated as a white solid (m / z 480.12 [MH+]) (26 mg, 0.054 mmol, 12% yield).

[0918] The following compounds were synthesized according to the same procedure:

[0919]

[0920] Example 17: Synthesis of 7-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 173)

[0921] Step A

[0922]

[0923] Sodium hydride (69.69 mg, 1.74 mmol, 1.2 eq) was added to a solution of 1-oxo-3,4-dihydro-2H-isoquinoline-7-carbonitrile (250 mg, 1.45 mmol, 1 eq) in DMF (10 mL). After 15 minutes, iodomethane (0.18 mL, 2.9 mmol, 2 eq) was added to the suspension, and the dark brown reaction mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the product was extracted with ethyl acetate. The aqueous layer was basified (K2CO3) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The product was used directly in the next step.

[0924] Step B

[0925]

[0926] A mixture of 2-methyl-1-oxo-3,4-dihydroisoquinoline-7-carbonitrile (234 mg, 1.26 mmol, 1 eq), sodium azide (163 mg, 2.51 mmol, 2 eq), and ammonium chloride (134 mg, 2.51 mmol, 2 eq) in DMF (3 mL) was stirred at 100° C. Water (15 mL) was added to the reaction mixture, followed by 1N HCl. The precipitated white solid was filtered, washed with water, and dried. The product was used in the next step without further purification.

[0927] Step C

[0928]

[0929] 2-Methyl-7-(2H-tetrazol-5-yl)-3,4-dihydroisoquinolin-1-one (100 mg, 0.436 mmol, 1 eq) and potassium carbonate (66 mg, 0.48 mmol, 1.1 eq) were suspended in DMF (1.5 mL). After 15 minutes, 2-[4-(bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate B, 126 mg, 0.436 mmol, 1 eq) was added to the suspension and the reaction mixture was stirred at room temperature for 1 hour. Complete conversion was observed by LC-MS. Water was added to the reaction mixture and the product was extracted into ethyl acetate. The organic phase was washed several times with saturated aqueous NaHCO3 and brine. After concentration under reduced pressure, the residue was purified by prep-HPLC using neutral conditions. The pure product (m / z 438.07 [MH+]) (95 mg, 0.217 mmol, 50% yield) was isolated as a white solid.

[0930] Example 18: Synthesis of 7-(2-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-2H-tetrazol-5-yl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 229)

[0931]

[0932] To a solution of 7-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]-3,4-dihydro-2H-isoquinolin-1-one (compound 83, 50 mg, 0.118 mmol, 1 equiv) in DMF was added sodium hydride (5 mg, 0.124 mmol, 1.05 equiv) at room temperature. After 30 minutes, iodomethane (18 mg, 0.130 mmol, 1.1 equiv) was added, and the reaction mixture was stirred at room temperature for 4 hours. An additional 0.5 equiv of sodium hydride and 1 equiv of iodomethane were added. The reaction mixture was stirred at room temperature overnight, then diluted with EtOAc and washed with NaHCO (4 times) and brine. The organic phase was dried over NaSO, filtered, and evaporated in vacuo. The crude material was purified by prep-HPLC and the pure product (m / z 452.03 [MH+]) (4 mg, 0.008 mmol, 6.5% yield) was obtained.

[0933] Example 19: Synthesis of N-(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)benzamide (Compound 156)

[0934]

[0935] Benzoyl chloride (42 mg, 0.29 g, 1.1 eq) and triethylamine (0.046 mL, 0.325 mmol, 1.2 eq) were added to a solution of 3-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]aniline (compound 129, 100 mg, 0.271 mmol, 1 eq) in DMF (2 mL). The reaction mixture was stirred at room temperature overnight and then diluted with water. Precipitation occurred. The solid was recovered by filtration and purified by prep-HPLC. The pure product (m / z 474.12 [MH+]) (31 mg, 0.064 mmol, 24% yield) was obtained.

[0936] Example 20: Synthesis of 1-(4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)piperidin-1-yl)ethan-1-one (Compound 257)

[0937] Step A

[0938]

[0939] To a solution of 4-(2H-tetrazol-5-yl)piperidine hydrochloride (125 mg, 0.659 mmol, 1 eq) in pyridine (1 mL) was added acetic anhydride (0.075 mL, 0.791 mmol, 1.2 eq). The reaction mixture was stirred at 60° C. overnight. The solvent was evaporated under reduced pressure and the crude material was used in the next step without any purification.

[0940] Step B

[0941]

[0942] 1-[4-(2H-tetrazol-5-yl)piperidin-1-yl]ethanone (128 mg, 0.656 mmol, 1 eq) and sodium hydride (65.6 mg, 1.64 mmol, 2.5 eq) were suspended in DMF (2 mL) and stirred to obtain a clear solution. 2-[4-(bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate B, 208.5 mg, 0.721 mmol, 1.1 eq) was then added and the reaction mixture was stirred at room temperature overnight. Complete conversion was observed by LC-MS. The reaction mixture was diluted with water and precipitation occurred. The solid was filtered and purified by prep-HPLC. The pure product (m / z 404.25 [MH+]) (16.6 mg, 0.041 mmol, 6.2% yield) was obtained.

[0943] Example 21: Synthesis of 3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-4-fluoro-N,N-dimethylbenzenesulfonamide (Compound 163)

[0944] Step A

[0945]

[0946] To a solution of 4-fluoro-3-(2H-tetrazol-5-yl)benzenesulfonyl chloride (100 mg, 0.381 mmol, 1 eq) and triethylamine (0.58 mL, 0.419 mmol, 1.1 eq) in THF (3 mL) was added dimethylamine (0.21 mL, 0.419 mmol, 1.1 eq) dropwise at -20 ° C. The reaction mixture was stirred at -20 ° C for 15 minutes and then warmed to 0 ° C. Complete conversion was observed by LC-MS after 1 hour. The solvent was evaporated under reduced pressure. The residue was dissolved in EtOH and the solvent was evaporated under reduced pressure. The crude material was used in the next step without purification.

[0947] Step B

[0948]

[0949] 4-Fluoro-N,N-dimethyl-3-(2H-tetrazol-5-yl)benzenesulfonamide (60 mg, 0.221 mmol, 1 eq) and potassium carbonate (61.14 mg, 0.442 mmol, 2 eq) were suspended in DMF (2 mL). After 30 minutes, 2-[4-(bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate B, 63.94 mg, 0.221 mmol, 1 eq) was added to the suspension and the reaction mixture was stirred at room temperature overnight. Complete conversion was observed by LC-MS. The reaction mixture was diluted with EtOH, washed with NaHCO3 and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by prep-HPLC to provide the pure product (24 mg, 0.05 mmol, 25% yield, m / z 479.93 [MH+]).

[0950] Example 22: Synthesis of N-(5-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-2H-tetrazol-5-yl)pyridin-2-yl)-2,2-difluoroacetamide (Compound 68)

[0951] Step A

[0952]

[0953] Sodium hydride (1.7 eq) was added to a solution of 5-(2H-tetrazol-5-yl)pyridin-2-amine (50 mg, 0.31 mmol, 1 eq) in 2 mL of THF at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Methyl 2-(chloromethyl)pyrimidine-5-carboxylate (1 eq) was added to the reaction mixture and stirred at room temperature overnight. Conversion was monitored by LC-MS, and the formation of both 2,5- and 1,5-substituted regioisomers was detected. The reaction mixture was diluted with EtOAc, washed with water, saturated aqueous NaHCO₃ (4 times), and brine, dried over MgSO₄, evaporated under vacuum, and dried to give a nearly pure compound (77 mg, 0.25 mmol, 80% yield), which was used in the next step without further purification. The regioisomer ratio was determined to be 9:1 by NMR.

[0954] Step B

[0955]

[0956] A suspension of methyl 2-[[5-(6-aminopyridin-3-yl)tetrazol-2-yl]methyl]pyrimidine-5-carboxylate (75 mg, 0.24 mmol, 1 eq) and hydrazine monohydrate (5 eq) in MeOH (2 mL) was stirred at 70° C. for 6 h. Complete conversion to the desired product was observed by TLC (DCM / MeOH 95:5) and confirmed by LC-MS. The reaction mixture was evaporated under vacuum and re-evaporated from acetonitrile to give the title compound (75 mg, 0.24 mmol, 100% yield). The product was used in the subsequent step without further purification.

[0957] Step C

[0958]

[0959] To a solution of 2-((5-(6-aminopyridin-3-yl)-2H-tetrazol-2-yl)methyl)pyrimidine-5-carboxylic acid hydrazide (75 mg, 0.24 mmol, 1 eq) in DMF (2 mL) was added portionwise difluoroacetic anhydride (1 eq). After 30 min, all the starting material was converted into the ring-opening intermediate difluoroacetyl hydrazide. Cyclization of the oxadiazole ring and concomitant aminopyridyl acylation were carried out by portionwise addition of additional difluoroacetic anhydride (4 x 1 eq), with conversion monitored by LC-MS. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO₃ (4 times) and brine, dried over Na₂SO₄, evaporated under vacuum and dried. The crude product was purified by prep-HPLC, thus obtaining the pure title compound (25 mg, 0.056 mmol, 23% yield, m / z 451.10 [MH⁺]).

[0960] Example 23: Synthesis of 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 5)

[0961]

[0962] Copper (II) sulfate pentahydrate (19 mg, 0.3 eq., 0.5 M aqueous solution) and sodium L-ascorbate (25 mg, 0.5 eq., 1 M aqueous solution) were added to a solution of 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate F, 70 mg, 0.279 mmol, 1.1 eq.) and 5-ethynylpyridin-2-amine (30 mg, 0.251 mmol, 1 eq.) in 1 mL of DMSO. The reaction mixture was stirred at 40° C. for 2 hours. Complete conversion of the starting material was detected by LC-MS. The reaction mixture was filtered through a syringe filter and submitted to prep-HPLC without any further treatment. After evaporation of the fractions, 45 mg of the target compound (0.122 mmol, 48% yield) was obtained as an off-white solid (m / z 371.11 [MH+]).

[0963] The following compounds were synthesized according to the same procedure:

[0964]

[0965]

[0966] *[M+ACN+H] observed + .

[0967] Example 24: Synthesis of 5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,3-difluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 21)

[0968]

[0969] Copper (II) sulfate pentahydrate (4 mg, 0.1 eq., 0.5 M aqueous solution) and sodium L-ascorbate (16 mg, 0.5 eq., 1 M aqueous solution) were added to a solution of 2-(4-(azidomethyl)-2,3-difluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate H, 48 mg, 0.168 mmol, 1 eq.) and 5-ethynylpyridin-2-amine (20 mg, 0.168 mmol, 1 eq.) in 1 mL of DMSO. The reaction mixture was stirred at 40 ° C for 2 hours. Complete conversion of the starting material was detected by LC-MS. The reaction mixture was filtered through a syringe filter and submitted to prep-HPLC without any further treatment. After evaporation of the fractions, 19 mg of the target compound (0.05 mmol, 28% yield) (m / z 406.10 [MH + ]) were obtained as an off-white solid.

[0970] The following compounds were synthesized according to the same synthetic route:

[0971]

[0972] Example 25: Synthesis of 5-(1-((6-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 198)

[0973] Step A

[0974]

[0975] To a stirred solution of methyl 6-(bromomethyl)pyridazine-3-carboxylate (1 eq), tert-butyl (5-ethynylpyridin-2-yl)carbamate (85 mg, 0.389 mmol, 1 eq), and sodium azide (1.1 eq) in DMSO (2 mL) was added 0.5 M aqueous copper(II) sulfate pentahydrate (234 μL, 0.3 eq) and 1.0 M aqueous sodium L-ascorbate (195 μL, 0.5 eq). The resulting mixture was stirred at room temperature for 1 hour. An additional 0.4 eq of methyl 6-(bromomethyl)pyridazine-3-carboxylate was added over 2 hours to achieve complete conversion, which was monitored by LC-MS. The reaction mixture was diluted with EtOAc, washed with water, saturated aqueous NaHCO (3 times), and brine, dried, and evaporated under reduced pressure. The resulting residue was used in the next step without purification (115 mg, 0.28 mmol, 72% yield).

[0976] Step B

[0977]

[0978] A suspension of methyl 6-((4-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazine-3-carboxylate (115 mg, 0.28 mmol, 1 eq) and hydrazine monohydrate (5 eq) in MeOH (5 mL) was stirred at 70 ° C for 3 hours. Complete conversion to the desired product was observed by LC-MS. The reaction mixture was evaporated in vacuo and re-evaporated with acetonitrile to provide the target compound (115 mg, 0.28 mmol, 100% yield) as an off-white suspension. The product was used in the subsequent step without further purification.

[0979] Step C

[0980]

[0981] Difluoroacetic anhydride (3 eq) was added to a solution of tert-butyl (5-(1-((6-(hydrazinecarbonyl)pyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)carbamate (35 mg, 0.085 mmol, 1 eq) in DMF (2 mL). After 30 min, all the starting material was converted to the ring-opening intermediate. Some Boc deprotection / difluoroacylation side reaction occurred. Cyclization was carried out by adding Burgess reagent (3 eq + 1 eq until completion) and the conversion was monitored by LC-MS. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 (4 times) and brine, dried over Na2SO4, evaporated under vacuum and dried. The obtained nearly pure title compound (22 mg, 0.047 mmol, 54% yield) was used in the next step without purification.

[0982] Step D

[0983]

[0984] A solution of tert-butyl (5-(1-((6-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)carbamate (15 mg, 0.032 mmol, 1 equiv) and TFA (50 μL) in DCM (300 μL) was stirred at room temperature for 3 h. Complete conversion was detected by LC-MS. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO (twice) and brine, dried over NaSO and evaporated under vacuum. The residue obtained was purified by prep-HPLC. The title compound (3 mg, 0.007 mmol, 22% yield) was obtained as a white solid (m / z 372.11 [MH]).

[0985] Example 26: Synthesis of 6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)isoindolin-1-one (Compound 109)

[0986] Step A

[0987]

[0988] Copper(II) sulfate pentahydrate 0.5 M aqueous solution (572 μL, 0.3 eq) and sodium L-ascorbate 1.0 M aqueous solution (477 μL, 0.5 eq) were added to a stirred solution of 2-[4-(bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate B, 1 eq), 6-ethynyl-2,3-dihydroisoindole-1-one (150 mg, 0.954 mmol, 1 eq), and sodium azide (1 eq) in DMSO (2 mL). The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water, and the precipitate was filtered off. Purification by prep-HPLC (C18, water / ACN) afforded the product in 32% yield (132 mg, 0.32 mmol, m / z 409.11 [MH+]).

[0989] The following compounds were synthesized according to the same procedure:

[0990]

[0991] Example 27: Synthesis of N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine (Compound 10)

[0992] Step A

[0993]

[0994] Copper (II) sulfate pentahydrate (0.2 eq., 0.5 M aqueous solution) and sodium L-ascorbate (0.4 eq., 1 M aqueous solution) were added to a solution of 2-(4-(azidomethyl)-phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate G) (60 mg, 0.239 mmol, 1 eq.) and 5-ethynylpyridin-2-amine (36 mg, 0.311 mmol, 1.3 eq.) in 1 mL of DMSO. The reaction mixture was stirred at 40 ° C for 2 hours. Complete conversion of the starting material was detected by LC-MS. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure to provide a brown solid, which was used directly in the next step (84 mg, 0.228 mmol, 95% yield).

[0995] Step B

[0996]

[0997] Mercury(II) chloride (1.1 eq) was added to a solution of 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline (84 mg, 0.228 mmol, 1 eq), N,N'-di(tert-butoxycarbonyl)imidazolidine-2-thione (1 eq), and triethylamine (1.3 eq) in 1 mL of DCM at 0°C. The resulting mixture was stirred at 0°C for 1 hour and at room temperature for 2 days. The reaction mixture was diluted with water and DCM, filtered, and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to provide a yellow oil that was used directly in the next step (145 mg, 0.228 mmol, 100% yield).

[0998] Step C

[0999]

[1000] Di-tert-butyl 2-((4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)imino)imidazolidine-1,3-dicarboxylate (145 mg, 0.228 mmol, 1 eq) was dissolved in 2 mL of DCM and TFA (20 eq) was added. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3 and brine. During the brine wash, precipitation occurred. The solid was filtered, washed with water, and dried under vacuum to obtain the title compound (55 mg, 0.121 mmol, 53% yield, m / z 436.95 [MH+]).

[1001] The following compounds were synthesized according to the same procedure:

[1002]

[1003] Example 28: Synthesis of (5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)methanamine (Compound 155)

[1004] Step A

[1005]

[1006] Tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate (500 mg, 1.74 mmol, 1 eq) was dissolved in triethylamine (9.7 mL, 40 eq) and the resulting mixture was degassed. Ethylene (trimethyl) silane (1.2 eq) was then added to the reaction mixture, which was degassed. Bis (triphenylphosphine) palladium (II) dichloride (0.02 eq) and copper (I) iodide (0.04 eq) were added, and after degassing, the reaction mixture was stirred at 70 ° C overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic phases were dried over MgSO 4 , filtered and concentrated to provide the crude product, which was used in the next step without any further purification (530 mg, 1.74 mmol, 100% yield).

[1007] Step B

[1008]

[1009] Tert-butyl ((5-((trimethylsilyl)ethynyl)pyridin-2-yl)methyl)carbamate (530 mg, 1.74 mmol, 1 eq) was dissolved in 5 mL of THF. Tetrabutylammonium fluoride (2 eq) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water. The organic phase was dried over NaSO and evaporated. The crude residue was purified by flash column chromatography (0-1% MeOH / DCM) to provide the pure product (305 mg, 1.31 mmol, 74% yield).

[1010] Step C

[1011]

[1012] Copper (II) sulfate pentahydrate (0.2 eq., 0.5 M aqueous solution) and sodium L-ascorbate (0.4 eq., 1 M aqueous solution) were added to a solution of 2-(4-(azidomethyl)-phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate G, 16 mg, 0.062 mmol, 1.1 eq.) and tert-butyl N-[(5-ethynylpyridin-2-yl)methyl]carbamate (13 mg, 0.056 mmol, 1 eq.) in 300 μL of DMSO. The reaction mixture was stirred at 40° C. for 2 hours. Complete conversion of the starting material was detected by LC-MS. Water was added to the reaction mixture and extracted with MTBE. The organic layer was washed with brine, dried over MgSO 4 , filtered, and concentrated under reduced pressure to provide the desired product, which was used in the next step without further purification (23 mg, 0.043 mmol, 76% yield).

[1013] Step D

[1014]

[1015] Tert-butyl ((5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)methyl)carbamate (23 mg, 0.043 mmol, 1 eq) was dissolved in 2 mL of DCM and TFA (20 eq) was added. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with saturated aqueous NaHCO₃ and brine. The organic phase was dried over Na₂SO₄, filtered, and evaporated. The crude residue was purified by prep-HPLC to afford the title compound (6.1 mg, 0.016 mmol, 30% yield, m / z 384.2 [MH⁺]).

[1016] The following compounds were synthesized according to the same synthetic route:

[1017]

[1018] Example 29: Synthesis of 7'-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1',4'-dihydro-3'H-spiro[piperidin-4,2'-quinoxaline]-3'-one (Compound 36)

[1019] Step A

[1020]

[1021] Chloroform (3 equivalents) was added to a mixture of 1-Boc-piperidin-4-one (1 g, 5 mmol, 1 equivalent) and magnesium chloride (3 equivalents) in 15 mL of THF. The reaction mixture was cooled in a dry ice / acetone bath. A solution of lithium bis(trimethylsilyl)amide in THF (1.5 equivalents, 1 M solution) was added dropwise over 10 minutes while maintaining the internal reaction temperature below -72°C. The reaction was stirred overnight at low temperature and then allowed to warm to room temperature. The reaction mixture was carefully quenched with water and then partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure.

[1022] The residue was purified by flash column chromatography (hexanes / EtOAc 3:1) to afford the product (956 mg, 2.99 mmol, 59% yield) as a white solid.

[1023] Step B

[1024]

[1025] Tert-butyl-4-hydroxy-4-(trichloromethyl)piperidine-1-carboxylate (1.3 equiv), 4-iodobenzene-1,2-diamine (540 mg, 2.3 mmol, 1 equiv), and benzyltriethylammonium chloride (0.1 equiv) were dissolved in DCM under argon. The resulting mixture was cooled to 0°C, and sodium hydroxide (5 equiv, 50% aqueous solution) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour and then allowed to reach room temperature overnight. The reaction mixture was diluted with water (until any solids had dissolved) and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / EtOAc 8:2 to 1:1) to provide a beige solid (763 mg, 1.67 mmol, 72% yield, mixture of isomers).

[1026] Step C

[1027]

[1028] [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)DCM complex (0.05 eq) and copper(I) iodide (0.1 eq) were added to a solution of tert-butyl iodo-3-oxospiro[1,4-dihydroquinoxaline-2,4'-piperidine]-1'-carboxylate (480 mg, 1.08 mmol, 1 eq, a mixture of 6-iodine and 7-iodine isomers) in 5 mL of DMF. The mixture was purged with Ar. Ethynyl(trimethyl)silane (1.5 eq) and triethylamine (1.1 eq) were added. The flask was sealed and the reaction mixture was stirred at 70°C overnight. Complete conversion to the trimethylsilyl-protected intermediate was observed.

[1029] Tetrabutylammonium fluoride solution (1.05 equiv) was added dropwise, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with water, saturated aqueous NaHCO 3 solution, and brine, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (hexane / EtOAc 3:1 to 1:1) to provide a mixture of products as a yellow solid (414 mg, 1.17 mmol, 69% yield).

[1030] Step D

[1031]

[1032] Tert-butyl ethynyl-3'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoxaline]-1-carboxylate (200 mg, 0.58 mmol, 1 eq, mixture of 6'-ethynyl and 7'-ethynyl isomers), 2-[6-(bromomethyl)pyridin-3-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate A, 1 eq), and sodium azide (1 eq) were dissolved in 2.5 mL of DMSO. Copper(II) sulfate pentahydrate (0.2 eq, 0.3 M aqueous solution) and sodium L-ascorbate (0.4 eq, 0.2 M aqueous solution) were added, and the resulting mixture was stirred at room temperature overnight. Complete conversion was observed by LC-MS. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude yellow solid thus obtained was purified by flash chromatography (hexane / EtOAc 1:1 to 5:95) to afford the separated isomers as white solids.

[1033] Isomer A: 80 mg, 0.13 mmol;

[1034] Isomer B: 118 mg, 0.2 mmol.

[1035] Step E

[1036]

[1037] tert-Butyl 7'-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoxaline]-1-carboxylate (Isomer B from the previous step, 118 mg, 0.2 mmol, 1 eq) was dissolved in 1.5 mL of DCE and TFA (12 eq) was added. The reaction mixture was stirred at room temperature overnight. Complete conversion was detected by LC-MS. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile and concentrated under reduced pressure (3 times). The dark red oily residue obtained was purified by prep-HPLC (formic acid) to provide the product as a white solid (8 mg, 0.016, 8% yield). The structure of the compound was confirmed by NOESY (m / z 494.08 [MH+]).

[1038] The following compounds were synthesized following the same synthetic route:

[1039]

[1040] Example 30: 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)spiro[indoline-3,3'-pyrrolidin]-2-one (Enantiomer B) (Compound 274), 5-[1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]-2 Synthesis of tert-butyl 5-[1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-1'-carboxylate (enantiomer A) (Compound 265) and tert-butyl 5-[1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-1'-carboxylate (enantiomer B) (Compound 266)

[1041] Step A

[1042]

[1043] Under argon, at room temperature, a mixture of tert-butyl 2-oxospiro[1H-indole-3,3'-pyrrolidine]-1'-carboxylate (1.15 g, 4 mmol, 1 equivalent) and N-iodosuccinimide (1.2 equivalents) in acetic acid (7 mL) was stirred overnight. Conversion was monitored by LC-MS. Water was added to the reaction mixture and precipitation occurred. The product was extracted with ethyl acetate and the organic layer was washed with 10% Na2S2O3 aqueous solution and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to provide a thick yellow oil (1.66 g, 4 mmol, 100% yield), which was used directly in the next step.

[1044] Step B

[1045]

[1046] [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride DCM complex (0.05 eq) and copper(I) iodide (0.1 eq) were added to a solution of tert-butyl 5-iodo-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (1.66 g, 4 mmol, 1 eq) in 8 mL of DMF. The mixture was purged with Ar. Ethynyl(trimethyl)silane (1.5 eq) and triethylamine (1.1 eq) were added. The flask was sealed and the reaction mixture was stirred at 65°C overnight. Complete conversion to the trimethylsilyl-protected intermediate was observed.

[1047] Tetrabutylammonium fluoride solution (1.05 equiv) was added dropwise, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with water, saturated aqueous NaHCO 3 solution, and brine, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (hexane / EtOAc 3:1 to 1:1) to provide the product as a yellow solid (504 mg, 1.61 mmol, 40% yield).

[1048] Step C

[1049]

[1050] Copper(II) sulfate pentahydrate (0.2 eq, 0.12 M aqueous solution) and sodium L-ascorbate (0.4 eq, 0.25 M aqueous solution) were added to a solution of 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate F, 153 mg, 0.61 mmol, 1 eq) and tert-butyl 5-ethynyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (190 mg, 0.61 mmol, 1 eq) in 2 mL of DMSO. The reaction mixture was stirred at room temperature overnight. Complete conversion of the starting material was detected by LC-MS. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexanes / EtOAc 1 :2 to 1 :9) to afford the desired product (240 mg, 0.42 mmol, 70% yield) as a white solid.

[1051] Step D

[1052]

[1053] Tert-Butyl 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (123 mg, 0.21 mmol) was dissolved in MeOH to 20 mg / mL and then purified by SFC. The combined fractions of each enantiomer were then evaporated to dryness under reduced pressure. The resulting solid was then dried in a vacuum oven at 35° C. and 5 mbar until the weight remained constant, providing the pure enantiomer as a colorless glass.

[1054] (Enantiomer A): Compound 256 (49 mg, 0.087 mmol, 99.4% ee, m / z 565.20 [MH+])

[1055] (Enantiomer B): Compound 266 (50 mg, 0.087 mmol, 98.2% ee, m / z 565.23 [MH+])

[1056] Step E

[1057]

[1058] tert-Butyl 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (Enantiomer B, 50 mg, 0.089 mmol, 1 eq) was dissolved in 1 mL of DCE and TFA (12 eq) was added. The reaction mixture was stirred at room temperature for 4 hours. The mixture was then concentrated under reduced pressure and the residue thus obtained was dissolved in acetonitrile and concentrated under reduced pressure (3x). The crude residue was purified by prep-HPLC (formic acid) to provide the product as a white solid (8 mg, 0.017 mmol, 19% yield, m / z 465.01 [MH+]).

[1059] The following compounds were prepared according to the same procedure:

[1060]

[1061] Example 31: Synthesis of 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-ethyl-1H-benzo[d]imidazol-2-amine (Compound 18)

[1062] Step A

[1063]

[1064] 4-Iodobenzene-1,2-diamine (600 mg, 2.56 mmol, 1 equivalent) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1 equivalents) were dissolved in 15 mL of isopropanol and stirred at 120 ° C for 30 minutes under microwave irradiation. The reaction mixture was diluted with EtOAc and washed with water (2x) and brine. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to provide the crude product (730 mg, 2.54 mmol, 99% yield).

[1065] The next step was directed to the crude product.

[1066] Step B

[1067]

[1068] N-Ethyl-5-iodo-1H-benzo[d]imidazol-2-amine (730 mg, 2.54 mmol, 1 eq) and ethynyl(trimethyl)silane (1.5 eq) were dissolved in a solution of triethylamine (2 eq) in DMF (8 mL). The mixture was degassed with Ar, and copper iodide (0.1 eq) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex in DCM (0.1 eq) were added. The reaction mixture was degassed again, heated to 80°C, and stirred overnight. Complete conversion to the TMS-protected intermediate was observed by LC-MS. The reaction mixture was diluted with EtOAc and evaporated over silica gel (15 g). The intermediate product was purified by flash column chromatography (0-5% MeOH / DCM, dry load).

[1069] The purified intermediate was dissolved in MeOH and potassium carbonate (2 equivalents) was added. The reaction mixture was stirred at room temperature for 1 hour. The MeOH was then evaporated and the residue was suspended in EtOAc and filtered. The desired product was in the filtrate, which was concentrated to dryness to provide the product (430 mg, 2.32 mmol, 91% yield).

[1070] Step C

[1071]

[1072] N-Ethyl-5-ethynyl-1H-benzimidazol-2-amine (80 mg, 0.432 mmol, 1 eq), 2-[6-(bromomethyl)pyridin-3-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate A, 125 mg, 0.432 mmol, 1 eq), and azide (1 eq) were dissolved in DMSO. Copper(II) sulfate pentahydrate (0.2 eq, 0.12 M aqueous solution) and sodium L-ascorbate (0.4 eq, 0.25 M aqueous solution) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was subjected to prep-HPLC (C-18 neutral conditions) without any workup to obtain 18.6 mg of the pure product (0.042 mmol, 10% yield, m / z 438.12 [MH+]).

[1073] The following compounds were prepared according to the same procedure:

[1074]

[1075] Example 32: Synthesis of 2-amino-N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)acetamide (Compound 144) and tert-butyl (2-((3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-oxoethyl)carbamate (Compound 172)

[1076] Step A

[1077]

[1078] Copper (II) sulfate pentahydrate (0.1 eq., 0.05 M aqueous solution) and sodium L-ascorbate (0.5 eq., 0.25 M aqueous solution) were added to a solution of 2-(4-(azidomethyl)-2,3-difluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate I, 1.1 eq.) and 3-aminophenylacetylene (145 mg, 1.24 mmol, 1 eq.) in 5 mL of DMF. The reaction mixture was stirred at 35° C. overnight. Complete conversion of the starting material was detected by LC-MS.

[1079] The reaction mixture was diluted with EtOAc and washed with water. The aqueous phase was extracted with EtOAc (3x). The combined organic layers were dried over MgSO4 and concentrated by rotary evaporation to provide the crude product as a solution in DMF, which was used in the next step.

[1080] Step B

[1081]

[1082] Boc-glycine (3 eq) and HATU (3 eq) were stirred in 2.5 mL of DMF for 30 minutes. Then, 3-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]triazol-4-yl]aniline (0.618 mmol, 1 eq, 0.25 M solution in DMF) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water. The aqueous phase was extracted with EtOAc (3x). The combined organic phases were dried over MgSO4 and evaporated to provide the crude product, which was purified by flash column chromatography (0-2% MeOH / DCM) (Compound 172, 87 mg, 0.155 g, 25% yield, m / z 561.68 [MH+]).

[1083] Step C

[1084]

[1085] Tert-butyl N-[2-[3-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]triazol-4-yl]phenylamino]-2-oxoethyl]carbamate (80 mg, 0.142 mmol, 1 eq) was dissolved in 6 mL of DCM, and TFA (15 eq) was added. The reaction mixture was stirred at room temperature overnight.

[1086] The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO 3 . The organic phase was dried over Na 2 SO 4 and evaporated to afford the crude product, which was purified by pTLC (4-6% MeOH / DCM) (17 mg, 0.036 mmol, 25% yield, m / z 461.95 [MH + ]).

[1087] Example 33: Synthesis of 5-((4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)benzyl)amino)-2-methoxynicotinamide (Compound 154)

[1088] Step A

[1089]

[1090] 4-Ethynylbenzaldehyde (60mg, 0.46mmol, 1 equivalent) and 5-amino-2-methoxypyridine-3-carboxamide (1.1 equivalents) are dissolved in 20mL MeOH. The mixture is stirred overnight and detected by LC-MS until it is completely converted into the corresponding imines. Sodium borohydride (12 equivalents) is added in batches and the reaction mixture is stirred overnight. The reaction mixture is evaporated, dissolved in EtOAc and washed with water. The aqueous phase is extracted with EtOAc (3x). The organic phase merged is dried and evaporated to provide a crude product, which is purified by pTLC (0-4% MeOH / DCM) (28mg, 0.1mmol, 22% yield).

[1091] Step B

[1092]

[1093] Copper(II) sulfate pentahydrate (0.1 eq, 0.01 M aqueous solution) and sodium L-ascorbate (0.5 eq, 0.05 M aqueous solution) were added to a solution of 2-(4-(azidomethyl)-2,3-difluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate I, 1.1 eq) and 5-((4-ethynylbenzyl)amino)-2-methoxynicotinamide (28 mg, 0.1 mmol, 1 eq) in 2 mL of DMF. The reaction mixture was stirred at 40° C. overnight. Complete conversion of the starting material was detected by LC-MS. The reaction mixture was diluted with EtOAc and washed with water. The aqueous phase was extracted with EtOAc (3×). The organic phases were combined, dried over Na 2 SO 4 , filtered, and evaporated to provide the crude product. Purification by pTLC (2% MeOH / DCM) and then by prep-HPLC (0.1% FA / ACN / water C-18) afforded after evaporation of the fractions 9 mg of the title compound (0.02 mmol, 17% yield) as an off-white solid (m / z 569.20 [MH+]).

[1094] Example 34: Synthesis of 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2-amine (Compound 17)

[1095] Step A

[1096]

[1097] 4-Bromo-1-N-methylbenzene-1,2-diamine (500 mg, 2.49 mmol, 1 equivalent) was dissolved in 10 mL of EtOH. Cyanogen bromide (1.1 equivalents) was added and the resulting mixture was stirred at room temperature overnight. Complete conversion was observed by LC-MS. The reaction mixture was concentrated and dried under reduced pressure.

[1098] The crude intermediate and ethynyl(trimethyl)silane were dissolved in a solution of triethylamine (1.6 eq) in DMF (7 mL), and the resulting mixture was degassed with Ar. Copper iodide (0.1 eq) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.1 eq) were added. The reaction mixture was degassed again and then stirred at 80°C for 4 hours. LC-MS indicated the formation of the desired product. The reaction mixture was diluted with EtOAc and evaporated over 40 g of silica gel. Purification by flash column chromatography (0-5% MeOH / DCM, dry loading) provided 137 mg of the product (0.53 mmol, 22% yield).

[1099] Step B

[1100]

[1101] 1-Methyl-5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-2-amine (137 mg, 0.53 mmol, 1 eq) was dissolved in 5 mL of MeOH and potassium carbonate (2 eq) was added. The reaction mixture was stirred at room temperature for 1 hour. The volatiles were removed by evaporation, and the residue was suspended in EtOAc and filtered. The filtrate was evaporated to provide the product (76 mg, 0.44 mmol, 83% yield).

[1102] Step C

[1103]

[1104] 5-Ethynyl-1-methyl-1H-benzo[d]imidazol-2-amine (76 mg, 0.44 mmol, 1 eq), 2-[6-(bromomethyl)pyridin-3-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate A, 129 mg, 0.44 mmol, 1 eq), and sodium azide (1 eq) were dissolved in 2 mL of DMSO. Copper(II) sulfate pentahydrate (0.2 eq, 0.09 M aqueous solution) and sodium L-ascorbate (0.4 eq, 0.18 M aqueous solution) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was subjected to prep-HPLC (C-18 neutral conditions) without further treatment to obtain 36 mg of the pure product (0.085 mmol, 19% yield, m / z 423.95 [MH+]).

[1105] The following compounds were prepared according to the same procedure:

[1106]

[1107]

[1108] Example 35: Synthesis of 4-(5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-2-yl)morpholine (Compound 174)

[1109] Step A

[1110]

[1111] 2-Chloro-5-iodo-1H-benzimidazole (500 mg, 1.8 mmol, 1 eq), ethynyl(trimethyl)silane (1.2 eq) and triethylamine (1.5 eq) were dissolved in 5 mL of DMF and the resulting mixture was degassed. Bis(triphenylphosphine)palladium(II) dichloride (0.1 eq) and copper(I) iodide (0.1 eq) were added and, after degassing, the reaction mixture was stirred at 80° C. overnight. The conversion of the starting material to the TMS-protected intermediate was monitored by LC-MS.

[1112] The mixture was cooled to room temperature and tetrabutylammonium fluoride (2 equivalents, 1 M in THF) was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated aqueous NH4Cl. The product was then extracted with EtOAc and washed with water (2x) and saturated aqueous NaHCO3 (2x). The organic extracts were combined and dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (DCM / MeOH 95:5) to provide the product (292 mg, 1.48 mmol, 82% yield).

[1113] Step B

[1114]

[1115] Morpholine (8 equivalents) was added to a solution of 2-chloro-5-ethynyl-1H-benzo[d]imidazole (40 mg, 0.23 mmol, 1 equivalent) in 1 mL of DMSO. The reaction mixture was stirred at 70°C overnight. 75% conversion was detected by LC-MS. Excess morpholine was removed by evaporation. The residual DMSO solution was used in the next step without further purification.

[1116] Step C

[1117]

[1118] 2-(4-(Azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate G, 1 equiv) was added to a DMSO solution of 4-(5-ethynyl-1H-benzo[d]imidazol-2-yl)morpholine (0.17 mmol, 1 equiv, 0.17 M solution) obtained in Step E. Copper(II) sulfate pentahydrate (0.25 equiv, 0.1 M aqueous solution) and sodium L-ascorbate (0.5 equiv, 0.2 M aqueous solution) were added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was subjected to prep-HPLC (basic conditions) without any prior workup to obtain the pure title compound (17 mg, 0.033 mmol, 14% yield over two steps, m / z 479.5 [MH+]).

[1119] The following compounds were prepared according to the same procedure:

[1120]

[1121] Except for step B, the following compounds were synthesized according to the same procedure:

[1122]

[1123] Example 36: 8-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)-4-methyl-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepine Synthesis of -2-ketone (Compound 237)

[1124] Step A

[1125]

[1126] A mixture of 4-bromo-1-(bromomethyl)-2-nitrobenzene (5.3 g, 17.9 mmol, 1 eq), methyl sarcosinate (2.5 g, 17.9 mmol, 1 eq), and potassium carbonate (1.5 eq) in acetonitrile (50 mL) was heated to 60° C. and stirred overnight. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 20% hexane / DCM) to obtain a yellow oil (2.37 g, 7.47 mmol, 42% yield).

[1127] Step B

[1128]

[1129] N-(4-bromo-2-nitrobenzyl)-N-methylglycine methyl ester (1.5 g, 4.7 mmol, 1 eq) was dissolved in MeOH (40 mL) and iron powder (5 eq) was added in small portions. The reaction mixture was heated to 70 ° C and ammonium chloride (10 eq, 4.7 M aqueous solution) was added dropwise. The resulting mixture was then refluxed for 1 hour. After the addition of ammonium chloride, the mixture turned from yellow to brown and became turbid. After heating for 1 hour, complete conversion was observed by TLC. The reaction mixture was washed with water and purified by HPLC. The filtrate was concentrated and the resulting residue was dissolved in water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated to provide the product as a brown oil (1.26 g, 4.26 mmol, 90% yield).

[1130] Step C

[1131]

[1132] Methyl N-(2-amino-4-bromobenzyl)-N-methylglycine (1.26 g, 4.26 mmol, 1 eq) was dissolved in 20 mL of THF and lithium hydroxide monohydrate (3 eq, 1.2 M aqueous solution) was added dropwise. The resulting mixture was stirred at room temperature over the weekend. The reaction mixture was then diluted with water and the pH was adjusted to 4 by the careful addition of 4 M HCl. The product was then extracted with EtOAc. The combined organic phases were dried over NaSO, filtered, and concentrated (1.2 g, 4.12 mmol, 97% yield).

[1133] Step D

[1134]

[1135] N-(2-amino-4-bromobenzyl)-N-methylglycine (654 mg, 2.22 mmol, 1 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.6 eq) and HOBt (1.6 eq) were dissolved in 10 mL of DMF. After stirring the mixture for 10 minutes, N,N-diisopropylethylamine (5 eq) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and aqueous NaHCO3 solution and extracted with MTBE and BuOH. The organic phases were combined, dried and concentrated. The crude product was purified by flash column chromatography (DCM / hexane 1:1, then DCM) (400 mg, 1.57 mmol, 70% yield).

[1136] Step E

[1137]

[1138] 8-Bromo-4-methyl-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepine -2-ketone (184 mg, 0.69 mmol, 1 equivalent) was dissolved in triethylamine (3.9 mL, 40 equivalents) and the resulting mixture was degassed. Ethylene (trimethyl) silane (1.2 equivalents) was then added to the reaction mixture and degassed. Bis (triphenylphosphine) palladium (II) dichloride (0.02 equivalents) and copper (I) iodide (0.04 equivalents) were added, and after degassing, the reaction mixture was stirred at 70 ° C overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic phases were dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (hexane / EtOAc to EtOAc) (107 mg, 0.356 mmol, 53% yield).

[1139] Step F

[1140]

[1141] 4-Methyl-8-((trimethylsilyl)ethynyl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepine -2-ketone (107 mg, 0.356 mmol, 1 eq) was dissolved in 2 mL of THF and TBAF (2 eq, 1 M solution in THF) was added. The reaction mixture was stirred overnight, then diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated to provide 131 mg of a light brown solid. The product was pure enough to proceed to the subsequent step (70 mg, 0.35 mmol, 96% yield).

[1142] Step G

[1143]

[1144] Copper(II) sulfate pentahydrate (0.1 eq., 0.07 M aqueous solution) and sodium L-ascorbate (0.5 eq., 0.35 M aqueous solution) were added to a mixture of 2-(4-(azidomethyl)-3,5-difluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate I, 10 mg, 0.035 mmol, 1 eq.) and 8-ethynyl-4-methyl-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepine. -2-ketone (7 mg, 0.035 mmol, 1 eq) was added to a solution of 200 μL DMF. The reaction mixture was stirred at 35°C overnight. Complete conversion was detected by LC-MS. The reaction mixture was subjected to prep-HPLC (basic conditions) without any prior workup to obtain the pure title compound (3.5 mg, 0.007 mmol, 20% yield, m / z 488.11 [MH+]).

[1145] Example 37: Synthesis of N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-4-methylpiperazine-1-carboxamide (Compound 51)

[1146] Step A

[1147]

[1148] 3-Ethynylaniline (100 mg, 0.85 mmol, 1 eq) was dissolved in 1 mL of pyridine and 4-methylpiperazine-1-carbonyl chloride (1.1 eq) was added. The reaction mixture was stirred at 60° C. for 2 hours. Pyridine was then removed by evaporation and the crude residue was used in the next step without any further purification.

[1149] Step B

[1150]

[1151] Crude N-(3-ethynylphenyl)-4-methylpiperazine-1-carboxamide (2.5 equiv) obtained in the previous step, 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate A, 0.34 mmol, 1 equiv), and sodium azide (1 equiv) were dissolved in 1 mL of DMSO. Copper(II) sulfate pentahydrate (0.25 equiv, 0.2 M aqueous solution) and sodium L-ascorbate (0.5 equiv, 0.3 M aqueous solution) were added. The reaction mixture was stirred at room temperature overnight.

[1152] The crude mixture was submitted to prep-HPLC (ACN+0.1% FA, H2O+0.1% FA) without any treatment to afford 25 mg of the desired product (0.049 mmol, 14% yield, m / z 496.17 [MH+]).

[1153] The following compounds were synthesized according to the same procedure:

[1154]

[1155] Example 38: Synthesis of N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-1-methylazetidine-3-carboxamide (Compound 86)

[1156] Step A

[1157]

[1158] 1-Methylazetidine-3-carboxylic acid (1.3 eq) and HATU (1.3 eq) were suspended in 5 mL of DMF and ultrasonically shaken for 10 minutes until a clear solution was obtained. 3-Ethynylaniline (763 mg, 6.5 mmol, 1 eq) was then added and the mixture was stirred at room temperature for 64 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried and evaporated. The crude product thus obtained was subjected to prep-HPLC (0.1% TFA / ACN / H2OC-18). Fractions were evaporated to provide 60 mg of the desired product (0.28 mmol, 3% yield), which was isolated as a TFA salt.

[1159] Step B

[1160]

[1161] Copper(II) sulfate pentahydrate (0.1 eq., 0.05 M aqueous solution) and sodium L-ascorbate (0.5 eq., 0.25 M aqueous solution) were added to a solution of 2-(4-(azidomethyl)-3,5-difluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate I, 24 mg, 0.084 mmol, 1.1 eq.) and N-(3-ethynylphenyl)-1-methylazetidine-3-carboxamide trifluoroacetate (25 mg, 0.076 mmol, 1 eq.) in 300 μL DMSO. The reaction mixture was stirred at 40° C. overnight. Complete conversion of the starting material was detected by LC-MS. The reaction mixture was submitted to prep-HPLC (basic conditions) without any prior workup to obtain the pure target compound (9.7 mg, 0.019 mmol, 25% yield, m / z 502.15 [MH+]).

[1162] The following compounds were prepared according to the same procedure:

[1163]

[1164] Example 39: Synthesis of N-(5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)-2,2-difluoroacetamide (Compound 88)

[1165] Step A

[1166]

[1167] Copper (II) sulfate pentahydrate (0.3 eq., 0.2 M aqueous solution) and sodium L-ascorbate (0.5 eq., 0.34 M aqueous solution) were added to a stirred solution of methyl 2-(bromomethyl)pyrimidine-5-carboxylate (63 mg, 0.34 mmol, 1 eq.), 5-ethynylpyridin-2-amine (1 eq.) and sodium azide (1.05 eq.) in DMSO (1 mL). The resulting mixture was stirred at room temperature for 2 hours. Complete conversion was confirmed by LC-MS. The reaction mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO3 (3 times) and brine. The organic phase was dried over MgSO4 and evaporated under reduced pressure. The obtained residue was used in the next step without purification (48 mg, 0.15 mmol, 46% yield).

[1168] Step B

[1169]

[1170] A suspension of methyl 2-((4-(6-aminopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyrimidine-5-carboxylate (45 mg, 0.145 mmol, 1 eq) and hydrazine monohydrate (5 eq) in MeOH (1 mL) was stirred at 70° C. for 3 h. Complete conversion to the desired product was observed by LC-MS. The reaction mixture was evaporated in vacuo and re-evaporated twice from acetonitrile to provide the title compound (45 mg, 0.145 mmol, 100% yield) as an off-white suspension. The product was used in the subsequent step without further purification.

[1171] Step C

[1172]

[1173] Difluoroacetic anhydride (6 equivalents) was added portionwise to a solution of 2-((4-(6-aminopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyrimidine-5-carboxylic acid hydrazide (35 mg, 0.085 mmol, 1 equivalent) in DMF (2 mL). The reaction was complete after 2 hours, with the title compound as the major product. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO₃ (4 times) and brine, dried over MgSO₄, and evaporated under vacuum. The crude residue was purified by prep-HPLC. After purification, 18 mg of the pure compound was obtained (0.039 mmol, 27% yield, m / z 449.89 [MH⁺]).

[1174] Example 40: Synthesis of 5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 117)

[1175] Step A

[1176]

[1177] A solution of methyl 4-(1-bromoethyl)benzoate (2 g, 8.22 mmol, 1 eq) in DMSO (10 mL) was added to a solution of sodium azide (1.4 eq) in DMSO. The reaction mixture was stirred vigorously at room temperature overnight. The reaction was quenched with water (200 mL) and the product was extracted with EtOAc (3 times). The organic layers were collected together, washed with brine, dried over MgSO4, and concentrated under reduced pressure to provide the product as a colorless oil, which was used in the next step without any further purification (1.69 g, 8.22 mmol, 100% yield).

[1178] Step B

[1179]

[1180] Methyl 4-(1-azidoethyl)benzoate (1.69 g, 8.22 mmol, 1 eq) was dissolved in MeOH (20 mL) and hydrazine monohydrate (5 eq) was added with stirring. The mixture was stirred at 70° C. overnight. LC-MS (and TLC) indicated complete conversion of the methyl ester to hydrazide. The reaction mixture was concentrated under reduced pressure and the residue was diluted in water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous NaHCO 3 solution, brine, dried, filtered, and concentrated under reduced pressure. The obtained product (1.69 g, 8.22 mmol, 100% yield) was used in the subsequent step without further purification.

[1181] Step C

[1182]

[1183] 4-(1-azidoethyl)benzohydrazide (844 mg, 4.1 mmol, 1 eq) was dissolved in dry DMF (10 mL) under argon. Difluoroacetic anhydride (3 eq) was slowly added, maintaining the temperature below 30°C (ice / NaCl bath). After the addition was complete, the temperature was allowed to reach room temperature. The flask was sealed and the reaction mixture was stirred at room temperature overnight. Complete conversion was observed by LC-MS. Aqueous NaHCO3 solution was added to the reaction mixture to quench the excess difluoroacetic anhydride. Water was then added and the product was extracted with ethyl acetate (3x). The organic layers were collected together, washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude residue was purified by flash column chromatography (hexane / EtOAc 95:5) to provide the product (506 mg, 1.9 mmol, 46% yield) as a yellow oil.

[1184] Step D

[1185]

[1186] Copper (II) sulfate pentahydrate (0.3 eq., 0.5 M aqueous solution) and sodium L-ascorbate (0.5 eq., 1 M aqueous solution) were added to a solution of 2-(4-(1-azidoethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (78 mg, 0.296 mmol, 1 eq.) and 5-ethynylpyridin-2-amine (35 mg, 0.296 mmol, 1 eq.) in 1 mL of DMSO. The reaction mixture was stirred at 40 ° C for 2 hours. Complete conversion of the starting material was detected by LC-MS. The reaction mixture was filtered through a syringe filter and submitted to prep-HPLC without any further treatment. After evaporation of the fractions, 67 mg of the target compound (0.169 mmol, 57% yield) was obtained as an off-white solid (m / z 384.14 [MH + ]).

[1187] Example 41: Synthesis of 2-(4-(6-aminopyridin-3-yl)-1H-1,2,3-triazol-1-yl)-2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethan-1-ol (Compound 94)

[1188] Step A

[1189]

[1190] Sodium azide (2 equivalents) and ammonium chloride (2 equivalents) were dissolved in 2 mL of water. 4-(oxirane-2-yl)benzoic acid methyl ester (600 mg, 3.36 mmol, 1 equivalent) was added as an 8 mL THF solution. The reaction mixture was stirred at 90 ° C overnight. Almost complete conversion was observed by LC-MS. The reaction mixture was diluted with EtOAc and washed with water (3 times) and brine. The organic phase was dried over Na SO , filtered and concentrated. The crude product thus obtained was an inseparable mixture of positional isomers, which was used in the next step without further purification (600 mg, 2.7 mmol, 81% yield).

[1191] Step B

[1192]

[1193] The positional isomer mixture obtained in step A (600 mg, 2.7 mmol, 1 equivalent) was dissolved in MeOH (10 mL) and hydrazine monohydrate (5 equivalents) was added under stirring. The mixture was stirred at 70 ° C overnight. LC-MS observed that the methyl ester was completely converted to the corresponding hydrazide. The reaction mixture was concentrated under reduced pressure and the residue was diluted in water and extracted with ethyl acetate. The organic phase was washed with saturated NaHCO3 aqueous solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was resuspended in dry DMF (10 mL) under argon. Difluoroacetic anhydride (3 equivalents) was slowly added, maintaining the temperature below 30 ° C (ice / NaCl bath). After the addition was complete, the temperature was allowed to reach room temperature. The flask was sealed and the reaction mixture was stirred at room temperature overnight. Complete conversion was observed by LC-MS.

[1194] Saturated aqueous NaHCO3 was added to the reaction mixture to quench the excess difluoroacetic anhydride. Water was then added and the product was extracted with ethyl acetate (3x). The organic layers were collected together, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude residue was purified by flash chromatography (hexane / EtOAc 8:2) to provide the product as a mixture of isomers (176 mg, 0.5 mmol, 18% yield).

[1195] Step C

[1196]

[1197] Copper sulfate (II) pentahydrate (0.1 equivalent, 0.5M aqueous solution) and L-sodium ascorbate (0.5 equivalent, 1M aqueous solution) are added to a solution of 10mL DMSO of the azide (176mg, 0.5mmol, 1 equivalent) and 5-ethynylpyridine-2-amine (58mg, 0.5mmol, 1 equivalent) obtained in step B. The reaction mixture is stirred at room temperature overnight. The reaction mixture is supplied to prep-HPLC without any further treatment. The mixture of isomers thus obtained is further purified by phenyl column to isolate the desired product (6.4mg, 0.014mmol, 3% yield) as formate. The structure is confirmed by NOESY (m / z 400.36[MH+]).

[1198] The following compounds were synthesized according to the same procedure:

[1199]

[1200] Example 42: Synthesis of 5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 158)

[1201] Step A

[1202]

[1203] Toni's reagent (1.5 eq) and tetraacetonitrile copper (I) hexafluorophosphate (0.05 eq) were dissolved in 5 mL of DMA and placed in a dry, sealed tube purged with argon. Methyl 4-vinylbenzoate (160 mg, 0.99 mmol, 1 eq) and trimethylsilyl azide (2 eq) were added. The reaction mixture was stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate and then washed with water and brine. The organic layer was concentrated under vacuum. The yellow oil residue was purified by flash chromatography (hexane / AcOEt 96:4 to 3:1) to provide the product as a colorless oil (130 mg, 0.48 mmol, 48% yield).

[1204] Step B

[1205]

[1206] Methyl 4-(1-azido-3,3,3-trifluoropropyl)benzoate (130 mg, 0.48 mmol, 1 eq) was dissolved in MeOH (2 mL), and hydrazine monohydrate (5 eq) was added with stirring. The mixture was stirred at 70°C overnight. LC-MS (and TLC) indicated complete conversion of the methyl ester to the hydrazide. The reaction mixture was concentrated under reduced pressure, and the residue was diluted in water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous NaHCO3, brine, dried, filtered, and concentrated under reduced pressure. The product (130 mg, 0.404 mmol, 100% yield) was used in the subsequent step without further purification.

[1207] Step C

[1208]

[1209] 4-(1-Azido-3,3,3-trifluoropropyl)benzohydrazide (130 mg, 0.404 mmol, 1 eq) was dissolved in dry DMF (1.5 mL) under argon. Difluoroacetic anhydride (3 eq) was slowly added, maintaining the temperature below 30°C (ice / NaCl bath). After the addition was complete, the temperature was allowed to reach room temperature. The flask was sealed and the reaction mixture was stirred at room temperature overnight. 85% conversion was observed by LC-MS.

[1210] Water was added to the reaction mixture, which was extracted with ethyl acetate (3x). The organic layers were collected together, washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, and evaporated to dryness under reduced pressure. The crude residue was purified by flash column chromatography (hexane / EtOAc 9:1 to 8:2) to provide the product (73 mg, 0.217 mmol, 46% yield) as a colorless oil.

[1211] Step D

[1212]

[1213] Copper (II) sulfate pentahydrate (0.2 eq, 0.5 M aqueous solution) and sodium L-ascorbate (0.4 eq, 1 M aqueous solution) were added to a solution of 2-(4-(1-azido-3,3,3-trifluoropropyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (70 mg, 0.21 mmol, 1 eq) and 5-ethynylpyridin-2-amine (25 mg, 0.21 mmol, 1 eq) in 1.2 mL of DMSO. The reaction mixture was stirred at room temperature overnight. Complete conversion of the starting material was detected by LC-MS. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-HPLC using neutral conditions to afford the product as a white solid (44 mg, 0.097 mmol, 46% yield, m / z 452.12 [MH+]).

[1214] Example 43: Synthesis of 5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(pyrrolidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 124)

[1215] Step A

[1216]

[1217] Methyl 4-(2-bromoacetyl)benzoate (600 mg, 2.3 mmol) was dissolved in 7 mL of ethanol and pyrrolidine (2 equivalents) was added. The reaction mixture was stirred at room temperature overnight. 90% conversion to the intermediate ketone was detected by LC-MS. Sodium borohydride (1.1 equivalents) was added to the reaction mixture in batches and stirred at room temperature for 1 hour. Complete reduction to the corresponding alcohol intermediate was detected. The reaction mixture was diluted with EtOAc and washed with brine (3 times). The organic layer was dried over Na2SO4 and concentrated under reduced pressure.

[1218] Step B

[1219]

[1220] Crude methyl 4-(1-hydroxy-2-(pyrrolidin-1-yl)ethyl)benzoate (1 equivalent) obtained in Step A was dissolved in 20 mL of DCM, and triethylamine (2 equivalents) and methanesulfonyl chloride (1 equivalent) were added with stirring. The reaction mixture was stirred at room temperature overnight. LC-MS indicated predominantly chlorination. The reaction mixture was diluted with EtOAc and washed with brine. The organic fraction was dried over NaSO, filtered, and evaporated.

[1221] Step C

[1222]

[1223] The crude residue obtained in step B was dissolved in DMSO and sodium azide (1.2 equivalents) was added. The reaction mixture was stirred at room temperature for 1 hour. Complete conversion was observed by LC-MS. The product thus obtained (120 mg, 0.43 mmol, 19% yield over 3 steps) was used in the subsequent step without further purification.

[1224] Step D

[1225]

[1226] Methyl 4-(1-azido-2-pyrrolidin-1-ylethyl)benzoate (120 mg, 0.43 mmol, 1 eq) was dissolved in MeOH (5 mL), and hydrazine monohydrate (5 eq) was added with stirring. The mixture was stirred at 70°C overnight. Complete conversion of the methyl ester to hydrazide was observed by LC-MS (and TLC). The reaction mixture was concentrated under reduced pressure, and the residue was diluted in water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous NaHCO3, brine, dried, filtered, and concentrated under reduced pressure. The crude residue was dissolved in dry DMF (3 mL) under argon. Difluoroacetic anhydride (3 eq) was slowly added, maintaining the temperature below 30°C (ice / NaCl bath). After the addition was complete, the temperature was allowed to reach room temperature. The flask was sealed and the reaction mixture was stirred at room temperature overnight. Complete conversion was observed by LC-MS. Saturated aqueous NaHCO3 was added to the reaction mixture to quench the excess difluoroacetic anhydride. Water was then added, and the product was extracted with ethyl acetate (3 times). The organic layers were collected together, washed with saturated aqueous NaHCO 3 solution and brine, dried over Na 2 SO 4 and evaporated to dryness under reduced pressure. The crude residue was purified by flash column chromatography to provide the product (100 mg, 0.3 mmol, 72% yield) as a yellow semisolid.

[1227] Step E

[1228]

[1229] Copper (II) sulfate pentahydrate (0.15 eq., 0.5 M aqueous solution) and sodium L-ascorbate (0.3 eq., 1 M aqueous solution) were added to a solution of 2-(4-(1-azido-2-(pyrrolidin-1-yl)ethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (50 mg, 0.15 mmol, 1 eq.) and 5-ethynylpyridin-2-amine (18 mg, 0.15 mmol, 1 eq.) in 1 mL of DMSO. The reaction mixture was stirred at 40 ° C for 2 hours. Complete conversion of the starting material was detected by LC-MS. The reaction mixture was filtered through a syringe filter and submitted to prep-HPLC without any further treatment. After evaporation of the fractions, 26 mg of the target compound (0.057 mmol, 38% yield) (m / z 453.20 [MH + ]) were obtained as a yellow solid.

[1230] The following compounds were synthesized according to the same synthetic route:

[1231]

[1232] Example 44: Synthesis of 5-(1-(2-(4-chlorophenyl)-1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 231)

[1233] Step A

[1234]

[1235] A reaction vessel equipped with a pressure balance was charged with palladium(II) acetate (0.030 equiv), 1,1'-bis(diphenylphosphino)ferrocene (0.035 equiv), 3-(4-chlorophenyl)propanoic acid (500 mg, 2.93 mmol, 1 equiv), and (4-(methoxycarbonyl)phenyl)boronic acid (1.2 equiv). THF (4 mL), water (0.25 equiv), and trimethylacetic anhydride (1.5 equiv) were added sequentially. The flask was purged with argon and the reaction mixture was heated at 60°C overnight. After removing the volatiles under reduced pressure, the residue was dissolved in a minimum amount of DCM, transferred to the top of a basic alumina pad, and eluted with a hexane / EtOAc gradient. The crude product was further purified by flash column chromatography (hexane / AcOEt 4:1) (205 mg, 0.712 mmol, 25% yield).

[1236] Step B

[1237]

[1238] Methyl 4-[2-(4-chlorophenyl)acetyl]benzoate (205 mg, 0.712 mmol, 1 equivalent) was dissolved in 3 mL of methanol. Sodium borohydride (1.5 equivalents) was added to the reaction mixture in portions at 0°C. The reaction mixture was stirred for 3 hours. Complete reduction to the corresponding alcohol intermediate was detected. The mixture was concentrated in vacuo. The residue was suspended in cold water to quench the excess sodium borohydride. The mixture was extracted with DCM, and the organic layer was dried over anhydrous Na2SO4 and concentrated by rotary evaporation. The product thus obtained (174 mg, 0.6 mmol, 82% yield) was used in the next step without further purification.

[1239] Step C

[1240]

[1241] To a solution of methyl 4-[2-(4-chlorophenyl)-1-hydroxyethyl]benzoate (174 mg, 0.6 mmol, 1 eq) in 10 mL of dichloromethane was added triethylamine (2 eq) and methanesulfonyl chloride (1.2 eq) at 0°C. The reaction mixture was allowed to reach room temperature and then stirred for 12 hours. The mixture was then diluted with DCM, washed with water and brine, and dried over Na2SO4. The volatiles were removed under reduced pressure, and the crude product thus obtained (215 mg, 0.58 mmol, 97% yield) was used in the subsequent step without further purification.

[1242] Step D

[1243]

[1244] Crude methyl 4-(2-(4-chlorophenyl)-1-((methylsulfonyl)oxy)ethyl)benzoate (215 mg, 0.58 mmol, 1 eq) was dissolved in 5 mL of DMSO and sodium azide (1.4 eq) was added. The reaction mixture was stirred at room temperature for 1 hour. Complete conversion was observed by LC-MS. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was suspended in water and freeze-dried to provide a colorless oil (182 mg, 0.58 mmol, 99% yield) which was used in the next step without further purification.

[1245] Step E

[1246]

[1247] Under gentle stirring, a solution of methyl 4-(1-azido-2-(4-chlorophenyl)ethyl)benzoate (182 mg, 0.58 mmol, 1 equivalent) in methanol (5 mL) was added dropwise to hydrazine monohydrate (4 equivalents). The mixture was refluxed overnight. LC-MS (and TLC) were used to observe that the methyl ester was completely converted into hydrazides. The reaction mixture was concentrated under reduced pressure and the crude product (171 mg, 0.54 mmol, 93% yield) thus obtained was used in the next step without further purification.

[1248] Step F

[1249]

[1250] 4-(1-azido-2-(4-chlorophenyl)ethyl)benzohydrazide (171 mg, 0.54 mmol, 1 eq) was dissolved in dry DMF (5 mL) under argon. Difluoroacetic anhydride (3 eq) was added slowly, maintaining the temperature below 30°C (ice / NaCl bath). After the addition was complete, the temperature was allowed to reach room temperature. The flask was sealed and the reaction mixture was stirred at room temperature overnight. Complete conversion was observed by LC-MS.

[1251] Saturated NaHCO3 aqueous solution was added to the reaction mixture to quench the excess difluoroacetic anhydride. Water was then added and the product was extracted with ethyl acetate (3x). The organic layers were collected together, washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude residue was purified by flash column chromatography (hexane / EtOAc 85:15) to provide the product (102 mg, 0.27 mmol, 50% yield) as a colorless oil.

[1252] Step G

[1253]

[1254] Copper (II) sulfate pentahydrate (0.1 eq., 0.5 M aqueous solution) and sodium L-ascorbate (0.5 eq., 1 M aqueous solution) were added to a solution of 2-(4-(1-azido-2-(4-chlorophenyl)ethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (50 mg, 0.13 mmol, 1 eq.) and 5-ethynylpyridin-2-amine (15 mg, 0.13 mmol, 1 eq.) in 1 mL of DMSO. The reaction mixture was stirred at 40 ° C. for 2 hours. Complete conversion of the starting material was detected by LC-MS. The reaction mixture was filtered through a syringe filter and submitted to prep-HPLC without any further treatment. After evaporation of the fractions, 44 mg of the target compound (0.089 mmol, 67% yield) was obtained as a beige solid (m / z 494.13 [MH + ]).

[1255] Example 45: Synthesis of 5-(1-(2-cyclobutyl-1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 242)

[1256] Step A

[1257]

[1258] The reaction was initiated by adding a solution of DIBAL-H in hexane (1 M, 0.02 eq) to a suspension of magnesium turnings (244 mg, 1.5 eq, dried under vacuum) in anhydrous diethyl ether (4 mL). A few drops of (bromomethyl)cyclobutene (1 g, 6.7 mmol, 1 eq) in dry diethyl ether (4 mL) were then added at room temperature. After a few minutes, the remaining solution was added. The resulting mixture was heated in a warm water bath and stirred overnight. This mixture was added dropwise to a solution of methyl 4-formylbenzoate (1.1 g, 6.7 mmol, 1 eq) in THF at -78°C. The reaction mixture was stirred at -78°C for 2 hours and at room temperature for an additional 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexanes / EtOAc 9:1 to 7:3) to afford the product (375 mg, 1.6 mmol, 24% yield) as a yellow oil.

[1259] Step B

[1260]

[1261] To a solution of methyl 4-(2-cyclobutyl-1-hydroxyethyl)benzoate (375 mg, 1.6 mmol, 1 eq) in 6 mL of dichloromethane was added triethylamine (2 eq) and methanesulfonyl chloride (1.2 eq) at 0°C. The reaction mixture was allowed to reach room temperature and then stirred overnight. Water was added to the reaction mixture and the product was extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered and concentrated under reduced pressure to provide a yellow solid which was used in the next step without further purification (499 mg, 1.6 mmol, 100% yield).

[1262] Step C

[1263]

[1264] Crude methyl 4-(2-(4-chlorophenyl)-1-((methylsulfonyl)oxy)ethyl)benzoate (499 mg, 1.6 mmol, 1 eq) was dissolved in 4 mL of DMSO, and sodium azide (1.2 eq) was added. The reaction mixture was stirred vigorously at room temperature overnight. Complete conversion was observed by LC-MS. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / EtOAc 96:4) to provide the desired product (332 mg, 1.28 mmol, 80% yield) as a colorless oil.

[1265] Step D

[1266]

[1267] Under gentle stirring, a solution of methyl 4-(1-azido-2-(4-chlorophenyl)ethyl)benzoate (330 mg, 1.27 mmol, 1 equivalent) in methanol (5 mL) was added dropwise to hydrazine monohydrate (5 equivalents). The mixture was refluxed overnight. LC-MS (and TLC) revealed that the methyl ester was completely converted into hydrazide. The reaction mixture was concentrated under reduced pressure and the crude product (330 mg, 1.27 mmol, 100% yield) was used in the next step without further purification.

[1268] Step E

[1269]

[1270] 4-(1-azido-2-cyclobutylethyl)benzohydrazide (330 mg, 1.27 mmol, 1 equivalent) was dissolved in dry DMF (5 mL) under argon. Difluoroacetic anhydride (3 equivalents) was slowly added, maintaining the temperature below 30 ° C (ice / NaCl bath). After the addition was complete, the mixture was allowed to reach room temperature. The flask was sealed and the reaction mixture was stirred at room temperature overnight. 75% conversion was observed by LC-MS. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate (3x). The combined organic layers were washed with saturated NaHCO3 aqueous solution and brine, dried over MgSO4 and evaporated to dryness under reduced pressure. The crude residue was purified by flash chromatography (hexane / EtOAc 96: 4 to 8: 2) to provide the product (193 mg, 0.6 mmol, 47% yield) as a yellow oil.

[1271] Step F

[1272]

[1273] Copper (II) sulfate pentahydrate (0.2 eq., 0.5 M aqueous solution) and sodium L-ascorbate (0.4 eq., 1 M aqueous solution) were added to a solution of 2-(4-(1-azido-2-cyclobutylethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (75 mg, 0.235 mmol, 1 eq.) and 5-ethynylpyridin-2-amine (28 mg, 0.235 mmol, 1 eq.) in 1.4 mL of DMSO. The reaction mixture was stirred at 40 ° C for 2 hours. Complete conversion of the starting material was detected by LC-MS. The reaction mixture was filtered through a syringe filter and submitted to prep-HPLC using acidic conditions. After evaporation of the fractions, 30 mg of the target compound (0.067 mmol, 29% yield) (m / z 438.19 [MH + ]) was obtained as a white solid.

[1274] The following compounds were synthesized according to the same procedure:

[1275]

[1276] Example 46: Synthesis of N-{3-[1-(6-aminopyridin-3-yl)-1H-1,2,3-triazol-4-yl]-3-{4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}propyl}methanesulfonamide (Compound 62)

[1277] Step A

[1278]

[1279] Methyl 4-(2-cyanoacetyl)benzoate (900 mg, 4.4 mmol, 1 eq), di-tert-butyl dicarbonate (2 eq), and nickel chloride hexahydrate (0.02 eq) were dissolved in 50 mL of anhydrous MeOH. The mixture was cooled to -10°C, and sodium borohydride (7 eq) was added portionwise. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, and filtered. The volatiles were evaporated to provide the crude product (1.2 g, 3.9 mmol, 87% yield), which was used in the subsequent step without further purification.

[1280] Step B

[1281]

[1282] Methyl 4-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)benzoate (600 mg, 1.94 mmol, 1 eq) was dissolved in 10 mL of DCM. Trifluoroacetic acid (10 eq) was added and the solution was stirred at room temperature overnight. Complete conversion to the desired deprotected intermediate was observed by LC-MS. Excess TFA was removed by evaporation.

[1283] The residue was dissolved in 10 mL of DCM and triethylamine (5 eq.) and methanesulfonyl chloride (2.5 eq.) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM, washed with brine (twice), dried over MgSO 4 , filtered and concentrated.

[1284] The crude intermediate thus obtained was dissolved in 5 mL of DMSO and sodium azide (1.5 equivalents) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with MTBE, washed with brine (twice), dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography (hexane / EtOAc 8:2 to 1:1) to obtain 225 mg of the desired product (0.72 mmol, 37% yield).

[1285] Step C

[1286]

[1287] A solution of methyl 4-(1-azido-3-(methylsulfonylamino)propyl)benzoate (225 mg, 0.72 mmol, 1 eq) in methanol (10 mL) was added dropwise to hydrazine monohydrate (5 eq) under gentle stirring. The mixture was refluxed overnight. Complete conversion of the methyl ester to hydrazide was observed by LC-MS (and TLC). The reaction mixture was concentrated under reduced pressure. The obtained crude N-(3-azido-3-(4-(hydrazinecarbonyl)phenyl)propyl)methanesulfonamide was dissolved in dry DMF (3 mL) under argon. Difluoroacetic anhydride (2.5 eq) was slowly added, maintaining the temperature below 30°C (ice / NaCl bath). After the addition was complete, the mixture was allowed to reach room temperature. The flask was sealed and the reaction mixture was stirred at room temperature overnight. Complete conversion was observed by LC-MS. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate (3x). The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered under reduced pressure, and evaporated to dryness. The crude residue was purified by flash chromatography (hexanes / EtOAc 8:2 to 1:1) to afford the desired product (220 mg, 0.59 mmol, 82% yield).

[1288] Step D

[1289]

[1290] Copper (II) sulfate pentahydrate (0.15 eq., 0.5 M aqueous solution) and sodium L-ascorbate (0.15 eq., 1 M aqueous solution) were added to a solution of N-[3-azido-3-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]propyl]methanesulfonamide (46 mg, 0.124 mmol, 1 eq.) and 5-ethynylpyridin-2-amine (15 mg, 0.124 mmol, 1 eq.) in 1 mL of DMSO. The reaction mixture was stirred at 40 ° C for 2 hours. Complete conversion of the starting material was detected by LC-MS. The reaction mixture was filtered through a syringe filter and submitted to prep-HPLC (neutral conditions). After evaporation of the fractions, 34 mg of the target compound (0.069 mmol, 56% yield) (m / z 491.50 [MH + ]) were obtained as a white solid.

[1291] The following compounds were synthesized according to the same procedure:

[1292]

[1293] Example 47: Synthesis of 5-(1-(1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 59), (R)-5-(1-(1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 32), and (S)-5-(1-(1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 171)

[1294] Step A

[1295]

[1296] 6-acetylonitrile (500 mg, 2.79 mmol, 1 equivalent) was dissolved in 20 mL of methanol. Sodium borohydride (1.2 equivalents) was added to the reaction mixture in batches at 0 ° C. The reaction mixture was stirred for 1 hour, and the conversion was subsequently observed by LC-MS. The reaction was quenched with water and extracted with EtOAc. The collected organic layer was washed with brine, dried over MgSO4, filtered and concentrated by rotary evaporation. The product (345 mg, 1.9 mmol, 68% yield) was obtained as a yellow oil, which was used in the next step without further purification.

[1297] Step B

[1298]

[1299] To a solution of methyl 6-(1-hydroxyethyl)nicotinate (345 mg, 1.9 mmol, 1 eq) in 10 mL of dichloromethane was added triethylamine (2 eq) and methanesulfonyl chloride (1.2 eq) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes and then allowed to reach room temperature for 4 hours. The mixture was then diluted with DCM, washed with water and brine, dried over magnesium sulfate, and filtered. The volatiles were removed under reduced pressure to obtain the product as a yellow solid (408 mg, 1.57 mmol, 82% yield), which was used in the subsequent step without further purification.

[1300] Step C

[1301]

[1302] Crude methyl 6-(1-((methylsulfonyl)oxy)ethyl)nicotinate (387 mg, 1.49 mmol, 1 eq) was dissolved in 5 mL of DMSO, and sodium azide (1.4 eq) was added. The reaction mixture was stirred at room temperature overnight. Partial conversion was observed by LC-MS. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to provide a yellow oil (248 mg, 1.2 mmol, 80% yield), which was used in the next step without further purification.

[1303] Step D

[1304]

[1305] Under gentle stirring, dropwise add the solution of methyl alcohol (5mL) of 6-(1-azidoethyl)nicotinate (190mg, 0.92mmol, 1 equivalent) to hydrazine monohydrate (4 equivalents).Mixture is refluxed overnight.Observe that methyl ester is converted into hydrazide completely by LC-MS (and TLC).Reaction mixture is concentrated under reduced pressure and crude product (190mg, 0.92mmol, 100% productive rate) is used to next step without further purification.

[1306] Step E

[1307]

[1308] 6-(1-azidoethyl)nicotinamide hydrazide (190 mg, 0.92 mmol, 1 eq) was dissolved in dry DMF (3 mL) under argon. Difluoroacetic anhydride (3 eq) was slowly added, maintaining the temperature below 30°C (ice / NaCl bath). After the addition was complete, the temperature was allowed to reach room temperature. The flask was sealed and the reaction mixture was stirred at room temperature overnight. Complete conversion was observed by LC-MS. Saturated aqueous NaHCO3 solution was added to the reaction mixture to quench the excess difluoroacetic anhydride. Water was then added and the product was extracted with ethyl acetate (3x). The organic layers were collected together, washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude residue was purified by flash column chromatography (hexane / EtOAc 85:15) to provide the product (137 mg, 0.51 mmol, 56% yield) as a yellow oil.

[1309] Step F

[1310]

[1311] Copper(II) sulfate pentahydrate (0.2 eq, 0.5 M aqueous solution) and sodium L-ascorbate (0.4 eq, 1 M aqueous solution) were added to a solution of 2-[6-(1-azidoethyl)pyridin-3-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (80 mg, 0.30 mmol, 1 eq) and 5-ethynylpyridin-2-amine (35.5 mg, 0.30 mmol, 1 eq) in 1.5 mL of DMSO. The reaction mixture was stirred at 40° C. overnight. Complete conversion of the starting material was detected by LC-MS. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO 3 solution and brine, dried over MgSO 4 , filtered and concentrated under reduced pressure to provide a yellow solid, which was purified by flash column chromatography (hexane / EtOAc 95 / 5 to 9 / 1) to provide compound 59 (84 mg, 0.22 mmol, 72% yield, m / z 385.1 [MH +]) as a beige solid.

[1312] Step G

[1313]

[1314] 5-(1-(1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 59) was dissolved in EtOH at 5 mg / mL and purified by SFC. The combined fractions of each enantiomer were then evaporated to dryness by rotary evaporation. The resulting solid was then dried in a vacuum oven at 35° C. and 5 mbar until the weight remained constant, providing the pure enantiomer as a white solid.

[1315] Compound 32: (25 mg, 0.065 mmol)

[1316] Compound 171: (25 mg, 0.065 mmol)

[1317] Compound 32 was also synthesized by mirror-specific synthesis, and its absolute configuration was confirmed.

[1318] The following compounds were prepared according to the same procedure:

[1319]

[1320] Example 48: Synthesis of N-(3-(4-(6-aminopyridin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)propyl)methanesulfonamide (Compound 293)

[1321] Step A

[1322]

[1323] To a solution of potassium tert-butoxide (1.1 eq) in 100 mL of anhydrous THF was added ACN (1.1 eq) at -35°C, and the mixture was stirred for 30 minutes. Dimethyl pyridine-2,5-dicarboxylate (5 g, 25.6 mmol, 1 eq) was added as a suspension in 50 mL of anhydrous THF. The reaction mixture was stirred at room temperature overnight. 60% conversion was observed by HPLC. A yellow solid formed and was collected by filtration. The obtained solid was dissolved in water, and the pH of the solution was adjusted to approximately 5. The formed precipitate was filtered and dried (1.5 g, 7.3 mmol, 29% yield).

[1324] The structure of the product was confirmed by NOESY.

[1325] Step B

[1326]

[1327] Methyl 6-(2-cyanoacetyl)nicotinate (1.5 g, 7.3 mmol, 1 eq) was dissolved in 80 mL of MeOH. The mixture was cooled to 0° C., and di-tert-butyl dicarbonate (2 eq) and nickel(II) chloride hexahydrate (0.2 eq) were added. Sodium borohydride (7 eq) was then added portionwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the crude residue was suspended in water and extracted with MTBE. The organic layer was dried over MgSO , filtered, and concentrated. The crude product obtained was used in the subsequent step without any further purification (2 g, 6.4 mmol, 88% yield).

[1328] Step C

[1329]

[1330] The crude 6-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)nicotinate (1 g, 3.2 mmol, 1 equivalent) from the previous step was dissolved in 15 mL of DCM and TFA (10 equivalents) was added. The reaction mixture was stirred for 2 hours. Complete conversion was observed by HPLC. The mixture was evaporated to dryness to provide the Boc-deprotected intermediate.

[1331] The crude intermediate was dissolved in 10 mL of DCM. Triethylamine (4 equiv.) and methanesulfonyl chloride (2.5 equiv.) were added, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated.

[1332] The crude mesylate intermediate was dissolved in 5 mL of DMSO and sodium azide (1.4 equivalents) was added. The reaction mixture was stirred for 2 hours. The reaction mixture was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4, filtered, and evaporated. The crude residue was purified by flash column chromatography (hexane / EtOAc 8:2 to 6:4) to isolate two products:

[1333] Methyl 6-(1-azido-3-(methylsulfonylamino)propyl)nicotinate (43 mg, 0.13 mmol, 4% yield)

[1334] Methyl 6-[1-hydroxy-3-[(2,2,2-trifluoroacetyl)amino]propyl]pyridine-3-carboxylate (110 mg, 0.36 mmol, 11% yield)

[1335] Step D

[1336]

[1337] Methyl 6-(1-azido-3-(methylsulfonylamino)propyl)nicotinate (43 mg, 0.13 mmol, 1 eq) was dissolved in 2 mL of MeOH, and hydrazine hydrate (5 eq) was added. The reaction mixture was refluxed with stirring for 2 hours. The reaction mixture was concentrated, and the residue was dissolved in DMF. Difluoroacetic anhydride (3 eq) was added, and the reaction mixture was stirred at room temperature for 90 minutes. An additional 4 eq of difluoroacetic anhydride was added, and the mixture was stirred for a further 4 hours. 50% of the desired product was observed in the mixture. The reaction mixture was diluted with saturated aqueous NaHCO₃ and extracted with MTBE. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The crude product (41 mg, 0.055 mmol, 40% yield) was used in the next step without any further purification.

[1338] Step E

[1339]

[1340] Crude N-[3-azido-3-[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]propyl]methanesulfonamide (41 mg, 0.055 mmol, 1 eq) and 5-ethynylpyridin-2-amine (1 eq) obtained in the previous step were dissolved in 1 mL of DMSO. Sodium L-ascorbate (0.15 eq) and copper sulfate pentahydrate (0.15 eq) were added as aqueous solutions. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was subjected to prep-HPLC (ACN / HO + 0.1% FA) without further treatment to obtain the desired product as the formate salt (3.8 mg, 0.008 mmol, 14% yield, m / z 491.92 [MH]).

[1341] The following compounds were prepared according to the same procedure:

[1342]

[1343] Example 49: Synthesis of 5-(1-(1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-(pyrrolidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 301)

[1344] Step A

[1345]

[1346] Methyl 6-bromopyridine-3-carboxylate (1.9 g, 8.8 mmol, 1 equiv), potassium ethylene trifluoroborate (1.8 equiv), and cesium carbonate (1.9 equiv) were dissolved in a 4:1 EtOH / water mixture (50 mL). After degassing the mixture with Ar, tetrakis(triphenylphosphine)palladium(0) (0.1 equiv) was added. The reaction mixture was stirred at 100°C overnight. Complete conversion was observed by HPLC. The resulting white precipitate was filtered off, and the filtrate was diluted with water and extracted with MTBE. The organic layer was dried over Na2SO4, filtered, and concentrated.

[1347] The crude ethyl ester product (1.55 g, 8.8 mmol, 100% yield) was used in the next step without any further purification.

[1348] Step B

[1349]

[1350] 6-vinylpyridine-3-carboxylic acid ethyl ester (800 mg, 4.5 mmol, 1 equivalent) was dissolved in a 3:1 tBuOH / water mixture (20 mL), and the resulting mixture was warmed to 40 ° C. N-bromosuccinimide (1.5 equivalents) was added and the mixture was stirred at 40 ° C for 2 hours. The starting material was consumed. The reaction mixture was cooled to 0 ° C, and NaOH (1 equivalent) was added as an aqueous solution. The resulting mixture was stirred for 3 hours to obtain the desired epoxide. The reaction mixture was diluted with water and the product was extracted into MTBE. The organic phases were collected together, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (hexane / EtOAc 95: 5 to 6: 4) to provide the pure desired product (185 mg, 0.96 mmol, 21% yield).

[1351] Step C

[1352]

[1353] 6-(Oxiran-2-yl)nicotinate ethyl ester (185 mg, 0.96 mmol, 1 equivalent) was dissolved in 4 mL of DCM and pyrrolidine (2.5 equivalents) was added. 3 mL of chloroform was added. The reaction mixture was then stirred at 50 ° C for 72 hours. Complete conversion was observed. The mixture was cooled to 0 ° C, and triethylamine (2 equivalents) and methanesulfonyl chloride (2 equivalents) were added. The reaction mixture was stirred at room temperature for 2 hours. Complete conversion to the mesylate intermediate was observed. The mixture was diluted with EtOAc and washed with saturated NaHCO3 aqueous solution and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to provide the crude intermediate. The residue was dissolved in 2 mL of DMSO and sodium azide was added. The mixture was stirred at room temperature overnight. Complete conversion to the desired azide was observed. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (hexanes / EtOAc 8:2 to 2:8) to afford the pure desired product (180 mg, 0.62 mmol, 65% yield).

[1354] Step D

[1355]

[1356] Ethyl 6-(1-azido-2-(pyrrolidin-1-yl)ethyl)nicotinate (180 mg, 0.62 mmol, 1 eq) was dissolved in 5 mL of MeOH. Hydrazine hydrate (5 eq) was added. The mixture was refluxed with stirring for 3 hours. Methanol and hydrazine were removed by evaporation. The intermediate hydrazide was dissolved in 3 mL of DMF and difluoroacetic anhydride (4 eq) was added. The mixture was stirred at room temperature overnight. The mixture was then diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by pTLC (hexane / EtOAc 8:2 to 2:8) to provide the desired product (34 mg, 0.1 mmol, 16% yield).

[1357] Step E

[1358]

[1359] 2-(6-(1-azido-2-(pyrrolidin-1-yl)ethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (34 mg, 0.1 mmol, 1 eq) and 5-ethynylpyridin-2-amine (1 eq) were dissolved in 0.5 mL of DMSO. Sodium ascorbate (0.4 eq) and copper sulfate pentahydrate (0.2 eq) were added as aqueous solutions. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was subjected to prep-HPLC (ACN / HO / 0.1% FA) without further treatment to obtain the desired product as a bisformic acid salt (2.8 mg, 0.006 mmol, 6% yield, m / z 454.11 [MH]).

[1360] Example 50: Synthesis of N-(3-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1,2,4-oxadiazol-5-yl)phenyl)morpholine-4-carboxamide (Compound 145)

[1361] Step A

[1362]

[1363] Under stirring, a solution of 20mL MeOH of 4-(cyanomethyl)-3,5-difluorobenzoic acid methyl ester (2.1g, 10mmol, 1 equivalent), sodium bicarbonate (1.05 equivalents) and hydroxylamine hydrochloride (1.05 equivalents) was refluxed overnight. Complete conversion was detected by TLC. The reaction mixture was concentrated under reduced pressure. Water and EtOAc were added to the residue. The formed solid was collected by filtration and rinsed with water and methanol. The precipitated powder (1.7g, 7mmol, 70% yield) was dried under reduced pressure.

[1364] Step B

[1365]

[1366] A solution of 3-((tert-butoxycarbonyl)amino)benzoic acid (1 eq), EDC (1.1 eq), and HOBt (1.05 eq) in 8 mL of DMF was stirred at room temperature for 1 hour. The amidoxime obtained in step A (515 mg, 2.1 mmol, 1 eq) was added. The reaction mixture was stirred for 4 hours. Complete conversion to product was detected by HPLC. The reaction mixture was diluted with water. The resulting white solid was washed with water and air-dried (862 mg, 1.86 mmol, 88% yield).

[1367] Step C

[1368]

[1369] To a solution of methyl 4-(2-amino-2-(((3-((tert-butoxycarbonyl)amino)benzoyl)oxy)imino)ethyl)-3,5-difluorobenzoate (862 mg, 1.86 mmol, 1 equiv) in THF was added tetrabutylammonium fluoride (2.4 equiv) portionwise. The reaction mixture was stirred at room temperature for 18 h and heated to 40° C. for 2 h. Complete conversion was observed by TLC (DCM / MeOH 95:5). The reaction mixture was diluted with water and MTBE. The organic layer was washed with water (3 times) and brine, dried over MgSO 4 , evaporated in vacuo and dried to afford the target compound as a light yellow solid. The crude residue was used in the next step without purification (735 mg, 1.65 mmol, 89% yield).

[1370] Step D

[1371]

[1372] A solution of methyl 4-((5-(3-((tert-butoxycarbonyl)amino)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-3,5-difluorobenzoate (735 mg, 1.65 mmol, 1 eq) and hydrazine hydrate (15 eq) in 20 mL of MeOH was stirred at reflux overnight. Complete conversion was detected by LC-MS. The reaction mixture was concentrated to dryness under vacuum to afford the pure target compound (685 mg, 1.54 mmol, 93% yield) as a white solid.

[1373] Step E

[1374]

[1375] To a solution of tert-butyl-(3-(3-(2,6-difluoro-4-(hydrazinecarbonyl)benzyl)-1,2,4-oxadiazol-5-yl)phenyl)carbamate (685 mg, 1.54 mmol, 1 eq) in 5 mL of DMF was added difluoroacetic anhydride (4 eq) at 0 °C. The reaction mixture was heated to 70 °C and stirred for 5 hours. The mixture was then allowed to reach room temperature and stirred overnight. Conversion was confirmed by LC-MS. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (DCM / EtOAc 97:3 to 95:5) to obtain the product (80 mg, 0.16 mmol, 10% yield).

[1376] Step F

[1377]

[1378] Tert-butyl (3-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1,2,4-oxadiazol-5-yl)phenyl)carbamate (80 mg, 0.16 mmol, 1 eq) was dissolved in 3 mL of DCM and trifluoroacetic acid (10 eq) was added. The reaction mixture was stirred at room temperature for 2 hours and the conversion was monitored by TLC. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated and dried in vacuo to provide 61 mg of the product (0.15 mmol, 95% yield).

[1379] Step G

[1380]

[1381] Morpholine-4-carbonyl chloride (2.5 equiv) and triethylamine (4 equiv) were added to a solution of 3-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1,2,4-oxadiazol-5-yl)aniline (61 mg, 0.15 mmol, 1 equiv) in 2 mL of DCE. The reaction mixture was stirred at 80° C. for 5 hours. Conversion was checked by LC-MS. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO 3 solution and brine, dried over MgSO 4 , evaporated under vacuum, and dried. The residue was submitted to prep-HPLC. Product-containing fractions were evaporated to obtain 22 mg of the title compound (0.043 mmol, 28% yield, m / z 519.13 [MH + ]).

[1382] The following compounds were synthesized according to the same procedure:

[1383]

[1384] *[M+ACN+H] observed + .

[1385] Example 51: Synthesis of 3-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,2,4-oxadiazol-3-yl)benzamide (Compound 226)

[1386] Step A

[1387]

[1388] A solution of 3-cyanobenzamide (1 g, 6.8 mmol, 1 eq), sodium bicarbonate (2 eq) and hydroxylamine hydrochloride (2 eq) in 15 mL of MeOH was refluxed overnight with stirring. Conversion was monitored by LC-MS. The reaction mixture was filtered and concentrated under reduced pressure. The obtained white solid was used in the next reaction without further purification (940 mg, 5.2 mmol, 76% yield).

[1389] Step B

[1390]

[1391] A solution of 2-(4-(methoxycarbonyl)phenyl)acetic acid (250 mg, 1.2 mmol, 1 eq), EDC (1.2 eq), and HOBt (1.1 eq) in 5 mL of DMF was stirred at room temperature for 1 hour. The amide oxime obtained in step A (230 mg, 1.2 mmol, 1 eq) was added. The reaction mixture was stirred for 2 hours. Complete conversion to product was detected by LC-MS. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried, and evaporated in vacuo to give the pure title compound (213 mg, 0.6 mmol, 46% yield).

[1392] Step C

[1393]

[1394] Tetrabutylammonium fluoride (1.5 eq) was added portionwise to a solution of (Z)-methyl 4-(2-(((amino(3-carbamoylphenyl)methylene)amino)oxy)-2-oxoethyl)benzoate (213 mg, 0.6 mmol, 1 eq) in 8 mL of THF. The reaction mixture was stirred at room temperature overnight. Complete conversion was observed by TLC. The reaction mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO₃, and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (DCM / MeOH 98:2 to 9:1) to provide the target compound (77 mg, 0.23 mmol, 38% yield) in sufficient purity.

[1395] Step D

[1396]

[1397] A solution of methyl 4-((3-(3-carbamoylphenyl)-1,2,4-oxadiazol-5-yl)methyl)benzoate (77 mg, 0.23 mmol, 1 eq) and hydrazine hydrate (5 eq) in 5 mL of MeOH was stirred at reflux overnight. Complete conversion was detected by LC-MS. The reaction mixture was concentrated. The residue was suspended in acetonitrile and evaporated twice to provide the desired product, which was dried under vacuum (77 mg, 0.023 mmol, 100% yield).

[1398] Step E

[1399]

[1400] To a solution of 3-(5-(4-(hydrazinecarbonyl)benzyl)-1,2,4-oxadiazol-3-yl)benzamide (77 mg, 0.023 mmol, 1 eq) in 2 mL of DMF was added difluoroacetic anhydride (3 eq) at 0°C. The reaction mixture was heated to 50°C and stirred for 4 hours. Complete conversion was observed by LC-MS. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC to provide the target compound (15 mg, 0.036 mmol, 16% yield, m / z 397.89 [MH+]).

[1401] The following compounds were synthesized according to the same procedure:

[1402]

[1403] Example 52: Synthesis of 5-(5-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)difluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine (Compound 243)

[1404] Step A

[1405]

[1406] Methyl 4-iodobenzoate (5 g, 19.3 mmol, 1 eq) was dissolved in MeOH (5 mL) and hydrazine monohydrate (5 eq) was added with stirring. The mixture was stirred at 70°C overnight. LC-MS (and TLC) indicated complete conversion of the methyl ester to the hydrazide. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous NaHCO3, brine, dried, filtered, and concentrated under reduced pressure. 4.37 g (16.2 mmol) of the intermediate hydrazide was obtained.

[1407] The crude intermediate was dissolved in dry DMF (3 mL) under argon. Difluoroacetic anhydride (4 equivalents) was slowly added, maintaining the temperature below 30°C (ice / NaCl bath). After the addition was complete, the temperature was allowed to reach room temperature. The flask was sealed and the reaction mixture was stirred at 70°C for 3 hours. Complete conversion was observed by LC-MS, forming 50% of the desired product.

[1408] The reaction mixture was diluted with water to form a white precipitate, which was collected by filtration, rinsed with water, and air-dried overnight. The resulting solid was suspended in 60 mL of chloroform, filtered, and rinsed twice with more chloroform. The filtrate was concentrated and the residue was dried in vacuo (3.5 g, 9.7 mmol, 50% yield).

[1409] Step B

[1410]

[1411] Copper powder (2.6 eq) was stirred in 0.1 M HCl for 10 minutes and then filtered. This procedure was repeated with water, methanol, and acetone. The powder was dried in vacuo for 10 minutes and added to a solution of 2-(difluoromethyl)-5-(4-iodophenyl)-1,3,4-oxadiazole (500 mg, 1.55 mmol, 1 eq) and ethyl difluorobromoacetate (1 eq) in DMSO (6 mL). The reaction mixture was stirred at 60°C overnight. LC-MS confirmed complete conversion to the product. The mixture was diluted with EtOAc, filtered, washed with water (twice), saturated aqueous NaHCO₃ (twice), and brine, dried, and evaporated in vacuo. The residue was purified by flash chromatography (hexane / EtOAc 9:1 to 8:2) to provide the pure desired product (367 mg, 1.15 mmol, 74% yield).

[1412] Step C

[1413]

[1414] Ethyl 2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)-2,2-difluoroacetate (150 mg, 0.47 mmol, 1 equivalent) and lithium hydroxide monohydrate were dissolved in a 2:1 mixture of THF and water. The resulting mixture was stirred at room temperature for 30 minutes. Complete conversion was detected by TLC (eluent: DCM / MeOH 98:2). The reaction mixture was evaporated, resuspended in acetonitrile, and concentrated. The resulting residue was used in the next step without purification (139 mg, 0.46 mmol, 99% yield).

[1415] Step D

[1416]

[1417] A solution of tert-butyl (5-cyanopyridin-2-yl)carbamate (853 mg, 3.9 mmol, 1 equivalent), sodium bicarbonate (1.1 equivalents) and hydroxylamine hydrochloride (1.1 equivalents) in 10 mL of methanol was refluxed overnight under stirring. Conversion was monitored by LC-MS. The reaction mixture was filtered and concentrated under reduced pressure. The residue was suspended in acetonitrile and evaporated twice. The obtained white solid was used in the next step without further purification (978 mg, 3.87 mmol, 99% yield).

[1418] Step E

[1419]

[1420] A solution of lithium 2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)-2,2-difluoroacetate (37 mg, 0.125 mmol, 1 eq.), EDC (2.2 eq.) and HOBt (1.1 eq.) obtained in step C in 1 mL of DMF was stirred at room temperature for 15 minutes. The amide oxime (31 mg, 0.125 mmol, 1 eq.) obtained in step D was added to the reaction mixture, which was stirred for 40 hours. Complete conversion to the product was detected by LC-MS. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 solution and brine, dried and evaporated under vacuum to provide the target compound (38 mg, 0.075 mmol, 60% yield). The crude residue was used in the subsequent step without further purification.

[1421] Step F

[1422]

[1423] Tert-butyl (5-(5-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)difluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)carbamate (38 mg, 0.075 mmol, 1 equivalent) was dissolved in a 40% solution of TFA in DCM (850 μL), and the resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed twice with saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄, evaporated, and subjected to prep-HPLC. After evaporation of the product-containing fractions, 5.8 mg of the title compound (0.014 mmol, 19% yield, m / z 448.14 [M+H+ACN]) were obtained. + ).

[1424] Example 53: Synthesis of 5-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine (Compound 218)

[1425] Step A

[1426]

[1427] A solution of methyl 6-((tert-butoxycarbonyl)amino)nicotinate (1 g, 3.9 mmol, 1 eq) and hydrazine hydrate (5 eq) in 20 mL of MeOH was stirred at 70° C. overnight. Complete conversion was detected by TLC (DCM / MeOH 95:5). The reaction mixture was concentrated to dryness. The residue was resuspended in acetonitrile and evaporated again to yield the pure target compound (1 g, 3.9 mmol, 100% yield).

[1428] Step B

[1429]

[1430] A mixture of 2-(4-(methoxycarbonyl)phenyl)acetic acid (766 mg, 3.9 mmol, 1 eq) and HATU (1.5 eq) in 4 mL of DMF was stirred at room temperature for 10 minutes. The hydrazide obtained in the previous step (1 eq) was then added, and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 1 M HCl, saturated aqueous NaHCO₃, brine, dried over MgSO₄, filtered, and concentrated under reduced pressure. The resulting beige crude residue (an almost 1:1 mixture of product and by-product) was used directly in the next step without further purification.

[1431] Step C

[1432]

[1433] Methyl 4-(2-(2-(6-((tert-butoxycarbonyl)amino)nicotinyl)hydrazino)-2-oxoethyl)benzoate (1.1 g, 2.56 mmol, 1 eq) was dissolved in 10 mL of THF. Burgess reagent (2.5 eq) was added portionwise to the stirred mixture at room temperature for 6 hours. The reaction mixture was then diluted with EtOAc, washed four times with saturated aqueous NaHCO3 and once with brine, dried over MgSO4, filtered, and evaporated under vacuum. The residue thus obtained was purified by flash column chromatography to provide 300 mg of the target compound as a white solid (0.73 mmol, 28% yield).

[1434] Step D

[1435]

[1436] A solution of methyl 4-((5-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)benzoate (150 mg, 0.365 mmol, 1 eq) and hydrazine hydrate (15 eq) in 10 mL of MeOH was stirred at reflux overnight. Complete conversion was detected by LC-MS. The reaction mixture was concentrated to dryness under vacuum to afford the pure title compound (150 mg, 0.365 mmol, 100% yield) as a white solid.

[1437] Step E

[1438]

[1439] To a solution of tert-butyl (5-(5-(4-(hydrazinecarbonyl)benzyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)carbamate (150 mg, 0.365 mmol, 1 eq) in 5 mL of DMF was added difluoroacetic anhydride (3 eq) at 0°C. The reaction mixture was allowed to reach room temperature and then stirred for 1 hour. Conversion was confirmed by LC-MS. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 (4 times) and brine, dried over MgSO4, evaporated and dried in vacuo. The residue obtained was submitted to prep-HPLC. After fraction evaporation, 15 mg of the desired product was obtained (0.032 mmol, 9% yield).

[1440] Step F

[1441]

[1442] Tert-butyl (5-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)carbamate (15 mg, 0.032 mmol, 1 eq) was dissolved in a 50% mixture of TFA (10 eq) in DCM.

[1443] The reaction mixture was stirred at room temperature for 1 hour and the conversion was monitored by TLC. The mixture was evaporated to dryness and the residue was triturated with ether to afford the pure product as a TFA salt (15 mg, 0.032, 100% yield, m / z 371.2 [MH+]).

[1444] The following compounds were synthesized according to the same procedure:

[1445]

[1446] Example 54: Synthesis of 5-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)isoxazol-3-yl)pyridin-2-amine (Compound 202)

[1447] Step A

[1448]

[1449] Methyl 4-iodobenzoate (5 g, 19.3 mmol, 1 eq) was dissolved in MeOH (5 mL), and hydrazine monohydrate (5 eq) was added with stirring. The mixture was stirred at 70°C overnight. LC-MS (and TLC) indicated complete conversion of the methyl ester to the hydrazide. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. 4.37 g (16.2 mmol) of the intermediate hydrazide was obtained.

[1450] The crude intermediate was dissolved in dry DMF (3 mL) under argon. Difluoroacetic anhydride (4 equivalents) was slowly added, maintaining the temperature below 30°C (ice / NaCl bath). After the addition was complete, the temperature was allowed to reach room temperature. The flask was sealed and the reaction mixture was stirred at 70°C for 3 hours. Complete conversion was observed by LC-MS, forming 50% of the desired product.

[1451] The reaction mixture was diluted with water to form a white precipitate, which was collected by filtration, rinsed with water, and air-dried overnight. The resulting solid was suspended in 60 mL of chloroform, filtered, and rinsed twice with more chloroform. The filtrate was concentrated and the residue was dried in vacuo (3.5 g, 9.7 mmol, 50% yield).

[1452] Step B

[1453]

[1454] Triethylamine (1 eq) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.1 eq) were added to a degassed mixture of 2-(difluoromethyl)-5-(4-iodophenyl)-1,3,4-oxadiazole (1.5 g, 4.6 mmol, 1 eq), ethynyl(trimethyl)silane (1.5 eq), and copper iodide (0.1 eq) in 20 mL of DMF. The reaction mixture was degassed for 20 minutes, heated at 40°C, and stirred overnight. Complete conversion to the desired intermediate was observed by LC-MS.

[1455] Tetrabutylammonium fluoride (1 equivalent) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with MTBE (3 times). The combined organic layers were washed with saturated aqueous NaHCO 3 solution, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (DCM) to obtain 230 mg (1 mmol, 22% yield) of the desired product.

[1456] Step C

[1457]

[1458] 2-(Difluoromethyl)-5-(4-ethynylphenyl)-1,3,4-oxadiazole (210 mg, 0.95 mmol, 1 equivalent) and 5-ethynylpyridin-2-amine (5 equivalents) were dissolved in a 1:1 mixture of methanol and pyridine (10 mL). The mixture was degassed with argon, and copper acetate (2 equivalents) was added under an argon stream. The reaction mixture was stirred at room temperature overnight.

[1459] The reaction mixture was then filtered and the solid obtained was washed with MeOH, EtOAc and DCM. The organic phase was concentrated and combined. The residue was dissolved in EtOAc and washed with water (3 times), dried over MgSO4, filtered and evaporated. The crude product was purified by flash column chromatography (EtOAc / DCM) to obtain 50mg of the desired product (0.15mmol, 15% yield).

[1460] Step D

[1461]

[1462] 5-[4-[4-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]buta-1,3-diynyl]pyridin-2-amine (50 mg, 0.15 mmol, 1 eq) was dissolved in DMSO (2 mL). Triethylamine (6 eq) and hydroxylamine hydrochloride (3.5 eq) were added. The reaction mixture was stirred at 110°C overnight. After cooling to room temperature, the mixture was subjected to prep-HPLC (0.1% FA / ACN / water) to provide the desired product (4.4 mg, 0.012 mmol, 9.6% yield, m / z 369.71 [MH+]).

[1463] The following compounds were prepared according to the same procedure:

[1464]

[1465] Example 55: Synthesis of 2-(difluoromethyl)-5-(4-((5-phenyl-1,3,4-thiadiazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 238)

[1466] Step A

[1467]

[1468] A solution of 2-(4-(methoxycarbonyl)phenyl)acetic acid (300 mg, 1.5 mmol, 1 eq), EDC (1.2 eq), and HOBt (1.1 eq) in 4 mL of DMF was stirred at room temperature for 10 minutes. Benzohydrazide (1 eq) was added, and the reaction mixture was stirred for 2 hours. Complete conversion to product was detected by LC-MS. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried, and evaporated in vacuo to give the pure title compound (343 mg, 1.1 mmol, 71% yield).

[1469] Step B

[1470]

[1471] A mixture of methyl 4-(2-(2-benzoylhydrazino)-2-oxoethyl)benzoate (343 mg, 1.1 mmol, 1 equivalent) and Lawesson's reagent (1.5 equivalents) in THF (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO₃, water, and brine, dried over MgSO₄, and evaporated in vacuo. The title compound thus obtained was used in the next step without further purification (340 mg, 1.1 mmol, 99% yield).

[1472] Step C

[1473]

[1474] A solution of methyl 4-((5-phenyl-1,3,4-thiadiazol-2-yl)methyl)benzoate (340 mg, 1.1 mmol, 1 eq) and hydrazine hydrate (5 eq) in 5 mL of methanol was stirred at reflux overnight. Complete conversion was detected by LC-MS. The reaction mixture was concentrated. The residue was suspended in acetonitrile and evaporated twice to provide the desired product, which was dried under vacuum (340 mg, 1.1 mmol, 100% yield).

[1475] Step D

[1476]

[1477] To a solution of 3-(5-(4-(hydrazinecarbonyl)benzyl)-1,2,4-oxadiazol-3-yl)benzamide (340 mg, 1.1 mmol, 1 equiv) in 5 mL of DMF was added difluoroacetic anhydride (3 equiv) at 0°C. The reaction mixture was heated to 70°C and stirred for 6 hours. Complete conversion was observed by LC-MS. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC to provide the target compound (41 mg, 0.11 mmol, 10% yield, m / z 370.85 [MH+]).

[1478] Example 56: Synthesis of N-(5-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)-2,2-difluoroacetamide (Compound 102)

[1479] Step A

[1480]

[1481] A solution of methyl 6-((tert-butoxycarbonyl)amino)nicotinate (1 g, 3.9 mmol, 1 eq) and hydrazine hydrate (5 eq) in 20 mL of MeOH was stirred at 70° C. overnight. Complete conversion was detected by TLC (DCM / MeOH 95:5). The reaction mixture was concentrated to dryness. The residue was resuspended in acetonitrile and evaporated again to afford the pure target compound (1 g, 3.9 mmol, 100% yield).

[1482] Step B

[1483]

[1484] A solution of 2-(5-bromopyridin-2-yl)acetic acid (342 mg, 1.58 mmol, 1 eq), EDC (1.2 eq) and HOBt (1.1 eq) in 4 mL of DMF was stirred at room temperature for 15 minutes. t-Butyl (5-(hydrazinecarbonyl)pyridin-2-yl)carbamate (1 eq) was added and the reaction mixture was stirred for 3 hours. Complete conversion to product was detected by LC-MS. The reaction mixture was diluted with water. The resulting precipitate was collected by filtration and rinsed with water (5 times), then dried under vacuum to provide the pure desired product (483 mg, 1.07 mmol, 68% yield) as a yellow solid.

[1485] Step C

[1486]

[1487] A mixture of tert-butyl (5-(2-(2-(5-bromopyridin-2-yl)acetyl)hydrazine-1-carbonyl)pyridin-2-yl)carbamate (483 mg, 1.07 mmol, 1 eq) and Lawesson's reagent (1.5 eq) in THF (5 mL) was stirred at 60° C. for 1 hour. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO 3 solution, water, and brine, dried over MgSO 4 , and evaporated in vacuo. The residue was purified by flash chromatography (hexane / EtOAc 9:1 to 1:1) to provide the target compound (221 mg, 0.49 mmol, 46% yield) as a pure solid.

[1488] Step D

[1489]

[1490] To a flame-dried flask was placed tert-butyl (5-(5-((5-bromopyridin-2-yl)methyl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)carbamate (220 mg, 0.49 mmol, 1 eq), N-formylsaccharin (1.5 eq), potassium fluoride (2.5 eq), and Xantphos (0.1 eq). Dry DMF (1 mL) was added. Pd(OAc) (0.05 eq) was added to the resulting mixture, which was degassed with argon and heated at 80°C with stirring for 2 days. Partial conversion of the starting material was detected by LC-MS. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO (4 times) and brine, dried over MgSO, filtered, and evaporated. The obtained residue was purified by column chromatography (DCM / MeOH / formic acid 9:1:0 to 8:2:0 to 9:1:0.02) to afford the target compound (59 mg, 0.14 mmol, 29% yield).

[1491] Step E

[1492]

[1493] A solution of 6-((5-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methyl)nicotinic acid (59 mg, 0.14 mmol, 1 eq), EDC (1.2 eq), and HOBt (1.2 eq) in 2 mL of DMF was stirred at room temperature for 10 minutes. A 1 M solution of hydrazine in THF (4 eq) was added, and the reaction mixture was stirred for 5 hours. Partial conversion was detected by LC-MS. The mixture was evaporated to dryness and purified by flash column chromatography (DCM / MeOH 95:5 to 9:1) to provide the target compound (7 mg, 0.016 mmol, 11% yield).

[1494] Step F

[1495]

[1496] To a solution of tert-butyl (5-(5-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)carbamate (7 mg, 0.016 mmol, 1 eq) in 0.5 mL of DMF was added difluoroacetic anhydride (4 eq). The reaction mixture was stirred at room temperature for 1 hour. Based on LC-MS, the starting material was fully converted to the Boc-protected intermediate and the desired product. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO, water, and brine, dried over MgSO, filtered, and concentrated in vacuo.

[1497] The crude intermediate was suspended in a 1:5 mixture of TFA:DCM (600 μL), and the resulting solution was stirred at room temperature for 2 hours. Complete conversion to the product was observed by LC-MS. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO (2 times) and brine, dried over MgSO, filtered, evaporated, and purified by prep-HPLC to provide the pure target compound (0.6 mg, 0.001 mmol, 9% yield, m / z 465.65 [MH]).

[1498] Example 57: Synthesis of 6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-imidazol-4-yl)isoindolin-1-one (Compound 292)

[1499] Step A

[1500]

[1501] A solution of 6-bromo-2,3-dihydroisoindole-1-one (500 mg, 2.36 mmol, 1 eq), bis(pinacolato)diboron (1.5 eq) and potassium acetate (3 eq) in 1,4-dioxane (10.0 mL) was degassed by purging with argon for 15 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.1 eq) was then added to the reaction mixture, which was again degassed with argon for 15 minutes. The resulting reaction mixture was heated to 85°C for 12 hours. After completion of the reaction, as confirmed by TLC, the reaction mixture was purified by The mixture was filtered through a pad of 4% paraffin wax. The filtrate was concentrated and the crude residue thus obtained was suspended in EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM / MeOH 95:5) to provide the product (690 mg, 1.87 mmol, 79% yield) as a beige solid.

[1502] Step B

[1503]

[1504] 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (234 mg, 0.9 mmol, 1 eq), 4-iodo-1H-imidazole (1 eq), and cesium carbonate (1.5 eq) were dissolved in a 4:1 mixture of 1,4-dioxane and water (2.5 mL). The reaction mixture was purged with argon and tetrakis(triphenylphosphine)palladium(0) (0.05 eq) was added. The reaction mixture was stirred at 110°C for 12 hours.

[1505] The reaction was then poured into water and extracted with EtOAc. The aqueous phase was further extracted with a 3:1 mixture of CHCl / IPA. The combined organic extracts were dried over NaSO and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM / MeOH 8:2) to provide the desired product (60 mg, 0.27 mmol, 30% yield).

[1506] Step C

[1507]

[1508] 2-[6-(Bromomethyl)pyridin-3-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate A, 39 mg, 0.13 mmol, 1 eq) was added to a solution of 6-(1H-imidazol-4-yl)-2,3-dihydroisoindole-1-one (1 eq) and potassium carbonate (2 eq) in 1 mL of DMF. The flask was sealed and the reaction mixture was stirred overnight at room temperature. After confirming complete conversion of the starting material, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain the pure title compound as a formate salt (12 mg, 0.03 mmol, 21% yield, m / z 409.07 [MH+]).

[1509] The following compounds were synthesized according to the same procedure:

[1510]

[1511] Starting from the corresponding boronate ester (Step B), the following compounds were synthesized according to the same procedure:

[1512]

[1513] Example 58: Synthesis of 6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-imidazol-4-yl)isoindolin-1-one (Compound 264)

[1514] Step A

[1515]

[1516] 3-(1H-imidazol-4-yl)aniline (1.25 equiv) was dissolved in 3 mL of DMF, and sodium hydride (1.25 equiv) was added. After stirring the mixture for 30 minutes, 2-[6-(bromomethyl)pyridin-3-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate A, 146 mg, 0.5 mmol, 1 equiv) was added. The reaction mixture was stirred for 1 hour, then diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was used in the next step without further purification (165 mg, 0.28 mmol, 45% yield).

[1517] Step B

[1518]

[1519] 3-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]imidazol-4-yl]aniline (135 mg, 0.23 mmol, 1 eq) was dissolved in 5 mL of pyridine and morpholine-4-carbonyl chloride (2.5 eq) was added. The reaction mixture was stirred at 50 ° C for 2 hours. Upon completion, the mixture was diluted with water and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude residue was purified by prep-HPLC (ACN / water) to obtain the desired product (45 mg, 0.09 mmol, 38% yield, m / z 481.86 [MH+]).

[1520] The following compounds were synthesized according to the same procedure:

[1521]

[1522] The following compounds were synthesized according to step A of this procedure:

[1523]

[1524] Example 59: Synthesis of 6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-imidazol-4-yl)isoindolin-1-one (Compound 22)

[1525] Step A

[1526]

[1527] Mercury(II) chloride (1.1 eq) was added to a solution of 4-(1H-imidazol-4-yl)aniline (250 mg, 1.57 mmol, 1 eq), di-tert-butyl 2-thioketoimidazolidine-1,3-dicarboxylate (1 eq), and triethylamine (3.1 eq) in 10 mL of DCM at 0°C. The resulting mixture was stirred at 0°C for 1 hour and then at room temperature for 2 days (d). The reaction mixture was diluted with water and DCM. The mixture was filtered and the filtrate was washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting beige solid was used in the next step without any further purification (470 mg, 1.1 mmol, 70% yield).

[1528] Step B

[1529]

[1530] Di-tert-butyl 2-((4-(1H-imidazol-4-yl)phenyl)imino)imidazolidine-1,3-dicarboxylate (250 mg, 0.58 mmol, 1 eq) and potassium carbonate (1.1 eq) were suspended in 2.5 mL of DMF. After 15 minutes, 2-[4-(bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate B, 1 eq) was added to the suspension and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, which was extracted with EtOAc. The organic phase was washed with saturated aqueous NaHCO3 (3x) and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / EtOAc 3:7 to 5:95) to provide the product (150 mg, 0.23 mmol, 40% yield) as a purple solid.

[1531] Step C

[1532]

[1533] Di-tert-butyl 2-((4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-imidazol-4-yl)phenyl)imino)imidazolidine-1,3-dicarboxylate (150 mg, 0.24 mmol, 1 eq) was dissolved in DCE and TFA (15 eq) was added. The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (ACN / water / FA) and freeze-dried to afford the product as a white solid (70 mg, 0.16 mmol, 68% yield, m / z 436.07 [MH+]).

[1534] The following compounds were synthesized according to the same procedure:

[1535]

[1536] Example 60: Synthesis of 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-imidazol-4-yl)pyridin-2-amine (Compound 12) and 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-imidazol-4-yl)pyridin-2-amine (Compound 126)

[1537] Step A

[1538]

[1539] Tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (400 mg, 1.25 mmol, 1 equiv), 4-iodo-1H-imidazole (1 equiv), cesium carbonate (2.5 equiv), and tetrakis(triphenylphosphine)palladium(0) (0.1 equiv) were suspended in a 3:1 dioxane / water solution (12 mL) and degassed with Ar. The reaction mixture was stirred at 85°C overnight. Conversion was confirmed by LC-MS.

[1540] The reaction mixture was diluted with EtOAc and passed through The organic phase was washed with water and evaporated. The crude material was purified by flash column chromatography to afford 228 mg of the desired product (0.876 mmol, 70% yield).

[1541] Step B

[1542]

[1543] A mixture of tert-butyl (5-(1H-imidazol-4-yl)pyridin-2-yl)carbamate (1.25 equiv) and potassium carbonate (2.5 equiv) in 5 mL of DMF was stirred at room temperature for 30 minutes. 2-[6-(bromomethyl)pyridin-3-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate A, 203 mg, 0.7 mmol, 1 equiv) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄, filtered, and concentrated. The crude residue was purified by flash column chromatography (DCM / MeOH 98:2 to 9:1) to provide the title compound (50 mg, 0.1 mmol, 15% yield).

[1544] Step C

[1545]

[1546] Tert-butyl (5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-imidazol-4-yl)pyridin-2-yl)carbamate (70 mg, 0.15 mmol, 1 eq) was dissolved in 0.5 mL of DCM and TFA (10 eq) was added at room temperature. According to LC-MS, the conversion was complete after 3 hours. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO (2x) and brine. The organic layer was dried over NaSO, filtered, and evaporated under vacuum. The resulting residue was purified by prep-HPLC to obtain the pure isolated target compound:

[1547] Compound 12: 18 mg, 0.05 mmol, 32% yield (m / z 369.73 [MH+]);

[1548] Compound 126: 5 mg, 0.01 mmol, 7% yield (m / z 447.89 [MH+]).

[1549] The following compounds were synthesized following the same procedure:

[1550]

[1551] Example 61: Synthesis of 5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-pyrazol-4-yl)pyridin-2-amine (Compound 211)

[1552] Step A

[1553]

[1554] 2-[4-(Bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate B, 500 mg, 1.73 mmol, 1.0 equiv) and 4-iodo-1H-pyrazole (1 equiv) were dissolved in DMF (10 mL). Potassium carbonate (2.0 equiv) was then added, and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO₃, and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.

[1555] The residue was purified by flash column chromatography (hexane / EtOAc 4:1) to afford the desired product (680 mg, 1.69 mmol, 98% yield).

[1556] Step B

[1557]

[1558] A solution of 2-(difluoromethyl)-5-(4-((4-iodo-1H-pyrazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (1079 mg, 2.68 mmol, 1 eq), LiCl (6 eq) and bis(triphenylphosphine)palladium(II) dichloride (0.05 eq) in 10 mL of 1,4-dioxane was degassed with argon. Bis(tributyltin) (1.1 eq) was added, the flask was sealed and the reaction mixture was stirred at 80° C. overnight. The mixture was allowed to reach room temperature and the volatiles were then removed under vacuum. The residue was partitioned between EtOAc and water. The organic layer was dried, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / EtOAc 4:1) to afford 175 mg of the desired product (0.23 mmol, 8% yield).

[1559] Step C

[1560]

[1561] A solution of 2-(difluoromethyl)-5-(4-((4-(tributylstannyl)-1H-pyrazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (175 mg, 0.23 mmol, 1 eq) and 5-iodopyridin-2-amine (1 eq) in 2 mL of DMF was degassed with argon. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)DCM complex (0.05 eq) was added, the flask was sealed, and the reaction mixture was stirred at 100°C overnight. Subsequently, the mixture was cooled to room temperature and heated to 400°C. The residue was purified by flash column chromatography (DCM / MeOH 9:1) to afford the product, which was further triturated with pentane and dried in vacuo (53 mg, 0.14 mmol, 61% yield, m / z 369.06 [MH+]).

[1562] Example 62: Synthesis of 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)pyridin-2-amine (Compound 13)

[1563] Step A

[1564]

[1565] A mixture of (6-aminopyridin-3-yl)boronic acid (250 mg, 1.14 mmol, 1 eq.), 4-iodo-1H-pyrazole (1 eq.) and cesium carbonate (3 eq.) in 3 mL of water / THF 2:1 was degassed with argon. Tetrakis(triphenylphosphine)palladium (0.05 eq.) was added and the resulting mixture was degassed again. The reaction vessel was sealed and the mixture was stirred at 80°C under an inert atmosphere overnight. Complete conversion to the product was confirmed by LC-MS. The mixture was diluted with EtOAc and water. The phases were separated and the organic layer was further extracted with water (twice). The combined aqueous layers were washed with EtOAc, concentrated, evaporated again from MeCN (3 times) and dried in vacuo. The obtained residue (mixture with cesium carbonate) was used in the next step without purification (150 mg, 0.94, 82% yield).

[1566] Step B

[1567]

[1568] A mixture of 5-(1H-pyrazol-4-yl)pyridin-2-amine (75 mg, 0.47 mmol, 1 eq) and potassium carbonate (2 eq) in 3 mL of DMF was stirred at room temperature for 20 minutes. 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate A, 1 eq) was added and the reaction mixture was stirred overnight. Complete conversion of the starting bromide was confirmed by LC-MS. The reaction mixture was concentrated and subjected to prep-HPLC to provide the target compound (16.5 mg, 0.044, 9% yield, m / z 370.97 [MH+]).

[1569] Example 63: Synthesis of N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 119)

[1570] Step A

[1571]

[1572] 3-(1H-pyrazol-4-yl)aniline (250 mg, 1.57 mmol, 1 equivalent) was dissolved in 5 mL of pyridine and morpholine-4-carbonyl chloride (1.2 equivalents) was added. The reaction mixture was heated to 60° C. and stirred overnight. The starting material was completely consumed, but the desired product accounted for only 25% of the obtained mixture. The reaction mixture was evaporated, dissolved in water, acidified to pH=3 and extracted with EtOAc.

[1573] The crude product was purified by flash column chromatography (0-10% MeOH / DCM).

[1574] Step B

[1575]

[1576] N-[3-(1H-pyrazol-4-yl)phenyl]morpholine-4-carboxamide (44 mg, 0.13 mmol, 1 eq) was suspended in 1 mL of DMF and potassium carbonate (1 eq) was added. The reaction mixture was stirred for 1 hour before the addition of 2-[6-(bromomethyl)pyridin-3-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate A, 1 eq). The mixture was stirred at room temperature overnight before being diluted with EtOAc and washed with saturated aqueous NaHCO (2x) and brine. The organic phase was dried over NaSO, filtered, and evaporated to afford the crude product, which was purified by prep-HPLC (C18, ACN / water) to afford the pure title compound (10 mg, 0.02 mmol, 8% yield, m / z 481.92 [MH]).

[1577] The following compounds were synthesized according to the same procedure:

[1578]

[1579] Example 64: Synthesis of N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-pyrazol-4-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine (Compound 269)

[1580] Step A

[1581]

[1582] Mercury (II) chloride (1.1 eq) was added to a solution of 4-(1H-imidazol-4-yl)aniline (242 mg, 1.52 mmol, 1 eq), di-tert-butyl 2-thioketoimidazolidine-1,3-dicarboxylate (1 eq) and triethylamine (3.1 eq) in 10 mL of DCM at 0°C. The resulting mixture was stirred at 0°C for 1 hour, then allowed to reach room temperature and stirred for 3 days. The reaction mixture was diluted with water and DCM. The layers were separated and the organic phase was filtered. The filtrate was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting beige solid was used in the next step without further purification (649 mg, 1.52, 100% yield).

[1583] Step B

[1584]

[1585] Di-tert-butyl 2-((4-(1H-pyrazol-4-yl)phenyl)imino)imidazolidine-1,3-dicarboxylate (300 mg, 0.70 mmol, 1 eq) and potassium carbonate (1.1 eq) were suspended in 2.5 mL of DMF. After 15 minutes, 2-(4-(bromomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate B, 1 eq) was added to the resulting suspension, and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic phase was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and filtered. After concentration under reduced pressure, the residue was purified by flash column chromatography (hexane / EtOAc 3:7 to 5:95) to provide the product (240 mg, 0.38 mmol, 54% yield) as a yellow solid.

[1586] Step C

[1587]

[1588] Di-tert-butyl 2-((4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-pyrazol-4-yl)phenyl)imino)imidazolidine-1,3-dicarboxylate (240 mg, 0.38 mmol, 1 eq) was dissolved in 2.5 mL of DCE and TFA (15 eq) was added. The reaction mixture was stirred at room temperature overnight. Complete conversion was observed by LC-MS. The reaction mixture was concentrated under reduced pressure, and the residue thus obtained was dissolved in acetonitrile and concentrated under reduced pressure (3 times). The dark red oily residue was purified by prep-HPLC to provide the desired product as a white solid in the form of a formate salt. This formate salt (22 mg) was dissolved in water / acetonitrile and solid sodium bicarbonate (pH slightly basic) was added. Precipitation occurred during stirring. The precipitate was collected by centrifugation and washed with a minimum amount of water and dried. The product was obtained as the free base after freeze drying (15 mg, 0.03 mmol, 9% yield, m / z 436.11 [MH+]).

[1589] The following compounds were synthesized according to the same procedure:

[1590]

[1591] Example 65: Synthesis of 5-(5-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)thio)-4-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (Compound 285)

[1592] Step A

[1593]

[1594] 6-((tert-Butoxycarbonyl)amino)nicotinic acid (300 mg, 1,47 mmol, 1 eq) and 4-methyl-3-thiosemicarbazide (1.1 eq) were suspended in DMF. T3P (1.5 eq, 50% solution in DMF) and DIPEA (1.8 eq) were added, and the reaction mixture was stirred at room temperature for 64 hours. LC-MS confirmed the formation of the reaction intermediate. The reaction mixture was diluted with EtOAc and water, and then 4M NaOH was added. The aqueous phase was separated and the organic layer was washed with 4M NaOH. The aqueous layers were collected and stirred at 60°C for 4 hours. The white solid formed was collected by filtration. The crude product thus obtained was used in the subsequent step without any further purification (230 mg, 0.75 mmol, 59% yield).

[1595] Step B

[1596]

[1597] Methyl 4-iodobenzoate (5.07 g, 19.3 mmol, 1 equivalent) was dissolved in MeOH (25 mL) and hydrazine monohydrate (5 equivalents) was added with stirring. The mixture was refluxed for 3 hours. Complete conversion of the methyl ester was observed by LC-MS (and TLC). The reaction mixture was concentrated and dried under vacuum. The obtained white solid (4.37 g) was dissolved in 10 mL of dry DMF and DFAA (3.5 equivalents) was added. The reaction mixture was stirred at 70 ° C for 3 hours. LC-MS confirmed that the starting material was completely converted to the product. A white precipitate was formed when the mixture was diluted with water. The solid was collected by filtration, rinsed with water and air-dried overnight. The obtained solid was suspended in 60 mL of chloroform, filtered and rinsed twice with fresh chloroform. The filtrate was concentrated and the residue was dried under vacuum to obtain the desired product (3.5 g, 9.8 mmol, 51% yield).

[1598] Step C

[1599]

[1600] Copper iodide (0.05 equiv), L-proline (0.1 equiv), and potassium carbonate (1.11 equiv) were dissolved in 3 mL of DMF. The reaction mixture was degassed, and then 2-(difluoromethyl)-5-(4-iodophenyl)-1,3,4-oxadiazole (115 mg, 0.358 mmol, 1.1 equiv) and tert-butyl (5-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamate (100 mg, 0.325 mmol, 1 equiv) were added under argon. The reaction mixture was stirred at 80° C. overnight and then diluted with water. A yellow solid precipitated (70% of the desired product). The crude product thus obtained (87 mg, 0.17 mmol, 53% yield) was used directly in the next step.

[1601] Step D

[1602]

[1603] tert-Butyl (5-(5-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)thio)-4-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamate (87 mg, 0.17 mmol, 1 eq) was dissolved in 1 mL of DCM. TFA (10 eq) was added and the reaction mixture was stirred at room temperature for 2 hours. DCM was added and the mixture was washed with saturated aqueous NaHCO (2x). The organic phase was separated, dried over NaSO, filtered, and evaporated. The crude product was purified by prep-HPLC (0.1% FA / ACN / water C-18) to afford 34 mg (0.085 mmol, 49% yield) of the title compound (m / z 402.0 [MH]).

[1604] Example 66: Synthesis of 5-(5-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)thio)-4-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (Compound 284)

[1605] Step A

[1606]

[1607] 6-((tert-Butoxycarbonyl)amino)nicotinic acid (300 mg, 1,47 mmol, 1 eq) and 4-methyl-3-thiosemicarbazide (1.1 eq) were suspended in DMF. T3P (1.5 eq, 50% solution in DMF) and DIPEA (1.8 eq) were added and the reaction mixture was stirred at room temperature for 64 hours. LC-MS confirmed the formation of the reaction intermediate. The reaction mixture was diluted with EtOAc and water, and then 4M NaOH was added. The aqueous phase was separated and the organic layer was washed with 4M NaOH. The aqueous layers were collected together and stirred at 60°C for 4 hours. The white solid formed was collected by filtration. The crude product thus obtained was used in the subsequent step without any further purification (230 mg, 0.75 mmol, 59% yield).

[1608] Step B

[1609]

[1610] 3,4,5-Trifluorobenzoic acid (2 g, 11.3 mmol, 1 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.4 equiv), and HOBt (1.4 equiv) were dissolved in 10 mL of anhydrous DMF. N,N-diisopropylethylamine (6 equiv) was added, and the reaction mixture was stirred at room temperature for 20 minutes. The solution was cooled to 0°C in an ice bath, and hydrazine monohydrate (5 equiv) was added in one portion. The resulting mixture was stirred at 0°C for 30 minutes, then allowed to reach room temperature and stirred overnight. Product formation was detected by LC-MS. The reaction mixture was diluted with water, and the formed precipitate was filtered off. The filtrate was extracted with MTBE to obtain the desired product (1.6 g, 5.9 mmol, 52% yield).

[1611] Step C

[1612]

[1613] 3,4,5-trifluorobenzoic acid hydrazide (1.6 g, 5.9 mmol, 1 equivalent) was dissolved in 10 mL of DMF and DFAA (4 equivalents) was added. The reaction mixture was stirred at 70 ° C for 3 hours. LC-MS confirmed that the starting material was completely converted to the product. A white precipitate was formed when the mixture was diluted with water. This solid was collected by filtration, rinsed with water, and air-dried overnight. The obtained solid was suspended in 60 mL of chloroform, filtered and rinsed twice with fresh chloroform. The filtrate was concentrated and the residue was dried under vacuum to obtain the desired product (1.47 g, 5.3 mmol, 90% yield).

[1614] Step D

[1615]

[1616] Tert-butyl N-[5-(4-methyl-5-thiosulfanyl-1,2,4-triazol-3-yl)pyridin-2-yl]carbamate (80 mg, 0.26 mmol, 1 equiv), 2-(difluoromethyl)-5-(3,4,5-trifluorophenyl)-1,3,4-oxadiazole (72 mg, 0.29 mmol, 1.1 equiv), and potassium carbonate (2.2 equiv) were suspended in 3 mL of DMF. The reaction mixture was heated at 70°C for 2 hours. Upon dilution with water, a yellow solid precipitated. The solid was collected by filtration to give the desired product (83 mg, 0.15 mmol, 59% yield).

[1617] Step E

[1618]

[1619] Tert-butyl N-[5-[5-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]thiosulfanyl-4-methyl-1,2,4-triazol-3-yl]pyridin-2-yl]carbamate (83 mg, 0.154 mmol, 1 eq) was dissolved in 2 mL of DCM. TFA (10 eq) was added, and the reaction mixture was stirred at room temperature for 2 hours. DCM was added and the mixture was washed with saturated aqueous NaHCO (2x). The organic phase was separated, dried over NaSO, filtered, and evaporated. The crude product was purified by prep-HPLC (0.1% FA / ACN / water C-18) to provide 20 mg (0.045 mmol, 29% yield) of the title compound (m / z 438.0 [MH]).

[1620] Example 67: Synthesis of 2-(4-(bromomethyl-d2)-2,3-difluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate R)

[1621] Step A

[1622]

[1623] Triphenylphosphine (1.2 eq) was added to a solution of methyl 4-(bromomethyl)-2,3-difluorobenzoate (1.23 g, 4.6 mmol, 1 eq) in a 1:1 mixture of D₂O / THF. The mixture was stirred at room temperature overnight. Potassium cyanide (1.2 eq) was then added to the reaction mixture, which was stirred at room temperature overnight. The mixture was extracted with EtOAc, dried over Na₂SO₄, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (Hex:EtOAc) to obtain the desired product (763 mg, 4.03 mmol, 87% yield).

[1624] Step B

[1625]

[1626] Methyl 2,3-difluoro-4-(methyl-d3)benzoate (763 mg, 4.03 mmol) was dissolved in MeOH (11 mL). Hydrazine monohydrate (5 equivalents) was added and the resulting mixture was stirred at 60° C. for 3 hours. The reaction mixture was evaporated and the residue (740 mg, 3.91 mmol, 97% yield) was used directly in the subsequent step.

[1627] Step C

[1628]

[1629] DFAA (2.5 equivalents) is added to a solution of 15mL DMF of 2,3-difluoro-4-(trideuteriomethyl)benzohydrazide (740mg, 3.91mmol, 1 equivalent). The mixture thus obtained is stirred for 3 hours. Then, 0.5 additional equivalents of DFAA are added and the mixture is stirred overnight. The reaction mixture is poured into a saturated NaHCO3 aqueous solution and then extracted with EtOAc. The organic layers are collected together, dried over Na2SO4, filtered and concentrated to provide a crude product, which is purified by flash column chromatography (Hex: EtOAc / 85: 15) (529mg, 2.12mmol, 54% yield).

[1630] Step D

[1631]

[1632] 2-(Difluoromethyl)-5-[2,3-difluoro-4-(trideuteriomethyl)phenyl]-1,3,4-oxadiazole (529 mg, 2.12 mmol, 1 eq) was dissolved in carbon tetrachloride (7 mL). Then, NBS (1.55 eq) and AIBN (0.1 eq) were added. The reaction mixture was degassed and refluxed (75 ° C) under argon for 3 hours. Then, NBS (0.5 eq) and AIBN (0.05 eq) were added. The reaction mixture was degassed and refluxed (75 ° C) under argon for 5 hours. The reaction mixture was cooled, diluted with DCM, washed twice with water, then with aqueous sodium thiosulfate solution and with aqueous NaHCO 3 solution. The organic phase was dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The crude residue was purified using flash column chromatography (Hex:EtOAc) to obtain the pure product (291 mg, 0.89 mmol) in 42% yield.

[1633] The same procedure was followed to prepare the following building blocks:

[1634]

[1635] Example 68: Synthesis of 2-(6-(bromomethyl-d2)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Intermediate X)

[1636] Step A

[1637]

[1638] Methyl 6-methylnicotinate (1.76 g, 11.6 mmol, 1 eq) was dissolved in deuterium oxide and sodium deuterium oxide (40 wt% in D2O, 3.6 eq) was added. The reaction mixture was stirred at 140°C under MW irradiation for 1 hour. The solvent was evaporated and the crude product was used directly in the next step without further purification (2.46 g, 10.6 mmol, 91% yield).

[1639] Step B

[1640]

[1641] Crude 6-(methyl-d3)nicotinic acid (4.2 g, 29.7 mmol, 1 equivalent) was dissolved in 150 mL of MeOH. The mixture was cooled to 0° C. with an ice bath and SOCl2 (10 equivalents) was added dropwise. The mixture was then allowed to reach room temperature and stirred overnight. The mixture was neutralized by adding a saturated aqueous NaHCO3 solution and the pH was adjusted to 9 with a 1 M NaOH solution. The product was extracted into EtOAc. The co...

Claims

1. A compound of formula (I) and its pharmaceutically acceptable salts and stereoisomers, in: X and X' are independently selected from CH, N, CF or CCl; Y and Y' are independently selected from CH, N or CF; A=C, N, O, S; B=C、N; D=C, N, O; E=C, N, O; M = C, N; Z=-CD 2- 、-CF 2- 、-CHR 3 -、-NH-、-S-; R 3 =H, C1-C4 alkyl or selected from the following substructures: L = absent, C1-C4 alkyl, -CHPh-, -CH2NHCH2-, or selected from the following substructures: R 4 =H, C1-C4 alkyl; R 1 = not present, -H, C1-C4 alkyl, -LR 2 ; When R 1 =-LR 2 When , the substitution on M does not exist; R 2 Selected from: R 5 and R 6 Independently selected from: -H, -D, -OH, -O-C1-C4 alkyl, C1-C4 alkyl, -halogen, CF3, -NR'R", -NHR 7 、-COOH、-COR 8 , -NO2, -CN, -Ph, -SO2NMe2, -CH2NH2, or selected from the following substructures: R 7 =-CH2Ph ​​or selected from the following substructures: R 8 =-NR'R", C1-C4 alkyl or selected from the following substructures: Wherein R' and R" are independently -H or C1-C4 alkyl; The conditions are: - When A, D and E = N; B and M = C, then Y and Y' = CH; X and X' are independently selected from CH or CF; Z = -S-; R1 = Me; - When A=C and B, D, E and M=N, then Y and Y'=CH; X and X' are independently selected from CH or N; R1=-LR2; The conditions are to exclude the following compounds: 2-(Difluoromethyl)-5-(4-((5-phenyl-1H-tetrazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-phenyl-1H-imidazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(4-((4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(4-((4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(4-((4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(4-((4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(4-((4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)ethyl)phenyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(4-((5-methyl-4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(5-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)-1,3,4-oxadiazole; 2-(6-((4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(6-((4-(2-chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(6-((4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(6-((4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(6-((4-(3,5-dichlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(2-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(2,6-difluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(6-((4-(3-chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(3-fluoro-4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; (3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzoic acid; (3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzoic acid; 2-(Difluoromethyl)-5-(4-((4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(4-((4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole; 2-(4-((4-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(4-((4-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole; 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzoic acid; 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzoic acid; 2-(Difluoromethyl)-5-(3-fluoro-4-((4-(p-tolyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(p-tolyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; (3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzoic acid; 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylaniline; N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)acetamide; 1-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)ethan-1-one; 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylaniline; 2-(Difluoromethyl)-5-(6-((4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(6-((4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(2-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(m-tolyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(o-tolyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(furan-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(6-((4-(6-chloropyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(6-((4-(5-chloropyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(5-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; (3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)(morpholinyl)methanone; (3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)(4-methylpiperazin-1-yl)methanone; 2-(Difluoromethyl)-5-(6-((4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-phenyl-1H-imidazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(pyrimidin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(4-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole; 1-(4-((1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)piperidin-1-yl)ethan-1-one; 2-(Difluoromethyl)-5-(6-((4-(2-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-phenyl-1H-pyrazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(3-fluoropyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(4-fluoropyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(6-((4-(5-bromopyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(4-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(6-((4-(5-bromopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(6-((4-(6-bromopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(3-fluoropyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(2-fluoropyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((5-(thiophen-2-yl)-2H-tetrazolyl-2-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((5-phenyl-2H-tetrazol-2-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylaniline; 2-(Difluoromethyl)-5-(4-((4-(3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(3-fluoro-4-((4-(3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(6-((4-(1H-indazol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(4-((4-(1H-indazol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(4-((4-(1H-indazol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(4-((4-(4-fluoro-3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(3-fluoro-4-((4-(4-fluoro-3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(4-((4-(4-fluoro-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(3-fluoro-4-((4-(4-fluoro-3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(4-((4-(2-fluoro-5-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(4-((4-(2-fluoro-5-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(4-((4-(2-fluoro-3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; 2-(4-((4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(4-((4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(2-fluoro-3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-fluoro-3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole; and 2-(Difluoromethyl)-5-(6-((4-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole.

2. The compound according to claim 1, wherein when A, D and E = N, B and M = C and when A = C and B, D, E and M = N, then R 2 Select from the following substructures: in: R 5 =-NH2 or selected from the following substructures:

3. The compound according to claim 1, wherein the five-membered heterocyclic nucleus ABDEM is selected from 1,2,3-triazole, 2,5-disubstituted tetrazole, 1,4-disubstituted pyrazole, imidazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole and isoxazole.

4. The compound according to claim 3, wherein the five-membered heterocyclic nucleus ABDEM is selected from 1,2,3-triazoles with B=C and M=N, 2,5-disubstituted tetrazoles, 1,4-disubstituted pyrazoles, 1,3,4-thiadiazoles, 1,2,4-oxadiazoles, 1,3,4-oxadiazoles and isoxazoles.

5. The compound according to claim 4, wherein the five-membered heterocyclic nucleus ABDEM is selected from 1,2,3-triazole with B = C and M = N, 1,3,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole and isoxazole.

6. The compound according to any one of claims 1 to 3, wherein at least one of X, X', Y and Y' is CF, or at least one of X and X' is CCl.

7. The compound according to any one of claims 1 to 3, wherein Z = -CD2-, -CF2-, -CHR 3 -, -NH-, -S-; Where R 3 Select from the following substructures:

8. A compound according to any one of claims 1 to 3, wherein R 2 Selected from: Where R 5 and R 6 At least one of: -OH, -NR'R", -NHR 7 、-SO2NMe2、CH2NH2、-COR 8 , or selected from the following substructures: R 7 Select from the following substructures: R 8 =-NR'R" or selected from the following substructures: wherein R' and R" are independently -H or C1-C4 alkyl.

9. The compound according to any one of claims 1 to 3, wherein X and X' are independently selected from CH, N or CF; Y and Y' are independently selected from CH, N or CF; A=C, N, S; B=C、N; D = C, N; E=C, N, O; M = C; Z=CH2、CHR 3 ; R 3 =Me or selected from the following substructures: L does not exist; R 2 Selected from: R 5 and R 6 Independently selected from: -OH, -OMe, -Br, NH2, -NHR 7 、-COR 8 , -COCH3, -CH3, -CH2NH2, or selected from the following substructures: R 7 =Me, Et or selected from the following substructures: R 8 =-NH2, -NHEt, -NMe2 or selected from the following substructures:

10. The compound according to claim 1, which is selected from: --6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzo[d]thiazol-2-amine (Compound 1); -N-(5-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)-2-hydroxyphenyl)morpholine-4-carboxamide (Compound 2); -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzo[d]thiazol-2-amine (Compound 3); -6-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)isoindolin-1-one (Compound 4); -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 5); -N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 6); -5-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)benzo[d]oxazol-2-amine (Compound 7); -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-2-amine (Compound 8); -2-(6-((4-(2-chloro-1H-benzo[d]imidazol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 9); -N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine (Compound 10); -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-1-methyl-1H-benzo[d]imidazol-2-amine (Compound 11); -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-imidazol-4-yl)pyridin-2-amine (Compound 12); -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)pyridin-2-amine (Compound 13); -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzo[d]thiazol-2-amine (Compound 14); -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 15); -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 16); -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2-amine (Compound 17); -6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-ethyl-1H-benzo[d]imidazol-2-amine (Compound 18); -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)spiro[indoline-3,4′-piperidin]-2-one (Compound 19); -N-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-imidazol-4-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine (Compound 20); -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,3-difluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 21); -N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-imidazol-4-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine (Compound 22); -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2-amine (Compound 23); -N-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine (Compound 24); -N-(5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2-hydroxyphenyl)morpholine-4-carboxamide (Compound 25); -5'-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)spiro[cyclopentane-1,3'-indolin]-2'-one (Compound 26); -7'-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)-1',4'-dihydro-3'H-spiro[cyclopentane-1,2'-quinoxaline]-3'-one (Compound 27); -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)spiro[indoline-3,3′-pyrrolidino]-2-one (Compound 28); -3-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)benzamide (Compound 29); -6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-2-amine (Compound 30); -3-(5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2-hydroxyphenyl)-1,1-dimethylurea (Compound 31); -(R)-5-(1-(1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 32); -(4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)phenyl)methanamine (Compound 33); -6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-methylquinolin-2-amine (Compound 34); -2-amino-4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenol (Compound 35); -7'-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1',4'-dihydro-3'H-spiro[piperidin-4,2'-quinoxaline]-3'-one (Compound 36); -N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)acetamide (Compound 37); -5-(3-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)phenyl)thiazol-2-amine (Compound 38); -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,5-difluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 39); -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-2H-tetrazol-5-yl)isoindolin-1-one (Compound 40); -6'-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1',4'-dihydro-3'H-spiro[piperidin-4,2'-quinoxaline]-3'-one (Compound 41); -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 42); -(4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)methanamine (Compound 43); -(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)methanamine (Compound 44); -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)pyridin-2-amine (Compound 45); -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)spiro[indoline-3,4′-piperidin]-2-one (Compound 46); -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 47); -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 48); -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)spiro[indoline-3,3'-pyrrolidino]-2-one (Compound 49); -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-2H-tetrazol-5-yl)benzamide (Compound 50); -N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-4-methylpiperazine-1-carboxamide (Compound 51); -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 52); -2-(difluoromethyl)-5-(6-((4-(2-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (Compound 53); -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)benzamide (Compound 54); -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)isoindolin-1-one (Compound 55); -4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenol (Compound 56); -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)isoindolin-1-one (Compound 57); -2-(difluoromethyl)-5-(4-((5-(3-(4-methylpiperazin-1-yl)phenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 58); -5-(1-(1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 59); -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-N-ethyl-1H-benzo[d]imidazol-2-amine (Compound 60); -5'-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)spiro[cyclopentane-1,3'-indolinoline]-2'-one (Compound 61); -N-(3-(4-(6-aminopyridin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)propyl)methanesulfonamide (Compound 62); -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-4-methylpiperazine-1-carboxamide (Compound 63); -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)pyridin-2-amine (Compound 64); -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2-methylpyridin-3-amine (Compound 65); -N-(3-(1-(1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 66); -2-(3,5-difluoro-4-((4-(imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 67); -N-(5-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-2H-tetrazol-5-yl)pyridin-2-yl)-2,2-difluoroacetamide (Compound 68); -(3-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)phenyl)(morpholinyl)methanone (Compound 69); -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)acetamide (Compound 70); -N-(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)morpholine-4-carboxamide (Compound 71); -2-amino-5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)benzamide (Compound 72); -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-3-amine (Compound 73); -2-(difluoromethyl)-5-(6-((4-(imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (Compound 74); -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)benzamide (Compound 75); -2-amino-5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)nicotinamide (Compound 76); -5-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-2H-tetrazol-5-yl)pyridin-2-amine (Compound 77); -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 78); -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)pyrimidin-2-amine (Compound 79); -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-N-(1-methylpiperidin-4-yl)benzamide (Compound 80); -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-N,N-dimethylbenzamide (Compound 81); -2-(4-((5-(5-bromopyridin-3-yl)-2H-tetrazol-2-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 82); -7-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (Compound 83); -7-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)quinazolin-4-amine (Compound 84); -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-1-methylazetidine-3-carboxamide (Compound 86); -2-(difluoromethyl)-5-(4-((5-(4-(piperidin-1-ylmethyl)phenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 87); -N-(5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)-2,2-difluoroacetamide (Compound 88); -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-2H-tetrazol-5-yl)benzamide (Compound 89); -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)pyridin-3-amine (Compound 90); -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-N-ethylbenzamide (Compound 91); -1-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-3,3-dimethylazetidin-2-one (Compound 92); -(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-2H-tetrazol-5-yl)phenyl)(morpholinyl)methanone (Compound 93); -2-(4-(6-aminopyridin-3-yl)-1H-1,2,3-triazol-1-yl)-2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethan-1-ol (Compound 94); -N-(5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)-2-hydroxyphenyl)morpholine-4-carboxamide (Compound 95); -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-N-(furan-2-ylmethyl)benzamide (Compound 96); -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-2H-tetrazol-5-yl)isoindolin-1-one (Compound 97); -N-(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)phenyl)morpholine-4-carboxamide (Compound 98); -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-N-ethylpyridin-2-amine (Compound 99); -(4-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1,2,4-oxadiazol-5-yl)phenyl)methanamine (Compound 100); -(5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)methanamine (Compound 101); -N-(5-(5-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)-2,2-difluoroacetamide (Compound 102); -2-(difluoromethyl)-5-(4-((5-(4-(piperazin-1-yl)phenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 103); -N-(3-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 104); -2-(3,5-difluoro-4-((4-(2-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 105); -(R)-5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 106); -6-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-2H-tetrazol-5-yl)isoindolin-1-one (Compound 107); -2-(difluoromethyl)-5-(4-((5-(3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 108); -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)isoindolin-1-one (Compound 109); -7'-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-1',4'-dihydro-3'H-spiro[cyclopentane-1,2'-quinoxaline]-3'-one (Compound 110); -2-(difluoromethyl)-5-(4-((5-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)phenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 111); -(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)phenyl)(morpholinyl)methanone (Compound 112); -2-(difluoromethyl)-5-(4-((5-(quinolin-2-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 113); -3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)-N-ethylaniline (Compound 114); -2-(difluoromethyl)-5-(6-((4-(2-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (Compound 115); -4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)benzamide (Compound 116); -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 117); -2-(difluoromethyl)-5-(4-((5-(isoquinolin-4-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 118); -N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 119); -(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)(morpholinyl)methanone (Compound 120); -4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline (Compound 121); -2-(3,5-difluoro-4-((4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 122); -6'-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)spiro[cyclopentane-1,3'-indolin]-2'-one (Compound 123); -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(pyrrolidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 124); -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 125); -N-(5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-imidazol-4-yl)pyridin-2-yl)-2,2-difluoroacetamide (Compound 126); -2-(difluoromethyl)-5-(4-((5-(isoquinolin-7-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 127); -2-(difluoromethyl)-5-(4-((5-(3,4-dimethoxyphenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 128); -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazolyl-5-yl)aniline (Compound 129); -4-(5-(3-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2H-tetrazol-5-yl)phenyl)thiazol-2-yl)morpholine (Compound 130); -2-(difluoromethyl)-5-(4-((4-(2-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 131); -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzo[d]thiazol-2-amine (Compound 132); -N-(5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2-methylpyridin-3-yl)acetamide (Compound 133); -5-(1-(2-chloro-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 134); -5-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine (Compound 135); -2-(4-((4-(2-chloro-1H-benzo[d]imidazol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 136); -(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-2H-tetrazol-5-yl)phenyl)(morpholinyl)methanone (Compound 137); -5-((4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzyl)amino)-2-methoxynicotinamide (Compound 138); -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)acetamide (Compound 139); -1-(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)ethan-1-one (Compound 140); -5-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1,2,4-oxadiazol-5-yl)pyridin-2-amine (Compound 141); -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-N-methylquinolin-2-amine (Compound 142); -(R)-5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)butyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 143); -2-amino-N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)acetamide (Compound 144); -N-(3-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1,2,4-oxadiazol-5-yl)phenyl)morpholine-4-carboxamide (Compound 145); -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-4-methylpiperazine-1-carboxamide (Compound 146); -2-(difluoromethyl)-5-(4-((5-(1-(pyridin-2-yl)cyclopropyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 147); -2-(difluoromethyl)-5-(4-((5-(6-(piperazin-1-yl)pyridin-3-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 148); -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-1-methylazetidine-3-carboxamide (Compound 149); -2-(difluoromethyl)-5-(4-((5-(2-nitrophenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 150); -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-imidazol-4-yl)pyridin-2-amine (Compound 151); -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)benzo[d]oxazol-2-amine (Compound 152); -2-(difluoromethyl)-5-(4-((5-(isoquinolin-5-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 153); -5-((4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)benzyl)amino)-2-methoxynicotinamide (Compound 154); -(5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)methanamine (Compound 155); -N-(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)benzamide (Compound 156); -7'-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-1',4'-dihydro-3'H-spiro[cyclohexane-1,2'-quinoxaline]-3'-one (Compound 157); -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)-3,3,3-trifluoropropyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 158); -(R)-2-(difluoromethyl)-5-(4-((5-(6-(3-methylpiperazin-1-yl)pyridin-3-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 159); -2-amino-4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)phenylmorpholine-4-carboxylate (Compound 160); -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)spiro[indoline-3,4′-piperidin]-2-one (Compound 161); -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-imide (Compound 162); -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-4-fluoro-N,N-dimethylbenzenesulfonamide (Compound 163); -4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-N1-methylbenzene-1,2-diamine (Compound 164); -N-(3-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorophenyl)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 165); -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2-amine (Compound 166); -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)isoindolin-1-one (Compound 167); -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Compound 168); -2-(difluoromethyl)-5-(4-((4-(4-((4-(ethylsulfonyl)piperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3,5-difluorophenyl)-1,3,4-oxadiazole (Compound 169); -1-(5-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-3-methylurea (Compound 170); -(S)-5-(1-(1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 171); -tert-butyl (2-((3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-oxoethyl)carbamate (Compound 172); -7-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 173); -4-(6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-2-yl)morpholine (Compound 174); -1-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)thiourea (Compound 175); -N-(5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2-(methylamino)phenyl)morpholine-4-carboxamide (Compound 176); -tert-butyl 5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (Compound 177); -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (Compound 178); -N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)benzyl)-N-methyl-1-(pyridin-4-yl)methanamine (Compound 179); -3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-N-ethylaniline (Compound 180); -2-(difluoromethyl)-5-(4-((5-(2-fluorophenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 181); -(S)-2-(difluoromethyl)-5-(4-((5-(6-(3-methylpiperazin-1-yl)pyridin-3-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 182); -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-N-(furan-2-ylmethyl)acetamide (Compound 183); -N-(3-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)propyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 184); -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorophenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 185); -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorophenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 186); -2-(difluoromethyl)-5-(2-((5-(thiophen-2-yl)-2H-tetrazolyl-2-yl)methyl)pyrimidin-5-yl)-1,3,4-oxadiazole (Compound 187); -2-(4-((5-(3-(1H-pyrazol-1-yl)phenyl)-2H-tetrazol-2-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 188); -N-(3-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorophenyl)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 189); -2-(difluoromethyl)-5-(4-((4-(2-(pyrrolidin-1-yl)-1H-benzo[d]imidazol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 190); -(4-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,2,4-oxadiazol-5-yl)phenyl)methanamine (Compound 191); -3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline (Compound 192); -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)butyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 193); -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)propyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 194); -6'-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-1',4'-dihydro-3'H-spiro[cyclopentane-1,2'-quinoxaline]-3'-one (Compound 195); -4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)-2-(morpholine-4-carboxamido)phenylmorpholine-4-carboxylate (Compound 196); -3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-imidazol-4-yl)aniline (Compound 197); -5-(1-((6-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 198); -N-(5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)pyridin-3-yl)morpholine-4-carboxamide (Compound 199); -5-(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)thiazol-2-amine (Compound 200); -N-(4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)benzyl)-N-methyl-1-(pyridin-4-yl)methanamine (Compound 201); -5-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)isoxazol-3-yl)pyridin-2-amine (Compound 202); -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2,3-dihydro-1H-inden-1-one (Compound 203); -2-(difluoromethyl)-5-(4-((5-(4-methoxyphenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 204); -N-(3-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)butyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 205); -N-(4-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1,2,4-oxadiazol-5-yl)benzyl)-2,2-difluoro-N-methylacetamide (Compound 206); -2-(4-((5-(Benzo[b]thiophen-3-yl)-2H-tetrazol-2-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 207); -4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2,3-dihydro-1H-inden-1-one (Compound 208); -6'-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-1',4'-dihydro-3'H-spiro[cyclohexane-1,2'-quinoxaline]-3'-one (Compound 209); -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (Compound 210); -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-pyrazol-4-yl)pyridin-2-amine (Compound 211); -2-(difluoromethyl)-5-(4-((5-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 212); -2-(difluoromethyl)-5-(4-((5-(4-(4-methylpiperazin-1-yl)phenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 213); -2-(3,5-difluoro-4-((4-(4-((3-(trifluoromethyl)azetidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 214); -N-(4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)benzyl)-N-methyl-1-(pyridin-4-yl)methanamine (Compound 215); -tert-butyl 5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate (Compound 216); -2-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-1,1,3,3-tetramethylguanidine (Compound 217); -5-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine (Compound 218); -2-(difluoromethyl)-5-(4-((5-(2-(pyridin-4-yl)propan-2-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 219); -2-(difluoromethyl)-5-(4-((5-(furan-2-yl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 220); -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)-2-phenylethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 221); -3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-imidazol-4-yl)benzamide (Compound 223); -2-(difluoromethyl)-5-(4-((5-(3-fluoro-4-(piperazin-1-yl)phenyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 224); -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)benzo[d]oxazol-2(3H)-one (Compound 225); -3-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,2,4-oxadiazol-3-yl)benzamide (Compound 226); -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-pyrazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 227); -N-(3-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,2,4-oxadiazol-5-yl)phenyl)morpholine-4-carboxamide (Compound 228); -7-(2-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-2H-tetrazol-5-yl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 229); -(4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)(morpholinyl)methanone (Compound 230); -5-(1-(2-(4-chlorophenyl)-1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 231); -4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-N-(1-methylpiperidin-4-yl)benzamide (Compound 232); -2-(difluoromethyl)-5-(4-((4-(2-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 233); -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 235); -5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)-2-phenoxyethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 236); -8-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)-4-methyl-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepine -2-Keto (Compound 237); -2-(difluoromethyl)-5-(4-((5-phenyl-1,3,4-thiadiazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 238); -N-(cyclopropylmethyl)-1-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)benzoyl)piperidine-3-carboxamide (Compound 239); -tert-butyl 3-(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (Compound 240); -2-(difluoromethyl)-5-(4-((4-(6-fluoro-2-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 241); -5-(1-(2-cyclobutyl-1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 242); -5-(5-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)difluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine (Compound 243); -N-(3-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 244); -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-3,3-dimethylisoindolin-1-one (Compound 245); -2-(4-((5-([1,1′-biphenyl]-3-yl)-2H-tetrazol-2-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 246); -5-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,2,4-oxadiazol-5-yl)pyridin-2-amine (Compound 247); -2-(difluoromethyl)-5-(4-((4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 248); -5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-N,N-dimethylbenzo[d]oxazol-2-amine (Compound 249); -(S)-5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)butyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine enantiomer (Compound 250); -2-(difluoromethyl)-5-(4-((5-(pyridin-2-ylmethyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 251); -5-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-2H-tetrazol-5-yl)-1-methyl-1H-benzo[d]imidazol-2-amine (Compound 252); -4-(5-(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)thiazol-2-yl)morpholine (Compound 253); -N-(4-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1,2,4-oxadiazol-5-yl)benzyl)-N-methyl-1-(pyridin-4-yl)methanamine (Compound 254); -(S)-5-(1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 255); -2-(difluoromethyl)-5-(4-((5-(1-phenylcyclopropyl)-2H-tetrazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 256); -1-(4-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)piperidin-1-yl)ethan-1-one (Compound 257); -N-(5-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)-2-(phenylthio)phenyl)morpholine-4-carboxamide (Compound 258); -N-(4-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,2,4-oxadiazol-5-yl)benzyl)-2,2-difluoro-N-methylacetamide (Compound 259); -3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)benzoic acid (Compound 260); -2-(difluoromethyl)-5-(4-((5-(thiophen-2-yl)-2H-tetrazolyl-2-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 261); -3-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1,2,4-oxadiazol-5-yl)benzamide (Compound 262); -2-(4-((5-(2,4-dichlorophenyl)-2H-tetrazol-2-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 263); -N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-imidazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 264); -tert-Butyl 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate Enantiomer A (Compound 265); -tert-Butyl 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate Enantiomer B (Compound 266); -N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-imidazol-4-yl)phenyl)morpholine-4-carboxamide (Compound 267); -tert-butyl 7'-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-3'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoxaline]-1-carboxylate (Compound 268); -N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-pyrazol-4-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine (Compound 269); -N-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine (Compound 270); -7'-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1',4'-dihydro-3'H-spiro[piperidin-4,2'-quinoxaline]-3'-one (Compound 271); -tert-butyl 2-(3-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)phenyl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (Compound 272); -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)spiro[indoline-3,3'-pyrrolidino]-2-one enantiomer A (Compound 273); -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)spiro[indoline-3,3'-pyrrolidino]-2-one enantiomer B (Compound 274); -2-(difluoromethyl)-5-(6-((5-(3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)-2H-tetrazol-2-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (Compound 276); -6'-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1',4'-dihydro-3'H-spiro[piperidin-4,2'-quinoxaline]-3'-one (Compound 277); -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)quinazolin-2-amine (Compound 278); -tert-butyl 6'-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-3'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoxaline]-1-carboxylate (Compound 279); -2-(difluoromethyl)-5-(4-((4-(imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 280); -4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylaniline (Compound 281); -N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzyl)-N-methyl-1-(pyridin-4-yl)methanamine (Compound 282); -1-((1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-1-ethyl-3-(2-methoxypyridin-3-yl)urea (Compound 283): -5-(5-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorophenyl)thio)-4-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (Compound 284); -5-(5-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)thio)-4-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (Compound 285); -5-((4-(4-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-1-yl)benzyl)amino)-2-methoxynicotinamide (Compound 286); -2-(difluoromethyl)-5-(4-((5-(pyrimidin-2-yl)-1H-tetrazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (Compound 287); -2-(4-((5-(Benzo[b]thiophen-3-yl)-1H-tetrazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 288); -2-(4-((5-(3-(1H-pyrazol-1-yl)phenyl)-1H-tetrazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound 289); -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 290); -5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-1H-tetrazol-5-yl)-1-methyl-1H-benzo[d]imidazol-2-amine (Compound 291); -6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-imidazol-4-yl)isoindolin-1-one (Compound 292); -N-(3-(4-(6-aminopyridin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)propyl)methanesulfonamide (Compound 293); -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-imidazol-4-yl)isoindolin-1-one (Compound 294); -N-(3-(4-(6-aminopyridin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)propyl)-2,2-difluoroacetamide (Compound 295); -4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline (Compound 296); -3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline (Compound 297); -6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-1H-tetrazol-5-yl)isoindolin-1-one (Compound 298); -2-(difluoromethyl)-5-(2-((5-(thiophen-2-yl)-1H-tetrazolyl-1-yl)methyl)pyrimidin-5-yl)-1,3,4-oxadiazole (Compound 299); -5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-imidazol-4-yl)benzo[d]thiazol-2-amine (Compound 300); -5-(1-(1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-(pyrrolidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (Compound 301).

11. The compound according to claim 1, which is selected from: -N-[2-[4-(6-aminopyridin-3-yl)triazol-1-yl]-2-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]ethyl]methanesulfonamide Compound 302 -5-[1-[1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]-4-piperidin-1-ylbutyl]triazol-4-yl]pyridin-2-amine Compound 303 -5-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoropyridin-2-yl]methyl]triazol-4-yl]pyridin-2-amine Compound 304 -3-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]imidazol-4-yl]benzamide Compound 305 -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]imidazol-4-yl]-1,3-benzothiazol-2-amine Compound 306 -6-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]imidazol-4-yl]-1,3-benzothiazol-2-amine Compound 307 -5-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]imidazol-4-yl]-1,3-benzoxazol-2-amine Compound 308 -5-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]imidazol-4-yl]-1,3-benzoxazol-2-amine Compound 309 -N-[(3S)-3-[4-(6-aminopyridin-3-yl)triazol-1-yl]-3-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]propyl]methanesulfonamide Compound 310 -N-[(3R)-3-[4-(6-aminopyridin-3-yl)triazol-1-yl]-3-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]propyl]methanesulfonamide Compound 311 -5-[1-[(1R)-1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]-2-pyrrolidin-1-ylethyl]triazol-4-yl]pyridin-2-amine Compound 312 -5-[1-[(1S)-1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]-2-pyrrolidin-1-ylethyl]triazol-4-yl]pyridin-2-amine Compound 313 -(2R)-2-[4-(6-aminopyridin-3-yl)triazol-1-yl]-2-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]ethanol Compound 314 -4-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-1-yl]aniline compound 315 -N-[4-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-1-yl]phenyl]-4,5-dihydro-1H-imidazol-2-amine Compound 316 -7-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]triazol-4-yl]quinazolin-4-amine Compound 317 -6-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]pyrazol-4-yl]-2,3-dihydroisoindole-1-one Compound 318 -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]pyrazol-4-yl]-2,3-dihydroisoindole-1-one Compound 319 -5-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]pyrazol-4-yl]-1-methylbenzimidazol-2-amine compound 320 -5-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]pyrazol-4-yl]-1-methylbenzimidazol-2-amine Compound 321 -5-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]imidazol-4-yl]-1,3-benzothiazol-2-amine Compound 322 -5-[1-[1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]-3-pyrrolidin-1-ylpropyl]triazol-4-yl]pyridin-2-amine Compound 323 -5-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]triazol-4-yl]-1,3-dihydroindolin-2-one Compound 325 -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]pyrazol-4-yl]-1,3-benzothiazol-2-amine Compound 326 -6-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]pyrazol-4-yl]-1,3-benzothiazol-2-amine Compound 327 -5-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]imidazol-4-yl]-1-methylbenzimidazol-2-amine Compound 328 -5-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]imidazol-4-yl]-1-methylbenzimidazol-2-amine Compound 329 -4-[5-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-1,3-oxazol-2-yl]aniline compound 330 -5-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]pyrazol-4-yl]-1H-benzimidazol-2-amine Compound 331 -5-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]pyrazol-4-yl]-1H-benzimidazol-2-amine Compound 332 -3-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]pyrazol-4-yl]benzamide Compound 333 -3-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]pyrazol-4-yl]benzamide Compound 334 -4-[4-(6-aminopyridin-3-yl)triazol-1-yl]-4-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]butan-1-ol Compound 335 -N-[3-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoropyridin-2-yl]methyl]triazol-4-yl]phenyl]morpholine-4-carboxamide Compound 336 -N-[3-[1-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]phenyl]morpholine-4-carboxamide Compound 337 -N-[3-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]phenyl]morpholine-4-carboxamide Compound 338 -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 339 -6-[1-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine compound 340 -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 341 -6-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoropyridin-2-yl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 342 -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 343 -5-[1-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine compound 344 -5-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine compound 345 -5-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine Compound 346 -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 347 -5-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]-1-methylbenzimidazol-2-amine Compound 348 -5-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoropyridin-2-yl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine Compound 349 -5-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine compound 350 -6-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine compound 351 -N-[3-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]phenyl]morpholine-4-carboxamide Compound 352 -2-(Difluoromethyl)-5-[5-fluoro-6-[[5-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl]tetrazol-2-yl]methyl]pyridin-3-yl]-1,3,4-oxadiazole Compound 353 -2-(Difluoromethyl)-5-[3-fluoro-4-[[5-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl]tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole Compound 354 -2-(Difluoromethyl)-5-[2,3-difluoro-4-[[5-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl]tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole Compound 355 -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]pyridin-2-amine compound 356 -N-[4-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]imidazol-4-yl]phenyl]-4,5-dihydro-1H-imidazol-2-amine Compound 357 -N-[4-[1-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]imidazol-4-yl]phenyl]-4,5-dihydro-1H-imidazol-2-amine Compound 358 -N-[4-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]imidazol-4-yl]phenyl]-4,5-dihydro-1H-imidazol-2-amine Compound 359 -N-[4-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]imidazol-4-yl]phenyl]-4,5-dihydro-1H-imidazol-2-amine Compound 360 -N-[4-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]imidazol-4-yl]phenyl]-4,5-dihydro-1H-imidazol-2-amine Compound 361 -5-[1-[dideuterio-[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]triazol-4-yl]pyridin-2-amine Compound 362 -N-[3-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]triazol-4-yl]phenyl]morpholine-4-carboxamide Compound 363 -2-(Difluoromethyl)-5-[2-fluoro-4-[[5-[3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)phenyl]tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole Compound 364 -2-[3-chloro-4-[[5-[3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)phenyl]tetrazol-2-yl]methyl]phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole Compound 365 -6-[5-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-1,2-oxazol-3-yl]-1,3-benzothiazol-2-amine Compound 366 -2-(Difluoromethyl)-5-[2,5-difluoro-4-[[5-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl]tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole Compound 367 -N-[4-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]imidazol-4-yl]phenyl]-4,5-dihydro-1H-imidazol-2-amine Compound 368 -N-[3-[1-[dideuterio-[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]triazol-4-yl]phenyl]morpholine-4-carboxamide Compound 369 -5-[2-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoropyridin-2-yl]methyl]tetrazol-5-yl]-1-methylbenzimidazol-2-amine compound 370 -5-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]tetrazol-5-yl]-1-methylbenzimidazol-2-amine Compound 371 -5-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]-1-methylbenzimidazol-2-amine Compound 372 -5-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]-1-methylbenzimidazol-2-amine compound 373 -5-[2-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]-1-methylbenzimidazol-2-amine compound 374 -4-[5-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-1,2,4-oxadiazol-3-yl]aniline compound 375 -6-[1-[dideuterio-[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine compound 376 -6-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-1-yl]-1,3-benzothiazol-2-amine Compound 377 -5-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine Compound 378 -N-[4-[5-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-1,2,4-oxadiazol-3-yl]phenyl]-4,5-dihydro-1H-imidazol-2-amine Compound 379 -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]triazol-4-yl]pyridin-2-amine Compound 381 -6-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine compound 382 -N-(4-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-1,2,4-oxadiazol-3-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine Compound 383 -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,3-difluorobenzyl)-1H-1,2,3-triazol-4-yl)thieno[2,3-d]pyrimidin-4-amine Compound 384 -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]pyridin-2-amine compound 385 -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)thieno[2,3-d]pyrimidin-4-amine Compound 386 -7-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]quinazolin-4-amine Compound 387 -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-2H-tetrazol-5-yl)-N-methylquinolin-2-amine Compound 388 -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]-N-methylquinazolin-2-amine Compound 389 -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]-N-methylquinazolin-2-amine Compound 390 -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]-N-methylquinazolin-2-amine Compound 391 -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]-N-methylquinazolin-2-amine Compound 392 -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]-N-methylquinazolin-2-amine Compound 393 -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]-N-ethylquinazolin-2-amine Compound 394 -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-N-ethylquinazolin-2-amine Compound 395 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]isoquinolin-1-amine Compound 396 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]isoquinolin-1-amine Compound 397 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]quinolin-3-amine Compound 398 -6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylquinolin-2-amine Compound 399 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]quinolin-3-amine compound 400 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]-N-methylquinolin-2-amine Compound 401 -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]-N,N-dimethylquinazolin-2-amine Compound 402 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]-N-methylquinolin-2-amine Compound 403 -6-(1-(2-chloro-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)isoquinolin-3-amine Compound 404 -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]isoquinolin-3-amine Compound 405 -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]isoquinolin-3-amine Compound 406 -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,3-difluorobenzyl)-2H-tetrazol-5-yl)-N-methylquinolin-2-amine Compound 407 -4-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-1,2,4-oxadiazol-3-yl)aniline compound 408 -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,5-difluorobenzyl)-2H-tetrazol-5-yl)-N-ethylquinolin-2-amine Compound 409 -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-2H-tetrazol-5-yl)-N-ethylquinolin-2-amine Compound 410 -5-(4-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-1-yl)pyridin-2-amine Compound 413 -5-[4-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}methyl)-1H-1,2,3-triazol-1-yl]-1-methyl-1H-1,3-benzodiazol-2-amine Compound 414 -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]thieno[2,3-d]pyrimidin-4-amine Compound 415 -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]thieno[2,3-d]pyrimidin-4-amine Compound 416 -6-[1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl}methyl)-1H-1,2,3-triazol-4-yl]thieno[2,3-d]pyrimidin-4-amine Compound 417 -7-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)quinazolin-4-amine Compound 418 -4-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1,2,4-oxadiazol-3-yl)aniline compound 419 -N-(4-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1,2,4-oxadiazol-3-yl)phenyl)-4,5-dihydro-1H-imidazol-2-amine Compound 420 -6-(2-(2-chloro-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)isoquinolin-1-amine Compound 422 -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,5-difluorobenzyl)-2H-tetrazol-5-yl)quinazolin-2-amine Compound 423 -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-2H-tetrazol-5-yl)quinazolin-2-amine Compound 424 -6-(2-(2-chloro-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)quinazolin-2-amine Compound 425 -2-(3-chloro-4-((5-(isoquinolin-6-yl)-2H-tetrazolyl-2-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole Compound 426 -2-(Difluoromethyl)-5-(3-fluoro-4-((5-(isoquinolin-6-yl)-2H-tetrazolyl-2-yl)methyl)phenyl)-1,3,4-oxadiazole Compound 427 -2-(2,5-difluoro-4-((5-(isoquinolin-6-yl)-2H-tetrazolyl-2-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole Compound 428 -6-(2-(2-chloro-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2H-tetrazol-5-yl)quinolin-3-amine Compound 429 -7-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,5-difluorobenzyl)-1H-1,2,3-triazol-4-yl)quinazolin-4-amine Compound 433 -7-(1-(2-chloro-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)quinazolin-4-amine Compound 434 -2-(Difluoromethyl)-5-[3-fluoro-4-[[5-(1-pyrazin-2-ylcyclopropyl)tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole compound 435 -2-(Difluoromethyl)-5-[2-fluoro-4-[[5-(1-pyrazin-2-ylcyclopropyl)tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole Compound 436 -2-(Difluoromethyl)-5-[2,3-difluoro-4-[[5-(1-pyrazin-2-ylcyclopropyl)tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole Compound 437 -2-(Difluoromethyl)-5-[2,5-difluoro-4-[[5-(1-pyrazin-2-ylcyclopropyl)tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole Compound 438 -2-(Difluoromethyl)-5-[3,5-difluoro-4-[[5-(1-pyrazin-2-ylcyclopropyl)tetrazol-2-yl]methyl]phenyl]-1,3,4-oxadiazole Compound 439 -2-[3-chloro-4-[[5-(1-pyrazin-2-ylcyclopropyl)tetrazol-2-yl]methyl]phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole compound 440 -6-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-3-amine Compound 441 -6-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-3-amine Compound 442 -6-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-3-amine Compound 443 -6-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-3-amine Compound 444 -6-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-3-amine Compound 445 -6-[2-[2-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-3-amine Compound 446 -2-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-4-amine Compound 447 -2-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-4-amine Compound 448 -2-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-4-amine Compound 449 -2-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-4-amine compound 450 -2-[2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-4-amine Compound 451 -2-[2-[2-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]propan-2-yl]pyridin-4-amine Compound 452 -2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]pyrimidin-5-amine compound 453 -2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]pyrimidin-5-amine compound 454 -2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]tetrazol-5-yl]pyrimidin-5-amine compound 455 -2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]pyrimidin-5-amine compound 456 -2-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]tetrazol-5-yl]pyrimidin-5-amine Compound 457 -2-[2-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]pyrimidin-5-amine compound 458 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]tetrazol-5-yl]isoquinolin-1-amine Compound 459 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]tetrazol-5-yl]isoquinolin-1-amine Compound 460 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]tetrazol-5-yl]quinolin-3-amine Compound 461 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]tetrazol-5-yl]quinolin-3-amine Compound 462 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]quinazolin-2-amine Compound 463 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]tetrazol-5-yl]quinazolin-2-amine Compound 464 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]tetrazol-5-yl]quinazolin-2-amine compound 465 -2-(Difluoromethyl)-5-[2-fluoro-4-[(5-isoquinolin-6-yltetrazolyl-2-yl)methyl]phenyl]-1,3,4-oxadiazole compound 466 -2-[2,3-difluoro-4-[(5-isoquinolin-6-yltetrazolyl-2-yl)methyl]phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole Compound 467 -2-[3,5-difluoro-4-[(5-isoquinolin-6-yltetrazolyl-2-yl)methyl]phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole compound 468 -2-(Difluoromethyl)-5-[2-fluoro-4-[(5-isoquinolin-1-yltetrazolyl-2-yl)methyl]phenyl]-1,3,4-oxadiazole compound 469 -2-[2,3-difluoro-4-[(5-isoquinolin-1-yltetrazolyl-2-yl)methyl]phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole compound 470 -2-[3,5-difluoro-4-[(5-isoquinolin-1-yltetrazolyl-2-yl)methyl]phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole Compound 471 -6-[2-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]-N-methylquinolin-2-amine Compound 472 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]-N-ethylquinolin-2-amine Compound 473 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]tetrazol-5-yl]-N-ethylquinolin-2-amine Compound 474 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]tetrazol-5-yl]-N-ethylquinolin-2-amine Compound 475 -6-[2-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]tetrazol-5-yl]-N-ethylquinolin-2-amine Compound 476 -6-[1-[(1R)-1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]ethyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 477 -6-[1-[(1R)-1-[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]ethyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 478 -6-[1-[(1R)-1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]ethyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 479 -6-[1-[(1R)-1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]ethyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 480 -6-[1-[(1R)-1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]ethyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 481 -6-[1-[(1R)-1-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]ethyl]triazol-4-yl]-1,3-benzothiazol-2-amine Compound 482 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]-N-methylquinazolin-2-amine Compound 483 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]-N-methylquinazolin-2-amine Compound 484 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]-N-methylquinazolin-2-amine Compound 485 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]-N,N-dimethylquinazolin-2-amine Compound 486 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]-N,N-dimethylquinazolin-2-amine Compound 487 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]-N,N-dimethylquinazolin-2-amine Compound 488 -6-[1-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]-N-methylquinazolin-2-amine Compound 489 -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]-N-ethylquinazolin-2-amine Compound 490 -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]triazol-4-yl]-N-ethylquinazolin-2-amine Compound 491 -6-[1-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]-N-ethylquinazolin-2-amine Compound 492 -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]triazol-4-yl]-N,N-dimethylquinazolin-2-amine Compound 494 -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]-N,N-dimethylquinazolin-2-amine Compound 495 -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]triazol-4-yl]-N,N-dimethylquinazolin-2-amine Compound 496 -6-[1-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]-N,N-dimethylquinazolin-2-amine Compound 497 -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]isoquinolin-3-amine Compound 498 -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]triazol-4-yl]isoquinolin-3-amine Compound 499 -6-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]triazol-4-yl]isoquinolin-3-amine compound 500 -6-[1-[[2-chloro-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]triazol-4-yl]thieno[2,3-d]pyrimidin-4-amine Compound 501 -7-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]quinazolin-4-amine compound 502 -7-[1-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,6-difluorophenyl]methyl]triazol-4-yl]quinazolin-4-amine Compound 503 -6-(2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2,5-difluorobenzyl)-2H-tetrazol-5-yl)-N-methylquinolin-2-amine Compound 504 -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]triazol-4-yl]pyridin-2-amine compound 505 -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]triazol-4-yl]pyridin-2-amine compound 506 -6-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine compound 507 -6-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine compound 508 -6-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]-1,3-benzothiazol-2-amine compound 509 -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine compound 510 -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine compound 511 -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine compound 512 -5-[1-[dideuterio-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-difluorophenyl]methyl]triazol-4-yl]-1-methylbenzimidazol-2-amine compound 513 -6-[5-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-1,2,4-oxadiazol-3-yl]-1,3-benzothiazol-2-amine compound 514 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]isoquinolin-1-amine compound 515 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]quinolin-3-amine Compound 516 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]-N-methylquinolin-2-amine Compound 517 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]isoquinolin-3-amine Compound 518 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]isoquinolin-3-amine Compound 519 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]isoquinolin-3-amine compound 520 -7-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]quinazolin-4-amine compound 521 -7-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]quinazolin-4-amine compound 522 -7-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]quinazolin-4-amine compound 523 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluorophenyl]methyl]tetrazol-5-yl]thieno[2,3-d]pyrimidin-4-amine Compound 524 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,5-difluorophenyl]methyl]tetrazol-5-yl]thieno[2,3-d]pyrimidin-4-amine compound 525 -6-[2-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]tetrazol-5-yl]thieno[2,3-d]pyrimidin-4-amine Compound 526.

12. A compound according to any one of claims 1 to 3, in combination with a drug selected from the group consisting of a proteasome inhibitor, an immunochemical inhibitor, a steroid, a bromodomain inhibitor, an epigenetic drug, a conventional chemotherapeutic agent, a proteasome inhibitor, a kinase inhibitor, a CTLA4, PD1 or PDL1 checkpoint inhibitor.

13. The compound of claim 12, in combination with a drug selected from the group consisting of cisplatin, paclitaxel, bortezomib, JAK family inhibitors, nivolumab, pemprolizumab, pidilizumab, BMS-936559, atezolizumab, avelumab, ipilimumab, and tremelimumab.

14. Use of a compound according to any one of claims 1 to 13 in the preparation of a medicament for treating one or more HDAC6-mediated diseases, the disease being selected from: chemotherapy-related cognitive impairment (CRCI), transplant rejection, GVHD, myositis, diseases associated with abnormal lymphocyte function, multiple myeloma, non-Hodgkin's lymphoma, peripheral neuropathy, autoimmune diseases, inflammatory diseases, cancer and neurodegenerative diseases, eye diseases.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 13 or at least one of its pharmaceutically acceptable salts and stereoisomers, and at least one pharmaceutically acceptable excipient.

16. The pharmaceutical composition according to claim 15, which is suitable for administration by enteral route, parenteral route, oral route, topical route, or inhalation route.

17. The pharmaceutical composition according to claim 15 or 16, which is in liquid or solid form.

18. The pharmaceutical composition according to claim 17, which is in the form of a capsule, tablet, coated tablet, powder, granules, cream or ointment.

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